US 2005O119315A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0119315 A1 Fedida et al. (43) Pub. Date: Jun. 2, 2005
(54) ION CHANNEL MODULATING ACTIVITY II (60) Provisional application No. 60/118,954, filed on Feb. 5, 1999. Provisional application No. 60/516,248, filed (75) Inventors: David Fedida, Vancouver (CA); on Oct. 31, 2003. Provisional application No. 60/516, Gregory N. Beatch, Vancouver (CA); 486, filed on Oct. 31, 2003. Provisional application Alan M. Ezrin, Miami, FL (US); Peter No. 60/544,941, filed on Feb. 13, 2004. Provisional M. R. Orth, Vancouver (CA) application No. 60/493,392, filed on Aug. 7, 2003. Correspondence Address: Publication Classification SEED INTELLECTUAL PROPERTY LAW GROUP PLLC 701 FIFTHAVE (51) Int. Cl." ...... C07D 211/82; A61K 31/455 SUTE 6300 (52) U.S. Cl...... 514/355; 546/315 SEATTLE, WA 98104-7092 (US) (73) Assignee: Cardiome Pharma Corp., Vancouver (57) ABSTRACT (CA) Methods, compositions, dosing regimes, and routes of (21) Appl. No.: 10/914,841 administration for the treatment or prevention of arrhyth (22) Filed: Aug. 9, 2004 mias. In these methods, arrythmias (e.g. atrial fibrillation, atrial flutter, early afterdepolarizations and prolongation of Related U.S. Application Data QT interval) may be reduced or eliminated by administering ion channel modulating compounds to a Subject in need (63) Continuation-in-part of application No. 10/674,684, thereof. The ion channel modulating compounds may be filed on Sep. 29, 2003, which is a continuation of cycloalkylamine ether compounds, particularly cyclohexy application No. 09/680,988, filed on Oct. 6, 2000, lamine ether compounds. Also described are compositions now abandoned, which is a continuation-in-part of of ion channel modulating compounds and drugs which application No. 09/283,873, filed on Mar. 31, 1999, induce early afterdepolarizations, prolongation of QT inter now abandoned. Val and/or Torsades de Pointes.
11 O 100 9 O 8O 70 : SO 50 s 40 O O. 1 Hz Ic = 2.7 uM 3O V 1 Hz Ic = 1.7M 2O A 3 Hz Ic = 0.693.M 1 O 10Hz Ic = 0.466M
1 E-4 1 E-3 OO1 O1 1 10 1 OO 1 OOO 10 OOO Compound B Patent Application Publication Jun. 2, 2005 Sheet 1 of 39 US 2005/0119315 A1 Figure 1
1 10 100 9 O 80 70 60 s 50 s 4 O D 0.1 Hz Ic = 2.71M 30 v 1 Hz Ic = 1.7.M 2O A 3Hz Ic = 0.693 uM 1 O 10Hz Ic = 0.466.M
1 E-4 1 E-3 0.01 O.1 1 10 100 1000 10000 Compound B Patent Application Publication Jun. 2, 2005 Sheet 2 of 39 US 2005/0119315 A1 Figure 2
A - son - B -100 mV Control 10 M Compound A
0.25 Hz 3 nA 0.25 / 1 / 1020 Hz
2ns
C 1.0 Q ------E 0.8 - TTT - - - - - s5 ------Tonic Block O is 0.6 D
ast 0.4 5 0.25H2 s l 0.2 1 Hz 10Hz 20Hz O.O. 10 50 100 Concentration of Compound A (uM) Patent Application Publication Jun. 2, 2005 Sheet 3 of 39 US 2005/0119315 A1
Figure 3
1.0 a -120 mV; tC =- 107 it 11 M (n=3) g A -100 mV: C = 60 it 4 uM (n=3) N/ O.8 o -80 mV; IC= 43 it 8 uM (n=5) D -60 mV; IC = 31 + 1 uM (n=5) 2 S. 0.6 c d g 9 04 S S O2 l
0.0 O 500 1000 1500 1. 10 OO 1000 Pulse number Compound A concentration (M) Patent Application Publication Jun. 2, 2005 Sheet 4 of 39 US 2005/0119315 A1
Figure 4
O. 8
O. 6
O. 4.
0. 2 ICs = 38 + 4 uM
O. O 1 10 100 1000 Compound A concentration (M) Patent Application Publication Jun. 2, 2005 Sheet 5 of 39 US 2005/0119315 A1
G?un61–
CO d Sir to N (Wu) epndue Juejuno eyes-ApeeS Patent Application Publication Jun. 2, 2005 Sheet 6 of 39 US 2005/0119315 A1
Figure 6
Trace Number -50 mW -80 mV.
1.
0.8
Ic = 21 it 3 (M 0.6
0.4
0.2
0.0 - -r 0.1 1 10 100 1000 Concentration of Compound A (M) Patent Application Publication Jun. 2, 2005 Sheet 7 of 39 US 2005/0119315 A1
Figure 7
68 O. 4.
0. 2 IC = 30 it 5 uM
O. O 0.1 1 10 100 1000 Compound A Concentration (uM) Patent Application Publication Jun. 2, 2005 Sheet 8 of 39 US 2005/0119315 A1
Figure 8
20 TV
Compound A-sensitive Current
B Compound A-sensitive component
TTX-sensitive ".' ' ' ' ' ' ' ' 'la Current
TTX-sensitive component
40 pA 2000 pA early
100 is 2ms Patent Application Publication Jun. 2, 2005 Sheet 9 of 39 US 2005/0119315 A1
Figure 9
A prepulse test pulse
B 50M Compound C C 50M Lidocaine O 5M Flecainide 2 n 2 nA 2 -
200 ms 200ms 200 ms E prepulse = 10 ms F prepulse = 100 ms G prepulse = 500 ms 10 -0 0.8 es 0.8 a control s s lidocaine s A Flecainide v Compound C al O 100 200 300 400 500 0 00 20 300 400 500 O 100 200 300 400 500 Inter-pulse interval (ms) Patent Application Publication Jun. 2, 2005 Sheet 10 of 39 US 2005/0119315 A1
Figure 10
trace 2:30 M Compound A
Yg-trace 3: trace 2 normalized to trace 1 trace 1: control1 Patent Application Publication Jun. 2, 2005 Sheet 11 of 39 US 2005/0119315 A1
Figure ll
1.O
O.8 O.6 C = 10 uM O4
1 1O OO Concentration of Compound A (M) Patent Application Publication Jun. 2, 2005 Sheet 12 of 39 US 2005/0119315 A1 Figure 12
1 O
O.8 Control O.6 rest block
O.4
0.2
O.O 5 uM Compound A Patent Application Publication Jun. 2, 2005 Sheet 13 of 39 US 2005/0119315 A1
Figure 13
s s
- 1.2 s 12 E 1.0 9 9 1.0"T 0 & 0 e e o e s e s O.8 0.8 0.6 0.6 O4 3c 04 t o 0.25 Hz control o 1 Hz control 02 0 0.25 Hz Compound A (5uM) 0.2 o 1 Hz Compound A (5M) E o w- o W 2. O 4000 8000 12000 Z O 4000 8000 12000 Time (ms) Time (ms)
s O 12 12 s al 1.0 8 10 Oeees ve5 '8865533555858ssssssssssssssssssessess s e O66000000 Caesaccacci S 0.8 0.8 0.6 se 0.6 io. > 04 s wa o w e 10 Hz control 0.2 u 20 Hz control
O2 o 10 Hz Compound A (5 M) is " o 20hz Compound A (5uM)
2 0.0 O 1000 2000 3000 4000 5 O 000 2000 . Time (ms) Time (ms) Patent Application Publication Jun. 2, 2005 Sheet 14 of 39 US 2005/0119315 A1
Figure 14 O O HNy.R class(Boo)2O >l O l N a) NaH, THF, reflux > O ul N THF (95%) fy"OH b) BzIBr, BuNi (cat) RX OBZ (>98%) 1R 2R TFA, rt (60-80%) OH a) MsCI, EtsN, CH2Cl Oo NR) OBzl - HO,- 80°C "6). OB: b) NaO OMe 4R (87%) 3R r OMe (1:1diastereomers) mixture of trans reflux, 68 h OMe OMe OMe OMe OMe MeO
O HPLC resolution RO m -- SO
c YN RX OBZ C N 6) OB: C. RX OBz. 5R (1:1 mixture of trans HCI/Et2O SRRR SSSR diastereomers, 71%) --> (12) H. Pd-C, ad HCl, PrOH H2, Pd-C, aq. HCl, PrOH
OMe OMe
1. NahCO ad/CH2Cl2 RO 2. AcCI/CH2Cl2 (17) O FN-r y o HCI Patent Application Publication Jun. 2, 2005 Sheet 15 of 39 US 2005/0119315 A1
Figure 15
Placebo +Placebo 0.5 mg/kg +1 mg/kg 2 mg/kg 3 mg/kg Patent Application Publication Jun. 2, 2005 Sheet 16 of 39 US 2005/0119315 A1 Figure 16
-O- 2.0 mg/kg + 3.0 mg/kg (n=10) -v- 2.0 mg/kg (n=7)
3. E s o 3. C
wkO
C d O. 1 O C O CD
400 600 800 1000 1200 1400 Time after the end of T1 (min) Patent Application Publication Jun. 2, 2005 Sheet 17 of 39 US 2005/0119315 A1
Figure 17
Purkinje fiber voltage recordings: Control: 1 SBCL 3 S BCL
O mV - O TV
-90 mV - -90 mV
300 nM dofetilide: 8 SBCL EAD
OVam -1
-90 mV - 300 nM dofetilide + 30 M coMPound A: 3 s BCL
O V
-90 mV Patent Application Publication Jun. 2, 2005 Sheet 18 of 39 US 2005/0119315 A1
Figure 18
ornw
90 mV -
SOs Patent Application Publication Jun. 2, 2005 Sheet 19 of 39 US 2005/0119315 A1
Figure 19
1.0 () 2 0.8 3 0.6 e s is 0.4 30 uM 5 COMPOUND A 0.2 0.0 Early Sustained Late hH1 Na current components
1.0
0.8
0.6 0.4 30 M lidocaine
O.2
O.O Early Sustained Late hH1 Nat current components Patent Application Publication Jun. 2, 2005 Sheet 20 of 39 US 2005/0119315 A1 Figure 20
+20 mV
:30 p.MTTX 2ms 30 uM Comford A 30 M to MAudd A
------: Y- Pre-drug
Gd s e s E
d 2 25 2. ho o 9. 2 4. c) Ol T30 M corneo. A
Trace number Patent Application Publication Jun. 2, 2005 Sheet 21 of 39 US 2005/0119315 A1
Figure 21
+20 V
lidocaine-sensitive:current A 88 - 8 - 8 e s - w a s as a s > -s a as as ......
docaine-sensitive component
TTX-Sensitive
late Current NTTX-sensitive component
40 pA early 2000 pA early
OOms 2nts Patent Application Publication Jun. 2, 2005 Sheet 22 of 39 US 2005/0119315 A1
Figure 22
40 40
3S 35
3. 30
2S) 25
20 2 150 - ---- 50
100 - --- 0.1 10 00 o ------10 O 10 predrug colore A. 300 nM Dofetilide Dofetide (nM) 30 M com four DA
40
350 300 30 250 250 200
150 compouno A 10 (M) Dofetilide predrug 300 nM (nM) 30 M Dofetilide corrrours A Patent Application Publication Jun. 2, 2005 Sheet 23 of 39 US 2005/0119315 A1
Figure 23
400
350
300
- 250
200
100
50
Pre-Drug 300 nM DOfetilide 30 uM come ound A - 300 nM DOfetilide Patent Application Publication Jun. 2, 2005 Sheet 24 of 39 US 2005/0119315 A1
Figure 24
400
350
300 22
1 5O
100
50
Pre-Drug 30 uM CoMovie A 30 uM Compose A o 300 nM DOfetilide Patent Application Publication Jun. 2, 2005 Sheet 25 of 39 US 2005/0119315 A1
Figure 25
120
100
8 O
dofetilide + DMSO 4060
20 dofetilide + 30 M Comavro A.
0.01 0.03 0.1 0.3 Dofetilide concentration (uM) Patent Application Publication Jun. 2, 2005 Sheet 26 of 39 US 2005/0119315 A1 Figure 26
120
1OO
80 dofetilide + DMSO
60 dofetilide +30M Conrolm A 40
20
0.01 O.03 O.1 0.3 Dofetilide concentration (uM) Patent Application Publication Jun. 2, 2005 Sheet 27 of 39 US 2005/0119315 A1
Figure 27
300M cofetide 15 min (BCL = 3s) Predrug (BCL = 3 s) | V 400 mS
300nM dofetilide 28 min (BCLs 10s) 300nM dofetitide - 30M Confouns. A 3min (BCL = 10s)
E on F 2 S
300nM do?etitide +30M Compound A 3.45 min (BCL = 10s) 300nM dofetitide +30M compourr. A 9.5 min (BCL = 3s) o mV 400 ms Patent Application Publication Jun. 2, 2005 Sheet 28 of 39 US 2005/0119315 A1 Figure 28
Carlsson in vivo rabbit model of Tdp in acute intervention experiments: when TodP occurs begin infusion of COMPOUNDA for 5 mins Clofilium i COMPOUNDA (throughout) (throughout) or Sodium Control no treatment Methoxamine Experimental endpoint, pentobarbital recording (control) (throughout) terminate all infusions
Surgery 0 mins 5 mins 10 mins 20 nins 35 tins 50 mins A 4. Blood sample Blood sample taken (PK and taken (PK and Patent Application Publication Jun. 2, 2005 Sheet 29 of 39 US 2005/0119315 A1 Figure 29
Control COMPOUND A Pretreatment no drug no drug
500 ms ------r methoxamine 1 pmol/kg/min COMPOUNDA --|--|--|--clofilium + methoxamine (1 min) !---|--|--|--methoxamine + COMPOUNDA clofilium+ methoxamine (2.5min) clofilium + methoxamine + COMPOUNDA (15mins)
500 ns forsades de pointes Patent Application Publication Jun. 2, 2005 Sheet 30 of 39 US 2005/0119315 A1
Figure 30 A B
150 Ol o O s no 100 3 hisO 5 O 50 2 s ? O Control O. 1 0.3 1 Control O.1 0.3 1 Dose of COMPOUNDA DOSe of COMPOUNDA (umol/kg/min) (mol/kg/min) Patent Application Publication Jun. 2, 2005 Sheet 31 of 39 US 2005/0119315 A1 Figure 31
Control 9 9 9 9 O O 03 9 9 9 9 3 O 9 9 9 9 6 220 -- Control 200 a -a- 0.3 pmol/kg/min : 180 -0-1|mol/kg/min 160 9 140 s 120 of
methoxamine--
O 5 10 15 20 25 30 35 Time (min)
350
300
2 5O
200
150 O 5 O 15 20 25 30 35 Time (min) Patent Application Publication Jun. 2, 2005 Sheet 32 of 39 US 2005/0119315 A1
Figure 32
A COMPOUNDA infusion began (t=0)
TP
B normal sinus rhythm (t-2.3 min)
30
- 25 1st minute () NY 2nd minute 20 3rd minute E 4th minute
OC 15 5th minutew O S 10 ? 5
O No intervention 1 pmol/kg/min 3 pmol/kg/min (control) ACute DOSe Of COMPOUNDA Patent Application Publication Jun. 2, 2005 Sheet 33 of 39 US 2005/0119315 A1
Figure 33
Mechanism (Of ACO?
Compount A. Slows Atrial Conduction Only at Fibrillatory Cycle Lengths
d E H 9. 3 s s O O
G C C s d SS Patent Application Publication Jun. 2, 2005 Sheet 34 of 39 US 2005/0119315 A1
Figure 34
compound. A vs. Dofetide on Rabbit Purkinje Fibre APO
S Vehicle O) A DOfetitide g 1 O 25 .. V Comfound A. O 2 H-1 * p < 0.05 " p < 0.01 -8 -7 -6 -5 -4 log Dose (M) Patent Application Publication Jun. 2, 2005 Sheet 35 of 39 US 2005/0119315 A1 Figure 35
COMPOUND A reverses DOfeti ide's Vividening of Purkinje Fibre APD
o Compouno A DMSO
10 100 Dofetilide concentration (nM) Patent Application Publication Jun. 2, 2005 Sheet 36 of 39 US 2005/0119315 A1 Figure 36
Yechanism of Action
ceneous AProlongs Action Potentia. Duration
by Blocking land SUS
C ar N v. N control wash i. tri-----s-six w ...iln. r -SarN SSessrsairst A corro Wash control Wash 50ms 100ns Patent Application Publication Jun. 2, 2005 Sheet 37 of 39 US 2005/0119315 A1 Figure 37
Atrial Selective effect on Refractoriness in Primates
2.5 mg/kg 5 mg/kg CoMou?e A Dose Doses infused over 5 min, Dosing interval 30 min Patent Application Publication Jun. 2, 2005 Sheet 38 of 39 US 2005/0119315 A1 Figure 38
Atrial Selectivity: Electrically Remodeled Dogs
LA-ERPg 300 ms. BCL mRVERPesoonsec CRV-ERPetoxins BC r
corpoured A Dose Patent Application Publication Jun. 2, 2005 Sheet 39 of 39 US 2005/0119315 A1
aalso Soved) US 2005/01 19315 A1 Jun. 2, 2005
ION CHANNEL MODULATING ACTIVITY of ventricular tachycardia (VT) and ventricular fibrillation (VF) in animal models and in humans. In isolated hearts, RELATED PATENTS AND PATENT these effects have been shown to be due to Sodium channel APPLICATIONS blockade. EAD generation is thought to be a major cause of TdP in humans. In addition, EADS have been shown to 0001. This patent application is a continuation-in-part of contribute to reinduction of atrial fibrillation (AF) following U.S. patent application Ser. No. 10/674,684 filed Sep. 29, termination in isolated coronary-perfused canine right atria. 2003, which is a continuation of U.S. patent application Ser. Sodium channel blockers have been shown to prevent iso No. 09/680,988 filed Oct. 6, 2000 (now abandoned), which proterenol-induced TcP in a canine model and also abbre is a continuation-in-part of U.S. patent application Ser. No. viate action potential duration in M-cells of the ventricular 09/283,873 filed Mar. 31, 1999 which claims priority to U.S. myocardium. Provisional Patent Application 60/118,954 filed Feb. 5, 1999 and 60/080,347 filed Apr. 1, 1998, which are herein incor 0008 High densities of voltage-gated sodium channels in porated by reference in their entirety. excitable tissues lead to a rapid membrane depolarization when excitable cells reach the threshold for Sodium channel 0002 This patent application claims the priority benefit activation. The role of Sodium channels in the action poten of U.S. provisional patent application 60/493,392 (filed Aug. tial upstroke (Phase 0) has been well-characterized and 7, 2003), 60/544.941 (filed Feb. 13, 2004), 60/516,486 (filed block of Sodium channels can affect cellular refractorineSS Oct. 31, 2003), and 60/516,248 (filed Oct. 31, 2003), which and regulate heart rhythms. Sodium channels rapidly inac are hereby incorporated by reference in their entirety. tivate following initial opening during Phase 0 and during 0003 U.S. Provisional application 60/467,159 (filed May repolarization. Recovery of these inactivated channels is 2, 2003) is incorporated by reference in its entirety. critical in determining the ability of a cell to generate another action potential. The period during which the cell TECHNICAL FIELD cannot generate another action potential is known as the 0004. The compounds and methods described in this effective refractory period (ERP). Blockade of sodium chan patent application are ion channel modulating compounds nels can lengthen the refractory period of the cell and this and their uses, and include but are not limited to ion channel activity is known to have antiarrhythmic consequences due modulating compounds and their uses as antiarrhythmics, to prolongation of the effective wavelength of the tissue, particularly for the treatment or prevention of atrial fibril reducing the Size of reentrant wavelets which the tissue can lation, atrial flutter, Torsades de Pointes, acquired long Support. Blockade of Sodium channels can also Suppress QT-Syndrome, multifocal ventricular arrhythmias, and ectopic beats which may also play a role in the genesis of Supraventricular arrhythmias. fibrillatory activity in the heart. Indeed, the selective sodium channel blocker tetrodotoxin (TTX) has been shown to prevent VF in isolated rabbit hearts. Recent evidence has BACKGROUND shown that Sodium channel activity contributes not only to 0005 Cardiac arrhythmias often occur as complications the action potential upstroke, but also can affect the action to cardiac diseaseS Such as myocardial infarction and heart potential plateau (Phase 2) and repolarization (Phase 3). This failure. In Serious cases, arrhythmias can cause Sudden Sustained activity is thought to be a result of 3 Separate death. Treatment of arrhythmias is complex and aspects of mechanisms. The first of Such mechanisms has been care, especially the decision to control the Ventricular rate described as channel bursting in which the channel fails to VS. convert the arrhythmia, remain controversial. inactivate. A Second component is known as window current and occurs at potentials at which the Steady-State activation 0006 Class III antiarrhythmics (I blockers) are com and inactivation curves overlap. The third mechanism is a monly used to treat arrhythmia; however these drugs have non-equilibrium phenomenon in which the Sodium channels also been shown to be proarrhythmic and cause greater recover from inactivation during the repolarization phase. lengthening in Purkinje fiber action potentials relative to The Sustained inward sodium current contributed by these those in Ventricular muscle, presumably due to a greater three mechanisms can modulate repolarization during Phase contribution of I in repolarization of Purkinje fibers. For 2 and Phase 3 of the action potential when the membrane example, dofetilide (10 nM) has been shown to increase the potential is regulated by Small amounts of both inward and APD90 (the action potential duration at 90% repolarization) outward current. Modulation of currents contributing to of rabbit Purkinje fibers by 83%, (basic cycle lengths, or Phase 0, 2 and 3 of the action potential can have important BCL=1000 ms). Similarly, quinidine (10 uM) increased roles in regulating refractoriness, action potential duration APD90 by 93% in the rabbit. In addition to drug induced dispersion of repolarization, drug induced early after depo and EAD generation. larizations (EADS) are thought to be an important cause of 0009. The ion channel modulating compounds described Torsades de Pointes (TdP) both clinically and in animal herein are atrially-Selective, and block Sodium channels in a models. frequency (or Stimulation) dependent manner. Further, these ion channel modulating compounds are capable of blocking 0007 Class III agents have been shown to be proarrhyth the late, early and Sustained components of a Sodium chan mic due to blockade of the hERG potassium channel (I. nel current to prevent EADS without Substantially interfering current in human ventricle). hERG channels refer to the product of expression of the human ether-a-go-go related with cardiac activity. gene, normally considered to be a potassium-conducting ion SUMMARY channel. It has been shown that combination therapy with quinidine (class III agent) and mexiletine (class I agent and 0010 Described in this patent are compositions, meth Sodium channel blocker) is more effective in the prevention ods, formulations and dosage regimes for the treatment, US 2005/01 19315 A1 Jun. 2, 2005 prevention, and/or termination of arrhythmias. In particular, this patent described compositions, methods, formulations and dosage regimens for the treatment, prevention and/or O OCH3. termination of EADS Such as EADS caused by drugs that prolong QT interval and/or trigger TaP. Compositions and methods are provided in which the proarrhythmic effects % OCH (e.g., prolonging QT interval) of a drug (Such as a Class III II iOH antiarrhythmic) may be reduced or eliminated by adminis OHC tering an ion channel modulating compound as described herein. 0016. In one version, the ion channel modulating com 0.011 Various subjects to which the ion channel com pound is a cycloalkylamine ether compound of formula pound or compounds may be administered are described in detail in the Detailed Description section. In one version of (Ia) the methods, the Subject is a human Subject. 0012 Various formulations, routes of administration, and dosing regimes that may be used are described in detail in the Detailed Description section. In one version of the methods, the formulation is an intravenous formulation. In one version of the methods, the formulation is an oral R. R. formulation. The formulations may include one or more ion channel modulating compounds together with other optional components. The formulations may be administered in a 0017 where n=1,2,3, or 4 and the other substituents are variety of dosing regimes, including administering one or as defined in the Detailed Description section. more formulations that may or may not be administered via 0018 For all ion channel modulating compounds the same route of administration. The formulations may also described above and elsewhere in this patent, isolated enan be delivered by repeat dosing and by Substantially continu tiomeric, diastereomeric and geometric isomers of the com ous dosing. pounds may be used and mixtures of the compounds may be used. In addition, Solvates or pharmaceutically acceptable 0013 Compositions of an ion channel modulating com Salts of the compounds may be used. pound and a compound which prolongs QT interval are 0019. In some versions, the compound that prolongs QT described herein. interval is an antiarrhythmic, Such as a class III antiarrhyth 0.014. In one version, the ion channel modulating com mic drug. Examples of class III antiarrhythmic drugs pound is a compound that blocks an early component of a include: amiodarone, Sotalol, ibutilide, azimilide, clofilium, dofetilide, Sematilide, d.l-Sotalol, quinidine, tedisamil, cardiac Sodium channel current, wherein the ion channel procainamide, disopyramide, and dronedarone. Other com modulating compound further blocks the early component of pounds which prolong QT intervals are antibiotics, bron a cardiac Sodium channel current approximately as much as chodilators, anesthetics, anti-nausea drugs, anti-malarials, or more than it blocks a Sustained component of a cardiac antipsychotics, appetite SuppreSSants, decongestants, Sodium channel current. In Some versions, the ion channel vasodilators, anti-fungals, anti-cancer drugs, antihistamines, modulating compound blocks a late component of a cardiac gastrointestinal prokinetics, antispasmodics, or antidepres Sodium channel approximately 20% more than it blocks the Sants. Examples of Specific drugs that prolong QT interval early component of a cardiac Sodium channel current. In one are: albuterol, alfuZoSin, amantadine, amiodarone, amitrip version, the ion channel modulating compound is a com tyline, amoxapine, amplicillin, amphetamine/dextroamphet amine, arsenic trioxide, atomoxetine, azithromycin, bepridil, pound of the formula: chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, clarithromycin, clomipramine, cocaine, desipramine, disopyramide, dobutamine, dolfetilide, dolas etron, domperidone, dopamine, doxepin, droperidol, ephe drine, epinephrine, erythromycin, felbamate, fenfluramine, flecainide, fluconazole, fluoxetine, foScarnet, foSphenyloin, galantamine, gatifloxacin, granisetron, halofantrine, halo peridol, ibutilide, imipramine, indapamide, isoproterenol, isradipine, itraconazole, ketoconazole, levalbuterol, leVof loxacin, levomethadyl, lithium, meSoridazine, metaproter enol, methadone, methylphenidate, mexiletine, midodrine, 0.015 or a solvate or pharmaceutically acceptable salt moexipril/HCTZ, moxifloxacin, nicardipine, norepineph thereof, wherein R22 and R2 are independently hydrogen, rine, nortriptyline, Octreotide, ondansetron, paroxetine, pen hydroxy or C-Calkoxy. In one version, the ion channel tamidine, phentermine, phenylephrine, phenylpropanola modulating compound is a monohydrochloride Salt of the mine, pimozide, procainamide, protriptyline, formula: pseudoephedrine, quetiapine, quinidine, risperidone, rito US 2005/01 19315 A1 Jun. 2, 2005
