(12) STANDARD PATENT (11) Application No. AU 2015247850 B2 (19) AUSTRALIAN PATENT OFFICE
(54) Title Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
(51) International Patent Classification(s) A61K9/14 (2006.01) A61K 31/47 (2006.01) A61K 9/16 (2006.01) A61K 45/06 (2006.01) A61K9/20 (2006.01) C07D 209/04 (2006.01) A61K 31/404 (2006.01) C07D 215/00 (2006.01)
(21) Application No: 2015247850 (22) Date of Filing: 2015.04.14
(87) WIPO No: WO15/160787
(30) Priority Data
(31) Number (32) Date (33) Country 61/979,848 2014.04.15 US 62/059,287 2014.10.03 US
(43) Publication Date: 2015.10.22 (44) Accepted Journal Date: 2019.07.18
(71) Applicant(s) Vertex Pharmaceuticals Incorporated
(72) Inventor(s) Phenix, Brian Dean;Bagnol, Laurent Jean-claude;Brodeur, Geoffrey Glen;Chandran, Sachin;Dokou, Eleni;Ferris, Lori Ann;Knezic, Dragutin;McCarty, Katie Lynn;Medek, Ales;Waggener, Sara A.
(74) Agent / Attorney AJ PARK, Level 24, Tower 2, Darling Park 201 Sussex St, Sydney, NSW, 2000, AU
(56) Related Art Vehring (Pharmaceutical Research, Vol. 25, No. 5, Published May 2008Pages 999-1022) WO 2011133951 A1 WO 2013185112 A1 WO 2014014841 A1 "Study of VX-661 Alone and in Combination With VX-770 in Subjects Homozygous to the F508del-CFTR Mutation", INTERNET CITATION, (2013-07-18), pages 1-4, URL: http://clinicaltrials.gov/archive/NCT01531673/2013_07_18, (2014-09-08) (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIN International Bureau (10) International Publication Number (43) International Publication Date WO 2015/160787 Al 22 October 2015 (22.10.2015) WIPO I PCT
(51) International Patent Classification: 02472 (US). MEDEK, Ales; 14 Lockland Road, A61K 45/06 (2006.01) C07D 209/04 (2006.01) Winchester, MA 01890 (US). WAGGENER, Sara, A.; 40 A61K31/404 (2006.01) A61K 9/14 (2006.01) Treble Cove Road, N. Billerica, MA 01862 (US). A61K 31/47 (2006.01) A61K 9/16 (2006.01) (74) Agent: WEBER, Andrew, N.; Honigman Miller Schwartz C07D 215/00 (2006.01) A61K 9/20 (2006.01) And Cohn LLP, 350 East Michigan Avenue, Suite 300, (21) International Application Number: Kalamazoo, MI 49007-3800 (US). PCT/US2015/025 722 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 14 April 2015 (14.04.2015) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (26) Publication Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (30) Priority Data: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 61/979,848 15 April 2014 (15.04.2014) US PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/059,287 3 October 2014 (03.10.2014) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (71) Applicant: VERTEX PHARMACEUTICALS INCOR TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. PORATED [US/US]; 50 Northern Avenue, Boston, MA (84) Designated States (unless otherwise indicated, for every 02210 (US). kind of regional protection available): ARIPO (BW, GH, __ (72) Inventors: PHENIX, Brian, Dean; 13 Robert Road, Ac- GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, ~~ ton, MA 01720 (US). BAGNOU, Uaurent, Jean-claude; TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, ~~ 362 Cambridge Street, Burlington, MA 01803 (US). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, BRODEUR, Geoffrey, Glen; 43 Calvin Street, Apt. 3, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Somerville, MA 02143 (US). CHANDRAN, Sachin; 7 Maxwell Green, 311, Somerville, MA 02144 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). DOKOU, Eleni; 60 Fairfield Street, Unit 1, Cambridge, MA 02140 (US). FERRIS, Lori, Ann; 60 Cushing Street, Published: Medford, MA 02155 (US). KNEZIC, Dragutin; 28 Frank — with international search report (Art. 21(3)) es lin Street, Watertown, MA 02472 (US). MCCARTY, _ Katie, Uynn; 219 Dexter Avenue, Apt. D, Watertown, MA A l
(54) Title: PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR MEDIATED DISEASES
2015/160787(57) Abstract: The present invention features compositions comprising a plurality of therapeutic agents wherein the presence of one therapeutic agent enhances the properties of at least one other therapeutic agent. In one embodiment, the therapeutic agents are cystic fibrosis transmembrane conductance regulators (CFTR) such as a CFTR corrector or CFTR potentiator for the treatment of CFTR mediated diseases such as cystic fibrosis. Methods and kits thereof are also disclosed. WO 2015247850 04 Jun 2019 phenylalanine relatively resistance In transport. Europe. thereto. ( causing et (1990) disease associated among gastrointestinal death accumulation epithelia children Cystic documents 61/979,848, [0004] [0003] [0002] [0001] [0005] http://www.genet.sickkids.on.ca/cftr/app
al. addition, PHARMACEUTICAL FIBROSIS
(1990) in
Fibrosis
Cell females
causing
mutations
CF and Despite leads
In Cystic The This Sequence
high
to
The gene,
are
patients
61:863:870; the patients.
filed Proc. cholera adults
present
in
PCT
at
to hereby
frequency
resulting
TRANSMEMBRANE Transmembrane with majority problems
mutations fibrosis
the
individuals position
progress reduced
on
Natl. in
analysis in application
lung with
April cystic and the
invention
In the incorporated
Acad.
(CF)
addition decrease and
of CF
to BACKGROUND and CF,
508 of United and
apical in (Cutting, 15,
fibrosis.
males dehydration
of COMPOSITIONS
the with gene
the Kerem,
the
mutations is pancreatic of 2014,
FIELD FIELD
Sci. the
claims
features
a CF
Conductance
treatment anion the
accompanying
States to a recessive in
have with
CFTR
USA
single by
gene respiratory G.
anion CFTR In and B-S.
priority
secretion OF reference OF
R. cystic been contrast
CONDUCTANCE and
combination resulting in
87:8447-8451).
DISEASES insufficiency 62/059,287, within
). gene
copy
et et
transport of
CFTR THE THE amino
genetic
approximately OF The al. al. identified
CF,
fibrosis
Regulator to
of
of disease,
(1990) (1989)
to
the THE
microbial causing FOR most in INVENTION INVENTION
U.S.
CF there from endogenously the acid the
their disease
population. contributes
chromosomes compositions
filed
are CF
prevalent provisional
INVENTION severe
that, THE
Nature sequence, Science
diarrhea is CF
entireties.
(CFTR) an
infertile To associated no
infections on
30,000 that
patients if
imbalance
REGULATOR TREATMENT
cure. date,
effects
left October 346:366-369;
245:1073-1080;
affects to - mutation expressed
mediated
and
untreated,
perhaps
and application greater enhanced children
and has typically gene of
that is
fertility
3, in
approximately two
methods revealed commonly
2014.
ion ultimately
is exhibit than
explaining
in
diseases
and copies
a
results
Dean,
MEDIATED
and OF respiratory suffer
deletion nos.
is
1000
adults
Both Kerem,
decreased
of a CYSTIC fluid increased
variety of
M.
referred treating in
related from cause disease
the
of the
death. 30,000 in of et
B-S
these
al. CF
of
to
2015247850 04 Jun 2019 hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide yljcyclopropanecarboxamide pharmaceutical providing 2727). the the to composition (2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- methods Lond. membrane leading less folding of of such otherwise, external least an alter in and as [0007a] [0007] [0006] [0008] 12347-50).
the defective AF508-CFTR. one the
object
membrane mutation is than
anion provide documents,
plasma
common associated 354: therapeutic
Studies correctly. to
documents, In
of Accordingly, observed The The
of
a
defective
reference are secretion
this 526-528; treatment
context In trafficking, the
has results
the present membrane. deletion
functional, and
addition
have general specification compositions present
improved public
or with
This
This agent in the
such for
ion in
or to and shown,
Denning cells invention thereof.
a of
defective
defective
there
mutation such other
results discussing knowledge to invention with
synthesis, and severe
are
modify sources residue
albeit As AF508-CFTR,
expressing properties.
SUMMARY
fluid improved
external is however,
a where sources
a (Compound comprising
et useful In in a
disease. result, relates
less gating need channel
al., disease occurs
508 of the one transport.
to and/or the
in
reference information,
go supra;
than
inability
documents of
in choice.
embodiment, the
wild-type for
the features by that
to
lead
some AF508-CFTR in information,
progression
gating.
pharmaceutical other channel art. novel the wild-type (7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l- OF number
1) approximately the
Pasyk
to
(Quinton,
and
presence
way has THE of
reduced reduced of
disease
treatments
2 CFTR.
the is in N-[2,4-bis(l,l-dimethylethyl)-5- Together,
the
been and gating of towards
not
the any
INVENTION CFTR.
mutant
channels this and/or invention.
Foskett
prevents
P. of
to causing present made numbers
anion jurisdiction,
In
could
is M. compositions be another 70%
meeting of addition
the generally
protein (Dalemans severity.
construed
(1990), (Compound to transport
CFTR (1995), present
be of invention reduced
mutations the patent
of Unless
the therapeutic up-
AF508-CFTR nascent this to
to
mediated are
FASEB
cases
for
or J. in
exit
impaired specifications,
as across
wherein
et number need,
specifically
prior Cell.
down-regulated the
the features
an 2), in al.
the
of protein
CFTR membrane
admission
purpose
wherein (1991),
J. agent,
Biochem. art, and/or epithelia cystic ER, diseases.
4: of trafficking, the
or in
2709
channels and
from
that
properties kits,
stated the
form fibrosis
Nature
to
of other the
traffic
that at
result is 270:
It
and to
part
far
is
in
2015247850 04 Jun 2019 JV-[2,4-bis( bis( pharmaceutical hydroxypropyl relative total methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide wherein methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide methylcellulose total methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide second solid (Compound difluorobenzo fibrosis (Compound difluorobenzo composition fibrosis of (Compound (2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- composition [2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide [0008c] [0008b] [0008a] [0008d]
Compound
1
weight weight , dispersion, 1
-dimethylethyl)-5
wherein wherein wherein
solid 187.5 125
to in in the
More In In In the a a
1
mg
medicament
patient patient , of of 2) 2) 2)
comprising of a a a dispersion, 1
mg
[d] [d] -dimethylethyl)-5-hydroxyphenyl]- total
1 third
fourth second
the the
relative relative in
methylcellulose
the of
composition the the the
and specifically, relative
and [1,3] [1,3]
of the
a
first first
first weight
pharmaceutical first comprising comprising second
first aspect, a
100
0.5
aspect, manufacture
dioxol-5 dioxol-5 second aspect,
to to solid solid
aspect.
solid
to -hydroxyphenyl] solid a mg wt% is
the the
blend
of the solid formulated the
to as
the
dispersion dispersion in
the total total solid
the dispersion
of -yl)-N-( -yl)-N-( dispersion
total
present 200 defined orally orally a
acetate
present of
sodium dispersion first present first
of weight weight
dispersion
a mg composition weight
first
a
solid
aspect, administering administering 1 1
medicament for invention
-(2,3 -(2,3 of succinate in
and and
invention
comprises lauryl
which
- invention
solid
of of Compound the 1 oral
of dispersion,
,4-dihydro-4-oxoquinoline-3-carboxamide comprises
20 -dihydroxyprop -dihydroxyprop 10
the the
the
which first the
administration wt% wt% dispersion sulfate
comprises
3 second second
is
provides present relative 1 first
provides aspect.
,4-dihydro-4-oxoquinoline-3-carboxamide
a
provides 70
for
to to of to tablet comprises
2.
solid 70 relative wt%
30 the the hydroxypropyl treating
solid solid
invention
to
wt%
wt% and
use patient patient 80 which
yl)-6-fluoro-2-( a yl)-6-fluoro-2-( dispersion, to the a
method dispersion, dispersion,
wt%
(Compound (Compound (Compound and method of a 90
to to
of
80 cystic total second
amorphous the 90
wt% comprises
hydroxypropyl the a
comprises
wt% of provides
tablet
wt% weight total
amorphous of pharmaceutical
fibrosis of methylcellulose of
solid of
treating
and treating 19.5
amorphous of
weight
comprising amorphous 1) 1) 1)
1 1
of 25 a
amorphous
-hydroxy-2- -hydroxy-2-
(R)- a
dispersion, relative relative and
pharmaceutical wt%
in
the mg
cystic
a
1-(2, (R)- of cystic amorphous
patient,
second to of
the
(7?)-l- to to
2- 1-(2, JV-[2,4- 125
the the N-
2- mg
2015247850 04 Jun 2019 bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide the In methylcellulose hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide 2- hydroxypropyl methylcellulose medicament difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- dispersion (Compound (7?)-1 crystallinity. (Compound second solid Compound (Compound [2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide [0008f] [0008e] [0008g] 1 1-
relative
methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide (2, an
solid 2-difluorobenzo[d][l,
-(2,2-difluorobenzo[d] dispersion, eighth
29.6 243.9 29.6 243.9 5.9 5.9 solid
125 187.5
dispersion
to
In In In
comprises
2
mg
mg mg the aspect, 2), 2), 2) is
a a mg dispersion, a mg relative mg mg mg
seventh sixth fifth
formulated in methylcellulose
of
wherein and
total
croscarmellose croscarmellose relative acetate magnesium magnesium
and
microcrystalline microcrystalline of the
a
aspect,
the of first a aspect, a
0.5 weight
manufacture less to polymer, second
the
aspect,
present
succinate
the the to solid wt%
than
sixth 3]dioxol-5-yl)-N-(l-(2, for
the the
the total
solid
[1,3] of
stearate. stearate.
solid
of oral dispersion
the
present total
15%
present the wherein invention sodium, sodium, acetate or
sodium weight
dioxol-5-yl)-N-(
dispersion
and
present
cellulose, cellulose, of seventh administration dispersion first
weight crystallinity.
a
hydroxypropyl
invention medicament
invention
succinate
solid the
of and and lauryl
which
provides invention
aspects.
the of polymer
is dispersion
which the
second free
sulfate comprises 4
provides
provides relative
first 3 and 1
a -(2,3 -dihydroxyprop
of for
provides
pharmaceutical comprises is
methylcellulose,
polymer comprises
solid solid relative
selected treating
-dihydroxypropyl)-6-fluoro-2-( and
to
use a 80
dispersion, dispersion, the 20 solid
a
wt% of
(Compound
to
solid and 80 wt%
cystic total from
(Compound
(7^)-1-(2,2- a
the
dispersion
tablet wt%
yl)-6-fluoro-2-(l-hydroxy- of comprises
composition dispersion of weight total hydroxypropyl
amorphous
fibrosis,
and
hydroxypropyl 19.5 of
comprising (Compound
weight
amorphous 1) wherein
of wt%
comprising 1)
and less
wherein the comprising and
Compound of comprising /V-[2,4- of
than second
the /V-[2,4-
the
1),
1 solid the 15%
-
(7?)-
N-
2015247850 04 Jun 2019 7V-[2,4-bis(l bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide. pharmaceutical methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide, methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. wherein hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide method about difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- oxoquinoline-3-carboxamide. second difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- and second agent agent agent agent agent agents, aspect. (Compound (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l- aspect [0011] [0010] [0009] [0008h] [0014] [0013] [0012] 1:10
the
to
is is is is and
180 for
agent agent wherein about
second
of about about about about the In In In In Described In
a use The
°C. treating
second one one one one one medicament , 2)
1 is is
10:1
-dimethylethyl)-5-hydroxyphenyl]- in 2:3
1:6 1:3 1 present
in agent
N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4- : a composition
embodiment, embodiment, embodiment, embodiment, the embodiment, 1 treating
CFTR the
by by by by
by
cystic
therapeutic dispersion herein
weight. weight, weight, weight, is manufacture weight.
invention
a
potentiator.
comprises cystic CFTR fibrosis
is
of
a
the the the the the In In In
In
In is spray
agent. the fibrosis
potentiator.
also one one one
substantially one one plurality in ratio spray spray first
of
eighth
a a
dried embodiment, embodiment, embodiment,
In provides a pharmaceutical embodiment,
embodiment, patient
agent of medicament
in dried dried one
the
aspect. a of dispersion
patient. embodiment, is
In
first comprising therapeutic dispersion dispersion
free a a
one 5 pharmaceutical CFTR
1 agent
The
,4-dihydro-4-oxoquinoline-3-carboxamide the the the of
the the for embodiment, The
composition a comprising
ratio ratio ratio
present
ratio first polymer. corrector. treating
to has
is
present agents administering
the
the substantially
of of of agent of a
first
Tg second the the the
invention and the
In
cystic consists composition
invention
of a the
is one first first first In agent
as
first the plurality
from (//)-1-(2,2-
one
defined
first
agent
fibrosis embodiment,
second agent agent agent
agent
to
amorphous.
is
also of
embodiment, (Compound
about
agent the
a
also a
is
CFTR of
to to to
provides first of to in
patient from agent in
therapeutic
the the the
provides the the the
80 is
a
therapeutic
(R)-l-(2,2- patient,
°C second second second corrector
second about eighth eighth the is
the
to
1) use N-[2,4- the
and a
of
2015247850 04 Jun 2019 polymer. particle methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide; methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. second agent agent agent agent agent. difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- oxoquinoline-3-carboxamide. second difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- and second agent agent agent agent second agents. [2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide. [0018] [0017] [0016] [0015] [0022] [0021] [0020] [0019] 1:10 1:10
the
to to
is is is is is is is is
therapeutic agent
agent agent about about second comprises about about about about about about about about In In Described In In In Described In
one one one one one one
is is is
10:1 10:1 2:3 2:3 1:6 1:3 1 1:6 1:3 1
agent
N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4- : : a a embodiment, embodiment, embodiment, embodiment, embodiment, embodiment, 1 1
CFTR CFTR
by by by by by by by by
by by a agent.
herein herein plurality
weight. weight, weight, weight, weight. weight, weight, weight, is weight. weight.
a
potentiator. potentiator.
CFTR
is is
a a
of there the the the the the In In In In In In
In In In spray spray
therapeutic potentiator.
one one one one one one
one one one particle ratio ratio first first
are
dried dried embodiment, embodiment, embodiment, embodiment, embodiment, embodiment, In In embodiment, embodiment,
embodiment,
agent agent
of of
two one one
the the consists
dispersion dispersion
therapeutic
embodiment, embodiment, agents, is is
In first first
a a
one 6 CFTR CFTR
agent agent
essentially
the the the the the the
the the the and embodiment,
consisting comprising
ratio ratio ratio ratio ratio ratio
ratio ratio first corrector. corrector. agents, to to the
the the the the
particle of of of of of of agent of of
first first of
second second the the the the the the
and the the a In
a of
first
a the
is first one first first first first first first In In agent agent
first first
the
a particle,
is
(7?)-l-(2,2-
plurality one one
therapeutic first
agent agent
substantially embodiment,
agent agent agent agent agent agent agent second agent agent
is is
embodiment, embodiment,
agent a a
is is wherein
CFTR CFTR
to to to to to to and to to
of from from agent
the the the the the the
the the
is
therapeutic a agent
(7?)-l-(2,2-
second
second second second second second second corrector corrector
free second second about about
the
is the
N-
the the
and
of
a
a
2015247850 04 Jun 2019 bis( mg mg microns methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide, methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. croscarmellose comprises comprises filler, Compound one Compound spray about of about difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- oxoquinoline-3-carboxamide. second difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- and [0028] [0027] [0026] [0025] [0024] [0023] [0031] [0030] [0029]
about
to of 1 the embodiment, ,
1 dried a
100 about 180
a -dimethylethyl)-5
agent
disintegrant, second
lubricant. to 15 In In In In Described In In In In
°C. microns. microcrystalline from
about
2. dispersion.
1. microns. one one one one one one one one 36
is
In In
agent
sodium. mg N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4- about embodiment, embodiment, embodiment, embodiment, embodiment, embodiment, embodiment, embodiment,
30 one one the
In
of
herein
In microns.
a
is tablet one
embodiment, embodiment,
a
100 lubricant,
one
a disintegrant.
-hydroxyphenyl] In
CFTR embodiment,
mg
is
embodiment, one cellulose. comprises
a
the the the the the the the the
In to pharmaceutical In
embodiment,
potentiator.
or
one about one pharmaceutical particle tablet tablet tablet tablet spray spray
any the the
embodiment, In embodiment, In
about
tablet tablet
300
the combination dried dried comprises comprises comprises comprises one
one the - has 1
lubricant ,4-dihydro-4-oxoquinoline-3-carboxamide.
mg
embodiment,
particle 50
In embodiment, comprises comprises the dispersion dispersion a
composition
mean of one mg 7
tablet composition
a
an one from from
the
the of filler. embodiment,
thereof.
has comprises
particle additional
Compound
particle
or first comprises
about about
about about has is a
more
the mean In substantially the
agent comprising
a
one
diameter In
disintegrant
Tg
25 150 100 100 is tablet and has
In excipients
magnesium
therapeutic one particle
a
mg
of embodiment, the is
one
from
1. tablet. mg mg mg a the
(R)- from
mean
embodiment,
comprises to first
embodiment,
of to of second
of
about any about amorphous.
1 diameter
about
Compound Compound
-(2,2- about
about
agent selected comprises particle
stearate. of agent.
1 agent 125
the
200
the
mg from
80 5 is
microns
of
preceding mg (R)- the diameter from
°C filler
to
mg the is
about 2. about 1.
to about tablet of N-[2,4-
1
of
-(2,2-
In a
to
5
12
5
[0032] In one embodiment, the additional therapeutic agent is another CFTR corrector different from Compound 1. In one embodiment, the additional therapeutic agent is another CFTR potentiator different from Compound 2. 2019
[0033] In one embodiment, the additional therapeutic agent is selected from Jun
04
O 2015247850
[0034] In one aspect, the present invention features a pharmaceutical composition comprising an amorphous form of Compound 1, and an amorphous form of Compound 2.
[0035] In one embodiment, the pharmaceutical composition is a tablet.
[0036] In one embodiment, the tablet comprises from about 25 mg to about 125 mg of Compound 1. In one embodiment, the tablet comprises about 100 mg of Compound 1. In one embodiment, the tablet comprises about 50 mg of Compound 1.
[0037] In one embodiment, the tablet comprises from about 100 mg to about 200 mg of Compound 2. In one embodiment, the tablet comprises about 150 mg of Compound 2.
[0038] In one embodiment, the ratio of Compound 1 to Compound 2 is from about 1:10 to about 10:1 by weight. In one embodiment, the ratio of Compound 1 to Compound 2 is about 1:1 by weight. In one embodiment, the ratio of Compound 1 to Compound 2 is about 1:3 by weight. In one embodiment, the ratio of Compound 1 to Compound 2 is about 1:6 by weight. In one embodiment, the ratio of Compound 1 to Compound 2 is about 2:3 by weight.
8 2015247850 04 Jun 2019 mg tablet to In wt% to to to about embodiment, embodiment, dispersion. composition 90 embodiment, one spray first comprising about croscarmellose cellulose. excipients comprises [0044] [0043] [0042] [0041] [0040] [0039] [0046] [0045]
about about about about one wt%
of
embodiment,
spray of
dried
comprises
100 1 Compound embodiment,
Compound wt%
of 20 50 10 15
In In In In In In In In
mg
dried In from selected
Compound
dispersion wt% wt% a wt% wt% one one one one one one one another
comprises of one first
the the the to
sodium.
a
about embodiment, embodiment, embodiment, embodiment, embodiment, embodiment, embodiment,
dispersion
200
about
of of of of
polymer tablet tablet
lubricant. embodiment, the 2. spray
from
the a a Compound 1
aspect,
the
mg disintegrant. filler. and first
15 comprises 2
50
first comprises comprises
from
dried second
and In a
of wt%
from
mg spray comprises filler,
comprises
one the Compound spray
In In
from about
the the the the the the the of dispersion
to
one
one about present the
1. embodiment, spray dried
a Compound
about an pharmaceutical pharmaceutical pharmaceutical pharmaceutical pharmaceutical
second first
dried about
about about
disintegrant, In
pharmaceutical In embodiment, embodiment, 15
amorphous
hydroxypropyl
one
10
one dried dispersion an spray wt%
invention
45 2.
dispersion.
25 wt%
100 10
and amorphous
spray
embodiment,
embodiment, wt% In
wt% mg to dispersion
dried
1.
mg
a one the
to
about
second
dried
to a
In of
9 form
about
of to the
comprises the pharmaceutical features lubricant,
composition composition composition composition composition embodiment,
dispersion
125 one Compound
composition
Compound about
In
60 methylcellulose. filler form lubricant
dispersion
of
mg spray
30 embodiment, comprises one
the wt% the
Compound
wt%
30 a comprises of of
pharmaceutical embodiment,
or pharmaceutical disintegrant from
dried
wt% of Compound Compound further
any
2. comprises
comprises further comprises is comprises of
the 1. the comprises further
a composition
about from the
of
dispersion, In combination
tablet. tablet second
2.
the
comprises the microcrystalline one polymer.
comprises
about
comprises 70
tablet comprises
polymer.
the 1. 1, magnesium embodiment, comprises from from from
In
wt%
from spray composition and composition
In
pharmaceutical
one
70
wherein
comprises
comprises one
about about about
a In the thereof.
to
wt% about
one dried polymer.
one a about
second
polymer. about
30 or 5 5 stearate. to
the 1 wt% wt% the
more
about
wt%
wt% 90
150 In
2015247850 04 Jun 2019 therapeutic therapeutic magnesium tablet another corrector lubricant. disintegrant. filler. about first one embodiment, filler. filler, [0051] [0050] [0049] [0048] [0047]
embodiment, spray
a 250 comprises
In In
disintegrant, CFTR
In In In In In one one different
mg dried
agent agent. one one one one one stearate.
In embodiment, embodiment, the of potentiator
embodiment, embodiment, embodiment, embodiment, embodiment, one dispersion.
about the
tablet
is the
from In
selected
embodiment, second a
disintegrant one
lubricant,
1 comprises
Compound wt%
embodiment, different
the the
spray In from
the the the the the of
tablet filler one
or a
pharmaceutical tablet tablet tablet tablet
comprises the dried from lubricant.
any embodiment, from
1 comprises
comprises
.
tablet
In
the combination about comprises comprises comprises comprises dispersion.
Compound
one
additional
N H
comprises
croscarmellose
In
embodiment, 1
microcrystalline
10 wt% from one
the composition
from from from one
embodiment,
thereof.
2. tablet to
about therapeutic
or
from
about In about about about
more
one
comprises
12 the about sodium.
O
10
30 30 100
further mg
embodiment, excipients
additional ΌΗ cellulose.
wt%
■OH
mg wt% agent
the to mg 1
,
mg
or
about to
In lubricant
from
comprises of to to
is about to
one
a about about
another selected therapeutic disintegrant.
about In 36 about
embodiment, the
one
85 mg
300 comprises 50
additional an
5 mg
150
CFTR of wt% from mg
mg additional
of a
mg agent
of
of the of In a
a
to
a
the a
is
2015247850 04 Jun 2019 pharmaceutical previously pharmaceutical pharmaceutical patient therapeutic the one one concurrently agent. [0057] [0056] [0055] [0054] [0053] [0052]
additional embodiment, embodiment,
In comprising
In Described In In In In one
described.
agent one one one one one
with
therapeutic embodiment,
compositions composition. compositions embodiment, embodiment, embodiment, embodiment, aspect,
is the the any
administering
selected herein
patient additional
of
the
the agent
is
present the
from spray is
a previously of the the the the
kit
heterozygous
additional is
therapeutic the
to kit patient patient patient comprising a
dried invention
CFTR the invention.
further
patient
dispersions described. is is is
therapeutic
potentiator.
homozygous further orally
agent comprises
in features
any
any 11 the
administered is
of
administered AF508 of
a or
the
a agent CFTR
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an pharmaceutical method In
spray in
spray
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CFTR
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corrector.
administered
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dried AF508
O
the
of dried an
mutation.
treating
spray additional
dispersions therapeutic
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CFTR compositions In
dried
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mutation. therapeutic
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additional
or agent.
fibrosis or
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In In
or in
or
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2015247850 04 Jun 2019 providing ratio the thereof. difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- and second first first from second conditions substantially container. dispersions containers. dispersions [0060] [0059] [0058] [0063] [0062] [0061]
second
the
agent agent
of about
agent agent. the second In In In Described In In
a
to to
to
agent
first 1:10 or or mixture one one one one one In
the the free is generate
pharmaceutical the
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agent
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agent embodiment, embodiment, embodiment, embodiment, embodiment,
to second second
in
CFTR of pharmaceutical
embodiment,
about
the herein polymer; of
is
to the
a mixture a
potentiator. agent agent
the plurality CFTR
10:1
spray is
second
a
the the the the the and
by compositions in is method
is
potentiator. dried
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weight. plurality ratio first container additional of compositions about forcing
agent
additional therapeutic mixture In
dispersion.
agent
of of 1:3
one 1
the : generating
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is
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is
first therapeutic mixture weight. a
a
therapeutic
weight.
about bottle,
12
one previously mixture CFTR agents
embodiment, agent
embodiment,
a
1:6
through
In vial,
spray
corrector. and described to In agent
is
agents one by
the
the
one agent
about described blister a
weight.
dried
solvent,
first embodiment,
and
second a embodiment, the
consists nozzle
and
2:3
are the
In agent any pack, dispersion ratio
one by
any
In stored are first agent wherein
of
under
of one
weight. is
or
of
stored embodiment, the of
agent
a the any
the
a
in the in embodiment, CFTR
the
spray
first comprising:
spray
first the the
the ratio
combination
spray in is ratio
agent mixture mixture
same separate (70-1-(2,2- agent dried corrector
drying of
of dried
the the
and
the
to
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is is
a
2015247850 04 Jun 2019 psi pressurized boiling bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide. methanol, In nitrogen. to to methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide, methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. are solvent from further embodiment, embodiment, of about about agent, 90 solvent. an forced difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- oxoquinoline-3-carboxamide. second [0065] [0064] [0068] [0067] [0066] 100
the about one about
outlet, °C to
substantially °C.
about
about mixture 90
1,500 to and
embodiment, through
comprises agent point
to
150 about 120 It
psi In In In In Described
and In water IP the
is
70:30 gas. one one one one
2,000 psi.
A, to one
psi. °C. understood of is the the
the
solvent. as
the 150 about
N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-
THF,
the
embodiment, embodiment, embodiment, embodiment,
is
free
embodiment, In In
polar it spray In
inlet to water.
psi.
about nozzle.
enters
°C.
solvent, one one herein one about the
of DCM, 150
is organic In
dried In
polymer, In embodiment, embodiment, spray
embodiment, 90:10 heated
that
In
psi. the
one
one 95:5 one is In
one such
or
dispersion a
nozzle. in
the the the the
one embodiment,
dried
embodiment,
In the
In
spray embodiment, by solvent any
by
certain to embodiment,
one as, one wherein method method solvent spray
embodiment, volume. pressurized volume. a
combination
dispersion
temperature for
dried
embodiment, embodiment, the the In the
comprises
embodiments,
dryer
is example one
pressurized pressurized comprises
further further spray
the dried dispersion
the
In the the embodiment,
is
particles the
gas one is
pressurized 13
heated pressurized dryer the
at mixture
thereof.
that
comprises comprises dried under
methylethyl ratio has a
embodiment, the the
method temperature a
is gas gas comprising is polar the
a
to under pressurized
comprise of first
high greater
positive heated
is
has is a In the
temperature
the
forced
temperature
gas
organic inert agent further gas filtering drying
one
pressure
reduced polar a
nozzle ketone,
and
positive
to than In has
comprises
embodiment, pressure both of the to
a is a through one
the
the gas
plurality organic comprises
the temperature from a
solvent.
(7?)-l the ratio the
positive
comprises
conditions. pressure.
a
embodiment, methyltertbutyl may
second spray has
first
pressure CFTR boiling of mixture
about -(2,2- of
of
the from
molecular
a
be solvent
agent,
of from the positive dried In
pressure
nozzle applying agent the below
corrector
particles
50
point one
In about polar of an before of
about
solvent
°C
the
dispersion. one from
inlet to from
the is
the pressure by
of
to
water organic
second
50 N-[2,4- ether,
of
heat
it
the that
and about 1,000 and about a
°C is
is a
2015247850 04 Jun 2019 protons polymer polymer the which In wherein through the Compound atoms of substantially Compound scanning Compound as identifiable embodiment, consists amorphous; CFTR [0072] [0071] [0070a] [0070] [0069] [0074] [0073] 10:1
Compound one defined
particles scope
to
and is potentiator,
embodiment,
about
on
a essentially the
of of not
Figure Figure Figure In Described Described The
calorimetry of nozzle
protons in
Compound
the the 2. 2, 2. by
the
mixture and
the
have within
free the
the
following 1:10; showing
1
a present present
description
and claimed the
person 2 3
appended 1 under biological
of
a
A) is is wherein on
the
of Tg the
herein herein plurality polymer
Compound the is
a an
(DSC)
Compound depicts
a
plot
substantially particles invention invention 1, of BRIEF a
scope spray
plurality XRPD skilled figures biological
invention. glass and
from
is is claims. of in the medium
analysis
a a of
of drying B)
of solid
this heat
transition
biological spray
ratio pattern about in DESCRIPTION
are particles the
2, have the
graphic
formulated formulated of
the
1
specification
generated medium flow
provided state
and present
therapeutic
appended free
of
conditions is
dried of 80 a art
for an CFTR
mean
spin
the as
temperature °C of 1
depicting and is
medium H
in
the
dispersion a
substantially a invention is NMR neat
to
vivo function diffusion
with with by by may polymer. particle
an corrector neat claims. about
reference agents 14 to
way cross
spray
in
biological
OF
a a assist
spectra generate
comprising the
spray vitro 1 1
of
180 : :
(Tg)
diameter of THE
generated formulated 1 1
polarization
between
cross dried and That
ratio, ratio,
example to
in temperature
free
biological dried °C;
may
for
CFTR of putting
a
the FIGURES
medium. subject polarization
dispersion
solvent;
the by by of 124° the
Compound be
dispersion of spray protons
by a
weight, weight,
and particles
neat potentiator
with made polymer.
about
into C.
from
providing medium. matter
generated are dried and
spray
a
practice
substantially on to
15 fluorine
1 of of not
between
forcing : substantially
are
subject 1 1 Compound should
microns dispersion,
Compound Compound
and ratio, dried
intended is
a substantially In
from by mixture the
Compound one
atoms
the
by dispersion matter fluorine be differential
invention or
about free weight, mixture
readily
to
greater;
1
free to 1 1
that
and limit
and and
of
of
2.
2015247850 04 Jun 2019 polymer polymer polymer polymer polymer relative FedSIF time. neat weight, neat (squares), and fed Compound Compound scanning Compound Compound Compound dried [0080] [0079] [0078] [0077] [0076] [0075] [0083] [0082] [0081]
state
in coSDD spray
dispersion
the
solutions humidity of
of and of of of simulated Figure Figure Figure Figure Figure Figure Figure Figure Figure calorimetry
presence and Compound dried
the the the the 2 2, 2. 2 2
substantially
alone
formulated at at
showing
a present present present present
5000x. 5000x.
tablet dispersion substantially
4 9 8 7 6 5
10 12 11 in when
depicts is is is is depicts
as
intestinal
of the depicts depicts compares
an a an an (DSC)
measured
Compound comprising
1 plot
invention invention invention invention a
in presence XRPD SEM SEM and
Tg with
free a the an
substantially of
the dissolution
Compound of Compound analysis
fluid
overlay
free image image heat results a the of
155 pattern results by 1:1
polymer formulated formulated formulated formulated of
crystallization
of Compound (FedSIF) 1
flow
concentration °C.
ratio, Compound in of of
polymer, of of of
a of
for
the the
data
2
kinetic the as 2. solid neat free
kinetic by
free
and
the a neat neat
neat
solutions of
function weight, with with with with of coSDD
state 2 tablet neat alone
and
Compound
dissolution 15 polymer spray 1 spray
(triangles).
spray kinetics
dissolution
versus in a a a a
cryoground/cryomilled
spray 13
1:3 1:3 1 1:3
a (circles), as and C
:
substantially of 1 neat in dried dried
dried NMR measured ratio, ratio, ratio, ratio,
temperature the
time.
formulated dried 19 for
coSDD 2 F
experiments
dispersion dispersion
presence
dispersion
experiments NMR in
Compound
by by by by (top) a
dispersion
fasted spray
weight, weight, weight, weight,
by
free substantially spectra (bottom)
with concentration
generated
of dried simulated
substantially substantially
of
substantially
of Compound of of of of
1
of
a polymer. substantially
at Compound for
Compound Compound Compound Compound Compound dispersion 1
Compound
spectra : 80 1
the
by ratio,
free °C fluids
neat
differential
versus
and
2 free free
for of free by
in
alone 1 spray
1
free
1 1 1 1
75% the
2
and a of in of and and and and
of
in
of
2015247850 04 Jun 2019 protein. AF508, results this the within nucleotides refers regulator. relative G551D, Top. open gene. are Compound of identifying and spray (squares), "Pharmacological [0089] [0088] [0087] [0086] [0085] [0084] [0092] [0091] [0090]
the
useful
codon phenylalanine 75%
Med. probability
dried to
fluorine
the in
has humidity
G178R,
A a
As As As As I. Figure Figure The The relative
the
for for and mutation CFTR
Chem.
"CFTR the dispersion the 1 in
used used used used
production and present term treating amino
a a atom DEFINITIONS tablet
same
gene tablet
compared 14 13 S549N,
protein. humidity. when
Compound herein, herein, herein, herein,
3: Rescue
residue. "CFTR mutation"
in depicts compares to
acid
91-120
mutation components
in invention
cystic
comprising the of protons
in
general
of
S549R, Compound a a phenylalanine "mutations" "CFTR"
of
CFTR a The
gating patient
"AF508
to a
a Compound The
(2008)). fibrosis.
Mutant
CFTR
2 solid refers normal
the
on mutation
on resulting DETAILED provides results
upper protein.
G551S,
mutation"
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state
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CFTR
1
CFTR
Gating can
the
a
and
allele. spectrum in
is
2
at
mutation *H
is
in pharmaceutical
for
G970R, free "homozygous" a bottom
A refer
position
a
a the NMR mutation function for
as
deletion genetic (Van cystic spray DESCRIPTION
mutations
2 tablet or 1
used
growth
which to 16 and (triangles).
kinetics "F508-del is
spectrum spectrum in G1244E, mutations
Goor,
dried fibrosis the 508,
spin herein (circles), defect the
for in of
the
of reference
the include, the
the
CFTR
resulting
F., dispersion formulations diffusion
for for the predominant
means or transmembrane CFTR mutation" is three S1251N, of
Treatment Hadida
in Compound a
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a generated mutation,
a
particular
gene, the
spray
tablet
but
nucleotides 1
in H
a protein between CFTR
of S. CFTR NMR
CFTR are
and S1255P,
dried
is
comprising and Compound
and of defect
not by or
a
mutation, 1 2
a
Cystic gene
translated
specific
at
compositions spectrum
peak. Grootenhuis mutation a
protein "CFTR
cross dispersion conductance protons limited
change 70
that
is and
or
°C a
Fibrosis", polarization
comprise the
low 2
a
G1349D. mutation
that mutation"
e.g.,
and to,
on blend at in that from
CFTR
channel 70
the
lacks 75% P.,
that
°C
that
of
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2015247850 04 Jun 2019 pancreatic patient. human transport. AF508, of growth subject. improvement Technology one The improvement and gastrointestinal fluid gastrointestinal solvent increasing channel amount "therapeutic [0100] [0099] [0098] [0097] [0096] [0095] [0094] [0093] [0102] [0101]
coughing
refer skilled exact
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"Treatment", As As As A As As As As As The to
non-human
the amount
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in this "patient",
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terms for in of the subject,
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fluid fluid. of mutation
amount of CF CF
example, activity, art
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will dissolving
CFTR
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using
would
CFTR
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increased A
as
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simulated
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protein
interchangeably one produces
terms term term terms term term term
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or
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located
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of who
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Improvements to simulated
vivo or
or
CF purpose
includes,
the the the
"effective is lessening and
gain,
includes
or
cases gastrointestinal
at 1
"heterozygous" corrector, potentiator" corrector" desired cell
pharmaceutical
system"
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lessening the a
to
reduction
different (see,
medium" of as
intestinal surface,
of
but Compound 17 cell are refer "treating",
the
in mammals
the amount" chest effect
e.g., in fluid
used is
inducing refers
surface,
potentiator,
treatment, refers
to severity the not or
refers mutation
resulting
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Lloyd
fluid lessening for would
interchangeably
severity fluid biologically limited for
to
mucus
ingredient", are and
to 2.
such
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resulting a
CFTR to
a
(FedSIF).
of a
to system used (1999)
such
particular the and be compound a
or
in on CF
a as to,
compound in
of
the
an real and/or it
like
other enhanced
will the
humans. interchangeably as activity, the
or the CF
is
in
in The comprising active severity
what
or its
administered
"API", other generally
lungs,
vitro be following:
or enhanced A
mechanism.
and mutation, simulated
reduced symptoms
Art,
that real a ascertainable
exists
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compound. refers symptom
allele. ion gastrointestinal refer
improved
and of Science increases
increases transport.
refer any
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these
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the
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2015247850 04 Jun 2019 particular percent. pharmacological patient. the the term how the 3-carboxamide. compound fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. 6%, amount, amounts, agents compounds conditions "approximately" [0105] [0104] [0103] [0106]
art. compoundN-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline- compound
5%, the "about"
being
value Specifically or
4%, As As As The
or value
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percent
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"in to according
concurrent 3,
the that
order
combination of 2" or 1" or
N H
within
or
structure:
ordinary "approximately" and and 4
obtained of
[1,3] In 0.05% standard of
a by to "Cmpd "Cmpd certain
administration
with, composition
30%,
dioxol-5-yl)-N-( 18 standard one
skill
when of
from with",
deviations. OH or
of
a 25%, 2" embodiments, 1"
given
in subsequent ordinary
are are used the
methods
the when means
20%,
used used or specified
value
art, includes in
a OH
In referring
connection 1 dosage skill
interchangeably interchangeably 15%, which an -(2,3
OH
and
certain to or
the acceptable
in each range. dose,
-dihydroxyprop the techniques 10%,
term the form, depends
to
compounds embodiments, other
amount, art with
two
9%, "about"
mean
to error
or
to
in doses,
8%, provide to to known
more the part
a refer refer
or for
or
7%, dose, yl)-6-
or
This
weight
on
a
the
in
to to a
2015247850 04 Jun 2019 below polymer). ppm) 2004/0006237 melting range wt%, that refer colloidal (the substance, crystallinity. amorphous' crystallinity amorphous little in crystalline characteristic are defined liquids (rubbery of concentration compound, about [0109] [0108] [0107] [0111] [0110]
its a
generally
mixture solid continuous
or to
XRPD less of
order 0.5
which
in
no a arrangement, points.
another
state).
particles As As As As As
mixture phase wt which than
the For as long
materials impurity,
in
includes
or used used used used used pattern. or
%,
the
isotropic, determined
crystalline of
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dispersed
for about example, less
material
phase
range For (glassy less
the dopant, less physical
herein, herein, herein, herein, herein, or position of a
than
comparison example, molecules
than material
nanometer the than have 1000
Broad or
e.g., order or
i.e.
state),
is material
about phase,
compound, descriptor, a peak(s)
vehicle).
the the the the by "glass
about
properties
about
mixture substantially molecular less ppm, of exhibit
in peaks
XRPD).
term term term terms
that its
an
and the 5%
than are
is
0.1
transition
dimension,
of molecules. or 1 in amorphous (e.g.,
has
distributed,
wt%
position "substantially "amorphous" "dispersion"
are crystallinity). arranged above similar
or The XRPDs
less "substantially
its wt%,
'amorphous', about impurity,
of
packing,
dispersion
a
Instead, characteristic X-ray polymer)
amorphous (e.g., size concentration than free
which less
temperature" properties
15%
of
of
to
of in
of
Amorphous about material power
less
than
its in
an
or and multiple one
the a the refers
crystallinity 19
refers
amorphous
discrete random that
is amorphous"
molecules.
material which amorphous It than free"
dispersed no compound, about 500 or absent materials
is
diffraction
of
is in
to several is
also
of long
to
about
an ppm) and
substantially
microns all or a refers
a
less units, manner
a solids 1000
solid
(e.g., disperse from
amorphous
noted "Tg"
solid directions range
"neat"
materials
(e.g.,
phase
0.5 For vary than material of broad refers
to
ppm, impurity,
throughout (XRPD) material
a
polymer).
are polymer. refer
material in wt
that materials so example,
order. mixture
less about in
are
system size). can
generally peaks
%, to that
or
free a
the
and to
behave
used solid. and
than manner
a
less vary less
the pattern having
solid there Amorphous 1
or term
having of
In do or
(e.g., wt%
crystalline in
A a having substantially
material interchangeably about than than
temperature
a
considerably general,
material second
not See,
which
dopant, supercooled
like polymer material is
'substantially
similar
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US
10%
liquids no
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when material. (0%)
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2015247850 04 Jun 2019 polyoxyethylene pharmaceutical phosphates, pharmaceutical polymer modified with wetting tablets the and/or compositions dibasic a compositions croscarmellose composition surfactants), composition. dispersion constituting (continuous dispersion dispersed dispersed [0115] [0114] [0113] [0112] [0118] [0117] [0116]
lubricant
continuous
enhanced
talc. and
calcium agents
(continuous
As As As As As As As
cellulose phases and
includes can includes ejection
phase); starches, the used used used used used used used binders, and
that with Examples continuous
include include cohesion phase.
and/or compositions composition. dispersed phosphate,
20 aids can
herein, herein, herein, herein, herein, herein, herein, are
enhanced
(e.g.,
the of magnesium or sorbitan
phase). be glidants, sugars pressed in
sodium a
alternatively, a sodium drug
tablet tablet solids, or
of crystalline hydroxymethyl
a a a a a a an phases phase,
"wetting "lubricant" "diluent" "disintegrant" "glidant" tensile "binder" excipients sucrose,
"excipient" (e.g., constituting mono-oleate flow
In with
Examples into
of starch dispersion. lubricants,
lauryl liquids,
stearate.
some
and are a
properties.
mannitol, strength tablets. pharmaceutical enhanced
drug
is agent" com
an both or is glycolate. the
sulfate
include embodiments,
an is
an
"filler" or amorphous
is
of cellulose).
(dispersed drug an the
(maize)
excipient
is disintegrants,
solids. excipient (e.g., gases.
an
Examples
The
(e.g., fillers or
an excipient
sucrose,
dispersed (SLS),
solubility
inactive Examples a fdlers constitute
excipient is
20 lubricant Tween™), "surfactant"
hardness).
an In In starch, include
composition
that drug
phase) that
sodium pharmaceutical the excipient
or a
or of
that ingredient
phase, solid
and/or
diluents,
imparts or
the case disintegrants
imparts
the (dispersed of that microcrystalline aids
lactose,
is
the
in or glidants
like)
stearyl
Examples continuous dispersion is
added of
hydrates
an in and any wetability. that like. an
a
a
from
compaction a wetting amorphous
or in
solid
pharmaceutical
excipient
sorbitol, the pharmaceutical combination
adds
to
fumarate a phase)
any include applications,
pharmaceutical a include
pharmaceutical polymer
a
dispersion, of
die
includes bulkiness combination phase. pharmaceutical
agents
binders cellulose, Examples
press. in
celluloses,
that
colloidal
polymer
of
(SSF), an sodium
constituting
thereof. granules Or,
(e.g., imparts the amorphous
composition include
a Example to the
a solid
polymer and
a of
thereof. solid
silica
calcium
into
of
2015247850 04 Jun 2019 having hydroxyphenyl]- yl)cyclopropanecarboxamide, therapeutic POLYMER Related (Tg) about about about about 5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- is oxoquinoline-3-carboxamide. second (l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. agent agents, other interpreting [0125] [0124] [0123] [0122] [0121] [0120] [0119] [0118a] [0128] [0127] [0126] 1:10
a
CFTR
to
of
features is 2:3
1:6 1 1
a :3 : wherein agent about from terms 1 (7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-
mean
And, As In In In In In Described II. In by by by by
potentiator.
agent
some some some some some some statements
used
weight. weight. weight. weight.
about
is
10:1
besides such
A, in SPRAY particle
N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4- the
1
some and herein, embodiments, embodiments, embodiments, embodiments, embodiments, embodiments, ,4-dihydro-4-oxoquinoline-3-carboxamide.
by
80 as dispersion herein
In In In weight. a
the “ °C Spray
diameter embodiments, comprise in For second
DRIED some some other
the to features this
is
example, about
Dried term
a
examples, specification
examples, examples, and For is spray therapeutic
DISPERSIONS the the the the ” of the the substantially
and prefaced “
the 180 example,
Dispersions about comprising
plurality ratio second first spray spray
dried
the
the second “ °C. comprises
the agent the the first 5 of
first
dried dried
dispersion
agent.
to by and
agent
the the ratio ratio ratio
of agent
agent about
agent free ” this is
21
claims first therapeutic ratio dispersion dispersion means
a ” of SUBSTANTIALLY of of is
of term CFTR
are is is
a 100 the is the the agent
of
a comprising CFTR
N-[2,4-bis(l,l-dimethylethyl)-5- (7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-
a which to polymer. “
the first in first first CFTR microns. consisting
be corrector.
to each
comprises has
first agents
interpreted potentiator. agent agent agent
the include
a
corrector
statement
agent glass
second
a
In
to consists to to plurality at
For
some the the the the
least
a transition to
plurality
FREE
in
agent
example, the and second second second term For
can
similar in embodiments, of
of
second
the part
example,
a also is “
OF therapeutic
comprising
first
temperature of agent agent agent from second
of
manner. the be
particles
agent ’
.
present.
about first
is
is is When the
agent
the
is ”
,
2015247850 04 Jun 2019 plurality plurality having hydroxyphenyl]- yl)cyclopropanecarboxamide, about spray (Tg) about about about about 5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- is oxoquinoline-3-carboxamide. second (l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. agent a agents. about spray [0134] [0133] [0132] [0131] [0130] [0129] [0137] [0136] [0135] 1:10
first a
CFTR
to of
dried is dried 2:3 5 5 therapeutic
1:6 1:3 1
a : agent about from to to 1 (7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-
of of mean
And, In In In In In In Described In
by by by by
about about potentiator.
particles particles dispersion dispersion some some some some some some some
weight. weight. weight. weight.
about is 10:1
in particle
N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-
30 30
1
some
embodiments, embodiments, embodiments, embodiments, embodiments, embodiments, embodiments, agent ,4-dihydro-4-oxoquinoline-3-carboxamide.
by
80 microns. microns. herein
having having
In In In weight.
°C
comprises comprises diameter embodiments, For
and some some other
to
is
example,
about a a a
a
In In mean mean second examples,
examples, and examples, For spray
some some the the the the the of the the
a a
the 180 example,
plurality plurality about
particle particle ratio second first spray spray spray spray
dried
the
therapeutic
the second embodiments, embodiments, °C.
the agent the the first 5 of
first
dried dried dried dried
dispersion
to
agent
diameter diameter the of of the ratio ratio ratio
agent
agent about
agent
particles particles is
22
first ratio dispersion dispersion dispersion dispersion
a agent. of is of of
CFTR
is is
a
100 the is the the agent
the the
of
of of consisting CFTR
N-[2,4-bis(l,l-dimethylethyl)-5- (7?)-l-(2,2-difluorobenzo[d][l,3]dioxol- a
having having the
first about about first first CFTR microns. spray spray
corrector.
to
consists is comprises has first
potentiator. agent agent agent the substantially
15 15
dried dried a corrector a a
agent of
glass second
mean mean microns. microns.