drine, Salmeterol, Sertraline, Sibutramine, Sotalol, Sparfloxa 0024. In some versions, the therapeutically effective cin, tacrolimus, tamoxifen, tellithromycin, terbutaline, thior amount of an ion channel modulating compound is an idazine, tizanidine, trimethoprim-Sulfa, trimipramine, amount Sufficient to block a late component of a cardiac Vardenafil, Venlafaxine, Voriconazole, and Ziprasidone. This Sodium channel current approximately as much as or more list is not intended to be exhaustive, and other drugs which than it blocks an early component of a cardiac Sodium prolong QT interval are intended to be included (see, for channel current, and blocks the early component of a cardiac example, Appendix I). Sodium channel current approximately as much as or more than it blocks a Sustained component of a cardiac Sodium 0020 Methods of using compositions of ion channel channel current. In Some versions, the therapeutically effec modulating compounds and compounds which prolong QT tive amount of an ion channel modulating compound is interval are also described. For example, a method of Sufficient to block a late component of a cardiac Sodium treating an arrhythmia includes administering a therapeuti channel approximately 20% more than it blocks the early cally effective amount of a composition of an ion channel modulating compound and a compound which prolongs QT component of a cardiac Sodium channel current. interval to a patient in need thereof. 0025. Also described herein are methods of reducing and/or eliminating chemically-induced TaP in a Subject 0021. Also described herein are compositions of ion given a therapeutically effective amount of a drug capable of channel modulating compounds and compounds which inducing TaP by administering to the Subject a therapeuti induce TdP. Compounds which induce TdP include antiar cally effective amount of an ion channel modulating com rhythmicS Such as Class III antiarrhythics. Examples of class pound. The ion channel modulating compound may be III antiarrhythmic drugs include: amiodarone, Sotalol, ibutil administered before, concurrently with or after the drug that ide, azimilide, clofilium, dofetilide, Sematilide, and d.l- is capable of prolonging the QT interval. Sotalol. Other compounds which induce TdP are antibiotics, bronchodilators, anesthetics, anti-nausea drugs, anti-malari 0026. Also described herein are methods of treating and/ als, antipsychotics, appetite Suppressants, decongestants, or preventing TaP comprising administering to a Subject in vasodilaltors, anti-fungals, anti-cancer drugs, and antide need thereof an ion channel modulating compound as preSSants. Examples of Specific drugs that induce TdP are: described herein. albuterol, alfuZosin, amantadine, amiodarone, amitriptyline, amoxapine, amplicillin, arsenic, atomoxetine, azithromycin, 0027. Also described herein are methods of terminating bepridil, chloral, chloroquine, chlorpromazine, ciprofloxa and/or preventing EADS comprising administering to a cin, cisapride, clarithromycin, clomipramine, cocaine, dis Subject in need thereof an ion channel modulating com opyramide, dobutamine, dofetilide, dolasetron, domperi pound as described herein. In one version, the EADS are done, dopamine, doxepin, droperidol, ephedrine, chemically induced. In one version, the EADS are induced epinephrine, erythromycin, felbamate, fenfluramine, by a genetic mutation in the Subject, Such as the genetic flecainide, fluconazole, fluoxetine, foScarnet, foSphenyloin, mutations in long-QT syndrome or JerVell and Lang-Nielson galantamine, aatifloxacin, granisetron, halofantrine, halo Syndrome. peridol, ibutilide, imipramine, indapamide, isoproterenol, 0028. Other aspects of the methods, compounds and isradipine, itraconazole, ketoconazole, levalbuterol, compositions provided in this patent are described in detail levomethadyl, lithium, mesoridazine, metaproterenol, in the Detailed Description section. methadone, methylphenidate, midodrine, moexipril/HCTZ, moxifloxacin, nicardipine, norepinephrine, nortriptyline, BRIEF DESCRIPTION OF THE DRAWINGS octreotide, ondansetron, paroxetine, pentamidine, phenter mine, phenylephrine, phenylpropanolamine, pimozide, 0029 FIG. 1 illustrates rate- and concentration-depen procainamide, pseudoephedrine, quetiapine, quinidine, Sal dent inhibition of Sodium current (IN) in human atrial meterol, Sibutramine, Sotalol, tamoxifen, terbutaline, thior myocytes by COMPOUND B. idazine, trimethoprim-Sulfa, trimipramine, and Vardenafil. This list is not intended to be exhaustive, and other drugs 0030 FIG. 2 shows a concentration- and frequency which induce TdP are intended to be included (see, for dependent inhibition of hH1 Sodium channels by COM example, Appendix I). POUND A. 0022 Methods of using compositions of ion channel 0031 FIG.3 shows a voltage-dependent block of hH1 by modulating compounds and compounds which induce TdP COMPOUND A. are also described. For example, a method of treating an 0032 FIG. 4 shows a concentration-dependent inhibition arrhythmia includes administering a therapeutically effec of Kv4.2 at 1 Hz. tive amount of a composition of an ion channel modulating compound and a compound which induces TaP to a patient 0033 FIG. 5 shows the concentration-dependent inhibi in need thereof. tion of Kv1.5 channels by COMPOUND A at 1 Hz. 0023. Also described herein are methods of reducing 0034 FIG. 6 shows a concentration-dependent inhibition and/or eliminating the prolongation of QT interval in a of hERG channels. Subject given a therapeutically effective amount of a drug 0035 FIG. 7 shows a concentration-dependent inhibition capable of prolonging QT interval by administering to the of Kv4.3 channels at 1 Hz. Subject a therapeutically effective amount of an ion channel modulating compound. The ion channel modulating com 0036 FIG. 8 shows an example of the TTX- and COM pound may be administered before, concurrently with, or POUND A-sensitive components of the early, Sustained, and after the drug that is capable of prolonging the QT interval. late Sodium current observed during a step/ramp protocol. US 2005/01 19315 A1 Jun. 2, 2005
0037 FIG. 9 illustrates a protocol to test level of inac 0055 FIG. 27 shows the termination of dofetilide-in tivated state inhibition by COMPOUND C, flecainide, and duced EADs by COMPOUNDA in isolated Purkinje fibers. lidocaine. 0056 FIG.28 shows a timeline of the method for testing 0038 FIG. 10 illustrates hH1 sodium current traces the effects of COMPOUNDA on chemically-induced TaP in exemplifying minor changes in waveform kinetics in the anaesthetized rabbits. presence of COMPOUND A. 0.039 FIG. 11 illustrates concentration-dependent block 0057 FIG. 29 shows control traces with TaP induced by of Ike by COMPOUND A in isolated guinea pig atrial clofilium infusion using the method of FIG. 28 and preven myocytes at 0.1 Hz. tion of TdP induction by COMPOUND A. 0040 FIG. 12 shows a lack of rate-dependent inhibition 0.058 FIG.30 shows the effect of COMPOUNDA on the of Kv1.5 by COMPOUND A. incidence of TdP and duration of episodes of TdP under the TdP induction model of FIG. 28. 0041 FIG. 13 shows a lack of use-dependent inhibition of Kv1.5 by COMPOUND A. 0059 FIG. 31 shows an example of the changes in QTc (corrected QT) interval and heart rate in control and COM 0.042 FIG. 14 illustrates an exemplary reaction scheme POUND A pre-treated animals in the chemically-induced to Synthesize an ion channel modulating compound as TdP model described in FIG. 28. described herein. 0060 FIG. 32 shows an example of the effect of COM 0.043 FIG. 15 Cumulative percentage of patients termi POUND A on electrocardiogram (ECG) waveforms and nating atrial fibrillation (AF) after infusions of placebo, 0.5 duration of TdP during acute termination of TdP as and 1 mg/kg COMPOUND A or 2.0 and 3.0 mg/kg COM described in the chemically-induced TcP model described in POUND A, in patients with recent onset AF. FIG. 28. 0044 FIG.16 Plasma concentrations of COMPOUNDA after infusion in patients dosed at 2 mg/kg i.v. and those 0061 FIG. 33 shows slowing of atrial conduction by additionally dosed at 3 mg/kg i.v. COMPOUND A only at fibrillatory cycle lengths 004.5 FIG. 17 shows action potentials and EADS induced 0062 FIG. 34 shows effect of an ion channel modulating in an isolated rabbit Purkinje fiber preparation. compound on Rabbit Purkinje fiber action potential duration 0.046 FIG. 18 shows late stage EAD suppression by compared to dofetilide and vehicle. COMPOUND A. 0063 FIG. 35 shows the reversal of dofetilide-induced widening of action potential duration by an ion channel 0047 FIG. 19 shows the fraction of each component of modulating compound the TTX-sensitive current blocked by 30 M lidocaine and 30 uM COMPOUND A. 0.064 FIG. 36 shows block of Ito and I by an ion 0048 FIG. 20 shows unsubtracted current traces channel modulating compound resulting in prolonging obtained from HEK293 cells expressing hH1 Na channels action potential duration in the rat Ventricular myocyte. Note before and during exposure to 30 uM COMPOUND A and that the rat has an abnormally short Ventricular action COMPOUND A plus 30 uM TTX. potential that is intended to be representative of human atrium, and is not intended to be a model of effects on human 0049 FIG. 21 shows an example of the TTX- and or primate ventricle. lidocaine-Sensitive components of the early, Sustained, and late Sodium current observed during a step/ramp protocol. 0065 FIG. 37 shows atrial selectivity of an ion channel modulating compound (COMPOUNDA) in primates. 0050 FIG. 22A and FIG. 22B show APDs, and FIG. 22C and FIG. 22D show APD in the presence of escalat 0.066 FIG. 38 shows the atrial selectivity of an ion ing concentrations of COMPOUND A (FIG.22A & FIG. channel modulating compound in electrically remodeled 22C) or dofetilide (FIG. 22B & FIG. 22D) followed by dogs. perfusion with COMPOUNDA (30 uM) and dofetilide (300 0067 FIG. 39 shows in tabular form that an ion channel nM). modulating compound terminates AF and increases atrial 0051 FIG. 23 shows ERP values obtained in the pres fibrillation cycle length (AFCL) in goats. ence of dolfetilide or a combination of dolfetilide and COM POUND A. DETAILED DESCRIPTION 0.052 FIG. 24 shows ERP values obtained in the pres 0068. Described in this patent application are ion channel ence of COMPOUNDA or a combination of COMPOUND modulating compounds that may be used for treating and/or A and dofetilide. preventing a variety of diseases and conditions, including but not limited to treating, and/or preventing recurrence of 0053 FIG. 25 shows the percent increases in APD50 atrial fibrillation or atrial flutter. The effects of ion channel when Purkinje fibers were co-treated with dofetilide and modulating compounds on certain ion channel characteris either 30 uM COMPOUND A or DMSO control. tics and other physiological characteristics are also 0054 FIG. 26 shows the percent increases in APD90 described. The effect of ion channel modulating compounds when Purkinje fibers were co-treated with dofetilide and to enhance, modify, Suppress or eliminate the effects of other either 30 uM COMPOUND A or DMSO control. drugs (e.g., Class III antiarrhythmics) is also described. US 2005/01 19315 A1 Jun. 2, 2005
0069 Definitions 0078. As used in this patent application, “equivalently inhibits” and “equivalently inhibited” means equally inhibits 0070 AS used in this patent application, a “subject” may or equally inhibited. In one version, equivalently inhibits generally be any human or non-human animal that would means that there is no Statistically significant difference in benefit from the methods described in this application. In inhibition of currents due to application of an ion channel one version of the methods, a Subject is a human Subject. In modulating compound. For example, the early and Sustained Some versions of the methods, a Subject is a mammal. In Some versions, the Subject is any domestic animal, includ Sodium currents are equivalently inhibited if there is no ing, but not limited to dogs, and cats. In Some versions, the Statistically significant difference in the effect of an ion Subject is any livestock animal, including but not limited to channel modulating compound on early and Sustained horses, pigs, and cattle. In Some versions, the Subject is any Sodium currents. ZOO animal, including but not limited to Bengal tigers. 0079 AS used in this patent application, “rapidly associ ated and dissociated” means that a compound has blocking 0071 AS used in this patent application, unless the con and unblocking kinetics of the fast-on, fast-off form Such text makes clear otherwise, “treatment,” and Similar word as the fast-on, fast-off kinetics defined by Carmeliet and Such as “treated,”“treating” etc., is an approach for obtaining Mubagwa (Prog. Biophys. Molec. Biol. 70, 1-72, 1998). For beneficial or desired results, including and preferably clini example, an ion channel modulating compound rapidly cal results. Treatment can involve optionally either the asSociates and dissociates from Sodium channels where the amelioration of Symptoms of the disease or condition, or the ion channel modulating compound has fast-on, fast-off delaying of the progression of the disease or condition. kinetics as defined by Carmeliet and Mubagwa. 0.072 AS used in this patent application, unless the con 0080. As used in this patent application, “rate-indepen text makes clear otherwise, “prevention,” and Similar word dent and use-independent' inhibition means inhibition that Such as "prevented,”“preventing” etc., is an approach for is predominantly heart rate and/or Stimulus rate and use preventing the onset of a disease or condition or preventing independent Such that there is no Statistically significant the occurrence of the Symptoms of a disease or condition, or effect of Steady-state or transient changes in heart rate or optionally an approach for delaying the onset of a disease or Stimulus rate with respect to the inhibition. For example, an condition or delaying the occurrence of the Symptoms of a ion channel modulating compound that inhibits KV1 chan disease or condition. AS used herein, "prevention' and nels in a “rate-independent and use-independent manner Similar words also includes reducing the intensity, effect, means that there is no influence of the heart rate or Stimulus Symptoms and/or burden of a disease or condition prior to rate on the amount of inhibition produced by the ion channel onset of the disease or condition. modulating compound on KV1 channels. 0073. As used in this patent application, an “effective 0081. As used in this patent application, “affects atrial amount” or a “therapeutically effective amount of a sub repolarizing currents' means “has a Statistically significant stance is that amount Sufficient to affect a desired biological effect, Such as beneficial results, including clinical results. effect on atrial repolarizing current amplitudes.” 0082. As used in this patent application, “prolongs atrial 0.074 As used in this patent application, unless the con refractoriness” means “has a Statistically significant pro text makes clear otherwise, “inhibition' and similar words Such as “inhibit of any ion channel means any decrease in longing effect on atrial refractoriness.” current through that channel. When “inhibition” is used in 0083. As used in this patent application, “has substan the context of a specified concentration, it is determined by tially no effect on Ventricular tissue' means “has no Statis the ICso. For example, an ion channel modulating compound tically significant effect on normal human Ventricular action which inhibits an ion channel at a concentration of 1 uM, the potential duration or refractoriness.” Any apparent differ ion channel may be said to have an ICso of 1 uM for that ion ence in effect, therefore, is attributed to intrinsic variability, channel modulating compound. This example is for illus Such as in one aspect, less than a 10% difference. trative purposes only and is in no way intended to be limiting. 0084. As used in this patent application, “does not sub Stantially slow conduction” means “has no Statistically Sig 0075 AS used in this patent application, unless the con nificant effect on Slowing conduction in the Ventricles.” AS text makes clear otherwise, “ICso or "ICso concentration' Such, any apparent difference in effect, therefore, is attrib means a drug concentration at which the Specified current uted to intrinsic variability. In one aspect, the ion channel amplitude (peak or steady-state, or integrated current) is modulating compound has no Statistically significant effect inhibited by 50%. on the slowing of conduction wherein the compound pro 0.076 AS used in this patent application, unless the con duces less than a 15%, preferably less than a 10%, increase text makes clear otherwise, “blocking” or “block” of an ion in cardiac QRS duration at physiological heart rates. channel means any block or inhibition of current through 0085. As used in this patent application, “rate-dependent that ion channel. inhibition' of an ion channel means that the level of inhi bition of the ion channel changes with the frequency of 0.077 As used in this patent application, unless the con Stimulation. text makes clear otherwise, “recovery time constant of inhibition” refers to a time constant at which recovery of 0086 The terms early component, late component and current amplitude occurs, presumed to reflect dissociation of Sustained component are used as known in the art; for a drug from its binding site, as for example, a Sodium example, the early, Sustained and late components of a channel when the stimulus rate is decreased from 10 Hz to cardiac sodium channel current are as shown in FIG. 8, and 1 Hz. as described in Example 9 and Example 18 below. US 2005/01 19315 A1 Jun. 2, 2005
0087. The term “QT interval” is used as is known in the phous forms, metabolites, metabolic precursors or prodrugs art; for example, the QT interval as measured from an of the compound are also Separately described by the electrocardiogram. AS used herein, unless the context makes chemical Structural formula or chemical name. clear otherwise, the term “prolongs” or “prolong generally 0099 AS used in this patent, unless the context make means extends or lengthens as in duration. plain otherwise, the following terms are defined to have 0088. The term “antiarrhythmic' is used as is known in following meanings: the art; for example, as a compound which prevents or alleviates irregularities in heart rate. 0100 "Acid addition salts' refer to those salts which retain the biological effectiveness and properties of the free 0089. The term “induces” as used herein, unless the bases and which are not biologically or otherwise undesir context indicates otherwise, generally means to Stimulate the able, formed with inorganic acids Such as hydrochloric acid, occurrence of. hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid 0090 The term “chemically induced” or “chemically and the like, or organic acids Such as acetic acid, propionic induces is used as is known in the art. AS used herein, acid, glycolic acid, pyruvic acid, Oxalic acid, maleic acid, unless the context makes clear otherwise, the term “termi malonic acid, Succinic acid, fumaric acid, tartaric acid, citric nating” or "terminates' generally means to bring to an end acid, benzoic acid, cinnamic acid, mandelic acid, methane or to halt. Sulfonic acid, ethaneSulfonic acid, p-toluenesulfonic acid, Salicylic acid and the like. 0091) Ion Channel Modulating Compounds 0101 “Acyl' refers to branched or unbranched hydrocar 0092] Ion channel modulating compounds include but are bon fragments terminated by a carbonyl-(C=O)- group not limited to compounds exhibiting one or more of the containing the Specified number of carbon atoms. Examples characteristics described in the Effect of ion channel modul include acetyl CH (C=O)-, a C-acyl and propionyl lating compounds on certain ion channel characteristics and CHCH (C=O), a Cacyl). other physiological characteristics Section. 0102) “Alkanoyloxy' refers to an ester substituent 0.093 Specific ion channel modulating compounds that wherein the ether oxygen is the point of attachment to the may be used are described in this Section and in detail molecule. Examples include propanoyloxy elsewhere in this patent application. (CH-CH (C=O)-O-, a Calkanoyloxy) and ethanoy 0094. In this section are described various compounds loxy ICH (C=O)-O-, a Calkanoyloxy). and classes of compounds that may be used as ion channel modulating compounds in the methods, formulations, etc. 0.103 "Alkoxy' refers to an O-atom substituted by an described in this patent. alkyl group, for example, methoxy-OCH, a Calkoxy. 0.095. In this section are first described a series of specific 0104 “Alkoxyalkyl” refers to an alkylene group substi classes of ion channel modulating compounds together with tuted with an alkoxy group. For example, methoxyethyl Specific example compounds, followed by a general descrip CHOCH2CH-) and ethoxymethyl (CHCHOCH2-) tion of compounds that may be used as ion channel modu are both Calkoxyalkyl groups. lating compounds. 0105. “Alkoxycarbonyl' refers to an ester substituent 0.096 Specific Classes of Ion Channel Modulating Com wherein the carbonyl carbon is the point of attachment to the pounds and Exemplary Ion Channel Modulating Com molecule. Examples include ethoxycarbonyl pounds CHCHO(C=O)-, a Calkoxycarbonyl and methoxy carbonyl (CHO(C=O)-, a Calkoxycarbonyl). 0097 Examples of specific classes of ion channel modu lating compounds and exemplary ion channel modulating 0106 “Alkyl” refers to a branched or unbranched hydro compounds are described below and in U.S. provisional carbon fragment containing the Specified number of carbon patent application No. 60/516,248, U.S. patent application atoms and having one point of attachment. Examples Ser. No. 10/674,684, each of which applications is incorpo include n-propyl (a Calkyl), iso-propyl (also a Calkyl), and rated herein by reference in its entirety. t-butyl (a Calkyl). 0098. In the variations described in this section on Spe 0107 “Alkylene' refers to a divalent radical which is a cific Classes of Ion Channel Modulating Compounds and branched or unbranched hydrocarbon fragment containing Exemplary Ion Channel Modulating Compounds, all enan the Specified number of carbon atoms, and having two points tiomeric and diastereomeric forms of the ion channel modu of attachment. An example is propylene -CH2CH2CH2-, lating compounds are intended. Pure Stereoisomers, mix a Calkylene. tures of enantiomers and/or diastereomers, and mixtures of 0.108 “Alkylcarboxy' refers to a branched or unbranched different ion channel modulating compounds are described. hydrocarbon fragment terminated by a carboxylic acid group Thus, the ion channel modulating compounds may occur as -COOH). Examples include carboxymethyl HOOC racemates, racemic mixtures and as individual diastereomers CH-, a Calkylcarboxy and carboxyethyl HOOC or enantiomers with all isomeric forms being included in the CHCH-, a Calkylcarboxy. present description. A racemate or racemic mixture does not imply a 50:50 mixture of stereoisomers. Where a given 0109 "Aryl” refers to aromatic groups which have at Structural formula or chemical name is presented for a least one ring having a conjugated pi electron System and compound it is intended that all possible Solvates, pharma includes carbocyclic aryl, heterocyclic aryl (also known as ceutically acceptable Salts, esters, amides, complexes, che heteroaryl groups) and biaryl groups, all of which may be lates, Stereoisomers, geometric isomers, crystalline or amor optionally Substituted. Carbocyclic aryl groups are generally US 2005/01 19315 A1 Jun. 2, 2005 preferred in the compounds, where phenyl and naphthyl 0120) “Pharmaceutically acceptable salt” refers to salts of groups are preferred carbocyclic aryl groups. the compounds derived from the combination of Such com pounds and an organic or inorganic acid (acid addition salts) 0110) “Aralkyl” refers to an alkylene group wherein one or an organic or inorganic base (base addition salts). The of the points of attachment is to an aryl group. An example compounds described herein may be used in either the free of an aralkyl group is the benzyl group CHCH-, a base or Salt forms, with both forms being considered as Czaralkyl group. being within the Scope intended herein. 0111 “Cycloalkyl” refers to a ring, which may be satu 0121 Aminocyclohexyl Ether Ion Channel Modulating rated or unsaturated and monocyclic, bicyclic, or tricyclic Compounds formed entirely from carbon atoms. An example of a cycloalkyl group is the cyclopentenyl group (C5H7-), 0.122 One class of compounds that are ion channel which is a five carbon (C) unsaturated cycloalkyl group. modulating compounds are compounds that comprise an aminocyclohexyl ether core Structure having an ether oxy 0112 “Carbocyclic” refers to a ring which may be either gen atom at position 1 of a cyclohexane ring, and an amine an aryl ring or a cycloalkyl ring, both as defined above. nitrogen atom at position 2 of the cyclohexane ring. This core Structure is shown below, with other positions num 0113 “Carbocyclic aryl” refers to aromatic groups bered in corresponding order: wherein the atoms which form the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic car bocyclic aryl groups Such as phenyl, and bicyclic carbocy clic aryl groupS Such as naphthyl, all of which may be (B) optionally Substituted. 0114) “Heteroatom” refers to a non-carbon atom, where boron, nitrogen, oxygen, Sulfur and phosphorus are pre ferred heteroatoms, with nitrogen, oxygen and Sulfur being particularly preferred heteroatoms. 0115) “Heteroaryl” refers to aryl groups having from 1 to 9 carbon atoms and the remainder of the atoms are heteroa toms, and includes those heterocyclic Systems described in 0123 The bonds from the cyclohexane ring of (B) to the “Handbook of Chemistry and Physics,” 49th edition, 1968, 1-oxygen and 2-mitrogen atoms in the above formula may be R. C. Weast, editor; The Chemical Rubber Co., Cleveland, relatively disposed in either a cis or trans relationship. In one Ohio. See particularly Section C, Rules for Naming Organic variation, the Stereochemistry of the amine and ether Sub Compounds, B. Fundamental Heterocyclic Systems. Suit Stituents of the cyclohexane ring is either (R,R)-trans or able heteroaryls include furanyl, thienyl, pyridyl, pyrrolyl, (S,S)-trans. In another variation, the Stereochemistry at these pyrimidyl, pyrazinyl, imidazolyl, and the like. positions is either (R.S)-cis or (S,R)-cis. 0116 “Hydroxyalkyl” refers to a branched or unbranched 0.124. In one variation, an ion channel modulating com hydrocarbon fragment bearing a hydroxy (-OH) group. pound or derivative thereof as disclosed herein is not an Examples include hydroxymethyl (-CHOH, a aminocycloalkyl ester containing compound. In another Chydroxyalkyl) and 1-hydroxyethyl (-CHOHCH, a variation, an ion channel modulating compound or deriva Chydroxyalkyl). tive thereof as disclosed herein is not an aminocyclopentyl 0117 “Thioalkyl” refers to a sulfur atom substituted by ester, an aminocyclohexyl ester, an aminocycloheptyl ester, an alkyl group, for example thiomethyl (CHS-, a or an aminocyclooctyl ester containing compound. C, thioalkyl). 0.125. In one version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modulating 0118 “Modulating” in connection with the activity of an compound is a compound of the formula: ion channel means that the activity of the ion channel may be either increased or decreased in response to administra tion of a compound or composition or method described (I) herein. Thus, the ion channel may be activated, So as to R5 transport more ions, or may be blocked, So that fewer or no n ions are transported by the channel. asX O R1 0119) “Pharmaceutically acceptable carriers” for thera A peutic use are well known in the pharmaceutical art, and are Nin described, for example, in Remingtons Pharmaceutical Sci ences, Mack Publishing Co. (A. R. Gennaro edit. 1985). For example, Sterile Saline and phosphate-buffered Saline at physiological pH may be used. Preservatives, Stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. For example, Sodium ben 0126 Compounds of formula (I) are aminocyclohexyl Zoate, Sorbic acid and esters of p-hydroxybenzoic acid may ethers. More specifically, these aminocyclohexyl ethers are be added as preservatives. Id. at 1449. In addition, antioxi Substituted at position 2 of the cyclohexyl ring with an amine dants and Suspending agents may be used. Id. group -NRR. The cyclohexyl ring may also be Substi US 2005/01 19315 A1 Jun. 2, 2005 tuted with additional Substituents (designated as R and Ra) 0131 Alternatively, R and R, when taken together with as described in more detail below. Examples of Specific the 2-amino nitrogen of formula (I), may complete a bicyclic compounds represented by formula (I) are described below. ring. Bicyclic rings include, for example, 3-azabicyclo 3.2.2]nonane, 2-azabicyclo2.2.2]octane, 3-azabicyclo 0127 Depending upon the selection of substituents R. 3.1.0 hexane, and 3-azabicyclo3.2.0]heptane. For these and R2, the compounds of formula (I) may be primary, derivatives, the 2-substituents of the cyclohexyl ethers of Secondary, or tertiary amines (i.e., both R and R are formula (I) are the following groups: 3-azabicyclo3.2.2 hydrogen, only one of R and R is hydrogen, or neither of nonan-3-yl, 2-azabicyclo2.2.2]octan-2-yl, 3-azabicyclo R and R2 are hydrogen, respectively). In one embodiment, 3.1.0 hexan-3-yl, and 3-azabicyclo3.2.0heptan-3-yl. the compounds of formula (I) are tertiary amines, i.e., neither R nor R2 is hydrogen. Where the amine is tertiary, 0132 R and R2, when taken together may contain only it may be a cyclic amine. Amine Substituents R and R may a single heteroatom. Preferred heteroatoms include nitrogen, be independently selected from Substituents which include oxygen and Sulfur. An example of a ring in which R and R hydrogen, alkyl groups containing from one to eight carbon together include an oxygen heteroatom is the morpholinyl atoms (i.e., C-Calkyl), alkoxyalkyl groups containing group. An example of a ring where R and R together from three to eight carbon atoms (i.e., C.-Calkoxyalkyl), include a Second nitrogen heteroatom is the piperazinyl alkyl groups containing from one to eight carbon atoms grOup. where one of the carbon atoms is substituted with a hydroxyl 0.133 Cyclohexane substituents R and R may be inde group (i.e., C.-Chydroxyalkyl), and aralkyl groups contain pendently attached to ring positions 3, 4, 5 or 6 (i.e., both R ing from Seven to twelve carbon atoms (i.e., C7-Caralkyl). and R may be attached to the same ring position or each In one version, R and R2 are independently Selected from attached to different ring position). R and R are indepen hydrogen, C-Calkyl, C-Calkoxyalkyl, dently Selected from hydrogen, hydroxy, C-Calkyl, and C-Chydroxyalkyl, and C7-Caralkyl. In another version, C-Calkoxy, and, when both R and R are attached to the R and R are independently selected from Same cyclohexane ring atom, may together form a Spiro five C-Calkoxyalkyl, C-Chydroxyalkyl, and C7-Caralkyl. or Six-membered heterocyclic ring containing one or two 0128. Alternatively, R and R, when taken together with heteroatoms Selected from oxygen and Sulfur. Preferred the nitrogen atom to which they are directly attached in heterocyclic Substituents contain either a single oxygen or a formula (I), may form a ring denoted by formula (II): Single Sulfur ring atom. 0.134 Depending upon the identity of X, the ether side chain, -CH(R)-X-A, in formula (I) may take several -R1. (II) forms. For example, a compound of formula (I) may have X N ) as a -C(R,R)-Y-group, where Y may be any of a NuR2 direct bond, an oxygen atom (O), a Sulfur atom (S) or a C-C alkylene group. R. and Rare independently selected from hydrogen, C-C alkyl, aryl and benzyl, or R and R, 0129 wherein the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring when taken together with the carbon to which they are atoms independently Selected from carbon, nitrogen, oxy attached, may form a Spiro C-C cycloalkyl. Thus, com gen, and Sulfur, where any two adjacent ring atoms may be pounds described herein include compounds of formula (I) joined together by Single or double bonds, and where any where R and R are hydrogen and Y is a direct bond, Such one or more of the additional carbon ring atoms may be that X may be CH-. Substituted with one or two Substituents selected from hydrogen, hydroxy, C-C-hydroxyalkyl, oxo, C-Cacyl, 0.135 Alternatively, X may be an alkenylene moiety, e.g., C-C alkyl, C-C alkylcarboxy, C-Calkoxy, a cis-or trans-alkenylene moiety, C(R)=CH, where R. C-Coalkanoyloxy, or may be Substituted to form a spiro may be any of hydrogen, C-Calkyl, C-C cycloalkyl, aryl five- or Six-membered heterocyclic ring containing one or or benzyl. For compounds of formula (I) where X is an two heteroatoms Selected from oxygen and Sulfur (e.g., an alkenylene moiety, X is preferably a trans-alkenylene moi acetal, thioacetal, ketal, or thioketal group); and any two ety. adjacent additional carbon ring atoms may be fused to a 0.136 Alternatively, X may be a direct bond. Independent C-C carbocyclic ring, and any one or more of the additional of the Selections for A, X and other variables, Rs is selected nitrogen ring atoms may be Substituted with Substituents from hydrogen, C-C alkyl, aryl and benzyl. Selected from hydrogen, C-C alkyl, C-Cacyl, C-C hydroxyalkyl and C-Calkoxyalkyl. Examples of 0137 In one variation, X is either a -C(R,R)-Y- Substituents containing a fused ring System include the or a C(R)=CH group, and is not a direct bond. In another perhydroindolyl and 1,2,3,4-tetrahydroisoquinolinyl groups. variation, the compounds exclude those compounds wherein X is a direct bond when R and R2 are hydrogen. In another 0130. In connection with the ring of formula (II), any two adjacent ring atoms may be joined together by Single or variation, X is selected from a direct bond, -C(R,R)- double bonds. Thus, the ring of formula (II) may be satu Y-, and -C(R)=CH-, with the proviso that when X is rated or unsaturated, and an unsaturated ring may contain a direct bond and A is formula (III) then at least one of R, one, or more than one, Sites of unsaturation. In other words, Rs and Ro is not hydrogen. In another variation, the com the ring of formula (II) may contain one or more double pounds exclude those compounds wherein X is a direct bond bonds, it being understood, however, that the unsaturated when A is formula (III) and each of R7, Rs and Ro is ring of formula (II) is chemically stable. hydrogen. In another variation, the compounds exclude US 2005/01 19315 A1 Jun. 2, 2005 those compounds wherein X is a direct bond when A is 0140. A suitable “A” group in the formula above is a formula (III). In another variation, when X is a direct bond, phenyl ring represented by formula (III): R and R are H, and A is of formula (III), at least one of R7, Rs and R is not hydrogen. In another variation, when X is (III) a direct bond, R and R are H, and A is of formula (III), at least two of R7, Rs and Ro are not hydrogen. In another variation, when X is a direct bond and A is formula (III) then at least one of R, R and Rs is not hydrogen. In another variation, when X is a direct bond, R and R2 are H, and A is of formula (III), at least one of R, R and Rs is not hydrogen. In another variation, when X is a direct bond and 0141 where R, R and Ro are independently selected A is of formula (III), at least two of R, R and Rs are not from bromine, chlorine, fluorine, carboxy, hydrogen, hydrogen. In another variation, when X is a direct bond, R hydroxy, hydroxymethyl, methaneSulfonamido, nitro, Sul famyl, trifluoromethyl, C-Czalkanoyloxy, C-C alkyl, and R are H, and A is of formula (III), at least two of R, C-Calkoxy, C-Czalkoxycarbonyl, C-Cthioalkyl, aryl R and Rs are not hydrogen. and N(R,R) where Rs and R are independently 0138 Ether side chain component A is generally a hydro Selected from hydrogen, acetyl, methaneSulfonyl, and phobic moiety. Typically, a hydrophobic moiety is com C-Calkyl. prised of non-polar chemical groupS. Such as hydrocarbons 0142 For compounds of formula (I) where X is a direct or hydrocarbons Substituted with halogens or ethers or bond or CH, at least one of R7, Rs and Ro is preferably heterocyclic groups containing nitrogen, oxygen, or Sulfur Selected from amine (-NRSR, where Rs and Rs are ring atoms. Suitable hydrocarbons include Cs-Calkyl, independently hydrogen, acetyl, methaneSulfonyl, and C-Cacarbocyclic rings, C-C cycloalkyl rings and an C-Calkyl), bromine, chlorine, fluorine, carboxy, hydrogen, unsubstituted C-C aryl ring. Particularly preferred cyclic hydroxy, hydroxymethyl, nitro, trifluoromethyl, hydrocarbons include Selected aromatic groups Such as C-C,alkanoyloxy, C-Calkyl, C-Calkoxy, phenyl, 1-naphthyl, 2-naphthyl, indenyl, acenaphthyl, and C-C,alkylcarbonyl, C-Cthioalkyl or aryl groups. For fluorenyl and are represented by formulae (III), (IV), (V), compounds of formula (I) when X is CH=CH, and R and (VI), (VII), or (VIII), respectively. R are hydrogen, at least one of R7, Rs and Ro is preferably 0.139. In one variation, A is selected from the group a Substituent other than hydrogen. One variation presents consisting of Cs-C2alkyl, a C-C carbocyclic ring and compounds of formula (I) where A includes phenyl groups ring systems selected from the formulae (III), (IV), (V), of formula (III) Such that at least one of R7, Rs and Ro is not (VI), (VII) and (VIII). In one variation, A is selected from hydrogen, i.e., formula (III) is a phenyl group that contains the group consisting of Cs-C2alkyl, a C-C aryl ring, a at least one non-hydrogen Substituent. In another variation, R7, Rs and Ro are Selected from amine (-NRSR, where C-C cycloalkyl ring and ring systems selected from the Rs and R are independently hydrogen, acetyl, methane formulae (III), (IV), (V), (VI), (VII) and (VIII). In another Sulfonyl, and C-Calkyl), bromine, chlorine, fluorine, car variation, A is Selected from the group consisting of boxy, hydrogen, hydroxy, hydroxymethyl, nitro, trifluorom Cs-Calkyl, a C-C cycloalkyl ring, an unsubstituted ethyl, C-Czalkanoyloxy, C-Calkyl, C-Calkoxy, C-C, aryl ring and ring systems selected from the formulae C-C-alkylcarbonyl and C-Cthioalkyl, i.e., none of R7, Rs (III), (IV), (V), (VI), (VII) and (VIII). In one variation, when or R is aryl. In another variation, A does not include a A is a C-C carbocyclic ring, Rs is not hydrogen. In phenyl ring of formula (III) when X is a direct bond. another variation, when A is a C-C carbocyclic ring, one of R and R is not hydrogen. In one variation, when A is a 0143. Other suitable “A” groups are 1-naphthyl groups as C-C aryl ring, R is not hydrogen. In another variation, represented by formula (IV): when A is a C-C aryl ring, one of R and R2 is not hydrogen. In another variation, when X is a direct bond and A is a C-C aryl ring, then A is not an aryl ring Substituted (IV) by another aryl ring. In another variation, when X is a direct bond and A is a C-C carbocyclic ring, then A is not an aryl ring Substituted by another aryl ring. In another variation, when R and R2 are independently Selected from hydrogen or C-Calkyl, or R and R together with the nitrogen atom to which they are directly attached represent a phthalimido group, and A is a C-C carbocyclic ring, then A is not an 0144 where Ro and R are independently selected from aryl ring which is Substituted by another aryl ring. In another bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, variation, when R and R2 are independently Selected from hydroxymethyl, methaneSulfonamido, nitro, Sulfamyl, trif hydrogen or C-Calkyl, or R and R together with the luoromethyl, C-Czalkanoyloxy, C-Calkyl, C-Calkoxy, nitrogen atom to which they are directly attached represent C-Czalkoxycarbonyl, C-C thioalkyl, and N(Rs,R) a phthalimido group, and A is a C-C aryl ring, then A is where Rs and R are independently Selected from hydro not an aryl ring which is Substituted by another aryl ring. gen, acetyl, methaneSulfonyl, and C-Calkyl. US 2005/01 19315 A1 Jun. 2, 2005
0.145) Other suitable “A” groups are 2-naphthyl group as 0151. Still another suitable “A” group is the fluorenyl represented by formula (V): group represented by formula (VIII): (V) se-- (VIII)
0146 where Ro and R are independently selected from 0152. In some variations, ether side chain component A is bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, an acenapthyl or fluorenyl group only when X is a direct hydroxymethyl, methaneSulfonamido, nitro, Sulfamyl, trif bond or CH2. In other variations, the acenaphthyl group is a luoromethyl, C-Czalkanoyloxy, C-Calkyl, C-Calkoxy, 1-acenaphthyl group, and the fluorenyl group is a 9-fluore C-Czalkoxycarbonyl, C-C thioalkyl, and N(R,R) nyl group. where Rs and R are independently Selected from hydro gen, acetyl, methaneSulfonyl, and C-Calkyl, as defined 0153. In a particular variation of formula (I), X is above. (CH) Y. For these variations, Y is preferably a direct bond, an oxygen atom, or a Sulfur atom. In another variation, 0.147. Other suitable “A” groups are aromatic groups Y is a direct bond or an oxygen atom. In Still another represented by formula (VI): variation Y is a direct bond and X is C(R,R), where R. and R are as defined above. In yet another variation, X is C(R)=CH, and R is a hydrogen atom. For these varia (VI) tions, R and R may be independently attached to the cyclohexane ring at the 4- or 5-positions. 0154) In another version of the aminocyclohexyl ether R N - ion channel modulating compounds, the ion channel modu lating compound is a compound of the formula (I), O155 wherein: independently at each occurrence, 0148 where R is selected from bromine, chlorine, fluo rine, carboxy, hydrogen, hydroxy, hydroxymethyl, methane 0156 X is selected from a direct bond, -C(R, Sulfonamido, nitro, Sulfamyl, trifluoromethyl, R)-Y- and -C(R)=CH-, with the proviso C-C, alkanoyloxy, C-Calkyl, C-Calkoxy, that when X is a direct bond and A is formula (III) C-Czalkoxycarbonyl, C-C thioalkyl, and N(Rs,R) then at least one of R7, Rs and Ro is not hydrogen; where Rs and R are independently selected from hydro 0157 Y is selected from a direct bond, O, S and gen, acetyl, methaneSulfonyl, and C-Calkyl, and Z is C-C alkylene; selected from CH, CH, O, N and S, where Z may be directly 0158 R is selected from hydrogen, C-C alkyl, bonded to “X” as shown in formula (I) when Z is CH or N, C-C cycloalkyl, aryl and benzyl, or Z may be directly bonded to R, when Z is N, and R, is 0159 R and R are independently selected from Selected from hydrogen, C-C alkyl, C-C cycloalkyl, aryl hydrogen, C-Calkyl, C-Calkoxyalkyl, and benzyl. C-Chydroxyalkyl, and C7-Caralkyl, or 014.9 The aryl groups of formula (VI) are derivatives of 0160 R and R are independently selected from indene, indole, benzofuran, and thianaphthene when Z is C-Calkoxyalkyl, C-Chydroxyalkyl, and methylene, nitrogen, oxygen, and Sulfur, respectively. Pre C7-Caralkyl, or ferred heterocyclic groups of formula (VI) include indole 0161 R and R, when taken together with the where Z is NH, benzofuran where Z is 0, and thianaphthene nitrogen atom to which they are directly attached in where Z is S. As described below, in a preferred embodi ment, Z is O, S or N-R7, and in a particularly preferred formula (I), form a ring denoted by formula (II): embodiment Z is O or S. 0150. Another suitable “A” group is acenaphthyl groups as represented by formula (VII): -R1. (II)
(VII) 0162 wherein the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently Selected from carbon, nitrogen, oxy gen, and Sulfur, where any two adjacent ring atoms may be joined together by Single or double bonds, and where any one or more of the additional carbon ring atoms may be Substituted with one or two Substituents selected from hydrogen, hydroxy, C-C-hydroxyalkyl, Oxo, C-Cacyl, US 2005/01 19315 A1 Jun. 2, 2005
C-C alkyl, C-C alkylcarboxy, C-Calkoxy, C-Coalkanoyloxy, or may be Substituted to form a spiro -continued five- or Six-membered heterocyclic ring containing one or (V) two heteroatoms Selected from oxygen and Sulfur, and any two adjacent additional carbon ring atoms may be fused to 4N1N R11 a C-C carbocyclic ring, and any one or more of the R10 additional nitrogen ring atoms may be Substituted with N 2 Substituents Selected from hydrogen, C-Calkyl, C-Cacyl, C-C hydroxyalkyl and C-Calkoxyalkyl, or 0168 where Ro and R are independently selected 0163 R and R, when taken together with the from bromine, chlorine, fluorine, carboxy, hydrogen, nitrogen atom to which they are directly attached in hydroxy, hydroxymethyl, methaneSulfonamido, formula (I), may form a bicyclic ring System Selected nitro, Sulfamyl, trifluoromethyl, C-Czalkanoyloxy, from 3-azabicyclo3.2.2]nonan-3-yl, 2-azabicyclo C-C alkyl, C-Calkoxy, C-Czalkoxycarbonyl, 2.2.2]octan-2-yl, 3-azabicyclo3.1.0hexan-3-yl and C-C thioalkyl, and N(Rs.R.) where Rs and R. 3-azabicyclo3.2.0heptan-3-yl; are independently Selected from hydrogen, acetyl, methaneSulfonyl, and C-Calkyl, 0.164 R and R are independently attached to the cyclohexane ring shown in formula (I) at the 3-, 4-, 5- or 6-positions and are independently Selected from (VI) hydrogen, hydroxy, C-C alkyl and C-Calkoxy, and, when both R and R are attached to the same cyclohexane ring atom, may together form a Spiro five- or Six-membered heterocyclic ring containing y one or two heteroatoms Selected from oxygen and -C Sulfur, 0169 where R is selected from bromine, chlorine, 0.165 Rs, R. and R are independently selected fluorine, carboxy, hydrogen, hydroxy, hydroxym from hydrogen, C-Calkyl, aryl and benzyl, or R ethyl, methaneSulfonamido, nitro, Sulfamyl, trifluo and R, when taken together with the carbon to romethyl, C-C,alkanoyloxy, C-C alkyl, which they are attached, may form a Spiro C-C alkoxy, C-Czalkoxycarbonyl, C-C thioalkyl, C-C cycloalkyl, and N(Rs.R.) where Rs and Rs are independently Selected from hydrogen, acetyl, methaneSulfonyl, 0166 A is selected from Cs-Calkyl, a and C-Calkyl; and Z is selected from CH, CH, O, C-Cacarbocyclic ring, and ring Systems Selected N and S, where Z may be directly bonded to “X” as from formulae (III), (IV), (V), (VI), (VII) and (VIII): shown in formula (I) when Z is CH or N, or Z may be directly bonded to R, when Z is N, and R, is Selected from hydrogen, C-C alkyl, (III) C-C cycloalkyl, aryl and benzyl,
(VII)
0.167 where R7, Rs and Ro are independently Selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methane Sulfonamido, nitro, Sulfamyl, trifluoromethyl, (VIII) C-Czalkanoyloxy, C-Calkyl, C-Calkoxy, C-Czalkoxycarbonyl, C-C thioalkyl and N(Rs, se Re) where Rs and Rs are independently Selected from hydrogen, acetyl, methaneSulfonyl and C-C alkyl, 0170 including isolated enantiomeric, diastereo meric and geometric isomers thereof and Solvates (IV) and/or pharmaceutically acceptable Salts of any of the foregoing.