In
to
to to a
of
dispersion dispersion
For plurality
some the the the
a
two transition to
particle particle plurality
agent
example, the and second second second For
amorphous. therapeutic embodiments,
second
the
example,
of is
diameter diameter comprises comprises
temperature therapeutic of agent agent agent from second
the
particles
agent
about first agents,
is
is is the
agent of of
the a a is
2015247850 04 Jun 2019 plurality polymer. particle having hydroxyphenyl]- yl)cyclopropanecarboxamide, dispersion, about spray (Tg) about about about about 5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- is oxoquinoline-3-carboxamide. second (l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. agent agent. [0143] [0142] [0141] [0140] [0139] [0138] [0147] [0146] [0145] [0144] 1:10
a
CFTR
to of
dried is 2:3 5
1:6 1:3 1
a :
agent about from to comprises 1 (7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-
of mean
And, In In In In In In In Described Described by by by by
about
potentiator.
wherein particles dispersion some some some some some some some
weight. weight. weight. weight.
about is 10:1
in particle
N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-
30
1
some
embodiments, embodiments, embodiments, embodiments, embodiments, embodiments, embodiments,
,4-dihydro-4-oxoquinoline-3-carboxamide.
by a
80
microns.
herein herein the
plurality having
In In In weight.
°C
comprises
diameter embodiments, For
spray some some other
to
is is
example, about a
a a
of In dried mean examples,
examples, and examples, For pharmaceutical spray
therapeutic some the the the the the the the of
a
180 the example,
plurality about
dispersion particle particle ratio spray spray second first spray
dried
the
the second embodiments, °C.
the agent the first the 5 of
first
dried dried dried
dispersion
to
agent
agents, diameter the of the consists ratio ratio ratio
agent
agent
about
agent comprises particles composition is
23
first ratio dispersion dispersion dispersion
a of is of of
CFTR
is and is
a
100 is the the the agent
essentially the
of
of comprising CFTR
(7?)-l-(2,2-difluorobenzo[d][l,3]dioxol- N-[2,4-bis(l,l-dimethylethyl)-5- a
the having the
first about first first CFTR microns.
spray
a corrector.
to
first is comprises has
particle first comprising
potentiator. agent agent agent the substantially
15
dried a corrector
a particle
of
agent
glass
second
mean microns. a
In
to a to to
particle,
is
first dispersion
For
some
the the the
a substantially transition to
particle plurality a consisting
agent
example, the and second agent second second spray For
amorphous. embodiments,
wherein
second
the example,
is
and diameter dried comprises
temperature of agent agent agent from second
the essentially
particles free a
agent
the second
about first
is
is is
the
of
agent of
the
a is a
2015247850 04 Jun 2019 pharmaceutically particles particle particle particle particle Polymer having hydroxyphenyl]- yl)cyclopropanecarboxamide, evaporation dispersed such converts Compound about first about 5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- is oxoquinoline-3-carboxamide. second (l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. agent second of [0152] [0151] [0150] [0149] [0148] [0154] [0153]
a an
CFTR
particle,
as
amorphous is 30
1:10
a agent. agent fluidized is is is is (7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-
have a mean microns. And, In In In In
Starting
liquid
liquid potentiator. about about about about to
2
some some some some and
the may is
about
a
B, in particle
N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-
mean
suspension
drying
1 second
2:3
feed bed first 1:6 1:3 1 some
acceptable from embodiments, embodiments, embodiments, embodiments, ,4-dihydro-4-oxoquinoline-3-carboxamide. be : In
1
10:1
by by by by
prepared
drying some particle agent
to Methods
diameter embodiments, Compound
For of
weight. weight. weight. weight. particle, a by
the dried
example, embodiments,
and weight. or
or levels.
liquid diameter and by solution,
vacuum
of
In In In particulate a
the the the of the
or
spray second
Preparing some some other the
1 about
both
ratio spray second first
droplets. Typically, For or
the
the second
of
Compound drying drying and
examples,
examples, examples,
example, agent particles first particle of 5
first
about dried the
to form.
agent
the a a
agent
agent
about sufficient first
agent
The Spray
is may methods.
24
spray
first dispersion
15
a
consisting
is Optionally, have
the
particle, the preparation CFTR the
the
2,
microns. is is
be a
100 is particle
Dried
drying
the CFTR
N-[2,4-bis(l,l-dimethylethyl)-5- (7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-
ratio
ratio a ratio ratio
used
a
volume CFTR microns.
mean
Spray amorphous corrector.
comprises
Dispersion the of
of
of of
to essentially to involves potentiator.
a
the
the
the the
reduce to
the particle second corrector
secondary drying of
be
first
first first first In
hot second
spray For
some form
contacting a
residual
particle particle, air particle particle Substantially particle
is diameter plurality of
example, and a For
to
an particle
drying dried of process embodiments,
produce
the amorphous Compound example,
to solvents
to to to or
can
of a of second
the
process
the the the both highly the is
that particles about
be Free
from second
second second second first
the to any
agent
1 of
5 the
or to
2015247850 04 Jun 2019 mg/ml. mg/ml, have mixture more non-volatile mixture temperature microwave reference. Monogr. Hill Engineering the the dimethyl-2-imidazolidinone dichloromethane, solvents about a fluid line example, Commercially collector current solution, [0158] [0157] [0156] [0155] [0160] [0159]
boiling
spent selected
of book
bed solubilities
non-volatile 8%,
spray of
30
at of
include
In point In In Removal Series (e.g. coarse Exemplary Techniques
drying air commercial
co. warm
less mg/ml, less
solvents,
drying,
one one some
spray
to solvents. Handbook, is
driers
(1984);
a
available than than about sent of
2
cyclone). process,
suspension, embodiment, filtered those (e.g., of
processes, Ν,Ν less (1954).
drying solvents, 35 of
manufactured
rotary at to about about
for
solvents 200
and
the mg/ml, and
least spray than -dimethylacetamide a from solvents Where
example condenser
6th types gas
the
solvent apparatus.
°C). methods Marshall drum 5%, All 15%, The
about about
for about
dryers Ed., that slurry, (DMI), solvent solvents
40
that mixtures the
three of
less spent
example, where
drying e.g.,
mg/ml,
evaporates R.
a may apparatus
100 10 by solid room
could
to for mixture are than
"Atomization colloidal
references H.
dimethyl mg/ml, includes
Niro)
In less gas capture
are
°C.
require Compound spray
manufactured
Perry,
or dispersion
of one
temperature about
be
45
is where
those than biconical
solvents
In
(DMA), (see,
then tested may of
mg/ml,
procedure, the
drying (e.g.,
dispersion, some
and D. a
a sulfoxide volatile
3%, about
are
solvents volatile
25
subsequent
the solvent US be exhausted W.
potentially and
include at is 1 incorporated
or are embodiments, used
Ν,Ν 50
may non-volatile vacuum
has 2004/0105820; Green
fluid to least 12%,
by
less
Spray-Drying" solvents
mg/ml, used,
about the
solvent,
and -dimethylformamide
a (DMSO), where Buchi be to or
solubility bed about acetone, than
less
preparation with & conduct paste
drying found
conveys drying
the
recycle
100 J.
dried.
or than Compound Ltd. about
or
herein O. the for 15 mixture
solvent
that greater).
the °C), a
in
dioxane,
step, cyclohexane,
Maloney,
mg/ml,
mixture (e.g., example And the solvent, of about US
Perry's
the the 2%. 50, may solvent
at vacuum
in
is
spray
2003/0144257). such
is
Niro solvent. dried
can least Chem. from their
sprayed
10%, be present
In 1 20
ethyl
of Chemical
or
and a
include
as eds.), (DMF), includes drying. atomized
other
(e.g.,
mg/ml, about
product solvent
entirety volatile about alternatively
drying,
tray less
Eng. Compound acetate,
into
in
McGraw- processes,
the
than
20
drying,
one
room the
Prog.
1,3- For 25
having a a
to
by and PSD using
or ethyl a
2
2015247850 04 Jun 2019 use bioavailability provide particles may temperatures, present ethylenediamine Tristearate, (Docusate), lauryl esters appropriate decrease crystallization solid size optimal for In water methanol, Sodium dissolve amorphous about about dioxane/water. solvents (NMP), ether, [0161] [0162] 1000
some
example,
in
would
optionally
dispersions
succinate
is 99.9%. glacial (e.g.,
10%. sulfate connection
from
an solid methyl present Oleate,
embodiments both include can the A The
optimal lead Compound spray hexadecyltrimethyl surfactant Spans®),
dioxycholic
interfacial
lead MEK, In about acetic (SLS), dispersion. particle Compound a
In or
of
(TPGS),
include In tert-butyl sufficient some
to Sodium from
acetone/DMSO,
tetraacetic
some
for
chemical Compound dried
to
with
a improved
isopropyl
particle 0.1%
acid DCM,
two fluffy downstream sodium
preferred about polyoxyethylene
size
or the
preferred the tension dispersion a 1
Lecithin, Myristate,
acid
solvent (HAc),
surfactant
to is surfactant. As
1 ether amount
solvent
and
present particles
water, degradation
and size a about 0.1% acid
solvent dodecylbenzene would alcohol, component sodium 1
the
or between (MTBE),
embodiments, the ammonium
and
methyl system,
(EDTA), embodiments,
acetone/DMF, processing methanol,
to
of MW Compound system 15%, temperature substantially
invention
polymer.
Sodium mixture
that, be
an about the removal. A
salt isopropyl
appreciated
sorbitan optimal 677-692, surfactant of
for ethyl
the
solvent
the under of tetrahydrofuran (DOSS),
includes
Vitamin Compound 15%,
example
a bromide Stearate,
may
solid IPA,
solvents include,
such
Suitable ketone solid
sulfonate 2
water
Applicants
drying
some 26 water
drying from free acetate, fatty
may
for acetone/water,
Glutanic also and
dispersion
or as
three Sorbitan amorphous by E
example
of
about is
surfactant (HTAB), (MEK),
tableting. acid
Sodium not circumstances a can but
d-alpha
mixtures
enhance is
range 1 skilled solvents
temperature.
a polymer solid
(SDBS)
or DCM, a solvents.
co-solvent
be
are be
(THF),
co-solvent esters
have acid Compound 9%
Monostearate, removed.
present may dispersion.
and not
about N-methyl-2-pyrrolidinone tocopheryl practitioners, Palmitate,
aqueous
Sodium to dispersion,
thereof. monosodium and include mixture
MEK/water, At
found of dioctyl
(e.g.,
limited an
pentane, be about
In
higher
the
9%
toluene.
with aqueous do modified in
with
instances
Tweens®), however,
present 2
The of N-lauroylsarcosine,
not those to
solubility
sodium would 11%,
may Gelucire to, The MEK polyethylene
from
temperatures, about acetone
acetonitrile, preferred
provide Sorbitan
methods a
sorbitan
THF/water,
Exemplary medium. monohydrate, described surfactants small occur. e.g.,
to
embodiment
generally where where
about
sulfosuccinate
that 11%, prepare
44/14, and
sodium about where
particle optimal
solvents smaller herein At fatty
0.1%
water e.g.,
glycol
An
above,
lower
co
10%. for an
acid
to
is
2015247850 04 Jun 2019 providing preferably preferably polymers to mixture the the the 2%, Pluronic Labrasol, agent agent first and drying substantially about embodiments, dispersion sulfate are example Solutol [0166] [0165] [0164] [0163] [0168] [0167]
the
not invention surfactant solid
a about agent
second to to 6%, second
conditions (SLS), limited
HS-15,
is
the the F108, of
dispersion In In Described In Candidate The
(Pluronics®) PEG
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the free
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agent in amount more is Vitamin to
the
to, 8 and polyethylene be about
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caprylic/capric
1%,
of implementations, implementations, manner
to
surfactant Span between
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embodiments, Pluronic than
agent agent in
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generate
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or
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TPGS,
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to
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about about surfactant that
F127 would about
glycol/hydroxystearate,
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method 12%, - (or
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glycerides,
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spray
to
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be polyglycolized the the
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Tween
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amount
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described components) by weight. weight.
generating
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Transcutol, weight. : about 20, SLS)
by of 1
dispersion.
the
weight. in of
in by copolymers.
27 the
weight polyoxyethylene-polyoxypropylene
Capryol
agents
connection
of the about
an 2%
mixture weight. In
relative
0.5
for it first therapeutic glycerides
amount
surfactant
some
For a is
or Taurocholic at
to testing can In
spray 10%,
is from and agent about least diethylene
4%,
90,
example,
some preferred.
through to be In examples,
a
with
of
SLS
Pluronic about
dried about the
about
other
solvent, tested
about polymers. to
1%. (Gelucirs®)).
relative no agents examples,
the
total this
is
Acid, more
a
dispersion
the 9%,
examples, 0.5% An glycol
0.5%.
0.5 generally for nozzle second
the
invention weight F108,
wherein consists
ratio
to embodiment
to about suitability than Pluronic
to
ratio
the the monoethyl 3%, In
under
about
agent of
sodium
about
these Specific total of
comprising preferred. ratio the 8%,
of the the about of
include, the
the
F68, ratio a
spray in 10%,
first for mixture about weight
of first 15%,
solid
wherein
lauryl the co first
0.5
ether,
the use
of
agent
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7%,
to
and
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is
2015247850 04 Jun 2019 nozzle. through hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide. yl)cyclopropanecarboxamide, yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- further combination of spray example, 90 elemental first gas. inlet is a a oxoquinoline-3-carboxamide. second (l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. agent [0174] [0173] [0172] [0171] [0170] [0169] [0178] [0177] [0176] [0175]
suitable CFTR heated
polar psi
agent, is Examples
dried is
to
heated comprises agent
the (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2- organic This potentiator.
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the pore nitrogen.
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dispersion a nozzle. some some some some some some some
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solvents a
implementations, implementations, implementations, implementations, implementations, implementations, implementations,
water. suitable temperature
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to
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pressure.
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solvent.
suitable pressurized methanol, the dried
to
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2015247850 04 Jun 2019 providing ketone/water/IPA. nozzle. through hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide. yl)cyclopropanecarboxamide, yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- to mixture water a a oxoquinoline-3-carboxamide. second (l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. agent agent agent first and dried forcing 70:30 instance, [0183] [0182] [0181] [0180] [0179] [0186] [0185] [0184]
suitable CFTR
the
a agent
dispersion. second to to is is second to
agent
the
the (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2- is This potentiator. about the the
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pore a to from
mixture
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solvent
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size
implementations implementations N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4- about second
implementations, implementations, implementations, implementations, implementations,
For
(e.g., agent agent in out herein by
consisting Such
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the 1:10
volume.
example, of
volume. agent
20 be example, is is mixture filtering
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solvent the the the the the
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comprise comprise instances,
by weight. weight.
spray generating accomplished
of
ketone/water, by using
1 agent and
agent agent weight. :
of the 1
weight. agent
by
agent the 29 dry a
polar of
any
plurality
is
weight. In
applying filtering is is
the
first
therapeutic
drying (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5- is
a a some For a
suitable is
N-[2,4-bis(l,l-dimethylethyl)-5- CFTR CFTR organic ratio In spray
a
agent
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heat of
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corrector corrector. therapeutic other heating
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polar
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or
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element.
to
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generate water ratio agents;
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filter
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2015247850 04 Jun 2019 polar ketone/water, to mixture agent agent first first and conditions agents spraying instances, examples, combination of spray example, 90 elemental first gas. inlet is [0192] [0191] [0190] [0189] [0188] [0187] [0194] [0193]
heated
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Examples
organic second to to dried second
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a about In In Described In In In In to Some
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other the
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volume.
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2015247850 04 Jun 2019 nozzle. through hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide. yl)cyclopropanecarboxamide, yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- further combination of spray example, 90 elemental first gas. inlet is a a oxoquinoline-3-carboxamide. second (l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. agent [0200] [0199] [0198] [0197] [0196] [0195] [0204] [0203] [0202] [0201]
suitable CFTR heated
polar psi
agent, is Examples
dried is
to
heated comprises agent
the (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2- organic This potentiator.
about In In In In In In In to Some Some Some
the pore nitrogen.
the
dispersion a nozzle. some some some some some some some
thereof, spray heating is temperature
to
second
size 150 of implementations implementations implementations N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-
solvents a
implementations, implementations, implementations, implementations, implementations, implementations, implementations,
water. suitable temperature
dried (e.g., psi.
Such
For can such
agent, is
dried dispersion 20 include be example,
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using agent
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agent agent the include
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In
comprises agent
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solvent
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filtering from drying applying is is forced reduced
gas (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5- is
to
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point
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about
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heating
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2015247850 04 Jun 2019 ketone/water/IPA. the hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide. yl)cyclopropanecarboxamide, yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- therapeutic water suitable CFTR oxoquinoline-3-carboxamide. second (l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. agent agent agent agent second is agent a drying dispersion agents, 70:30 instance, [0208] [0207] [0206] [0205] [0211] [0210] [0209]
second from
nozzle.
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conditions agent wherein agent
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(R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2- pore about the the the
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a
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agents second some some some some some Such second second second
solvent generated
size is in
1:10
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95:5
N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4- embodiments the the In
filtering (e.g., embodiments, embodiments, embodiments, embodiments, embodiments,
to
and
to
some For
agent. For mixture agent agent agent dispersion herein by
generate
by could about
a volume. by
example, 20 example, volume.
solvent; embodiments,
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providing
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be and about or is spray
In
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by
substantially the and the accomplished spray less).
2:3 1:6 1:3 the other
weight.
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(ii)
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dried
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forcing weight. weight. weight.
of mixture agent
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plurality weight.
agent the
For
the
dispersion. of
agent
free filtering is is
32 using is
first
therapeutic
polar
example, the
a a
In In is that (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-
the
of CFTR CFTR
is
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a comprising
any CFTR N-[2,4-bis(l,l-dimethylethyl)-5- organic
consists ratio
other polymer, therapeutic the
THF/water,
corrector corrector. suitable the to examples, examples,
mixture of agents
potentiator. examples, through the
ratio
the solvent essentially
second and
a
polar
filter
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agents plurality of
and before
For or wherein the the a
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nozzle
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the organic media
agent water ratio ratio
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For first
consists of
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2015247850 04 Jun 2019 under plurality ketone/water/IPA. psi water heated nozzle. agent second is and agents, 70:30 instance, further combination of spray example, elemental first gas. inlet [0217] [0216] [0215] [0214] [0213] [0212] [0220] [0219] [0218]
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second to dried is about spray to
to heated comprises agent wherein
about
organic This about the
about
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the a nitrogen.
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150
solvent thereof,
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1:10
to 90:10
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embodiments embodiments of
the the
solvents psi. a
implementations, embodiments, embodiments, embodiments, embodiments, embodiments, water.
suitable temperature
to
For dried conditions mixture agent dispersion by herein
by could such can about
agent,
is
volume.
agents example, that volume.
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1
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weight.
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of DCM/methanol. ketone/water, using
dispersion
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under
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For
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include the
and
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In
(i)
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comprises of 33
first
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gas solvent polar
example, °C
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In
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point
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to
has In
agent some those forcing
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In
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50
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methanol,
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2015247850 04 Jun 2019 psi heated nozzle. the hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide. yl)cyclopropanecarboxamide, yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- of spray example, elemental first gas. inlet suitable CFTR oxoquinoline-3-carboxamide. second (l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. agent agent agent [0226] [0225] [0224] [0223] [0222] [0221] [0230] [0229] [0228] [0227]
polar
to nozzle.
agent, is Examples
to to dried is about
potentiator.
to heated agent
pore (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2- This organic the the
In In In In In In In Some Some Some
the a nitrogen.
the
temperature
dispersion some some some some some some some Such second second 150
spray heating size is
to
second
of embodiments embodiments embodiments N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-
solvents psi.
a
filtering implementations, embodiments, embodiments, embodiments, (e.g., embodiments, embodiments, embodiments,
suitable temperature
dried For agent agent
can
agent, is
20 example, that
dried
dispersion include be
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can pressurized pm
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first solvent. comprise comprise comprise
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weight. weight. agent
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boiling comprises agent under
is include
90 ketone, agent In
filtering drying applying is is
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gas
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reduced
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point
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50
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2015247850 04 Jun 2019 polymer, particle polar ketone/water, hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide. yl)cyclopropanecarboxamide, yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- through CFTR oxoquinoline-3-carboxamide. second (l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. agent agent agent agent second is agent a generate solvent; instances, examples, combination [0233] [0232] [0231] [0236] [0235] [0234]
second from
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agent agent
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comprises (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2- a the the the and
the agent. In In In In In Described
and
nozzle, a the the
second some some some some some
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spray (ii)
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is in
wherein solvent ratio 1:10 THF/water, solvent
N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4- the forcing In
wherein embodiments, embodiments, embodiments, embodiments, embodiments,
dried a to
some of
agent. For mixture agent agent agent
herein plurality
about to
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example,
the water
dispersion. other
embodiments,
polar is is is
spray
or the is
mixture 10:1 about about about is
methylethyl a
comprises of
mixture
and is about examples,
spray organic
dried therapeutic the the the the the by from the
2:3 1:6 1:3 the
weight.
plurality ratio through second first first 1 dried first
dispersion
by by by : about second comprises
1
solvent
the water.
by
agent agent
the weight. weight. weight. ketone/water/IPA. of agent
dispersion
plurality weight.
agent
agents,
the 70:30 For a solvent
of
agent
nozzle
is is
to 35 is For first
therapeutic
example, is
a a a In In water is (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-
to
plurality CFTR CFTR generated
and instance, is
a In
agent of some some further
about
under comprising CFTR N-[2,4-bis(l,l-dimethylethyl)-5-
other therapeutic
the is
corrector corrector. the about to examples, examples,
95:5 particle
agents spray comprises
of
potentiator.
examples, For the the by
ratio
therapeutic
by
(i) 90:10
second solvent example,
a drying
comprises
agents particle, of
spraying volume. and is
For the the
the substantially
by water.
the
the
agent could ratio ratio example, conditions
For first
volume. consists
agents
the ratio
second
wherein
In a
a example,
of of In
agent
mixture in ratio
be other first
of
the the
the other
and
methylethyl
the of
the
agent free
of
agent to to first first mixture the
a
a
first
the
first
the first the
of
is
and
a
a
2015247850 04 Jun 2019 polar ketone/water, psi heated nozzle. the Compound for of cryogrounding/cryomilling substantially identical such Compound instances, examples, combination of spray example, elemental first gas. inlet suitable [0243] [0242] [0241] [0240] [0239] [0238] [0237] [0244]
polar Compound
to nozzle.
100
agent, is
Examples as,
organic dried about
to
heated
minutes pore organic This
for
overlay In In In In In Some Some Some
the a
nitrogen. the
the
the temperature
2 2, dispersion some some some some some example, Such
150
thereof. free
spray heating size
may
solvent ratio THF/water, substantially solvent to 1
second
embodiments embodiments of
embodiments
and at solvents psi.
a
of filtering of
implementations, implementations, embodiments, embodiments, embodiments, (e.g.,
suitable
also temperature 15 of dried
13 polymer Compound
can
to C cyrogrounding/cryomilling
the cycles/minute. In further
agent, is
be
20 that spectra
water
other
dried dispersion include be
polar
prepared can or pressurized
pm
free techniques.
is
accomplished
methylethyl and prepared comprises further further further
be is examples,
less at or
of organic between
of 2
the the the
from
a methylethyl the
accomplished less).
from was
polymer temperature than
by
the a is pressurized mixture nozzle
solvent. comprise comprise comprise
composition A
about dried hot cryoground/crymilled by
gases
about
solvent solvent
the
composition In water.
amorphous
the
ketone/water/IPA.
spray
melt using
the
boiling comprises may
under
70:30
is include solvent
90 ketone,
In
present
applying filtering drying forced
to comprises 36 of extrusion using For
drying
gas be
°C one any
techniques.
water from reduced
comprising to
point
prepared
instance,
to has
Compound
further those
suitable example, comprising about
any THF,
through the an
example, about
techniques
the
about is a heat
of
inlet
techniques.
spray positive
suitable a
about pressurized
pressure.
mixture
95:5
the DCM, polar comprises
by at For 150 to
the heating
50 Figure
and the amorphous
the
solvent. liquid the
dried non-spray
a
1 by
90:10 °C amorphous solvent
example, °C.
organic
nozzle and 1:1 described pressure pressurized filter an
methanol,
mixture
volume. before
to
4 In
outlet, element. dispersion. ratio nitrogen
Compound gas about by water. (top)
other media
For could
by
solvent.
volume.
Compound that drying it
by the
of
as
In a and
herein discloses example, is Compound
100 or
examples,
weight pressurized from
In
it gas ratio having temperatures be are forced other
IPA,
enters
the other
°C. For
techniques,
2 methylethyl comprises inert Examples
and
about of
inlet
or
sample
through
a
1 a the the
the
and to near any the 1
is
90
and the
2015247850 04 Jun 2019 because polymer unexpectedly the Polymer dried dried compositions Compound compared in is in analogous could dried The of concentration substantially of depicts another. stability SDD [0248] [0247] [0246] [0245] [0250] [0249] lh, 11
the
the bars compositions the
depicts present 3h,
fact
(50% dispersions dispersion dispersion neat be neat present
labeled 5h, fluid
a and that HPMCAS. formulated As In For The The The
polymer to
coSDD set the
coSDD
29h,
invention. HPMCAS), 2
addition
with
dissolution the stability
greater free
example,
alone present
same stability demonstrate of of invention of results
C. Neat
and
of of the of set experiments
Compound
would of Compound
of
of the is Compound Compound
unexpected
in
of present polymer 72h. without
and to 1:1
Achievement
Compound considered
of Compound of invention
a
Beneficial
of
bar present Compound
increased
20%
which
over
dissolution be Compound rates coSDD
more Compound
graphs improved advantageous
invention
1
the by
72h featured
in 1 are
in invention consistent is
2
1 in phenomena
features
Figure weight
is
additional
necessary alone and
Compound mg/ml
Properties 1 physical improved 1 compared labeled Figure
the of and 1 and
rate
1
and properties
Compound 1
such
in have in
neat
in
and Compound
Compound 10. SDD
and compositions experiments
fed the
in
Compound
9, the stability for Compound
stability
stability
polymer coSDD volume in
FedSIF. unexpectedly
one when
Figure exist
to of present state each
1 neat high with
the
alone the Spray
37 over can
2
for
art bar simulated
one coSDD
is
the drug
set
(circles)
2 in 10 of 2 of
in
see
(triangles). invention. achieved
The in individual Compound 2 to
substantially
for of Dried
2 along solution, of Compound therapeutic polymer depicts the a where
in
a achieve SDD
load the polymer. the
bar
a
50%
set the increased
absence of tablet
present increased Dispersions the and
intestinal
graphs formulations of Compound presence properties (20%
fluid is by
HPMCAS. Compound bars
x
formulations. Along stable
a
truly The 2
comprising
weight axis
tablet
agent 1 free as of
HPMCAS), stability
invention and dissolution labeled labeled
neat
can
a
unexpected.
stability fluid
represents
spray
of the of polymer
such
is Compound comprising Substantially
1 SDD each be
polymer
co-spray because in
y and
2
(FedSIF).
Compound Neat
of
axis seen
dried the the
in as
over
Figure
other of with Compound Compound
rates. the which physical
is
neat presence
time: is Compound in
1
dispersions. surprising
featured more 72 :
Such dried
1 the 2 a the
co-spray
coSDD 9 spray
h Free Figure The is
0.5h,
1
drug spray
of
2 2
set
of in
2
2015247850 04 Jun 2019 polymer, presence Figure Figure they vivo THERAPEUTIC showing scanning Compound compounds, spray Compound alone. and Compound coSDD The dissolution dispersion [0253] [0252] [0251] [0256] [0255] [0254] 1:1
Compound
neat
area increased for do
dried
2 3
not of
Compound
co-spray
under depicts one Unlike III. of Without When Table calorimetry the depicts
Compound of
rates
2 behave dispersion 1 1
Compound
respectively.
spray transition Compound and and alone.
dissolution 2
A,
SPRAY the 1. Compound
the a for
the
Compound Compound dried being
differential
AGENTS curve dried
as
Neat 2. Comparison
previously Compound
solid Individual (DSC)
completely Relative Spray 1 showing
(Ratio) Tablets
Table
at dispersion
2 DRIED bound and
dispersions
increases
coSDD/
1 unexpectedly
a rate
state Figure
and Tg 2
Compound
trace
Dried
2 2 is 1
scanning
translates
of
by shows as showing Compound
NMR described
spin
in 2 DISPERSIONS
6 155 individual over an
of theory, the of
by
Dispersions depicts
diffusion
of a amorphous
Compound
Property °C. spectra presence 73% Cmax dog AUC
1:3
those
the
interacts calorimetry
norm norm 2 one into
embodiments
the of neat pK
2 present and an
wt
wt transition species. the
of
demonstrates statistically
inventors of results interactions XRPD
coSDD 47%, of 38 Compound
present a to entity. 1
COMPRISING Compound 1:1
and
embodiment such (DSC) Mean
Geometric
respectively, for pattern Figure Compound
at
Compound
146.73 172.93 of submit
which
invention Figure
an
Compound significant a
Compound
between
Ratio a trace Tg 2 extent
significant
1
of in
1 of were
depicts that ,
7
the a may the of
124 depicts
1:3 1
that relative
relative
2
AMORPHOUS a
protons Compound to absence
maximum substantially
increases
2 as
1:1 comprise
neat °C.
Lower
1 101.19 121.95 Compound an in even
90%
an and
increase
neat
a a XRPD
Interestingly,
coSDD amorphous to to
tablet differential
on Compound when of
a
Compound coSDD in
the tablet Compound concentration a 1
in polymer. exposure
pattern of in
free
2 in of
different 212.75 245.20 Upper
the 90% the neat
media
of
of
of entity.
neat 2
of
co
2
in
1 a
.
2015247850 04 Jun 2019 polymer underlying under polymer polymer mobility transition within the temperature when HPMCAS, 2 embodiments, about stability about least glass inert. of soluble enteric of solid dispersion. Compound Compound Starting [0258] [0257] [0259] 160 140
and
the the
drug °C, °C,
about
amorphous transition
the a dry polymers
10%. 120 stomach, In
about
polymers.
polymer. in
at at
from of may (i.e., (or or
at order Additionally, In
Solid pH
temperatures conditions). the °C,
least least
the mechanism room 100 or composition 2 2
one The solid (Tg) For
10 is may are
be
Compound Compound less pyrrolidone
at
the
to amorphous
dispersions
temperature above °C, about about for
may to embodiment,
the solid present.
least
dispersion
temperature, of improve
present
Exemplary state
polymer be acidic The
about example, at
the purpose
be prepared
about least amorphous 165 145 5-6.
term carrier) the
Without is
of polymer
pH
is
environment 15
that as
1). 1
the
°C, °C, the containing
solid hygroscopicity characterized including has about An
or
independent includes °C at
"enteric amorphous 125
of a
polymers
Other
polymers
a physical a
Compound at at
which least by polymer
also appropriate
less of
comparison polymer polymer
wishing
dispersion. °C, least least should
105
dispersion, the the
than are polymers equal
at polymer"
one
amorphous can polymers
spray °C, drug about about of
least
stability
included include
that include
be compounds
about to or is with
at the
or be
at to 2,
of
able (i.e., polymer be as about pH
dry
more in
about least is 170 150 a or the
intestine
the
generally
a have high
crucial bound
this
insoluble refers
10%
dependent.
greater
39 cellulosic higher such methods to
at of
Compound amorphous °C, °C, herein. polymers
Compound
about 60%
additional
least dissolve the 130 application, as
a
water should
as
or at
as
to
glass
by
factor possible. relative
solid
relative Tg than
°C,
least a at includes
PVP/VA. about a
110
theory, in
component For described
polymer
least polymers
generally absorption,
transition at should acidic
in The
be
the
dispersions, form °C,
in about 1).
excipients,
1 example,
least
90 aqueous to
chemically
and stabilizing humidity. about
the
glass
For latter at Examples it
Compound the
°C,
of aqueous
be is
that In about least 155 hygroscopicity Compound previously
such
has example,
more Compound believed
of temperature at
transition as some 175 include
for
media. Compound is °C,
least a
about low, such
lower
the
135
preferentially as solid
°C example
the In
acid and
media of at
embodiments,
HPMC,
glass
1
about some
e.g., (as
°C,
as least
suitable physical that
polymers one
and 115
biologically except molecular
amorphous 2, The environment
temperature
a
1 measured
at
but and
that surfactant. transition less
the or or
°C, Compound preferred of about
1 95 less solubility least
and more
soluble a
a that glass
is °C, than at
than
have
about least
the at a
of
a
2015247850 04 Jun 2019 polymethacrylates 20%, the hydroxypropyl methyl hydroxypropyl but partially dispersion otherwise example example, acetate (CAT), (CMC) cellulose dependent as including Eudragit® hydroxypropylcellulose resulting moisture hygroscopicity glycols dispersions less about [0262] [0261] [0264] [0263] [0260]
HPMC
total are than
and 9%,
not phthalate cellulose hydroxypropylcellulose or (PEG);
weight
water-soluble
with As about In In In In solid adsorbed
acetate
avinylpyrrolidone/vinyl
preferably for
specified, E50, a
less enteric are E);
limited
as some one yet embodiments salt discussed
example
an
described given
cyclodextrins dispersions,
than methyl methyl polyvinyl 4%, can
HPMC
another of embodiment, thereof
phthalate acetate HPMC,
(HPMCAP),
embodiments, polymers
the
(e.g., to, in
also
less about
percentages in
at
the
cellulose
solid PVP-VA
herein, cellulose cellulose polymer(s).
weight E15, least
embodiment, (e.g.,
affect (HPC)) than
Eudragit® succinate
above.
polymers HPMCAS,
alcohols where 8%,
(CAP)), which
dispersion
include, about
or (e.g.,
about
a
the
the the and percentages.
less
HPMC sodium
derivatives
acetate
(polyvinylpyrollidone-vinyl or acetate acetate the Compound
of
polymer
will acetate polymer physical
(HPMCAS).
β methylcellulose (PVA); 30%,
ethylcellulose; than can
hydroxypropyl 3%,
drug, S). -cyclodextin) Water-soluble
polymer but
or the
further
ranges E3.
greatly
salt PVP/VA phthalate
or succinate succinate about In for are
polymer polymer co-polymer
acrylates, is less
can stability some (e.g.,
such
example,
not The
1 one is
reduce from
7%,
forms reduce
be than 40
hydroxypropylmethylcellulose
limited In
as
hydroxypropylmethylcellulose amount
embodiments, polymer, or
(HPCAP), and
HG (HPMCAS),
polyvinylpyrrolidones a is
and
or less methyl some
acetate
(CMC-Na)); about
of pH-dependent more
about
a
such
a
the
partially
(PVP/VA). at
copolymers the
polyvinylpyrrolidone grade the
solid other than
to,
least
physical
embodiments,
of
water-soluble 0.1% Tg
as
solid 2%
cellulose phthalate the cellulose
polymer
about dispersion (HPMCAS-HG).
excipients hydroxypropylmethyl-cellulose polymethacrylate
acetate). of
about
water water-soluble
amount
carboxymethylcellulose
to dispersions. the the
cellulose
stability
99% and 6%, enteric
polymer polymers 35%,
phthalates
absorption. (MCAP), derivatives is
derivatives of less typically with
by as the polymer(s)
(PVP); polymer
at
described polymer. acetate weight.
of
than polymer
least
a co-polymer, is polymers
Generally,
the as polymer,
or (e.g., hydroxypropyl (HPMCP), (HPMC),
well (e.g., about (HPMC), at
polyethylene
The
solid about
trimellitate thereof,
relative
least
Unless or
within is
Such
as
5%, include
40%,
for the about
such for
pH-
to
a
2015247850 04 Jun 2019 25%, would w/w to In represent weight the roughly AS-MG, about Compound crystallization effective about 7%, as embodiments, Compound and HPMCAS succinate. specifically, an 65% and at [0266] [0268] [0267] 1 [0265] 10%
or
least a some 15%
amount
percentage
preferably Compound surfactant less Compound total
or of
about 2%, 65%,
prevent
of
about
w/w the less,
equal
embodiments,
than
AS-HG.
for In In In In
1% solid the
about
is of
dispersion, 1 1
about 30%, some some some
embodiments
total between
stabilizing about
available
or or up to 45%, dispersions. about
amounts, Compound of
(e.g., at weight about
content
1 20% 2 Compound Compound
to
1%,
least
Compound solid about or embodiments, embodiments, embodiments, is 70%,
Each
60%
about or
6%, present Compound
SLS).
80% w/w or about
about of
a
in for
content Compound
of
the about 35%, for about portion or of less
the a
50%
the including
total or example 1
For
less,
number these
In
solid example 40% 2 2
or in 50%
dispersion. than
less, 1
about non-solid from are
75%,
some
0.5%.
about of Compound example, or
of solid
or
2 (e.g.,
the Compound Compound
grades
and dispersion.
present the (e.g., Compound the about
is for
about
1
amorphous of
less
40%, or
a embodiments,
dispersion present
each
or content
80%. total
50%, non-solid
example polymer, about varieties,
greater)
49.5%).
Compound
dispersion varies than 5%,
the
55% For
in
about of
weight
2 such
an 5%, in polymer
the 1 and 1 less
of about example,
Stabilizing 2.
or
or or
with
about about amount
of to
further
41 the
the
dispersion including
45%,
polymer
as
The about Such less. the
Compound than Compound
crystalline of Compound
prior the
about polymer 9%, 2 non-solid the
the polymer
75% 50%.
amount and
is
about
about
stabilizing In surfactant
includes the
10%, greater percent
present
less
dispersion to
includes
one
49%, and the
AS-LF,
or polymer prior spray
In
50%,
4%, than should
about 2, form. 2
less,
polymer is embodiment, dispersion combined the 1
another
than and
about and substitution
typically or in other
to
less drying.
about
is drug
would
inhibiting about about AS-MF,
about Compound
spray
the
15%, (and present polymer be For half is
than 49.5%, minor
present
combined embodiment, make present polymer
8%,
example,
represent
55%, of 70% even inhibit 20% prior about drying. about
about
the AS-HF,
the in
of
less or ingredients,
up are
or
or more and
in
to 2 less about
in percentage acetate
preventing, polymer
20%,
99% the
combined
about
about from
present less, than about 3%, spray
represent an
In
the
Compound about than
conversion
AS-LG,
some amount
60%,
or
about less polymer about
about half
50%). and
49.5% drying.
less,
about
is in 11% such
than
in
of 5%
the
2015247850 04 Jun 2019 polymer or Compound amorphous increase Compound Compound aqueous solid or drying about than than more rate 50°C Compound example of example, converting [0272] [0271] [0275] [0274] [0273] 160 120 [0270] [0269]
Compound Compound Compound
of °C, °C,
the about
dispersion higher of
100
relaxation processes
at at the glass the and will
to The The The The The The Suitable by
°C,
least least
10-15 from
2, 2 2 2. form Compound
following
solubility than
measuring
physiologically
dissolve when in
polymer polymer polymer polymer, polymer glass transition either 2. 2. at 1 In
about about
the
or or
an least
a relative the some °C of polymers
solid
Compound in
transition combined amorphous absence
the
from lower
desired
a
about
in 160 130 properties: of
should should should should
liquid when instances,
1 the amorphous
temperature dispersion
one
amorphous or to
a °C, °C,
than
glass
solid that Compound for
of 105
relative or storage
combined temperature
suspension, with have improve increase decrease or at
2.
polymer
to use more
the
of
°C, least greater. transition amorphous
the a
Compound a such similar in material, glass crystalline
at
temperature of reference Compound media
of glass about combination
the least the
the
Compound 2
with or the as
transition
that
should of
physical
manufacturability relative relaxation or transition an temperature
either same about
140
the dispersion Compound or
better converts
amorphous
polymer. form. 1
42
by
polymer °C,
or 1 increase of
solvents
relative
105
or
to measuring with temperature Compound 1 and/or
solubility the
at
or temperature Compound the Stabilization rate
°C, least
to
of drug Compound or
Compound
For 1
solubility
should
crystalline
solid
of
the to the or chemical from at or
about
the
the product. least of example, solvent Compound
solubility the in solid
2.
dispersion,
Compound
of
a
amorphous solubility have solvents
2
solubility liquid of
In about 150
Compound by can
of
2, dispersion,
stability 1
the Compound some
systems
Compound or reducing a
and
For °C, be the
temperature
of
polymer suspension.
110 Compound
2,
suitable
measured,
in polymer at Compound example, of embodiments, should
for 1 or
substance.
°C, of general least
or Compound as
bioavailability
1
measuring example
the
Compound
Compound or Compound
1 at
is
1 for have about
or
amount least greater could or
2, at of for
at spray
1
least for no
least one
in in about
1
the
the
less
a
or of
1 or
2.
1
2015247850 04 Jun 2019 potentiator. previously preparation properties methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide, wherein methylpropan-2-yl)-1 mediated the difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- comprising dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide. difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- CFTR a solubility candidate conditions, composition composition. spray components, [0280] [0279] [0278] [0277] [0276] [0284] [0283] [0282] [0281]
second
formation
drying
corrector
the
therapeutic In In In Described The The The The
crystallization,
relative composition
of
described.
by a of some some one first
could
methods Compound for
mixture polymer polymer spray suitability
of The
neat at B,
aspect,
and
example crystals, spray
least
embodiments, embodiments,
to
candidate
be
amorphous dried
herein
the crystalline agent,
H-indol-5
of tested
(or
50 Blends
should should
dried could
the
second of
a
or
1 %, dispersion or
other excipients.
first
or is a
present wherein
the
other
to
dispersion 75 composition candidate
a be
Compound of not improve
spray spray
determine Compound
percent -yl)cyclopropanecarboxamide. methods)
Compound
therapeutic %, tested the the Spray
interact properties,
invention or
the second first
of dried dried
100%
to
polymer
one Dried the
conversion comprises first
agent
2. determine described whether can unfavorably
dispersion present dispersion
1
or agent 1
agent
as
therapeutic
or
provides or and Dispersions be more
is well
43
Compound (or Compound
compared
an compared
is
is
it amorphous embodiment
at
other
herein of
if an as an amorphous inhibits
a comprising
and
it
the
a with the amorphous amorphous given
has pharmaceutical agent
component)
a handling, reference to
2.
in 2. second other
to improved
the
form
time
terms (R)-l-(2,2- For is a and
may
form time reference an
pharmaceutical a
under example, an
form the form
spray first
amorphous administration
of preparation,
include
to of amorphous
can bioavailability
second stability,
therapeutic onset
of composition (R)-l-(2,2- of
controlled
dried
be preparation,
a N-[2,4-bis(l,l-
a
CFTR a tested
of
candidate spray
surfactant
dispersion,
form
resistance
solvent
or
or using
agent a dried
of
or storage
e.g.,
a
as
the and
to
a
2015247850 04 Jun 2019 polymer. by HPMC methylcellulose 2:3 to yl)cyclopropanecarboxamide ratio yl)cyclopropanecarboxamide yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- weight. methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide examples, spray dispersion spray dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-l dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- carboxamide amorphous fluoro-2-( amorphous carboxamide amorphous fluoro-2-( amorphous dihydro-4-oxoquinoline-3-carboxamide. dispersion [0285] [0287] [0286] l,4-dihydro-4-oxoquinoline-3-carboxamide l,4-dihydro-4-oxoquinoline-3-carboxamide
second
weight. by
of
dried dried
weight.
to amorphous In
In In In
1 1 For spray
amorphous the
is comprises
-hydroxy-2-methylpropan-2-yl)- -hydroxy-2-methylpropan-2-yl)-
some N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3- N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3- (R)- (R)- dispersion For dispersion some some some
about ranging is
example, ratio
about example, 1 1 dried (HPMC).
-(2,2-difluorobenzo[d] -(2,2-difluorobenzo[d]
examples, embodiments, embodiments, embodiments,
1 of (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3- :
1 amorphous from
dispersion
(R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3- 1:1
first to to by
the
second second the
by weight.
spray
For
about first the
weight.
ratio to to
example, ratio
spray amorphous amorphous the the the
spray is spray dried N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-
1:10
of In about
pharmaceutical pharmaceutical first of
first In other
dried to dispersion dried dried
amorphous
[1,3] [1,3]
other
the spray about
1:3 spray
examples,
1 1
N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]- N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]- dispersion
is is
dioxol-5-yl)-N dioxol-5-yl)-N first dispersion dispersion H-indol-5 H-indol-5 by
examples,
about about
dried
44 10:1
dried weight.
spray to
(R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-
second by composition composition 2:3 dispersion 1:6
dispersion the
-yl)cyclopropanecarboxamide -yl)cyclopropanecarboxamide
further dried weight.
that is
by by the In
about ratio
-(1-(2,3 -(1-(2,3
some weight. weight.
spray is
ratio dispersion
to from
comprises
of
further
For 1:6 to
amorphous
comprises comprises H-indol-5 examples, of first dried
-dihydroxyprop -dihydroxyprop
second
about by
example, In amorphous
spray
weight. some comprises
dispersion comprises
hydroxypropyl
1:10 spray -
a a the N-[2,4-bis(l,l-
dried examples,
ratio ratio the
is to
In ratio
(R)-l-(2,2-
dried
about
about ratio
a
dispersion some
is yl)-6- yl)-6- a of of
cellulose
ratio
about of
to to first
of
1:3
the first 10:1
of
by
2015247850 04 Jun 2019 by hydroxyphenyl]-l methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide wherein particle amorphous spray difluorobenzo is comprising wt% to to having having having hydroxypropyl yl)cyclopropanecarboxamide ratio yl)cyclopropanecarboxamide second about first cellulose dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- [0294] [0291] [0290] [0289] [0288] [0293] [0292]
generated
about about weight.
spray to of
dried 30
a a a
spray about HPMC
having
the 95 30
mean mean mean microns. In In In In In In One polymer.
dried
Compound For dispersion a wt% microns.
some other some some some some first by
mixture dried
95 [d] aspect
particle particle particle
methylcellulose a to
combining example,
dispersion
wt% spray (e.g., [1,3] mean
embodiments, embodiments, embodiments, embodiments, embodiments, embodiments, ,4-dihydro-4-oxoquinoline-3-carboxamide amorphous
In dispersion For
of
dioxol-5 In some of
(e.g.,
comprises from
dried
particle diameter diameter diameter
1 the example,
some a
to the
first
a
present comprises
embodiments, amorphous from
about
first dispersion
ratio
ranging is (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-
-yl)-N-( comprises embodiments,
spray
diameter
acetate
from the the the the the the of of of
about spray the amorphous
75 of
invention about about about
second pharmaceutical second first spray spray
dried amorphous second
wt% about
from a 1-(2,3
succinate dried Compound 75 particle comprises
of
spray a 5 5
15
dried dried the
particle wt% to
dispersion
to to about about spray
1:3 spray
-dihydroxyp
microns.
spray N-[2,4-bis( the
provides dispersion about
about about first
dried
45 to having to
dispersion dispersion
second Compound
(HPMCAS).
dried 1:10 15 dried about
amorphous about
dried having spray 2
85
composition 100 100
microns. dispersion
ranging
and
a wt%)
to
a
dispersion
dispersion
and pharmaceutical
spray
1:5. ropyl)-6-fluoro-2-( microns. microns. dispersion 1,1 85 dried mean about
a a
comprises comprises
-dimethyl
second wt%)
mean
a of
1 (Compound
from
second (Compound (R)- dried
to dispersion
particle
Compound 1:1. comprises
amorphous comprises
of particle
In In further 1-(2,2-
comprises
about
spray further
dispersion
In Compound
some some ethyl)-5- spray a a
diameter some plurality plurality
composition
1:10 dried
comprises 2).
comprises
diameter
from comprises 1),
embodiments, embodiments,
1. 1 dried
a
-hydroxy-2-
Compound
instances,
from
ratio
and to
comprises dispersion
about
2. of of of about dispersion,
the
of about
particles particles about of
a
a
particle second 70 about
10:1 the
2
70 wt%
5
the the a that
is
to
5
2015247850 04 Jun 2019 pharmaceutical polymer. volume. volume. methylethyl In methylethyl HPMC to hypromellose methylcellulose to example, example, solvent Compound combining and Compound spray cellulose Compound Compound about [0299] [0298] [0297] [0296] [0295] [0301] [0300] 1,
a amorphous generate other
a cellulose
solvent; drying
1
: to
comprises
1 examples,
In In In In In In In One polymer.
the a by For Compound
the
DCM/methanol the 2
1 1 1; some some some other some other other
ketone/water, ketone,
weight. conditions ratio
to ranging is polymer,
aspect acetate example, Compound (iii) (iv)
first
second
composition about amorphous (HPMC).
implementations, instances, embodiments, implementations, implementations, implementations, embodiments,
of a providing forcing
the spray For polar
THF,
of
the
In succinate from
1 1:3
solvent spray
and
the
example, is the to
other polar
dried by
2
organic from methanol, the
THF/water, generate
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a first mixture. Compound is
the
comprising dried weight. a solvent;
about examples, second further second organic
dispersion about (HPMCAS).
ratio spray the the
the 1:10
solvent.
dispersion
invention
the
the the the the
second
first
1:6 In DCM,
of
second
In mixture (ii) 1:3 comprises
mixture dried to
solvent methanol/water,
cellulose other first first first cellulose 2
the
by
some
(i)
the spray about forcing is to
and
Examples weight. polar
providing spray about
or
dispersion spray mixture mixture about ratio
spray
provides examples,
comprising
through examples,
the to IPA,
comprising dried 46 1:1
polymer water. polymer
water organic the
dried of 2:3
dried second
1:5 dried by
or In
amorphous further comprises dispersion
first
by of
a (e.g., weight.
a any a some
further
is dispersion
or first
the dispersion
method For nozzle polar dispersion
weight. the
solvent amorphous mixture from
spray
of of
methylethyl Compound combination
solvent
about
comprises
mixture instance, the examples, ratio the
organic comprises
For
about a under
further
dried Compound second of first
ratio to
of through
1:4)
further
comprising
example, generating further further water
amorphous
comprising
mixture Compound 70:30
dispersion. the spray
2,
of solvents
by a ketone/water/IPA. comprises
the
mixture
thereof,
solvent,
a HPMC hydroxypropyl
solvent weight.
comprises is
a cellulose comprises comprises ratio
to drying
nozzle 1 about the
is
to
a about
amorphous
include
HPMC.
of is such Compound ratio amorphous to Compound
2; and
could
a
HPMCAS. 90:10
amorphous
conditions under
and cellulose
polymer, 95:5
a
the as water.
of
be (v)
for by
by
For
1
2015247850 04 Jun 2019 blend presence pressure. before the represent humidity Figures through volume. volume. methylethyl In methylethyl HPMCAS of stable stable separate about spray second a example, example, solvent Compound [0305] [0304] [0303] [0302] [0306]
suitable
other Compound
Compound
dried of 30
towards in
it
spray
comprises
12 the examples,
spray the
the is
°C of Figures In In In
Some Some and the the a pore
In
to
and forced
DCM/methanol
2 dispersion,
nozzle.
some some Compound other
ketone/water, ketone, two to tablet
other
ratio same Compound ranging dried
80
1
dried crystallization about size 2 13 implementations implementations .
separate °C
free
12 instances, implementations, implementations,
through
depict of a examples,
formulation
the tablet dispersion
(e.g.,
polar and THF, Such dispersion and
the 60 tablet from
solvent
the
2
°C. 70
polar
13 2 the 20 formulation
is spray
filtering organic
methanol, the THF/water,
second
is
about
°C, mixture. present formulation, show the
pm
Compound
the from
in
or nozzle.
further organic
with of respectively.
dried ratio
the or both. further spray further
1:14
that
Compound solvent. spray
can about
less).
even the the
presence
Compound In
DCM, of
just dispersions
comprises
the
to be
solvent methanol/water, dried For
other second second
the
comprise comprise
dried 1 one
in about 1:4
Likewise,
accomplished same lacking crystallization
Examples polar example, a or
to dispersion examples, can
blend of Triangles
1 dispersion,
to IPA,
mixture mixture . about 47
1:2
surprising 2 Compound
water. Comparing water
organic see of
than Compound drying filtering
by
of
or the Compound
the that
of 1:6
weight.
two any
in
is further comprises represent or is second the
using For polar
spray
the kinetics solvent (e.g., the Compound
from
or
dried
stability methylethyl separate combination the
solvent
2.
instance,
both, the first
separate
2.
any organic
first
dried comprises For Compound about
about mixture
at
1 tablet
Squares
to a
spray and under
a a is
suitable
of
tablet example, mixture
further spray water
temperature ratio dried dispersion,
70:30 1:5) 1
Compound the spray Compound
solvents blend ketone/water/IPA.
is
dried may thereof, 75%
of formulation
represent significantly solvent dried
a by is
under
filter comprises 1
solvent,
before
to HPMCAS
dried about
is also the
formulation weight. relative dispersion,
about
also include
dispersion.
i.e., such media ratio of
reduced
be could 2. 1
dispersion
90:10
it
the from in
more
and
filtered the 95:5 is
Circles
as water. of of the
more to
forced having
be
the first for
a
by
the
to
by
For
2015247850 04 Jun 2019 NMR polymer. bottom to weight. For disintegrant; comprising about about combination Compound is Compound of amorphous co-spray Compound in Compound spectrum spray in 3A), spray [0310] [0309] [0308] [0307] [0314] [0313] [0312] [0311]
about the the amorphous Compound
example,
a
dried dried 45 two 60 growth spectra
blend
spectrum
In 1:3
dried wt% wt% Another In In In In One One is
For compounds
other
2 Compound dispersion dispersion a 1 1 1 some the some some some by
of a thereof.
spray to is and and
the of of aspect explanation example, Compound of of 1,
surfactant; C. dispersion
weight.
two reference about
amorphous
the a
Compound
examples,
amorphous amorphous
ratio is
Compound spin embodiments, embodiments, embodiments, embodiments, aspect tablet
dried generated spray Compound of
1:6 Co-Spray
diffusion of of of interacting
1 the the In
comprising
of
and dispersion amorphous Compound Compound
by substantially 1H 2 a
dried for
some
present
binder; spray the the is Compound
2,
weight. Compound Compound NMR
2 amorphous this by about
a
present exists ratio
dispersions
2 between
Dried the the the the examples, solvent,
cross
dried peak. on phenomenon
invention a
spectrum
and 2:3 spray spray spray spray
a of
Compound 2 wetting a 1
In in
blend
Dispersions polarization molecular
at and
free invention
amorphous dispersion 2
by the some
one Surprisingly,
2.
1 protons Compound and 70 ranging
. dried dried dried dried
Compound weight. the of comprising
blend
of °C
or
provides agent, identifying a
polymer. examples,
ratio
a polymer. more 48
is and
dispersion dispersion dispersion dispersion
spray
1
provides on level.
from shown at comprises
to
Compound Comprising
of
a 75% of
Compound
temperatures 2
excipients amorphous
lubricant,
molecular the
a
prepared dried 2
amorphous about
Compound
Figure spray
substantially the the in
relative
fluorine
a
comprises comprises further comprises
Figure
pharmaceutical
dispersion ratio tablet
HPMC,
1:10
dried
1
14 Multiple or selected
by
1
to interaction Compound
humidity.
of
above and
atom to comprises depicts any Compound
components 14. co-spray amorphous
1 dispersion
amorphous
about and
HPMCAS,
from from a free
Compound combination
As
ratio of
to
from the
APIs Compound
Compound solid
protons of was
about about
10:1
between
composition The Tg
drying 2 of
polymer a
a
1 is
comprising cellulose
Compound
seen
amorphous
and state as filler;
by to Compound upper
about or
20 35
2
well
on amorphous
weight.
a the any
resulting thereof, in
wt% wt%
1H 2
mixture
a
1 (Figure
the
results
1:1 as
and
to to
the
co
2 by
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2015247850 04 Jun 2019 plurality the methylethyl methylethyl having wherein of spray example, suitable solvent from comprises examples, solvent spray and generated amorphous about spray (Tg) Compound [0319] [0318] [0317] [0316] [0315] [0323] [0322] [0321] [0320]
another
nozzle. (ii)
of
about dried dried dried 5
a
from to comprises forcing to pore
the
of mean In In In In One The Some Some
the
by water the about water. therapeutic
70:30 particles 2. Compound dispersion dispersion. dispersion
some some some some Such spray ketone/water/IPA. ketone,
about spray (i) size
phenomena aspect solvent
D.
particle the implementations embodiments
providing is
30
filtering
to implementations, (e.g., embodiments, embodiments, embodiments, For dried a
about
mixture dried 80
microns.
polar
THF, about having of
further instance, Beneficial °C agent
comprises is
diameter
20 1 the dispersion
dried 90:10 dispersion and
to
of
organic can DCM,
95:5 a pm
present
through
about a
mixture is one
amorphous comprises further In mean
be
at not or
by the by
For
some
the the the
of
therapeutic further a Properties methanol, accomplished a less).
solvent.
volume.
180
limited temperature volume.
comprises plurality invention solvent about
the particle is example,
a spray spray spray
comprising comprise
nozzle
dried embodiments, °C.
second
water. comprise
Compound 5
dried dried dried to
could Examples to
or under of diameter
of In
agent the under
provides amorphous the
about
IPA,
particles Spray filtering other mixture
49
of using In
dispersion dispersion dispersion neat
Compound
be
ratio
from drying reduced other having
spray
or
methylethyl
100
instances,
2,
the
Dried co-spray of of
any
a any
of
wherein further the
about
having
spray about examples, polar microns.
spray
the
the drying Compound suitable improved
combination pressure.
is comprises has mixture Dispersions
1, spray polar
substantially
30
organic
dried
15 dried
dried comprises Compound a the a
the
conditions
glass ketone/water, °C
mean microns.
In filter ratio organic the dried
before
spray
dispersion to properties dispersions
dispersion
some In 1
a
transition solvents
solvent about
particle and
plurality other media thereof. of of
dispersion.
a dried
amorphous. Amorphous 2, it the
solvent embodiments, amorphous solvent, to
is 60 and
examples,
generate
polar further
having
comprising in
forced THF/water, include
diameter
comprises
dispersion
°C. In substantially temperature of
a the
to
other
solvent; particles
and organic
For presence
water through a
APIs
the
the
the
of
the
a
is
or
is
2015247850 04 Jun 2019 the therapeutic when humidity has dispersion The of sets of Compound in crystallization Compound embodiment free [0325] [0324] [0327] [0326]
the Compound another
presence
increased of of first
only presence
bar polymer
of At This Table Table in
therapeutic of graphs
10%
2 agents these
1 the
about
of of
Compound spray SDD
physical
phenomena 1 of
of 2. 3. Compound a absence previously of and
blend
an sets
on Compound
25 are
Compound and dried
Compound 80%
the
hours, of
co-spray agent
stability
Compound
of
of bars
far dispersion, 1 by
two of
Compound and described. 2
right 46% is weight
increased
is labeled
2
individual also
1
HPMCAS, not dried in
in 2, crystallized
demonstrate of
a a nor (Hrs.) (Hrs.)
Time Time 2
limited demonstrated
blend 14.7
tablet 168 SDD
5.2 Compound 26 21 25 as 14 SDD
Compound 0 7 0 0 0 0 9 6 from
a This 2.
stability demonstrated
blend
spray
of
Table of
of
at the without
to phenomena
Compound
when a
the 80 Crystallization Crystallization the
that same Compound of
50 dried
when
°C 3
1 present
1 the
neat in
crystallized lists
Compound the 46.4 SDD (%) (%) Compound
at
0.7 88 10 the solvent. 6 5 0 3 8
two
dispersions.
in
75% one
co-spray unexpected the
present
is Tables 1 (50% invention
individual
over therapeutic demonstrated
% 1 relative
spray
crystallization Referring
in
2
HPMCAS)
2.
time dried 2
embodiment
was
the
and
The dried For
stability comprising humidity.
spray
at absence present.
dispersion
3.
agent
remaining example, 80
to
dispersion in Table
°C Figure dried
is
the
of
of is
a where of at
Compound
in
spray present a Compound
2
75% Compound dispersions. embodiment blend
Compound
the lists two 9,
and
two the
dried presence relative
the
sets
of
a
three
%
1 of 1
2,
in
1
2015247850 04 Jun 2019 unpredictable present. bars bars unexpected present. bars bars nucleation within where which HPMCAS), 2 where which HPMCAS), 2 Compound solvent (20% see Compound dispersion set spray see Compound [0328] [0330] [0329]
spray spray
of that that
represent represent labeled labeled
HPMCAS) bars dried
the the is is a
systems dried dried
concentration concentration
patient a a Greater Greater As IV. Without
concentration concentration 2:1 2:1 Compound on of
2, dispersion 1, 1, stability
which which
with 1 1:1
dispersion dispersion each
the : by the Compound Compound the the ratio ratio 1 PHARMACEUTICAL
after as, coSDD coSDD
stability stability
structure.
far formulation. the inventors being concentration concentration
other.
is is for of of
in
right ingesting a a neat
stability stability Compound Compound 2 (50% spray spray FedSIF example,
bound (20% (20%
with with and of of
can can 2, 2, Such co-spray labeled
Compound Compound
submit
and and HPMCAS, HPMCAS)
dried dried
HPMCAS, HPMCAS,
also also HPMCAS), HPMCAS),
is is Compound by solutions phenomena,
of of polymer.
a FedSIF, greater greater
Compound polymer. theory, 1 1 be be
dispersion dispersion
Compound Compound that dried to to
seen seen
Compound Compound
2
1
Compound
COMPOSITIONS
without
formulation.
in for for is is to to dispersion
or when
in in
which which Comparing
1
more more not
those those
in sometimes Compound Compound
Comparing prior the the
of of 2
vivo 2 1 limited
51
SDD
it
Compound Compound Compound within within 2:1 2:1
consistent consistent
is is labeled labeled
comes to, 2 2
1 solvent
a a of spray spray
coSDD coSDD
and subsequent (20% 1:1 1:1
concentrations Compound to
referred
a a 2
1
concentrations
to
ratio ratio Compound Compound Compound co-spray co-spray Compound
over over dried dried
HPMCAS) systems than than
solvent
2 1. 1 (20% (20%
alone alone
of of the the
The
dispersion dispersion to that that
to, Compound Compound
dried HPMCAS) dried HPMCAS) as 1 72 72
systems,
remaining such with with
or and
in in
2 2
poisoning 1 1. h h of
concurrently SDD act
SDD is the the of when when
In dispersion dispersion
Compound Compound
HPMCAS, HPMCAS, as, a
Compound
to
with with Figure Compound Compound spray-dried
for such (50% (20%
impede 1 1
Compound Compound
set set two to to
nucleation, HPMCAS, HPMCAS, example,
Compound Compound as of of
10,
sets of of
with 2 2,
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the
in 1
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vitro 1 of
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1
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2015247850 04 Jun 2019 pharmaceutical pharmaceutically preparation the this the preservatives, used pharmaceutically composition least filler any starches cellulose carboxymethyl composition. comprise otherwise in contents Troy, desired. suspension additionally dispersions Technology, [0334] [0336] [0335] [0333] [0332] [0331]
formulating
chemical compounds combination invention.
herein, about
in Lippincott
an
(e.g.
of Remington: As Fillers In Described Thus, acetate,
a interacting
amount
40 thereof.
filler, aids, each or
one
comprise
includes described
eds. comprises stability,
com
Exemplary
solid wt%) combinations
A, pharmaceutically
cellulose,
in of composition,
embodiment, suitable
of surface
Williams
thereof. J.
a acceptable acceptable
one microcrystalline the
starch,
of
disintegrant,
which Swarbrick
binders, herein by
Except
in The any
at invention,
a Pharmaceutically embodiment, the above,
weight from pharmaceutically
a least active for
ethyl fillers Science and potato deleterious physical
In is & is
the
insofar lubricants incorporated of
vehicle, composition, one about a
Wilkins, i.e., 5
the all the
and
pharmaceutical
of agents, wt% cellulose spray
invention
include: and
acceptable starch), such
solvents, embodiment,
pharmaceutical the they pharmaceutical and
J. cellulose, stability,
10
as the
(e.g., a
C. dried adjuvant,
composition. manner
as
Practice lubricant. wt% Philadelphia, do any isotonic and
pharmaceutical Boylan,
Acceptable by hydroxymethyl sugars celluloses,
by not
acceptable are at
its diluents,
conventional dispersions the
to
producing compositions
or least reference
calcium use substantially with compatible
about
like, composition the the or agents, 52 of
(e.g., 1988-1999,
is compositions compositions about carrier. Pharmacy,
filler any biological
For contemplated or as modified Vehicles,
and 60
carrier,
sorbitol) phosphates,
other suited any herein,
other
thickening described
wt% composition example,
20 is Encyclopedia carrier cellulose,
with
and
microcrystalline undesirable reduce wt%,
comprising
liquid Marcel
component(s) adjuvant, (e.g.,
to
activity 21st celluloses,
known Adjuvants, disclose the lactose,
of medium the of
at above
the
to
the dibasic the or ingredients the edition, from vehicle,
hydroxypropylcellulose), particular
least
Dekker,
be
comprises emulsifying
pharmaceutical
techniques of solubility, present
present
or
of sucrose, various biological
within any and about
the is about
(e.g.
Pharmaceutical vehicle, and
calcium
2005, incompatible of dispersion
cellulose.
of pharmaceutical
a New
dosage invention the
sodium invention of Carriers 20
the the
30 carriers at or
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for ed.
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2015247850 04 Jun 2019 press. pharmaceutical weight the wt% wt% improve and/or granulate-bead from comprises about about composition. another from comprises an embodiment, the they microcellulose, croscarmellose composition (e.g., example, cellulose, comprises of about [0338] [0339] [0337] 1
wt%
filler,
amount pharmaceutical biological
do or or about about
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20
the reduce
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25
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55
to other the about (e.g., from
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102, with pharmaceutical comprise In disintegrant, disintegrant, wt% less)
examples, by least about about wt% ingredients compressed
1.5
pharmaceutical comprises
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30
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7 1.5 weight 53
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2015247850 04 Jun 2019 physical pharmaceutical biological tablets tablets the to wt% In magnesium and embodiment, The composition, ink. colorant, composition image a chemical composition. colorants, 5 composition. example, or comprises or an stearate, composition, [0341] [0340] [0342]
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i.e., i.e., tablets text wt%) 5 colorants In Suitable 3
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compositions
fragrances suitable not not (e.g., behenate, be
from inks a
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be
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or
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or stearate. fragrances 4.0
hardness,
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other weight less) logo, wt%
54
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2015247850 04 Jun 2019 pharmaceutical powder potentiator. than herein pharmaceutical therapeutic available grade and 0.01% colored ingredient The of suitable coated than agent(s). dispersion is further active colorant. 3 [0344] [0343] [0346] [0345]
wt%
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6
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3
core West
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the wt%
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Carnauba
Opacode® and then or of
a
4 4
labeled
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In ingredient with wax
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S-l-17823,
a a
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55
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3 3 additional ink,
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a amount comprising core from:
of
described
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strength about the
with
a text
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a
3-(6-(1-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin- 2-yl)benzoic acid, or pharmaceutically acceptable salt thereof; 2019
Jun
04
(7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l- hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof; or 2015247850
4-(3-(1-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1- yl)benzoic acid, or pharmaceutically acceptable salt thereof.
[0347] In another embodiment, the pharmaceutical composition of the present invention comprises a spray dried dispersion of the present invention and 3-(6-(1-(2,2- difluorobenzo [d] [1,3] dioxol-5 -yl) cyclopropanecarboxamido)-3 -methyipyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.
[0348] In another embodiment, the pharmaceutical composition of the present invention comprises a spray dried dispersion of the present invention and (7?)-1 -(2,2- difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.
[0349] In another embodiment, the pharmaceutical composition of the present invention comprises a spray dried dispersion of the present invention and 4-(3-(1-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-l-yl)benzoic acid, or pharmaceutically acceptable salt thereof.
[0350] In another embodiment, the additional therapeutic agent is selected from Table 4.
[0351] Table 4: Additional agents for combination therapies.
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7,659,268 In In In 7,671,221 7,645,789 7,407,976
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2015247850 04 Jun 2019 reference, reference, reference, reference reference, reference, reference, reference, Compounds Compounds Compounds Compounds Compounds Compounds Compounds incorporated Compounds Compounds Compounds Compounds Compounds Compounds Compounds Compounds Compounds Compounds Compounds Compounds [0034]-[0056];
disclosed disclosed disclosed disclosed disclosed disclosed disclosed disclosed disclosed disclosed 1-47 1-78 1-13 1-498 1-289 1-306 1-2 1-422 1-959 herein
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[0241]) herein herein herein 40; 47; 47; 66; 67; 18; herein
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2015247850 04 Jun 2019 N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide, pharmaceutically [0354] reference reference, thereof. reference, Compounds Compounds Compounds Compounds Compounds Compounds Compounds Compounds Compounds [0031]-[0162]; [0012]-[0013]; [0102]-[0263]; [0028]-[0044]; [0012]-[0013]; [0012]-[0013];
In
another
disclosed disclosed disclosed disclosed disclosed disclosed disclosed disclosed 1-117
acceptable Compounds Compounds [01 [0054]-[0079]) [0066]-[0141]) [0030]-[0051])
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17]-[0128]) in
Table
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US US US US US US US PCT
salt
1 1-28 1-15 Application Published Published Published Published Published Published
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application thereof;
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paragraph
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additional
Table Table
or Application Application Application Application Application Application
No.
W02008141
1 1 [0340])
at at herein herein herein herein
60
therapeutic
11/047,361 paragraph paragraph
incorporated by by by by
No. No. No. No. No. No.
reference, reference, reference, reference, 119
2011-0251253 2011-0263654 2009-0253736 2009-0170905 2009-0143381 2013-0116238
[0163]) [0264]) agent incorporated
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is
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or
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combinations
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or reference, from
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2015247850 04 Jun 2019 All N-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)- methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide; yl)benzoic applications and difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido) comprising ditert-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide. difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- comprising acid; difluorobenzo comprising (trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-l,4-dihydroquinoline-3-carboxamide. oxo-lH-quinoline-3-carboxamide (3-( 6-fluoro-2-( 2-yl)benzoic 3-(6-(1-(2, comprising [0356] [0360] [0359] [0358] [0357] [0355] l,4-dihydroquinoline-3-carboxamide,
US 1 c)
-(2,2-difluorobenzo[d] and
N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide.
Patents,
In In In In In Table c)
2-difluorobenzo[d][l,3]dioxol-5-yl)
acid;
a) a) a) a)
another another another another another N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide. 1
are
-hydroxy-2-methylpropan-2-yl)- acid,
[d] a a a a
6:
published spray spray spray spray incorporated and
[1,3]
(7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)- Additional
embodiment, embodiment, embodiment, embodiment, embodiment, c)
dioxol-5 dried dried dried dried
a
compound
US
[ dispersion dispersion dispersion dispersion
1
herein ,3]dioxol-5-yl)cyclopropanecarboxamido)
agents -yl) Patent
the the the the the or cyclopropanecarboxamido)-3
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N-(4-(7-azabicyclo[2.21]heptan-7-yl)-2- Applications, for
invention invention invention additional invention
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reference
combination pharmaceutically
the the the the
from present present present present 1
H-indol-5
cyclopropanecarboxamido)-3-methylpyridin- 61
features features features features therapeutic
in
N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-
and
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invention; invention; invention; invention;
therapies.
published
a a a a
-yl)cyclopropanecarboxamide,
entirety. pharmaceutical pharmaceutical pharmaceutical pharmaceutical
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isoquinolin-l-yl)benzoic
and
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international
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4-(3-(1-(2,2- a (7?)-l-(2,2- 3-(6-(1-(2,2- c)
compound selected
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2015247850 04 Jun 2019 by paragraphs 20;Table Compounds Compounds Compounds Compounds Tablet) Compounds Compounds Compounds Table Compounds Table Compounds incorporated Compounds Table Compounds Compounds Table Compounds Table [00100]-[00101]; [00146]; [0172]; [0173]; [00145];
reference,
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incorporated
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[0391]-[0392])
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1) 1)
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No. No. No. No.
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Application Application combinations 62
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Application 1 7,495,103 7,598,412 8,354,427 8,367,660
by at
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No. No. I- 1
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No.
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in [0169]) 21, 46, 38, 36, 2011-0008259 2010-0249180
22, 51, 51, 57, 2007-0105833
Tables
In In In In
In In In In
43-col 20-col 47-col 1-col
3-col 31-col 1-col 14-col incorporated
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2015247850 04 Jun 2019 pioglitazone, useful hydroxyphosphoryl]oxy-hydroxyphosphoryl] Exemplary Exemplary mucolytes thereof, oxooctahydrocyclopenta[b]pyran-5-yl}heptanoic (7-{(2R, lancovutide, ("PTC124®"; CFTR agent, formulation amino-2-oxopyrimidin-l-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] allowing lung salmeterol, suitable including azithromycin, antibiotics inflammatory agent, [[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-l-yl)-3, [0365] [0364] [0363] [0362] [0361] [0367] [0366]
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7aR)-2-[(3S)-l,l-difluoro-3-methylpentyl]-2-hydroxy-6- the
that
embodiment, embodiment, embodiment, embodiment, embodiment, liquid. formulations than
ibuprofen,
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include
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bronchitol cleared anti-inflammatory in
sinapultide, inhaled from ([[(3S,5R)-5-(4-
and
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reference
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is
is
inhibitors, HSP
embodiments, curcumin, WO2006127588, W02006044503, US20050164973,
WO
a pancrelipase. EGFR-inhibitors,
embodiment, embodiment, embodiment, embodiment, embodiment, milrinone, or Pat. benzo[cjquinolizinium entireties.
B,
agents 90 Pancreacarb®, a 2004110352,
geniestein,
benzopyran No. or
or inhibitors,
inhibitors,
ester; herein
the
betamimetics, glutathione cyclophosphamide,
6,992,096,
-benzenesulfonylamino)-propionic include thereof. W020041
tadalafil, like.
In
the [4-(3-
in the the the the the another
W02006044502, or
additional
W020061 their MPR4-inhibitors,
HSP
WO derivative pancrelipase dopamine additional additional additional additional additional
Ultrase®, W02007044560, {2-[(Z)-3,5-diamino-6-chloro-pyrazine-2-
inhalation. US20060148864, amrinone,
11014,
entirety 2005094374,
70 embodiment, anticholinergics,
derivative
inhibitors, cAMP/cGMP
therapeutic 10483,
64
that agonists,
therapeutic therapeutic therapeutic therapeutic agent W02005035514, 4-phenylbutyrate, or
by
(pancreating
isoproterenol,
Creon®, In exhibits
reference.
or
is W02006044456, that one iNOS-inhibitors,
WO
proteosome the W02004091502, incorporated a
Hl-antihistamines,
compound
agent US20060148863, embodiment, exhibits
agent agent agent agent
additional augmenters corticosteroids, 2005120497, CFTR Liprotomase®
enzyme
In
is acid
albuterol, is is is is
W02005049018, miglustat, another a
CFTR inducing
a a an selected inhibitors compound
disclosed herein nutritional
compound
agent ENaC
replacement), or W02006044682, or the
or
incorporated inducing SYK-inhibitors, inducers embodiment,
PDE4-inhibitors, (formerly
and
additional by
is WO PAF- from or
felodipine,
inhibitor
such
a
in reference
augmenting disclosed
almeterol,
compound
agent. selected
U.S.
the
as or such
Pat. herein
the
as
in in
or
2015247850 04 Jun 2019 benzenesulfonylamino)-methyl]-cyclobutanecarboxylic phenoxy]-acetic propyl)-phenoxy]-acetic piperidin- benzyloxycarbonylmethyl butoxycarbonylmethyl pyrazine-2-carbonylimino]-l,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic 2-oxo-2-(2-trifluoromethyl-pyrrolidin-l-yl)-ethyl hydroxy-ethyl)-methyl-carbamoyl]-methyl 3,5-diamino-6-chloro-pyrazine-2-carbonylimino]l,3,8-triaza-spiro[4.5]decane-8-carbonyl}- or spiro and spiro[4.5]decane-8-carbonyl}-phenyl)-ureido]-propionic 3- chloro-pyrazine-2-carbonylimino]-l,3,8-triaza-spiro[4.5]decane-8-carbonyl}- 6-chloro-pyrazine-2-carbonylimino]-l,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)- diamino-6-chloro-pyrazine-2-carbonylimino]- acid carbonylimino]-l,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic dipropylcarbamoylmethyl carbonylimino]-l,3-,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic carbonylimino]-l,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic diethylcarbamoylmethyl carbonylimino]-l,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic carbonylimino]-l,3,8-triaza- dipropylcarbamoylmethyl carbonylimino]-l,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic dimethylcarbamoylmethyl carbonylimino]-l,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid carbonylimino]-l, acid carbonylimino]-l,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic l,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic
solvate [3
l-[(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-l,3,8-triaza-
2-oxo-2-(2-trifluoromethyl-pyrrolidin-l-yl)-ethyl cyclohexyloxycarbonylmethyl cyclohexyloxycarbonylmethyl
-(3 [4.5]
-
{2-
decane-8-carbonyl} 1 thereof.
-yl-ethyl
[(E)-3
acid
,5 3, In
-diamino-6-chloro-pyrazine-2-carbonylimino] 8-triaza-spiro[4.5]decane-8-carbonyl}-benzene ester;
2-morpholin-4-yl-2-oxo-ethyl another
ester;
acid ester;
[2-chloro-4-(3 ester; ester; ester; ester;
-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic
[4-(3-
-benzenesulfonylamino)-methyl] 2-(2-oxo-piperidin-l-yl)-ethyl embodiment,
[4-(3-
3-(3- [4-(3- [4-(3- [4-(3-
{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]- ester; ester;
{2-[(E)-3,5-diamino-6-chloro-pyrazine-2- {2-[(E)-3,5-diamino-6-chloro-pyrazine-2- {2-[(E)-3,5-diamino-6-chloro-pyrazine-2- {2-[(E)-3,5-diamino-6-chloro-pyrazine-2- {2-[(E)-3,5-diamino-6-chloro-pyrazine-2-
-
{2- 3-(3- [4-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-
ester; the
[(E)-3 1,3-,
{2-[(E)-3,5-diamino-6-chloro-pyrazine-2- 65 additional
[4-(3- ester; 8-triaza-spiro[4.5]dec-8-yl}-3-oxo- ,5
ester;
-diamino-6-chloro-pyrazine-2-
ester;
{2-[(E)-3,5-diamino-6-chloro- or acid
acid
therapeutic l-[(3-{2-[(E)-3,5-diamino-6- a
pharmaceutically ester; [2-chloro-4-(3-{2-[(E)-3,5- dipropylcarbamoylmethyl
dipropylcarbamoylmethyl
-cyclobutanecar-
acid
-1,3 [4-(3-{2-[(E)-3,5-diamino-
sulfonylamino)-propionic
agent , 8-triaza-
is
acceptable 3-(3-{2-[(E)-
boxylic acid acid acid acid acid
acid acid
2-oxo-2- [(2-
tert
ester;
acid
ester;
salt
2015247850 04 Jun 2019 benzo phenyl)-l propylamino] benzoxazin-8-yl] butylamino] phenylethoxy)propyl] by benzenesulfonylamino)-propionic hydroxy-8- trimethylphenyl)-ethylamino]- hydroxy-2-[2-(4-phenoxy-acetic trifluormethylphenyl)-2-tert-butylamino)ethanol; hydroxy-2-isopropylaminobutyl)-2H- methoxyphenyl)- hydroxy-3-oxo-4H-l,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2- methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-( hydroxyphenyl)-2-[4-(l-benzimidazolyl)-2-methyl-2-butylamin- hydroxy-ethyl] hydrochloride hydroxyphenyl)-ethylamino]-5,6,7,8-tetrahydro-2-naphthyloxy]-N,N-dimethylacetamide Pirbuterole, Levosalbutamole, reference dimethyl-ethylamino]-ethyl}-4H-benzo[l,4]oxazin-3-one; dimethylaminoph- ethylamino] Clenbuterole, from disclosed embodiment, Soterenole, 8,247,436 [0373] l-(2-chloro-4-hydroxyphenyl)-t-butylaminoethanole;
reference.
Albuterole, [
1,4]
In , in in
1 and oxazin-3-one;
{1
-dimethyl-ethylamino]-ethyl}
Sulphonterole, -hexyl- another ethanol; Procaterole, United their
ethanol; the -hydroxy-2-[2-(4-hydroxy-phenyl)-
Fenoterole,
monohydrate;
International -8-hydroxy-
-2-[3 Arformoterole, additional 1
entireties.
Mabuterole, ,2,4-triazol-3-yl]-2-methyl-2-butylamino enyl)-2-methyl-2-propylamino]ethanol;
oxy} States
embodiment, 1
sulphonyl} -(4-methoxyphenyl)-2-methyl -[2H-5 1
-
[2H-5
-butyl)-benzyl-sulfonamide; Reproterole,
6-Hydroxy-8-
Formoterole,
Publication Terbutaline, 1
agent PCT H-quinoline-2-one;
In
-hydroxy-3 3-(4-
-hydroxy-3
1 Meluadrine, another
-hydroxy-ethyl}
ethyl]-amino} acid Bambuterole,
Publication
the
is {6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)- acid
a
additional ethylester)- 1
Rimiterole, compound No.
,4-benzoxazin-3
dipropylcarbamoylmethyl {1 embodiment, Hexoprenaline, Tiaramide,
-oxo-4H-
-4H-benzo[
-hydroxy-2-[2-(4-phenoxy-acetic -oxo-4H-
20130316981,
Metaproterenole,
WO
ethy-l]-2(3H)-benzothiazolone; Bitolterole,
66
-6-hydroxy-4H-benzo[ therapeutic 4-hydroxy-7-
1
disclosed 1 1
6-hydroxy-8- 1
Ritodrine, -benzimidazolyl)-2-m- 2011113894, , ,
,4-benzoxazin-8-yl] 1 1 1 Tolubuterole,
-2 ,4-benzoxazin-8-yl] -dimethyl-ethylamino]-ethyl}-4H- -dimethyl-ethylamino]-e-thyl}
1 the 5 (-)-2-[7(S)-[2(R)-hydroxy-2-(4- ,4]oxazin-3-one; -propylamino]
- -(4H)-one; Ibuterole,
[2-(5
additional
incorporated
8-{2-[l,l-Dimethyl-2-(2,4,6- Broxaterole,
in } l-[2H-5-hydroxy-3-oxo-4H-l,4-
agent
ethanol; Salmefamole, ,6-diethyl-indan-2-ylamino)-
Milveterol, United [2-
{1 incorporated
{[2-
o]ethanol; -hydroxy-2-[2-(4-methoxy-
Zinterole, Isoetharine, ester. is 1
agent -(4-amino-3 a
ethanol; {[3 5 States
betamimetic
-hydroxy-8 -2-
1,4] herein 6-hydroxy-8-
-2- -(2- Carbuterole, In
ethyl-2- Orciprenaline, [3 is
oxazin-3-one;
{4- Salmeterole, another
acid)-
-(4-N,N- Patent Nolomirole, a l-[3-(4-
herein
1 compound in
[3 Isoprenaline, - 1 [2H-5 -chloro-5
-(4- -(2-fluoro-4- its
1,1- -(
No.
-4H- selected
entirety 1
by
- {1
-
-
and - 6-
1
-
2015247850 04 Jun 2019 phenylbutoxy)hexyl] phenyl)-ethylamino] phenylamino]-phenyl} phenyl)-l benzof hydroxyethyl)-2-(hydroxymethyl)phenol; hydroxy-ethyl)-2-(hydroxy-methyl)phenol; hydroxymethyl-phenyl)- hydroxymethyl-phenole; 4-(2- hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hepty- methyl-phenyl]-urea; hexylamino)-ethyl]-lH-quinolin-2-one; ylamino hydroxy-2- 4-(4- (hydroxymethyl)- (hydroxymethyl)phenol; (R,S)-4-[2-({6-[2-(3-bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-l-hydro- difluoro-2-phenylethoxy)hexyl] (hydroxymethyl)phenol; (R,S)-[2-({6-[2,2-difluoro-2-(3-methylphenyl)ethoxy]hexyl} (2,2-difluoro-2-phenylethoxy)hexyl] (hydroxymethyl)phenol; (2- difluoro-4-phenylbutoxy)hexyl] ethyl)-2-hydroxymethyl-phenole; formamide; carbonylamino-3 dimethyl-ethylamino]-l ethylamino]-2-methyl-propyl}-phenoxy)-butyric ethylamino]-!-hydroxy-ethyl}-6-hydroxy-4H-benzo[l,4]oxazin-3-one; ethylamino]-ethyl} {6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]hexyl- {[4,4,515
{ [6-(2,
{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-8-yl)- {6-
1
,4]oxazin-3-one; } [4-(3 -tetrafluoro-6-(3-phenylpropoxy)-hexyl]amino -ethyl)- 2-difluoro-2-phenylethoxy)hexyl]amino} ,
1
{2- -dimethyl-ethylamino]- 8-hydroxy-5-(l-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-eth-
-cyclopentanesulfonyl-phenyl)-butoxy]
[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]
1 -cyano-5
H-quinolin-2-one; phenyl]-ethyl}amino)hexyl]oxy}ethyl)phenyl]urea;
-4H-benzo[
-hexyl-
amino
4-(2-
-ethylamino)-
-hydroxy-ethyl}
4-(1 (R,S)-4-(2- (R,S)-N-[3-(l,l-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3- ethylamino]-propyl}-phenyl)-acetamide; N-adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3- 6-hydroxy-8-
-fluorophenyl)-2-(tert-butylamino)ethanol;
{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy- }
oxy} -1
R)-2-
-hydroxy-ethyl)-2-(hydroxymethyl)phenol;
1
amino} amino ,4]oxazin-3-one;
-butyl)-benzenesulfonamide; 3-(4-
{ 1 [6-(2,
-hydroxy-ethyl} { amino 1 8-Hydroxy-5
[4,4-difhioro-6-(4-phenylbutoxy)hexyl]amino} -hydroxy-ethyl]
} {1
-1 {6-
-1
-6-hydroxy-4H-benzo[ 5-[2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-
-hydroxy-2-[2-(4-isopropyl-phenyl)-
-hydroxy-ethyl-)-2-hydroxy-phenyl] 2-difluoro-2-phenylethoxy)hexyl]amino -hydroxy-ethyl)-2-(hydroxymethyl)phenol; (R,S)-2-(hydroxymethyl)-4-(
[2-hydroxy-2-(4-hydroxy-3
}
(R,S)-4-(2-{ -1
-hydroxy-ethyl)-8 67
8- acid;
-
[
-1 {2-[2-(4-Ethyl-phenyl)-
1
-6-hydroxy-4H-benzo[ -hexylamino
-hydroxy-2-(6-phenethylamino- -hydroxy-ethyl)-2- -8
8-
-hydroxy- } loxy}-propyl)-benzenesulfonamide;
[6-(4,
ethyl)phenol; {2-[2-(3,4-difluor-phenyl)-
-ethylamino
amino)- 4-difluoro-4-
3-(3-(7- 1
-hydroxyquinolin-2( ,4]oxazin-3-one;
}
1
-1
(R,S)-4-(2- H-quinolin-2-one;
-hydroxy-ethyl)-2-
1 N-
-hydroxymethyl
-hydroxyethyl] 3-[3-( (R,
[2-hydroxy-2-(4- 1 8-{2-[2-(4-Ethoxy-
}
[2-hydroxy-5 -hydroxy-2-
-ethyl)-phenyl]
S)- (R,S)-5
1 oxy}-butyl)-5- 1
, ,4]oxazin-3-one; 1
[5 1
formamide; ,
1 { -dimethyl 1
, -(2- [6-(2,2-
-difluoro-2- xyethyl]-2- 1
dimethyl
1 } -(2-
-(4-ethoxy-
-1 { [6-(2,2- 1,1-
-1 1
- -2-
(R, -(
H)-one; {[6- [3-(4-
-
-
1
-
- S)-4-
2015247850 04 Jun 2019 preferred bromide, bromide pharmaceutically benzothiazol-2-one; benzothiazol-7-yl)-ethylamino]-ethyl}propionamide; tetrafluorbenzil mentioned hydro-p-toluenesulfonate. hydrocitrate, hydrophosphate, hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl} hydroxy-ethyl-)-2-(hydroxymethyl)phenol; methoxyphenyl)ethoxy]hexyl}amino)-l-hydroxyethyl]-2-(hydroxymethyl)phenol; ester-methobromide; diphenylacetic ester-methobromide; fumarate, salt, salt, from group Chloro-phenyl)-ethylamino]-propylsulfanyl} ethylamino)- ethoxy)-propionamide; (3-chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro- difluoro-3 difluorohexyl]amino}-l-hydroxyethyl)-2-(hydroxymethyl)phenol; (hydroxymethyl)phenol; one; amino)hexyl]oxy} [0374] { { [6-(2, [6-(
Aclidinium Flutropium
4-(( {2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} Tiotropium
consisting 2-difluoro-2-phenyl
lR)-2- salt,
In iodide, anticholinergics
tartrate, -phenylpropoxy)hexyl]
salts,
one
1 hydrofumarate, Trospium
-hydroxy-ethyl]
acid
{
acid
embodiment,
salts, [4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino} salts,
the sulfate, hydromethansulfonate, of salts,
acceptable
ethyl)phenyl]imidazolidine-2,4-dione; oxalate,
hydrochloride, scopine
pharmaceutically
optionally
scopine 2,2-diphenylpropionic 3,3',4,4'-tetrafluorbenzil
preferably preferably
preferably
7- salts,
phosphate, (R,
[2-(2-
are
ethoxy)hexyl] succinate,
ester-methobromide; S)-4-(2-
salts, ester-methobromide; hydrotartrate,
preferably
the selected -4-hydroxy-3H-benzothiazol-2-one;
in
{3-
the
the amino
additional racemic the
solvates [2-(2-chloro-phenyl)-ethylamino]-propylsulfanyl} hydrobromide,
methansulfonate, {
bromide bromide
benzoate, [6-(3 bromide
active from
}
the amino} hydronitrate, -1
,3 form,
-hydroxyethyl)-2-(hydroxy-methyl)phenol;
hydrooxalate, or
(R,S)-(2-
among
chloride -difluoro-3 therapeutic acid
part ethylamino)-
salt, salt,
hydrates. acid salt,
68 or
-1
as
scopine is
2-fluor-2,2-diphenylacetic
-hydroxyethyl)-8-hydroxy p-toluenesulfonate. 4,4'-difluorbenzil Ipratropium
hydroiodide,
Glycopyrronium tropenole
enantiomers, Oxitropium 2,2-diphenylpropionic the
salt, {
N-(2-diethylamino-ethyl)-N-{2-[2-(4-
nitrate, [6-(2,2-difluoro-2-phenylethoxy)-4,4- hydromaleate,
-phenylpropoxy)hexyl]
cation, agent Preferred
(R,S)-4- ester-methobromide; hydrosuccinate, Tolterodin. 1
-hydroxyethyl]-4-hydroxy-3H-
ester-methobromide;
maleate,
is
possible salts,
-1
salts, hydrosulfate,
- an diastereomers,
[2-( -hydroxy-ethyl)-2-
salts or
-3-(2 (R,S)-4-(2-{
anticholinergic
salts,
acid
preferably
hydroacetate,
7-
preferably {6-
From
Further acetate,
are [( anions -naphthalen-l-yl-
[2,2-difluoro-2-(3
tropenole 1
preferably
hydrobenzoate, R)-2-(2-
acid selected
the
quinolin-2( acid
amino
examples are 2-fluor-2,2- citrate,
tropenole [6-(2,2- the or above the
tropenole
3,3',4,4'- chloride,
as
{3 5-((lR)-2- selected
bromide ester- from bromide
the
} -[2-(2- -
-1 3
- 1H)- -
of [2-
the
and -
2015247850 04 Jun 2019 preferred tetrahydro-furan-3S-yl)ester; Prednisolone, Dexamethasone, xanthene-9-carbon methobromide; methobromide; tropine methobromide; hydroxy-fluorene-9-carbon tropenole methobromide; diastereomers, carboxylic oxo-17alpha-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-l,4-diene-17beta- 3-oxo-androsta-l,4-dien-17-carbothion (nitrooxymethyl)benzoate]; cyclohexanecarboxylate en-3-one}; from ester acid carbon 9-hydroxy-xanthene-9-carbon cyclopropyl carbon diphenylpropionic scopine fluorene-9-carbon acid [butylidenebis(oxy)]-6alpha,9alpha-difluoro- [0375] 1 11 6-methyl-3
-hydroxy-
tropenole tropenole
methobromide. Beclomethasone,
acid acid
ester-methobromide; estermethobromide;
In salts ester-methobromide;
acid 9-fluoro-l
one
scopine cyclopropyl -oxo- tropine 1
7-(methylthio)androst-4-en-3
Prednisone,
and ester-methobromide; ester-methobromide;
or
9-methyl-xanthene-9-carbon 4,4'-difluorbenzil 4,4'-difluorbenzil 9-fluor-fluorene-9-carbon cyanomethyl embodiment,
Etiprednole,
as 17
acid
acid derivatives acid
ester-methobromide; -propionyloxy-androsta- pharmaceutically ester
lbeta,
Betamethasone, tropenole
cyclopropyl
tropenole tropine 17-cyclopropanecarboxylate;
methobromide;
Rofleponide,
acid 17,
6,
benzil 9-hydroxy-fluorene-9-carbon
ester; or
the 9-difluoro- Flunisolide, acid
are 21-trihydroxy-16alpha-methylpregna-l,4-diene-3,20-dione 3,3'-difluorbenzil
6alpha,9alpha-difluoro-l ester-methobromide; tropenole
estermethobromide;
additional acid acid ester alkali
tropenole
optionally
acid tropine 9-hydroxy-fluorene-9-carbon or
acceptable methylester scopine
9-hydroxymethyl-xanthene-9-carbon
methobromide;
acid Budesonide,
Triamcinolone, cyclopropyl salts,
1
9-methyl-xanthene-9-carbon 9-methyl-xanthene-9-carbon
7-[(2-furanylcarbonyl)oxy]-l acid Fluticasone, ester-methobromide;
-one;
ester-methobromide; therapeutic
(S)-fluoromethylester;
1 acid 11
ester-methobromide;
,4-dien-
i.e., in
ester-methobromide; scopine
69 beta-hydroxy-
racemic flunisolide-2
acid salts,
scopine
sodium cyclopropyl
Butixocorte, tropine
9-methyl-fluorene-9-carbon 17 9-methyl-fluorene-9-carbon scopine
16,17-butylidenedioxy-6,9-difluoro- solvates, ester Loteprednole,
9-difluormethyl-xanthene-9-carbon agent Tipredane, -carbothion
lbeta-hydroxy-16alpha-methyl-3- form,
estermethobromide;
or acid
ester-methobromide; methobromide; potassium
1 1 is
ester-methobromide;
- 7beta-(methylthio)androsta-4-
tropine as
[4 cyclopropyl 9-fluor-fluorene-9-carbon a or
9-hydroxy-xanthene-9-
Ciclesonide,
acid corticosteroid enantiomers,
9-hydroxy-xanthene-9- hydrates. 6,
{20R-16alpha,17alpha- 3,3'-difluorbenzil acid
9-difluoro- Mometasone,
acid acid scopine
ester-methobromide;
1 salts,
-hydroxy- (S)-(2-oxo-
tropenole cyclopropyl
tropine acid 9-methyl-
Examples sulfobenzoates,
9-ethyl-
Deflazacorte, ester
1 selected
scopine
1-hydroxy-
2,2- acid acid
16-methyl-
9- ester
ester
acid
of
21-
2015247850 04 Jun 2019 benzo[s][l,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide; pyridinyl)- pyridinone; palmitates, phosphates, hydrobromide, racemic )p-[(4aRU methyl- methylphenyl)methyl] 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)- methyl-4-oxo-1 Pumafentrine, solvates dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-l,2,4-triazolo[4,3-a]pyridine; ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-l,2,4- cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-yliden]acetate; cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-yliden]acetate; cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-ol]; (3 cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carbon (3,5-dichloro-l-oxo-pyridine-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxy-benzamide; e]pyrazin-6(-5H)-one; isoindole-2-propanamide; isopropyl-3H-purine; (cyclopentyloxy)-4-methoxyphenyl] fluorophenyl)methyl] dichloropyrid-4-yl)-[l-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]glyoxyl oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(trifluo- 5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamide]-8-methoxy-quinoline; from [(3 [0376] l-(4-N'-[N-2-cyano-S-methyl-isothioureido]-benzyl)-2-pyrrolidone; -cyclopropylmethoxy-4-difluoromethoxyphenyl)-cyclohexan-
-cyclopentyloxy)-4-methoxyphenyl]
Enprofylline,
1 form, or -oxido-4-pyridinyl)ethyl]-alpha,alpha-bis(trifluoromethyl)-benzenemethanol; In
1
1 hydrates.
pivalates,
ObS one 2- isonicotinates, (2H)-phthalazinone;
[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-
as Lirimilaste, hydroiodide,
-phenylpyrrolo[3,2, *)-9-ethoxy- embodiment,
enantiomers,
Theophylline,
-N-methyl-2-(trifluoromethyl)-9H-purine-6-amine; Preferred or beta-
(3 5
-
furoates. S
[3
,5
9-ethyl-2-methoxy-7-methyl-5
Apremilaste, [3 -(cyclopentyloxy)-4-methoxyphenyl] acetates,
S)-2-piperidinone;
1,2,3 hydrosulfate,
-(cyclopentyloxy)-4-methoxyphenyl]
the
diastereomers,
salts
,4,4a, (3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8- additional Roflumilaste, 1
-2 dichloroacetates, -jk- are -phenylethyl]-pyridine;
1
-2
0b-hexahydro-8-methoxy-2-methyl- Arofylline, selected ][ 1 -pyrrolidone;
-naphthalenyl]- hydrophosphate, 1
,4]benzodiazepin-3-yl]-4-pyridinecarboxamide; therapeutic
or
triazolo[4,3-a]pyridine; 4-[
70
Ariflo
as from
1
-
pharmaceutically
Atizorame, [3
propionates,
,4-bis(difhioromethoxy)phenyl]
the (Cilomilaste), 3
agent
romethyl)-quinoline; 1 acid]; -(cyclopentyloxy-4-methoxyphenyl)-
-propyl-imidazo -naphthalenyl]-2-pyridinyl]
1 group
-(2-methoxyethyl)-2( hydromethansulfonate,
(R)-(+)-l-(4-bromobenzyl)-4-
is N-[(3R)-3,4,6,7-tetrahydro-9- 2-Carbomethoxy-4-cyano-4-
Oglemilastum,
9-cyclopentyl-5,6-dihydro-7- (S)-(-)-ethyl[4-(3- 1 -3 a consisting
-one;
PDE4-inhibitor -1,3 - (R)-(+)-ethyl[4-(3- dihydrogenphosphates,
[(3
cis[4-cyano-4-(3- acceptable
Tofimilaste,
- or -dihydro- 5-[N-(3,5-dichloro-l-
cis[4-cyano-4-(3
acid
9-cyclopentyl-5,6- 4-
[
1,5
[(2R)-2- of
amide);
-a]pyrido N-(3,5-
hydrochloride,
Tetomilaste;
1,3
salts, optionally 1H)-
selected
-dioxo-2H-
[3
9-[(2- -4-(3-
-2-(3- -
[3,2- N- -
(-
in
2015247850 04 Jun 2019 palmitates, propyl)phenyl)thio)methylcyclopropane-acetic yl] 4-fluorophenyl)amino] 4-[(3 hydrosuccinate, hydromaleate, hydroiodide, Preferred thiazolyl)-5-benzofuranyl] methylethyl)phenyl)propyl)thio)methyl)cyclopropane hydrooxalate, hydronitrate, oxo-morpholine-4-yl)-1 3 ((R)-6-methyl-2-oxo-morpholine-4-yl)- fluorophenyl)amino] oxo-2-butene- cyclopropylmethoxy-quinazoline; diethylamino)-l-oxo-2-butene-l-yl]amino}-7-cyclopropylmethoxy-quinazoline; cyclopropylmethoxy-quinazoline; from sulfobenzoates, optionally enantiomers, dichlorothieno acid; acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propyl- fluorophenyl)butoxy]phenyl] Guay from [(3 [0377] [0378]
-yl)oxy]
amino -chlor-4-fluorophenyl)amino]
-chlor-4-fluorophenyl)amino]
Montelukast, Cetuximab; l-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2- et
al,
}
In In -quinazoline; salts
-7 preferred
pivalates, Bioorg. one one -cyclopropylmethoxy-quinazoline;
hydrosulfate, hydromaleate, diastereomers,
hydrosuccinate, 1
[3 hydroacetate, are
-yl-
phosphates, embodiment, embodiment, hydrobenzoate, ,2-b]pyridin-5
Trastuzumab;
selected
Pranlukast, ] Med.
amino salts
-6- or
-6- 4-
-oxo-2-butene-1 { furoates.
[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-
[(3 Chem. and
{
oxymethyl]phenyl]
} hydrophosphate, [4-(N,N-dimethylamino)- from
-7-cyclopentyloxy-quinazoline;
hydroacetate, -chlor-4-fluorophenyl)amino] isonicotinates, or hydrocitrate,
ethenyl]
derivatives the the
hydrobenzoate,
-yl)-(E)-ethenyl)phenyl)-3 Zafirlukast, as
Panitumumab;
and
-6- the Lett.
additional additional pharmaceutically 4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(N,N- 4- -6-
[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]
hydro-p-toluenesulfonate. group [(R)-(
-2-(1
{ 8 [4-(morpholine-4-yl)-
1 (1998) -yl]
-oxo-2-butene-
are
hydrofumarate,
H-tetrazole-5 hydrocitrate,
1 consisting Masikulast,
acetates,
-phenyl-ethyl)amino] amino hydromethansulfonate, therapeutic therapeutic
alkali
acetic
and
453-458); Gefitinib; acid; 71 4-
[(3
}
hydro-p-toluenesulfonate.