4N1N R11 and 0171 In another version of the aminocyclohexyl ether R10 ion channel modulating compounds, the ion channel modu N 2 lating compound is a compound of the formula (IX), or a Solvate or pharmaceutically acceptable Salt thereof: US 2005/01 19315 A1 Jun. 2, 2005 12
0184. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu (IX) A. lating compound is a compound of the formula (XI), or a n1n R1 Solvate or pharmaceutically acceptable Salt thereof: \ YR, (XI) R4
0172 wherein, independently at each occurrence, 0173 X is selected from a direct bond, -CH=CH- and -C(R,R)-Y-; 0.174 Y is selected from a direct bond, O and S; and 0185 wherein, independently at each occurrence, 0175) R, R2, Rs, R, R6, R7, Rs, Ro, Rio, R11, R12, R, A and Z are defined as above for compounds of 0186 RandR are defined as above for compounds formula (I). of formula (I); 0176). In one variation, the compounds as recited by the 0187 R and R are independently attached to the formulae herein are compounds other than any one or any cyclohexane ring at the 4- or 5-positions, and are combination of two or more compounds Selected from the independently Selected from hydrogen and methoxy, group consisting of 2-benzyloxycyclohexylamine, 3-benzy and loxycyclohexylamine, 4-benzyloxycyclohexylamine, 2-(4- benzoxazol-2-ylbenzyloxy)cyclohexylamine, trans-2-(4- 0188 A is selected from Cs-Calkyl, 4-chloro benzoyl-benzyloxy)cyclohexylamine, 2-(4- C-C cycloalkyl, and any of formulae (III), (IV), benzooxazol-2-yl-benzyloxy)-cyclohexylamine. (V), and (VI) as above for compounds of formula (I), wherein Z, R7, Rs, Ro, Rio, R and R are defined 0177. In another version of the aminocyclohexyl ether as above for compounds of formula (I). ion channel modulating compounds, the ion channel modu 0189 In another version of the aminocyclohexyl ether lating compound is a compound of the formula (X), or a ion channel modulating compounds, the ion channel modu Solvate or pharmaceutically acceptable Salt thereof: lating compound is a compound of the formula (XII), or a Solvate or pharmaceutically acceptable Salt thereof: (X) (XII)
0.178 wherein, independently at each occurrence, 0179 X is selected from a direct bond, 0.190 wherein, independently at each occurrence, -CH=CH- and -C(R,R)-Y-; 0191 R and Rare defined as above for compounds 0180 Y is selected from a direct bond, O, and S; of formula (I); 0181 R, R, R and R are defined as above for 0192 R and R are independently attached to the compounds of formula (I); cyclohexane ring at the 4- or 5-positions, and are 0182 R and R are independently attached to the independently Selected from hydrogen and methoxy, cyclohexane ring at the 4- or 5-positions, and are and independently Selected from hydrogen and 0193 A is selected from Cs-Calkyl, C-C alkoxy; and C-C cycloalkyl, and any of formulae (III), (IV), 0183) A is selected from Cs-Calkyl, (V), and (VI) as above for compounds of formula (I), C-C cycloalkyl, and any of formulae (III), (IV), wherein Z, R7, Rs. Ro, Rio, R and R2 are defined (V), and (VI) as above for compounds of formula (I), as above for compounds of formula (I). wherein Z, R7, Rs. Ro, Rio, R and R2 are defined 0194 In another version of the aminocyclohexyl ether as above for compounds of formula (I). ion channel modulating compounds, the ion channel modu US 2005/01 19315 A1 Jun. 2, 2005 13 lating compound is a compound of the formula (XIII), or a lating compound is a compound of the formula (XV), or a Solvate or pharmaceutically acceptable Salt thereof: Solvate or pharmaceutically acceptable Salt thereof:
(XIII) (XV)
0205 wherein, independently at each occurrence, 0.195 wherein, independently at each occurrence, 0206 RandR are defined as above for compounds of formula (I); and 0196) X is selected from -C(R,R)-Y- and -CH=CH-; 0207 A is selected from any of formulae (III), (IV), (V) and (VI) as defined above for compounds of 0.197 Y, R, R, R and R are defined as above for formula (I), wherein R7, Rio, R, and R2, are compounds of formula (I); hydrogen, Rs and Ro are independently Selected from 0198 R and R are independently attached to the hydrogen, hydroxy, fluorine, chlorine, bromine, cyclohexane ring at the 4- or 5-positions, and are methaneSulfonamido, methanoyloxy, methoxycarbo independently Selected from hydrogen and methoxy, nyl, nitro, Sulfamyl, thiomethyl, trifluoromethyl, and methyl, ethyl, methoxy, ethoxy and NH, with the proviso that at least one of Rs and Ro is not hydrogen; 0199 A is selected from C-C cycloalkyl and any of and Z is selected from O and S. formulae (III), (IV), (V), (VI), (VII) and (VIII) as above for compounds of formula (I), where Rs and 0208 In another version of the aminocyclohexyl ether R are defined as above for compounds of formula ion channel modulating compounds, the ion channel modu (i); R7, Rio, R and R2 are hydrogen, and Z is lating compound is a compound of the formula (XVI), or a selected from O, S and N-R, where R, is selected Solvate or pharmaceutically acceptable Salt thereof: from hydrogen and methyl. 0200. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu (XVI) lating compound is a compound of the formula (XIV), or a Solvate or pharmaceutically acceptable Salt thereof:
(XIV)
0209 wherein, independently at each occurrence, 0210 X is selected from a direct bond, trans CH=CH-, -CH- and -CH-O-, 0211 R and R are both methoxyethyl or, when 0201 wherein, independently at each occurrence, taken together with the nitrogen atom to which they are attached, complete a ring Selected from pyrro 0202 R and R are defined as above for compounds lidinyl, 2-ketopyrrolidinyl, 3-ketopyrrolidinyl, 2-ac of formula (I); etoxypyrrolidinyl, 3-acetoxypyrrolidinyl, 2-hy 0203) A is selected from any of formulae (III), (IV), droxypyrrolidinyl, 3-hydroxypyrrolidinyl, (V) and (VI) as above for compounds of formula (I), thiazolidinyl, piperidinyl, 2-ketopiperidinyl, 3-ke wherein R-7, Rio, R1, and R2, are hydrogen, Rs and topiperidinyl, 4-ketopiperidinyl, acetylpiperazinyl, Ro are independently Selected from hydrogen, 1,4-dioxa-7-azaspiro4.4non-7-yl, hexahydroazepi hydroxy, fluorine, chlorine, bromine, methane nyl, morpholinyl, N-methylpiperazinyl and 3-azabi Sulfonamido, methanoyloxy, methoxycarbonyl, cyclo3.2.2]nonanyl; and nitro, Sulfamyl, thiomethyl, trifluoromethyl, methyl, 0212 A is selected from cyclohexyl, monochlo ethyl, methoxy, ethoxy and NH, with the proviso rophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, that at least one of Rs and R is not hydrogen; and Z 2-bromophenyl, 2,4-dibromophenyl, 3-bromophe is selected from O and S. nyl, 4-bromophenyl, 3,4-dimethoxyphenyl, 1-naph 0204. In another version of the aminocyclohexyl ether thyl, 2-naphthyl, 3-benzo(b)thiophenyl, 4-benzo(b- ion channel modulating compounds, the ion channel modu )thiophenyl, (2-trifluoromethyl)phenyl, 2,4- US 2005/01 19315 A1 Jun. 2, 2005
di(trifluoromethyl)phenyl, and 0226 including isolated enantiomeric, diastereo (4-trifluoromethyl)phenyl. meric and geometric isomers thereof. 0213. In another version of the aminocyclohexyl ether 0227. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu ion channel modulating compounds, the ion channel modu lating compound is a compound of the formula (XVII), or a lating compound is a compound of the formula (IXX); or a Solvate or pharmaceutically acceptable Salt thereof: Solvate or pharmaceutically acceptable Salt thereof:
(XVII) (DXX) O-- al-(y R8 - Ev R20 1NO NU2 2
0214 wherein, independently at each occurrence, 0228 wherein, independently at each occurrence, 0215 n is selected from 1, 2 and 3; 0229 n is selected from 1, 2 and 3; 0216 Rs is either hydrogen or methyl and is inde 0230 Rs is either hydrogen or methyl and is inde pendently attached to the cyclohexane ring shown in pendently attached to the cyclohexane ring shown in formula (XVII) at one of the 3-, 4-, 5- or 6-positions; formula (XVII) at one of the 3-, 4-, 5- or 6-positions; 0231 Rio is selected from a group consisting of 0217 R is selected from a group consisting of bromine, chlorine, fluorine and hydrogen; and bromine, chlorine, fluorine and hydrogen; and 0232 R is selected from a group consisting of 0218 Rao is selected from a group consisting of bromine, chlorine and fluorine; bromine, chlorine and fluorine; 0233 including isolated enantiomeric, diastereo 0219 including isolated enantiomeric, diastereo meric and geometric isomers thereof. meric and geometric isomers thereof. 0234. In another version of the aminocyclohexyl ether 0220. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XX), or a lating compound is a compound that is a trans configuration Solvate, pharmaceutically acceptable Salt, ester, amide, com of formula (XVII) as represented by formula (XVIII), or a plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet Solvate or pharmaceutically acceptable Salt thereof: ric isomer, crystalline or amorphous form, metabolite, meta bolic precursor or prodrug thereof.
(XVIII) (XX) R21 O r R8 - -o-c-().Ev R20 N us R22 Nea1NO U2 O).Cott 0235 wherein, R, R22 and R2 are independently 0221 wherein, independently at each occurrence, Selected from hydrogen, hydroxy and C-Calkoxy, including isolated enantiomeric, diastereomeric and 0222 n is selected from 1, 2 and 3; geometric isomers thereof, and mixtures thereof, 0223 R is either hydrogen or methyl and is inde with the proviso that R, R22 and R cannot all be pendently attached to the cyclohexane ring shown in hydrogen. formula (XVII) at one of the 3-, 4-, 5- or 6-positions; 0236. In another version of the aminocyclohexyl ether 0224 Rio is selected from a group consisting of ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XX), or a bromine, chlorine, fluorine and hydrogen; and Solvate, pharmaceutically acceptable Salt thereof, including 0225 Rao is selected from a group consisting of isolated enantiomeric, diastereomeric and geometric iso bromine, chlorine and fluorine; mers thereof, and mixtures thereof. US 2005/01 19315 A1 Jun. 2, 2005
0237. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XX), or a (XXI) Solvate, pharmaceutically acceptable Salt thereof, wherein, R, and R2s are independently selected from hydroxy and C-Calkoxy, including isolated enantiomeric, diastereo meric and geometric isomers thereof, and mixtures thereof. 0238. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XX), or a 0244 wherein, R, R22 and R2 are independently Solvate, pharmaceutically acceptable Salt thereof, including Selected from hydrogen, hydroxy and C-Calkoxy, isolated enantiomeric, diastereomeric and geometric iso including isolated enantiomeric, diastereomeric and mers thereof, and mixtures thereof, wherein, R is hydro geometric isomers thereof, and mixtures thereof. gen, R22 and R2 are independently Selected from hydroxy and C-Calkoxy. 0245. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu 0239). In another version of the aminocyclohexyl ether lating compound is a compound of formula (XXI), or a ion channel modulating compounds, the ion channel modu Solvate, pharmaceutically acceptable Salt thereof, including lating compound is a compound of formula (XX), or a isolated enantiomeric, diastereomeric and geometric iso Solvate, pharmaceutically acceptable Salt, ester, amide, com mers thereof, and mixtures thereof. plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet 0246. In another version of the aminocyclohexyl ether ric isomer, crystalline or amorphous form, metabolite, meta ion channel modulating compounds, the ion channel modu bolic precursor or prodrug thereof, including isolated lating compound is a compound of formula (XXI), or a enantiomeric, diastereomeric and geometric isomers thereof, Solvate, pharmaceutically acceptable Salt thereof, wherein, and mixtures thereof, wherein, R is hydrogen, R and R R, and R2s are independently selected from hydroxy and are independently selected from C-Calkoxy. C-Calkoxy, including isolated enantiomeric, diastereo 0240. In another version of the aminocyclohexyl ether meric and geometric isomers thereof, and mixtures thereof. ion channel modulating compounds, the ion channel modu 0247. In another version of the aminocyclohexyl ether lating compound is a compound of formula (XX), or a ion channel modulating compounds, the ion channel modu Solvate, pharmaceutically acceptable Salt thereof, including lating compound is a compound of formula (XXI), or a isolated enantiomeric, diastereomeric and geometric iso Solvate, pharmaceutically acceptable Salt thereof, including mers thereof, and mixtures thereof, wherein, R, is hydro isolated enantiomeric, diastereomeric and geometric iso gen, R and R2 are independently Selected from mers thereof, and mixtures thereof, wherein, R, is hydro C-C alkoxy. gen, R22 and R2 are independently Selected from hydroxy and C-C alkoxy. 0241. In another version of the aminocyclohexyl ether 0248. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XX), or a lating compound is a compound of formula (XXI), or a Solvate, pharmaceutically acceptable Salt, ester, amide, com Solvate, pharmaceutically acceptable Salt, ester, amide, com plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet ric isomer, crystalline or amorphous form, metabolite, meta ric isomer, crystalline or amorphous form, metabolite, meta bolic precursor or prodrug thereof, including isolated bolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R is hydrogen, R and R and mixtures thereof, wherein, R is hydrogen, R and R are Calkoxy. are independently Selected from C-Calkoxy. 0242. In another version of the aminocyclohexyl ether 0249. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XX), or a lating compound is a compound of formula (XXI), or a Solvate, pharmaceutically acceptable Salt thereof, including Solvate, pharmaceutically acceptable Salt thereof, including isolated enantiomeric, diastereomeric and geometric iso isolated enantiomeric, diastereomeric and geometric iso mers thereof, and mixtures thereof, wherein, R is hydro mers thereof, and mixtures thereof, wherein, R is hydro gen, R and R2 are independently Selected from gen, R22 and R2 are Calkoxy. C-Calkoxy. 0243 In another version of the aminocyclohexyl ether 0250 In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XXI), or a lating compound is a compound of formula (XXI), or a Solvate, pharmaceutically acceptable Salt, ester, amide, com Solvate, pharmaceutically acceptable Salt, ester, amide, com plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet ric isomer, crystalline or amorphous form, metabolite, meta ric isomer, crystalline or amorphous form, metabolite, meta bolic precursor or prodrug thereof: bolic precursor or prodrug thereof, including isolated US 2005/01 19315 A1 Jun. 2, 2005
enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R is hydrogen, R and R and mixtures thereof, wherein, R is hydrogen, R and R are independently Selected from C-Calkoxy. are Calkoxy. 0258. In another version of the aminocyclohexyl ether 0251. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XXII), or a lating compound is a compound of formula (XXI), or a Solvate, pharmaceutically acceptable Salt thereof, including Solvate, pharmaceutically acceptable Salt thereof, including isolated enantiomeric, diastereomeric and geometric iso isolated enantiomeric, diastereomeric and geometric iso mers thereof, and mixtures thereof, wherein, R is hydro mers thereof, and mixtures thereof, wherein, R is hydro gen, R and R2 are independently Selected from gen, R22 and R2 are Calkoxy. C-Calkoxy. 0252) In another version of the aminocyclohexyl ether 0259. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XXII), or a lating compound is a compound of formula (XXII), or a Solvate, pharmaceutically acceptable Salt, ester, amide, com Solvate, pharmaceutically acceptable Salt, ester, amide, com plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet ric isomer, crystalline or amorphous form, metabolite, meta ric isomer, crystalline or amorphous form, metabolite, meta bolic precursor or prodrug thereof: bolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R is hydrogen, R and R (XXII) are Calkoxy. 0260. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XXII), or a C.y AQ4 22 Solvate, pharmaceutically acceptable Salt thereof, including isolated enantiomeric, diastereomeric and geometric iso OH mers thereof, and mixtures thereof, wherein, R is hydro gen, R22 and R2 are Calkoxy. 0253 wherein, R, R and R are independently 0261. In another version of the aminocyclohexyl ether Selected from hydrogen, hydroxy and C-Calkoxy, ion channel modulating compounds, the ion channel modu including isolated enantiomeric, diastereomeric and lating compound is a compound of formula (XXIII), or a geometric isomers thereof, and mixtures thereof. Solvate, pharmaceutically acceptable Salt, ester, amide, com plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet 0254. In another version of the aminocyclohexyl ether ric isomer, crystalline or amorphous form, metabolite, meta ion channel modulating compounds, the ion channel modu bolic precursor or prodrug thereof. lating compound is a compound of formula (XXII), or a Solvate, pharmaceutically acceptable Salt thereof, including (XXIII) isolated enantiomeric, diastereomeric and geometric iso R21 mers thereof, and mixtures thereof. -O Xs 0255 In another version of the aminocyclohexyl ether --R ion channel modulating compounds, the ion channel modu N %-4 lating compound is a compound of formula (XXII), or a R23 Solvate, pharmaceutically acceptable Salt thereof, wherein, OH R, and Rs are independently selected from hydroxy and C-C alkoxy, including isolated enantiomeric, diastereo meric and geometric isomers thereof, and mixtures thereof. 0262 wherein, R, R22 and R2 are independently 0256 In another version of the aminocyclohexyl ether Selected from hydrogen, hydroxy and C-Calkoxy, ion channel modulating compounds, the ion channel modu including isolated enantiomeric, diastereomeric and lating compound is a compound of formula (XXII), or a geometric isomers thereof, and mixtures thereof. Solvate, pharmaceutically acceptable Salt thereof, including 0263. In another version of the aminocyclohexyl ether isolated enantiomeric, diastereomeric and geometric iso ion channel modulating compounds, the ion channel modu mers thereof, and mixtures thereof, wherein, R is hydro lating compound is a compound of formula (XXIII), or a gen, R and R are independently selected from hydroxy Solvate, pharmaceutically acceptable Salt thereof, including and C-Calkoxy. isolated enantiomeric, diastereomeric and geometric iso 0257. In another version of the aminocyclohexyl ether mers thereof, and mixtures thereof. ion channel modulating compounds, the ion channel modu 0264. In another version of the aminocyclohexyl ether lating compound is a compound of formula (XXII), or a ion channel modulating compounds, the ion channel modu Solvate, pharmaceutically acceptable Salt, ester, amide, com lating compound is a compound of formula (XXIII), or a plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet Solvate, pharmaceutically acceptable Salt thereof, wherein, ric isomer, crystalline or amorphous form, metabolite, meta R, and Rs are independently selected from hydroxy and bolic precursor or prodrug thereof, including isolated C-Calkoxy, including isolated enantiomeric, diastereo enantiomeric, diastereomeric and geometric isomers thereof, meric and geometric isomers thereof, and mixtures thereof. US 2005/01 19315 A1 Jun. 2, 2005
0265. In another version of the aminocyclohexyl ether including isolated enantiomeric, diastereomeric and ion channel modulating compounds, the ion channel modu geometric isomers thereof, and mixtures thereof. lating compound is a compound of formula (XXIII), or a Solvate, pharmaceutically acceptable Salt thereof, including 0272. In another version of the aminocyclohexyl ether isolated enantiomeric, diastereomeric and geometric iso ion channel modulating compounds, the ion channel modu mers thereof, and mixtures thereof, wherein, R is hydro lating compound is a compound of formula (XXIV), or a gen, R22 and R2 are independently Selected from hydroxy Solvate, pharmaceutically acceptable Salt thereof, including and C-Calkoxy. isolated enantiomeric, diastereomeric and geometric iso 0266. In another version of the aminocyclohexyl ether mers thereof, and mixtures thereof. ion channel modulating compounds, the ion channel modu 0273. In another version of the aminocyclohexyl ether lating compound is a compound of formula (XXIII), or a ion channel modulating compounds, the ion channel modu Solvate, pharmaceutically acceptable Salt, ester, amide, com lating compound is a compound of formula (XXIV), or a plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet ric isomer, crystalline or amorphous form, metabolite, meta Solvate, pharmaceutically acceptable Salt thereof, wherein, bolic precursor or prodrug thereof, including isolated R, and R2s are independently selected from hydroxy and enantiomeric, diastereomeric and geometric isomers thereof, C-Calkoxy, including isolated enantiomeric, diastereo and mixtures thereof, wherein, R is hydrogen, R and R meric and geometric isomers thereof, and mixtures thereof. are independently Selected from C-Calkoxy. 0274. In another version of the aminocyclohexyl ether 0267 In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XXIV), or a lating compound is a compound of formula (XXIII), or a Solvate, pharmaceutically acceptable Salt thereof, including Solvate, pharmaceutically acceptable Salt thereof, including isolated enantiomeric, diastereomeric and geometric iso isolated enantiomeric, diastereomeric and geometric iso mers thereof, and mixtures thereof, wherein, R22 and R2 are mers thereof, and mixtures thereof, wherein, R is hydro independently Selected from hydroxy and C-Calkoxy. gen, R and R2 are independently Selected from C-C alkoxy. 0275. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu 0268. In another version of the aminocyclohexyl ether lating compound is a compound of formula (XXIV), or a ion channel modulating compounds, the ion channel modu Solvate, pharmaceutically acceptable Salt, ester, amide, com lating compound is a compound of formula (XXIII), or a plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet Solvate, pharmaceutically acceptable Salt, ester, amide, com ric isomer, crystalline or amorphous form, metabolite, meta plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet bolic precursor or prodrug thereof, including isolated ric isomer, crystalline or amorphous form, metabolite, meta enantiomeric, diastereomeric and geometric isomers thereof, bolic precursor or prodrug thereof, including isolated and mixtures thereof, wherein, R22 and R2 are indepen enantiomeric, diastereomeric and geometric isomers thereof, dently Selected from C-C alkoxy. and mixtures thereof, wherein, R is hydrogen, R and R are Calkoxy. 0276. In another version of the aminocyclohexyl ether 0269. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XXIV), or a lating compound is a compound of formula (XXIII), or a Solvate, pharmaceutically acceptable Salt thereof, including Solvate, pharmaceutically acceptable Salt thereof, including isolated enantiomeric, diastereomeric and geometric iso isolated enantiomeric, diastereomeric and geometric iso mers thereof, and mixtures thereof, wherein, R22 and R2 are mers thereof, and mixtures thereof, wherein, R is hydro independently Selected from C-Calkoxy. gen, R22 and R2 are Calkoxy. 0277. In another version of the aminocyclohexyl ether 0270. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XXIV), or a lating compound is a compound of formula (XXIV), or a Solvate, pharmaceutically acceptable Salt, ester, amide, com Solvate, pharmaceutically acceptable Salt, ester, amide, com plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet plex, chelate, Stereoisomer, Stereoisomeric mixture, geomet ric isomer, crystalline or amorphous form, metabolite, meta ric isomer, crystalline or amorphous form, metabolite, meta bolic precursor or prodrug thereof, including isolated bolic precursor or prodrug thereof: enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R22 and R2 are Calkoxy. 0278 In another version of the aminocyclohexyl ether (XXIV) ion channel modulating compounds, the ion channel modu lating compound is a compound of formula (XXIV), or a Solvate, pharmaceutically acceptable Salt thereof, including isolated enantiomeric, diastereomeric and geometric iso mers thereof, and mixtures thereof, wherein, R and R are Calkoxy. 0279. In another version of the aminocyclohexyl ether 0271 wherein, R and R are independently ion channel modulating compounds, the ion channel modu Selected from hydrogen, hydroxy and C-Calkoxy, lating compound is a compound of the formula (XXV), US 2005/01 19315 A1 Jun. 2, 2005 18
0291 R and R are independently selected from C-Calkoxyalkyl, C-Chydroxyalkyl, and (XXV) C7-Caralkyl, or 0292 R and R, are taken together with the nitro gen atom to which they are directly attached in formula (XXVI) to form a ring denoted by formula (II):
(II) /R 0280 wherein: -CNuR2 0281 R, R and R are independently selected from hydrogen, hydroxy and C-C alkoxy; or, 0293 wherein the ring of formula (II) is formed from the 0282) R, R are independently selected from nitrogen as shown as well as three to nine additional ring hydroxyl and C-Calkoxy and R2 is hydrogen; or, atoms independently Selected from carbon, nitrogen, oxy 0283 R, R are both C-Calkoxy and R is gen, and Sulfur, where any two adjacent ring atoms may be hydrogen; or joined together by Single or double bonds, and where any one or more of the additional carbon ring atoms may be 0284) R, R are both methoxy and R is hydro Substituted with one or two Substituents selected from gen, Or hydrogen, hydroxy, C-C-hydroxyalkyl, Oxo, C-Cacyl, 0285 including isolated enantiomeric, diastereo C-C alkyl, C-C alkylcarboxy, C-Calkoxy, meric and geometric isomers thereof, and mixtures C-Coalkanoyloxy, or may be Substituted to form a Spiro thereof, with the proviso that R, R2 and R cannot five- or Six membered heterocyclic ring containing one or all be hydrogen; and two heteroatoms Selected from oxygen and Sulfur, and any two adjacent additional carbon ring atoms may be fused to 0286 vvvv indicates a bond that provides a R ste a C-C carbocyclic ring, and any one or more of the reoisomer or a S Stereoisomer at the position to additional nitrogen ring atoms may be Substituted with which the bond is attached. Substituents selected from hydrogen, C-Calkyl, C-Cacyl, 0287. In one variation, the hydroxyl substituent is posi C-Chydroxyalkyl and C-Calkoxyalkyl, or tioned at the 3 position of the pyrrolidinyl ring in (XXV). In another variation, the Stereochemistry at the position of the 0294 R and R are taken together to form cycloalkyl ring of (XXV) containing the nitrogen group is racemic, which may be provided for any of the variations mentioned above. 0288. In another version of the aminocyclohexyl ether ion channel modulating compounds, the ion channel modu lating compound is a compound of the formula (XXVI): 0295 wherein the OH group may be at any position on the pyrrolidinyl ring, including the 3-position; (XXVI) R21 0296 R and R, when taken together with the O nitrogen atom to which they are directly attached in formula (XXVI), may form a bicyclic ring system selected from 3-azabicyclo3.2.2]nonan-3-yl, -*. 2xa 2-azabicyclo2.2.2]octan-2-yl, 3-azabicyclo3.1.0) R22 hexan-3-yl and 3-azabicyclo3.2.0heptan-3-yl; and 0297 R and R are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methaneSulfonamido, 0289 wherein: nitro, Sulfamyl, trifluoromethyl, C-Czalkanoyloxy, 0290 the-bond to the ether oxygen indicates that C-C alkyl, C-Calkoxy, C-Czalkoxycarbonyl, the ether and amine groups attached to the cyclo C-C thioalkyl and N(R,R) where Rs and R. hexyl group are in a trans configuration. and the C-1 are independently Selected from hydrogen, acetyl, and C-2 carbons of the cyclohexyl group may be methaneSulfonyl and C-C alkyl. either R,R configuration or S.S configuration; R and 0298. In one version of formula (XXVI), R and R are R2 are independently Selected from hydrogen, independently Selected from hydrogen, hydroxyl and C-Calkyl, C-Calkoxyalkyl, C-Chydroxyalkyl, C-Calkoxy. In another version of formula (XXVI), both and C7-Caralkyl, or R, and R22 are C, -Calkoxy. In another variation, both R2 US 2005/01 19315 A1 Jun. 2, 2005
and R2 are methoxy. In Still another variation of formula (XXVI), R and R are positioned at the 3 and 4 positions of the aromatic ring, wherein the position on the aromatic ring containing the alkyl chain is designated the 1 position, this variation may be combined with any other variation mentioned above. O C C 0299. In another version of the aminocyclohexyl ether y ion channel modulating compounds, the ion channel modu K (1R,2R)-2-(4-morpholinyl-1-(2-naphthenethoxy) cyclohexane lating compound is of the formula shown as Compound A, or (1S,2S)-2-(4-morpholinyl)-1-(2-naphthenethoxy)cyclohexane or pharmaceutically acceptable Salts or Solvates thereof. or a mixture of (1R,2R)-2-(4-morpholinyl)-1-(2-naphthenethoxy) cyclohexane and (1S,2S)-2-(4-morpholinyl)-1-(2-naphthenethoxy) cyclohexane Compound A O OCH
'/N OCH III iOH cr? ( O) 0300 (1R,2R)-2-(3R)-hydroxypyrrolidinyl)-1-(3,4- (1R,2R)-2-(4-morpholinyl-1-(1-naphthenethoxy) cyclohexane or (1S,2S)-2-(4-morpholinyl)-1-(1-naphthenethoxy)cyclohexane dimethoxyphenethoxy)cyclohexane or a mixture of (1R,2R)-2-(4-morpholinyl)-1-(1-naphthenethoxy) cyclohexane 0301 In another version of the aminocyclohexyl ether and (1S,2S)-2-(4-morpholinyl)-1-(1-naphthenethoxy) ion channel modulating compounds, the ion channel modu lating compound is a pharmaceutically acceptable Salt of Compound A, Such as the compound of the formula (XXVII), COy Br (XXVII) 8. O OCH (1R,2R)-2-(4-morpholinyl-1-(4-bromophenethoxy) cyclohexane or (1S,2S)-2-(4-morpholinyl)-1-(4-bromophenethoxy)cyclohexane or a mixture of (1R,2R)-2-(4-morpholinyl)-1-(4-bromophenethoxy) cyclohexane 2 % N OCH and (1S,2S)-2-(4-morpholinyl)-1-(4-bromophenethoxy) cyclohexane OH OCI -CO 0302 (1R,2R)-2-(3R)-hydroxypyrrolidinyl)-1-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride. 0303. In one variation, the ion channel modulating com pound comprises a cycloalkyl ring, Such as a cyclohexyl ()O ring, wherein the cycloalkyl ring comprises two adjacent (1R,2R)-2-(4-morpholinyl-1-(2-(2-naphthoxy)ethoxycyclohexane Substituents, Such as Substituents at the 1 and 2 position of or (1S,2S)-2-(4-morpholinyl)-1-(2-(2-naphthoxy)ethoxycyclohexane or a mixture of the cycloalkyl ring, wherein the two adjacent Substituents (1R,2R)-2-(4-morpholinyl)-1-(2-(2-naphthoxy)ethoxycyclohexane are situated in trans Stereochemical positions relative to one and (1S,2S)-2-(4-morpholinyl)-1-(2-(2-naphthoxy)ethoxycyclohexane another. In one variation, one of the two adjacent Substitu ents is an amino Substituent bound to the cycloalkyl ring via a nitrogen atom and one of the two adjacent Substituents is an ether Substituent bound to the cycloalkyl ring via an C ror Br OXygen atom. y 0304. In another version of the aminocyclohexyl ether K (1R,2R)-2-(4-morpholinyl)-1-(2-(4-bromophenoxy)ethoxycyclohexane ion channel modulating compounds, the ion channel modu or(1S,2S)-2-(4-morpholinyl)-1-(2-(4-bromophenoxy)ethoxycyclohexane lating compound is a compound or any Salt thereof, or any or a mixture of (1R,2R)-2-(4-morpholinyl)-1-(2-(4-bromophenoxy)ethoxycyclohexane Solvate thereof, or mixture comprising one or more Said and (1S,2S)-2-(4-morpholinyl)-1-(2-(4-bromophenoxy)ethoxy compounds or any Salt thereof, or any Solvate thereof, cyclohexane Selected from the group consisting of:
US 2005/01 19315 A1 Jun. 2, 2005 23
0305 Also described here is a composition that includes -continued one or more of the compounds or mixtures listed in the O OMe above table, or includes a Solvate or a pharmaceutically acceptable Salt of one or more of the compounds or mixtures N OMe listed in the above table. The composition may or may not
OH OHCI include additional components. Additional components that may be used are described elsewhere in detail in this patent. (1R,2R)-2-(3-hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride or (1S,2S)-2-(3-hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride or a mixture of 0306 In another version of the aminocyclohexyl ether (1R,2R)-2-(3-hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride and ion channel modulating compounds, the ion channel modu (1S,2S)-2-(3-hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride, wherin the hydroxyl moiety in lating compound is a compound or mixture comprising any of the above may be in the R or S stereochemical configuration. compounds, or any Solvate thereof, Selected from the group consisting of:
Structure Chemical name
(1R,2R)-2-(3R)/(3S)-Hydroxypyrrolidinyl-1- (3,4-dimethoxyphenethoxy)- cyclohexane or (1S,2S)-2-(3R)/(3S)-hydroxypyrrolidinyl-1- (3,4-dimethoxyphen ethoxy)- cyclohexane or a COCN OCH mixture of (1R,2R)-2-(3R)/(3S)- OH hydroxypyrrolidinyl-1-(3,4- dimethoxyphenethoxy)-cyclohexane and (1S,2S)-2-(3R)/(3S)-hydroxypyrrolidinyl-1- (3,4-dimethoxyphenethoxy)-cyclohexane, where the designation (3R)/(3S) indicates the stereochem istry at the 3-position may be R or S. O OCH (1R,2R)-2-(3R) Hydroxypyrrolidinyl-1-(3,4- a. dimethoxyphenethoxy)-cyclohexane or (1S,2S)- 2-(3R)-hydroxypyrrolidinyl-1-(3,4- dimethoxyphenethoxy)-cyclohexane and a N OCH mixture of (1R,2R)-2-3R)- I I IOH hydroxypyrrolidinyl-1-(3,4 phenethoxy)-cyclohexane and (1S,2S)-2- (3R)-hydroxypyrrollidinyl-1-(3,4- henethoxy)-cyclohexane O OCH3 Y dimethoxyphenethoxy)-cyclohexane or (1S,2S)- 2-(3S)-hydroxypyrrolidinyl-1-(3,4- dimethoxyphenethoxy)-cyclohexane and a N OCH mixture of (1R,2R)-2-(3S) OH hydroxypyrrolidinyl-1-(3,4 dimethoxyphenethoxy)-cyclohexane and (1S,2S)-2-(3S)-hydroxypyrrolidinyl-1-(3,4- dimethoxyphenethoxy)-cyclohexane O o OCH dimethoxyphenethoxy)-cyclohexane(1R,2R)-2-(3R)-Hydroxypyrrolidinyl-1-(3,4-
N OCH3 ... I I IOH
(1R,2R)-2-(3S)-Hydroxypyrrolidinyl-1-(3,4- dimethoxyphenethoxy)-cyclohexane
CrN OCH OH
US 2005/01 19315 A1 Jun. 2, 2005 25
-continued
Structure Chemical name (1R,2R)-2-(3R)/(3S)-Hydroxypyrrolidinyl-1- OCH (3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride or (1S,2S)-2-(3R)/(3S)- hydroxypyrrolidinyl-1-(3,4- N OCH dimethoxyphenethoxy)-cyclohexane OH monohydrochloride or a mixture of (1R,2R)-2- HCI (3R)/(3S)-hydroxypyrrolidinyl-1-(3,4- dimethoxyphenethoxy)-cyclohexane monohydrochloride and (1S,2S)-2-(3R)/(3S)- hydroxypyrrolidinyl-1-(3,4- dimethoxyphenethoxy)-cyclohexane monohydro chloride, where the designation (3R)/(3S) indicates the stereochemistry at the 3 position may be R or S. OCH (1R,2R)-2-(3R)-Hydroxypyrrolidinyl-1-(3,4- dimethoxyphenethoxy)-cyclohexane monohydrochloride or (1S,2S)-2-(3R)- N OCH hydroxypyrrolidinyl-1-(3,4 III iOH .HCl dimethoxyphenethoxy)-cyclohexane monohydrochloride or a mixture of (1R,2R)-2- (3R)-hydroxypyrrollidinyl-1-(3,4 dimethoxyphenethoxy)-cyclohexane monohydrochloride and (1S,2S)-2-(3R)- hydroxypyrrolidinyl-1-(3,4- hoxyphenethoxy)-cyclohexane monohwdrochloride OCH (1R,2R)-2-(3S)-Hydroxypyrrollidinyl-1-(3,4- hoxyphenethoxy)-cyclohexane monohydrochloride or (1S,2S)-2-(3S)- hydroxypyrrolidinyl-1-(3,4- OCH hoxyphenethoxy)-cyclohexane monohydrochloride or a mixture of (1R,2R)-2- HCI (3S)-hydroxypyrrolidinyl-1-(3,4- hoxyphenethoxy)-cyclohexane monohydrochloride and (1S,2S)-2-(3S)- hydroxypyrrolidinyl-1-(3,4- hoxyphenethoxy)-cyclohexane monohwdrochloride OCH (1R,2R)-2-(3S)-Hydroxypyrrollidinyl-1-(3,4- hoxyphenethoxy)-cyclohexane monohydrochloride OCH HCI
OCH (1S,2S)-2-(3S)-Hydroxypyrrolidinyl-1-(3,4- dimethoxyphenethoxy)-cyclohexane monohydrochloride
OCH HCI
0307 Also described here is a composition that includes 1-(3,4-dimethoxyphenethoxy)-cyclohexane free base or any one or more of the compounds or mixtures listed in the salt thereof, or any solvate thereof; (1S,2S)-2-(3R)-hy above table, or includes a Solvate or a pharmaceutically droxypyrrolidinyl-1-(3,4-dimethoxyphenethoxy)-cyclo acceptable Salt of one or more of the compounds or mixtures hexane free base or any Salt thereof, or any Solvate thereof; listed in the above table. The composition may or may not (1S,2S)-2-(3S)-hydroxypyrrolidinyl-1-(3,4-dimethox include additional components. Additional components that yphenethoxy)-cyclohexane free base or any Salt thereof, or may be used are described elsewhere in detail in this patent. any solvate thereof: (1R,2R)-2-(3R)-hydroxypyrrolidinyl 0308. In another version of the aminocyclohexyl ether 1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydro ion channel modulating compounds, the ion channel modu chloride, or any solvate thereof: (1R,2R)-2-(3S)-hydroxy lating compound is one of the following compounds: (1R, pyrrolidinyl-1-(3,4-dimethoxyphenethoxy)-cyclohexane 2R)-2-(3R)-hydroxypyrrolidinyl-1-(3,4-dimethox monohydrochloride, or any solvate thereof; (1S,2S)-2- yphenethoxy)-cyclohexane free base or any Salt thereof, or (3R)-hydroxypyrrolidinyl-1-(3,4-dimethoxyphenethoxy)- any solvate thereof: (1R,2R)-2-(3S)-hydroxypyrrolidinyl cyclohexane monohydrochloride, or any Solvate thereof; or US 2005/01 19315 A1 Jun. 2, 2005 26
(1S,2S)-2-(3S)-hydroxypyrrolidinyl-1-(3,4-dimethox yphenethoxy)-cyclohexane monohydrochloride, or any Sol -continued vate thereof. \ (E) 0309. In another version of the aminocyclohexyl ether 1. ion channel modulating compounds, the ion channel modu 2 lating compound is a protonated version of any of the 8 3 aminocyclohexyl ether compounds described in this patent. 7 4 That is, for each aminocyclohexyl ether compound described in this patent, the quaternary protonated amine 6 5 form of the compound may also be considered as an ami nocyclohexyl ether ion channel modulating compound. These quaternary protonated amine forms of the compounds 0313 The bonds from the cycloalkyl ring to the 1-oxygen may be present in the Solid phase, for example in crystalline and 2-mitrogen atoms in the above formula may be relatively or amorphous form, and may be present in Solution. These disposed in either a cis or trans relationship. In one version, quaternary protonated amine forms of the compounds may the Stereochemistry of the amine and ether Substituents of be associated with pharmaceutically acceptable anionic the cycloalkyl ring is either (R,R)-trans or (S,S)-trans. In counter ions, including but not limited to those described in another version, the Stereochemistry is either (R.S)-cis or for example: “Handbook of Pharmaceutical Salts, Proper (S,R)-cis. ties, Selection, and Use', P, Heinrich Stahl and Camille G. 0314. In one version of the aminocycloalkyl ether ion Wermuth (Eds.), Published by VHCA (Switzerland) and channel modulating compounds, the ion channel modulating Wiley-VCH (FRG), 2002. compound is a compound of formula (XXVIII): 0310 Aminocycloalkyl Ether Ion Channel Modulating Compounds with 5, 7, and 8 Membered Cycloalkyl Rings (XXVIII) 0311 One class of compounds that are ion channel modu lating compound comprise an aminocycloalkyl ether core Structure having an ether oxygen atom at position 1 of a N cycloalkyl ring, and an amine nitrogen atom at position 2 of R4 2. YR, the cycloalkyl ring. In one version the cycloalkyl ring is a 5, 7, or 8 membered ring. \de, 0312. In one version of the aminocycloalkyl ether ion channel modulating compounds, the ion channel modulating 0315 wherein the substituents A, R., R., R., R. R. and compound is a compound having an ether oxygen atom X are as described above for formula (I) and wherein Q is ((Q=O) in formula (XXVIII)) at position 1 of a cycloalkyl an ether oxygen atom (Q=O in formula (XXVIII)) and ring, and an amine nitrogen atom at position 2 of the wherein n is 1, 3 or 4. Such that a cyclopentyl, cycloheptyl or cycloalkyl ring, where the cycloalkyl ring is either cyclo cyclooctyl ring is provided. pentyl, cycloheptyl or cyclooctyl, with other positions num 0316 Compounds of formula (XXVIII) are cycloalky bered in corresponding order as shown below in Structure lamines Such as aminocycloalkyl ethers. More specifically, (C) for cyclopentane, structure (D) for cycloheptane, and these aminocycloalkyl ethers are Substituted at position 2 of Structure (E) for cyclooctane: a cycloalkyl ring with an amine group -NRR. The C-1 position is an ether (Q=O in formula (XXVIII)). The cycloalkyl ring may also be Substituted with additional (C) Substituents (designated as R and R) as described in more detail below. In formula (XXVIII), n is selected from 1,3 and 4, and represents a number of carbon atoms Such that when n equals 1, the ring shown in Formula (XXVIII) is a Substituted cyclopentane (i.e., a cyclopentyl group), when in equals 3, the ring shown in Formula (XXVIII) is a substi
(D) tuted cycloheptane (i.e., a cycloheptyl group), and when in equals 4, the ring shown in Formula (XXVIII) is a substi tuted cyclooctane (i.e., a cyclooctyl group). Examples of specific compounds represented by formula (XXVIII) are described below. 0317 Depending upon the selection of Substituents R. and R, the compounds of formula (XXVIII) may be pri mary, Secondary, or tertiary amines (i.e., both R and R2 are US 2005/01 19315 A1 Jun. 2, 2005 27 hydrogen, only one of R and R is hydrogen, or neither of nonan-3-yl, 2-azabicyclo2.2.2]octan-2-yl, 3-azabicyclo R and R are hydrogen, respectively). Where the amine is 3.1.0 hexan-3-yl, and 3-azabicyclo3.2.0heptan-3-yl. tertiary, it may be a cyclic amine. Amine Substituents R and R may be independently Selected from Substituents which 0322 Preferably for formula (II), R and R, when taken include hydrogen, alkyl groups containing from one to eight together, contain only a Single heteroatom. Preferred het carbon atoms (i.e., C-Calkyl), alkoxyalkyl groups contain eroatoms include nitrogen, oxygen and Sulfur. An example ing from three to eight carbon atoms (i.e., of a ring in which R and R together include an oxygen C-Calkoxyalkyl), alkyl groups containing from one to heteroatom is the morpholinyl group. An example of a ring eight carbon atoms where one of the carbon atoms is where R and R together include a Second nitrogen het Substituted with a hydroxyl group (i.e., C.-Chydroxyalkyl), eroatom is the piperazinyl group. and aralkyl groups containing from Seven to twelve carbon 0323 Cycloalkyl substituents R and R may be indepen atoms (i.e., C7-Caralkyl). dently attached to any of the ring positions except positions 0318. Alternatively, R and R, when taken together with 1 and 2 (e.g., both R and R may be attached to the same the nitrogen atom to which they are directly attached in ring position or each attached to different ring positions). R formula (XXVIII), may form a ring denoted by formula (II): and R are independently selected from hydrogen, hydroxy, C-Calkyl, and C-C alkoxy, and, when both R and R are (II) attached to the Same cycloalkyl ring atom, may together /R form a Spiro five- or six-membered heterocyclic ring con -C)N-R taining one or two heteroatoms Selected from oxygen and sulfur. Preferred heterocyclic substituents contain either a Single oxygen or a single Sulfur ring atom. 0319 wherein the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring 0324 Depending upon the identity of X, the ether atoms independently Selected from carbon, nitrogen, oxy sidechain, -CH(R)-X-A, in formula (XXVIII) may take gen, and Sulfur, where any two adjacent ring atoms may be Several forms. For example, a compound of formula joined together by Single or double bonds, and where any (XXVIII) may have X as a -C(R,R)-Y-group, where one or more of the additional carbon ring atoms may be Y may be any of a direct bond, an oxygen atom (O), a Sulfur Substituted with one or two Substituents selected from atom (S) or a C-C alkylene group. Re and R are inde hydrogen, hydroxy, C-C-hydroxyalkyl, OXO, C-Cacyl, pendently Selected from hydrogen, C-Calkyl, aryl and C-C alkyl, C-C alkylcarboxy, C-Calkoxy, benzyl, or R and R, when taken together with the carbon C-Coalkanoyloxy, or may be Substituted to form a spiro to which they are attached, may form a Spiro five- or Six-membered heterocyclic ring containing one or C-C cycloalkyl. Thus, compounds may include compounds two heteroatoms Selected from oxygen and Sulfur (e.g., an acetal, thioacetal, ketal, or thioketal group); and any two of formula (XXVIII) where R and R are hydrogen and Y adjacent additional carbon ring atoms may be fused to a is a direct bond, such that X may be CH. C-C carbocyclic ring, and any one or more of the additional 0325 Alternatively, X may be an alkenylene moiety, e.g., nitrogen ring atoms may be Substituted with Substituents a cis-or trans-alkenylene moiety, C(R)=CH, where R. Selected from hydrogen, C-C alkyl, C-Cacyl, may be any of hydrogen, C-Calkyl, C-C cycloalkyl, aryl C-C hydroxyalkyl and C-Calkoxyalkyl. Examples of or benzyl. For compounds of formula (XXVIII) where X is Substituents containing a fused ring System include the an alkenylene moiety, X is preferably a trans-alkenylene perhydroindolyl and 1,2,3,4-tetrahydroisoquinolinyl groups. moiety. 0320 In connection with the ring of formula (II), any two adjacent ring atoms may be joined together by Single or 0326 Alternatively, X may be a direct bond. Independent double bonds. Thus, the ring of formula (II) may be satu of the Selections for A, X and other variables, Rs is Selected rated or unsaturated, and an unsaturated ring may contain from hydrogen, C-C alkyl, aryl and benzyl. one, or more than one, Sites of unsaturation. In other words, 0327 Ether side chain component A is generally a hydro the ring of formula (II) may contain one or more double phobic moiety. Typically, a hydrophobic moiety is com bonds, it being understood, however, that the unsaturated prised of non-polar chemical groupS. Such as hydrocarbons ring of formula (II) is chemically stable. or hydrocarbons Substituted with halogens or ethers or 0321) Alternatively, R and R, when taken together with heterocyclic groups containing nitrogen, oxygen, or Sulfur the 2-amino nitrogen of formula (XXVIII), may complete a ring atoms. Suitable hydrocarbons are Cs-Calkyl and bicyclic ring. Bicyclic rings include, for example, 3-azabi C-C carbocyclic rings. Particularly preferred cyclic cyclo3.2.2]nonane, 2-azabicyclo2.2.2]octane, 3-azabicy hydrocarbons include Selected aromatic groupS. Such as clo3.1.0 hexane, and 3-azabicyclo3.2.0 heptane. For these phenyl, 1-naphthyl, 2-naphthyl, indenyl, acenaphthyl, and derivatives, the C-2 substituents of the cycloalkyl ethers of fluorenyl and are represented by formulae (111), (IV), (V), formula (1) are the following groups: 3-azabicyclo3.2.2 (VI), (VII), or (VIII), respectively. US 2005/01 19315 A1 Jun. 2, 2005 28
0328. A suitable “A” group within the compounds 0333 Other suitable “A” groups in compounds described described herein is a phenyl ring represented by formula herein are 2-naphthyl group as represented by formula (V): (III): (V) (III)
0334 where Ro and R are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methaneSulfonamido, nitro, Sulfamyl, trif luoromethyl, C-Czalkanoyloxy, C-Calkyl, C-Calkoxy, 0329 where R, R and Ro are independently selected C-Czalkoxycarbonyl, C-C thioalkyl, and N(R,R) from bromine, chlorine, fluorine, carboxy, hydrogen, where Rs and R are independently Selected from hydro gen, acetyl, methaneSulfonyl, and C-Calkyl, as defined hydroxy, hydroxymethyl, methaneSulfonamido, nitro, Sul above. famyl, trifluoromethyl, C-Czalkanoyloxy, C-Calkyl, 0335) Other suitable “A” groups in compounds described C-C alkoxy, C-Czalkoxycarbonyl, C-C thioalkyl, aryl herein are aromatic groups represented by formula (VI): and N(Rs.R.) where Rs and Rs are independently Selected from hydrogen, acetyl, methaneSulfonyl, and (VI) C-C alkyl. 0330 For compounds of formula (XXVIII) where X is a R- N - direct bond or CH2, at least one of R7, Rs and Ro is preferably selected from amine (-NRR, where Rs and R are independently hydrogen, acetyl, methaneSulfonyl, 0336 where R is selected from bromine, chlorine, fluo rine, carboxy, hydrogen, hydroxy, hydroxymethyl, methane and C-C alkyl), bromine, chlorine, fluorine, carboxy, Sulfonamido, nitro, Sulfamyl, trifluoromethyl, hydrogen, hydroxy, hydroxymethyl, nitro, trifluoromethyl, C-Czalkanoyloxy, C-Calkyl, C-Calkoxy, C-Czalkoxycarbonyl, C-C thioalkyl, and N(R,R) C-Czalkanoyloxy, C-Calkyl, C-Calkoxy, where Rs and R are independently Selected from hydro C-C, alkylcarbonyl, C-Cthioalkyl or aryl groups. For gen, acetyl, methaneSulfonyl, and C-C alkyl, and Z is selected from CH, CH, O, N and S, where Z may be directly compounds of formula (I) when X is CH=CH, and R and bonded to “X” as shown in formula (XXVIII) when Z is CH R are hydrogen, at least one of R7, Rs and Ro is preferably or N, or Z may be directly bonded to R, when Z is N, and R, is selected from hydrogen, C-C alkyl, a Substituent other than hydrogen. C-C cycloalkyl, aryl and benzyl. 0337 The aryl groups of formula (VI) are derivatives of 0331 Other suitable “A” groups in compounds described indene, indole, benzofuran, and thianaphthene when Z is herein are 1-naphthyl groups as represented by formula (IV): methylene, nitrogen, oxygen, and Sulfur, respectively. Pre ferred heterocyclic groups of formula (VI) include indole where Z is NH, benzofuran where Z is O, and thianaphthene (IV) where Z is S. As described below, in a preferred embodi ment, Z is O, S or N-R7, and in a particularly preferred embodiment Z is O or S. 0338 Another suitable “A” group in compounds described herein are acenaphthyl groups as represented by formula (VII):
0332) where Ro and R are independently Selected from (VII) bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methaneSulfonamido, nitro, Sulfamyl, trif luoromethyl, C-Czalkanoyloxy, C-Calkyl, C-Calkoxy, C-Czalkoxycarbonyl, C-C thioalkyl, and N(R,R) where Rs and R are independently selected from hydro gen, acetyl, methaneSulfonyl, and C-Calkyl. US 2005/01 19315 A1 Jun. 2, 2005 29
0339 Still another suitable “A” group in compounds one or more of the additional carbon ring atoms may bear described herein is the fluorenyl group represented by for one or two Substituents Selected from hydrogen, hydroxyl, mula (VIII): C-C-hydroxyalkyl, OXO, C-Cacyl, C-C alkyl, C-C alkylcarboxy, C-Calkoxy, C-Coalkanoyloxy, or may form a Spiro five- or Six-membered heterocyclic ring (VIII) containing one or two heteroatoms Selected from oxygen and Sulfur, and any two adjacent additional carbon ring atoms may be fused to a C-C carbocyclic ring, and any one se or more of the additional nitrogen ring atoms may bear Substituents Selected from hydrogen, C-Calkyl, C-Cacyl, C-C hydroxyalkyl and C-Calkoxyalkyl, or 0352 R and R are taken together with the nitrogen 0340 Preferably, ether sidechain component A is an atom to which they are directly attached in formula acenapthyl or fluorenyl group only when X is a direct bond (XXVIII) to form a bicyclic ring system selected or CH2. In other variations, the acenaphthyl group is a from 3-azabicyclo3.2.2]nonan-3-yl, 2-azabicyclo 1-acenaphthyl group, and the fluorenyl group is a 9-fluore 2.2.2]octan-2-yl, 3-azabicyclo3.1.0hexan-3-yl and nyl group. 3-azabicyclo3.2.0heptan-3-yl; 0341) In another variation of (XXVIII), X is (CH)-Y. 0353 R. and R are independently attached to the For these variations, Y is a direct bond, an oxygen atom, or cycloalkyl ring shown in formula (XXVIII) at other a Sulfur atom. In a particular variation, Y is a direct bond or than the 1 and 2 positions and are independently an oxygen atom. In another variation, Y is a direct bond and Selected from hydrogen, hydroxyl, C-Calkyl and X is C(R,R), where R and R are as defined above. In C-C alkoxy, and, when both R and R are attached another variation, X is C(R)=CH, and R is a hydrogen to the same cycloalkyl ring atom, may together form atom. For these variations, R and R are preferably inde a Spiro five- or six-membered heterocyclic ring con pendently attached to the cycloalkyl ring at the 4- or taining one or two heteroatoms Selected from oxygen 5-positions. and Sulfur, 0342. Ion channel modulating compounds of formula 0354 Rs, R. and R are independently selected (XXVIII) may be provided, wherein: independently at each from hydrogen, C-Calkyl, aryl and benzyl, or R OCCurrence, and R, when taken together with the carbon to 0343 n is selected from 1, 3 and 4; which they are attached, may form a Spiro C-C cycloalkyl, 0344) Q is either O (oxygen) or S (sulfur); 0355 A is selected from Cs-Calkyl, a 0345 X is selected from a direct bond, -C(R, C-Cacarbocyclic ring, and ring Systems Selected R)-Y- and -C(R)=CH-; from formulae (III), (IV), (V), (VI), (VII) and (VIII): 0346 Y is selected from a direct bond, O, S and C-C alkylene; (III) 0347 R is selected from hydrogen, C-Calkyl, C-C cycloalkyl, aryl and benzyl, 0348 R and R are independently selected from hydrogen, C-Calkyl, C-Calkoxyalkyl, C-Chydroxyalkyl, and C7-Caralkyl, or 0349 R and R are independently selected from C-Calkoxyalkyl, C-Chydroxyalkyl, and 0356 where R, Rs and R are independently C7-Caralkyl, or Selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methane 0350 R and Rare taken together with the nitrogen Sulfonamido, nitro, Sulfamyl, trifluoromethyl, atom to which they are directly attached in formula C-Czalkanoyloxy, C-Calkyl, C-Calkoxy, (XXVIII) to form a ring denoted by formula (II): C-Czalkoxycarbonyl, C-C thioalkyl, aryl and N(Rs.R.) where Rs and Rs are independently (II) Selected from hydrogen, acetyl, methaneSulfonyl and /R C-C alkyl, -CNuR2 (IV) 0351 wherein the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently Selected from carbon, nitrogen, oxy gen, and Sulfur, where any two adjacent ring atoms may be joined together by Single or double bonds, and where any US 2005/01 19315 A1 Jun. 2, 2005 30