-7-cyclopropylmethoxy-quinazoline;
salts, acceptable
acid;
propionates, -chlor-4-fluorophenyl)amino] 1
l-(((l(R)-3(3-(2-(2,3-
of -oxo-2-butene-1 acetic
L-733321 hydrofumarate, -yl)-4H-
1 agent agent
hydrochloride,
i.e. -yl]amino} -(2-(1
optionally (E)-8-[2-[4-[4-(4- Canertinib;
-6- hydrotartrate,
4- sodium acid;
1 {
-oxo-2-butene-
is is [4-((R)-2-methoxymethyl-6-
[(3
-hydroxy- salts,
Further 1 a an
-chlor-4- -6- -benzop
dihydrogenphosphates, (see LTD4-antagonist or
EGFR-inhibitor 1
hydronitrate,
-7-[(S)-(tetrahydrofuran- { in
solvates -oxo-2-butene-1 or
[2-[[2-(4-tert-butyl-2- [4-(morpholine-4-yl)- Erlotinib;
-yl]
compound
racemic
potassium
hydrotartrate, hydrobromide, examples
hydrooxalate, phenoxy]-butyric 1 yran-4-one;
amino
-
1 or
-yl]
form, Mab
hydrates.
}
4-[(3-chlor-
-7-
2ab amino for
salts, -6-
selected
selected
- ICR-62;
-7- 4-[6- {[4- as
of
}
4 D.
-7-
1
-
2015247850 04 Jun 2019 phenyl)amino] propyloxy] butene-l-yl}amino)-7-cyclopentyloxy-quinazoline; phenyl-ethyl)amino]-6-( yl)quinazoline; hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine; methoxy-ethoxy)-quinazoline; tetrahydrofuran-3-yloxy)-quinazoline; methoxy-ethyl)-N-methyl-amino]-l yl}amino)-7-cyclopropylmethoxy-quinazoline; 4-fluorophenyl)amino] methyl-amino]-l-oxo-2-butene-l-yl}amino)-7-cyclopropylmethoxy-quinazoline; methoxy-quinazoline; chlor-4-fluorophenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-6-[(S)- oxo-morpholine-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline; ethoxy]-7-methoxy-quinazoline; quinazoline; oxo-2-butene- quinazoline; (3-fluor-benzyloxy)-phenyl]amino} 6- (tetrahydrofuran-2-yl)methoxy]-quinazoline; fluorophenyl)amino]-6- quinazoline; (N-cyclopropyl-N-methyl-amino)- dimethylamino)-l-oxo-2-butene-l-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline; fluorophenyl)amino] amino] quinazoline; ethyl)-amino)- cyclopentyloxy-quinazoline; [(3-chlor-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-l-oxo-2- 1 1 {
-oxo-2-butene-1 -yl] [4-(morpholine-4-yl)-
{ [4-(N,N-dimethylamino)-
amino -1
-oxo-2-butene-1
-6- }
-7- 4-[(3-chlor-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)- 4-[(3-chlor-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-l- 4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-l-oxo-2-butene- 4-[(R)-( [(vinylcarbonyl)amino]-quinazoline; 1
-6- 1
[(R)-(tetrahydrofuran-2-yl)methoxy] -yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline;
4-[(R)-(l-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)- -oxo-2-butene-
-yl]
{ [4-(5
-6-
amino 1
-phenyl-ethyl)amino]-6-( 4-[(3-chlor-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-
-6- 1
,5 { {
-oxo-2-butene-1 {4-[N-(2-methoxy-ethyl)-N-ethyl-amino]- [4-(N,N-dimethylamino)- [4-(N,N-dimethylamino)- -yl}
-dimethyl-2-oxo-morpholine-4-yl)- { [4-(N,N-dimethylamino)-
}
-7
4-[(R)-(l-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy- amino)-7-cyclopropylmethoxy-quinazoline; 1
-methoxy-quinazoline; -oxo-2-butene-1 4-[(3 1
-yl]
4- 1 [(3
amino -6-(5- -oxo-2-butene- -oxo-2-butene-1 -Chlor-4-fluorophenyl)amino]
-chlor-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6- 4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(N,N-
-yl]
{ }
[(2-methansulfonyl- -7-cyclopropylmethoxy-quinazoline;
amino
4-
-yl]
72 {4-[N-(tetrahydropyran-4-yl)-N-methyl- 4-[(R)-(l-phenyl-ethyl)amino]-6-({4-[N-(2- [(3 3-cyano-4-[(3-chlor-4-fluorophenyl)amino]-
} -ethinyl-phenyl)amino]-6,7-bis-(2-
amino 1 1 1
4-[(R)-(l-phenyl-ethyl)amino]-6-(4-
-7-
-oxo-2-butene- -oxo-2-butene- 4-[(3-chlor-4-fluorophenyl)amino]-6-{[4- -quinazoline; -yl} -yl] 1
-oxo-2-butene-1 4-
[(tetrahydrofuran-2-yl)methoxy]
amino
amino)-7-cyclopropylmethoxy- [(3
}
-7-ethoxy-quinoline;
-chlor-4-fluorophenyl)amino] 1
} -oxo-2-butene-
-7-cyclopentyloxy- ethyl)amino]methyl}-furan-2-
4-
-7- 1 1 1
-oxo-2-butene- [(3 -yl] -yl]amino}
[3
-yl]
-chlor-4-
-(morpholine-4-yl)-
amino
amino 4-
4-[(3-ethinyl- [(3 1
}
-yl]
-chlor-4- -7-((R)- -7-[(S)-
4-
} 4-
-7-
4-[(3-chlor- {[3
amino
[(R)-(
1 4-[(3-
-
-chlor-4-
-
}
1
-6-
- -
4-
2015247850 04 Jun 2019 piperidine-4-yloxy} methoxy-acetyl)-piperidine-4-yl-oxy]-7-(2-methoxy-ethoxy)-quinazoline; yloxy)-7-(2-methoxy-ethoxy)-quinazoline; methyl-amino yl)sulfonylamino] 4-fluorophenyl)amino]-6-{trans-4-[(morpholine-4-yl)carbonylamino]-cyclohexane- yloxy)-7-(2-methoxy-ethoxy)-quinazoline; yloxy)-7-hydroxy-quinazoline; yloxy)-7-ethoxy-quinazoline; yloxy] methyl-piperidine-4-yloxy)-7-methoxy-quinazoline; methoxy-quinazoline; ethoxy-quinazoline; quinazoline; fluorophenyl)amino] quinazoline; cyclohexane-l-yloxy)-7-methoxy-quinazoline; fluorophenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}- aminocarbonylmethyl-piperidine-4-yloxy)-7-methoxy-quinazoline; ethoxy)-quinazoline; fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetyl-amino-ethoxy)-quinazoline; 7-methoxy-quinazoline; quinazoline; quinazoline; fluorophenyl)amino]-6- (tetrahydropyran-3-yloxy)-7-methoxy-quinazoline; cyclohexane-l-yloxy)-7-methoxy-quinazoline; quinazoline; fluorophenyl)amino]-6-[l-(tert-butyloxycarbonyl)-piperidine-4-yloxy]-7-methoxy- oxo-morpholine-4-yl)-piperidin-l-yl]-ethoxy}-7-methoxy-quinazoline; (tetrahydro [(dimethylamino)sulfonylamino] [(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline; [(3-chlor-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methane- {N-
[(morpholine-4-yl)carbonyl]
-7 -methoxy-quinazoline;
furan-2-yl)methoxy]
4-[(3-chlor-4-fluorophenyl)amino]-6-(l-methansulfonyl-piperidine-4-yloxy)-7- 4-[(3-chlor-4-fluorophenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)sulfonyl]-N- 4-[(3-chlor-4-fluorophenyl)amino]-6-[l-(2-acetylamino-ethyl)-piperidine-4- 4-[(3-chlor-4-fluorophenyl)amino]-6-(piperidine-3-yloxy)-7-methoxy- 4-[(3
}
-cyclohexane-
-chlor-4-fluorophenyl)amino] -cyclohexane-
-7-methoxy-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-(
-6-(trans-4-ethansulfonylamino-cyclohexane- 4-[(3-chlor-4-fluorophenyl)amino]-6-{l-[(piperidine-l-yl)carbonyl]-
4-[(3-chlor-4-fluorophenyl)amino]-6-(trans-4-methansulfbnylamino-
{1 4-[(3-chlor-4-fluorophenyl)amino]-6-{trans-4-[(morpholine-4-
-[(methoxymethyl)carbonyl]-piperidine-4-yloxy}
1 4-[(3-chlor-4-fluorophenyl)amino]-6-((S)-tetrahydrofuran-3-
-yloxy)-7-methoxy-quinazoline;
4-[(3-chlor-4-fluorophenyl)amino]-6-(tetrahydropyran-4- -quinazoline; 4-
-N-methyl-amino 1
-cyclohexane-
-yloxy}
[(3
-chlor-4-fluorophenyl)amino]
-7-methoxy-quinazoline;
4-[(3 4-[(3-chlor-4-fluorophenyl)amino]-6-{trans-4-
4- 4-
1 4-[(3-chlor-4-fluorophenyl)amino]-6- 4-[(3-chlor-4-fluorophenyl)amino]-6-(cis-4-
73 [(3 [(3 -6-(trans-4-amino-cyclohexane-
-yloxy} -chlor-4-fluorophenyl)amino]
}
-chlor-4-fluorophenyl)amino] -chlor-4-fluorophenyl)amino]
-cyclohexane- 4-[(3-chlor-4-fluorophenyl)amino]-6-(
4-
[(3
-7-methoxy-quinazoline;
-chlor-4-fluorophenyl)amino]
1
-methansulfonyl-piperidine-4-
4- 1
[(3
-yloxy)-7-methoxy-
1 4-[(3 -6-(tetrahydropyran-4-
-yloxy)-7-methoxy- 4-[(3-chlor-4-
-chlor-4-
4-[(3-chlor-4- -chlor-4-
4-[(3-chlor-4- 4-[(3-chlor-4-
-7-methoxy-
sulfonylamino-
-6- 1
-6-( -6-
-yloxy)-7-
[ 4-
1
-(2-
{2-
[(3
1 1
-yloxy} -
[4-(2- -chlor-
-6-
1
{1
4-
-
-
-
2015247850 04 Jun 2019 N-methyl-amino] phenyl)amino] phenyl)amino] piperidine-4-yloxy)-7-methoxy-quinazoline; piperidine-4-yloxy} methyl-amino)-cyclohexane- methoxy-quinazoline; methoxyethyl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline; yloxy)-7-methoxy-quinazoline; yloxy yl)carbonyl] methansulfonyl-piperidine-4-yloxy)-7-methoxy-quinazoline; methoxy-quinazoline; methyl-amino fluorophenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexane-l-yloxy]-7-methoxy- fluorophenyl)amino]-6-{l-[(3-methoxypropyl-amino)-carbonyl]-piperidine-4-yloxy}-7- fluorophenyl)amino]-6- carbonyl] quinazoline; 6-[ 7-methoxy-chinazoline; quinazoline; fluorophenyl)amino]-6-( acetyl-piperidine-4-yloxy)-7-methoxy-quinazoline; chlor-4-fluorophenyl)amino] cyclohexane-l-yloxy)-7-methoxy-quinazoline; fluorophenyl)amino] quinazoline; quinazoline; fluorophenyl)amino]-6-(cis-4-acetylamino-cyclohexane-l-yloxy)-7-methoxy-quinazoline; [(3 [(morpholine-4-yl)carbonylamino] [(3-ethinyl-phenyl)amino]-6-[l-(tert-butyloxycarbonyl)-piperidine-4-yloxy]-7-methoxy- [(3 {1
-
-chlor-4-fluorophenyl)amino] -chlor-4-fluorophenyl)amino] 1 [(2-methyl-morpholine-4-yl)carbony-l]
-(2-methoxy-acetyl)-piperidine-4-yloxy] }
-7-methoxy-quinazoline;
-piperidine-4-yloxy}
-piperidine-4-yloxy} 4- 4-[(3-chlor-4-fluorophenyl)amino]-6-(cis-4-{N-[(piperidine-l-yl)carbonyl]-N- 4-[(3-chlor-4-fluorophenyl)amino]-6-{l-[cis-2,6-dimethyl-morpholine-4-yl)- 4-[(3-ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-
}
-6- -6-(piperidine-4-yloxy)-7-methoxy-quinazoline;
[(3 -cyclohexane-
-cyclohexane-
{1 -chlor-4-fluorophenyl)amino]
-7-(2 -
-6-(cis-4- [(morpholine-4-yl)carbonyl]
4-[(3-chlor-4-fluorophenyl)amino]-6-[cis-4-(N-methansulfonyl-N- 4-[(3-chlor-4-fluorophenyl)amino]-6-{l-[(morpholine-4-yl)carbonyl]-
{1
4-[(3-chlor-4-fluorophenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)- 1 -methoxy-ethoxy)-quinazoline;
-methyl-piperidine-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline;
-[(N-methyl-N-2-methoxyethyl-amino)-
-6- 1 1
-yloxy] -7-methoxy-quinazoline; {N-[(4-methyl-piperazine- -yloxy)-7-methoxy-quinazoline;
1 4- {1 4-[(3
-6- -6-(
-yloxy} -7
[(3 -[2-(2-oxopyrrolidine-
-cyclohexane- -methoxy-quinazoline;
{1
1
-chlor-4-fluorophenyl)amino]
-chlor-4-fluorophenyl)amino] -isoprop -7-methoxy-quinazoline; -
[(S
-7-methoxy-quinazoline; ,
-piperidine-4-yloxy} S)-(2-oxa-5
-7-methoxy-quinazoline; 4-[(3-ethinyl-phenyl)amino]-6-(l-
yloxycarbonyl-piperidine-4-yloxy)-7-methoxy-
4-[(3-chlor-4-fluorophenyl)amino]-6-{cis-4-
74 -6-(cis-4-methylamino-cyclohexane- 1
-piperidine-4-yloxy
-yloxy
4-[(3-ethinyl-phenyl)amino]-6-(l-methyl-
-aza-bicyclo
4-
} 4- 1 1
-7
-yl)ethyl] [(3 -yl)- 4-
[(3 -methoxy-quinazoline;
[(3 -chlor-4-fluorophenyl)amino] 4-
-ethinyl-phenyl)amino]
4-[(3-chlor-4- carbonyl] -7
4- 4-[(3 -chlor-4- [(3 -methoxy-quinazoline;
[(3 4-[(3
-chlor-4-
[2.2.1] -6-
carbonyl]-piperidine-4-
-6-( -piperidine-4-yloxy
-chlor-4- -ethinyl-phenyl)amino]
}
{1 -7-methoxy- 4- 4-[(3-chlor-4-
1 -ethinyl-
- -ethyl-piperidine-4-
[(3
-N-methyl-amino
[(2- -hept-5
-ethinyl-
-
4-
1
-6-(
[(3 -yloxy)-
}
-7
- 4
1
- -
} -6- 4-
4
-
-
2015247850 04 Jun 2019 N-methyl-amino toluenesulfonate. hydro hydromethansulfonate, hydrochloride, Diphenhydramine, Mizolastine, hydrooxalate, hydronitrate, hydrobromide, racemic Pramipexole, hydrooxalate, hydronitrate, hydrobromide, racemic methansulfonyl-piperidine-4-yloxy)-7-methoxy-quinazoline; 4-fluorophenyl)amino]-6-(trans-4-dimethylamino-cyclohexane-l-yloxy)-7-methoxy- methansulfonyl-N-methyl-amino)-cyclohexane-l-yloxy]-7-methoxy-quinazoline; yloxy)-7-methoxy-quinazoline; salts, optionally Cexchlorpheniramine, selected solvates selected solvates fluorophenyl)amino]-6-( (tetrahydrofuran-2-yl)methoxy]-quinazoline; fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-[(S)- quinazoline; quinazoline; [0379] [0380]
solvates fumarate,
form, form, from from or or In In
in hydrates. hydrates.
another another
4-[(3-chlor-4-fluorophenyl)amino]-6-(trans-4- 4-[(3-chlor-4-fluorophenyl)amino]-6-(trans-4-methylamino-cyclohexane- Ketotifene,
racemic hydromaleate, hydromaleate,
Roxindole, Epinastine, Bromocriptine, hydrosuccinate, hydrosuccinate, or
as as
hydrobromide, hydroiodide, hydroiodide, hydrotartrate,
} hydrates. enantiomers, enantiomers,
-cyclohexane-
Promethazine,
embodiment, embodiment,
Preferred Preferred form,
Pheniramine, hydronitrate,
Emedastine, 1
Ropinirole, -cyano-piperidine-4-yloxy)-7-methoxy-quinazoline;
Cetirizine,
Preferred
as hydroacetate, hydroacetate, hydrosulfate, hydrosulfate,
Cabergoline, hydrooxalate, hydrobenzoate, hydrobenzoate, hydroiodide, enantiomers, diastereomers, diastereomers,
are salts 4-[(3-chlor-4-fluorophenyl)amino]-6-[trans-4-(N- 1
-yloxy)-7-methoxy-quinazoline;
the the Ebastine,
salts
Doxylamine, are
Azelastine, hydromaleate, are Talipexole, additional additional Dimetindene,
selected selected salts
hydrocitrate, hydrocitrate, hydrophosphate, hydrophosphate,
Alpha-dihydroergocryptine,
hydrosulfate, diastereomers, Olopatadine, hydrosuccinate,
4-[(3-chlor-4-fluorophenyl)amino]-6-(
or or selected and and 75
therapeutic therapeutic
as as Fexofenadine, from from Terguride,
Chlorphenoxamine,
hydro-p-toluenesulfonate. hydro-p-toluenesulfonate.
pharmaceutically pharmaceutically hydroacetate, Clemastine,
the the from
hydrofumarate, hydrofumarate,
Desloratidine, hydrophosphate, group group
or {N-[(morpholine-4-yl)carbony-
hydromethansulfonate, hydromethansulfonate,
agent agent the and
hydrobenzoate,
or4-[(3-chlor-4- as
Levocabastine,
group
Bamipine, pharmaceutically Viozane, consisting consisting
hydrocitrate, 4- is is
[(3 an a
acceptable acceptable
dopamine consisting
Dimenhydrinate,
-chlor-4-
antiallergic
hydrotartrate, hydrotartrate, Lisuride, and
optionally
of of
Meclozine, and
hydrochloride, hydrochloride,
optionally
Loratadine,
salts, salts,
antagonist
hydro-p-
of
Pergolide,
4-[(3-chlor-
acceptable agent
1
in -
1
-
in
1]-
2015247850 04 Jun 2019 pyridinyl)ethyl] monomethyl-L-arginin), methylisothiourea, 4H-l,3-thiazine-2-amine hydrooxalate, hydronitrate, hydrobromide, racemic taurolithocholic hydrooxalate, hydronitrate, hydrobromide, racemic (S)-6-acetimidoylamino-2-amino-hexanoic (N (2-aminoethyl)isothio-urea, solvates, sulfinpyrazone, glucuronide, dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid glycolithocholic sulphate, estradiol- glucuronide, from solvates, chlorophenyl)-5 diindolo[l,2,3-fg:3',2',r-kl]pyrrolo[3,4-i][l,6]benzodiazo-cine-10-carboxylic difluorophenyl)amino] selected [0382] [0381] [0383] “ -nitro-L-arginin),
sulphate, N-acetyl-dinitrophenyl-cysteine,
form, form, from
or or In In In estrone-3-sulphate, 17
hydrates. -beta-glucuronide, hydrates. one one one
nitrobenzyl dehydroepiandrosterone-3-sulphate, hydromaleate, hydromaleate,
Bentamapimod, hydrosuccinate, hydrosuccinate, methotrexate,
as as
hydroiodide, hydroiodide,
amino] taurochenodeoxycholate, -( embodiment, embodiment, embodiment, acid
acid enantiomers, enantiomers, 1
-methyl-4-piperidinyl)- S-ethylisothiourea,
sulphate, sulphate, L-NAME Preferred Preferred
-2-(2, -4-pyrimidinyl]
L-NIO mercaptopurine (AMT),
aminoguanidine, hydroacetate, hydroacetate, 4-difluorophenyl)-3-pyridine
hydrosulfate, (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[3- hydrosulfate,
flurbiprofen,
the the the
Doramapimod, hydrobenzoate, hydrobenzoate, topotecan, diastereomers, diastereomers, estradiol-3 ibuprofen,
(N salts are (Ν
additional additional additional L-canavanin, “ ω
-nitro-L-argininmethylester), salts
-iminoethyl-L-ornithin), are
-2 cGMP, S-methylthiocitrulline,
-benzothiazole
selected selected
riboside,
, trequinsin, taurocholate,
indomethacin, hydrocitrate, hydrocitrate, hydrophosphate, hydrophosphate, 1 1 folate,
7-disulphate, H-pyrazole-4-yl]
acid therapeutic therapeutic therapeutic
2-aminomethylpyridine,
or or 5-Carbamoylindole, cholate, and and
76 2-iminopiperidine,
(lH-tetrazole-5-yl)-amide; as as
N5-formyl-tetrahydrofolate, from from dilazep,
probenecid, hydro-p-toluenesulfonate. hydro-p-toluenesulfonate. pharmaceutically pharmaceutically
zaprinast
diclofenac, the the
taurodeoxycholate, hydrofumarate, hydrofumarate, acetonitrile, agent agent is
indoprofen, estradiol-3
carboxamide,
dinitrophenyl-S-glutathione, an acid, group group hydromethansulfonate, hydromethansulfonate,
-pyrimidine,
iNOS-inhibitor
L-NIL
is is S-ethylthiocitrulline,
or valspodar,
alpha-naphthyl-beta-D- an an
consisting consisting L-NMMA dipyridamol,
dehydroepiandrosterone-3-
S-isopropylisothiourea, 6-[(aminocarbonyl)(2,6- MRP4-inhibitor MAP
-glucuronide,
9,1
(Ν ketoprofen, acceptable acceptable
5,6-dihydro-6-methyl-
2-epoxy- ω hydrotartrate, hydrotartrate, alpha-
-iminoethyl-lysin),
kinase optionally sildenafil,
taurolithocholate,
N-[[3-
of of (Ν
selected
acid,
glycocholate,
[2-[ hydrochloride, hydrochloride, optionally ω
salts, salts, inhibitor
1 -
lithocholic
H- estradiol-3 [2-(3
or
L-NA
selected
in
from 4-[3-(4-
-
in
S-
S-
-
2015247850 04 Jun 2019 propanediamine; b] pyrrolidine-2-carbon piperazine-1-carbon pyrimidine-4-yloxy)-piperidine- butylsulfanyl)-6-methoxy-nicotinonitrile; methoxyphenyl)-!,6-naphthyridine-5-yl]-l,3-propanediamine; hydrosuccinate, hydromaleate, hydroiodide, Preferred ylideneamine, methyl-2-aza-bicyclo[4. trifluoromethyl-phenylsulfanyl)-4-thiazole-5 hydroxy-l-thiazole-5-yl-butylsulfanyl)-5-chlor-benzonitrile;(2S,4R)-2-amino-4-(2-chlor-5- hydroxy- fhioro-2-[3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H-pyrido[3,2- (3 from disclosed antisense-oligonucleotide iNOS-inhibitors as (2,4-difluor-phenyl)-6-[2-(4-imidazole-l-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine, aminotetrahydrobiopterine, 3-ylamin(4R,5R)-5 isoquinolinamine amino-4-hydroxy-1 ((R)-3-amino- amino-buturic (aminomethyl)phenyl]methyl]-ethanimidamide; [0384] 1 {
-thiazole-5 [(benzo
-1 ,4-dimethoxyphenyl)imidazo enantiomers, ,4-oxazin-3(4H)-one;
2-
[(2-aminoethyl)amino]
[
In 1
salts in 1,3]
-thiazole-5
-yl-butylsulfanyl)-5 another WO
hydrosulfate,
dioxol-5
1 (4R,5R)-5-ethyl-4-methyl-selenazolidine-2-ylideneamine, hydroacetate, acid; are
-phenyl-propoxy)-4-chlor-5-fluorbenzonitrile;
diastereomers, hydrobenzoate,
which 01/52902, 7-(4-methoxyphenyl)-N-methyl-
as selected
-ethyl-4-methyl-thiazolidine-2-ylideneamine,
-thiazole-5
embodiment, 2-[2-(4-methoxy-pyridine-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine; for acid
-yl-butylsulfanyl)-6-trifluoromethyl-nicotinonitrile; acid
-ylmethyl)-carbamoyl]
may
instance 1
.0]hept-2-ene-3-ylamin, methylester,
N-[3-bromo-7-(4-methoxyphenyl)- binding (2-benzo[l,3]dioxol-5-yl-ethyl)-amide,
hydrophosphate,
from
(E)-3-(4-chlor-phenyl)-N-(l-{2-oxo-2-[4-(6-trifluormethyl- incorporated
be hydrocitrate,
-yl-butylsulfanyl)-4-chlor-benzonitrile;
-4-
or mentioned [
-chlor-nicotinonitrile;4-((S)-3
1 and 1 the
lS,5S,6R)-7-chlor-5-methyl-2-aza-bicyclo[4.1.0]hept-2-ene-
,2-c]pyrimidine-5 -yl]-ethylcarbamoyl}-2-pyridine-2-yl-ethyl)-acrylamide, [(3
the as iNOS-coding
-bromophenyl)amino] hydro-p-toluenesulfonate. group pharmaceutically
additional or
herein (R)-l-(2-imidazole-l-yl-6-methyl-pyrimidine-4-yl)-
or hydrofumarate,
include consisting
hydromethansulfonate,
substituted -yl-butane- -methyl}
77
by therapeutic nucleic (S)-4-(2-acetimidoylamino-ethylsulfanyl)-2-
(4R,5R)-5-ethyl-4-methyl-thiazolidine-2- 1
antisense-oligonucleotide,
-yl] reference ,6-naphthyridine-5-amine;
of -4-(2-imidazole-
acceptable amino]
1
3-phenyl-3,4-dihydro-l- acids, hydrochloride,
-ol;
hydrotartrate,
-5
agent
-pyrimidinecarboxamide; 2-(( in
1 -amino-4-hydroxy-1 -3
2-((
,6-naphthyridine-5-yl] examples N-[7-(2-thienyl)-l
its Further -pyridinecarboxamide;
1 (
salts,
is R,3 1 1 optionally entirety.
R,3S)-3-amino-4-
S
hydronitrate, a
,5
S)-3 SYK-inhibitor 2-((
S 1
solvates,
hydrobromide, -yl-pyrimidine-4-yl)- examples
,6R)-7-chlor-5 hydrooxalate,
therefore 4- 2-((1
-amino-4-hydroxy- 1 R,
especially in
3
N-[7-(4- R,3
S)-3
racemic
or
,6-
of -phenyl- S)-3 are
-amino-4- hydrates.
preferred
-1,3- selected
-
- 2-[[7-
6-[[5-
2- those form,
3-
3-
2015247850 04 Jun 2019 Ν,Ν' N'-methyl- biphenyl] pyridinylmethyl)-l,6-naphthyridine-5-amine; propanediamine; propanediamine; biphenyl]-4-yl)-l,6-naphthyridine-l,3-propanediamine; propanediamine; propanediamine; naphthyridine-5-yl] yl]-N-methyl- naphthyridine-5 methylethyl)phenyl]-l,6-naphthyridine-5-yl]-l,3-propanediamine; naphthyridine-5-yl] naphthyridine-5yl] naphthyridine-5-yl]-l,3-propanediamine; yl naphthyridine-5-yl-l,3-propanediamine; (diethylamino)phenyl] (dimethylamino)-3-methoxyphenyl] (diethylamino)phenyl] (dimethylamino)phenyl]- 5-yl]-2,2-dimethyl- (dimethylamino)phenyl]- (dimethylamino)phenyl] (dimethylamino)phenyl] (dimethylamino)phenyl] (dimethylamino)phenyl]-N-methyl- 5-yl]-l,3-propanediamine; 5-yl]-l,3-propane-diamine; (4-chlorophenyl)-l,6-naphthyridine-5-yl]-l,3-propanediamine; fluorophenyl)-l,6-naphthyridine-5-yl]-l,3-propanediamine; 5-yl] [4-(methylthio)phenyl] l,6-naphthyridine-7-yl]-N,N-dimethyl-benzenamine; ]-1,3 -dimethyl-1 -1
-propanediamine; ,2-ethanediamine; -3 1 -yl] ,3-propanediamine; 1 -1 ,3-propanediamine;
-yl] ,3-propanediamine;
N-[7-(4-methylphenyl)-l,6-naphthyridine-5-yl]-l,3-propanediamine; N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]- N-[7-(4-fluorophenyl)- N-(7-phenyl-l,6-naphthyridine-5-yl)-l,3-propanediamine; ,6-naphthyridine-5-yl] -1
amino] -1 1 amino]-2-propanole; ,3-propanediamine; ,3-propanediamine; ,3-propanediamine; -3 -1 -1
-1 -1 -Ν,Ν -methyl- ,6-naphthyridine-5-yl]
N-[7-(4-methoxyphenyl)-3 ,6-naphthyridine-5-yl] N-[7-(4-methoxyphenyl)-2-(trifluoromethyl)- 1 1
,6-naphthyridine-5-amine; ,6-naphthyridine-5-yl]oxy]- ,6-naphthyridine-5 ,6-naphthyridine-5 -1 N-[7-(4-bromophenyl)-l,6-naphthyridine-5-yl]-l,3-
N-[7-[4-(4-morpholinyl)phenyl]-l,6-naphthyridine-5-yl]-l,3-
-butanole; -dimethyl-1
N-[7-[4-(dimethylamino)phenyl] 1 ,6-naphthyridine-5-yl]
N-[7-[4-(dimethylamino)phenyl]
1 -1 1 ,6-naphthyridine-5-amine;
-amino-3 ,6-naphthyridine-5-yl]
N-[7- -1
1 7- N-[7-[4-(dimethylamino)phenyl]- N-[7-(4-fluorophenyl)- N-[7-[4-(dimethylamino)phenyl]-l,6-naphthyridine-
,6-naphthyridine-5 N-[7-[4-(diethylamino)phenyl] N-[7-[3-(trifluoromethoxy)phenyl]-l ,6-naphthyridine-5-yl] ,3-propanediamine; [4-(dimethylamino)phenyl]-N-(3
[4-(dimethylamino)phenyl] -yl] -yl] N-[(2-aminophenyl)methyl]-7-[4-
-1 - -1 78
[
-1,5 [7-[4-(dimethylamino)phenyl] -1 ,3-propanediamine; ,3-propanediamine; ,4-butanediamine;
-phenyl-
-pentanediamine;
N-[7-[6-(dimethylamino)[ 4-[[7-[4-(dimethylamino)phenyl]-l,6- 1
-propanole; N-[7-[4-(dimethylamino)phenyl]-l,6- -1 ,3-propanediamine;
-amine; N-[7-(3-chlorophenyl)-l -1 1
,6-naphthyridine-5 N- ,3-propanediamine;
N-[7-(4'-methyl[l,l'- 7-[4- -1 1 [7-[3 -1 ,6-naphthyridine-5-yl] ,3-propanediamine;
7-[4- ,6-naphthyridine-5-yl]
4-[5-(4-aminobutoxy)- N-[7-
-1
N-[7- -chloro-4- N- N-[7-
,6-naphthyridine-5-yl] 3 1
-
,6-naphthyridine-5- [7- -1
-1 [
[7- [4- ,6-naphthyridine-5 [4- 1 ,6-naphthyridine- 1
[4-( [4-
- ,6-naphthyridine- ,6-naphthyridine- N-[7-(3-
[4-
,6-
N-[7-(3 -1,6- 1
1,1'-
- -yl]
N-
-1,3-
,6-
[7-[4- N-
'- N-[7-
-1,3-
[7-
-
-
-
2015247850 04 Jun 2019 N- pyridinyl)phenyl]-l,6-naphthyridine-5-yl]-l,3-propanediamine; benzodioxol-5-yl)phenyl] propanole; propanole; propanole; propanole; propanediamine; naphthyridine-5-yl] thienyl)phenyl] naphthyridine-5 naphthyridine-7-yl] naphthyridine-5-yl]-l,3-propanediamine; methoxyphenyl)- (trifluoromethyl)phenyl] aminopropyl)amino] amine; amine; 3-pyrrolidinole; (dimethylamino)phenylj- (dimethylamino)phenyl]-N-4-pyrimidinyl-l,6-naphthyridine-5-amine; (dimethylamino)phenyl] (dimethylamino)phenyl]- (4'-methoxy[l 5-yl]-l,3-propanediamine; aminopropyl)-7-(4-methoxyphenyl)-N2-(phenylmethyl)-2,5-diamine; (phenylmethoxy)- aminopropyl)-7-(4-methoxyphenyl)-2,5-diamine; fluorofl [5-(l-piperazinyl)-l,6-naphthyridine-7-yl]-benzenamine; [7-(4'-fluoro[l,r-biphenyl]-4-yl)-l,6-naphthyridine-5-yl]-l,3-propanediamine; 1 1 1.6- 1
- ■ .6-
[3 [ [3 [7-[4-(dimethylamino)phenyl]
naphthyridine-5 naphthyridine-5-yl]-l,3-propanediamine; -[ '-
[7-[4-(dimethylamino)phenyl] [5-[(3
7- 1 ,
- l'-biphenyl]-3-yl)-l
[7-[4-(dimethylamino)phenyl] [4-(dimethylamino)phenyl]
1 1 1 1
-aminopropyl)amino] -amino-3
-amino-3 -amino-3 -amino-3 ,
l'-biphenyl]-4-yl)-l -1
-yl] 7-[4-(dimethylamino)phenyl]-N-(2-furanylmethyl)-
1 ,6-naphthyridine-5-yl] 1 1
,6-naphthyridine-5 -amino-3 ,6-naphthyridine-5
-4-piperidinole; -Ν,Ν -1
-yl]
-1
-
,3-propanediamine; -[ -[ -[
[
,6-naphthyridine-7-yl] [7-(4-bromophenyl)-
[7-(3 [7-(4'-methoxy [7-(2'-fluoro -1,3
-N-(3 -1 -dimethyl-benzeneamine; 1 1 -1
,6-naphthyridine-5-yl]- ,6-naphthyridine-5-yl]amino]-ethyl]thio]-ethanole; ,6-naphthyridine-5-yl] N-[7-(3,4-dimethylphenyl)-l,6-naphthyridine-5-yl]-l,3-
-propanediamine;
,6-naphthyridine-5-yl] -[
,4,5 ,6-naphthyridine-5-yl]-l
[7-(2-naphthalenyl)-
-methyl-5
-trimethoxyphenyl)- -1 -1
,6-naphthyridine-5-yl]-2,2-dimethyl-l
,6-naphthyridine-5-yl]amino] ,6-naphthyridine-7-yl]
[1,1 -1 1
-N-[3 - -yl]
-yl] [7-[4-(dimethylamino)phenyl] ,6-naphthyridine-5
[
1
’ -1 -1 -isoxazolyl)- -biphenyl]
, -1
1
-1 N-[7-(3,4,5-trimethoxyphenyl)-l,6-naphthyridine- 7-[4-(dimethylamino)phenyl]-N-(4- ,3-propanediamine; ,6-naphthyridine-5
’ -( -biphenyl] ,6-naphthyridine- ,6-naphthyridine- 1 1
,6-naphthyridine-5
[1,1 H-imidazole- N- N-[7-(6-methoxy-2-naphthalenyl)-l,6- 79
[7-(2'-fluoro
-1 ’
-biphenyl] 1 N-[7-(4-methoxyphenyl)-2-
-1 1
-4-yl)- ,3-cyclohexane 1 ,3-propanediamine; ,6-naphthyridine-5
- ,3-propanediamine; 1
1
[7-[4-(dimethylamino)phenyl] ,2-ethanediamine; -4-yl)- ,6-naphthyridine-5 ,6-naphthyridine-5
-yl] 1
4-[5-(2-methoxyethoxy)-l,6- [1,1 ,6-naphthyridine-5 1
-3 -yl)propyl] 1
1,3 am -yl]
[1,1 ,6-naphthyridine-5
1,3
’ N-[7-[4-fluoro-3 -yl] -biphenyl]
-propanediamine;
-yl] i
N-[7-(l,3-benzodioxol-5-yl)- -4-piperidine -propanediamine; no]
-2 ’ -biphenyl]
-acetamide;
diamine; -propanole;
amino]
propyl
-1 1
,6-naphthyridine-5-
-yl] N-[7-(2-naphthalenyl)-
,6-naphthyridine-5
N-[7-[4-
-1 N-[7-
N-[7-(4-
N-
-yl]
-3 -amine; ,3-propanediamine; ,6-naphthyridine-5
amino]
] -2 -yl]-acetamide; -2-pyrrolidinone; [7-
-4-yl)-
amino] N,N-dimethyl-4- -propanole;
[4-(3 -yl]
N-[7-[4-( carboxamide; [4-(2- 7-[4-
- 2-[
N-[4'-[5-[(3-
-yl]
-2- amino]
7- N,N'-bis(3
- [2-[ 1,6- N5
-2- [4- -1,6- amino]
-(3 [7-[4-
1,3-
-2-
N- -
-yl]
-2- N-
[7-
-
-
-
2015247850 04 Jun 2019 butanediamine; piperidinyl)-l,6-nap- pyridinylmethyl)- hydroiodide, Preferred yl]- naphthyridine-5-yl]-l,4-cyclohexane-diamine; naphthyridine-5-yl] naphthyridine-5 naphthyridine-5-yl] naphthyridine-5-yl]-l,3-propanediamine; naphthyridine-5-yl]-l,3-propanediamine; naphthyridine-5-yl]-l,3-propanediamine; naphthyridine-5 yl]-l,4-cyclohexanediamine; naphthyridine-5-yl]oxy]- naphthyridine-5 naphthyridine-5-yl]-l naphthyridine-5 naphthyridine-5-yl]-l,2-cyclohexanediamine, naphthyridine-5-yl]methylamino]-propanenitrile; enantiomers, (dimethylamino)propyl] dimethyl-4-[5-(4-methyl-l-piperazinyl)-l,6-naphthyridine-7-yl]-benzenamine; (dimethylamino)ethyl]methylamino]phenyl]- cyclohexanediamine; (dimethylamino)propyl]methylamino]phenyl]-l,6-naphthyridine-5-yl]-l,4- (phenylmethyl)-4-piperidinyl]- [7 [7-[3 1 1 1 1 .6- .6- .6- .6-
-
[4-[
naphthyridine-5-yl]- naphthyr- naphthyridine-5 naphthyridine-5 amino]propyl]-carbamic -bromo-4-(4-morpholinyl)phenyl]
[2-(dimethylamino)ethyl]methylamino]phenyl]
salts
hydrosulfate, diastereomers,
idine-5-yl] are
-yl] -yl] -yl] -yl] or 1
selected [3 ,6-naphthyridine-5-amine;
-1 -1 -1 -1,3 -1,3 -1
-yl] -yl]
-[
hthyridine-5-amine; ,4-cyclohexanediamine; ,4-cyclohexanediamine; N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-l,6- ,3-propanediamine; ,3-propane-diamine; ,4-butanediamine;
[5
-1 -propan- -propanediamine; -1
methylamino]phenyl]
1 -[(3 -,3 1 ,2-cyclohexanediamine; ,4-cyclohexanediamine; ,2-benzene
-butanole;
hydrophosphate, from -propanediamine;
-aminopropyl)amino]
or acid- 7-[4-(dimethylamino)phenyl]-N-(2,2,6,6-tetramethyl-4-
1 as
,6-naphthyridine-5-amine; ediamine; the
pharmaceutically 1,1
group N-[7-[4-(dimethylamino)phenyl]- dimethanamine; -dimethylethyl -1
N-[7-
,6-naphthyridine-5-yl]
N-[7-[3-(trifluoromethyl)phenyl]-l N-[7-[4-[[3- N-[7-(3-bromo-4-methoxyphenyl)-l N-[7-[4-(trifluoromethyl)phenyl]-l 4-[
N-[7-[3-bromo-4-(dimethylamino)phenyl]-l,6-
N-[7-(3'-fluoro[ consisting N-
hydromethansulfonate,
[7-
1
N-
-1 [7-( 3-[ [3 N-[7- N-[7-[4-(dimethylamino)-3 (lR,2S)-rel-;
,6-naphthyridine-5-yl]oxy]-cyclohexanole; 4-[[7-[4-[[2-
80 [4-(dimethylamino)phenyl]
,6-naphthyridine-5 ',5 [7-(3
[7-[4-(dimethylamino)phenyl]
7-[4-(dimethylamino)phenyl]-N-[ 1 -7-(4-methoxyphenyl)- N- N-[7-[4-(4-morpholinyl)phenyl]
’
-bis(trifluoromethyl) -methyl-
acceptable [3
ester, [7-[4-(dimethylamino)phenyl]
'-methoxy
of N-[7-[4-(diethylamino)phenyl]- -1 -bromo-4-(4-morpholinyl)phenyl] ,6-naphthyridine-5 hydrochloride,
1 optionally
N-[7-[4-(dimethylamino)phenyl]- N-[7-[4-(dimethylamino)phenyl]-
1 ,
1 H-indole-5
'-biphenyl]-4-yl)-l
salts, -1 [
1 ,3-propane-diamine; ,
1 -yl]
’ hydronitrate,
-biphenyl]-4-yl)- solvates
in
oxy]
1
[1,1 hydrobromide, -yl)- racemic ,6-naphthyridine-5- 1
-methoxyphenyl] ,6-naphthyridine-2-
-yl]
-cyclohexanole;
-1,6-
’ -biphenyl] 1,6-
,6- ,6- or
,6- -1
-1,6- 4-[[7-[4-[[3-
hydrates. ,6- ,4- form,
-1,6-
-1,6-
1
-
1,6-
1,6-
N,N- -4-yl] as
-1,6-
N-
- N-
-
2015247850 04 Jun 2019 magnesium the the be comprising form comprising 75 from some example, from Compound Compound surfactant; and comprising medical mg hydrosuccinate, hydromaleate, concurrently compositions containing [0390] [0389] [0388] [0392] [0391] [0387] [0386] [0385]
employed mg
tablet disintegrant of Compound
of about a instances,
a
of bulking
Compound compound procedures.
And, In In It In One One These a the comprises
a about binder.
will
2. 1 a Compound a 1 some some some stearate.
binder;
. with,
tablet in
mg tablet, first further
aspect aspect
hydroacetate, in
agent,
pharmaceutical 2 combination also comprises the hydrobenzoate,
to 25 some
and embodiments, embodiments, embodiments,
agent
prior
of comprises In
bulking about 1, wherein mg, from a be
of of
comprise And,
one a Compound wetting some and
embodiments,
the the appreciated 1 disintegrant,
and to,
50
and
5 about
or
the
croscarmellose
in present present
or
mg mg,
agent instances,
a hydrocitrate, more the
therapies;
binder.
some second second from subsequent
agent,
a
of compositions
and 12 the the the tablet 100 filler;
1, comprises a
excipients
invention invention mg
examples, about that
lubricant. tablet tablet Compound first
hydro-p-toluenesulfonate. mg, a and
agent,
agent For
the
the lubricant,
comprises a to that
the
disintegrant;
agent
a
125
tablet about
to, example, hydrofumarate, 100 binder
sodium. comprises comprises lubricant.
pharmaceutical is, comprises
wherein
microcrystalline
provides one provides
selected
mg, are
mg the
the In further
81 36 comprises 2,
a
comprises or administered
a some
tablet to
150 binder, compositions or
mg spray
In the
more
about
the both. from from
or
from
some mg, comprises a a an
of first instances,
pharmaceutical pharmaceutical comprises a
first
dried a
amorphous other
hydrotartrate,
or
lubricant,
one about about 200 300
disintegrant.
In a compositions hydroxypropyl spray
examples,
any
filler; agent
cellulose.
this
or as dispersion mg, mg desired
can
25
combination 100 a
more oral
the dried
aspect,
first from of
comprises a 250
mg be or
disintegrant; mg form
lubricant a formulations
the
combinations
bulking excipients therapeutic administered
spray
to dispersion mg, composition composition hydrooxalate, about In
In to
of
the of
about tablet
of
other methylcellulose. some about
the
300 Compound
dried Compound pharmaceutical
thereof. an
25
comprises
agent.
invention
75 mg, comprises
examples,
amorphous
instances, mg 200
selected a
comprises
agents
dispersion mg
thereof. or to
mg
In For
of
400 about
1
2.
of can or
2015247850 04 Jun 2019 bulking tablet the the more wt% wt% disintegrant instances, first about croscarmellose about comprises about combination about about dispersion dispersion from [0398] [0397] [0396] [0395] [0394] [0393] [0402] [0401] [0400] [0399]
tablet second
agent.
to of about excipients 5 comprises 30
1 1 15
about the wt% wt% wt% agent,
wt% wt% In In In In In In In In In In
comprises
the
microcrystalline
comprises comprising
agent.
binder. 70
some some some some some some some some some some comprises
thereof. to to of
30
bulking
to to wt%
a
sodium.
about about a
selected disintegrant, from
wt% about about
lubricant. embodiments, embodiments, embodiments, embodiments, embodiments, embodiments, embodiments, embodiments, embodiments, embodiments,
In
to
from
from
20
For 10 of agent about
some about
Compound croscarmellose 50 60
the wt% wt% from
about example, wt% wt%
about cellulose.
comprises In examples, binder. 90 12
a
of of
a
some lubricant, of of mg
wt%
bulking 100 the the the the the the the the the the the a 70
the a 2 disintegrant.
to
the bulking
pharmaceutical pharmaceutical pharmaceutical pharmaceutical pharmaceutical pharmaceutical tablet tablet tablet wt% and second mg first examples, of
second
about
sodium.
microcrystalline the
pharmaceutical
Compound
to a agent,
agent. to a
binder.
comprises comprises comprises
binder about binder,
agent about agent. 36
agent.
a mg 82 the In
In
disintegrant,
300
comprises further
90
For some
or some of lubricant In
1 composition composition composition composition composition composition
one from from and wt%
mg
any a
some example,
composition disintegrant.
cellulose.
examples,
examples,
comprises of or from combination
of about about
instances, a more
hydroxypropyl comprises
Compound bulking a
about
lubricant,
the
30 150 further further further comprises further further excipients
In
the
the
second mg a further
In mg
10 other
second agent.
the
tablet thereof.
disintegrant
magnesium to
some wt%
comprises comprises comprises comprises comprises 2 to
a bulking
about
and
examples,
binder, spray about comprises
a methylcellulose.
selected
comprises
In spray to tablet. instances,
from
For
some about 85
dried
250 agent
or one from from less from dried mg comprises stearate.
example, about
from
the any mg 30 from
of or than
from
the
of
the a 10
2015247850 04 Jun 2019 before process pharmaceutical mixtures mechanical to tablets herein) therapeutic substances formulation ingredients Compound amorphous seem dry further any acceptable amorphous stable an correctors examples, additional stearate. about [0406] [0405] [0404] [0403] [0407]
be admixture
granulations combination
a to
1 three-dimensional
compression that simple, processing.
different mg causes be
Formulations In In thereof) Granulation The
described therapeutic the
excipients (neither critical.
comply 2 of Compound Compound agent to process, some some with
and or tablets
additional the about
the inexpensive
dosage
composition,
steps. from
thereof)
good is the in present embodiments, embodiments,
powder
with in
Dry another However,
into
contrast 5 which herein)
of
excipients
(e.g. and the agent the mg
stability as unit 2 1 the The
granulation
the tablets. therapeutic shape
can and
can form compositions described Compound
Compression of
to filler,
present
transfers
and forms CFTR order
demand (e.g., different
to a
be amorphous agglomerate
be for at
lubricant.
(e.g., of wet properties.
efficient
made
subject the solid least subjected diluent, Dry
example,
any aqueous and
of
potentiator
invention
granulation
herein
pharmaceutical
can energy agent of
all a
granulation from 2. one forms, of together the tablet).
mass
and
to shapes
improve
way the Compound disintegrant,
For
number
of
into dry is solutions, to may powder Compound
Dry
to formulations
additional
another the
variation including can instance, a
of
(e.g.,
the granulation
As prior larger dry
and 83 processes, be
granulation providing
excipients
be the
of
mixture of used
produced
granulation
or
sizes,
any produced composition
amorphous
to
2 the CFTR flowability solutions
particles
granules,
surfactant,
or and the
tablet 1 powders APIs herein,
. of
mixing
content and
whether
In
also or lubricant without close
the the
and corrector
can
other using described
wet compression
thus
by
having included CFTR based
process. "tablet" contemplated
under
amorphous Compound be comprising physical and
of
further uniformity. glidant, compacting high
examples, results coated one any
carried a
comprises
granulation
mixture on
potentiators (e.g.,
pressure a
shear herein).
use or
includes
size pharmaceutically
organic comprises The
contact binder, or in more
seem,
out
of any Compound
1 the uncoated. a suitable
granulation
the dry herein.
to or and any tablet
by
magnesium
to
of
mixing
active In
produce
compressed
compressing solutes,
steps additional surprisingly,
granulation between lubricant,
form a
amorphous described liquid the
some an
for
CFTR do
agents
a and land
or
not
the
or
2015247850 04 Jun 2019 Next, pharmaceutical binder, pharmaceutical based pharmaceutical herein. without Maschinen+Processengineering ingredients. into and composition coated granular compacted can can embodiment equipment contact crushed compacted, intensive compaction. Generally, [0411] [0410] [0409] [0408] [0413] [0412] lkp
be comprise amorphous to a
the tablet on
about lubricated with
a
between Next, any in
composition
Another In In Brief In In glidant, organic mechanical granules
a the is
or
between
some some some another a
having use
sieve
For comprising the
15 Minipactor® An
compaction/slugging film,
slugged all mechanical
Manufacturing
formulations composition formulation Compound
kP;
of
resulting the
example, example
of a solutes, with
embodiments, embodiments, embodiments,
aspect to
can any surfactant, colorant
a the embodiment, such
ingredients
two form
dissolution compacting
of
blends
a be
liquid intragranular
suitable the
an
of
counter as
or
further
core of
a process a
a
2 the
admixture particulate or
invention 1.5 of mixtures pharmaceutical
comprising Gerteis an
in and are substances
a Procedure
other
the or
invention
to
accordance alternative lubricant, can AG.
the tablet roller
lubricant,
of
milled lubricated rotating
tablet one of a
12.5 invention
requires
of
wet at
be
ingredients coating. one 3W-Polygran
ingredients
thereof),
or
the
least can
of
compaction compression obtained.
kP, matter.
has granulation
into
more an
or
(neither a provides powder
rollers a
be
composition for method
preferably
more about compaction with admixture a with, disintegrant,
composition
from granules
compressed compressive
excipients example, i.e.,
84 In are
the to
are
substances. in
An 50% for
admixture
an this
a from is
a for
make
weighed
process
the according
method invention.
sifted
dry admixture example, a example
and
in
of particulate dry in granulation
form such comprising
magnesium
Gerteis
the
granulation and powders
selected comprising about a
on
sifted
strength granulation and solid
is
range
for and according suitable as of compressing
In
performed
to of magnesium
mixed
30 the
Optionally
aqueous of producing
to
some sheet
sized
the roller
matter,
from:
is
of powdered
minutes.
process obtain
in one
amorphous
stearate. pressed,
invention process.
2 an
punches
well. the
that embodiments,
ingredients. is
to
compaction to provided
a admixture
solutions,
slugging.
to a range the filler, the 10
the
is a the stearate. close comprising yield
The
pharmaceutical
kP.
subsequently and that
desired formula The
composition into In tablets
can
Compound of a
ingredients
mechanical
a by liquid the is diluent,
next from typical various
occur of solutions
Next,
roller roller
Next,
a size.
a can set
highly
step about
the a be
the
1
2015247850 04 Jun 2019 provided binder ingredients a admixture Examples magnesium required the with more average ingredients glidant, Compound component of above each in or other accordance size granular a ingredients suitable ingredients a composition pm [0414] [0415]
diluent, diluent, disintegrant,
the more ingredients
powder
or
and
a
of
excipients coating.