2S)-2-(4-morpholinyl)-1-(2-naphthalenethoxy) -continued cyclopentane HCl monohydrochloride or a mixture (V) of (1R,2R)-2-(4-morpholinyl)-1-(2-naphthaleneth oxy) cyclopentane monohydrochloride and (1S,2S)- 2-(4-morpholinyl)-1-(2-naphthalenethoxy) cyclo 4N1N R11 pentane monohydrochloride (1R,2R)-2-(3- R10 Ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy) N 2 cyclopentane monohydrochloride or (1S,2S)-2-(3- ketopyrrolidinyl)-1-(2,6-i ethoxy) cyclopentane 0357 where Rio and R are independently selected monohydrochloride or a mixture of (1R,2R)-2-(3- from bromine, chlorine, fluorine, carboxy, hydrogen, ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy) cyclo hydroxy, hydroxymethyl, methanesulfonamido, pentane monohydrochloride and (1S,2S)-2-(3-keto nitro, Sulfamyl, trifluoromethyl, C-C,alkanoyloxy, pyrrolidinyl)-1-(2,6-dichlorophenethoxy) C-C alkyl, C-Calkoxy, C-C,alkoxycarbonyl, cyclopentane monohydrochloride C-C thioalkyl, and N(Rs.R.) where Rs and R. 0362. In a preferred embodiment, the ion channel modu are independently selected from hydrogen, acetyl, lating compound has the formula methaneSulfonyl, and C-C alkyl; (Ia) (VI)
R1 / C y N YR, R.A.l rJ.R. 0358 where R is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxym ethyl, methaneSulfonamido, nitro, sulfamyl, trifluo 0363 or solvates or pharmaceutically acceptable romethyl, C-Czalkanoyloxy, C-C alkyl, salts thereof; wherein, C-C alkoxy, C-Czalkoxycarbonyl, C-C thioalkyl, and N(Rs.R.) where Rs and Rare independently 0364) n=1, 2, 3, or 4; Selected from hydrogen, acetyl, methanesulfonyl, 0365 X is a direct bond, -C(R,R)-Y-, or and C-Calkyl; and Z is selected from CH, CH, O, -C(R)=CH-, with the proviso that when X is N and S, where Z may be directly bonded to “X” as a direct bond and A is formula (III) then at least shown in formula (XXVIII) when Z is CH or N, or one of R7, Rs and Ro is not hydrogen; Z may be directly bonded to R, when Z is N, and R is selected from hydrogen, C-C alkyl, 0366 Y is a direct bond, O, S, or C-C alkylene; C-C cycloalkyl, aryl and benzyl; 0367) R. is hydrogen, C-C alkyl, C-C cycloalkyl, aryl, or benzyl; (VII) 0368 R and R are independently hydrogen, C-Calkyl, C-Calkoxyalkyl, C-Chydroxyalkyl, or C7-Caralkyl; or 0369 R and R, when taken together with the nitrogen atom to which they are directly attached in formula (Ia), form a ring denoted by formula (VIII) (II):
(II) /R CO -C)N-R 0359 including isolated enantiomeric, diastereomeric and geometric isomers thereof; 0370) wherein the ring of formula (II) is formed from the nitrogen as shown as well as three to nine 0360. In another version of the aminocycloalkyl ether ion additional ring atoms independently carbon, nitro channel modulating compounds, the ion channel modulating gen, OXygen, or Sulfur, where any two adjacent ring compound is one of the following compounds or mixtures of atoms may be joined together by single or double compounds. bonds, and where any one or more of the additional 0361) (1R,2R)-2-(4-Morpholinyl)-1-(2-naphthale carbon ring atoms may be substituted with one or nethoxy) cyclopentane monohydrochloride or (1S, two Substituents selected from the group consisting US 2005/01 19315 A1 Jun. 2, 2005 31
of hydrogen, hydroxy, C-C-hydroxyalkyl, OXo, C-Cacyl, C-C alkyl, C-C alkylcarboxy, -continued C-Calkoxy, and C-Coalkanoyloxy, or may be (V) substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms 4N1N R11 of oxygen or Sulfur, and any two adjacent additional R10 carbon ring atoms may be fused to a N 2 C-C carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be Substituted with Substituents of hydrogen, C-C alkyl, 0376 where Rand R are independently bromine, C-Cacyl, C-Chydroxyalkyl O chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxym C-Calkoxyalkyl, or ethyl, methaneSulfonamido, nitro, Sulfamyl, trifluoromethyl, C-Czalkanoyloxy, C-Calkyl, C-Calkoxy, 0371 R and R, when taken together with the C-Czalkoxycarbonyl, C-C thioalkyl, or N(Rs,R) where nitrogen atom to which they are directly attached in Rs and R are independently hydrogen, acetyl, methane formula (Ia), may form a bicyclic ring System of Sulfonyl, or C-Calkyl, 3-azabicyclo3.2.2]nonan-3-yl, 2-azabicyclo2.2.2 octan-2-yl, 3-azabicyclo3.1.0hexan-3-yl, or 3-azabicyclo3.2.0heptan-3-yl; (VI) 0372 R and R are independently attached to the cyclohexane ring shown in formula (Ia) at the 3-, 4-, 5- or 6-positions and are independently hydrogen, hydroxy, C-C alkyl, or C-Calkoxy, and, when both R and R are attached to the same cyclohexane ring atom, may together form a Spiro five- or six 0377 where R is bromine, chlorine, fluorine, carboxy, membered heterocyclic ring containing one or two hydrogen, hydroxy, hydroxymethyl, methaneSulfonamido, heteroatoms of oxygen or Sulfur, nitro, Sulfamyl, trifluoromethyl, C-Czalkanoyloxy, 0373) R, R and R are independently hydrogen, C-Calkyl, C-Calkoxy, C-Czalkoxycarbonyl, C-C alkyl, aryl or benzyl, or R and R, when C-C thioalkyl, or N(Rs,R) where Rs and Rs are inde taken together with the carbon to which they are pendently hydrogen, acetyl, methaneSulfonyl, or C-Calkyl; and Z is CH, CH, O, N or S, where Z may be attached, may form a Spiro C-C cycloalkyl, directly bonded to “X” as shown in formula (Ia) when Z is 0374) A is Cs-Calkyl, a C-C carbocyclic ring, or CH or N, or Z may be directly bonded to R, when Z is N, ring Systems comprising formulae (III), (IV), (V), and R7 is hydrogen, C-Calkyl, C-C cycloalkyl, aryl or (VI), (VII) or (VIII): benzyl;
(III) (VII)
21y S (VIII) 0375 where R7, Rs and Ro are independently bro mine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methaneSulfonamido, se nitro, Sulfamyl, trifluoromethyl, C-Czalkanoyloxy, C-C alkyl, C-Calkoxy, C-Czalkoxycarbonyl, C-C thioalkyl or N(Rs,R) where Rs and Rs are independently hydrogen, acetyl, methaneSulfonyl, or 0378. In another version of the aminocycloalkyl ether ion C-C alkyl, channel modulating compounds, the ion channel modulating compound is a protonated version of any of the aminocy cloalkyl ether compounds described in this patent. That is, (IV) for each aminocycloalkyl ether compound described in this patent, the quaternary protonated amine form of the com pound may also be considered as an aminocycloalkyl ether ion channel modulating compound. These quaternary pro tonated amine forms of the compounds may be present in the Solid phase, for example in crystalline or amorphous form, and may be present in Solution. These quaternary protonated US 2005/01 19315 A1 Jun. 2, 2005 32 amine forms of the compounds may be associated with 0384. In one variation, the cardiac early repolarizing pharmaceutically acceptable anionic counter ions, including currents referred to above comprise ionic currents which but not limited to those described in for example: “Hand activate rapidly after depolarization of membrane Voltage book of Pharmaceutical Salts, Properties, Selection, and and which effect repolarization of the cell. The early repo Use", P. Heinrich Stahl and Camille G. Wermuth (Eds.), larizing currents may comprise the cardiac transient outward Published by VHCA (Switzerland) and Wiley-VCH (FRG), potassium current (I) and/or the ultrarapid delay rectifier 2002. current (IK). The cardiac transient outward potassium 0379 General Description of Ion Channel Modulating current (I) and/or the ultrarapid delay rectifier current Compounds (I) may comprise at least one of the Kv4.2, Kv4.3, Kv2.1, Kv1.4 and Kv1.5 currents. 0380 Generally, any compound that modulates ion chan nel activity may be an ion channel modulating compound. A 0385 Ion channel modulating compounds may generally compound that modulates ion channel activity may be a have any pKa, however ion channel modulating compounds compound that increases or decreases ion channel activity. typically have pKa values of between 4-9, and may have An ion channel modulating compound that decreases ion pKa values that are less than 8, including pKa values channel activity may be a compound that blockSion channel between 5-7.5. Methods to determine pKa values are well activity completely or partially. known in the art (see, e.g., Perrin, "Dissociation Constants 0381. In another version, any compound that either singly of Organic Bases in Aqueous Solution', Butterworth, Lon or together with one or more additional compounds Selec don, 1972). For ion channel modulating compounds with the tively inhibit certain combination of cardiac ionic currents is Specific ranges of pKa described above, the fraction of the an ion channel modulating compound. The cardiac currents charged (protonated) species will be increased under the may be the Sodium currents and early repolarizing currents. pathological conditions Such as cardiac arrhythmias and the Ion channel modulating compounds may block cardiac presence of an arrhythmogenic Substrate in the heart as currents from extracellular loci. Such compounds may act described above due to the increase in cardiac milieu acidity. on an external locus of the ion channel that is accessible Where the charged form of a compound is active, its potency from the extracellular Surface. This facilitates access to the increases under conditions associated with an increase in ion channel and provides rapid onset kinetics and exhibits cardiac milieu acidity. frequency dependent blockade of currents. Such properties 0386 Particular ion channel modulating compounds have are all beneficial for compounds used to treat arrhythmias. Structural characteristics that may be determined by various 0382 An ion channel modulating compound may selec physical methods, Such as Single crystal X-ray crystallog tively inhibit cardiac early repolarizing currents and cardiac raphy. For instance, Some ion channel modulating com Sodium currents. Ion channel modulating compounds may pounds comprise a cycloalkane ring and Substituents J and be used to Selectively inhibit cardiac early repolarizing K as shown below in structure T, wherein the relative currents and cardiac Sodium currents under conditions where positions of J and K provide a “C” shaped angle and wherein an "arrhythmogenic Substrate” is present in the heart. An n=1, 2, 3 or 4. "arrhythmogenic Substrate' is characterized by a reduction in cardiac action potential duration and/or changes in action potential morphology, premature action potentials, high (T) heart rates and may also include increased variability in the "C" angle time between action potentials and an increase in cardiac milieu acidity due to ischaemia or inflammation. Changes Such as these are observed during conditions of myocardial ischaemia or inflammation and those conditions that precede the onset of arrhythmias such as atrial fibrillation or atrial flutter. An ion channel modulating compound may be an 0387 Typically, one of J and K comprises a hydrophobic atrial Selective agent. An ion channel modulating compound moiety, Such as but not limited to a moiety comprising alkyl may treat or prevent Ventricular arrhythmia. An ion channel and/or aryl moieties. In one variation, one of J and K modulating compoundblock may cardiac Sodium currents or comprises a hydrophobic aromatic moiety, which may be cardiac early repolarizing currents. An ion channel modu attached to the cycloalkane ring of Structure T via an ether lating compound may inhibit multiple cardiac ionic currents. bond. Typically, one of J and K comprises a hydrophilic An ion channel modulating compound may be used to treat moiety, Such as a heteroatom containing moiety, including or prevent arrhythma, including ventricular or atrial arrhyth but not limited to a nitrogen containing moiety that is available to form a quaternary Salt and/or a hydroxyl moiety. mia, particularly atrial fibrillation or atrial flutter. In one variation, one of J and K comprises a nitrogen 0383. The ion channel modulating compounds may block containing moiety Substituted with a hydroxyl moiety or the the cardiac ion channels responsible for early repolarizing like, Such as a pyrrolidinyl moiety. In a particular variation currents and Sodium currents, and/or block cardiac early of Structure T, n=2, J comprises a aromatic moiety and K repolarizing currents and cardiac Sodium currents under comprises a nitrogen containing moiety Substituted with a conditions where an arrhythmogenic Substrate is present in hydroxyl moiety or the like. The cycloalkane ring may be the heart; and/or block the cardiac ion channels responsible optionally Substituted. for early repolarizing currents and Sodium currents under conditions where an arrhythmogenic Substrate is present in 0388. In one version, the cycloalkane ring may be the heart; and/or block cardiac early repolarizing currents replaced by a structural moiety imparting rigidity to the and cardiac Sodium currents from extracellular loci in car relative positions of the J and K groups. For example if the diac cells. J and K groups are attached to atoms L and M that are US 2005/01 19315 A1 Jun. 2, 2005 33 directly bonded to each other, any group that does not allow Hooz, J. Methods of Formation of the Ether Linkage. In Substantial rotation about the bond between atoms L and M Patai, Wiley: New York, 1967; pp. 445-492) between an can impart rigidity to the relative positions of the J and K activated form of aminoalcohol 4R with the alkoxide of groups. For example, the ion channel modulating compound 3,4-dimethoxyphenethyl alcohol in a polar Solvent Such as may be a compound of formula dimethoxyethane (ethylene glycol dimethyl ether) (DME) (FIG. 1) that provided the corresponding aminoether 5R in high yield. Subsequent resolution of the diastereomerS Such P J as by chromatographic Separation (e.g., HPLC) to afford 5RRR and 5SSR followed by hydrogenolysis provided s compound 1 and compound 2, respectively. M R1 0395 (1R,2R)-2-(3S)-Hydroxypyrrolidinyl)-1-(3, 4-dimethoxyphenethoxy)cyclohexane free base and the corresponding monohydrochloride (compound 0389 where J and K are as described above and groups 6) and (1S,2S)-2-(3S)-hydroxypyrrolidinyl)-1-(3,4- P and R are moieties such that there is not substantial dimethoxyphenethoxy)cyclohexane free base and rotation about the L-M bond. In one example P and R taken the corresponding monohydrochloride (compound together form a cyclic moiety that prevents Substantial 7) are obtained using a similar Synthetic sequence rotation about the L-M bond. but starting with 3-(S)-hydroxypyrrolidine. 0390. In one version, the ion channel modulating com 0396 Hydrogenolysis of (1R,2R)/(1S,2S)-2-(3R)-ben pound comprises an amino Substituted 5, 6, 7 or 8-mem Zyloxypyrrolidinyl-1-(3,4-dimethoxyphenethoxy)cyclo bered ring, which may be a 5, 6, 7, or 8-membered substi hexane (5R) provided (1R,2R)/(1S,2S)-2-(3R)-hydroxy tuted or unsubstituted cycloalkyl ring. The amino Substituted pyrrolidinyl-1-(3,4-dimethoxyphenethoxy)cyclohexane cycloalkane ring may be an aminocyclohexyl ring and may free base and the corresponding monohydrochloride (com be further Substituted with one or more additional moieties. pound 4). Similarly, starting with 3-(S)-hydroxypyrrolidine In one version, the amino Substituted cycloalkane ring is instead of 3-(R)-hydroxypyrrolidine and following the same further Substituted with an ether moiety. In Some instances, synthetic sequence will afford (1R,2R)/(1S,2S)-2-(3S)-ben the ion channel modulating compound comprises an ami Zyloxypyrrolidinyl-1-(3,4-dimethoxyphenethoxy)cyclo nocyclohexyl ring that is further substituted with an ether hexane. The latter on hydrogenolysis will provide (1R,2R)/ moiety. (1S,2S)-2-(3S)-hydroxypyrrolidinyl-1-(3,4- dimethoxyphenethoxy)cyclohexane free base and the 0391) In another version, the ion channel modulating corresponding monohydrochloride (compound 5). (1R,2R)/ compound is a protonated version of any of the ion channel (1S,2S)-2-(3R)/(3S)-Hydroxypyrrolidinyl-1-(3,4- modulating compounds described in this patent. That is, for dimethoxyphenethoxy)-cyclohexane free base and the cor each ion channel modulating compound described in this responding monohydrochloride (compound 3) can also be patent, the quaternary protonated amine form of the com Synthesized by Similar process by Starting with racemic pound may also be considered as an amino ion channel 3-hydroxypyrrolidine. modulating compound. These quaternary protonated amine forms of the compounds may be present in the Solid phase, 0397 Dosage Forms, Routes of Administration, and For for example in crystalline or amorphous form, and may be mulations of Ion Channel Modulating Compounds present in Solution. These quaternary protonated amine 0398. Dosage forms, routes of administration, and for forms of the compounds may be associated with pharma mulations of the ion channel modulating compounds include ceutically acceptable anionic counter ions, including but not but are not limited to those described in U.S. application Ser. limited to those described in for example: “Handbook of No. 10/674,684, titled Ion Channel Modulating Compounds, Pharmaceutical Salts, Properties, Selection, and Use', P. in U.S. provisional application No. 60/516,248, titled Ami Heinrich Stahl and Camille G. Wermuth (Eds.), Published nocyclohexyl Ether Compounds and Uses Thereof, and in by VHCA (Switzerland) and Wiley-VCH (FRG), 2002. U.S. provisional application 60/516,486, titled Aminocyclo 0392 Methods of Making Ion Channel Modulating Com hexyl Ether Compounds and Uses Thereof, each of which pounds are incorporated herein by reference. Any effective dosage forms, routes of administration, and formulations may gen 0393 Methods that may be used to synthesize the ion erally be used with any and all other aspects described in this channel modulating compounds for use in the methods, patent application. formulations etc. described in this patent application include but are not limited to the synthesis methods described in 0399. The ion channel modulating compounds and for U.S. application Ser. No. 10/674,684 titled Ion Channel mulations described herein may be formulated in a dosage Modulating Compounds, in U.S. provisional application No. form suitable for delivery via a variety of administration 60/516,248, titled Aminocyclohexyl Ether Compounds and routes, including but not limited to oral, parenteral, mucosal, Uses Thereof, in U.S. provisional application 60/516,486, nasal, Sublingual, transdermal, buccal, topical, vaginal, rec titled Aminocyclohexyl Ether Compounds and Uses tal, ocular or other administration. An ion channel modu Thereof, in PCT/US03/34655 (filed Oct. 31, 2003), and WO lating compounds as described herein may be in the form of 99/50225, each of which is incorporated herein by reference an immediate and/or modified release formulation or it may in its entirety. be designed to release the ion channel modulating com pound in a relatively fast manner in order to enable a 0394. In one method, illustrated in FIG. 14, compounds relatively fast onset of the therapeutic effect. AS used herein are prepared by a Williamson ether synthesis (Feuer, H.; “compounds” and “compositions' of ion channel modulat US 2005/01 19315 A1 Jun. 2, 2005 34 ing compounds includes the ion channel modulating com tachyarrhythmia, atrial fibrillation, atrial flutter, Ventricular pounds as described herein alone or in combination with fibrillation, Ventricular flutter etc.) and other diseases and/or other materials. conditions discussed herein may be treated and/or prevented 04.00 Use of Ion Channel Modulating Compounds to using an ion channel modulating compound which exhibits Treat or Prevent Certain Diseases and Conditions two or more of the following characteristics: 04.01 Ion channel modulating compounds may be used to 0406 1. the compound exhibits rate-dependent inhi treat or prevent various diseases and conditions as described bition of a Sodium channel over a physiologically in this patent application. The compounds, compositions, and pathophysiologically significant range of heart formulations, methods, etc. described in this patent appli rateS, cation may be used in the treatment and/or prevention of a 04.07 2. the compound minimally effects cardiac variety of diseases and conditions, including arrhythmias QRS duration; Such as Ventricular arrhythmias (e.g., Ventricular tachycar dia, Ventricular fibrillation, premature Ventricular contrac 0408. 3. the compound exhibits voltage-dependent tions), Supraventricular arrhythmias (e.g., Supraventricular inhibition of Sodium channels; tachycardia, atrial fibrillation, atrial flutter, Wolff-Parkinson White Syndrome, atrial flutter, premature Supraventricular 04.09 4. the compound inhibits Kv potassium chan contractions), heart block, Long QT Syndrome, and Sick nels with an ICso in the micromolar range; Sinus Syndrome. Other diseases or conditions that may be 0410) 5. the compound exhibits predominantly open treated and/or prevented include but are not limited to channel inhibition of Kv1 subfamily channels; disease of the central nervous system (CNS disorders), Lou Gehrig's disease (Amyotrophic Lateral Sclerosis), Alzhe 0411) 6. the compound inhibits Kv1 channels in a imer, AIDS-related dementia, Multiple Sclerosis (MS), con non-rate and non-use-dependent manner; Vulsion, Seizures, epileptic spasms, depression, insomnia, anxiety, Schizophrenia, Parkinson's disease, trigeminal pain, 0412 7. the compound does not inhibit hERG chan phantom limb pain, back pain, Smoke cessation, respiratory nels, except at ICso concentrations greater than 1, 10, disorders, cystic fibrosis, asthma, cough, inflammation and 20 uM; inflammatory disorders, irritable bowel disorders, irritable 0413 8. The compound does not substantially bowel Syndrome Crohn's disease, prostatic hyperplasia, inhibit L-type Calcium Channels, (ICsod100 uM); insect bites, pSoriasis, arthritis, allergies, gastrointestinal disorders, urinary incontinence, cardio-vascular disorders, 0414. 9. the compound prolongs atrial refractori arrhythmia, heart failure, hypotension, cerebral or myocar neSS, dial ischemias, hypertension, long-QT syndrome, Stroke, migraine, ophthalmic diseases, diabetes mellitus, myopa 0415 10. the compound inhibits acetyl choline thies, Becker's myotonia, myasthenia gravis, paramyotonia dependent or adenosine dependent potassium chan congenita, malignant hyperthermia, hyperkalemic periodic nels (Kir3 channels) with an ICso in the micromolar paralysis, Thomsen's myotonia, autoimmune disorders, range, graft rejection in organ transplantation or bone marrow 0416) 11... the compound has neutral effects on ven transplantation, alopecia, diseases or dysfunctions of ion tricular repolarization; channels and receptors, diseases of Voltage-gated ion chan nels, paralysis. This list is illustrative of the kinds of 0417. 12. the compound inhibits early, Sustained and disorders which could be treated and/or prevented as late components of Sodium currents, the compound described herein, and is not intended to be either limiting or inhibits the late component of Sodium current as exhaustive. much or more than it inhibits the early component of Sodium current, and the compound inhibits the early 0402. The compounds, compositions and methods component of Sodium current as much or more than described hereinmay be used as antitoxins, anti-Venoms, it inhibits the Sustained component of Sodium cur antivirals, antibiotics, antiparasitics, antineoplastics, anti rent, and the compound inhibits the late component nociceptives, Sedatives, anesthetics, analgesics, painkillers, of Sodium current more than it inhibits the Sustained antipsychotics, local anaesthetics, topical anesthetics, anti angiogenics, cardioplegias, and cardioprotectants. component of Sodium current; 0403 Effect of Ion Channel Modulating Compounds on 0418 13. the compound exhibits state-dependent Certain Ion Channel Characteristics and Other Physiological inhibition of Sodium channels; Characteristics 0419) 14. the compound rapidly associates and dis 04.04 The effects of ion channel modulating compounds Sociates from Sodium channels, on certain ion channel characteristics and other physiologi 0420 15. the compound exhibits pathology-selec cal characteristics are described below. The effects described tive inhibition of a Sodium channel, and atrial Selec in this Section may generally be used with any and all other tivity; aspects described in this patent application to identify ion channel modulating compounds useful for treating any of 0421) 16. the compound affects atrial repolarization the diseases and/or conditions described herein. but has Substantially no effect on Ventricular tissue; 0405. In one set of methods described in this patent 0422 17. the compound affects atrial conduction but application, cardiac arrhythmia (Such as Supraventricular has Substantially no effect on Ventricular conduction; US 2005/01 19315 A1 Jun. 2, 2005 35
0423 18. the compound prolongs atrial refractori 0438 33. the compound delays conduction in the neSS but has Substantially no effect on Ventricular atria by inhibition of Sodium channels and prolongs refractoriness, refractoriness in the atria via inhibition of I, hERG 0424. 19. the compound prolongs atrial refractori and Ikach neSS and AV nodal conduction and Suppresses induc 0439 34. the compound delays conduction in the ible atrial tachycardia but has substantially no effect atria by inhibition of Sodium channels and prolongs on Ventricular tissues; the compound produces a refractoriness in the atria via inhibition of Ik, I, selective increase in atrial ERP and prolonged AFCL hERG and Ikach; in AF; 0440 35. the compound inhibits sodium channel 0425 20. the compound delays conduction in the activity in a frequency dependent manner, delaying atria by inhibition of Sodium channels and prolongs conduction in the atria and inhibits Io and IK, refractoriness in the atria via inhibition of Is; prolonging refractorineSS in the atria; 0426 21. the compound delays conduction in the 0441 36. the compound does not substantially alter atria by inhibition of Sodium channels and prolongs the conduction or the Voltage time course of repo refractoriness in the atria via inhibition of I; larization in ventricular muscle or Purkinje fibers 0427 22. the compound delays conduction in the 0442. In another embodiment, one set of methods atria by inhibition of Sodium channels and prolongs described in this patent application, the diseases and condi refractoriness in the atria via inhibition of hERG; tions, with a proviso excluding cardiac arrhythmia (Such as Supraventricular tachyarrhythmia, atrial fibrillation, atrial 0428 23. the compound delays conduction in the flutter, ventricular fibrillation, ventricular flutter etc.) atria by inhibition of Sodium channels and prolongs described in the patent application may be treated and/or refractoriness in the atria via inhibition of Iki, prevented using an ion channel modulating compound 0429 24. the compound delays conduction in the which exhibits one or more of the following characteristics: atria by inhibition of Sodium channels and prolongs 0443) 1... the compound exhibits rate-dependent inhi refractoriness in the atria via inhibition of Ik and bition of a Sodium channel over a physiologically Ito: and pathophysiologically significant range of heart 0430 25. the compound delays conduction in the rateS, atria by inhibition of Sodium channels and prolongs 0444 2. the compound minimally effects cardiac refractoriness in the atria via inhibition of Ik and QRS duration; hERG; 0445 3. the compound exhibits voltage-dependent 0431 26. the compound delays conduction in the inhibition of Sodium channels; atria by inhibition of Sodium channels and prolongs refractoriness in the atria via inhibition Of Ik and 0446 4. the compound inhibits Kv potassium chan IKACh: nels with an ICs in the micromolar range; 0432) 27. the compound delays conduction in the 0447 5. the compound exhibits predominantly open atria by inhibition of Sodium channels and prolongs channel inhibition of Kv1 subfamily channels; refractoriness in the atria via inhibition of I and 0448 6. the compound inhibits Kv1 channels in a hERG; non-rate and non-use-dependent manner; 0433 28. the compound delays conduction in the 0449 7. the compound does not inhibit hERG chan atria by inhibition of Sodium channels and prolongs nels, except at ICso concentrations greater than 1, 10, refractoriness in the atria via inhibition of I and 20 uM; IKACh: 0450 8. The compound does not substantially 0434 29. the compound delays conduction in the inhibit L-type Calcium Channels, (ICso-100 uM); atria by inhibition of Sodium channels and prolongs refractoriness in the atria via inhibition of hERG and 0451 9. the compound prolongs atrial refractori KAch neSS, 0435 30. the compound delays conduction in the 0452 10. the compound inhibits acetyl choline atria by inhibition of Sodium channels and prolongs dependent or adenosine dependent potassium chan refractoriness in the atria via inhibition of Ik, I nels (Kir3 channels) with an ICso in the micromolar and hERG; range, 0436 31. the compound delays conduction in the 0453 11... the compound has neutral effects on ven atria by inhibition of Sodium channels and prolongs tricular repolarization; refractoriness in the atria via inhibition of Ik, I 0454) 12. the compound inhibits early, Sustained and and IKAch: late components of Sodium currents, 0437. 32. the compound delays conduction in the 0455 13. the compound inhibits the late component atria by inhibition of Sodium channels and prolongs of Sodium current as much or more than it inhibits refractoriness in the atria via inhibition of Ik, the early component of Sodium current and inhibits hERG and Ikach; the early component of Sodium current as much or US 2005/01 19315 A1 Jun. 2, 2005 36
more than it inhibits the Sustained component of 0472. 30. the compound delays conduction in the Sodium current, and the compound inhibits the late atria by inhibition of Sodium channels and prolongs component of Sodium current more than it inhibits refractoriness in the atria via inhibition of hERG and the Sustained component of Sodium current; KAch 0456) 14. the compound exhibits state-dependent 0473 31. the compound delays conduction in the inhibition of Sodium channels; atria by inhibition of Sodium channels and prolongs 0457 15.. the compound rapidly associates and dis refractoriness in the atria via inhibition Of Ik, I Sociates from Sodium channels, and hERG; 0458 16. the compound exhibits pathology-selec 0474 32. the compound delays conduction in the tive inhibition of a Sodium channel, and atrial Selec atria by inhibition of Sodium channels and prolongs tivity; refractoriness in the atria via inhibition Of Ik, I and Ikach 0459 17. the compound affects atrial repolarization 0475 33. the compound delays conduction in the but has Substantially no effect on Ventricular tissue; atria by inhibition of Sodium channels and prolongs 0460 18. the compound affects atrial conduction but refractoriness in the atria via inhibition Of Ik, has Substantially no effect on Ventricular conduction; hERG and Ikach; 0461) 19. the compound prolongs atrial refractori 0476. 34. the compound delays conduction in the neSS but has Substantially no effect on Ventricular atria by inhibition of Sodium channels and prolongs refractoriness, refractoriness in the atria via inhibition of I, hERG 0462. 20. the compound prolongs atrial refractori and IKAch: neSS and AV nodal conduction and Suppresses induc 0477 35. the compound delays conduction in the ible atrial tachycardia but has substantially no effect atria by inhibition of Sodium channels and prolongs on Ventricular tissues; the compound produces a refractoriness in the atria via inhibition of Ik, I, selective increase in atrial ERP and prolonged AFCL hERG and Ikach; in AF; 0478. 36. the compound inhibits sodium channel 0463. 21. the compound delays conduction in the activity in a frequency dependent manner, delaying atria by inhibition of Sodium channels and prolongs conduction in the atria and inhibits I and Ik, refractoriness in the atria via inhibition of Ik; prolonging refractorineSS in the atria; 0464. 22. the compound delays conduction in the 0479. 37. the compound does not substantially alter atria by inhibition of Sodium channels and prolongs the conduction or the Voltage time course of repo refractoriness in the atria via inhibition of I; larization in ventricular muscle or Purkinje fibers. 0465. 23. the compound delays conduction in the 0480. Described herein are ion channel modulating com atria by inhibition of Sodium channels and prolongs pounds that exhibit one or more of the above characteristics refractoriness in the atria via inhibition of hERG; for the treatment and/or prevention of diseases and condi tions except cardiac arrhythmia (Such as Supraventricular 0466 24. the compound delays conduction in the tachyarrhythmia, atrial fibrillation, atrial flutter, Ventricular atria by inhibition of Sodium channels and prolongs fibrillation, ventricular flutter etc.) described in the patent refractoriness in the atria via inhibition of Ika, application. Described in this patent are ion channel modu 0467 25. the compound delays conduction in the lating compounds that exhibit any combination of any atria by inhibition of Sodium channels and prolongs number of the above characteristics for the treatment and/or refractoriness in the atria via inhibition of Ik and prevention of diseases and conditions except cardiac Ito: arrhythmia (Such as Supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular 0468. 26. the compound delays conduction in the flutter etc.) described in the patent application. atria by inhibition of Sodium channels and prolongs 0481 Specific methods described in this patent applica refractoriness in the atria via inhibition of Ik and tion include (1) a method for treating atrial arrhythmia by hERG; administering to a Subject a therapeutically effective amount 0469 27. the compound delays conduction in the of an ion channel modulating compound which exhibits two atria by inhibition of Sodium channels and prolongs or more of the above listed characteristics (#1 to 36); (2) a refractoriness in the atria via inhibition of Ik and method for preventing atrial arrhythmia by administering to KACh: a Subject in need thereof an ion channel modulating com pound which exhibits two or more of the above listed 0470 28. the compound delays conduction in the characteristics (#1 to 36); (3) a method for treating and atria by inhibition of Sodium channels and prolongs preventing atrial arrhythmia by administering to a Subject in refractoriness in the atria via inhibition of I and need thereof an ion channel modulating compound which hERG; exhibits two or more of the above listed characteristics (#1 0471) 29. the compound delays conduction in the to 36); (4) a method for treating atrial fibrillation or atrial atria by inhibition of Sodium channels and prolongs flutter by administering to a Subject in need thereof an ion refractoriness in the atria via inhibition of Io, and channel modulating compound which exhibits two or more IKACh: of the above listed characteristics (#1 to 36); (5) a method US 2005/01 19315 A1 Jun. 2, 2005 37 for preventing atrial fibrillation or atrial flutter by adminis- 0489) 5. the ion channel modulating compound tering to a Subject in need thereofanion channel modulating blocks a late component of a Sodium channel current compound which exhibits two or more of the above listed approximately equivalently to the amount that it characteristics (#1 to 36); and (6) a method for treating and blocks an early component of a Sodium channel preventing atrial fibrillation or atrial flutter by administering current. In one version, the ion channel modulating to a Subject in need thereof an ion channel modulating compound produces a block of an early component compound which exhibits two or more of the above listed of a Sodium channel current and a block of a late characteristics (#1 to 36). Generally, any compound exhib component of a Sodium channel current, and the iting two or more of the above listed characteristics (#1 to difference between the block of the early component 36) may be used as an ion channel modulating compound in of a sodium channel current and the block of the late these methods. In one aspect, Compound A, Compound B, component of the Sodium channel current is less than or Compound C is used. about five percent of the block of the late component 0482 Specific compounds that may be used include the of the Sodium channel current. In one version, the compounds described in the Ion channel modulating com difference in block is less than about ten percent of pounds Section of this patent application. Specific dosage the block of the late component of the sodium forms, routes of administration, and formulations that may channel current. In one version, the difference in be used include the dosage forms, routes of administration, block is less than about twenty percent of the block and formulations described in the Dosage forms, routes of of the late component of the Sodium channel current. administration and formulation of Ion channel modulating In one version, the difference in block is less than compounds Section of this patent application. Specific dis about thirty percent of the block of the late compo eases and conditions that may be targeted are described in nent of the Sodium channel current. In one version, the Uses of ion channel modulating compounds to treat or the difference in block is less than about fifty percent prevent certain diseases and conditions Section of this patent of the block of the late component of the sodium application. Preferably the Subject is a human Subject. channel current. 0483. In one version, unless the context makes plain 0490 6. the ion channel modulating compound otherwise, the ion channels on which the ion channel modu inhibits the late component of Sodium current lating compounds may act to exert its effects are those approximately as much as or more than it inhibits the present in human atrial myocytes. In one version, the ion early component of Sodium current and inhibits the channels on which the ion channel modulating compounds early component of Sodium current approximately as act to exert an effect are Voltage-gated ion channels present much as or more than it inhibits the Sustained com in human atrial myocytes. ponent of Sodium current, and the compound inhibits the late component of Sodium current more than it 0484. In one version, the ion channel modulating com inhibits the Sustained component of Sodium current. pounds may be used for prevention of one or more diseases In one version, the phrase “inhibits the late compo and conditions including but not limited to TaP, acquired nent of Sodium current approximately as much as or long-QT syndrome, multifocal ventricular arrhythmias, more than it inhibits the early component” (or Supraventricular arrhythmias, and polymorphic ventricular “blocks the late component of Sodium current tachycardia. The ion channel modulating compound may be approximately as much as or more than it blocks the used to prevent and/or treat EADS. The ion channel modu early component’) means that the difference lating compounds may be used by administering a thera between the percentage of the late component of the peutically effective amount of an ion channel modulating Sodium current blocked and the percentage of the compound to a Subject in need thereof, wherein the ion early component of the Sodium current blocked is channel modulating compound is a compound with any one less than 25%. In one version, the difference is less or more of the following characteristics: than 20%. In another version, the difference is less 0485 1. the ion channel modulating compound than 15%. In one version, the Sodium channel current blocks at least one component of a Sodium channel is a cardiac Sodium channel current. current. In one version, the ion channel modulating compound blocks a late component of a current 0491 7. the ion channel modulating compound through a Sodium channel. inhibits the early component of a Sodium channel current approximately as much as or more than it 0486 2. the ion channel modulating compound inhibits the Sustained component of Sodium current. blocks a human heart Sodium channel, hH1. In one version, the phrase “inhibits the early com 0487 3. the ion channel modulating compound ponent of Sodium current approximately as much as blocks at least one component of a Sodium channel or more than it inhibits the Sustained component” (or current in vivo, in vitro or in vivo and in vitro. In one “blocks the early component of Sodium current version, the ion channel modulating compound approximately as much as or more than it blocks the blocks a late component of a Sodium channel current Sustained component’) means that the difference in vivo, in vitro or in vivo and in vitro. In one between the percentage of the early component of version, the ion channel modulating compound the Sodium current blocked and the percentage of the blocks at least one component of a Sodium channel Sustained component of the Sodium current blocked current in Vivo in human. is less than 25%. In one version, the difference is less 0488 4. the ion channel modulating compound than 20%. In another version, the difference is less blocks a Sodium channel current stably expressed in than 15%. In one version, the Sodium channel current HEK cells. is a cardiac Sodium channel current. US 2005/01 19315 A1 Jun. 2, 2005 38
0492 8. the ion channel modulating compound drugs that induce EADS are not limited to those blocks a late component of a Sodium channel current listed and may include equivalent drugs that are not approximately five percent, ten percent, twenty per now known. cent, twenty-five percent, thirty percent, or fifty 0496 12. the ion channel modulating compound percent more than it blocks a Sustained component of terminates, prevents, or terminates and prevents TaP. a Sodium channel current. In one version, the ion channel modulating com pound prevents TcP. In one version, the ion channel 0493 9. the ion channel modulating compound modulating compound terminates TaP. In one ver blocks a late component of a Sodium channel current Sion, the ion channel modulating compound termi in vivo within one hour after administration. In one nates, prevents, or terminates and prevents TaP in a version of the methods, the ion channel modulating dose-dependent fashion. In one version, the ion compound blocks a late component of a Sodium channel modulating compound prevents TodP from channel current within 45 minutes, 30 minutes, 25 being induced. In one version, the ion channel modul minutes, 20 minutes, 10 minutes, 5 minutes, or 1 lating compound terminates induced TaP. In one minute after administration. version, the ion channel modulating compound ter 0494 10. the ion channel modulating compound minates chemically induced TcP. In one version, the blocks a late component of a Sodium channel current ion channel modulating compound prevents chemi in vitro within one hour after contact with the Sodium cally induced TcP. In one version, the ion channel channel current. In one version of the methods, the modulating compound terminates TaP induced by ion channel modulating compound blocks a late any one or more of the drugs listed in Appendix I. component of a Sodium channel current within 45 The list of drugs in Appendix I is published by minutes, 30 minutes, 25 minutes, 20 minutes, 10 www.torSades.org through the University of Arizona minutes, 5 minutes, or 1 minute after administration. Center for Education and Research on Therapeutics based on information from the FDA-approved drug 0495 11... the ion channel modulating compound labeling and the medical literature. In one version, terminates, prevents, or terminates and prevents the ion channel modulating compound prevents TaP EADS. In one version, the ion channel modulating from being induced by any one or more of the drugs compound prevents EADS. In one version, the ion listed in Appendix I. In one version, the ion channel channel modulating compound terminates EADS. In modulating compound terminates TcP induced by one version, the ion channel modulating compound any one or more of the following drugs: Sotalol, terminates EADS in isolated rabbit Purkinje fibers. In cisapride, amiodarone, erythromycin, ibutilide, ter one version, the ion channel modulating compound fenidine, quinidine, clarithromycin, haloperidol, flu terminates EADS induced by dofetilide in isolated oxetine, digoxin, procainamide, terodiline, flucona rabbit Purkinje fibers. In one version, the ion channel Zole, disopyramide, bepridil, furosemide, modulating compound terminates EADS induced by thioridozine, flecainide, loratidine. In one version, blockade of hERG (IKr) channels or by blockade of the ion channel modulating compound prevents TaP long QT syndrome type (LQTS1) channels (IKs) or from being induced by any one or more of the by delay in the inactivation of Sodium channels (e.g., following drugs: Sotalol, cisapride, amiodarone, ATX-II), or by augmentation of inward currents, or erythromycin, ibutilide, terfenidine, quinidine, by prolonging the QT interval. In one version, the ion clarithromycin, haloperidol, fluoxetine, digoxin, channel modulating compound terminates EADS procainamide, terodiline, fluconazole, disopyramide, induced by compounds which result in blockade of bepridil, furosemide, thioridozine, flecainide, lorati hERG (IKr) channels or by blockade of LQTS1 dine. In one version, the ion channel modulating channels (IKs) or by delay in the inactivation of compound terminates TcP induced by an arrhythmic Sodium channels (e.g., ATX-II), or by augmentation agent. In one version, the ion channel modulating of inward currents, or by prolonging the QT interval. compound prevents TaP from being induced by an In one version, the ion channel modulating com arrhythmic agent. In one version, the ion channel pound terminates EADS induced by class III antiar modulating compound terminates TaP induced by rhythmics, antihistamines, antimicrobials, tricyclics, clofilium. In one version, the ion channel modulating or psychotopics. In one version, the ion channel compound prevents TaP from being induced by modulating compound terminates EADS induced by clofilium. In one version, the ion channel modulating any genetic mutation that leads to EADS. In one compound terminates chemically-induced TaP in a version, the ion channel modulating compound ter dose-dependent fashion. In one version, the ion minates EADS induced by long QT syndromes channel modulating compound prevents chemically (LQT1-6) or by Jervell and Lange-Nielsen syndrome induced TaP from being induced, in a dose-depen (JLNS). In one version, the ion channel modulating dent fashion. In one version, the ion channel modul compound terminates EADS induced by any one or lating compound Substantially terminates, prevents more of the drugs listed in Appendix I. The list of or terminates and prevents TaPat infusion rates less drugs in Appendix I is published by www.torSades than 100 umol/kg/min, at infusion rates less than 10 .org through the University of Arizona Center for tumol/kg/min, at infusion rates less than 1 umol/kg/ Education and Research on Therapeutics based on min, at infusion rates less than 0.1 umol/kg/min. In information from the FDA-approved drug labeling one version, the ion channel modulating compound and the medical literature. The list is revised and delays or prevents the onset of TdP at infusion rates updated on a regular basis by www.torSades.org. The less than 100 umol/kg/min, at infusion rates less than US 2005/01 19315 A1 Jun. 2, 2005 39
10 umol/kg/min, at infusion rates less than 1 umol/ 0504 Voltage-Dependent Inhibition of Sodium Channels kg/min, at infusion rates less than 0.1 limol/kg/min. In one version, the ion channel modulating com 0505 As used in this patent application, unless the con pound reduces the effect of TdP when compared to text makes clear otherwise, "Voltage-dependent inhibition' the untreated State at infusion rates less than 100 refers to a change in the level of inhibition of an ion channel tumol/kg/min, at infusion rates less than 10 umol/kg/ when the ion channel is activated after being held at different min, at infusion rates less than 1 umol/kg/min, at resting potentials. Voltage-dependention channel inhibition infusion rates less than 0.1 umol/kg/min. may be different than “state-dependence of inhibition”. 0506 The diseases and conditions described in this patent 0497. In one version of the methods, the method is used application, and Specifically atrial fibrillation or atrial flutter, for treating, preventing, or treating and preventing an may be treated and/or prevented using an ion channel arrhythmia, particularly acquired long-QT syndrome, mul modulating compound that demonstrates a Voltage-depen tifocal ventricular arrhythmias or Supraventricular arrhyth dent inhibition of Sodium channels. In one version, the mias. In one version of the methods, the method is used for Voltage-dependent inhibition is demonstrated in that the ICso treating, preventing, or treating and preventing one or more of the ion channel modulating compound is decreased by of TdP, and polymorphic ventricular tachycardia. about 10xwhen the potential that cells are held at prior to 0498 Rate-Dependent Inhibition of Sodium Channels step depolarization to -30 mV (at 1 Hz) is changed from about -120 mV to about -60 mV. In one version, the 0499. The diseases and conditions described in this patent Voltage-dependent inhibition of Sodium channels is demon application, and Specifically atrial fibrillation or atrial flutter, Strated in that the ICso of the ion channel modulating may be treated and/or prevented using an ion channel compound is decreased by about 4xwhen the potential that modulating compound which exhibits a rate-dependent inhi cells are held at prior to step depolarization to -30 mV (at bition of Sodium channels over a physiologically and patho 1 Hz) is changed from about -120 mV (ICs of approxi physiologically significant range of heart rates. AS used in mately 107 uM in HEK cells expressing hH1) to about -60 this patent application, unless the context makes clear oth mV (ICs of approximately 31 uM in HEK cells expressing erwise, A “and/or B means A or B, or A and B. In one hH1) (FIG. 3). version, the ion channel modulating compound exhibits a rate-dependent inhibition in the range of about a 2-fold to 0507 Failure to Inhibit Calcium Channels about a 100-fold (2x-100x) rate-dependent increase in the 0508 The diseases and conditions described in this patent inhibition of Sodium channels as the frequency of activation application, and Specifically atrial fibrillation or atrial flutter, of the Sodium channel increases from about 0.25 Hz to about may be treated and/or prevented using an ion channel 20 Hz. In one version, the ion channel modulating com modulating compound which does not Substantially inhibit pound exhibits a rate-dependent increase in inhibition in the calcium currents at therapeutic concentrations. In one ver range of about a 5-fold to about a 10-fold rate-dependent Sion, the ion channel modulating compound does not inhibit increase in the inhibition of Sodium channels as the fre L-type calcium channels at therapeutic concentrations. In quency of activation of the Sodium channel increases from one version, the ion channel modulating compound inhibits 0.25 to 20 Hz (as shown in FIGS. 1 and 2). As a nonlimiting L-type calcium channels with an ICso greater than 200 um. example, in human atrial myocytes, at 22 C., the ion channel modulating compound may exhibit an ICs of >2 0509 Inhibition of Kv Potassium Channels with ICso uM at 0.1 Hz and <0.5 uM at 10 Hz (FIG. 1). Values in the Micromolar Range 0510) The diseases and conditions described in this patent 0500 AS used in this patent application, unless the con application, and Specifically atrial fibrillation or atrial flutter, text makes clear otherwise, a physiological heart rate means may be treated and/or prevented using an ion channel a beating rate that falls within the accepted normal distri modulating compound which inhibits KV1 channels at con bution for a healthy individual of that age, and a pathophysi centrations between about at least 2 uM and about 1000 uM ologically significant range of heart rates includes, for and inhibits Kv2 and Kv4 channels at concentrations example, those which occur during atrial fibrillation or atrial between about 0.1 uM and about 1000 uM. In one version, flutter, or other disorders of heart rhythm. the ion channel modulating compound is a compound which 0501 Minimal Effect on QRS Duration does not inhibit KV channels, expressed heterologously in human embryonic kidney cells (HEK) with an ICso of about 0502. The diseases and conditions described in this patent 8 uM, but does inhibit KV channels expressed in HEK cells application, and Specifically atrial fibrillation or atrial flutter, with an ICso between about 8 uM and about 100 uM (as may be treated and/or prevented using an ion channel shown in FIGS. 4 and 5). modulating compound which does not Substantially increase the QRS duration of a heart. AS used in this patent appli 0511 AS used in this patent application, unless the con cation, unless the context makes clear otherwise, “QRS text makes clear otherwise, “KV' channels may include any duration” means the interval of the QRS wave, for example, member of the Subfamilies of potassium channels that are from an ECG. comprised of four Subunits of six-transmembrane domains. In one embodiment, Kv1.5 is inhibited by an ion channel 0503. In one version, the ion channel modulating com modulating compound with an ICs of between 10 and 50 pound produces less than a 15% increase in QRS duration at luM. In one embodiment, Kv1.5 is inhibited by an ion therapeutic concentrations. In one version, the ion channel channel modulating compound with an ICso of approxi modulating compound produces less than a 10% increase in mately 13+1 uM. In one embodiment, Kv1.5, expressed in QRS duration at therapeutic concentrations (as shown in HEK cells, is inhibited by an ion channel modulating Example 2, below). compound with an ICso of approximately 13t1 uM (as US 2005/01 19315 A1 Jun. 2, 2005 40 shown in FIG. 5) and Kv4 subfamily members are inhibited channel is less than the ICso concentration at which the ion with an ICso of about 10 uM or greater (FIG. 4). In one channel modulating compound inhibits another (the non embodiment, Kv1.5, expressed in HEK cells, is inhibited by preferential) channel. an ion channel modulating compound with an ICs of 0520. In one version, the ion channel modulating com approximately 13+1 uM (as shown in FIG. 5) and Kv4 pound is a compound for which inhibition (measured by Subfamily members are inhibited with an ICs of about 30 ICs) of hERG is between about 1.x and 20x the potency for uM or greater (as shown in FIGS. 4 and 7). inhibition of Kv4.3 in HEK cells expressing these channels, 0512 Open Channel Inhibition of Kv1. and for which inhibition (measured by ICs) of Kv1.5 is between about 1.x and 20x the potency for inhibition of 0513. The diseases and conditions described in this patent Kv4.3 in HEK cells expressing these channels. In one application, and Specifically atrial fibrillation or atrial flutter, version, the ion channel modulating compound is a com may be treated and/or prevented using an ion channel pound for which inhibition (measured by ICs) of hERG is modulating compound which inhibits KV1 channels pre between about 1.x and 8x the potency for inhibition of Kv4.3 dominantly as an open channel blocker (as shown in FIG. in HEK cells expressing these channels, and for which 5). In one version, the ion channel modulating compound is inhibition (measured by ICs) of Kv1.5 is between about 1x a compound that is predominantly an open KV1 channel and 8x the potency for inhibition of Kv4.3 in HEK cells blocker that exhibits substantially no rate-dependence (FIG. expressing these channels. In one version, the ion channel 12) or use-dependence (FIG. 13) in inhibiting the channel modulating compound is a compound for which inhibition when it is activated at a frequency between approximately (measured by ICs) of hERG is between about 1.x and 4x the 0.1 and 20 Hz. In one version, the ion channel modulating potency for inhibition of Kv4.3 in HEK cells expressing compound inhibits Kv1.5 as an open channel blocker. these channels, and for which inhibition (measured by ICso) of Kv1.5 is between about 1.x and 4x the potency for 0514) Inhibition of hERG Channels inhibition of Kv4.3 in HEK cells expressing these channels 0515. The diseases and conditions described in this patent (FIG. 7). In this last example the inhibition of Kv1.5 and of application, and Specifically atrial fibrillation or atrial flutter, hERG are about equivalent (FIGS. 5 and 6). may be treated and/or prevented using an ion channel modulating compound which does not inhibit hERG chan 0521. In one version, the ion channel modulating com nels except at micromolar concentrations. In one version, the pound is a compound for which inhibition (measured by ion channel modulating compound is a compound which ICso) of hERG is approximately equivalent to the potency inhibits hERG channels at ICso concentrations of greater for inhibition of Kv4.3 in HEK cells expressing these than about 1 uM and less than about 100 uM. In one version, channels, and for which inhibition (measured by ICso) of the ion channel modulating compound is a compound which KV1.5 is approximately equivalent to the potency for inhi inhibits hERG channels at ICso concentrations of greater bition of Kv4.3 in HEK cells expressing these channels. than about 10 uM and less than about 50 uM. In one version, 0522 Prolonged Atrial Refractoriness the ion channel modulating compound is a compound which 0523 The diseases and conditions described in this patent inhibits hERG channels at ICso concentrations of greater application, and Specifically atrial fibrillation or atrial flutter, than about 10 uMandless than about 25uM (as seen in FIG. may be treated and/or prevented using an ion channel 6). modulating compound which prolongs atrial refractoriness. 