Examples
and less, surfactant to
these
a
mill. diameter, colorants, then
Each size. composition
In sequentially granulate
surfactant, a and
below. comprises in
50 glidant, blend. is is added in are with 1 another stearate
comprising
the
and ingredients compressed
provided provided
a Next, any can of Next,
are pm
sifted
disintegrant).
selected
below.
the Examples the
or
amorphous
to measured be weighed Furthermore, suitable or
one
A
the
a
water
embodiment,
and water invention.
the extra ingredients
a
provided less,
a surfactant, and fluid of
or
diluent,
or powder
composition in in
admixture. the a In amorphous in
from: (and
mixed more
a a on with
45 disintegrant, granular may
manner. other
below. some any as
powder powder
invention by
suitable
pm Compound
per
Next,
any
a in
blend. a Optionally, a optionally flavors, light combination
the
of than a lubricant, in
binder
filler,
embodiments,
or any
the the
lubricant,
optional
a
this excipients
The
admixture form form less, Next,
of
the Compound
scattering, high
punches admixture water formula order. can Next,
amorphous a
for
exemplary and/or or ingredients sized
diluent, 40 2,
(e.g., (e.g.,
shear be
be the
water a example,
the
additives)
can and
pm
a disintegrant,
the of In removed
sifted
granules dried
can set disintegrant, into can one tablets provided provided
85 additions;
one
of also or the any or
comprises wet 1 with
a
herein.
be and
250 low Compound comprise binder, admixture less, various
or
for relative constituting granules
embodiment,
one be croscarmellose granules
added
more
a in can
amorphous
from
can shear pm sufficient used surfactant
or
or the as as
and Next,
be and,
a 35
pharmaceutical or be
more a particles particles and
fragrances
by
concentrations the
glidant, admixture
optional with
composition can granulator
coated
is less pm
a can further
1 blending the
a filler, admixture described all the
and
of optionally time
filler,
or the or
optionally (e.g., and Compound
ingredients of
the
admixture
with sodium. less)). having having a without amorphous
lubricant additives,
lubricated
wherein the
surfactant, to
a as
are
wherein excipients;
using 150 binder
(for
obtain
described a
intragranular
of
above
by also formulations (e.g.,
film,
For be a a
pm
amorphous be example surfactant
Next, mean mean
drying
water 2
or each
can milled
is
to
presented
milled such instance, the and
or with each Compound
colorant and wt%)
combination the a granulate
less, be
a
lubricant,
above correct of the diameter, or
one or
binder,
the last as, in
of
to a
these
using water of
and/or
the
filler,
100 these one in or
the
the
or and
2,
a
a
2015247850 04 Jun 2019 processed be minutes the water than water. water 2 by binder, and some 5.5 compressed dissolution compressed compressions. also formulated admixture filling lubricant, amorphous substantially a Compound measured pm is comprises or [0417] [0416]
surfactant, wt%,
provided
less,
accomplished light
kP, same
or 20
noted 2
instances,
by by
less, a wt%,
kP. In a 45 at less
scattering, form or
weight weight pressure In In surfactant,
by least some a into
a that of
pm
about
for 40 of Compound in disintegrant, 1, than another another using using composition
less a
free light
amorphous
(e.g.,
amorphous about a
lubricant,
or pm granular the encapsulation
about In
powder embodiments, the
of of
than
1 using 60% less,
of
another during a a
scattering, or wt%, application
of the the
a
admixture
embodiment, embodiment, die die water. 50% a
mold) less, 6
250 1 lubricant, 40
or
ingredient. ingredient.
kP,
a
1, press press wt%,
form.
form
less
a
and die Compound
more of each
pm
or
amorphous Compound example, or disintegrant, pm
at
Each with
amorphous
more
press
than 35 a
of or according to that less least (e.g.,
or
of The compression each is filler, at
produce 250 pm less, a
less the compressed
pressure
of about
the compressing than applies 0.75 disintegrant, at
or
about For granules
provided
of the
or the
about pm admixture
wherein
1, other or (e.g., admixture Compound 2
the
less)).
0.75 wt%,
instance,
amorphous and and 30 admixture
Compound 35 ingredients to
or a
7
sufficient
to ingredients
known
tablet 30 kP, minutes).
similar pm
less 150
a any wt%, or
can
the less as
to filler, each minutes
using
at
or and the
pm particles 86 and (e.g.,
produce combination
then comprises
admixture the hardness
than least
2, less)).
less methods
of apparatus.
of admixture
Compound or a wherein
comprises pressure applying 1, a
admixture
different
filler, powdered
be
For 150 these diluent,
less, comprises amorphous than 0.5 about (e.g.,
sized having a In
instance, pm
wt%, of
tablet
in 0.5 a wherein 100 in ingredients
another
about
each
to 10 composition at pressure
of:
or the into
the a pressures In and
less
wt%, 2,
comprises least form
pm glidant, kP, ingredients or
a less, a hardness
some
less
pharmaceutical
of and form
mean Compound
a
binder, 55% compressed less
than
the
or or example, tablet each
these
about or a
than
100 excipients
to less,
at tablet embodiments, admixture
than
is can
less or 5 a
diameter, during
admixture.
least
of
substantially
surfactant, wt%
pm a ingredients of a of is 5 more
5
50 be
or
composition glidant,
these than 0.25 wt%
accomplished kP amorphous between
having
the
2, or
repeated granules 15 pm
into (e.g., the
(at
at
a
less, can
0.25 wt%)
kP). admixture
(e.g., art.
is ingredients
diluent, measured
or about
least tablets
a
a
be less
a This less,
50 the diluent, is about wt%) It
In
free
of less using
can
first
is
about
pm 30 of than
45 can a
or
by
of
be
of 5
2015247850 04 Jun 2019 prepared until be the methods homogenous, 2, In tablets weight and 0.1 air Compound is of successive ingredients like formulations, shear in into a amorphous granular lubricant, liquid comprises described [0419] [0418] [0421] [0420]
glidant,
mixed
and the
the still
compressed pressure
selected microns
20 using a the
wet
Examples granular
ingredients ingredients,
one further comprises microns. of
admixture composition until for In In incorporating In In
a
the a herein granule
hand
providing or
additions,
diluent,
or Compound disintegrant, 1
some some another another suitable excipients and producing
more and
tablet.
for and it combinations instances,
form into
mixing,
has 50 below
can
In
example
amorphous about embodiments, embodiments, or compaction compressing
the
excipients
is
microns. a tablets another
embodiment, embodiment, a
to using
combinations
be an In
continuously surfactant,
substantially comprising substantially
admixture
produce described
a amorphous or 1, certain 20 admixture coated a
the and pharmaceutical
mixer, amorphous
alternatively,
a a as %w/w
embodiment,
tablet roller
of coated
a
Compound In described
selected process
filler;
with ingredients instances, or particles
another
the tablets a a
herein. comprising
amorphous
the the
compacting of lubricant,
compactor as
blender, of of throughout
Compound homogenous, homogenous
tablets
admixture about
solids
mixing
described
present a method ingredients, Compound
as from:
solid comprising compressed/compacted above
embodiment,
having composition
2 set the the
3.0
can are in by any
a the forms, forth a
amorphous
particles invention colorant Compound using for a
wt% disintegrant,
the
weight or the added binder,
be
is 1 herein, suitable, 87
combination
a admixture
composition.
and producing
and in 2, mixed
labeled or significant admixture in ingredient
of a a the e.g. and
any
the amorphous sequentially,
pharmaceutical dry compressing/compacting
of comprise
a the suspension a size
can
Examples comprises
film an
one glidant, by
conventional Examples the
Compound combination
granulation 1 with particle
be admixture until is and
and stirring,
a
colorant or
coating thereof, into
addition, particle between pharmaceutical made
a
more
amorphous
a providing
into
a the
logo,
Compound
filler;
a
or below. jet diluent, size
mixing below.
granular
blending,
using
admixture granules
solution
comprising
1, excipients, suspension or
composition
size milling composition
of
milling thereof. other 0.1 is after
amorphous
mixing the
powdered
between
Alternatively, fraction microns the an a can
Pharmaceutical
Compound
like. the
surfactant, image form.
2
admixture used
amorphous using
composition
granules apparatus shaking,
occur in
is The the the
addition
e.g.
a or addition substantially
When
0.1
between colorant as to as admixture or
Compound and admixture Then and/or solution. admixture a
between a
coat set high text.
microns
binder,
2 or
a
10
of
using
of forth the can
the to the
all by
2015247850 04 Jun 2019 useful pharmaceutical particle the method which Pharmacopeial together have microns. microns. dispersion contents and like. a strips (LDPE) containers liquid and according single Compound still [0424] [0423] [0422] [0427] [0426] [0425]
desiccant,
spray
the formulations another
a
composed These
chromatography dose the for particle
impurity size of
and with using
V. In In In The Tablets
dried
In In
treating
active to
treating or and
form,
1
various some some
polyethylene
embodiment, D50 still another package or
Test
pharmaceutical and amorphous spray
METHODS chemical closures size polypropylene dispersions Convention, arts.
of
substance another
levels
prepared
of in
amorphous for implementations, embodiments, 711
cystic
cystic
aluminum
D50
dried embodiments,
a about embodiment,
example, materials sterile "Dissolution"
(HPLC). are
of
or of
fibrosis.
embodiment
fibrosis Compound dispersions
(PE),
amorphous 5
high-density
as
physical conveniently or is
15
to Inc., OF fashion
above composition. released Compound
the
or
microns. and/or
about a can polyvinylidene
TREATING the tablet.
high-density
Rockville, pharmaceutical in
Accordingly, the an
be
the
can a sterilization invention in after
100
glass, 1 and
additional patient Compound particle amorphous
used from
United
and
patient polyethylene be
measured
2 microns. pharmaceutical appropriate
subjected have
amorphous
to glassine the Md.,
comprising
polyvinyl size store
includes CYSTIC
States
is dichloride
88 dosage
one therapeutic a
techniques
orally
compositions 2005
1 Compound
particle
is by
In and
the aspect
foil,
between Pharmacopoeia to
(HDPE),
sterilization still techniques
forms. Compound use ("USP"), various
in administered amorphous chloride
FIBROSIS
aluminum administering
compositions
(PVDC), vitro size another
of
of commonly agent(s)
the 1
packaging
The 1.0
low-density D50
pharmaceutical and of dissolution
to
(PVC), such present
microns
the
of embodiment,
content
2
determine Compound PVC/PE/PVDC, amorphous of pouches,
to can the 29, the
invention.
about as
employed form to described
package United be
optionally materials spray high invention
the and
of polyethylene
evaluations formulated
5 a
and active
patient
the
performance unitary to
5
dried 2 compositions Compound
amorphous States microns.
have
about
and blisters rate in above
such
provides including
substance
the
and
any
its
at or a
30
as
are
the
or of
In
2
a
2015247850 04 Jun 2019 provides provides pharmaceutical A455E, pharmaceutical pharmaceutical human human mutation 2A->C, >A, mutation in chloride implementations in 711+5G->A, 3121-1G->A, in described after, additional S1251N, S549N, S1251N, [0432] [0431] [0430] [0429] [0428] [0433] 1898+1G->T, 1G->A,
a a a
patient patient patient 621+1G->T,
or
CFTR CFTR
405+3A->C, S549R, 4OO5+1G->A, D579G,
concurrently
transport
a a And, In In In In E193K, E193K, selected selected
above.
therapeutic method method
comprising comprising comprising some one one one
3120G->A,
4374+lG->T, mutation mutation 4005+2T->C, A, some
compositions compositions composition
aspect, and aspect, aspect,
S1235R,
of
312O+1G->A, F1052V, F1052V, implementations, from from relative
of of
this
S
implementations
treating treating with 1716G/A, 125
agent Mutations
1812-1G->A,
administering administering administering G178R, G178R, the the the selected selected aspect,
181 IN.
S945L, to
the and G1069R, invention invention invention
that 385O-1G->A, and described baseline
l+1.6kbA->G, of of a a In spray
G1069R.
the CFTR-mediated CFTR-mediated
G551S, G551S, 1811+1G->C, from from the the
1898+1G->A, is 621+3A->G. another
R1070W,
absent method
the
invention invention
dried R117C,
provides provides 1525-1G->A, provides chloride to E193K, to to G178R, further
above.
additional
G970R, G970R, the the the
implementation
In
from dispersion 2789+5G->A,
produces
patient patient patient F1074L,
one 711+3A->G,
D110H,
comprise
wherein Fl052V, wherein
G551S, transport. a a a
1898+5G->T, 711+1G->T, the 89
method method method disease disease implementation G1244E, G1244E,
therapeutic
spray 712-1G->T, any any any
a or D110E, R347H,
G970R, the greater the
administering and
of the of of
wherein wherein
of of of
dried
3849+10kbC->T, of
S1255P, S1255P, 1898+3A->G, patient the the patient the
treating treating treating pharmaceutical
G1069R. this 2622+lG->A,
3850-3T->G,
D1270N, agent spray spray spray R352Q,
than dispersion G1244E,
1248+1G->A,
aspect, of the the
possesses possesses
G1349D, G1349D, 10-fold a a a this is
dried dried dried
patient patient
CFTR-mediated CFTR-mediated CFTR-mediated
to
administered In E56K,
D1152H,
aspect, the the
S1255P, some 1717-8G->A,
or dispersions dispersions dispersions
IVS14b+5G->A, 4O5+1G->A,
increase composition
3272-26A->G, patient invention
possesses possesses a a
the
S549N, S549N, P67L, human human
1341+1G->A, the
G1349D, 1717-1G-
invention an
before,
in L206W,
CFTR CFTR S549R, S549R,
or or or
disease disease disease a a 1342-
the the the 406-
2015247850 04 Jun 2019 pharmaceutical A455E, pharmaceutical pharmaceutical pharmaceutical AF508, 2A->C, >A, mutation >T, >T, 2622+1G-+A, mutation D579G, mutation in 711+5G->A, 3121-1G->A, in from another implementation 3849+10kbC->T, in greater implementation S1251N, [0435] [0434] [0436] 1717-1G->A, 1898+3A->G, 1898+1G->T, 1G->A,
a a a
patient patient 3850-3T->G, patient 1248+1G->A, 621+1G->T,
2789+5G->A
or
R117H, implementation 405+3A->C, 4005+1G-+A, D579G, S1235R,
In In In E193K, selected selected selected
equal
comprising comprising comprising one one one
3120G->A,
4374+1G-+T, 1811+1.6kbA->G, 4005+2T->C, 4O5+1G->A, 1717-8G->A,
compositions compositions compositions compositions
to aspect, aspect, aspect, of of and
S1235R,
312O+1G->A, F1052V, S945L, IVS14b+5G->A, 3272-26A->G,
from from from
this this 10% 1341+1G->A, and
G551D.
1716G/A,
aspect, aspect, 1812-1G->A, R117C, administering administering administering G178R, the the the 3272-26A->G. 1717-1G->A, above of
R1070W, 181 S945L,
this G1069R, invention invention invention
4O6-1G->A, 385O-1G->A, and
1342-2A->C, l+1.6kbA->G, of of of of
the the the
aspect,
DI G551S,
1811+1G->C,
the the the the 1898+1G->A,
621+3A->G, 2789+5G->A,
711+5G->A,
3121-1G->A, R1070W, baseline patient method
10H,
1898+1G->T, F1074L,
invention invention invention invention
R117C,
provides 1525-1G->A, provides provides 621+1G->T, to to to
the
G970R,
the the the R347H, 4OO5+1G->A,
possesses
produces patient 2789+5G->A, 405+3 chloride
patient patient patient F1074L,
711+3A->G, D110E, D110H,
wherein wherein wherein wherein
and a a a 1898+5G->T, 3120G->A,
711+1G->T,
90 4374+lG->T,
3272-26A->G,
method method method G1244E, R352Q, A->C,
possesses 4005+2T->C,
a
312O+1G->A,
712-1G->T, any any any
transport. a an human
D110E, D1270N, human R347H,
the the the the
increase
of of of
1812-1G->A, 1716G/A, of of of
E56K, 3849+10kbC->T,
1898+3A->G, S1255P, patient the patient patient the patient the
1811+1.6kbA->G, treating treating treating
CFTR a 2622+1G-+A,
CFTR 3850-3T->G,
D1270N, human spray spray spray R352Q, 385O-1G->A,
andD1152H. and
in 1248+1G->A, and P67L,
possesses possesses possesses possesses 1898+1G->A,
chloride
mutation
1811+1G->C,
G1349D, a a a 3849+10kbC->T.
mutation dried dried dried 621+3A->G.
CFTR-mediated CFTR-mediated CFTR-mediated CFTR
1525-1G->A,
E56K,
L206W, D1152H,
1717-8G->A,
dispersions dispersions dispersions
IVS14b+5G->A, 4O5+1G->A, transport
3272-26A->G,
mutation a a a a selected
2789+5G->A,
S549N,
selected P67L, human human human human
In 711+3A->G, 1341+1G->A,
A455E,
711+1G->T,
one
1898+5G- 1717-1G- In
712-1G-
L206W,
which from
CFTR CFTR CFTR CFTR one S549R,
selected or or or disease disease disease from
In 1342-
the the the 406-
still
is
2015247850 04 Jun 2019 pharmaceutical pharmaceutical 26A->G, mutation this human >T, >T, 2622+lG->A, mutation D579G, mutation F1052V Rl mutation aspect, 3849+10kbC->T, in aspect, CFTR in increase G551D. disease implementation selected of S1251N, S1251N, [0438] [0437] 10% 1811+1.6kbA->G, 1898+3A->G,
a a treating 17H,
3850-3T->G, patient patient aspect, 1248+1G->A,
above
mutation
the CFTR the
wherein
and from S1235R, and
in
In In In E193K, and selected selected selected selected and
a
patient method
chloride the comprising the comprising some
one one
CFTR-mediated G551D. G1069R,
a a
G178R, mutation
4O5+1G->A,
1717-8G->A,
patient baseline human human
compositions compositions aspect, aspect, of selected the
F1052V, implementations
S945E, 3272-26A->G, IVS14b+5G->A,
from from from from
possesses
this 2789+5G->A, 1341+1G->A, produces
patient transport
In
G551S, possesses and CFTR
CFTR
aspect,
administering Rl administering G178R, AF508, the the 1717-1G->A, selected
chloride
one
from R1070W,
17C,
a and invention invention possesses
4O6-1G->A, human a implementation an
1342-2A->C,
disease relative mutation mutation of of
human AF508, the
G970R,
G1069R, Rl
increase DI G551S,
from the the
transport. a 711+5G->A, 3121-1G->A,
3272-26A->G,
invention
17H, human
of 10H,
1898+1G->T, F1074E, CFTR invention invention
wherein
provides provides
to this 621+1G->T, a AF508, to to CFTR Rl
selected
G1244E, selected human
and baseline G970R,
the the R347H, in
4OO5+1G->A, and
17H, aspect, CFTR
405+3 mutation chloride
patient patient
G551D. provides
mutation
of D110E, a
Rl the
wherein wherein
a a and CFTR 3120G->A, human
91 this 4374+lG->T, from
from
method method
G1244E, S1255P, R352Q, mutation 17H, chloride A->C, and the patient 4005+2T->C,
312O+1G->A, G551D.
any any
transport aspect,
selected
method
AF508, AF508, In 3849+10kbC->T, D1270N,
a mutation
selected and CFTR
the the
method
of of
1812-1G->A, still
1716G/A, of of
possesses
E56K,
G1349D,
transport.
S1255P, patient the patient the G551D. selected
treating 181 treating the
In
another
from produces Rl mutation Rl
which spray spray
385O-1G->A,
from l+1.6kbA->G, one invention selected andD1152H, of
17H, and P67E, 17H.
possesses possesses
1898+1G->A,
treating
AF508,
1811+1G->C, from implementation a G1349D, a a
In S549N,
dried dried is 2789+5G->A
621+3A->G, implementation
human CFTR-mediated CFTR-mediated and
1525-1G->A,
one greater
selected a E206W,
and from
greater 1717-1G->A, provides
G551D.
dispersions dispersions a Rl implementation
a
S549R, a CFTR a
2789+5G->A, CFTR
S549N,
E193K,
human and 17H, human human or 711+3A->G,
from
A455E, than
711+1G->T,
equal
1898+5G-
a
and
a and
and mediated In mutation human
of and method 712-1G-
AF508, of CFTR
CFTR 10-fold CFTR S549R,
or another or
disease disease this a
3272- to
this
the the
of
2015247850 04 Jun 2019 pharmaceutical pharmaceutical pharmaceutical pharmaceutical transport DI L206W, human method human human >T, >A, D1152H, P67L, human in in chloride selected implementation G551S, aspect, in 3849+10kbC->T, in S549N, S549N, [0440] [0439] [0442] [0441] 1248+1G-+A, 1898+3
a a a a
152H.
3850-3T-+G, patient patient patient patient 405+1G-+A,
L206W,
CFTR CFTR the CFTR CFTR
A->G,
produces
G970R, S549R, S549R, from A455E, transport.
In In In In which 1717-1G-+A,
In
patient
comprising comprising comprising comprising one one one one
one
E193K, mutation mutation mutations mutations
1717-8G-+A, 1341+1G-+A,
A455E,
compositions compositions compositions compositions is aspect, aspect, aspect, aspect, of S S1251N,
G1244E,
D579G,
implementation a
125 406-1G-+A, IVS14b+5G->A, 3272-26A->G, possesses greater
this greater
IN,
Fl
aspect, administering administering administering administering the the the the selected D579G, selected 621+1G->T,
selected selected
052V,
E193K, E193K, S1235R, or S1255P,
than invention invention invention invention
equal one
1342-2A->C, 3121-1G-+A, of of of of
the 4005+1G-+A,
and
10-fold
from the the the the from S1235R,
or
from from 711+5G->A,
of Fl F1052V,
patient
to
S945L, G1349D,
more 1898+1
G1069R. invention invention invention invention
this
052V,
312O+1G->A,
provides provides provides provides 10% to to to AF508, to G178R,
RI G178R,
increase the the the the aspect,
human
possesses
S945L, 17C,
above
405+3 R1070W, G->T, G1069R,
and 4374+1G-+T, patient patient patient patient
S549N,
RI 1812-1G-+A,
wherein wherein wherein wherein G551S, In
a a a a 3120G->A,
DI
G551S, 92 G1069R.
the
method method method method
in
CFTR 17H, the some A->C,
R1070W,
4005+2T-+C, 10H,
chloride any any any any method one
1898+1G->A,
baseline R117C, F1074L, S549R,
and
G970R,
the the the the
implementations
G970R, mutations R347H, of of of of
or 1716G/A,
of of of of
In
385O-1G->A,
the patient the patient the patient the patient G551D.
more
treating 1811+1.6kbA->G, treating treating treating
produces F1074L, 1525-1G->A,
transport
one
and D110H,
chloride spray spray spray spray
D110E, G1244E,
G1244E,
R352Q, and human
implementation
S1251N. possesses possesses possesses possesses
selected 711+1G-+T,
1811+1G-+C, a a a a
dried dried dried dried
621+3A-+G,
D110E, CFTR-mediated CFTR-mediated CFTR-mediated CFTR-mediated an relative
R347H, transport. D1270N,
CFTR 2789+5G->A, of increase S1255P, E56K,
S1255P, dispersions 712-1G-+T, dispersions dispersions dispersions
from this
In one one one one
D1270N,
to 711+3A->G, another
R352Q,
mutations
aspect,
P67L, 2622+ baseline G178R, or or or or
and
of
in 1898+5G- G1349D,
and
G1349D, more more more more
this chloride
or or or or
disease disease disease disease
a
1G- the E56K,
the the the the
2015247850 04 Jun 2019 pharmaceutical pharmaceutical this the mutations human human >T, >A, D1152H, P67L, human more mutations >G. >C, 2789+5G->A, >A, human CFTR G970R, in CFTR 3849+10kbC->T, in 3849+10kbC->T. 711+3A->G, S549N, S549N, [0443] [0444] 1248+1G-+A, 1G->A, 1898+3
a a
patient
3850-3T->G, patient patient aspect, 4O5+1G->A, 711+1G-+T, 1898+5G->T, In human
L206W,
mutations mutations
CFTR CFTR CFTR CFTR
A->G, one S549R, S549R, 712-1G-+T, G1244E,
In In
1717-1G-+A,
selected selected
possesses
the comprising comprising implementation one one
CFTR
1898+3A->G,
mutation mutation mutations mutations
3849+10kbC->T, 1717-8G-+A, 1341+1G-+A,
patient A455E,
compositions compositions aspect, aspect, S1251N, S
selected selected 2622+1G-+A, 125 406-1G-+A,
IVS14b+5G->A, 3272-26A-+G, S1255P,
In 3850-3T->G, from from
mutations
1248+1G->A,
one still IN,
possesses
administering administering the the selected D579G, selected
621+1G->T,
AF508, selected selected 1717-1G->A,
or E193K, E193K, another from from
G1349D, invention invention
more of 1717-8G-+A,
1342-2 3121-1G-+A, of of
selected
4005+1G-+A, this AF508, AF508,
4O5+1G->A, the from from the Rl S1235R, IVS14b+5G->A,
3272-26A->G, one
from from 71 implementation human F1052V, Fl052V,
aspect,
17H, 1898+1 1341+1G-+A, A->C,
1+5G-+A, invention invention
S549N, 312O+1G->A, or provides provides to AF508, to G178R,
G178R, 181 1717-1G->A, from
Rl R117H,
more
the the
and CFTR
S945L,
17H, 1342-2A->C,
l+1.6kbA->G, the
405+3 G->T, G1069R,
and 4374+1G-+T,
patient patient
2789+5G->A
S549R, G55
human
Rl 1812-1G-+A, 4O6-1G->A,
wherein wherein patient G551S,
a a 3120G-+A,
G551S,
93
G1069R,
and and mutations 711+5G->A, method method
17H, A->C,
R1070W,
ID. 4005+2T-+C, of 1898+1G->T, 3121-1G-+A,
any any G551D. G551D. 1898+1G->A,
this
R117C, 621+1G->T, CFTR
and
possesses
and In G970R,
the the
G970R,
of of
405+3A->C, 1716G/A, of of
aspect, one and S1251N, 2789+5G->A,
3850-1G-+A,
patient the patient the G551D, and 4OO5+1G->A, selected
treating treating 1811+1.6kbA->G,
mutations F1074L, 1525-1G-+A,
In implementation D110H,
one 3120G->A, spray spray
3272-26A->G. G1244E,
one another G1244E, and the 4374+lG->T, 4005+2T->C,
or possesses possesses
312O+1G->A,
711+1G-+T,
and 1811+1G-+C, and from
a a
patient dried dried or
more
621+3A-+G,
D110E, CFTR-mediated CFTR-mediated
R347H, 1716G/A,
selected
more one one
implementation
2789+5G-+A, 3272-26A->G, S1255P,
G178R,
S1255P, 1812-1G-+A, dispersions dispersions 712-1G-+T, 1811+1.6kbA->G, human
or
possesses or
one one human
D1270N,
of more 71
more
R352Q,
and 385O-1G->A, from
2622+
this or or 1811+1G-
1+3A-+G,
1898+1G- G551S, 1898+5G- G1349D, CFTR
and
G1349D,
more more 621+3A-
human
human CFTR E193K, aspect,
or one or disease disease
a
1G- E56K,
1525-
and
of the the
or
2015247850 04 Jun 2019 pharmaceutical pharmaceutical R1066H, human human >G, >C, 2789+5G->A, >A, human transport DI L206W, human than RI F1052V, CFTR or disease G551D. 3849+10kbC->T, selected one 711+3A->G, in G551D. in [0446] [0445] [0447] 1G->A,
a a the
17H, 152H,
patient patient implementation and 711+1G->T, 1898+5G->T, 10-fold
pharmaceutical
mutation
CFTR CFTR CFTR CFTR
in
712-1G->T, and
from one A455E,
In In In In In which and
T338I, and a
comprising comprising still one one one patient another
G551D. or increase
G1069R,
1898+3A->G,
one mutations mutations mutations mutations 1717-1G->A, 3849+10kbC->T,
more
compositions compositions implementation is aspect, aspect, another
selected
R334W, D579G,
2622+lG->A,
and or greater 3850-3T->G,
comprising
aspect,
of
more 1248+1G->A, human
in In one compositions
this and
administering administering the the
chloride
implementation some selected selected selected selected
from
S1235R, G85E, or or human
invention aspect, invention
one the
1717-8G->A, 1811+1.6kbA->G, equal CFTR
more
of of
R74W, implementations
invention administering
or
4O5+1G->A, the of the IVS14b+5G->A,
3272-26A->G, transport A46D, from from from from
CFTR
more to human the
this S945L,
mutations 1341+1G->A, invention invention of
provides provides
10% to to
R668C, patient
RI 2789+5G->A the AF508, 1717-1G->A, aspect,
human
the the I336K, of
mutations provides
17C,
CFTR relative above invention 1342-2A->C, R1070W,
this
patient patient
to
4O6-1G->A, possesses
selected wherein wherein
S977F, a a RI the
DI
2789+5G->A, 94
aspect, CFTR of H1054D, 711+5G->A, the method method
the mutations
17H,
this 1898+1G->T, 10H, 3121-1G->A, method to a
selected any any
patient
method
wherein baseline and 621+1G->T, baseline F1074L,
L997F, mutations
aspect, from the the
the
and
R347H, of of
one 405+3A->C, of of
3272-26A->G,
M1V,
patient the patient the produces patient
4OO5+1G->A,
treating treating any
G551D.
selected from AF508, of or
the
chloride 3120G->A, chloride the spray spray 3272-26A->G, K1060T, D110E,
treating more
of
R352Q,
E92K, 4374+lG->T, 4005+2T->C, patient
selected
AF508, method possesses possesses
possesses the 312O+1G->A,
a a
RI dried dried
an from
human
CFTR-mediated CFTR-mediated
spray 1716G/A,
transport.
D1270N,
transport.
increase 17H, a V520F,
A1067T,
possesses
and E56K,
CFTR-mediated
RI from 1812-1G->A, AF508, produces dispersions dispersions 1811+1.6kbA->G,
dried one one
CFTR one and 17H,
one and
and 385O-1G->A, AF508,
H1085R, P67L,
in
or or 1811+1G- and or G551D.
or 1898+1G- R1070Q, RI dispersions
and
a chloride
more more mutations 621+3A- more a
more
human
17H,
greater
or or disease disease
1525-
the the
In and
2015247850 04 Jun 2019 A1067T, A561E, V520F, A1067T, possesses A561E, the R560T, R1066H, mutation R74W, mutation L1065P, R560S, R334W, R560T, one disease CFTR from from T338I, S492F, S977F, [0452] [0451] [0450] [0449] [0448] [0454] [0453]
pharmaceutical or
R1066H, AF508,
mutation more
R334W,
L467P, L997F, R668C, in N1303K, H1085R, L927P, L927P, A559T, A559T,
G85E, Y569D, In In In In In In In
selected selected R1070Q, R1070Q, T338I, a a
human
one one one one patient a a another
human
R117H, further further
T338I,
K1060T, R347P,
R560S, A46D, R560S, S977F,
implementation, implementation, implementation, implementation, I336K, selected S492F, S492F,
R334W,
A561E, R560T, Ml from from
R1066H, R1066H, CFTR
compositions comprising CFTR aspect,
implementation, implementation, 101K,
and R334W,
I336K, AF508, AF508,
and L997F, H1054D, N1303K, N1303K,
L467P, L467P, from A1067T,
A559T, G85E, L927P, G551D. mutation
mutations
the S341P. L1077P,
T338I, T338I,
AF508,
H1054D, invention administering R117H, R117H, I336K, K1060T, R347P, R347P,
A46D, the the the the
of
M1V, Ml R560S, Ml
S492F, and
selected
the R334W, R334W,
patient patient human human
R1066M,
selected
101K, 101K, the the
R117H, R1070Q. H1054D,
invention and and
E92K, and and I336K,
M1V,
A1067T,
includes patient human N1303K, L467P,
possesses possesses L1077P, L1077P, G551D. G551D. CFTR CFTR from
S341P. S341P,
G85E, G85E,
to
from
and
R1066C, E92K, and 95
H1054D,
a
M1V, possesses
CFTR
R74W, wherein patient R347P,
a
and
mutation mutation G551D.
R74W, L927P.
Ml method A46D, A46D, and
R1066M, R1066M,
V520F, a a
R1070Q,
E92K,
101K,
mutation human human
a
L1065P,
any R668C,
M1V, and human the
R668C, a
I336K, I336K,
In of
is is
human
of
patient L1077P,
S341P,
H1085R, and
another treating selected selected
R1066C, R1066C, CFTR CFTR
the E92K, and
is CFTR S977F, Y569D,
L927P,
H1054D, H1054D, S977F, selected
spray
CFTR
a
possesses
and
mutation mutation
human
aspect, a R1066M, V520F, from from
R560T,
mutation CFTR-mediated
L1065P, L1065P,
L997F,
dried a A561E,
and
mutation
L997F,
human
from R1066H, R74W, M1V, M1V,
CFTR
the
a
H1085R,
possessing dispersions selected selected L927P, human
R1066C,
K1060T, R1066H, patient selected Y569D, Y569D,
A559T,
K1060T, CFTR E92K, E92K,
R668C, selected
T338I,
from from
or
2015247850 04 Jun 2019 pharmaceutical Y569D, V520F, A1067T, Y569D, V520F, mutations mutations H1085R, more L1065P, more mutations H1085R, L1065P, in and selected selected CFTR or disease selected selected [0459] [0458] [0457] [0456] [0455] [0462] [0461] [0460]
a the
patient one
human human
pharmaceutical
mutations
in
H1085R, H1085R,
or A561E, A561E, from from from from
Y569D, Y569D, In In In In In In In In R1070Q, R560T, R560T,
a selected selected selected
more
comprising one one patient one one another a one a
CFTR CFTR
further further R74W, R1066H, R74W, R1066H,
compositions
implementation, aspect, implementation, implementation, implementation,
A559T, A559T, human
selected A561E, A561E, R560T, R560T, L927P, L927P,
from from from R1066H,
comprising mutations mutations aspect,
implementation, implementation,
R668C, R668C, compositions
administering
the T338I, T338I,
CFTR
R1066H, R1066H, AF508,
S492F, S492F, R560S, R560S, from A559T, A559T, L927P, L927P,
invention the
T338I,
of S977F, S977F,
selected selected
R334W, R334W, mutations invention administering AF508,
the RI L467P, L467P,
the the the
the
N1303K, N1303K, R560S, R560S, T338I, T338I, S492F, S492F,
17H,
invention of R334W, patient patient patient patient
includes to L997F, L997F, the the
the from from R117H,
G85E, G85E, the
R347P, R347P,
and
includes
R334W, R334W, patient selected patient N1303K, N1303K, L467P, L467P, invention
Ml Ml
patient possesses possesses possesses possesses
R74W,
AF508,
G55 G85E,
to
K1060T, K1060T, wherein
a
A46D, A46D, 101K, 101K, 96
and method
the
and and possesses possesses
ID.
R347P, R347P, a from I336K, I336K,
any
patient Ml Ml
method G551D. A46D, R668C,
wherein RI
S341P. S341P,
L1077P, L1077P,
one one one one I336K, I336K,
the
A1067T, A1067T, 101K, 101K,
17H, of AF508, of
and and H1054D, H1054D, patient the
or or or or treating any one one
I336K,
of
S977F,
and and the more more more
more
L1077P, L1077P, H1054D, spray H1054D,
S341P. S341P,
treating
R1066M, R1066M, of or or RI
patient and and one G551D.
possesses the more more
17H, human human human human a
H1054D,
M1V, M1V, dried
L997F,
CFTR-mediated R1070Q. R1070Q,
or spray and
a R1066M, R1066M,
human Ml human M1V, more
and possesses
CFTR-mediated R1066C, R1066C,
dispersions one CFTR CFTR CFTR CFTR E92K, E92K,
V,
dried a K1060T, G551D.
M1V,
human human
E92K, E92K, or
and CFTR CFTR
more mutations mutations mutations R1066C, mutations R1066C, and and dispersions
one L1065P, L1065P,
one E92K,
CFTR CFTR V520F, V520F,
or disease L927P. L927P,
or human or
the
2015247850 04 Jun 2019 A561E, A561E, A559T, R560T, R1066H, mutation R74W, R560T, R1066H, R560S, R334W, L927P, mutation CFTR from from from CFTR or disease T338I, T338I, S492F, S977F, [0466] [0465] [0464] [0463] [0469] [0468] [0467]
the
R1066H, AF508, AF508,
pharmaceutical
mutation mutation
R334W, R334W,
L997F, E467P, R668C, in R560S, N1303K, E927P, E927P, A559T, A559T, S492F,
G85E, In In In In In In In selected selected T338I, T338I, a
one one patient one one another a a
R117H, R117H, further further
T338I,
R347P, K1060T,
N1303K,
R560S, A46D, R560S, L467P, S977F,
implementation, implementation, implementation, implementation, I336K, selected G85E, selected S492F, S492F, R334W, R334W,
Ml from from
comprising aspect,
implementation, implementation,
101K,
and and compositions R334W,
A46D,
I336K, R74W, AF508,
and E997F, H1054D, R347P, N1303K, N1303K,
E467P, E467P,
from from A1067T,
Ml G85E, G85E, G551D. G551D.
the S341P. E1077P,
101K,
AF508, R74W,
I336K,
H1054D,
invention administering R668C, RI
I336K, K1060T, and R347P, R347P,
A46D, A46D, the the the the
M1V, Ml Ml
17H, and
L1077P,
of S341P.
patient patient human human
R1066M,
101K, 101K, the the R668C, H1054D, RI
the R1070Q. H1054D,
S977F, and
E92K, and and I336K, I336K,
M1V,
A1067T, includes 17H, patient human
invention
possesses possesses E1077P, G551D. E1077P, CFTR CFTR
S341P, S341P,
R1066M, to
S977F,
and
R1066C, E92K, and 97 L997F,
H1054D, H1054D, M1V,
the
M1V, possesses CFTR
a
and
mutation mutation G551D.
E927P. patient
method and and wherein
R1066M, R1066M,
E997F, V520F, a a
E92K,
R1070Q, R1066C, K1060T,
E92K,
mutation human human
a a E1065P,
M1V, M1V, human human
any a
of
is is
human the
V520F,
K1060T,
H1085R, and
treating selected selected
R1066C, R1066C, of CFTR CFTR
E92K, E92K, A1067T, and patient L1065P,
is CFTR CFTR
Y569D,
the E927P,
selected
CFTR a
spray H1085R,
mutation mutation human
a V520F, V520F, from from
A1067T,
possesses R560T,
mutation mutation CFTR-mediated E1065P, E1065P,
Y569D, R1070Q, A561E, and
mutation
dried
from R1066H, R74W,
CFTR
a
H1085R, H1085R, R560T,
selected selected E927P, human
R1070Q,
dispersions
R1066H, selected selected Y569D, Y569D,
A561E, a A559T,
R1066H, human
R668C, selected
T338I,
from from
2015247850 04 Jun 2019 Y569D, V520F, A1067T, Y569D, V520F, A1067T, mutations H1085R, more L1065P, more mutations H1085R, L1065P, more selected selected CFTR or disease selected selected or disease [0474] [0473] [0472] [0471] [0470] [0476] [0475]
the the
human human human
pharmaceutical pharmaceutical
mutations
in in
H1085R, H1085R,
A561E, A561E, from from from from
Y569D, Y569D, In In In In In In In R1070Q, R1070Q, R560T, R560T,
a a selected selected
patient one patient one another another one another one
CFTR CFTR CFTR
R74W, R1066H, R74W, R1066H,
implementation, implementation, implementation, implementation,
A559T, A559T,
selected A561E, A561E, R560T, R560T, L927P, L927P,
from from R1066H, R1066H,
comprising comprising mutations mutations mutations aspect, implementation, aspect,
R668C, R668C, compositions compositions
T338I, T338I,
R1066H, AF508,
S492F, S492F, R560S, R560S, from A559T, A559T, L927P, L927P,
the the
T338I, T338I,
S977F, S977F,
selected selected selected
R334W, R334W, invention invention administering administering AF508,
RI L467P, L467P,
the the the the
N1303K, N1303K, R560S, R560S, T338I, S492F, S492F,
17H,
of of R334W, R334W, patient patient patient patient the
L997F, L997F,
the the from from from R117H,
G85E, G85E, patient
R347P, R347P, and
includes includes R334W, N1303K, N1303K, L467P, L467P, invention invention
Ml Ml
possesses possesses possesses possesses
R74W, R74W, AF508,
G55 G85E, G85E, to to K1060T, K1060T,
A46D, A46D, 101K, 101K, 98
and possesses
the the and and
ID.
R347P, R347P, a a I336K,
Ml patient Ml patient
method method G551D. A46D, A46D, R668C, R668C,
wherein RI wherein
S341P. S341P,
L1077P, L1077P, one one one one I336K, I336K,
A1067T, A1067T, 101K, 101K, 17H,
and and H1054D, one or or or or
any any
I336K, I336K,
of of
S977F, S977F, and and the the more more more more
L1077P, L1077P, H1054D, H1054D,
S341P. S341P,
or treating treating
R1066M, R1066M, of of
patient patient and and one more G551D.
the the
human human human human H1054D, H1054D,
M1V, L997F, L997F,
R1070Q. R1070Q,
or spray spray and
human a a R1066M, R1066M,
Ml M1V, more
possesses possesses
CFTR-mediated CFTR-mediated R1066C, R1066C,
one CFTR CFTR CFTR CFTR E92K,
V,
dried dried K1060T, K1060T,
M1V, M1V,
human
CFTR E92K, E92K, or and
more mutations mutations mutations mutations R1066C, R1066C, and dispersions dispersions
one one L1065P, L1065P,
one E92K, E92K,
CFTR V520F, V520F, L927P.
or or human or
2015247850 04 Jun 2019 A561E, A559T, pharmaceutical R560T, R1066H, mutation R74W, R560T, R1066H, R560S, R334W, L927P, mutation mutations from CFTR or disease T338I, T338I, in and S492F, S977F, [0482] [0481] [0480] [0479] [0478] [0477] [0484] [0483]
a the
patient one
AF508,
pharmaceutical
mutation
R334W, R334W,
L467P, L997F, R668C, in R560S, N1303K, L927P, L927P, A559T, S492F, or
G85E, In In In In In In In In selected selected T338I, T338I, a selected
more
comprising one patient one one one one another a a
R117H, further further
R347P, K1060T,
N1303K, compositions R560S, A46D, R560S, L467P,
S977F,
aspect, implementation, implementation, implementation, implementation, I336K, selected G85E, S492F, human R334W, R334W,
Ml from from
from
comprising aspect,
implementation, implementation,
101K, and compositions
A46D,
I336K, AF508, R74W, administering
the and L997F,
H1054D, R347P, N1303K, N1303K, CFTR
L467P, R1066H,
from A1067T,
Ml G85E, G85E, G551D.
invention the S341P. L1077P,
101K, of
R74W,
I336K,
H1054D, mutations
invention administering R668C,
RI K1060T, and
R347P,
the A46D, A46D, the the the the
M1V, Ml Ml
T338I, 17H, and
L1077P,
invention of S341P.
patient patient
human human
R1066M,
includes
101K, 101K, to the the R668C, H1054D,
the R1070Q.
S977F, and
E92K, and the I336K, I336K,
M1V,
A1067T, includes R334W, selected patient human
invention
patient possesses possesses L1077P, G551D. L1077P, CFTR CFTR
S341P,
R1066M,
to
wherein a
S977F,
E92K, R1066C,
99 and L997F,
H1054D, H1054D, method M1V, the
possesses CFTR
a from
I336K,
and
mutation mutation
any L927P. patient
method and wherein
R1066M, R1066M,
L997F, V520F, a a
E92K, the
R1070Q,
R1066C, K1060T,
AF508, of
mutation human human
of a L1065P,
M1V, M1V,
H1054D, human patient the
treating one any
of
is is
the
V520F,
spray K1060T,
H1085R,
treating
selected selected
R1066C, R1066C, of RI or CFTR CFTR
E92K, E92K, A1067T, and patient L1065P,
is
CFTR possesses
Y569D, the more
17H,
a
selected M1V, dried
CFTR-mediated a
H1085R, spray
mutation mutation human
a
V520F, V520F, from from
A1067T,
human and
possesses R560T,
mutation CFTR-mediated L1065P, L1065P,
Y569D, dispersions R1070Q, E92K, A561E,
dried a
G551D. from R1066H, R74W,
human CFTR
CFTR H1085R, H1085R, R560T,
selected selected L927P,
R1070Q,
and dispersions
R1066H, selected Y569D, Y569D,
A561E, a A559T,
R1066H, human
R668C,
CFTR or disease L927P,
T338I,
the
from from
2015247850 04 Jun 2019 V520F, A1067T, Y569D, Y569D, pharmaceutical L1065P, more mutations H1085R, H1085R, R1070Q, human A561E, more CFTR or disease selected selected disease selected CFTR from from [0489] [0488] [0487] [0486] [0490] [0485] [0491]
the
R1066H, AF508,
human human
pharmaceutical
mutations mutation
CFTR
in in
H1085R, A559T,
A561E, A561E, from from from
Y569D, In In In In In In In R1070Q, R560T, R560T, R1066H,
a a selected
patient one one patient one another a another another
CFTR CFTR R117H,
further R74W, R1066H, R74W, mutations
T338I,
compositions
implementation, implementation, implementation, selected
S492F, A559T, A559T,
selected A561E, R560T, L927P, L927P,
from R1066H,
T338I,
comprising administering mutations mutations aspect, aspect, implementation,
implementation,
and R668C, R668C, compositions R334W,
T338I,
L467P,
R1066H, selected
from
S492F, S492F,
R560S, R560S,
from A559T, L927P, G551D. R334W,
the the
T338I,
of
S977F, S977F,
AF508, selected selected
R334W, invention invention administering AF508,
I336K,
R347P,
the
L467P, L467P,
the the the
from
N1303K, N1303K, to R560S, T338I, S492F,
G85E,
invention of R334W,
the patient patient patient the
L997F, L997F, the
R117H,
R74W, the H1054D, from from R117H,
patient
G85E, and patient
R347P, R347P,
includes includes R334W, patient N1303K,
L467P, invention A46D,
Ml Ml
possesses possesses possesses R74W, S341P, AF508,
G85E,
to K1060T, K1060T,
wherein
R668C,
and 100 A46D, 101K, 101K, any
and possesses
the
and M1V, and possesses
R347P, I336K, a a
I336K,
G551D.
of
Ml patient
method method G551D. A46D, and R668C,
R117H, wherein
S341P. S341P.
L1077P, L1077P,
the one one one I336K,
the
S977F, A1067T, A1067T, E92K, 101K,
a
H1054D,
spray and human H1054D, a patient
or or or
any
one
I336K,
human of of
S977F, and the more more more
L1077P, H1054D,
S341P,
and L997F, treating treating
R1066M, R1066M,
of or dried
patient and and
G551D.
CFTR possesses
the more
L927P,
human human human H1054D, CFTR M1V,
M1V, L997F,
R1070Q. R1070Q,
dispersions spray and
K1060T, a a R1066M,
human Ml
possesses
mutation CFTR-mediated CFTR-mediated R1066C, R1066C,
E92K, mutation one CFTR CFTR CFTR E92K, and
V,
dried one K1060T,
M1V,
or E92K,
a and
CFTR
A1067T, or
human
V520F, more mutations mutations mutations R1066C,
and dispersions or
selected
one L1065P, L1065P,
more one
E92K,
selected the
V520F,
L927P.
or human
or
2015247850 04 Jun 2019 pharmaceutical Y569D, A559T, pharmaceutical Y569D, L927P, mutation H1085R, W1282X, R74W, L927P, mutation mutations mutations H1085R, T338I, in G542X, from and from T338I, in and selected [0496] [0495] [0494] [0493] [0492] [0498] [0497]
a a
patient 2184InsA. patient one
R1066H, R1066H,
R334W, R334W,
R668C, R560S, R560S,
S492F, or A561E, A561E, W1282X, from
In In In In In In In selected selected
R560T, R560T,
and2184InsA. selected selected
more
comprising comprising still one one one another a one
further R1066H,
T338I, T338I,
N1303K, N1303K, compositions compositions L467P,
S977F, aspect, implementation aspect, implementation, G85E, G85E, another A559T, A559T, human
L927P, L927P, from from
and from from
implementation
implementation,
R334W, R334W,
2184InsA. A46D, A46D, R74W, administering R74W, administering
the the L997F, T338I,
R347P, CFTR
implementation R1066H, AF508,
S492F, S492F, R560S, R560S, Ml Ml
invention invention
101K, 101K, of of
I336K, I336K,
R334W, mutations
R668C, R668C, I336K, G85E, K1060T,
S341P,
the the RI of L467P, L467P,
the
N1303K, N1303K, T338I,
this
17H,
L1077P, L1077P,
invention invention of patient
includes includes
to to the H1054D, H1054D, A46D,
H1054D, this
aspect,
I507del, S977F, S977F,
G85E,
the the
R347P, of R347P,
and
A1067T, R334W, selected patient
aspect, this Ml Ml patient patient possesses
R1066M, G55 R1066M,
I336K, wherein wherein
a a
the 101 A46D, 101K, 101K,
L997F, L997F,
aspect,
method method M1V, M1V,
G1061R, and M1V, S341P, possesses
ID.
from human I336K, the R1070Q,
any any
S341P, H1054D,
L1077P, L1077P,
one human
I336K,
E92K, E92K, the the
the R1066C, R1066C, K1060T, K1060T, E92K,
AF508, of of
of of I507del,
CFTR
H1054D, G542X, patient the patient the
or human treating treating one
I507del,
and
more
V520F, V520F,
CFTR spray H1054D, spray
L927P,
R1066M, R1066M, M1V, RI or
A1067T, A1067T, L1065P, L1065P, mutation one
G1061R,
possesses possesses
more CFTR
17H, W1282X, human a a
M1V, dried dried
mutation CFTR-mediated CFTR-mediated
or G1061R,
E92K, H1085R, H1085R, I507del,
human Ml more and
R1066C, mutation R1066C,
Y569D, dispersions Y569D, dispersions R1070Q, R1070Q, is CFTR E92K,
G542X,
V,
a a
G551D.
selected V520F,
and
human human human is
E92K,
G542X, G1061R, CFTR R560T, R560T,
selected
mutations 2184InsA. and
A561E, A561E, is L1065P, L1065P,
W1282X, R1066H, R1066H,
selected
CFTR CFTR CFTR from V520F,
or disease or disease L927P,
the the
2015247850 04 Jun 2019 Y569D, pharmaceutical A559T, R1066M, M1V, I507del, H1085R, R1070Q, human I507del, mutation R117H, R1066C, E92K, mutation R117H, G1061R, CFTR CFTR and in from G542X, G542X, selected and [0502] [0501] [0500] [0499] [0504] [0503]
a
2184InsA. patient a
AF508,
human
E92K,
mutations mutations V520F, CFTR
S492F, and and A561E, W1282X, W1282X, from
G1061R, G1061R,
In In In In In In
selected selected E1065P, R560T, R1066H, G542X, R1066C,
comprising
one one still another one another
G551D. G551D.
RI CFTR
V520F,
R74W, mutations
H1085R,
compositions
E467P,
implementation implementation aspect, another 17H,
A559T,
selected selected
E927P,
from from
W1282X, G542X, G542X, Y569D,
and and T338I,
E1065P, implementation implementation mutation
H1085R, and R668C,
2184InsA, 2184InsA,
administering R1066H, R1066H, the
R347P,
implementation selected R560T,
S492F,
R560S,
from from G551D.
R334W, W1282X, W1282X, A561E, invention
and Y569D,
selected of S977F,
R560T, R1066H, R74W,
S341P,
the
of of
2184InsA. E467P,
E927P, T338I, T338I, from
N1303K, and and
this this
A559T, G85E,
invention of of
A561E, includes and and
to E997F,
from
a a
R74W,
this this R668C, aspect, aspect,
E927P,
I507del,
human human
the R334W, R334W, of R347P, R560S,
T338I, 2184InsA. 2184InsA,
A46D,
aspect, aspect, this Ml AF508, S492F, patient
A559T,
K1060T,
wherein
a R668C,
the the
102 101K, R560S, CFTR CFTR S977F,
aspect,
method
R334W, G1061R,
N1303K, S341P,
I336K, G85E,
I336K, patient patient the the
any E467P, RI
and
E1077P, S492F,
patient patient mutation mutation
the 17H, S977F,
the E997F, A1067T, N1303K,
of
of
A46D, I507del,
a H1054D,
G85E,
H1054D,
possesses possesses
G542X, patient the
human patient Ml treating
R347P, and
E467P, possesses possesses
spray
101K, E997F, R1066M, K1060T,
selected selected I336K,
G551D. A46D,
R1070Q,
Ml G1061R,
possesses
possesses CFTR
W1282X, M1V, a
M1V, S341P, dried a one
CFTR-mediated 101K, E1077P,
R347P,
human K1060T,
H1054D,
I336K,
a one
or from from A1067T,
mutation R1066C,
E92K, human
dispersions E92K,
I507del,
more G542X, I507del,
E1077P,
one or a
and CFTR
S341P, AF508, AF508, human R1066M,
more
H1054D,
A1067T,
or
E927P,
human V520F, CFTR M1V, 2184InsA,
R1070Q,
selected E1065P,
more
G1061R,
W1282X,
mutation G1061R, human
I507del, CFTR or disease
the
2015247850 04 Jun 2019 A559T, pharmaceutical Y569D, pharmaceutical L927P, mutation E92K, human R1066M, M1V, mutations I507del, H1085R, R1070Q, human E92K, human T338I, in CFTR from G1061R, CFTR CFTR G551D. and in [0508] [0507] [0506] [0505] [0510] [0509]
a a
patient 2184InsA, patient
AF508,
E92K,
mutations mutations mutations L927P, L927P,
R334W, CFTR CFTR CFTR
R560S,
S492F, A561E,
G1061R,
In In In In In In selected R560T, R1066H, G542X,
R1066C, selected
comprising comprising one still still one one another
R117H, V520F,
mutations mutations mutations
I507del, I507del,
and
N1303K, compositions compositions L467P,
aspect, aspect, implementation G85E, another another
A559T,
selected selected selected
L927P, from W1282X,
G542X,
from T338I, one L1065P, implementation
H1085R, and
A46D, R74W, administering administering the the or G1061R, G1061R,
R347P,
implementation implementation AF508, selected selected selected
S492F,
R560S, Ml
from from from G551D.
more R334W, W1282X, invention invention
and Y569D,
101K, of of
I336K,
R668C, R560T, R1066H, R74W, AF508,
S341P, human
the R117H, the of
2184InsA, L467P,
from from from G542X, G542X, N1303K,
this
G85E, L1077P, invention invention of
A561E, includes includes and
to to
H1054D,
R74W, R1066H, R1066H,
this R668C, R117H, aspect, CFTR L927P,
I507del, S977F,
the the R347P, of of and
T338I,
2184InsA,
W1282X, W1282X,
A46D,
aspect, this this Ml and patient patient
R1066M, G55
A559T,
wherein wherein
mutations a a R668C,
the
103 101K,
L997F,
R560S,
S977F,
aspect, aspect,
and
method method
M1V, one R334W, T338I, T338I, G1061R, S341P,
ID.
I336K, patient the
any any
G551D. or and and and
L1077P,
S492F,
patient
E92K, the the S977F,
more the the L997F, R1066C, K1060T, N1303K,
of of R334W, R334W,
of of
I507del, 2184InsA. 2184InsA, selected one
G85E,
H1054D,
possesses
G542X, patient the patient the
patient patient treating treating
human
or
V520F, L467P, possesses
spray spray
L997F, R1066M, K1060T,
more
A46D,
A1067T, L1065P, I336K, I336K,
Ml G1061R, from
possesses possesses
possesses possesses
W1282X,
a a
M1V,
and dried dried one
CFTR
CFTR-mediated CFTR-mediated
101K,
R347P, human
H1085R,
K1060T, AF508,
I336K,
one one
or H1054D, H1054D, A1067T, R1066C,
dispersions Y569D, dispersions E92K,
R1070Q,
more mutations G542X,
L1077P,
one a or or one one
CFTR and human S341P,
more R117H, more
H1054D,
R560T,
A1067T,
or
or or human
V520F, 2184InsA.
R1070Q, M1V, M1V,
A561E, L1065P,
more
more more
W1282X,
R1066H,
human human
CFTR I507del, selected or disease or disease
and
the the
2015247850 04 Jun 2019 A559T, pharmaceutical Y569D, I507del, mutation R117H, R1066C, E92K, mutation R117H, L927P, mutation H1085R, W1282X, R74W, from G542X, G542X, selected and T338I, in G542X, from and from [0515] [0514] [0513] [0512] [0511] [0517] [0516]
a
patient 2184InsA. a
AF508, R1066H, R1066H, human
V520F,
R334W,
R668C,
R560S,
S492F, and and A561E, W1282X, W1282X, W1282X, from
G1061R,
In In In In In In In selected selected selected L1065P,
R560T, and2184InsA.
comprising one one still
another one another still
G551D. G551D.
Rl CFTR
R74W,
T338I, T338I, H1085R,
N1303K, compositions
L467P,
S977F, implementation implementation aspect, G85E, another another 17H, A559T,
L927P,
from from from
G542X, Y569D, and and and
implementation implementation mutation
and R668C, R334W, R334W,
2184InsA, 2184InsA, 2184InsA. A46D, R1066H, R1066H, R74W, administering the L997F,
R347P,
implementation implementation R560T,
S492F,
Ml R560S, G551D.
W1282X, A561E, invention
101K, selected of
S977F,
I336K,
R668C, I336K, G85E, K1060T,
S341P,
the
of of L467P,
L927P, T338I, T338I,
N1303K, and and
this this
A559T,
L1077P, invention of of
includes
and
to L997F,
H1054D, from A46D, a a
H1054D, this this aspect, aspect,
S977F, I507del,
human human
the
R334W, R334W, of R347P, of R560S,
A1067T, 2184InsA,
aspect, aspect, this this Ml AF508, S492F, patient
R1066M,
K1060T, I336K, wherein
a
the the
104 101K,
L997F,
CFTR CFTR aspect, aspect,
method
M1V,
G1061R,
M1V, N1303K, S341P, I336K, G85E,
patient human the the R1070Q,
any L467P, Rl
and
H1054D,
L1077P,
patient human mutation mutation
E92K, the 17H,
the the R1066C, K1060T, A1067T, E92K,
of
of
I507del, A46D, a H1054D,
possesses CFTR
G542X, patient the
human patient human Ml treating
R347P,
and I507del,
V520F,
possesses CFTR
spray
L927P,
101K, R1066M, M1V,
selected selected I336K,
G551D. A1067T, mutation L1065P, R1070Q,
G1061R,
possesses
possesses CFTR CFTR
W1282X, M1V, a
S341P, dried
a
mutation CFTR-mediated
L1077P,
G1061R,
E92K, human H1085R, I507del,
H1054D,
a
from from
mutation mutation R1066C,
E92K,
human
dispersions Y569D, R1070Q, is
I507del, G542X,
I507del,
a
a
selected
V520F,
and CFTR
human AF508, AF508, human R1066M, is
G542X, G1061R, R560T,
selected L927P,
CFTR M1V, 2184InsA,
A561E, selected is L1065P,
G1061R,
W1282X, R1066H,
mutation
G1061R,
selected
CFTR from CFTR or disease
the
2015247850 04 Jun 2019 Y569D, pharmaceutical Y569D, pharmaceutical mutations I507del, H1085R, R1070Q, human M1V, more R1066M, M1V, I507del, H1085R, R1070Q, human CFTR G551D. and in G1061R, CFTR CFTR and in [0522] [0521] [0520] [0519] [0518] [0523]
a a
2184InsA, patient 2184InsA. patient
human
E92K, E92K,
mutations mutations mutations CFTR CFTR
A561E, A561E, G1061R, G1061R,
In In In In In In R560T, R1066H, R560T, R1066H, G542X,
R1066C, selected
comprising comprising one one still one one another
CFTR V520F, L927P,
mutations mutations
and
compositions compositions
aspect, implementation aspect, implementation another
A559T, A559T,
selected selected selected
L927P, L927P, W1282X,
G542X, G542X,
from
T338I, T338I,
one L1065P, mutations implementation
I507del, H1085R,
administering administering the the or
implementation AF508, selected selected
S492F, S492F, R560S, R560S,
from from from
more R334W, R334W, W1282X, W1282X, invention invention
and Y569D,
of of G1061R, selected
R560T, R1066H, R74W, R74W,
human
the RI the of of
2184InsA. L467P, L467P,
from from N1303K, N1303K,
this this
17H, G85E, G85E, invention invention of
A561E, includes includes and and to to
R74W, R74W,
this from R668C, R668C,
aspect, aspect, CFTR L927P,
G542X,
the the R347P, R347P, of and
T338I, 2184InsA. 2184InsA,
A46D, A46D,
aspect,
this Ml Ml
patient patient
R1066H,
G55
A559T,
wherein wherein
a mutations a R668C, R668C,
the the 105 101K, 101K, R560S,
S977F, S977F,
aspect,
method method
R334W, W1282X, S341P, S341P,
ID.
I336K, I336K, patient patient the
any any
and
L1077P, L1077P, S492F,
T338I, patient
the the S977F, S977F,
wherein L997F, L997F, N1303K,
of of
of of
I507del, I507del,
selected one
G85E, H1054D, H1054D,
possesses possesses
patient the patient the
treating treating and
or
R334W, L467P, possesses
spray spray
L997F, L997F, R1066M, R1066M, K1060T, K1060T,
2184InsA.
the more A46D,
Ml G1061R, G1061R, from possesses possesses
a a patient
M1V, M1V, dried dried one one
CFTR-mediated CFTR-mediated
101K, R347P, human
K1060T, K1060T, I336K, AF508,
I336K,
one
or or A1067T, A1067T, R1066C, R1066C,
dispersions dispersions E92K, E92K,
possesses
more more G542X, G542X,
L1077P, one one or
CFTR
S341P,
H1054D,
more RI
H1054D,
A1067T, A1067T,
or or
human human V520F, V520F,
17H, R1070Q, R1070Q,
L1065P, L1065P, more more
W1282X, W1282X,
human
one I507del, or disease or disease
and
the the
or
2015247850 04 Jun 2019 pharmaceutical Y569D, A559T, pharmaceutical mutation H1085R, W1282X, R74W, L927P, mutation E92K, human R1066M, M1V, T338I, in G542X, from and from T338I, in CFTR from G1061R, CFTR [0527] [0526] [0525] [0524] [0530] [0529] [0528]
a a
patient 2184InsA. patient
R1066H, R1066H, AF508,
E92K,
mutations mutations
L927P, R334W, R334W, CFTR
R668C, R560S, S492F, A561E, W1282X,
In In In In In In In selected selected
R560T, G542X, R1066C, and2184InsA.
comprising comprising one one still one still another another
R117H, V520F,
mutations
I507del,
T338I, T338I,
N1303K, compositions compositions L467P,
S977F, aspect, implementation aspect, G85E, G85E, another another
A559T,
selected selected
L927P, from from
W1282X,
and
L1065P, implementation implementation
H1085R, and R334W, R334W,
2184InsA. A46D, A46D, R74W, administering R74W, administering the the L997F, G1061R,
R347P,
implementation implementation selected
S492F,
R560S, Ml from from G551D.
invention invention
and Y569D,
101K, of of
I336K, I336K,
R668C, R668C, AF508, R560T, R1066H, I336K, G85E, K1060T,
S341P,
the the of
2184InsA, L467P,
from G542X, N1303K,
this
L1077P, invention invention of of
A561E, includes includes
to to
H1054D, H1054D, A46D,
R1066H,
H1054D, this this R117H, aspect, L927P,
S977F, S977F, I507del,
the the
of of R347P, T338I, A1067T,
W1282X,
aspect, aspect, this this Ml and patient patient
R1066M,
A559T,
I336K, wherein wherein
a a
the
106 101K,
L997F, L997F, R560S,
aspect, aspect,
and
method method M1V, M1V, one R334W, T338I, G1061R, M1V, S341P,
human the the R1070Q,
any any
G551D. or and
H1054D,
L1077P,
S492F,
patient
human
E92K, E92K, the the more
the the R1066C, K1060T, K1060T, E92K, N1303K,
of of R334W,
of of I507del, 2184InsA,
G85E,
CFTR
G542X, patient the patient the
patient human treating treating
I507del, human
V520F, V520F,
L467P, possesses CFTR spray spray
L927P,
R1066M, M1V,
A46D,
A1067T, A1067T, mutation L1065P, I336K,
Ml G1061R,
possesses possesses
possesses CFTR
W1282X,
a a
and dried dried
CFTR
mutation
CFTR-mediated CFTR-mediated 101K,
G1061R, R347P,
E92K, H1085R, H1085R, I507del,
I336K, one one
H1054D,
mutation R1066C,
dispersions dispersions Y569D, R1070Q, R1070Q, is
mutations G542X,
L1077P,
a a
or or one
selected V520F,
and
human S341P, human
is
more
more G542X, G1061R, H1054D, R560T, R560T,
selected or
2184InsA.
M1V, A561E, is L1065P,
more
W1282X,
R1066H, R1066H,
human
human
selected
CFTR CFTR from I507del, selected or disease or disease
the the
2015247850 04 Jun 2019 Y569D, pharmaceutical A559T, R1066M, M1V, I507del, H1085R, R1070Q, human I507del, mutation R117H, R1066C, E92K, mutation R117H, L927P, G1061R, CFTR CFTR and in from G542X, G542X, selected and [0534] [0533] [0532] [0531] [0536] [0535]
a
2184InsA. patient a
AF508,
human
E92K,
mutations mutations V520F,
CFTR
R560S,
S492F, and and A561E, W1282X, W1282X, from
G1061R, G1061R,
In In In In In In
selected selected E1065P, R560T, R1066H, G542X, R1066C,
comprising
one still another one another one
G551D. G551D.
Rl CFTR
V520F,
R74W, mutations
H1085R,
N1303K, compositions
E467P,
implementation implementation aspect, another 17H,
A559T,
selected selected
E927P,
from from
W1282X, G542X, G542X, Y569D,
and and T338I,
E1065P, implementation implementation mutation
H1085R, and R668C,
2184InsA, 2184InsA,
administering R1066H, R1066H, the
R347P,
implementation selected R560T,
S492F,
Ml R560S,
from from G551D.
R334W, W1282X, W1282X, A561E, invention
and Y569D,
101K, selected of S977F,
R560T, R1066H, R74W,
S341P,
the
of of
2184InsA. E467P,
E927P, T338I, T338I, from
N1303K, and and
this this
A559T, G85E,
L1077P, invention of of
A561E, includes and and
to E997F,
from
a a
R74W,
this this R668C, aspect, aspect,
E927P,
I507del,
human human
the R334W, R334W, of R347P, R560S,
T338I, 2184InsA. 2184InsA,
A46D,
aspect, aspect, this Ml AF508, S492F, patient
R1066M,
A559T,
K1060T,
wherein
a R668C,
the the
107 101K, R560S, CFTR CFTR S977F,
aspect,
method
R334W, G1061R,
N1303K, S341P,
G85E, I336K,
I336K, patient patient the the
any E467P, Rl
and
E1077P, S492F,
patient patient mutation mutation
the 17H, S977F,
the R1066C, E997F, A1067T, N1303K,
of
of
A46D, I507del,
a H1054D,
G85E,
H1054D,
possesses possesses
G542X, patient the
human patient Ml treating
R347P, and
E467P, possesses possesses
spray
101K, E997F, R1066M, K1060T,
selected selected I336K,
G551D. A46D,
L1065P, R1070Q,
Ml G1061R,
possesses
possesses CFTR
W1282X, M1V, a
M1V, S341P, dried a one
CFTR-mediated 101K, E1077P,
R347P,
human K1060T,
H1054D,
I336K,
a one
or from from A1067T,
mutation R1066C,
E92K, human
Y569D, dispersions E92K,
I507del,
more G542X, I507del,
E1077P,
one or a
and CFTR
S341P, AF508, AF508, human R1066M,
more
H1054D,
A1067T,
or
E927P,
human V520F, CFTR M1V, 2184InsA,
R1070Q,
A561E, selected E1065P,
more
G1061R,
W1282X,
mutation G1061R, human
I507del, CFTR or disease
the
2015247850 04 Jun 2019 Y569D, pharmaceutical rhinosinusitis, E92K, human R1066M, M1V, mutations I507del, H1085R, R1070Q, human E92K, human congenital selected composition administering severity CFTR from G1061R, CFTR CFTR G551D. and in [0540] [0539] [0538] [0537] [0542] [0541]
a
2184InsA, patient
AF508,
E92K,
mutations mutations mutations E927P, E927P, CFTR CFTR CFTR
A561E, of, from G1061R,
In In In In In In R560T, R1066H, G542X,
R1066C,
selected bilateral
comprising or one still still one one another
of R117H,
V520F,
cystic
mutations mutations mutations an
symptomatically constipation, I507del, I507del,
and
the
compositions
aspect, aspect, implementation another another
A559T,
effective selected selected selected
E927P, W1282X,
G542X,
from invention T338I, one E1065P,
absence implementation fibrosis,
H1085R, and
administering the the or G1061R, G1061R,
implementation implementation AF508, selected selected selected
S492F,
R560S,
from from from G551D.
more amount R334W, W1282X,
invention invention
pancreatitis, of
and Y569D,
asthma, to of
the
R560T, R1066H, R74W, AF508,
treating
the
human
R117H, the of
2184InsA, E467P,
from from from G542X, G542X, N1303K,
vas of
this
patient, G85E, invention of
A561E, the includes also and smoke to
deferens
R74W, R1066H, R1066H,
this R668C, R117H, aspect, CFTR E927P,
a
the
R347P, of pancreatic of and
spray T338I,
2184InsA, disease
provides W1282X, W1282X,
A46D,
aspect, this this preferably Ml and patient
induced
G55
A559T,
wherein
mutations a
R668C,
the
108 dried 101K,
R560S,
S977F,
aspect, (CBAVD), aspect,
and method
one R334W, T338I, T338I,
S341P,
in ID.
I336K, patient
the
a
any
insufficiency,
G551D. a
or and and
and dispersion method
COPD, patient,
E1077P, S492F,
patient
a the
S977F,
more the the E997F, N1303K,
of R334W, R334W,
mammal,
of
I507del, 2184InsA. 2184InsA, selected one
G85E, H1054D,
possesses
patient the
patient patient treating mild
human
chronic of
or
E467P, the possesses
spray
E997F, R1066M, K1060T,
or treating,
more
pulmonary A46D,
I336K, I336K,
Ml G1061R, method from
possesses
male wherein possesses possesses pharmaceutical
a
M1V,
and dried one CFTR
CFTR-mediated
101K, bronchitis, R347P, human
K1060T,
AF508,
infertility
I336K,
one one
or H1054D, H1054D, A1067T, lessening
R1066C,
comprising dispersions E92K,
the
more mutations G542X,
E1077P,
disease, one or or one one
CFTR S341P,
disease
more R117H, more
H1054D,
A1067T,
or
or or human
V520F,
caused
R1070Q, M1V, M1V,
the E1065P,
more
more more W1282X,
human human
I507del,
selected or disease is
and
the
by
2015247850 04 Jun 2019 periodic protein to with muscular neurological neurodegenerative neprogenic hereditary melanoma, mellitus, hereditary dilated acquired deafness, seizures, epilepsy effective severity ciliary (PCD), epilepsy, (Thomson deposition), (including disease, spongiform lateral lysosomal such such idiopathic Sandhof/Tay-Sachs, [0543]
the
situs as as
patient,
sclerosis, aplasia.
cardiomyopathy, processing
protein a
familial
or of,
paralysis,
with
LQTS, myotonia, Laron In amount term lysosomal
atrophy,
autosomal-recessive
inversus pancreatitis, hypofibrinogenemia, storage emphysema, bone
and
Sjogren
DI, glycanosis or one encephalopathies,
Gorham's disorders
ferbrile preferably
symptomatically for
Becker
C Charcot-Marie
dwarfism,
hypercholesterolemia, aspect, repair, progressive Timothy
of
deficiency,
inherited
diseases, dentatorubal LQTS, defect), diseases ’
(also
s
paramyotonia
the storage
Crigler-Najjar
disease,
seizures
Syndrome, forms), CDG such
bone allergic the hereditary spray
known autosomal-dominant a
syndrome,
myleoperoxidase
mammal, LQTS/Brugada
Fabry
invention disorders such
such as disease,
type
regeneration, supranuclear
Type
osteoporosis, dried
plus such Bartter's
Huntington LQTS, Tooth
bronchopulmonary
pallidoluysian, treating as ACT
as as
disease,
1,
chloride congenital,
hemochromatosis,
Kartagener
(GEFS+), type 1 dispersion Alzheimer as I-cell congenital
Angelman
wherein persistent hereditary
of syndrome, also
deficiency, LQTS
hereditary
Type
syndrome
a the II,
disease/pseudo-Hurler, disease
plasy, provides Straussler-Scheinker ’
reducing
s, syndrome, channelopathies
polyendocrinopathy/hyperinsulemia,
osteopenia, structure
deficiency,
1 with
spinocerebullar
the
general potassium-aggravated LQTS,
’ or syndrome), chylomicronemia,
109 hyperthyroidism, and s hyperinsulinemic
syndrome,
angioedema,
Perlizaeus-Merzbacher
Pick disease,
pharmaceutical Creutzfeldt-Jakob disease
Diabetes in dysmorphic type
aspergillosis
myotonic a
bone a
method and/or
’
Dent coagulation-fibrinolysis epilepsy patient s autosomal-dominant
III,
bone disease, primary
is Parkinson resorption
PCD
and Dent's insipidus
disease, selected
such function
healing ataxia lipid of comprising dystrophy,
features, with Primary
syndrome,
treating, without several
(ΑΒΡΑ),
hypoparathyroidism,
osteogenesis as
composition hypolglycemia mucopolysaccharidoses, abetalipoproteinemia, disease,
processing
’
Osteopetrosis, myotonia disease type ferbile s from and
myotonia, (DI),
and of disease,
Ciliary polyglutamine congenital
cilia,
disease, situs increasing
as I, lessening
bone administering
generalized
liver neurophyseal hyperekplexia,
COPD,
spinal
and LQTS well (due
inversus including congenita deficiencies,
deficiencies, amyotrophic of imperfecta,
growth disease, hyperkalemic Dyskinesia aferbrile
as
to of Diabetes the
and
with
Bartter dry-eye
the and
prion bone infancy,
invention
bulbar
and
PCD
an DI,
2015247850 04 Jun 2019 polymorphic L206W, In genetic invention an severity genetic another genetic invention an severity genetic genetic invention an severity genetic invention an severity syndrome S549R, [0546] [0545] [0544] [0547] 1898+1G->A, 1G->A, 1717-1G->A, 1898+1G->A, 1G->A,
another effective effective effective effective
mutation mutation mutation mutation mutation mutation
S1251N, implementation, 621+1G->T, 621+1G->T, of, of, of, of, A455E, In In In In
to to to to
type implementation,
or or or
or one one one one amount amount amount amount the the the the
tachycardia.
621+1G->T, symptomatically symptomatically symptomatically symptomatically
3659delC, 3659delC, III,
patient, patient, patient, patient, aspect, aspect, aspect, aspect,
D579G, N1303K, AF508. selected is G551D. is E193K,
central any any
of of of of
2789+5G->A, 2789+5G->A,
the the the the
the the the the one one
preferably preferably preferably preferably
the
R347P, R347P, F1052V,
S1235R, In from
In core
spray spray spray spray
ΔΙ507, present present present present 312O+1G->A, the
of of
patient another another
G551D, AF508,
patient disease, G178R, treating treating treating treating
dried dried dried dried
R560T, R560T,
or
S945L, a a a a G1069R, invention invention invention invention
is
3849+10kbC->T, 3849+10kbC->T,
implementation, mammal, mammal, mammal, mammal, R560T. implementation,
heterozygous
dispersion dispersion dispersion dispersion G542X, is
G542X, malignant G551S, cystic cystic cystic cystic
heterozygous
1898+1G->A, R334W, R334W, R1070W,
R117C, is is is is
fibrosis fibrosis fibrosis fibrosis wherein wherein wherein wherein
110
N1303K,
directed directed directed directed N1303K, G970R,
or or or or
hyperthermia,
A455E, A455E,
pharmaceutical pharmaceutical pharmaceutical pharmaceutical in
F1074L, D110H,
the
the
R1162X, R1162X, in in in in
AF508 in the the the the
to to to to
G1244E,
711+1G->T,
W1282X, a a a a
patient G551D W1282X, patient
patient a patient a patient a patient a
patient patient patient patient 2184delA, 2184delA,
method method method method
R347H, wherein D110E,
G85E, G85E,
is
and
is wherein
S1255P,
comprising comprising comprising comprising possesses possesses possesses possesses
homozygous
R117H, homozygous composition composition composition composition R117H,
of of of of
catecholaminergic
2622+lG->A,
R352Q,
D1270N, the or or
312O+1G->A, 312O+1G->A, treating, treating, treating, treating,
711+1G->T. 711+1G->T.
the
other G1349D,
R553X,
R553X, the the the the
other
administering administering administering administering E56K,
lessening lessening lessening lessening
CFTR in CFTR CFTR D1152H, CFTR CFTR in of of of of
AF508.
G551D. CFTR the the the the
1717- 405+ S549N,
1717- P67L, ΔΙ507, ΔΙ507,
the the 1G- the the
In
2015247850 04 Jun 2019 A455E, possesses the >G, >A, genetic invention an severity greater embodiment genetic invention an severity chloride implementations composition administering selected spray invention genetic invention an severity 3272-26A->G, S S549R, [0548] [0550] [0549] 1717-8G->A, 1341+1G->A, 125
effective effective effective
severity IVS14b+5G->A, 4O6-1G->A,
IN. dried
or mutation mutation mutation
S D579G, of, of, of,
from transport In In In
125 provides to to to In the equal
dispersion, or or or
one one one
of, amount amount amount
the the the one of of
IN,
CFTR
G178R, an 1342-2A->C, symptomatically symptomatically symptomatically
3121-1G->A,
711+5G->A,
or
the this
patient, to patient, patient, aspect, aspect, aspect,
aspect, S1235R, of 4OO5+1G->A, selected effective selected E193K,
selected
relative symptomatically
10% a
invention
this
aspect,
of of of genetic method
1898+1G->T,
G551S,
the the the as
the the the above aspect, preferably preferably preferably the
Fl
described from from
S945L, to from amount spray spray spray present present present
the
present
405+3A->C,
052V, mutation
4374+lG->T, baseline 3120G->A, of to
the G970R,
method
G178R, 1717-1G->A, the treating treating treating treating the RI
1812-1G->A, dried dried dried
R1070W,
baseline
of
17C, a a a and invention invention method invention treating
patient,
invention above,
4005+2T->C, mammal, mammal, mammal,
the chloride
selected
dispersion dispersion dispersion
produces G1244E,
G1069R.
G551S, a cystic cystic cystic
Dl
181 spray CFTR 1716G/A,
chloride to 385O-1G->A, produces preferably 10H, cystic F1074L,
l+1.6kbA->G,
is is is
621+1G->T,
a is
fibrosis 1525-1G->A, fibrosis fibrosis transport. from wherein wherein wherein
111 dried
patient directed directed directed
G970R,
directed mediated
S1255P, an R347H,
or or or In
fibrosis and
transport. increase pharmaceutical pharmaceutical pharmaceutical E193K, 1811+1G->C,
one
dispersion a D110E,
a in in in greater
possessing 621+3A->G. the the the
mammal, to to to G1244E,
implementation to
a a a R352Q, 2789+5G->A,
G1349D,
in disease
312O+1G->A, patient a patient a patient a patient patient patient
a
711+3A->G,
712-1G->T, Fl052V, method method method in a
method
D1270N,
than patient
chloride or
E56K,
S1255P, wherein comprising comprising comprising comprising a pharmaceutical possesses possesses possesses
1898+5G->T,
10-fold S549N, composition composition composition human
of of of
of and comprising
treating, treating, treating,
andD1152H. transport treating,
3849+10kbC->T,
P67L, of 1248+1G->A,
1898+1G->A, 1898+3A->G, G1069R.
the
G1349D, increase
CFTR this S549R,
the the the
administering administering administering administering patient
L206W,
aspect,
lessening lessening lessening
CFTR CFTR CFTR lessening
of of of
3850-3T- which
mutation
the the the and in
In
S549N,
In
some the
is
one
the the the
a
2015247850 04 Jun 2019 possesses mutation >G, >A, L206W, treating, >G, >G. >C, 2789+5G->A, >A, genetic invention an severity 3272-26A->G, genetic invention an severity composition comprising genetic invention an severity 711+3A->G, 711+1G-+T, S549R, [0551] [0552] 1717-8G-+A, 1341+1G-+A, 1717-1G-+A,
effective effective effective
IVS14b+5G->A, 406-1G-+A, and 712-1G-+T, 1898+5G->T, In
mutation one mutation mutation
S1251N, of, of, of, 3849+10kbC->T. A455E, lessening In In
selected to to to the
or administering or or
one aspect, one amount amount amount
the the the
of
2622+1G-+A,
1898+3A->G, CFTR
621+1G->T, 1342-2 symptomatically symptomatically symptomatically
3121-1G-+A, 3849+10kbC->T,
71
the patient, patient, patient, aspect, aspect,
D579G, 1248+1G->A, selected 4005+1G-+A, selected selected E193K,
1+5G-+A,
from
the 3850-3T->G, invention the
of of of genetic
A->C,
1898+1
severity
present the the the AF508, the the preferably preferably preferably
F1052V, S1235R,
from from from
an
spray spray spray
present present In 312O+1G->A,
4O5+1G->A,
405+3A-+C, 1717-8G-+A, mutation
4374+1G-+T, 3120G-+A,
effective to
G->T, one
of, invention
G178R, G178R, RI 1717-1G->A, treating treating treating
the
1341+1G-+A,
1812-1G-+A, IVS14b+5G->A, 3272-26A->G, dried dried dried
aspect, or
17H,
S945L, a a a G1069R, invention invention patient,
4005+2T-+C, mammal, mammal, mammal, symptomatically
selected amount dispersion dispersion dispersion
G551S, G551S, and cystic cystic cystic
is 181
4O6-1G->A,
the 1716G/A,
1898+1G->A,
1342-2A->C,
R1070W, 3850-1G-+A, directed
preferably
G551D.
R117C, l+1.6kbA->G, present is is
181
fibrosis fibrosis 1525-1G-+A, fibrosis 3121-1G-+A, of from wherein wherein wherein
112
directed directed G970R, G970R, 711+5G->A,
the
or or or l+1.6kbA->G,
1898+1G->T, and
to pharmaceutical pharmaceutical pharmaceutical 2789+5G->A
1811+1G-+C,
spray F1074L, D110H, invention
treating
4OO5+1G->A, a a in in in
621+3A-+G, the the the
mammal, method to to 405+3
G1244E, G1244E,
711+1G-+T, a a a 2789+5G-+A,
patient patient a patient a dried patient patient patient
71 712-1G-+T, method method 4374+lG->T,
3120G->A,
R347H, D110E, cystic
A->C, 1+3A-+G, is
of 4005+2T-+C, 2789+5G->A, dispersion
directed
wherein S1255P, S1255P, and comprising comprising comprising possesses possesses possesses
1 treating,
898+5G->T, composition composition composition
and of of fibrosis
1812-1G-+A,
1716G/A, 2622+1G-+A, R352Q, 3272-26A->G. D1270N,
treating, treating,
3849+10kbC->T,
a
1248+1G-+A,
1898+3A-+G, 1811+1.6kbA->G,
to human
the
G1349D, G1349D,
385O-1G->A, or lessening
the the the a in
administering administering administering
pharmaceutical patient method
E56K, and 3272-26A-
a
lessening lessening
CFTR CFTR D1152H, CFTR 1811+1G-
of of of 3850-3T- patient CFTR
621+3A-
1525-1G- the the the
405+ S549N, S549N,
P67L, the
of
the 1G- the
2015247850 04 Jun 2019 A455E, possesses possesses >C, 2789+5G->A, >A, this human to this human treating, AF508, treating, AF508, 711+3A->G, 711+1G->T, genetic invention an severity genetic invention an severity composition comprising composition comprising S1255P, S549R, [0553] [0554] 10%
baseline effective effective
aspect, aspect, 712-1G->T, 1898+5G->T, above
CFTR CFTR
mutation mutation RI RI
S
D579G, of, of, lessening lessening G1349D, In In
125 to to the the
17H, 17H,
chloride
the the the administering administering or or
one one amount amount
the the
of of
2622+lG->A, IN,
1898+3A->G, CFTR CFTR
mutation mutation symptomatically symptomatically
3849+10kbC->T,
baseline method method
the the
patient, patient, aspect, aspect,
and and
S1235R, 1248+1G->A, selected selected E193K,
the the 3850-3T->G, S549N, invention invention
transport. of of G55 G55 genetic genetic
severity severity
the the produces produces
the the selected selected preferably chloride preferably
ID. ID.
Fl052V, from from
an an S945L,
spray spray S549R,
present present
4O5+1G->A,
1717-8G->A, mutation mutation
effective effective to to In In
of, of,
RI 1717-1G->A, treating treating
the the
1341+1G->A,
from from one one IVS14b+5G->A, 3272-26A->G, dried dried transport. an a
R1070W,
or or
17C, greater
and a a and invention invention
patient, patient,
increase
aspect, aspect, mammal, mammal, symptomatically symptomatically
AF508, AF508, selected amount amount dispersion dispersion
selected
S1251N, G1069R, DI cystic cystic
4O6-1G->A,
than
1342-2A->C,
10H,
preferably preferably
the the
F1074L,
in
is is 621+1G->T,
RI RI
fibrosis fibrosis 3121-1G->A, of of from
wherein wherein
113
from
chloride 10-fold
directed directed present present
711+5G->A, R347H,
and
17H, 17H, and the the
or or 1898+1G->T,
pharmaceutical pharmaceutical E193K,
G178R, a spray spray a D110E,
treating treating and 4OO5+1G->A, and
a a human in in
human increase the the
invention invention
mammal, mammal, to transport to 405+3A->C,
R352Q, a a
G551D. G551D. 312O+1G->A, patient a patient a dried dried patient patient
Fl052V,
method method 4374+lG->T,
G551S,
3120G->A, D1270N,
CFTR cystic cystic CFTR
in
4005+2T->C, dispersion dispersion
E56K,
which is is
wherein wherein
comprising comprising possesses possesses chloride
In In composition composition directed directed
of of
mutation fibrosis fibrosis
1812-1G->A, mutation G970R,
and 1716G/A, some one
treating, treating,
andD1152H,
P67L, is
1898+1G->A,
1811+1.6kbA->G, G1069R,
embodiment
greater the the
385O-1G->A, transport
or or
embodiments
to to the the in in
G1244E, administering administering
pharmaceutical pharmaceutical patient selected patient selected L206W,
and a a
a a
lessening lessening
1811+1G- CFTR CFTR
method method of of patient patient
or
621+3A-
1525-1G- the the and
relative
equal
and
from
from of a
of of
a
the the
of
to
2015247850 04 Jun 2019 patient, patient, mutation >G, >A, L206W, AF508, the >G, directed genetic invention an severity 3272-26A->G, genetic invention an severity selected amount or one 3849+10kbC->T, selected amount symptomatically S549R, S549R, [0555] [0556] 1717-1G-+A, 1717-8G-+A, 1341+1G-+A,
symptomatically
effective effective
present
aspect, IVS14b+5G->A, 406-1G-+A, and
mutation mutation
R117H. preferably preferably
S1251N, of of S of, of, to from a from A455E,
In In
selected 125
to to human
the the
a
invention
the or or one one
amount amount the the method
IN,
2789+5G->A 621+1G-+T, 1717-1G-+A, spray spray 1342-2 symptomatically symptomatically
3121-1G-+A, present 71
patient, patient, aspect, aspect,
D579G,
treating
selected 4005+1G-+A, selected E193K, E193K,
CFTR 1+5G-+A, and from
a a
treating
of of dried dried mammal, mammal,
of
A->C, is
1898+1 a
the the invention
AF508, the the treating, directed human
preferably preferably mutation
cystic
F1052V, Fl052V, S1235R, from from
dispersion dispersion
spray spray present present 312O+1G->A,
405+3A-+C, cystic and 1811+1.6kbA->G, 4374+1G-+T, 3120G-+A,
G->T,
wherein wherein
G178R, CFTR G178R, R117H, treating treating
fibrosis
1812-1G-+A, to 3272-26A->G,
lessening dried dried is
selected
fibrosis
a S945L, a a G1069R, and invention invention directed
4005+2T-+C,
method mammal, mammal, or or
mutation dispersion dispersion
the the
G1069R. pharmaceutical pharmaceutical G551S, G551S, and cystic in cystic
181
1716G/A,
1898+1G->A, the a in patient patient from R1070W, 3850-1G-+A,
to
G551D. patient
of R117C, l+1.6kbA->G, a is is
severity
fibrosis fibrosis 1525-1G-+A,
a wherein wherein
patient 114
2789+5G->A, treating, directed directed selected and G970R, G970R, AF508,
method
or or
In
possesses possesses and
comprising
a pharmaceutical pharmaceutical 1811+1G-+C,
one
F1074L, D110H, human
comprising in in of,
621+3A-+G,
the the
composition composition
R117H, to to lessening from
G1244E, G1244E, of
aspect, 711+1G-+T, a a
2789+5G-+A,
or
patient a patient a
patient patient
treating,
71
712-1G-+T, method the the method
symptomatically
CFTR
R347H, AF508, 3272-26A->G, D110E, 1+3A-+G,
administering
the CFTR CFTR and
S1255P, S1255P, comprising administering the comprising possesses possesses 1898+5G-+T,
present
composition composition mutation lessening
and of of of of G551D.
R117H,
severity 2622+lG->A, R352Q,
D1270N,
genetic genetic treating, the the treating,
3849+10kbC->T,
a
1248+1G-+A,
1898+3
human
invention invention G1349D, G1349D, invention
the the
selected and
an treating the In administering administering and of, E56K, mutation mutation
lessening lessening
CFTR D1152H, CFTR an one effective
of of
3850-3T- A->G, severity CFTR or G551D.
effective the the
405+ S549N, S549N, aspect,
to to
is P67L, from cystic
the the
the the 1G- of,
In
2015247850 04 Jun 2019 A455E, patient, present >G. >C, 2789+5G->A, >A, method mammal, genetic invention an severity 711+3A->G, 711+1G->T, genetic invention an severity greater embodiment genetic invention an severity chloride selected amount symptomatically G551S, dispersion fibrosis [0558] [0557]
effective effective effective
712-1G->T, 1898+5G->T, In
or mutation one mutation mutation invention preferably
produces
of in G970R, D579G, of, of, of, from transport.
In In
wherein
to to to
equal
a the or
or or or
one one aspect, patient amount amount amount
the the the
2622+lG->A, of pharmaceutical 1898+3A->G,
E193K, spray symptomatically symptomatically symptomatically 3849+10kbC->T,
this
patient, patient, to patient, aspect, aspect,
G1244E, S1235R, treating selected 1248+1G->A, selected selected a is
the
3850-3T->G, a 10%
the greater
comprising
aspect, directed of of of dried mammal,
patient Fl
present the the the
the the above preferably preferably preferably
052V,
cystic
from from from
S1255P, S945L, dispersion
spray spray spray than
present present the 4O5+1G->A,
1717-8G->A,
to
composition possesses
the wherein
invention
method
R117C, a 1717-1G->A, 1717-1G->A, administering treating treating treating and
fibrosis 1341+1G->A,
10-fold
IVS14b+5G->A, 3272-26A->G, dried dried dried method
R1070W, baseline
a a a G1349D, invention invention
G1069R.
mammal, mammal, mammal, or
dispersion dispersion dispersion
produces the
DI pharmaceutical increase the cystic in cystic cystic
is of 4O6-1G->A,
of
1342-2A->C, a
patient 10H, chloride directed
CFTR
treating, patient F1074L,
the S549N,
is is 621+1G->T,
181 an
In fibrosis fibrosis fibrosis 3121-1G->A, wherein wherein wherein
115
directed directed
711+5G->A,
R347H,
in invention
an effective
some
or or or l+1.6kbA->G,
possesses 1898+1G->T, genetic
chloride
comprising transport. increase to
pharmaceutical pharmaceutical pharmaceutical
lessening S549R, D110E,
4OO5+1G->A, a in in in
embodiments the the the
composition
to method to 405+3A->C,
R352Q, a a a
mutation
amount
to 312O+1G->A, patient a patient patient a patient patient patient
transport
method the method
4374+lG->T, in
and the 3120G->A, D1270N,
the
chloride
administering
CFTR
of
4005+2T->C, 2789+5G->A,
patient, E56K, S1251N.
comprising comprising comprising severity of possesses possesses possesses
treating,
selected composition composition composition
of of of
of the 1812-1G->A, relative 1716G/A,
genetic
treating, the treating,
andD1152H. this transport
P67L,
spray
preferably 1898+1G->A, 1811+1.6kbA->G,
of, invention
385O-1G->A,
In
lessening aspect,
from the the the
to an administering administering administering
or one
mutation dried L206W, and
3272-26A-
baseline lessening lessening
CFTR CFTR 1811+1G- CFTR
effective of of of
which
G178R,
aspect,
621+3A-
the 1525-1G- the the the
a
to
the In
the
is
one
the the the
2015247850 04 Jun 2019 patient pharmaceutical patient possesses a mutation >G, >A, E206W, treating, >G, selected a selected genetic invention an severity selected 3272-26A-+G, genetic invention an severity composition comprising S549R, S1255P, S549R, [0559] [0560] 1717-8G-+A, 1341+1G-+A, 1717-1G->A,
method method
effective effective
IVS14b+5G->A, 406-1G-+A, and
possesses comprising mutation mutation
S S1251N,
of, of, from from from 3849+10kbC->T. A455E, lessening
G1349D,
In In
selected 125 of of to to the
administering or or
one one
amount amount treating, treating, the the of
IN,
CFTR
AF508, AF508, AF508, 621+1G->T, 1342-2A-+C, symptomatically symptomatically
3121-1G-+A,
711+5G->A,
the composition patient, patient, aspect, aspect,
D579G, selected 4005+1G-+A, selected E193K, E193K,
the
from
the S549N, administering invention
of of
genetic
CFTR lessening lessening
RI RI R117H, 1898+1G->T, severity
the the AF508, the the preferably preferably
17H, 17H,
Fl052V, F1052V, S1235R,
from from
an
spray spray S549R, In present present 312O+1G->A,
405+3A->C, genetic mutation
4374+1G-+T, of 3120G->A, effective to
one
and and andG551D.
of,
the the
G178R, G178R, R117H, the treating treating the
1812-1G-+A, dried dried
an
aspect,
or
G551D. G551D.
severity severity and S945E, a a invention and G1069R, invention invention patient,
mutation
4005+2T->C, effective mammal, mammal, symptomatically
selected amount dispersion dispersion
S1251N, G1069R, G551S, G551S, and cystic cystic
181
the 1716G/A,
1898+1G->A,
R1070W, 385O-1G->A, of, of, preferably In In
G551D,
R117C, l+1.6kbA->G, to is present is selected
amount
1525-1G-+A, fibrosis fibrosis one one of from wherein or or wherein
116
directed directed the
G970R, G970R,
and
and the or or symptomatically symptomatically
and aspect, aspect,
patient,
pharmaceutical pharmaceutical 2789+5G->A
1811+1G-+C,
and one spray F1074E, D110H, invention one
of from treating
a in in
621+3A->G, the the
mammal, to to
G1244E, G1244E,
the 711+1G->T,
one a or a 2789+5G->A,
or
the the
patient a patient a
dried patient patient
preferably G178R,
more
711+3A->G, more 712-1G-+T, spray method method
or
R347H, present present D110E, cystic
is more
dispersion
human directed
human
S1255P, wherein S1255P, and comprising comprising dried possesses possesses treating treating 1898+5G-+T,
composition composition G551S,
and of of fibrosis
human
invention invention 2622+lG->A, R352Q, a 3272-26A->G. D1270N,
treating, treating,
mammal, dispersion 3849+10kbC->T,
a
CFTR 1248+1G->A, CFTR
1898+3A->G,
to
human the
cystic cystic G1349D, G1349D,
or
G970R,
the the a in CFTR
administering administering pharmaceutical patient method E56K,
a
mutations is is lessening lessening mutations
D1152H, CFTR CFTR
of of 3850-3T- patient
fibrosis fibrosis CFTR wherein directed directed
or
the the mutations
405+ G1244E, S549N, S549N,
P67E,
of
in in
1G- the the
the to to
a a
2015247850 04 Jun 2019 patient, A455E, patient pharmaceutical patient >G, >C, 2789+5G->A, >A, transport severity G551D. 3849+10kbC->T, selected amount or one 711+3A->G, 711+1G->T, genetic invention an severity greater embodiment or genetic invention an severity embodiments and [0562] [0561]
more symptomatically effective effective
aspect, one and 712-1G->T, 1898+5G->T,
possesses comprising
or
mutation mutation
preferably of D579G, human or of, of, of, from one
In In In
relative
to to equal
the
more
the or or
or one one one
amount amount
the the
or 2622+lG->A, of
1898+3A->G,
of 1717-1G->A, spray symptomatically symptomatically symptomatically
3849+10kbC->T,
present
more this CFTR composition
aspect, patient, to patient, aspect, aspect,
this human
S1235R,
1248+1G->A, selected selected to the
and
3850-3T->G, a 10% administering
treating
aspect, baseline
of of dried
mammal,
aspect, CFTR human
one
mutations
the the invention
the
the the above preferably preferably CFTR
from from
S945L, dispersion or
spray spray
present present present the
4O5+1G->A,
genetic cystic
1717-8G->A, the 1811+1.6kbA->G, CFTR of chloride more
the wherein
mutations method RI
the 1717-1G->A, treating treating treating
1341+1G->A, method
IVS14b+5G->A, 3272-26A->G, dried dried
selected
is an
R1070W, baseline
17C, fibrosis
human
invention a a invention invention invention mutations directed
mutation
effective mammal, mammal,
or transport.
dispersion dispersion
produces the
DI pharmaceutical cystic cystic cystic produces
4O6-1G->A,
selected
from
CFTR
1342-2A->C, in patient 10H, chloride
to F1074L,
is to a is is selected 621+1G->T,
amount
selected
fibrosis fibrosis fibrosis 3121-1G->A,
a wherein wherein
patient 117
AF508, 2789+5G->A,
directed
directed directed the
711+5G->A, R347H, method
an
mutations
or or
a possesses from 1898+1G->T,
patient,
greater transport. increase pharmaceutical pharmaceutical
D110E,
of
from 4OO5+1G->A,
comprising in in in from
RI
the the
AF508, composition
to to to
405+3A->C,
of the R352Q, a a a
17H,
a
312O+1G->A, patient a patient patient a
than patient patient treating, preferably E193K,
selected
AF508, method spray method the method 4374+lG->T, in
3120G->A, D1270N, 3272-26A->G,
chloride
RI and
CFTR 10-fold
4005+2T->C, E56K,
comprising comprising administering comprising dried possesses possesses 17H,
Fl052V,
G55 composition composition RI lessening
from of of of of
1812-1G->A,
1716G/A, a
genetic treating, 17H,
treating, the treating,
andD1152H, transport increase mammal, and dispersion P67L, ID.
1898+1G->A, AF508, 1811+1.6kbA->G,
invention 385O-1G->A,
G55
and the the In and
and the administering administering administering
mutation L206W, and
one
lessening
lessening lessening
CFTR 1811+1G- CFTR an in G551D. ID.
of of
which G1069R, RI severity wherein
or 621+3A-
chloride 1525-1G- effective the the
17H,
to In and
the
is some
one the In
the the and of,
the
2015247850 04 Jun 2019 AF508 AF508 K1060T. D1270N, R347H, mutation mutation. the mutation. 3849+10kbC->T. 711+5G->A, G1069R, a above. above. CFTR genetic invention an S1251N, [0570] [0569] [0568] [0567] [0566] [0565] [0564] [0563] [0572] [0571]
gating
effective AF508
mutations
and and
mutation
P67L, mutation
In In In In In In In In
and S1255P, RI L997F, to
For
CFTR
residual a
some some some some some some some some
amount the
162L,
splice 7T, a
example, R117C, residual
patient,
selected selected
R75Q, 1717-8G->A, mutation. implementations, implementations, implementations, implementations, implementations, implementations, implementations, implementations, selected
and
E56K,
mutation
mutation of
2. 1.
G1349D.
the
S945L,
function
preferably the R74W,
from from
F1074L, from spray
patient
selected RI Heterozygous Homozygous
S1235R, 2789+5G->A AF508,
1898+3A->G,
G551D, D579G, 17H. dried mutation
a DI is the the the the the the the the
mammal,
from heterozygous
dispersion 10E,
RI patient patient patient patient patient patient patient patient
I1027T, G178R, R1070Q,
selected 17H,
Mutations 2789+5G->A,
F1074L, Mutations
and
181 wherein is is is is is is is is
118 and
heterozygous heterozygous heterozygous heterozygous heterozygous homozygous homozygous homozygous R668C, S549N, or 3272-26A->G,
l+1.6kbA->G, F1052V, from
in
G551D. pharmaceutical E56K,
the
the
RI
R352Q, S549R, 3120G->A, AF508
patient
17H, DI R1070W,
in
in in in in in 10E, in in
A455E,
the a any and
human 3272-26A->G, G551S, the the the the any
G576A,
possesses human
composition
A1067T,
AF508
human human of AF508 AF508 one of
5T, R31C,
the
the CFTR
DI
or G970R,
71 mutation M470V,
mutations
human
mutations more 152H, human human the CFTR CFTR 1+3A->G,
E193K, D614G,
mutation
CFTR and of
human G1244E,
L206W,
CFTR mutation mutation D110H, the other CFTR CFTR
or recited S977F, recited
and than
2015247850 04 Jun 2019 until tablets twice may mg tablets these AF508 residual K1060T. D1270N, R347H, AF508 AF508 embodiment, (ql2h). one administered substantially (28 duration administering Compound substantially 3849+10kbC->T. 711+5G->A, G1069R, G1244E, [0577] [0576] [0575] [0574] [0573]
of days), tablet
be
amelioration
embodiments, per
substantially
are of and and and
administered
P67L, In mutation
of
In In In In
S1251N, RI
the L997F, day
For is
or
administered
a
a a a administration 1
some one some some
administered
162L,
further residual splice amorphous gating amorphous a
invention. 7T, at and two (bid). example, one
B, month R117C,
the embodiment,
R75Q, 1717-8G->A,
implementations, implementations, implementations, 150 RI tablets
of tablet
E56K, S1255P,
mutation same
amorphous mutation embodiment, the
In
the 17H.
to
function or mg Dosage
S945L, a
the the
dosage
every
longer. containing disease For Compound Compound R74W, are further time
of F1074L, daily may
patient patient and
substantially example, administered
selected selected
50
or Regime
mutation 12
S1235R, be Compound
amounts (qd). 1898+3A->G,
G1349D.
is embodiment, D579G,
In mg at
hours
two
less
achieved per
is
DI different one the the the 50
2 1, of
heterozygous
In from
from
tablets may 10E, administration
day. than mg
and
patient patient patient
substantially (ql2h).
embodiment,
selected a
I1027T, may
R1070Q,
amorphous
further twice
of
2. 2789+5G->A, be 150 F1074L, G551D,
a
In or times
week, substantially
are be
The one administered
181 is is is 119 until a mg
per
achieved further from
heterozygous heterozygous heterozygous R668C, administered embodiment,
l+1.6kbA->G,
tablet during duration
F1052V, in
of
day 1 G178R, a E56K,
amorphous
two
Compound of
a week, subject's substantially RI
mutation
embodiment, 50 (bid). is
17H,
R352Q, the tablets 3120G->A, by
amorphous administered
mg
of DI to
R1070W, 2
S549N,
administration day.
weeks,
administration a
A455E, daily physician in in in 10E, In of one
subject
Compound
other each
2 3272-26A->G,
a a a a substantially G576A,
In may mutation mutation mutation
amorphous tablet further
A1067T,
(qd). S549R,
a 3 the
5T,
comprising Compound R31C, than
DI
further weeks,
in be every
advises, two
is 71 152H,
In need M470V, embodiment,
achieved
AF508 administered
of
1
1+3A->G, other other other
G551S, a
may E193K, D614G, tablets
and
further 12 embodiment, one
four amorphous Compound thereof.
L206W, or
hours e.g.
50
continue 1,
than than than 150
and or
D110H,
weeks
by
and may G970R, mg
more
or S977F,
mg
two In
of 150
be
of
2
2015247850 04 Jun 2019 present present years the different different additional is composition compositions embodiment, embodiment, invention daily administered Compound composition. Compound [0582] [0581] [0580] [0579] [0578] [0586] [0585] [0584] [0583]
absent
administration
(qd). old.
invention invention,
from from And, from Another VI. In In In In In In
may therapeutic In
2 1 some some some some another another
of
once or once the another the of
For
the the the be in KITS
the
Compound the
patient patient some
is embodiments, embodiments, embodiments, embodiments, administered
aspect
example, first second spray such
of daily daily present
embodiment, administered embodiment, present
Compound
embodiment, agents
agent.
embodiments, as,
dried (qd) (qd). in is of
agent.
for 6 invention
the
the 2 a invention
to
followed described
tablet prior,
dispersion
In example,
previous present to 11
the the the the
one 1 once
an administration a years
or
the
patient of subsequent,
kit additional additional additional
effective
and
embodiment,
Compound the
for
the
by
daily patient invention
above. further
embodiments a
old.
or
instructions
the additional the tablet, present
wherein
the
(qd)
treatment
administration In
amount
is
therapeutic therapeutic therapeutic comprises 120 pharmaceutical
another or
may of 18 provides followed 2 invention
concurrent
a alone.
a the years
therapeutic
tablet
pharmaceutical be
for is of
patient of
embodiment, taking
supplemented the
use
an old
cystic
a In agent agent agent by of
may kit
of compositions additional
thereof. one
or the the with
is a
composition an comprising
agent
older.
fibrosis. is is is
■OH tablet be present 1 embodiment, administration
effective
another another selected to the administered
composition
5
is the
pharmaceutical by of therapeutic In years
selected
invention
patient Kalydeco
another addition
of
CFTR CFTR
a from amount described
pharmaceutical the old.
a
of present tablet
from any is
followed potentiator corrector of
In
agent of
is 150 12 of ™
the
another of
either
above. the to
once of
mg
the
that 18
the
by
of
2015247850 04 Jun 2019 pharmaceutical pharmaceutical amine and composition stored composition [0589] [0588] [0587] [0590] [0591]
the
moiety in
additional
the VII. In In Compound Scheme
other some
of same of
1-2 GENERAL
the the composition composition
embodiments, embodiments, 1 to therapeutic
container, : present present
form Preparation 1
may
compound
invention invention be SYNTHETIC
of of and
agent prepared
the the
the
the
of the
present present
Compound additional is additional
container are are 1-3
stored
by
stored stored followed
invention invention coupling SCHEMES
in
therapeutic therapeutic
is 121
in in 1 a
. a
separate the separate
by bottle,
the and is
same deprotection
stored
acid
the
vial, bottle, agent agent
containers. container.
additional halide
ο in
or
and and a
vial, blister
bottle,
according
moiety
the the
or In
For therapeutic
pharmaceutical pack. pharmaceutical
blister vial, some
example, 1-1
to or
with examples,
pack. Scheme
blister
agent
the the
pack,
1
are the .
2015247850 04 Jun 2019 [0593] [0592] [0595] [0594] °2 N F^^NH ^
2. 1. Compound Compound Scheme Scheme
NaOH HC1
2
2: 3: Et0Ac
NBS
Preparation Preparation 1-1 1-2
is is
°2Nx/^Br prepared prepared F^^NHs
of of
Compound Compound
according according Na Pd(dba) Toluene, 2. 1. NaOH Bu
3 BOMC1 Mg, PO
2) 3) 1) 4
122 to to NBr 1-1. 1-2. Zn(C10
4 H T THF Scheme Scheme 2 , s
2 ,
H OH-H N'^-OBn , Z-B
Pt(S)/C 2 O, u 4
3 ) 70°C 2 P 2
-2H 2. 3. O
2 0 * © 1-1 KOH DMSO, 75°C 3N
HC1, CN
2015247850 04 Jun 2019 moiety [0597] [0596]
with Compound Scheme
an
amine
4:
Synthesis 2
moiety can
be
according prepared of
the
4-oxo-
by
to
coupling Schemes
dihydroquinoline 123
a 4-6.
4-oxo-dihydroquinoline
carboxylic
acid
moiety. carboxylic
acid
[0598] Scheme 5: Synthesis of the amine moiety. 2019
H2, Pd/C, MeOH Jun
04
2015247850
[0599] Scheme 6: Coupling of the 4-oxo-dihydroquinoline carboxylic acid moiety with the amine moiety.
Compound 2
[0600] VIII. EXAMPLES
[0601] Analytical Methods
[0602] 1. Differential Scanning Calorimetry (DSC)
[0603] Referring to Figures 2 and 7, the differential scanning calorimetry (DSC) data of spray dried dispersions of the present invention were collected using a DSC Q2000 (TA Instruments, New Castle, DE). Temperature was calibrated with indium and heat capacity was calibrated with sapphire. Samples of 8-15 mg were weighed into T-zero aluminum pans
124 2015247850 04 Jun 2019 placed mixture mmol) 2.2.0.248 were nickel. (75 (7.28 charged solvent 5-yl)cyclopropanecarboxamide. 5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol- from: detector. dispersions Castle, numbers that °C [0608] [0607] [0606] [0605] [0611] [0610] [0609] 10 189 [0604]
°C/min. at
g, were (TA
used.
a g, 3°
316.5
on
was Samples heating DE).
was
was NasPCti
12.66 to
Instruments, represent A Synthesis Acid Example Referring Thermal
crimped Cu and zero-background
40°
reactor
charged of Data
A degassed mmol)
allowed The sealed
analyzed mmol). the
nitrogen
Moiety for rate
of
(155.7 were reported
present
gravimetric using
a single
of was 10-20 to 1:
of
was tube over total
to
(2,2-difluoro-l,3-benzodioxol-5-yl)-l-ethylacetate-acetonitrile via New Figures 2. 2° 3. collected Synthesis
A
by gas purged
stir g,
added lids
with C/min
mg 10 analyses. of nitrogen
10% invention
numbers 949.5 Universal
EIO%^ balance Castle,
for silicon
min 12
with were
XRPD
Thermogravimetric Ka 1 analysis
w/w
over
50 with minute
0 and by and
mmol), at
of
1 radiation
min, sparge
scanned
DE). wafers
23°
represent Thermal
solution purge pin
Compound were
1 6, with nitrogen (X-ray
Analysis C min.
"
the
scan (TGA)
C at hole.
followed
Temperature
a collected
for
from which of
at X-Ray
nitrogen
from Na After Touene, Pd(dba) was
Powder times.
of
Advantage
25 10 The no single and
software 3 was
tert-butylphosphine 125
a PO
ml/min °C.
used
less time 1: 25 nitrogen
charged stirring samples diffraction analysis by
4
performed on
(/f)-l-(2,2-difluorobenzo[d][l,3]dioxol-
2 ,
analyses.
°C
gas Diffraction) H For
, than
bis(dibenzylideneacetone) at
5-bromo-2,2-difluoro-l,3-benzodioxole ABu 2 a was
O,
to version and 40 Bruker Q purge each
for
purged 16 350
with 70
were 3 SeriesTM (TGA) equilibrated kV, P
a
h. (XRD) an
°C
sample, sample with °C of
900 40mA. Advance
4. scanned To additional
50 addition at ID
in a the
mL
F^ a
ml/min.
data
software TGA
(TA purge hexanes heating the
reactor by The of o
from
with of
XXA 20
Instruments, funnel. toluene. Curie 50 Q500
of
spray samples
The angles
min, rate 20
version Vantec- 90 (51.23 was
palladium
point V6.3 °C
reported
ml/min dried
of
λ The the then
The
Ν ranged
to were
O
g,
1
Build with 250 New
o 25.32
H
(0)
2015247850 04 Jun 2019 under by the with was 91.5% 66% acetonitrile distillation The and maintaining Hz, C 65° (2 cooled complete water mixture acetonitrile δ 70 [0613] [0612] 1H), 1.5
7.16
and
x
- HPLC
- extractions.
C. 3H). analyzed
solution observed 450
MTBE 80° 7.43 yield
2.0
(4.5 vacuum
diluted
- AUC to The
was
7.10 mL)
C
Synthesis
Torr. The 20 conversion
every (d,
mL) from
that until
was from
concentrate
an (2
- charged (corresponds
was
J=
by (m, DMSO to and (typically
25° at
x internal
in was (2,2-Difluoro-l,3-benzodioxol-5-yl)-acetonitrile
5-bromo-2,2-difluoro-l,3-benzodioxole then 1
The
active 900 HPLC
< 8.4 525 above
then 2H), - the one
C of 60°
2
equipped
Hz, mL combined
and was distilled with mL), solution h (2 combined
portion.
transferred
7.03
distillation C
temperature ,2-difluoro- for every was was after
with
1H), fdtered to
observed
to ethyl
with the
(d,
remove
charged charged
a
5
with from
DMSO 1 7.22
of
w/w
percent J= -
organic The
- cyanoacetate sufficient organics
(2,2-difluoro-l,3-benzodioxol-5-yl)-l-ethylacetate- 6 through
2
to
of
8.2 a h), (dd,
the (typically h 1
assay
mixture
< the equipment ,3-benzodioxol-5-yl)-acetonitrile. cooled
with the
with for
in
40° the Hz,
conversion
resulting
J= extracts
solvents.
preparation
solvent percent
were
DMSO, a
of
3 reaction 225mL time C.
1H),
celite 8.2,
N receiver
3N was 95%).
(71.6 100% The
HC1
concentrated 126
to appropriate 4.63 HC1, were
1.8
oil
ceased. heated conversion.
pad.
allow
(2,2-Difluoro-l,3-benzodioxol-5-yl)- DMSO
75
mixture of
was
(617.3
g, Hz, at
*H
conversion for flask.
(s,
the °C washed
633.0 125
NMR The
cooled
to 1H), 1H), Step for
(2 reactant The
and mL, -
70°
was
steps) The celite
complete for mmol)
to
130°
4.07
4.19 2. (500 with
solution When
concentrated to
C
300
1.85
a then after
solution
*H was
over 20
1.5
pad to and C
(s, (m,
MHz, 5%
mL
NMR over
mol)
the (oven -
heated
a -
5 2H).
isolated
phase
was
with
2H), 40 25° conversion was NaCl
2.5 -
under product.
5
was 8 DMSO) min
over
(500 rinsed
C temperature) min
Torr h),
cooled
an 1.23 to under
separation
(2 and
concentrated
as vacuum
the and HPLC 75°
20
followed MHz, x
vacuum
a (t,
extracted
with
After
375
min mixture
δ of clear vacuum analyzed to C
J= 7.44
>99% over
20
purity
CDCL) mL). while toluene
at
during 7.1
oil
and -
by (br 60
25° 1
was
at in
h of - s,
[0614] Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile. 2019
Bu4NBr, 50% w/w NaOH
Jun MTBE
04 [0615] A stock solution of 50% w/w NaOH was degassed via nitrogen sparge for no less
than 16 h. An appropriate amount of MTBE was similarly degassed for several hours. To a reactor purged with nitrogen was charged degassed MTBE (143 mL) followed by (2,2- difluoro-l,3-benzodioxol-5-yl)-acetonitrile (40.95 g, 207.7 mmol) and tetrabutylammonium bromide (2.25 g, 10.38 mmol). The volume of the mixture was noted and the mixture was degassed via nitrogen sparge for 30 min. Enough degassed MTBE is charged to return the
2015247850 mixture to the original volume prior to degassing. To the stirring mixture at 23° C was charged degassed 50% w/w NaOH (143 mL) over 10 min followed by l-bromo-2- chloroethane (44.7 g, 311.6 mmol) over 30 min. The reaction was analyzed by HPLC in 1 h intervals for % conversion. Before sampling, stirring was stopped and the phases allowed to separate. The top organic phase was sampled for analysis. When a percent conversion of >99 % was observed (typically after 2.5 - 3 h), the reaction mixture was cooled to 10° C and
was charged with water (461 mL) at such a rate as to maintain a temperature < 25° C. The temperature was adjusted to 20 - 25° C and the phases separated. Note: sufficient time should be allowed for complete phase separation. The aqueous phase was extracted with MTBE (123 mL), and the combined organic phase was washed with 1 N HC1 (163mL) and 5% NaCl (163 mL). The solution of (2,2-difluoro-l,3-benzodioxol-5-yl)- cyclopropanecarbonitrile in MTBE was concentrated to 164 mL under vacuum at 40 - 50° C. The solution was charged with ethanol (256 mL) and again concentrated to 164 mL under vacuum at 50 - 60° C. Ethanol (256 mL) was charged and the mixture concentrated to 164
mL under vacuum at 50 - 60° C. The resulting mixture was cooled to 20 - 25° C and diluted with ethanol to 266 mL in preparation for the next step. *H NMR (500 MHz, DMSO) δ 7.43 (d, .7=8.4 Hz, 1H), 7.40 (d, J= 1.9 Hz, 1H), 7.30 (dd, J= 8.4, 1.9 Hz, 1H), 1.75 (m, 2H), 1.53 (m, 2H).
[0616] Synthesis of 1-(2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid.
6 N NaOH
EtOH, 80 °C
127 2015247850 04 Jun 2019 preparation polish benzodioxol-5-yl)-cyclopropanecarbonitrile HPLC mL). was reactor with the to mL). the When hydrolysis monitored (2,2-difluoro-l,3-benzodioxol-5-yl)-acetonitrile difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic filtered C mL) combined after extracted separate. heated from ethanol [0618] [0617] l,3-benzodioxol-5-yl)-cyclopropanecarboxylic [0619]
to maintain
reaction mixture
cooled
give and MTBE the the
The The
a filtered
purity to
and
and from
percent
extraction
previous concentrated Isolation The The with an a
The
and material solution by
of
homogeneous
to the
a for the
condensed mixture (364 internal
the of temperature (2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarbonitrile
solution solution HPLC
5° bottom to concentrated DCM
the collected
reactor
99.0% conversion
previous
remove C
mL)
step
of next was was due over
was temperature after (164
1-(2,
organic to of of
and
is
to
AUC. and
to cooled
dried step.
2
solids. residual cooled (2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarbonitrile
164 concentrated 1-(2,
164 solution. 2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic < a mL). step 16 hours
stirred
collected of high under 25°
h. mL
under 2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic mL
phase ESI-MS > was
to
Note: Note: C.
to 99 and The
concentration
of at
inorganic 10° at at70-75°C. vacuum
25°
charged % After After 70 vacuum
77 60°
was maintained
solid combined
C
was
the under the - C - m/z
and
C
75°
collected 78°
and
warming stirring
aqueous consumption washed
for to observed
calc.
salts.
with
charged
and
at
vacuum
C. C 164
charged 20
55° 128
of acid over
organics
(3
at the 242.04, The
6 The min.
at mL. inorganic MTBE
with N and 5° steps phase C to
that primary as
(typically 45
with
mixture
NaOH for to
mixture 20
C
with
an the
Toluene
The
min. cold of
for acid 164 temperature including
found were -
17
was (123 off-white 6
both
top 25°
ethanol
N 3 solution
hours salts.
mL, (277
amide 1:1 was
hours. was The
somewhat
was HCI transferred aqueous
mL) C, 100% 241.58
(2,2-difluoro-l,3- (328
toluene/n-heptane
charged
isolated mL) the reaction then to
The
isolation) cooled
(290
(41
resulting was crystalline
was
provide
The for mL) conversion phases
over (M+l) organics heated mL) phase
mL) used 30 cloudy
cooled
mixture with to to in was progress
20 min, were
and
a 45° 79% were and
from at + l-(2,2-difluoro-
to was
to clean
; charged toluene min solid.
*H such
were
before rinse
to DCM
C, after the 100 with
monitored.
yield
was
back allowed
partial NMR
25°
(2
and
charged was
reactor
acid. solution
a
-
the
1-(2,2-
x
an 16
then
rate
(164
(328
C
and and 105° in from
123
acid
(500 h),
and
to as
in
MHz, DMSO) δ 12.40 (s, 1H), 7.40 (d, J= 1.6 Hz, 1H), 7.30 (d, J= 8.3 Hz, 1H), 7.17 (dd, J = 8.3, 1.7 Hz, 1H), 1.46 (m, 2H), 1.17 (m, 2H).
2019 [0620] Alternative Synthesis of the Acid Moiety
[0621] Synthesis of (2,2-difluoro-l,3-benzodioxol-5-yl)-methanol. Jun
04 1. Vitride (2 equiv) PhCH3 (10 vol)
2. 10% aq (w/w) NaOH (4 equiv)
86-92% yield
[0622] Commercially available 2,2-difluoro-l,3-benzodioxole-5-carboxylic acid (1.0 eq) is slurried in toluene (10 vol). Vitride® (2 eq) is added via addition funnel at a rate to maintain
2015247850 the temperature at 15-25 °C. At the end of addition the temperature is increased to 40 °C for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50 °C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 °C. The organic phase is cooled to 20 °C then washed with water (2 * 1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-l,3-benzodioxol-5- yl)-methanol that is used directly in the next step.
[0623] Synthesis of 5-chloromethyl-2,2-difluoro-1,3-benzodioxole.
1. SOC12 (1.5 equiv) DMAP (0.01 equiv) MTBE (5 vol) 2. water (4 vol) _ ------FxT^L 82-100 % yield F
[0624] (2,2-difluoro-l,3-benzodioxol-5-yl)-methanol (1.0 eq) is dissolved in MTBE (5 vol). A catalytic amount of DMAP (1 mol %) is added and SOCb (1.2 eq) is added via addition funnel. The SOCI2 is added at a rate to maintain the temperature in the reactor at 15 25 °C. The temperature is increased to 30 °C for 1 hour then cooled to 20 °C then water (4 vol) is added via addition funnel maintaining the temperature at less than 30 °C. After stirring for an additional 30 minutes, the layers are allowed to separate. The organic layer is stirred and 10% (w/v) aq. NaOH (4.4 vol) is added. After stirring for 15 to 20 minutes, the layers are allowed to separate. The organic phase is then dried (Na2SO4), filtered, and concentrated to afford crude 5-chloromethyl-2,2-difluoro-l,3-benzodioxole that is used directly in the next step.
129 [0625] Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile.
1. NaCN (1.4 equiv) DMSO (3 vol) 2019 30-40 degrees C 2. water (6 vol)
Jun MTBE (4 vol)
04 95-100% yield
[0626] A solution of 5-chloromethyl-2,2-difluoro-l,3-benzodioxole (1 eq) in DMSO (1.25 vol) is added to a slurry of NaCN (1.4 eq) in DMSO (3 vol) maintaining the temperature between 30-40 °C. The mixture is stirred for 1 hour then water (6 vol) is added followed by MTBE (4 vol). After stirring for 30 min, the layers are separated. The aqueous layer is extracted with MTBE (1.8 vol). The combined organic layers are washed with water (1.8 2015247850 vol), dried (Na2SO4), fdtered, and concentrated to afford crude (2,2-difluoro-l,3- benzodioxol-5-yl)-acetonitrile (95%) that is used directly in the next step.
[0627] The remaining steps are the same as described above for the synthesis of the acid moiety.
[0628] Amine Moiety
[0629] Synthesis of 2-bromo-5fluoro-4-nitroaniline.
NBS EtOAc 50%
[0630] A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22 °C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50 °C overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50% yield, 97.5% AUC). Other impurities were a bromo-regioisomer (1.4% AUC) and a di-bromo adduct (1.1% AUC). 1H NMR (500 MHz, DMSO) δ 8.19 (1 H, d, J= 8.1 Hz), 7.06 (br. s, 2 H), 6.64 (d, 1 H, J= 14.3 Hz).
130 [0631] Synthesis ofp-toluenesulfonic acid salt of (R)-l-((4-amino-2-bromo-5- fluorophenyl)amino)-3-(benzyloxy)propan-2-ol.
2019 CN 1) Χχ^ΟΒη cat. Zn(C104)2-2H20 Θ Jun
toluene, 80 °c 04 2) H2,Pt(S)/C
IPAc
3) TsOH-H2O OBn DCM
[0632] A thoroughly dried flask under N2 was charged with the following: Activated powdered 4A molecular sieves (50 wt% based on 2-bromo-5-fluoro-4-nitroaniline), 2- 2015247850 Bromo-5-fluoro-4-nitroaniline (1.0 equiv), zinc perchlorate dihydrate (20 mol%), and toluene (8 vol). The mixture was stirred at room temperature for NMT 30 min. Lastly, (R)-benzyl glycidyl ether (2.0 equiv) in toluene (2 vol) was added in a steady stream. The reaction was heated to 80 °C (internal temperature) and stirred for approximately 7 hours or until 2-bromo- 5-fluoro-4-nitroaniline was <5% AUC.
[0633] The reaction was cooled to room temperature and Celite (50 wt%) was added, followed by ethyl acetate (10 vol). The resulting mixture was filtered to remove Celite and sieves and washed with ethyl acetate (2 vol). The filtrate was washed with ammonium chloride solution (4 vol, 20% w/v). The organic layer was washed with sodium bicarbonate solution (4 vol x 2.5% w/v). The organic layer was concentrated in vacuo on a rotovap. The resulting slurry was dissolved in isopropyl acetate (10 vol) and this solution was transferred to a Buchi hydrogenator.
[0634] The hydrogenator was charged with 5 wt% Pt(S)/C (1.5 mol%) and the mixture was stirred under N2 at 30 °C (internal temperature). The reaction was flushed with N2 followed by hydrogen. The hydrogenator pressure was adjusted to 1 bar of hydrogen and the mixture was stirred rapidly (>1200 rpm). At the end of the reaction, the catalyst was filtered through a pad of Celite and washed with dichloromethane (10 vol). The filtrate was concentrated in vacuo. Any remaining isopropyl acetate was chased with dichloromethane (2 vol) and concentrated on a rotavap to dryness.
[0635] The resulting residue was dissolved in dichloromethane (10 vol). p-Toluenesulfonic acid monohydrate (1.2 equiv) was added and stirred overnight. The product was filtered and washed with dichloromethane (2 vol) and suction dried. The wetcake was transferred to
131 drying trays and into a vacuum oven and dried at 45 °C with N2 bleed until constant weight was achieved. p-Toluenesulfonic acid salt of (R)-l-((4-amino-2-bromo-5- fluorophenyl)amino)-3-(benzyloxy)propan-2-ol was isolated as an off-white solid. 2019
[0636] Chiral purity was determined to be >97 % ee. Jun
[0637] Synthesis of (3-Chloro-3-methylbut-l-ynyl)trimethylsilane. 04
HC1 neat ------► TMS 90% TMS
[0638] Propargyl alcohol (1.0 equiv) was charged to a vessel. Aqueous hydrochloric acid (37%, 3.75 vol) was added and stirring begun. During dissolution of the solid alcohol, a modest endotherm (5-6 °C) is observed. The resulting mixture was stirred overnight (16 h), 2015247850 slowly becoming dark red. A 30 L jacketed vessel is charged with water (5 vol) which is then cooled to 10° C. The reaction mixture is transferred slowly into the water by vacuum, maintaining the internal temperature of the mixture below 25° C. Hexanes (3 vol) is added and the resulting mixture is stirred for 0.5 h. The phases were settled and the aqueous phase (pH < 1) was drained off and discarded. The organic phase was concentrated in vacuo using a rotary evaporator, furnishing the product as red oil.
[0639] Synthesis of (4-(Benzyloxy)-3,3-dimethylbut-l-ynyl)trimethylsilane.
1. Mg
TMS 2. BnOCH2Cl TMS
[0640] Method IA,
[0641] All equivalent and volume descriptors in this part are based on a 25 Og reaction. Magnesium turnings (69.5 g, 2.86 mol, 2.0 equiv) were charged to a 3 L 4-neck reactor and stirred with a magnetic stirrer under nitrogen for 0.5 h. The reactor was immersed in an ice water bath. A solution of the propargyl chloride (250 g, 1.43 mol, 1.0 equiv) in THF (1.8 L, 7.2 vol) was added slowly to the reactor, with stirring, until an initial exotherm (~10° C) was observed. The Grignard reagent formation was confirmed by IPC using 1H-NMR spectroscopy. Once the exotherm subsided, the remainder of the solution was added slowly, maintaining the batch temperature <15° C. The addition required ~3.5 h. The resulting dark green mixture was decanted into a 2 L capped bottle.
[0642] All equivalent and volume descriptors in this part are based on a 500g reaction. A 22 L reactor was charged with a solution of benzyl chloromethyl ether (95%, 375 g, 2.31 mol,
132 2015247850 04 Jun 2019 below the then prepared benzyl then stirred temperature remainder the the of solution reagent as and addition spectroscopy. The indicating crude The drained and complete, out solution 0.8 [0644] [0645] [0643] 1.0
water, in
propargyl batch addition equiv) equiv) at the concentration
Grignard organic
added suspended Method
product a
25° for
chloromethyl
mixture batches rate
off
via of required
All Magnesium as temperature 10
the 0.5 the of in in C.
drop 15% and
described such a was phase <20° vol).
equivalent
THF THF
the
A
chloride vessel header reagent h. Grignard The as Neat Method
discarded. in
prepared to wise
was
ammonium
stopped propargyl
an
The as
1.0 C.
was THF The (1.5 give (4.5 was addition
orange
to benzyl
jacket
stirred
ether
vessel. into h.
The turnings Grignard
formation
reached above
keep solution carried solution
L, L,
concentrated IB,
the reagent (760 and The
and as the
6 3
addition
solution
product The temperature
chloride chloromethyl oil. required
for vol) vol).
the described
volume
chloride
were
mL, reaction An reactor, the
out 2° (106
0.5 was reagent was remaining internal initiation.
was was
exotherm mixture C.
The 1 using combined
required
h.
as via
vol). g,
added
cooled solution
descriptors
1.5 in
A added confirmed
was
maintaining
mixture After 4.35 an reactor above
an
vacuo solution
formation
was temperature
h. the
orange
ether
The stirred prepared
addition
organic slowly,
Once
was mol,
to The slowly
-1.5 same settling
set and were was
was using vessel 5° was
133 was
observed
to by
reaction
in
of
oil. until 1.0 the
then C. h.
added
procedure
was
the
25° cooled combined maintaining phase this
stirred the to funnel,
IPC in
charged
a the
The eq) exotherm Two below was
the 22
batch a transferred a
propargyl confirmed C.
part
using 30 phases, 13° were
slowly,
resulting mixture L was
reactor. in cooled in Grignard overnight.
Hexanes
maintaining
L
rotary
25° are
this C temperature to
an and jacketed
and
washed charged
'H-NMR
exotherm
subsided,
the
based the
ice-water
C. the
maintaining quench,
relative in
chloride
was then by into
evaporator,
After dark
reactor
batch Once an reaction aqueous (8
IPC
The
on
with stirred reactor the to L, added ice-water
the green
spectroscopy.
was 100
below which another
a a temperature amounts 8 the using bath.
ammonium
aqueous (760
addition
22 1 vol) water batch
mixtures
kg phase mL the transfer overnight
observed, slowly
solution (1.5 L providing
g, was 25° reaction. 1 was Two
reactor
H-NMR bath batch
was 500
temperature (2
4.35
kg of
work-up (pH
funnel
C. L, carried added to
Grignard materials
was mL added,
such in <20°
chloride
was
2 mol, The the
(16 The 9) and
8.5
the vol).
of
A
was and
that
h).
C.
kg
2015247850 04 Jun 2019 fluorophenyl)amino)-3-(benzyloxy)propan-2-ol. fluoroindole. primarily to material with resulting methanol (benzyloxy)propan-2-ol 7.18 organic aqueous diluted as set exotherm [0649] [0648] [0647] [0646] [0651] [0650] 1.25
5° monitored
to
(s, (t, a
C. 25
solution
with 2 phase 6H).
phase as
Potassium p-Tolucncsul °C.
Synthesis Synthesis A Syntheisis mixture
H, (2 a was
a single 30
J= water vol)
yellow-orange by A
was observed
Method L (pH
of
solution
7.2
HPLC. jacketed
was
was
KOH
impurity
(8 then of of
10-11) hydroxide of Hz),
vol)
N-benzylglycolated-5-amino-2-(2-benzyloxy- added (R)-l-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-l-yn-l-yl)-5- stirred
4-Benzyloxy-3,3-dimethylbut-
ionic
IC.
concentrated
(85%, as
was of Typical 7.10
reactor and was the
present. 4-benzyloxy-3,
oil. acid and
freebased for
(d, then potassium (85%, 0.4
drained
the
Typical 0.5
salt reaction was 1H,
equiv)
stirred
K resulting h.
*H
of down
Pd(OAc), 2 1.3 J= charged
CO
by
off
The NMR (/?)-l-((4-amino-2-bromo-5-fluorophcnyl)amino)-3-
purity equiv)
hydroxide 3 in 7.2
time for stirring , 3
2 and 88% MeOH KOH using Cui,
-dimethyl-1-trimethylsilylbut-l-yne phases water
steps
Hz),
mixture
0.5
(400
dppb, with
at
134 discarded.
water of was over
25°
a h.
the 4.35 this (8
rotary
MHz,
were methanol
dissolved. 1-yne.
added Hexanes
vol)
C solid
was
material
(s, is
allowed
followed Οόϋό)
evaporator, 3-4 2
stirred
The to in
H),
(6 the dichloromethane (6 h.
organic
The is
3.24 vol) δ vol)
The reactor. to until
in 7.28
1 by
jacket
, settle
the
1 which
(s, was reaction yielding
-dimethylethyl)
water
reaction OBn (d, phase
80% 2
added and H), A temperature 2
was
H,
(8 15-20°
range
was
then 1.91 mixture
the
vol). J= (5 completion,
then (1.0 and
vol)
washed title
(s, the 7.4
with
C
the equiv) -6- The cooled
1
and is Hz), was
H),
in
2015247850 04 Jun 2019 fluoroindole. reactor mixture (2.5 solution acetonitrile. complete heated without the washed Reaction solution carbonate vol) eq) dimethylbut-l-yn-l-yl)-5-fIuorophenyl)amino)-3-(benzyloxy)propan-2-ol (benzyloxy)propan-2-ol amino-2-(4-(benzyloxy)-3 The added. 5-fIuorophenyl)amino)-3-(benzyloxy)propan-2-ol fluorophenyl)amino)-3-(benzyloxy)propan-2-ol layers saturated [0653] [0654] [0652]
mixture
in
mixture vol). followed
acetonitrile
were
to The
and
with further is of is
Rzx-acetonitriledichloropalladium Synthesis Palladium progress NaHCCh
within 80°
(3 The sparged
washed
4-benzyloxy-3,3-dimethylbut-l-yne
mixture then separated is
is A eq) acetonitrile
C. by
polish
ethyl
cooled solvent manipulation.
suspended are 1-3 brine The
(9.5
is with with solution of
is acetate
suspended acetate h. monitored filtered
N-benzylglycolated-5-amino-2-(2-benzyloxy-
reaction
and
sparged to
vol and swap
The nitrogen aqueous
thus room (4
,3 the
total).
concentrated
(0.01
vol). in (5
-dimethylbut- solution
mixture
into into obtained
organic
a vol) progress with
temperature
in by solution
NH3-NH4CI
gas the
eq), ethyl The The acetonitrile
HPLC until
nitrogen
is is next for
dppb layer combined mixture
is
then filtered acetate
is
clear in of used 1 (MeCN)
monitored and reactor. 1 h
-yn- vacuo (7?)-l-((4-amino-2-(4-(benzyloxy)-3,3- and (0.015 (0.1
was
stirred and gas
solution organic (1.2 directly the
is (7.5 through
135
1
then (1.1
2
eq) free washed
-yl)-5 then filtrates for PdCI
sparged
to reaction free
vol).
eq), The with
vol)
and
another obtain eq) base filtered by
2 a
layer
-fluorophenyl)amino)-3
in (2
base
Cui solution celite acetonitrile
HPLC is
silica Cui in
with After
the are
x with
as
performed. is
acetonitrile 2.5
(77)- (0.015 was
(1
hour through next an (0.1 azeotroped
usually
and
saturated
gel
stirring nitrogen eq) vol)
and
oil. l-((4-amino-2-bromo-5- of achieved.
eq) procedure the and
(1.8
in
eq) (7?)-l-((4-amino-2-bromo-
1 the solution followed ,
complete l-dimethylethyl)-6- Celite. acetonitrile are
cake
then
for wt and
The (0.2
reaction NaHCCh gas
to charged
eq)
15
obtained
potassium is
dryness is The ethyl vol)
for of
(cyclization)
washed The minutes, by heated and
-
within (77)-1-((4-
1
resulting
is
is
10%
solution acetate h
(4.1 to cake
Si-TMT typically
added. and
and
above the to
with brine
vol) 3-5
a
is
80° then
then
(5
h.
is The (1
C.
is
2015247850 04 Jun 2019 fluoroindole. bromo-5-fluoroaniline acetonitrile crude 2 through to mixture 4-benzyloxy-3,3-dimethylbut-l-yne Hz), H), 2-ol solvent added (1.5 9.8, 5.13 amino-2-( oil oil (0.1 80° [0656] [0655] [0658] [0657]
L, be
thus is
7.32-7.23
C
4.4 kg, wt 2 is
4.09-4.04 (d,
complete dissolved
solution
and vol). to typically
eq)
have Hz), obtained which 3.0 a 1H, the Rzs-acetonitriledichloropalladium Synthesis Palladium
pad 1 then
-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-
for
(4 eq)
J= The
reactor. been 3.43
(m,
of
L,
was
Method
was 6
(m, after stirred in
are
obtained 4.9
h. combined celite
2 is
(dd, 6 DCM
collected,
vol). 2 of transferred
then charged then
H), After Hz), acetate
16 H), The
N-benzylglycolated-5-amino-2-(2-benzyloxy-
overnight.
1H, (1.5
(228 ID. h.
7.21
/ crystallized sparged
3.63 4.54 The
in heptane filtration, mixture
J= The
phases
kg,
(33
to 27-38% g). leaving (d,
combined
(d,
(s,
a back
9.8,
mixture
1.0 g,
The reactor. 1
with 2
1H,
H, IPC 0.04 (4
was are H), eq) 5.7
2. 3.
the
into
(70%, yield. from the reactor
vol) J=
J=
nitrogen
concentrated by MeCN Pd(OAc) dppb, MeCN, Hz), was (MeCN) 4.46 Silica
sparged eq),
resulting was
solutions
crude the
12.8 The 9.2
and HPLC
25%
1.1 dissolved
(144 dppb
*H
(br.
1.40 cooled reactor
and
K
Hz),
gel free then Hz),
product NMR 2 kg, gas 80 136
2 EtOAc with 2 CO
s, PdCl
celite is g, (s, filtration solution
(94
were
°C 3.56 based
2
purified
6.77 1.05 for carried 3
0.15
to
on
6 and H),
nitrogen
g, 2
in (400 H).
ambient
NLT
pad
/
in a (d, sparged
0.06 eq) (d,
4.45 acetonitrile the heptane eq) oil 22 1
7 h H-indol- is
out
1H, MHz,
were 2
by
L 1H, in benzylglocolated roto-vap L
F n concentrated was 1
eq),
(s,
(3.5 gas
h.
rotary
acetonitrile
and column J=
temperature
J=
with
2 washed
charged (4
The DMSO) and
for
H), vol) 9.2 1 the
1
9.0 vol). -yl)-3 (8.2 ,
evaporator
nitrogen l-dimethylethyl)-6-
bulb NLT
potassium mixture
4.33
Hz), reaction
chromatography. of Hz),
with L,
Crystalline
to
-(benzyloxy)propan- down. acetonitrile.
δ was was
1 (d,
4.1 3.49 and
7.38-7.34 the 6.06 h.
4-ammonium-2- acetonitrile gas
was
added 1 washed
is vol)
reactor.
A
then until H, carbonate (dd,
The
(s,
determined for solution heated
J=
and
(7?)-l 1
filtered
to NLT 1H, 8 residual (m, H),
with
L 12.4
the The
then
The
J=
of (2 to -(5-
4
of 1
x
2015247850 04 Jun 2019 NLT based under progress the washed was L, warming toluene toluene cyclopropanecarboxylic slurried dimethylethyl)-6-fluoroindole scavenger in combined celite shows h. (3.5 and (benzyloxy)-2-methylpropan-2-yl)-6-fluoro- funnel [0659] [0660]
The ethyl 2.5
mixture
triethylamine added vol)
3
(300
reduced
on
vol) complete and reaction
h.
(1 and with acetate in
is and Synthesis to l-(2,2-Difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic l-(2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic
The filtrates
(358 vol) toluene to followed the g).
monitored
25° was the
30% the 1
pressure mixture mixture
The M is
mixture (8.8 g) excess
C,
distilled consumption
organic
added
HC1 (3
ethyl and were (2.5
the of
reactor
L, by eq)
benzyl
by
heptane reaction (5 4.4 SOCI2
was vol, was
to 5%
acetate was while concentrated acid).
in
down HPLC, phase,
vol).
give
vol).
DCM and brine heated based
filtered
protected heated
were
of maintaining
as
(17.6 .V-bcnzylglycolatcd-5-amino-2-(2-bcnzyloxy-l,l- mixture to Thionyl filter A in
which
The
starting and
a
(5 (4 solvent heptane on 1
to brown
distilled to through vol
L, vol)
L) cake the solution l-(2,2-difluoro-l,3-benzodioxol-5-yl)-
60 to
80°
Compound 2.5
was
of
were is chloride an
°C. reaction material. is
swap paste
were washed
toluene. C (25
vol).
the oil cooled
stirred
a off 1 for The
added
H-indol-
sintered was
by L). batch
137
to washed using (1.4
NLT Silica (SOCh,
rotary
is resulting
into with washed to 1. overnight. The The
A
usually and
kg).
temperature
0°
rotavop. 16
solution
glass 1
methanol
gel
combined 5%
-yl)-3 reaction with C.
evaporation. the
h. 1.7
with
(3.5 mixture NaHCCh
The complete resulting In funnel.
acetonitrile
equiv) -(benzyloxy)propan-2-ol
Deloxan
process of
kg, Additional
20%
acid mixture
(2
below (7?)-l-(5-amino-2-(l- filtrates
1.8 vol)
was
was
The
ammonium chloride (3.5 mixture within The
wt. control ΤΗΡ
is stirred
10°
was acid) added filter (3 acid
vol),
were performed oil eq.)
toluene
L,
C.
II minutes.
filtered
was was solution
(1.3
was cake
1.5 by
metal of for 1 via concentrated The
M chloride
HPLC
silica vol).
dissolved stirred 2 equiv) (2.5
added
addition was NaOH
reaction
h.
through and
After in
(
vol, gel 1 The
The
for eq) and the was (5
resulting solution of (7?)-N-(l-(3-(benzyloxy)-2-hydroxypropyl)-2-(l-(benzyloxy)-2- methylpropan-2-yl)-6-fluoro-l/7-indol-5-yl)-l-(2,2-difluorobenzo[if|[l,3]dioxol-5- yl)cyclopropanecarboxamide in methanol is used without further manipulation in the next 2019
step (hydrogenolysis). Jun [0661] Synthesis of Compound 1. 04
H2, Pd / C
HC1 - MeOH
[0662] 5% palladium on charcoal (-50% wet, 0.01 eq) is charged to an appropriate
2015247850 hydrogenation vessel. The (7?)-N-( 1 -(3-(benzyloxy)-2-hydroxypropyl)-2-( 1 -(benzyloxy)-2- methylpropan-2-yl)-6-fluoro- l/7-indol-5-yl)-1 -(2,2-difluorobenzo[if| [ 1,3]dioxol-5- yl)cyclopropanecarboxamide solution in methanol (2 vol) obtained above is added carefully, followed by a 3 M solution of HC1 in methanol. The vessel is purged with nitrogen gas and then with hydrogen gas. The mixture is stirred vigorously until the reaction is complete, as determined by HPLC analysis. Typical reaction time is 3-5 h. The reaction mixture is filtered through celite and the cake is washed with methanol (2 vol). A solvent swap into isopropanol (3 vol) is performed. Crude compound 1 is crystallized from 75% IP A-heptane (4 vol, i.e. 1 vol heptane added to the 3 vol of IP A) and the resulting crystals are matured in 50% IPA-heptane (i.e. 2 vol of heptane added to the mixture). Typical yields of compound 4 from the two-step acylation/hydrogenolysis procedure range from 68% to 84%. Compound 4 can be recrystallized from IPA-heptane following the same procedure just described.
[0663] Compound 1 may also be prepared by one of several synthetic routes disclosed in US published patent application US20090131492, incorporated herein by reference.
138 2015247850 04 Jun 2019 hy [0666] [0665] [0664] Cmpd.
droxyphenyl] No. 1
Synthesis Example Table LC/MS 521.5 M+l
7.
-1
Physical
,4-dihydro-4-oxoq of 2:
4-oxo-l,4-dihydroquinoline-3-carboxylic LC/RT Synthesis min 1.69
data
J for 5.8 3.89 6.34 (s, 7.44 1.33 1H
of =
1H), NMR Compound 4.6 Hz, Compound
(s, (dd, (s, (d,
uinoline-3-carboxamide.
Hz,
3H) 1H), 7.27 1H), J 2. HCI/H 1.
J = (400.0
Method Method
2N 2N =
1H), 1.6
and 4.32 (d, 1.59 6.0,
2 NaOH HCI
O 139 1. Hz,
J 2: 3.21
1.18 MHz,
2 1 11.5 (dd, = (d,
N-[2,4-bis(l,l-dimethylethyl)-5-
1H), 8.3
J (dd,
(dd,
Hz, J
= CD
Hz, =
7.39 6.8
3.8, J J 3 1H),
NMR = CN) =
1H), Hz,
6.2, 3.7, (dd, 6.8
acid 3.63
d 2H), 7.20 26
O
H
7.2 Hz, 6.8 J 7.69
= (26). -
Hz, Hz, 4.15 (d, 3.52 1.7, 2H), O
(d,
J
2H)
1H),
8.3 J = - (m,
1.44
= 4.09 12.0
Hz,
7.7 ppm. 3.04 3H),
(s,
(m,
Hz, Hz, 1H),
3H), (t, 3.42
1H),
1H), 1H),
J 7.31
=
(d,
[0667] Procedure for the preparation of ethyl 4-oxo-l,4-dihydroquinoline-3-carboxylate (25). 2019
Jun
04
[0668] Compound 23 (4.77 g, 47.7 mmol) was added dropwise to compound 22 (10 g, 46.3 mmol) with subsurface N2 flow to drive out ethanol below 30 °C for 0.5 hours. The solution was then heated to 100-110 °C and stirred for 2.5 hours. After cooling the mixture to below 60 °C, diphenyl ether was added. The resulting solution was added dropwise to diphenyl 2015247850 ether that had been heated to 228-232 °C for 1.5 hours with subsurface N2 flow to drive out ethanol. The mixture was stirred at 228-232 °C for another 2 hours, cooled to below 100 °C and then heptane was added to precipitate the product. The resulting slurry was stirred at 30 °C for 0.5 hours. The solids were then filtrated, and the cake was washed with heptane and dried in vacuo to give compound 25 as brown solid. *H NMR (DMSO-d6; 400 MHz) δ 12.25 (s), δ 8.49 (d), δ 8.10 (m), δ 7.64 (m), δ 7.55 (m), δ 7.34 (m), δ 4.16 (q), δ 1.23 (t).
[0669] Procedure for the preparation of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (26).
q q Method 2A O O
f Method 2B N ------*" H 1.2NNaOH 25 2. 2N HCI 26
[0670] Method 2A,
[0671] Compound 25 (1.0 eq) was suspended in a solution of HCI (10.0 eq) and H2O (11.6 vol). The slurry was heated to 85-90 °C, although alternative temperatures are also suitable for this hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperature of from about 75 to about 100 °C. In some instances, the hydrolysis is performed at a temperature of from about 80 to about 95 °C. In others, the hydrolysis step is performed at a temperature of from about 82 to about 93 °C (e.g., from about 82.5 to about 92.5 °C or from about 86 to about 89 °C). After stirring at 85-90 °C for approximately 6.5 hours, the reaction was sampled for reaction completion. Stirring may be performed under
140 2015247850 04 Jun 2019 mL) dihydroquinoline-3-carboxamide hours mL) compound with compound °C and any 8.87 [0672] [0675] [0674] [0673] [0677] [0676]
and
filtered. of
and and 2 (s),
and
vol the then
Procedure δ triethylamine ethanol Compound To Total
filtered.
temperatures 8.26 H2O 26. 26
the a The
as solution
Method Method
synthesis
(m), until pH
a (100 reactor/cake
brown
The for was
δ the 25
mL). 7.87
(10.1 of 2B, 2C.
the cake suited
(11.3 adjusted pH of
solid. 2,4-di-terrtbutyl
preparation
29
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo- (m),
> The mL, was
g, 3.0. was for
δ
52
*H
solution
to
72.8 washed (Compound
7.80 the
rinsed The NMR mmol) 2-3
hydrolysis.
mmol),
(m),
with cake of
was with with
(DMSO-d6;
2,4-di-tert-butylphenyl phenol, was
δ
8% was
7.56
2). heated
was
water H 141 added
2 HC1.
then O
The
(m). 29, added
(2
(50 to
to 400 dried (10 vol solution The
reflux
a mL)
methyl
mixture g, O MHz) x mixture
under
2). 48.5mmol) 30
and for
was The
chloroformate δ
methyl
then 16
vacuum of
15.33 was then
cake hours, 10%
dried
then
in 1,4- cooled carbonate (s),
was
NaOH
at
diethyl cooled
in stirred δ 60
then 13.39
vacuo
(7.46 to °C
(aq)
20-25 ether
to
washed (30). to for
(s),
20-25 mL, to (10 give
0.5
(100 give δ °C
97
2015247850 04 Jun 2019 keeping mmol) methylene the heated Methyl methylene Hz, temperature methyl mmol) concentrated °C organic charged Triethylamine chromatography The complete filtered, chloroformate stir (31). [0678] [0679] [0680] 1.29
to
aqueous
for
1H), solution (s,
give
to
and an dropwise
chloroformate
chloroformate layers 9H). the with the
Procedure 7.29 To 23 and
additional a
chloride. chloride
2,4-di-tertbutyl
filtrate solution final layer and
- a
was
in
150
was
(dd, reactor were 28 was (76 Method
vacuo
then to
at
pH then
°C mL was
worked
J=
g,
then was
0 give
(415 for combined
temperature 2
and 751
of °C.
stir
water. vessel
was at then (52 concentrated 8.4, hours.
2D,
cooled the 5
added
compound
a g, stirred for mmol)
- The
g, up temperature
then
2.4
phenol preparation separated 313 6.
charged
550.3 an The
by
An mixture
and Hz, and The
to
added mL) addition
for
was fdtering,
between 0 mixture additional
(compound neutralized
the
1H),
mmol)
organic 30. °C, 20 to
and
with then and
and produce
reaction h was
hours. below
and 7.06 2
*H of
the so 1
extracted
then added 4-dimethylaminopyridine was 0 the was hours.
5-nitro-2,4-di-tert-butylphenyl NMR then
layer an 4
-
5 solution , (d,
20 hno
5 reaction mL
The
with
29, additional stirred washing 142 then
a stirred
°C. J=
allowed
and yellow °C was (400
At
triethylamine 3 103.5 reaction
with 2.5% added 8.4 to
The
the
this was then
at
overnight. MHz, was
150
Hz,
with
oil 15 to
g, solution 150 reaction
5 HC1 stage, agitated
washed dropwise
501.6 mL warm mL - allowed was and 1H),
mL water DMSO 20
(aq)
triethylamine to
purified the then
and °C
methylene 3.85
mmol) was to mixture
The give
until
with
at (2*),
reaction
for
to
room over -ί/ό) (DMAP, 3.7
cooled
a
cooled (s,
reaction
warm
compound temperature
35
all
water
using mL
was
δ followed 3H),
2.5
methyl temperature
was - 7.35 solids
was chloride.
45 to
methyl
to
- added to and
3.16
and
column
1.30 then
was 4 10 minutes room (d, 0
almost
hours,
carbonate dissolved.
3.7 -
-
30
by
J=
g,
(s, then slowly 5 of 15
mL in 25.7 brine. °C.
The 5 9H), 2.4 and
°C
while
and -
20
and
[0681] Method 2E.
[0682] To a stirred solution of compound 30 (6.77g, 25.6 mmol) was added 6 mL of a 1:1
2019 mixture of sulfuric acid and nitric acid at 0 °C dropwise. The mixture was allowed to warm
to room temperature and stirred for 1 hour. The product was purified using liquid Jun chromatography (ISCO, 120 g, 0-7% EtOAc/Hexanes, 38 min) producing about an 8:1 - 10:1
04 mixture of regioisomers of compound 31 as a white solid. *H NMR (400 MHz, DMSO-ί/ό) δ
7.63 (s, 1H), 7.56 (s, 1H), 3.87 (s, 3H), 1.36 (s, 9H), 1.32 (s, 9H). HPLC ret. time 3.92 min 10-99% CH3CN, 5 min run; ESI-MS 310 m/z (MH)+.
[0683] Method 2F,
[0684] To compound 30 (lOOg, 378 mmol) was added DCM (540 g, 408 mL). The mixture was stirred until all solids dissolved, and then cooled to -5 - 0 °C. Concentrated sulfuric acid 2015247850 (163 g) was then added dropwise, while maintaining the initial temperature of the reaction, and the mixture was stirred for 4.5 hours. Nitric acid (62 g) was then added dropwise over 2 4 hours while maintaining the initial temperature of the reaction, and was then stirred at this temperature for an additional 4.5 hours. The reaction mixture was then slowly added to cold water, maintaining a temperature below 5 °C. The quenched reaction was then heated to 25 °C and the aqueous layer was removed and extracted with methylene chloride. The combined organic layers were washed with water, dried using Na2SC>4, and concentrated to 124 - 155 mL. Hexane (48 g) was added and the resulting mixture was again concentrated to 124 - 155 mL. More hexane (160 g) was subsequently added to the mixture. The mixture was then stirred at 23 - 27 °C for 15.5 hours, and was then filtered. To the filter cake was added hexane (115 g), the resulting mixture was heated to reflux and stirred for 2 - 2.5 hours. The mixture was then cooled to 3 - 7 °C, stirred for an additional 1-1.5 hours, and filtered to give compound 31 as a pale yellow solid.
[0685] Procedure for the preparation of 5-amino-2,4-di-tert-butylphenyl methyl carbonate (32).
[0686] 2,4 -Di-tert-butyl-5-nitrophenyl methyl carbonate (1.00 eq) was charged to a suitable hydrogenation reactor, followed by 5% Pd/C (2.50 wt% dry basis, Johnson-Matthey Type
143 2015247850 04 Jun 2019 butylphenyl volumes performed relative as about 5 35 MeOH/H2O was and T3P 3-carboxamide 5 °C distilled filtered, 37). [0688] [0687] [0689] 1H),
to °C
described °C +/-
the
purged 10 charged 4.80 MeOH for
8.5 -
5
volumes
resulting
to 40
and under no °C. Preparation
of 4-Oxo-l,4-dihydroquinoline-3-carboxylic Once volumes
(s,
the at
°C
MeOH), less
with
methyl the
(8:2) (15.0 above. 2H), The vessel a
acid)
to vacuum
reaction the
(Compound
than reactor/cake
of N
give suspension
resultant
(2.00
3.82 vol) reaction 2
of
MeOH
was was carbonate, (g),
heated
1
MeOH, of
compound
hour, was
(s, at
temperature
vol). N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l, and washed added
no
3H), (e.g.,
slurry
was
charged to
2).
was and was more
was
from The
a
followed 32,
1.33
complete, temperature
from with
then filtered. 32. was heated washed
cake
than (1.1 about
to
of (s,
2-MeTHF *H pressurized cooled
about
the
25 eq) 9H), was 50
to by
NMR
7.5 with
The °C
reactor, the
°C 47.5 were
T3P®
dried 6
of 1.23 to to
+/-
to to resulting
cake
MeOH
144
(400 about
0 about
+/-
(0.6 about charged 8.00
5
(s, °C 50% under
to
and
°C.
5.0
acid, was
MHz, 2.0 9H). +/-
vol).
vol. 35
8
(4.00
9 the solution
°C When mixture
volumes
vacuum Bar washed
5
+ volumes to 26,
°C. system and Water 5 DMSO-rie) Pyridine
a
vol). with °C,
(1.0
reactor. Compound complete,
held The
in
was
once fdtered,
(-0.90
of
(2.00
H eq) of was The 2-MeTHF
2 slurry MeOH,
at (2.0
diluted MeOH,
(g).
and
2-MeTHF with
this δ
resulting closed.
bar vol) 4-dihydroquinoline-
7.05 the eq)
washed,
The 5-amino-2,4-di-tert-
was
temperature
2 0
and
or was with
reaction
was from °C (1.7
(s,
reaction
held about
The
-0.86
+/- filtrate
added (4.0 1H),
then
from eq).
and about
at system 5
7.7 was vol,
bar)
6.39 °C 0 added,
dried,
The about was
at for was °C
7
45
at
to
(s, 8 +/
2015247850 04 Jun 2019 dihydroquinoline- 9H). vol) +/- H2O/CH3CN to was was the resulting hours. 8.3 5.0 (reflux). added concentrations concentration less filtered solution for added 8.0 [0690]
40
no 5 mixture.
(s, °C. °C
than added quenched
4
°C vol
times. to followed less
1H), (internal
A solution
*H
was over
bring
Alternative 8.0 mixture The and sample
NaOMe/MeOH than
NMR
7.2
°C
polish
The relative the 5 The slurry
cycle
with
the to
hours, (s,
by reaction 1.0 (internal was
solution was
20 was reaction (400
3 resulting
total 1H),
4.0
-carboxamide
hour,
filtered 1 was
was
vol. Preparation concentrated
N
to taken
cooled
and vol MHz,
volume 7.9 HC1
the
repeated
temperature) then reaction
and
After
concentrated mixture
filtered. of
(1.7 (t, solid to starting and
(10.0
DMSO-t/e) H2O to
checked stirred remove 1H),
the of equiv) 25.0 checked
(Compound
2
(Compound of
temperature)
at to reaction vol),
was
7.8 final more The acid.
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l, no for make °C
under
any
for
to
(d, washed at
more and
cake no +/-
concentration
δ for
times perform no
This completion
particulates
1H), 12.8 a to
less
2.5
washed
reduced completion
final more
was
than 2) 40.0 2).
145 slurry
for to with
7.5 °C. (s, than was
20 washed
concentration
the
35 than vol a 1H), (t,
with 2-MeTHF
water total 5 pressure dried vol.
was °C methanolysis.
by
1H), (-16.5 hours. and to
35
11.8
by
HPLC. (jacket
0.1
20 of
heated
with The
in (10.0 °C placed
7.1 HPLC.
3 vol,
N (s,
a
vol to
(jacket The
additions
addition
was vacuum (s, 0.0
HC1
1H), of temperature) 20 vol)
to 16.0 Once
charged).
in
1H),
slurry
40 °C
added vol.
78.0 Once
(10.0
a
The 2 9.2
temperature)
vol vol +/-
second
times. complete,
1.4 oven of
of
CH3CN °C (s,
was
reaction complete, 5.0
of of vol). (12.5 CH3CN
CH3CN (s,
+/-
1H), To
CH3CN
10%
at
°C cooled and reactor. 9H), 2-MeTHF
50.0 this 5.0 vol) The
CH3CN was 8.9
the
no was
and and and °C
1.4 4-
solution
the
°C organic to
(s, to was less reaction
added
stirred
The
(s, no
dilute 4 0.0 +/ 1H),
was
(5
than
°C
2015247850 04 Jun 2019 butylphenyl 9H). 25 25 temperature) CH3CN and vol) mixture. resulting hours. relative 8.3 5.0 (reflux). CH3CN CH3CN of organic quenched less (1.7 and T3P [0692] [0691] 10%
CH3CN
°C °C
(s, °C.
no the than
equiv) was charged H2O/CH3CN
4 over
1H),
less A
resulting
to solution
times. was was and *H
charged mixture 4-Oxo-l,4-dihydroquinoline-3-carboxylic The The 1.0 The sample
with
the
and NMR 5 to than
7.2
methyl 4
charged added hour,
vessel hours, and
filtered slurry perform reaction
acid) concentrations
concentration 1.2 The (s,
8.0 was
suspension was no to was (400
relative
N and 1H),
to
was was resulting carbonate, and the was °C
less
polish
HCI/H2O followed
solution taken 40
cooled
the mixture
MHz, checked
(internal
reactor. 7.9
filtered.
washed added then than vol
methanolysis. to
(t, filtered and
was
and
the DMSO-t/e) solid to cycle
to
stirred 8.0
was
1H), by followed 32, was
(10.0
for
20 20 checked
with
reaction This
starting the heated
The °C 4.0
(1.1 concentrated (Compound
°C vol. was completion 7.8 washed to
solution for
(internal vol),
2-MeTHF vol solution cake remove
+/-
(d, eq)
repeated
no After
to by
δ for acid.
temperature) The of
5
and
1H), 47.5 12.8
was
were less T3P® with
°C. H2O completion
concentrated
reaction
reaction the was any
washed
146
by This 2)
washed 7.5
(s, than
+/-
at
2-MeTHF (0.6
charged water 2
to
50%
final
was
HPLC.
no particulates
more charged
1H),
(t,
5.0 acid, make
slurry 5 vol).
more
1H),
was dried hours. under with temperature) solution (10.0
concentration °C with
11.8 by
times to 26,
a
and Once was
Pyridine at
stirred was 7.1 with than HPLC. final
a 0.1
in
Compound
vol) CH3CN (1.0 (s, reduced no reactor.
The
for held and
a
(s, heated N in
added
1H), more 35 30% complete, vacuum
concentration
2
eq)
HCI/H2O 2-MeTHF at a
1H),
slurry
placed
times
°C at Once total
(2.0 to
25.0
9.2 (5 and to pressure
2-MeTHF
w/w
than this (12.5 to
20 (jacket
1.4
vol) 20
eq)
2 (s,
78.0 of was oven and 5-amino-2,4-di-tert-
°C complete, vol.
in
temperature
NaOMe/MeOH the (s, vol, 35
3
(10.0 vol)
1H), was heated
a +/- (1.7
2-MeTHF cooled additions
°C
9H), temperature) °C
to second reaction at The of
16.0
(4.0 5.0
to
then
20 8.9 50.0 +/-
eq). (jacket vol). 40
dilute 1.4
addition
to
the
°C vol. vol (s, to 5.0 vol vol,
added, reactor. °C
20
The
(s, for
was 20 of for
The
1H),
of (16.5
°C
of
to +/
the
to 8
no
[0693] Procedure for the recrystallization ofN-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo- 1,4-dihydroquinoline-3-carboxamide (Compound 2). 2019
Jun
04
[0694] Compound 2 (1.0 eq) was charged to a reactor. 2-MeTHF (20.0 vol) was added followed by 0.1N HCI (5.0 vol). The biphasic solution was stirred and separated and the top organic phase was washed twice more with 0.1N HCI (5.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered
2015247850 solution was concentrated at no more than 35 °C (jacket temperature) and no more than 8.0 °C (internal reaction temperature) under reduced pressure to 10 vol. Isopropyl acetate (IPAc) (10 vol) was added and the solution concentrated at no more than 35 °C (jacket temperature) and no more than 8.0 °C (internal reaction temperature) to 10 vol. The addition of IP Ac and concentration was repeated 2 more times for a total of 3 additions of IP Ac and 4 concentrations to 10 vol. After the final concentration, 10 vol of IP Ac was charged and the slurry was heated to reflux and maintained at this temperature for 5 hours. The slurry was cooled to 0.0 °C +/- 5 °C over 5 hours and fdtered. The cake was washed with IP Ac (5 vol) once. The resulting solid was dried in a vacuum oven at 50.0 °C +/- 5.0 °C.
[0695] Example 3: Preparation of Solid Dispersion of Amorphous Compound 1 and Amorphous Compound 2 (1:1) Substantially Free of Polymer.
[0696] 56.5 g of Compound 1 and 56.5 g Compound 2 were added to 895.9 g of 90:10 methyl ethyl ketone (MEK): water in a 2 L amber bottle. The material was stirred until both compounds had dissolved and was spray dried using a Buchi Mini Spray Dryer set to the parameters described below in Table 8:
[0697] Table 8: 50/50 Spray dried dispersion processing parameters.
Formulation Description: Compound 1/Compound 2 (50/50)
T inlet (setpoint) 115 °C
T outlet (start) 56 °C
T outlet (end) 42 °C
147 2015247850 04 Jun 2019 min. A DSC, in analysis dispersion. at spray Compound [0701] [0699] [0698] [0702] [0700]
Nitrogen Aspirator Run Filter Rotometer Pump Formulation Condenser and 60 Figure
°C
dried showing
Peak Time
D20: Reference: Temp Spinning: Sample 19
Pressure for and
F As Referring Referring The 3, PEAK
T
Pressure
2 dispersion
Referring B. the
'H-'H
illustrated
i overnight 0.1
Temp contact material (K): (spin
a
Prep: Figure following
Description:
-50 glass
A:
12.5kHz
275
29.5
spin
to to lattice 13
at
ms
C
Figure
Figure Compound to transition
was of
4
at in
diffusion ppm a
CPMAS (bottom) Figures
Compound
molecular 80 the solid
relaxation secondary
°C.
adamantane 4, 3, solid
state the
19
temperature
1
Figure
on F
1 is
and state and spray
and
level. peak
Compound NMR time):
1 dried
and 2,
13 Compound NMR 5
C dried
the C. presents
parameters Compound in solid 7-9
of amorphous
a
spectrum
148 dispersion
seconds vacuum 124 Compound 1 state and
an
2 °C.
were
NMR SEM
Compound were 2.
in oven
form
Figure underwent
Figure cryoground/cryomilled
image
used: spectra 1/Compound
with was
1 4 -60
2. 3,
h
40
120 -20 of 100 confirmed nitrogen (top) 40%
were 17
Compound
For mbar solid this mm
°C psi
% min
is
the spray recorded
state an 2
purge
NMR (50/50)
by overlay
dried
NMR
1 XRPD
and for
for for spectrum
2 of
100 the
hours
and Peak
2015247850 04 Jun 2019 parameters underwent methyl Amorphous compounds [0704] [0703] [0710] [0709] [0708] [0707] [0706] [0705]
RD: Reference: Reference: Temp Reference: Temp ethyl Spinning: Temp Spinning: Sample Spinning: Sample *HTi: ‘ 19 Η FTi:7-9s 29.94 Example Figure PEAK PEAK Thermogravimetric Sample Sample
Τι:
the
described had 2
ketone
Compound
(K): (K): (K):
s 0.85 0.85 following
Prep: Prep: g
dissolved B: 5 C:
A: B: of
12.5 12.0 12.0 presents
275 275 275 29.5 29.5 29.5 4: s s
19 13
Compound (MEK): 3 3
F C
spray spray
below
days days
Preparation kHz kHz kHz
MAS CPMAS ppm ppm ppm
processing:
2 and
an at dried dried at (1:3)
in
adamantane adamantane adamantane water
analyses
40
90 SEM
was Table
1
°C. °C dispersion dispersion Substantially and
spray in
image of under
9:
a 90.01 were
Solid 2
dried L
of vacuum,
amber
performed was was g
Dispersion this
Compound
using 149
Free dried dried
spray
bottle.
followed
a of
for for Buchi on dried Polymer.
of
2 The 72 72 the
Amorphous were
hr. hr.
mini dispersion. by
spray material
N
added
2 spray
purge. dried
was to
drier
Compound
dispersion 955.7
stirred
set
g
to
of until
the that
90:10 1
and both
2015247850 04 Jun 2019 parameters both methyl Amorphous and dried and oven [0712] [0711] [0715] [0714] [0713] Nitrogen Aspirator Run Filter Rotometer Pump Formulation Formulation T T Condenser T T T
outlet inlet DSC outlet outlet inlet Compound
compounds with dispersion.
Time
ethyl Pressure
(setpoint) 2.03 (setpoint) Example 700 Table Table showing
nitrogen (start) (end) (start)
Pressure described
ketone Compound Temp
g g
of 9: 10: 2 Description: Description: of
had
Referring (26%
25/75 solution
a Compound purge 5: 9/91
(MEK): glass
dissolved below Preparation
yield) Spray Spray
2 overnight transition
was
(1:10)
to
in water
was
Figures
1 dried dried Table spray
and and
Substantially recovered.
in
was at
temperature of
20.08 dispersion dispersion
dried. 10: a
80
6
Solid
0.5
spray and
°C.
g
L
The
Compound 7, Dispersion
Approximately amber
dried Figure
150 the processing processing
of material Free
amorphous
155 using Compound bottle. Compound
8
of
presents °C.
2
of Polymer.
was a
were parameters. parameters.
Amorphous Buchi The
20
secondary form
added
material g an 1/Compound 1/Compound
-45 of mini 120
25 40 120 57° 115 100 47° SEM 57°
40% 0°C was
amorphous
mbar
min mm
to
°C
psi C °C % C C spray
confirmed Compound dried 234.1 was image
dried stirred
in
2 g 2 of
Compound (25/75) of (9/91) a
this
vacuum set
by 90:10
until
1
XRPD to spray and
the
1
2015247850 04 Jun 2019 parameters both methyl Amorphous recovered. [0718] [0717] [0716] [0719] Nitrogen Nitrogen Aspirator Aspirator Run Filter Rotometer Pump Formulation Rotometer Pump Formulation T T T Condenser T
outlet outlet inlet outlet
compounds
Time
ethyl Pressure
(setpoint) 20.03 Approximately Example Table
(end) (start) (end)
Pressure Pressure described The
ketone Compound Temp
g 11:9/91 Description: Description: material
had of
6:
Compound (MEK):
dissolved below Preparation
Spray was
15 2
(10:1)
g in
water
secondary of
drying Table
and 1
amorphous and
Substantially
in
was of
11: a 2.04 dispersion
Solid
0.5
spray dried
g L
Compound
Compound Dispersion
amber
in dried 151
a
processing Free
vacuum
using bottle. Compound Compound
of
1 2
of
Polymer.
a and
were oven
Amorphous Buchi The parameters.
Compound
added
material at 1/Compound 1/Compound -50
21 40 mini 35 120 150 105 60 100 100 44° 56° 48° 35 35 2
mbar min °C mm mm
°C
% % to psi psi °C
% % C C C spray
Compound 231.1 was for
2
(68%
3
dried stirred
days.
g 2 2
of
(9/91) (91/9) yield)
set
90:10
until
1
to and
was
the
2015247850 04 Jun 2019 / Amorphous research heat room Amorphous recovered. exchanger Table contained [0723] [0722] [0721] [0720] [0726] [0725] [0724]
75 Run Filter Formulation Condenser
wt% exchanger
temperature
12. Atomizer Time
Pressure
flash Approximately Example Table The Compound Table Compound Compound
5% via The form
Compound Temp
resulting
solids atomizer. a
before
12: 13:
Description: material high Sheath
was in
7: Spray Spray Function
load. an pressure 1 2) 1
confirmed
entering Preparation and and suspension
appropriately using Gas
was Spray
11
2 dry dryer
The Compound compound (1:3)
Compound Compound g Pressure
secondary
Methanol Material materials of a pump.
actual the dryer solvent operating
amorphous via by
was nozzle.
of XRPD
hot
operating
(psi) The sized amounts
2
2
Solid
spray
system and 2 1
were dried
were pressure
parameters. solids
vessel. and
amounts.
Compound
Dispersion
dried
spray in added
152 of consisting parameters DSC.
a then
materials
vacuum
/
on
This dried
hot Compound to
Amount
dissolve a
methanol
PSD1 3553.0
temperature 1 suspension
of
46.7
in 140 of and
oven are
used Amorphous a
Parameter methanol.
1:3 Compound spray at listed (g)
at
in the 1/Compound to -50 ratio
20
60
this 2
form
was
dryer target
in
50
mbar min °C
°C
method.
(25 Table process
The
Setting
delivered Compound for a
2 using
wt% temperature suspension
(50%
resulting 3
13. days.
2 are
Compound a
(91/9)
yield)
Bend
to listed
a mixture 1
at
heat
and in
was
in
the
1
2015247850 04 Jun 2019 polymer particle until hypromellose Amorphous actual equipped according gas [0730] 14, [0729] [0728] [0727]
below: due
low
amounts
size to
MeOH DCM HPMC Total Total Total Compound
(HPMC,
A Example Wet Table levels with
to possible
solvent
resulting the Compound
/
SDD
Feed
a
Spray Solvents Solids Feed 80 of Outlet 14:
were magnetic Inlet ratio
El ingredients wt%
8: Solid oxidation system Function
was
Pressure 1 Rate
5
detected Temp
80 in Solution Temp Preparation grade)
Compound
collected values
wt%
spray
1 (g/min) stirrer
of
and (°C)
(°C)
(psi)
risks. and
dichloromethane and DCM (<10
dispersion Weight of
HPMC and
and Compound 0.24 solvents
The ppm). 1. of /
stir
20 placed
The a g/mL
residual
Polymer. plate. Solid wt%
ingredients
Dried used resulting
in and
1 MeOH,
Dispersion 153
(DCM) were
Into a
to levels
material a vacuum
generate D50
this mixture added
for
in
of and
of
solvent
an
amorphous Methanol was tray
Comprising 6
methanol according this appropriately
Parameter pm, contained
analyzed dryer
mixture system,
respectively.
Units
were 283 with
130 129
51 Compound
(MeOH), g g g g g g g to
12.5
for Substantially hypromellose Setting are the
tested a sized
nitrogen
bulk
recited wt% ratio 24000 21000 16800 Batch 4200 3000 2400
600
is container, for
density
1. solids. 20 formulated
over
in
sweep wt%
Table
24 and
The
hr
2015247850 04 Jun 2019 process the with MEK Amorphous reduce vapors. solvents The succinate containing 600ppm dispersion (Schlick were [0734] [0733] [0732] [0731] [0736] [0735]
ratio
resulting
a substantially /
magnetic
residual
10 parameters
The used of series 19.5
A A A Example Table The polymer
wt% of
<0.02% DCM high solvent spray
wet
Compound
amorphous mixture mixture wt% to
970/0 Nozzle Vacuum Vacuum Inlet Feed Process Parameter: Outlet solvents DI
15:
stirrer generate efficiency
product
and drier,
dissolved.
(HPMCAS)(HG
hypromellose water, 9: Spray MeOH recited system
Temperature Flow
S4),
to was contained
Temperature
Preparation
and
Gas Anhydro
Gas
to generate Drying Dryer
Compound was
this 2 was drying
was
mixed Rate in
and a of thermal cyclone and Flow
Flow level
Table MEK mixture transferred
heated
used
Temperature <0.06%
HPMCAS Time
10.5
dispersion MS-35 acetate
until Rate
dry Rate of
circuit. separated grade), under and 15, of
less 1 to wt%
spray
are .
it
a
below.
DCM.
a
DI
was succinate Spray Solid
than into
temperature recited
normal
solids.
water, SLS, dry Polymer. processing Into
substantially
the trays
about
Dispersion
154 Drier, dispersion
this Value: 4.2 24-72 40° 96-108° 2 45° 34
and
in wet
spray
formulated Kg/hr The /
and
Kg/hr
Table 0.5 Kg/hr C C 3000
solvent
Compound
product fitted
of
actual hours parameters
placed wt% drying
C 20
ppm
16, of homogenous Comprising
with
-
system,
SLS amorphous
amounts below. according 30 from
in mode, for
two 2
°C vacuum /
MeOH to were
80 the
in
hypromellose fluid generate
following wt%
of a
spray
and
Substantially added to reactor, Compound
ingredients
dryer
and 0.8mm
the
Compound all
gas
solid
ratio less according
components
for
the
equipped and
nozzle
than acetate
drying 90 spray dry
1, and solvent
wt%
2.
spray
to
to
[0737] Table 16: Solid spray dispersion ingredients for amorphous compound 2.
Units Batch 2019 Compound 2 Kg 70.0 Jun
HPMCAS Kg 17.1
04 SLS Kg 0.438
Total Solids Kg 87.5
MEK Kg 671
Water Kg 74.6
Total Solvents Kg 746 2015247850 Total Spray Solution Weight Kg 833
[0738] The mixture temperature was adjusted to a range of 20 - 45 °C and mixed until it was substantially homogenous and all components were substantially dissolved.
[0739] A spray drier, Niro PSD4 Commercial Spray Dryer, fitted with pressure nozzle (Spray Systems Maximum Passage series SK-MFP having orifice/core size 54/21) equipped with anti-bearding cap, was used under normal spray drying mode, following the dry spray process parameters recited in Table 17, below.
[0740] Table 17: Spray drying dispersion processing parameters to generate solid spray dispersion of amorphous Compound 2.
Parameter: Value:
Feed Pressure 20 bar
Feed Flow Rate 92- 100 Kg/hr
Inlet Temperature 93 -99°C
Outlet Temperature 53 -57°C
Vacuum Dryer Temperature 80° C for 2 hours then
110°C (+/-5 °C)
Vacuum Drying Time 20 - 24 hours
155 2015247850 04 Jun 2019 using / particle nozzle, HPMCAS-HG Amorphous transferred vapors. stir amounts (MEK) (HPMCAS, amorphous solvents [0744] [0743] [0742] [0741] [0746] [0745]
40
until wt%
a
magnetic / 1.5 size
The to
dissolved. of A MEK 10 Example The Table Compound Compound
a to
mm.
materials Compound high
wt%
HG
of wet level
Compound resulting a
was 17 and 4000
18:
grade)
efficiency product Spray DI stir
- of
Spray 10:
water added
Compound
19
water.
bar. less 2) 1 L used
and
mixture
2, using stainless pm dryer Preparation along
contained than 2
were dry containing
Compound and
in
Compound and cyclone (1:1). The
this
a operating materials
with about
stirred
mixed solvent
was a
1 HPMCAS-HG resulting steel
Compound Compound bulk process was
Material
20
separated 8.5
spray
Water 5000
MEK
<0.03%
of until
double 2
at wt% then density
2
system
- parameters and
was
Solid room were
9.7%
are mixture
dried ppm
dissolved.
added hypromellose
amounts.
added
2 1
cone listed
MEK
the
spray Dispersion of
temperature consisting
156 MEK
and on
0.27 Amount wet
and
contained
vacuum
a
to are in to and
dried 546.1 Buchi
60.7 30.1
and
the product - Table stirred 30 generate 15 listed
0.33 0.3%
MEK/water of 0.56 acetate
in of
(g) dryer in B-290
90
18.
a Amorphous g/cc. in 11%
until
an water.
from 1
-
wt% dry Table :
1 0.83%
appropriately for
succinate
solids ratio spray The dissolved.
spray the
methyl drying
mixture 19.
wet
spray (40 water
dryer load.
dry
Compound
product polymer wt%
to ethyl
dispersion gas
Lastly, and
using reduce and The sized
Compound
and
ketone
had allowed
actual was
a vessel
residual solvent
2
a 1
fluid mean of
and
to
1
2015247850 04 Jun 2019 / bulk Amorphous respectively. amounts (MEK) (HPMCAS, allowed ^Observed [0749] [0748] [0747] [0751] [0750]
27
wt%
density
/
to
of 10 Example Wet Table Compound Table Compound
dry
condition,
materials wt%
HG
Nitrogen and Compound
Condenser Filter SDD
Solution
until Outlet 20: 19: Rotometer
Inlet grade)
particle DI Aspirator
Spray 11: Spray
Function was Pressure residual
water.
2) 1 used
Temp Temp
not Pressure
and
using
Pump Preparation along
collected
Temp
size
2 dryer dry a
in
Compound (mm)
(%) set (2:1).
The (°C)
(°C)*
MEK
(psi)*
this
a resulting materials with (%)
parameter.
(°C) solvent (psi) operating
HPMCAS-HG resulting
Compound Compound process and
levels Material 20 Water
MEK
of
placed
wt%
2
in system and
Solid
were
were values are parameters. mixture
hypromellose amounts.
2 1 in listed
spray Dispersion consisting <5000 157
a
of
Amount vacuum
contained
in 0.33
dried 546.1
60.7
ppm. Table 20 40 15
g/mL
of acetate
in oven of (g)
Dried 20. 90
Parameter a Amorphous 11%
2:1 and
wt% at
succinate
solids ambient ratio material a
D50 methyl 100 122 120 -10 60 30 52 2
(53
load.
Setting of
Compound
temperature polymer wt% was
4.092 ethyl
The
analyzed Compound
ketone pm,
actual
1 and
and
for
1
2015247850 04 Jun 2019 bulk using Piccola respectively. nozzle, HPMCAS-HG Roller allowed stir *Observed [0754] [0753] [0752] [0758] [0757] [0756] [0755]
until
density
a
Compaction. magnetic
tablet 1.5
to dissolved. Example Wet MEK Turbula Table The
dry mm. condition,
Nitrogen and
Condenser resulting Filter press. SDD
Equipment:
Solution
until Outlet was and 21:
Rotometer
Inlet
particle
Spray Aspirator stir blender,
12: Spray
Function was water added Pressure residual Compound
bar.
Temp Temp not Pressure
mixture
dryer Pump Preparation
collected
Temp
size
were dryer a Compound and V-shell
(mm)
(%) set
(°C)
(°C)* MEK
(psi)* operating resulting
(%)
stirred
parameter.
(°C) mixed (psi) was operating 1
was
and
blender levels
spray
of until
placed 2 at then
in
parameters
was
a
room
were
values parameters.
Tablet dried
or dissolved. added
added
in a
temperature <5000 158 bin
a on
of
vacuum Formulation and
blender,
a to are 0.35
Buchi
the ppm. stirred listed
g/mL
MEK/water
oven
in B-290 Gerteis Dried
Parameter in until an
and
Table at from
appropriately
ambient spray dissolved. material a
Roller
D50 119 100 -10 120
40 60 54 Dry mixture 2 21.
dryer
Setting of
Compactor, Granulation
temperature was
4.682
Lastly,
using and sized
analyzed
pm, allowed
a vessel
2
and
fluid
for
to
2015247850 04 Jun 2019 bin prior mg. rotary the Compound as integrated clockwise/counterclockwise operated screen granulated components lubing dispersion dispersion x [0765] 15 [0764] [0763] [0762] [0761] [0760] [0759] [0768] [0767] [0766]
0.2885").
filler,
rpm,
blender blender.
to
tablet may with
or granulation
disintegrant with The The The The The
mill after comprising comprising using
in be
1 pocketed
may The presses,
The
and
blend roller compression solid solid
a different
performed Blending: Dry Blending: Screening/Weighing: Compression: equipped
weigh-out. roll
weight
combined be blending 150
dispersion dispersion Granulation:
compacted may gap speed
blended
such and,
rotor
mg substantially substantially
order.
of of be with
in
of if
as
clockwise/counterclockwise
time blend 2 and
the smooth/smooth Appropriate granulated
needed
a substantially of mm, the for
0.8mm
Turbula comprising comprising Additional
tablets
paddle granules 330/360
may
Piccola 10 may roll
or lubricant amorphous amorphous
be
mesh
pressure for be may
blender, agitator. using
10 degrees. may
screen press,
compressed
a amorphous lubing substantially substantially
or be dose rolls screen.
a
be using
may
lubed
Gerteis
159 using of a sizes
Compound Compound
The blended
of and step v-shell
4 The
be
50 a kNcm,
for Gerteis
with
are Tooling Turbula into might Compound lubed
ribbons mg roller
amorphous amorphous
of
4
blender, mesh with
minutes. the tablets of 80/80
roll
2, 2,
for be
roller
compactor. substantially
blender,
integrated Size extra-granular and and produced
30,
required. speed 4
rpm,
using minutes. or 2
excipients excipients
or
compactor D Compound Compound may
a
mesh Caplet
of
bin and V-shell
a
2 be may
0.8
single The
The
blender. oscillation rpm, amorphous
60. about
mm
Tooling
excipients may may
be blend may blending
blender
1, 1, agitator
station
milled
mesh
the the 400
be be
be The
may
(0.568" screened added
solid solid
or
milling or
or and with such speed
600
be a
to
[0769] Table 22. Tablet comprising 50 mg Compound 1 and 150 mg Compound 2.
Amount per tablet Ingredient (mg) 2019 Intra-granular Compound 1 SDD 62.5 Compound 2 SDD 187.5 Jun
Microcrystalline
04 116.35 cellulose
Croscarmellose 17.31 Sodium Magnesium Stearate 0.96 Total 384.62 Microcrystalline Extra-granular 87.74 cellulose 2015247850 Croscarmellose 7.21 Sodium Magnesium Stearate 1.20 Total 96.15
[0770] Example 13: Preparation of a lOOmg Compound 1 and 150mg Compound 2 Tablet Formulation from Dry Granulation Roller Compaction.
[0771] Equipment:
[0772] Turbula blender, V-shell blender or a bin blender, Gerteis Roller Compactor, MTS Universal Testing System
[0773] Screening/Weighing:
[0774] The solid dispersion comprising substantially amorphous Compound 1, the solid dispersion comprising substantially amorphous Compound 2, and excipients may be screened prior to or after weigh-out. Appropriate screen sizes are mesh 30, or mesh 60.
[0775] Blending:
[0776] The solid dispersion comprising substantially amorphous Compound 1, the solid dispersion comprising substantially amorphous Compound 2, and excipients may be added to the blender in different order. Additional lubing step might be required. The blending and lubing may be performed in a Turbula blender, a v-shell blender, or a bin blender. The components may be blended for 10 or may be lubed for 4 minutes.
[0777] Dry Granulation:
160 2015247850 04 Jun 2019 bin may rotary substantially Caplet as integrated clockwise/counterclockwise operated screen granulated [0783] [0782] [0781] [0780] [0779] 15 [0778]
filler, rpm,
blender.
be
tablet with Tooling
about
granulation
disintegrant with Table The The The
mill using
pocketed
presses,
The amorphous
blend roller compression 500 a
Blending:
Compression: equipped
23. Extra-granular (0.65" Intra-granular roll
combined blending
to
compacted may Tablet gap
speed
700 such and, rotor
x
of
0.33").
be Compound with
mg.
if
as
clockwise/counterclockwise time 2 blend comprising and
smooth/smooth
granulated
needed
of mm, the
0.8
paddle granules 330/360 may
The MTS
may mm roll
lubricant
Magnesium Magnesium 1 be weight
Compound Compound
pressure be
mesh
Universal and Microcrystalline agitator. Microcrystalline using 100 Croscarmellose Croscarmellose
10 degrees. may
compressed Ingredient
cellulose cellulose 150 or Sodium Sodium mg
rolls
Total Total screen.
of
a
be using may
Gerteis 161 of Compound mg the
The blended
and Testing Stearate Stearate 2
1 4 The
be
tablets of SDD SDD a kNcm,
Gerteis
with
Turbula
into substantially lubed
ribbons roller
of
with System,
the tablets for
80/80 roll 1
for
roller and compactor.
Amount
blender, a
integrated extra-granular produced
speed dose 4
rpm,
150 using minutes. using
compactor amorphous 480.80 120.20 109.68 145.45
21.65 187.5 (mg) of
9.02
1.50 1.20 mg 125 of
and
V-shell per
a 100 Tooling
2 may
0.8
single Compound The
oscillation rpm,
tablet
mg
mm
excipients
be blend may
blender
Compound
agitator of
station
milled Size mesh
be
may
2.
D
milling or
or with such speed
be
a
2
[0784] Example 14: Preparation of a 100 mg Compound 1 and 150 mg Compound 2 Tablet Formation from Dry Granulation Roller Compaction.
2019 [0785] Equipment:
[0786] Turbula blender, V-shell blender or a bin blender, Gerteis Roller Compactor, Jun
Courtoy tablet press, Omega coating system 04 [0787] Screening/Weighing:
[0788] The solid dispersion comprising substantially amorphous Compound 1, the solid dispersion comprising substantially amorphous Compound 2, and excipients may be screened prior to or after weigh-out. Appropriate screen sizes are 24R, or mesh 60.
[0789] Blending: 2015247850 [0790] The solid dispersion comprising substantially amorphous Compound 1, the solid dispersion comprising substantially amorphous Compound 2, and excipients may be added to the blender in different order. The blending may be performed in a Turbula blender, a v-shell blender, or a bin blender. The components may be blended for 25 minutes.
[0791] Dry Granulation:
[0792] The blend may be granulated using a Gerteis roller compactor. The blend may be granulated using combined smooth/smooth rolls and with the integrated 0.8 mm mesh milling screen with pocketed rotor and paddle agitator. The Gerteis roller compactor may be operated with a roll gap of 3mm, roll pressure of 10 kNcm, roll speed of 8 rpm, agitator speed 15 rpm, granulation speed clockwise/counterclockwise of 150/150 rpm, and oscillation clockwise/counterclockwise of 375/375 degrees. The ribbons produced may be milled with integrated mill equipped with 0.8mm mesh screen.
[0793] Blending:
[0794] The roller compacted granules may be blended with extra-granular excipients such as filler and, if needed lubricant using a Turbula blender, V-shell blender or a bin blender. The blending time may be 7 minutes or may be lubed for 5 minutes.
[0795] Compression:
[0796] The compression blend may be compressed into tablets using a single station or rotary tablet presses, such as the Courtoy tablet press, using Tooling Size D Caplet Tooling (0.625" x 0.334"). The weight of the tablets for a dose of 100 mg of substantially amorphous
162 2015247850 04 Jun 2019 modifications merely meaning reference water. of from intended of specifically onto coat mg. Compound [0799] [0798] [0797] [0800]
the the Total
suspension the such Total
terms invention
The exemplary
Extra-granular tablets fntra-granular to of All Table The
to
uncoated discussion
Film
be coated
required the 1 and the
in
publications
and
core
and
controlling.
Coating:
any
terms 24.
to same individually is as coat
150
achieve variations prepared
tablets embodiments defined Tablet of Tablet
Tablet amount
used and extent the mg
patents are
from of and
the Comprising in in
Furthermore, by
as substantially
of can indicated
this film
the patents desired
adding if the film
of
be OTHER each or following
disclosure, Microcrystalline Microcrystalline
coated Croscarmellose accompanying
the
made publications coating Magnesium
Compound Compound
referred
weight the
individual
to invention. 100
the be Ingredient using
amorphous therein EMBODIMENTS Opadry
Opadry
mg claims. Total Total
incorporated suspension
foregoing the gain.
to
163 a Compound
meaning incorporated in Stearate continuous 2 publication 1
without
yellow drawings
One
cellulose cellulose Sodium SDD SDD this
Compound
skilled discussion
disclosure (3%
by 20A120010 departing of
1
and
reference. the pan of and or
by in
the
patent claims, terms
Amount Omega the reference 2 150
discloses
are tablet may
from
art
mg
powder incorporated
in application
Should that will be
coater. this weight) the Compound
per
473.5 609.6 591.9 118.4 about 131.4 187.5 112.5 conflict
29.6
17.7 and 125 5.9 various
readily
spirit disclosure
to tablet
the
describes
purified
The 500 is
were
and
meaning with herein
sprayed recognize changes,
2. film (mg) to
scope
are 700 the
by
THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A pharmaceutical composition comprising a blend of a first solid dispersion and a
2019 second solid dispersion,
wherein the first solid dispersion comprises 70 wt% to 90 wt% of amorphous (7?)-l- Jun (2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-
04 methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide (Compound 1) relative to the
total weight of the first solid dispersion and 10 wt% to 30 wt% of hydroxypropyl methylcellulose relative to the total weight of the first solid dispersion, wherein the second solid dispersion comprises 70 wt% to 90 wt% of amorphous N- [2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 2) relative to the total weight of the second solid dispersion, and
2015247850 wherein the pharmaceutical composition is a tablet which comprises 25 mg to 125 mg of Compound 1 and 100 mg to 200 mg of Compound 2. 2. The pharmaceutical composition of claim 1, wherein the second solid dispersion further comprises 10 wt% to 30 wt% of a polymer relative to the total weight of the second solid dispersion. 3. The pharmaceutical composition of claim 2, wherein the polymer in the second solid dispersion comprises hydroxypropyl methylcellulose acetate succinate. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the first solid dispersion comprises 80 wt% of amorphous Compound 1 relative to the total weight of the first solid dispersion and 20 wt% of hydroxypropyl methylcellulose relative to the total weight of the first solid dispersion. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein the tablet comprises 100 mg of Compound 1. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the tablet comprises 150 mg of Compound 2. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the tablet comprises one or more excipients selected from a filler, a disintegrant, and a lubricant, or any combination thereof. 8. The pharmaceutical composition of claim 7, wherein the tablet comprises a filler in an amount of 30 wt% to 50 wt% relative to the total weight of the tablet. 9. The pharmaceutical composition of claim 8, wherein the filler comprises microcrystalline cellulose.
164 2015247850 04 Jun 2019 patient manufacture hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide yl)cyclopropanecarboxamide hydroxypropyl methylcellulose magnesium tablet. dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- second solid Compound comprises: comprises comprises comprises comprises croscarmellose comprises 1 17. 16. 15. 14. 13. 12. 11 10. 19. 18.
relative .
dispersion,
the A Use 29.6 243.9 The The The The The 5.9 The The The solid 187.5 125
method to
5.9 a a 12 100 pharmaceutical
2
mg pharmaceutical pharmaceutical pharmaceutical pharmaceutical pharmaceutical pharmaceutical pharmaceutical pharmaceutical of stearate.
mg disintegrant the lubricant
mg dispersion, of relative mg mg
mg
mg
amorphous
mg methylcellulose
sodium. of
a
total
croscarmellose relative magnesium
and
medicament microcrystalline of
to
of
of a to
first 36 a
treating
a 0.5 weight
300 to second in
lubricant. mg
the to an solid in wt%
mg
(7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-
composition the of
an amount composition composition composition composition composition composition composition composition total
of
cystic stearate.
solid
of
(Compound a
of dispersion for amount total
the disintegrant. sodium, acetate
a
sodium weight
treating filler.
cellulose,
dispersion first
fibrosis of weight
1 of
succinate
solid of wt%
of and of of of of of of of lauryl of which 1
cystic
1)
any
wt% the
of any any any claim any claim any in any
and dispersion relative
which the
a
second one 165
sulfate
one one one one one patient one
comprises to fibrosis
amorphous relative first 12, 10,
of 10
of of of of of of comprises
wherein wherein to
claims
wt%
solid solid relative
claims claims claims claims claims claims comprising
the and in
to
80
relative
a
total dispersion, dispersion, the
20
patient, /V-[2,4-bis(
(Compound
1
wt%
7 7 7 7 7
the the 1 to
to
80 wt% to to to to to total to
weight
the
17.
lubricant disintegrant
9,
wt% 15, 14, 13, 11, 16,
of orally to
of wherein weight total wherein
amorphous the wherein wherein wherein wherein wherein
hydroxypropyl
19.5 of
of 1,1
total 2) administering weight
amorphous
the -dimcthylcthyl comprises
of in wt%
the
the
comprises
tablet. the the the the weight the the the
tablet medicament Compound of of
tablet tablet tablet tablet tablet second
the
of
to
the
)-5- the
2015247850 04 Jun 2019 bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide patient A455E, per hydroxypropyl relative total methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide 28. transport 27. wherein 26. 25. 24. D1152H, 23. wherein 22. 21. 20. (Compound difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- of from G1349D. fromR117H, from gene is is in is
administered administered formulated any any
day.
weight mutation. E56K, G576A
one one A a The The The The The The The The
187.5 125
to D579G,
the the
tablet
which D1270N, method
the
of of
mg
method method method method method method method method patient patient of 2) P67L,
and
mg claims claims for G178R, total
the
relative comprising methylcellulose
of once once
is
71
oral
of R668C.
of
a
greater
first
R74W, weight
1+3A^G, 2789+5G->A, is is
first of of or or or of of of
a
treating per 1 per
19
administration second homozygous heterozygous
S549N,
to use use use any any any claim claim
to
solid to
solid day. day
17.
the than
21, of of of of DI one one one
cystic dispersion
18 18 followed claim claim claim solid the
total
dispersion 10E,
wherein
S549R, S945L, or
of of of acetate or or
first
equal
claims claims claims
3272-26A^G, weight use use
dispersion
DI for fibrosis 22, 22, 22, for
and
solid
S977F, 10H, by
G551D,
of of
the
the
wherein wherein wherein succinate a to and
which
AF508 comprises 18, 18, 18,
claim claim
the
of 10% AF508
administration
dispersion,
in R117C, 20
the 20 20 20
administration which a F1052V,
166 wt%
G551S,
above patient
19, 19, comprises the the and and and the second CFTR
relative
CFTR and
wherein wherein
second second second a
21 21, 21 E193K, of comprises
pharmaceutical
the
3849+lOkbC^T.
hydroxypropyl
comprising or or
G1244E, gene K1060T, wherein solid
gene
to baseline produces,
use use
80
CFTR CFTR CFTR
the the the
L206W, of mutation
dispersion, wt% of of (Compound mutation.
80 150 pharmaceutical pharmaceutical total
the any any S1251N, A1067T,
gene gene gene
wt% chloride
of orally
mg
an
method
weight
one one
R347H, composition amorphous
and
methylcellulose
increase of mutation mutation mutation of
of of 19.5 administering
Compound amorphous S1255P, a
R1070W, 1) transport.
claims claims of second produces,
relative R352Q, wt%
the
composition composition in
is is is (7^)-1
chloride
as
second
19 of 19 selected selected selected and CFTR
F1074L,
defined
to
2
A-[2,4- to to
-(2,2- or
once to
the
21, 21,
use
the
2015247850 04 Jun 2019 hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide yl)cyclopropanecarboxamide hydroxypropyl methylcellulose tablet 29. dispersion. sulfate 33. a 32. dried 31. solid (2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- 30. second solid Compound cystic oxoquinoline-3-carboxamide (Compound fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide second solid 1
surfactant. relative
dispersion, dispersion, dispersion
with comprising fibrosis,
in Use 29.6 243.9 A 5.9 29.6 243.9 The The The 5.9 solid solid 187.5 125
an solid to
a
2
mg
solid solid of solid
mg mg solvent. the 1) amount
mg mg dispersion, dispersion, relative mg mg mg
(7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-
wherein and methylcellulose dispersion
of
total
croscarmellose croscarmellose is relative magnesium magnesium
and and microcrystalline dispersion dispersion microcrystalline dispersion of
a free
7V-[2,4-bis(
first a
from 0.5 0.5 weight
to second
of
the
the to solid wt% wt%
polymer comprising
0.5
the
medicament
total
of of of of
stearate. stearate.
solid (Compound (Compound
wt% of of dispersion
total 1
claim claim claim
the , sodium, sodium, acetate
1 sodium sodium weight
-dimethylethyl)-5-hydroxyphenyl]
cellulose, cellulose,
and dispersion first
to weight
32, 30 30,
5 (7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-
comprises succinate
solid wt%
is or
of and and lauryl lauryl wherein wherein which
2)
1)
formulated
31, the of
in relative and dispersion
which the
wherein second 167
sulfate sulfate the comprises
/V-[2,4-bis(l,l-dimcthylcthyl)-5- relative the first Compound less
manufacture
comprises to surfactant
than for solid solid relative relative
the the and
to oral
80
solid
total 15%
dispersion, dispersion, the 20
(Compound
1 wt%
administration
to to
and wt% 80
total
comprises
of crystallinity. weight
dispersion the the
wt%
of a Compound
-1
medicament of weight total total
amorphous ,4-dihydro-4-
hydroxypropyl 19.5 of of
2),
weight weight
amorphous the sodium
further
of wt%
wherein and
solid
the 2
are Compound of of for comprises of
lauryl second comprises
the the
co-spray
treating
the
a
2015247850 04 Jun 2019 pharmaceutical pharmaceutical polymer wherein microcrystalline 45. 44. 43. the 42. the 41 40. to hydroxypropyl wherein hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide yl)cyclopropanecarboxamide disintegrant, composition glidant, composition composition 30 39. 38. comprises 37. 35 36. 35. crystallinity. (2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- 34.
. Compound
to wt% pharmaceutical total
38.
A A The The The The The The The The The The
a to the the weight are
pharmaceutical diluent, solid
from 60
pharmaceutical pharmaceutical pharmaceutical pharmaceutical pharmaceutical pharmaceutical solid solid solid solid polymer
lubricant co-spray comprises comprises is and/or
wt% 2
a methylcellulose, dispersion
composition composition
of is 20
cellulose, tablet.
dispersion dispersion dispersion dispersion
a 2:3
the
of wt%
composition. disintegrant, 1
is
dried comprises wt% Compound by pharmaceutical
selected from from
to
weight.
composition
comprising
wherein 45
of with
composition composition composition composition composition composition
of of of of
further comprises
30 5
(Compound a wt%
wt% any any claim claim lubricant.
from wt% and magnesium a a
1
solvent.
lubricant,
. one one of
the
comprises to
wherein
34 34,
to hydroxypropyl
(7?)-l-(2,2-difluorobenzo[d] Compound composition.
comprising
15 disintegrant of of
from 50
or of of of of of of wherein
wt% claims claims
1), 35,
wt% claim claim any any claim claim
stearate. a
15 the A-[2,4-bis(l,l-dimethylethyl)-5-
binder,
wherein one 168
of
one one wt%
of
solid
30 34
Compound 43 43, 39 39, 2. Compound
the
a or
comprises of of
to to
or or filler, methylcellulose
to wherein wherein
more
and
solid dispersion claims claims
37, 36,
the 44, 40, 45
a
wherein wherein
from wt%
solid wherein wherein
excipients dispersion surfactant.
(Compound
1,
1 39 39 the the croscarmellose
relative
Compound
of 1 dispersion
to to
comprises pharmaceutical pharmaceutical
wt%
[l,3]dioxol-5-yl)-N-(l-
Compound
the the 42, 41, the the
acetate
selected
of
ratio solid wherein wherein to pharmaceutical to filler
any
2), the 10
comprises 2,
less of
dispersion and
comprises succinate wt%
one total
sodium, and
2 Compound from
the the
than relative
a
of
the of polymer, weight
a claims
a
15%
from filler,
and/or
and
to
of
1
a
2015247850 04 Jun 2019 patient pharmaceutical 49. 48. 47. 46. as cystic oxoquinoline-3-carboxamide (Compound fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide 51. 50. fibrosis agent CFTR is
selected defined
is
fibrosis
modulator, A the A Use The The The
in a
pharmaceutical method CFTR
a in from pharmaceutical
pharmaceutical pharmaceutical pharmaceutical
of patient.
1) any
in (7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6-
and
composition
a
modulator.
a
one of mucolytic
and patient,
7V-[2,4-bis(
treating
of
an
claims
anti-inflammatory composition
wherein composition
composition composition composition
agent, further
cystic (Compound
1
39 , 1
-dimethylethyl)-5-hydroxyphenyl]
to
a fibrosis the
comprises
bronchodilator, 48.
of medicament
of
of of of
any 2)
any
claim claim any in
agent. in
one a
one an 169
the one patient
46 46, of additional
manufacture of
of
comprises
claims
or an
wherein claims
claims
comprising
47, antibiotic,
wherein 39
therapeutic 39
39 the
a to
to of pharmaceutical
to
48 additional
48. an a administering
45,
the
-1 medicament for
anti-infective ,4-dihydro-4-
wherein
additional use agent.
in therapeutic
treating
the composition
to for therapeutic
agent, the
treating
cystic
agent
a
WO 2015/160787 PCT/US2015/025722
1/15 Scale
-
Theta
-
(s»unoo) un WO 2015/160787 PCT/US2015/025722
2/15
(β/Μ) MO|J 1ΕΘΗ A9y frOO-l·
o 1--- 1—CN CM (°C)
Temperature
(β/Μ) moi d lean WO 2015/160787 PCT/US2015/025722
3/15 WO 2015/160787 PCT/US2015/025722
4/15
FIG. 3B WO 2015/160787 PCT/US2015/025722
5/15 4
FIG. WO 2015/160787 PCT/US2015/025722
6/15
FIG. 5 WO 2015/160787 PCT/US2015/025722 Scale
-
Theta
- WO 2015/160787 PCT/US2015/025722
8/15
(β/ΛΛ) MO|J »B8H Λ3Μ ομό - γ (°C)
Temperature
(β/Μ) M0| d lean WO 2015/160787 PCT/US2015/025722
9/15
FIG. 8 WO 2015/160787 PCT/US2015/025722
10/15 9
FIG.
(~|U1/I5lu) U0l)BJ)U90U03 WO 2015/160787 PCT/US2015/025722
11/15 10
Q cz) FIG.
COrtCN't-COCCrtCNO T--■ t-■ t-■ Ο Ο Ο O (~|iju/6uj) uoi)ej)ueouo9 WO 2015/160787 PCT/US2015/025722
12/15
Compound 2 1:3 Neat coSDD Tablet Compound 2 Individual Tablet
FIG. 11 WO 2015/160787 PCT/US2015/025722
13/15
Compound 2 - Free Tablet ■- Compound 1 Spray Dried Dispersion +- Compound 1/ Compound 2 Tablet
FIG. 12 WO 2015/160787 PCT/US2015/025722
14/15
Compound 2 - Free Tablet ■- Compound 1 Spray Dried Dispersion +- Compound 1/ Compound 2 Tablet
FIG. 13 WO 2015/160787 PCT/US2015/025722
15/15 A-Compound2 14
MCC FIG.