0516 Equivalent Block of hERG and Kv1.5 in HEK In one version, the ion channel modulating compound is a Cells compound which prolongs the atrial refractorineSS in human atria by preferentially inhibiting I (Kv1.5) or I (Kv4.3) 0517. The diseases and conditions described in this patent or Sodium channels (h1). In one version, the ion channel application, and Specifically atrial fibrillation or atrial flutter, modulating compound is a compound which prolongs the may be treated and/or prevented using an ion channel atrial refractoriness by inhibiting both I (Kv1.5) and modulating compound for which the inhibition of hERG and Sodium channels (h1). In one version, the ion channel the inhibition of Kv1.5 are about the same in HEK cells modulating compound is a compound which prolongs the heterologously expressing these channels. In one version, atrial refractoriness by inhibiting both I (Kv1.5) and I the ion channel modulating compound is a compound for (Kv4.3). In one version, the ion channel modulating com which inhibition (measured by ICs) of hERG is approxi pound is a compound which prolongs the atrial refractori mately equivalent to inhibition (measured by ICs) of Kv1.5 ness by inhibiting both I (Kv4.3) and Sodium channels in HEK cells expressing these channels (FIGS. 5 and 6). (hPI1). In one version, the ion channel modulating compound is a compound which prolongs the atrial refractorineSS by 0518) Preferential Block of hERG and Kv1.5 Over Kv4.2 inhibiting Is (Kv1.5), and I (Kv4.3), and Sodium chan and Kv4.3 in HEK Cells nels (hH1). 0519. The diseases and conditions described in this patent application, and Specifically atrial fibrillation or atrial flutter, 0524. Inhibition of Acetyl Choline Dependent or Adenos may be treated and/or prevented using an ion channel ine Dependent Potassium Channels (Kir3) with an ICs in modulating compound which inhibits hERG and Kv1.5 the Micromolar Range preferentially over Kv4.2 and Kv4.3 in HEK cells heterolo 0525) The diseases and conditions described in this patent gously expressing these channels. AS used in this patent application, and Specifically atrial fibrillation or atrial flutter, application, unless the context makes clear otherwise, pref may be treated and/or prevented using an ion channel erential inhibition means that the ICso concentration at modulating compound which inhibits Kir3 channels. Such as which the ion channel modulating compound inhibits one those which give rise to acetylcholine dependent potassium US 2005/01 19315 A1 Jun. 2, 2005
current Ika, at concentrations between about 0.1 uM and 1:1. Activated channels include those that are both open and about 1000 uM. In one version, the ion channel modulating also inactivated. In one version the ion channel modulating compound is a compound which does not inhibit Ika in compound is a compound that causes inhibition of activated guinea pig atrial cells with an ICs of less than about 1 uM, and closed hEI1 sodium channels expressed in HEK cells but does inhibit Ikach in guinea pig atrial cells With an ICso with an activated:closed potency ratio between about 10:1 between about 1 uM and about 50 uM (FIG. 11). and 1:1 when pulsed from a holding potential between about 0526 AS used in this patent application, unless the con -120 to -60 mV, to potentials that will open the channels. As text makes clear otherwise, “Kir3” channels may include used in this patent application, unless the context makes any member of the Subfamilies of potassium channels that clear otherwise, “pulse' or “pulsed” refers to a voltage are activated by acetylcholine or adenosine interaction with clamp Step of a defined amplitude in mV. In one version, the its associated receptor. In one embodiment, Kir3 or Ika is ion channel modulating compound is a compound that, inhibited by an ion channel modulating compound with an when used at about its ICso, causes inhibition of activated ICs of between 1 and 50 uM (at 1 Hz). In one embodiment, and closed hEI1 sodium channels expressed in HEK cells Kir3 or Ika is inhibited by an ion channel modulating with an activated:closed potency ratio of about 2:1 when compound with an ICs of approximately 10 um (at 1 Hz). pulsed from about -100 mV to about -30 mV at about 10 In one embodiment, Ikach in guinea pig atrial cells is HZ. inhibited by an ion channel modulating compound with an 0533. In one version, the ion channel modulating com ICso of approximately 10 uM (at 1 Hz, FIG. 11), and Kv1 pound is a compound that causes inhibition of Sodium and Kv4 Subfamily members are also inhibited with an ICso channels in the open-state to a greater extent than the of about 10 uM or greater (FIGS. 4 and 5). inactivated-State. In one version, the ion channel modulating compound is a compound that causes inhibition of Sodium 0527 Neutral Effect on Ventricular Repolarization channels in the open-state with an openinactivated potency 0528. The diseases and conditions described in this patent ratio (proportion of open channel inhibition relative to application, and Specifically atrial fibrillation or atrial flutter, proportion of inactivated channel inhibition, as proportions may be treated and/or prevented using an ion channel of total inhibition) of between about 100:1 and 5:1. In one modulating compound which has a neutral effect on Ven version, the ion channel modulating compound is a com tricular repolarization. In one version, the ion channel modu pound that causes inhibition of Sodium channels in the lating compound is a compound which has a neutral effect open-state with an with an open:inactivated potency ratio of on human ventricular repolarization in that the ion channel greater than about 10:1 when pulsed from about -80 mV to modulating compound inhibits Sodium current, including about -30 mV for about 200 milliseconds (see FIG. 9). late Sodium current, at Similar concentrations and/or higher potency than it inhibits the hERG channels. In one version, 0534 Rapid Association and Dissociation from Sodium the ion channel modulating compound is a compound which Channels inhibits sodium channels (hH1) expressed in HEK cells with 0535 The diseases and conditions described in this patent an ICso between 10-50 M and which also inhibits hERG application, and Specifically atrial fibrillation or atrial flutter, channels with an ICso greater than 10 M. may be treated and/or prevented using an ion channel modulating compound which rapidly associates and disso 0529 Equivalent Inhibition of Early and Sustained ciates from Sodium channels. In one version, the ion channel Sodium Currents modulating compound is a compound which rapidly asso 0530. The diseases and conditions described in this patent ciates and dissociates from Sodium channels at approxi application, and Specifically atrial fibrillation or atrial flutter, mately the ICso concentration that the ion channel modulat may be treated and/or prevented using an ion channel ing compound inhibits the Sodium channel. The rapid modulating compound which inhibits both the early and the asSociation of the compound may be exemplified by its late Sodium currents in approximately equivalent magnitude. minor effect on the time to peak of the inward Sodium In one version, the ion channel modulating compound is a current. The rapid dissociation of the compound may be compound which inhibits both the early and the late sodium inferred from the minor effect on the relaxation phase of the currents expressed in HEK cells in approximately equal macroscopic inward Sodium current, the Overall inhibiting magnitude (FIG. 8). effect therefore appearing as a Scaling down of the current waveform. Minor effect includes not having any effect, or 0531 State-Dependent Inhibition of Sodium Channels having less than 15%, 10% or 5% effect. 0532. The diseases and conditions described in this patent application, and Specifically atrial fibrillation or atrial flutter, 0536. In further experiments, rapid dissociation was may be treated and/or prevented using an ion channel assessed by applying continuous 1 Hz. Stimulation after a 10 modulating compound which exhibits a State-dependent HZ conditioning train in the presence of 10 uM COM inhibition of the Sodium channels. In one version, the ion POUND C and measuring the time constants of recovery of channel modulating compound is a compound which exhib early Sodium currents. The mean time constant of recovery its a State-dependent inhibition that affects Sodium channels (t1) was 0.19+0.05 s and this accounted for 76.6% of the in the activated State more than in the closed State. In one total current recovery. The conclusion of this experiment is version, the ion channel modulating compound is a com that almost complete Sodium current recovery from block by pound that causes inhibition of activated and closed hH1 COMPOUND C will occur in less than 1.5 s. Sodium channels expressed in HEK cells with an activated 0537 AS used in this patent application, unless the con :closed potency ratio (proportion of activated channel inhi text makes clear otherwise, “rapid association and dissocia bition relative to proportion of closed channel inhibition, as tion' includes the characteristics of “fast on/fast off inhi proportions of total inhibition) of between about 10:1 and bition of sodium currents (FIG. 10). US 2005/01 19315 A1 Jun. 2, 2005 42
0538 Pathology-Selective Inhibition of a Sodium Chan 0544 Typically, beta blockers block the beta adrenergic nel, and Atrial Selectivity receptors, either Selectively or nonselectively. Examples of 0539. The diseases and conditions described in this patent beta blocker which may be provided in combination with the application, and Specifically atrial fibrillation or atrial flutter, ion channel modulating compounds described herein may be treated and/or prevented using an ion channel include, but are not limited to Acebutolol (Acebutolol modulating compound which demonstrates a pathology Hydrochloride, Sectral), Atenolol (Tenormin, Tenoretic), Selective inhibition of Sodium channels. In one version, the Betaxolol (Kerlone), Bisoprolol (Zebeta, Ziac), Cartelol ion channel modulating compound is a compound which (Cartrol), Carvedilol (Coreg), Esmolol (Brevibloc), Labe brings about inhibition of Sodium channels during a pathol tolol (Normodyne, Trandate, Labetolol HCl), Metoprolol ogy that causes a depolarization of the membrane potential (Lopressor, Lopressor HCl, Toprol, Toprol XL), Nadolol (i.e. a voltage-dependence of inhibition). In one version (Corgard, Corzide), Bendroflumethiazide (Corzide), Triam Voltage-dependence of inhibition is demonstrated by terene (Dyazide), Hydrochlorothiazide (Dyazide), Penb between about a 1-fold and a 50-fold decrease in ICs for a utolol (Levatol, Penbutolol Sulfate), Pindolol (Visken), Pro resting potential change from about -120 to about -60 mV. pranolol (Inderal, Inderide, Innopran, Betchron, In one version this Voltage-dependence of inhibition is Propanolol), Sotalol (Betapace, Sotalol), Timolol (Blocad demonstrated by between about a 3-fold and a 20-fold ren, Timolide, Timoptic), Oxprenolol, Moprolol, Carazolol, decrease in ICso for a resting potential change from about Alprenolol, Bunolol. This list is not exhaustive, and addi -120 to about -60 mV. tional beta blockers known in the art are also contemplated. 0540 Combinations of Ion Channel Modulating Com 0545. In one example, COMPOUND A is used in com pounds and Other Drugs bination with one or more of the above listed beta blockers. The COMPOUND A and another drug may be administered 0541. The ion channel modulating compounds described at the same time, or at different times. COMPOUND A and in this patent application can be provided for treating and/or another drug may be administered via the Same route or by preventing a variety of diseases and conditions in combina different routes of administration. COMPOUND A and tion with other drugs including, but not limited to cardio another drug may be administered in one formulation or in vascular agents, beta-blockers, ACE inhibitors, antihyper different formulations. tensives, diuretics, antipsychotics, anticoagulants (antiplatelets), antidepressants, inotropes, Ca Sensitizers, Ca 0546 Angiotensin converting enzyme inhibitors (ACE channel blockers, adrenergic blocking agents, angiotensin II inhibitors) reduce peripheral vascular resistance via block receptor antagonists, Xanthine oxidase inhibitors (XOIs), age of the angiotensin converting enzyme, reducing myo natriuretic peptides, metabolic modulators, lipid/cholesterol cardial oxygen consumption. Examples of ACE inhibitors modulating agents, anti-inflammatory agents, vasodilators, which may be provided in combination with the ion channel anti-convulsants, antioxidants, antilipids, digitalis glyco modulating compounds described herein include, but are not Sides, rate control drugs, antihistamines, antisaspmodics, limited to Quinapril (Accupril, Accuretic), Perindopril antibiotics, antirejection drugs, immunomodulators, chemo (Aceon, Perindopril Erbumine), Ramipril (Altace), Capto therapeutics, and antiarrhythmics. pril (Capoten, Capozide), Benazepril (Lotensin, Benazepril HCl, Lotensin HCl, Lotrel), Trandolapril (Mavik, Tarka), 0542 Diseases and conditions that may be treated and/or Fosinopril (Monopril, Fosinopril Sodium), Lisinopril (Prini prevented using the combinations described in this Section vil, Zestril, Prinizide, Prinzide, Zestoretic), Moexipril include but not limited to (1) treating arrhythmia (2) pre (Univasc, Moexipril HCl, Uniretic), Enalapril (Vasotec, venting arrhythmia, (3) preventing reoccurrence of arrhyth LeXXel, Teczem, Vaseretic), Enalaprilat, Ziac (Hydrochlo mia (4) treating and preventing recurrence of arrhythmia, (5) rothiazide and Bisoprolol fumarate), Zebeta. This list is not treating atrial fibrillation, (6) preventing recurrence of atrial exhaustive, and additional ACE inhibitors known in the art fibrillation, (7) treating and preventing recurrence of atrial are also contemplated. fibrillation, (8) treating atrial flutter, (9) preventing of atrial flutter, and (10) treating and preventing of atrial flutter. 0547. In one example, COMPOUND A is used in com bination with one or more of the above listed ACE inhibi 0543. As used herein “combination” refers to any mixture tors. The COMPOUND A and another drug may be admin or permutation of ion channel modulating compound and istered at the same time, or at different times. COMPOUND another drug or drugs. Unless the context makes clear A and another drug may be administered via the same route otherwise, “combination” may include Simultaneous or or by different routes of administration. COMPOUNDA and Sequentially delivery of an ion channel modulating com another drug may be administered in one formulation or in pound with another drug or drugs. Unless the context makes different formulations. clear otherwise, “combination' may include dosage forms of an ion channel modulating compound with another drug or 0548 Examples of antihypertensives which may be pro drugs. Unless the context makes clear otherwise, “combi Vided in combination with the ion channel modulating nation” may include routes of administration of an ion compounds described herein include, but are not limited to channel modulating compound with another drug or drugs. Sulfonamide Diuretics (Hydrochlorothiazide, Chlorthali Unless the context makes clear otherwise, “combination” done, Furosemide, MefruSide, Indapamide), K-Retaining may include formulations of an ion channel modulating Diuretics (Amiloride Triamterene), Inhibitors of the Sym compound with another drug or drugs. Dosage forms, routes pathetic Nervous System, Drugs with Primarily Central of administration and formulations include but not limited to Actions (Methyldopa, Clonidine, Guanfacine, Guanabenz), those described in the Section entitled Dosage forms, routes Drugs with Primarily Peripheral Action (Amine Depleting of administration, and formulation of ion channel modulat and Adrenergic Neuron Blocking Agents Such as Reserpine, ing compounds. Guanethidine and/or a-Adrenoceptor Antagonists Such as: US 2005/01 19315 A1 Jun. 2, 2005 43
PraZosin, Indoramin, Urapidil, and/or b-Adrenoceptor described herein include, but are not limited to vitamin C, Antagonists such as: Propranolol, Metoprolol, Nadolol, Pin Vitamin E, beta-caroteine, lutein, lycopene, Vitamin B2, dolol, Timolol, Acebutolol, Labetalol), Smooth Muscle coenzyme Q10, cysteine as well as herbs, Such as bilberry, Relaxants (Cat" Channel Antagonists and Vasodilators), turmeric (curcumin), grape Seed or pine bark extracts, and Bidil (isosorbide dinitrate hydralizine combination). This ginkgo. This list is not exhaustive and additional antioxi list is not exhaustive, and additional antihypertensives dants known in the art are also contemplated. known in the art are also contemplated. 0555. In one example, COMPOUND A is used in com 0549. In one example, COMPOUND A is used in com bination with one or more of the above listed antioxidants. bination with one or more of the above listed antihyperten The COMPOUND A and an antioxidant may be adminis sives. The COMPOUND A and an antihypertensive may be tered at the same time, or at different times. COMPOUND administered at the same time, or at different times. COM A and an antioxidant may be administered via the Same route POUNDA and an antihypertensive may be administered via or by different routes of administration. COMPOUNDA and the same route or by different routes of administration. an antioxidant may be administered in one formulation or in COMPOUND A and an antihypertensive may be adminis different formulations. tered in one formulation or in different formulations. 0556 Examples of anticoagulants (antiplatelets) which 0550 Examples of antipsychotics which may be pro may be provided in combination with the ion channel Vided in combination with the ion channel modulating modulating compounds described herein include, but are not compounds described herein include, but are not limited to limited to Heparin (Bivalirudin), Coumadin (Warfarin), Thioridazine (Melleril, Aldazine), Pimozide, Clozapine, Miradon (Anisindione), Sintrom (Acenocoumarol), Warf Haloperidol (Haldol), Risperidone (Risperdal), Olanzapine, ilone, Dicumarol, Ardeparin, Dalteparin, Danaparoid, Enox Quetiapine, Ziprasidone, Aripiprazole, Sulpride, Chlorpro aparin, Ximelagatran, Eptifibatide, Aspirin (acetylsalicylic mazine (Thorazine). This list is not exhaustive, and addi acid, ASA), Clopidogrel (Plavix), Dipyridamole (Aggrenox, tional antipsychotics known in the art are also contemplated. Persantine), Ticlopidine (Ticlid), Abciximab (ReoPro), platelet GPIb-IIIa blockers. This list is not exhaustive and 0551. In one example, COMPOUND A is used in com additional anticoagulants (antiplatelets) known in the art are bination with one or more of the above listed antipsychotics. also contemplated. The COMPOUND A and an antipsychotic may be admin istered at the same time, or at different times. COMPOUND 0557. In one example, COMPOUND A is used in com A and an antipsychotic may be administered via the same bination with one or more of the above listed anticoagulants. route or by different routes of administration. COMPOUND The COMPOUND A and an anticoagulant may be admin A and an antipsychotic may be administered in one formu istered at the same time, or at different times. COMPOUND lation or in different formulations. A and an anticoagulant may be administered via the same route or by different routes of administration. COMPOUND 0552) Examples of anticonvulsants which may be pro A and an anticoagulant may be administered in one formu Vided in combination with the ion channel modulating lation or in different formulations. compounds described herein include, but are not limited to Barbiturates: Mephobarbital (Mebaral), Pentobarbital 0558 Examples of antidepressants which may be pro (Nembutal), Phenobarbital (Luminol, Solfoton); Benzodiaz Vided in combination with the ion channel modulating epines: Chlorazepate (Tranxene), Clonazepam (Klonopin), compounds described herein include, but are not limited to Diazepam (Valium); GABA Analogues: Gabapentin (Neu Amitriptyline (Tryptizol), Clomipramine (Anafranil), Cit rontin), Tiagabine (Gabitril); Hydantoins: Ethotoin (Pega allopram (Cipramil), Dothepin (Prothiaden), Doxepin (Sine none), Fosphentyoin (Mesantoin), Phenyloin (Dilantin, quan), Fluoxetine (Prozac), Imipramine (Tofranil), Diphenylhydantoin); Oxazolidinediones: Trimethadione Lofepramine (Gamanil), Mirtazapine (Zispin), Nortriptyline (Tridione); Phenyltriazines: Lamotrigine (Lamictal); Suc (Allegron), Paroxetine (Paxil, Seroxat), Reboxitine cinimides: Ethosuximide (Zarontin),MethSuximide (Celon (Edronax), Sertraline (Lustral), Trazodone (Molipaxin), tin), PhenSuximide (Milontin); and miscellaneous anticon Venlafaxine (Efexor), Amoxapine, Bupropion, Desipramine, Vulsants: Acetazolamide (Diamox), Carbamazepine Escitalopram Oxalate, Fluvoxamine, Imipramine, ISOcar (Carbatrol, Tegretol), Felbamate (Felbatol), Levetiracetam boxazid, Maprotiline, Phenylzine, Protriptylin, Tranyl (Keppra), Oxcarbazepine (Trileptal), Primidone (Mysoline), cypromine, Trimipramine, Venlafaxine. This list is not Topiramate (Topamax), Valproic acid (Depakene, Depa exhaustive and additional antidepressants known in the art kote), Zonisamide (Zonegran). This list is not exhaustive are also contemplated. and additional anticonvulsants known in the art are also contemplated. 0559). In one example, COMPOUND A is used in com bination with one or more of the above listed antidepres 0553. In one example, COMPOUND A is used in com sants. The COMPOUND A and an antidepressant may be bination with one or more of the above listed anticonvul administered at the same time, or at different times. COM sants. The COMPOUND A and an anticonvulsant may be POUND A and an antidepressant may be administered via administered at the same time, or at different times. COM the same route or by different routes of administration. POUND A and an anticonvulsant may be administered via COMPOUND A and an antidepressant may be administered the same route or by different routes of administration. in one formulation or in different formulations. COMPOUND A and an anticonvulsant may be administered 0560 Examples of inotropes which may be provided in in one formulation or in different formulations. combination with the ion channel modulating compounds 0554 Examples of antioxidants which may be provided described herein include, but are not limited to Dobutamine, in combination with the ion channel modulating compounds Dopamine, Epinephrine, Norepinephrine, Milrinone (Prima US 2005/01 19315 A1 Jun. 2, 2005 44 cor), Amrinone (Inocor), Adrenaline, Dopexamine, Ephe compounds described herein include, but are not limited to drine, Salbutamol, Methoxamine, Isophrenaline, Metarami Losartan (Cozaar), Valsartan (Diovan), Irbesartan (Avapro), nol, Phenylephrine, Noradrenaline, Adenosine, Digitalis, Candesartan (Atacand), Telmisartan (Micardis), Eprosartan, Amrinone, Digitoxin, Digoxin, Enoximone, PiroXimione. Tasosartan, ZolarSartan, Lisinopril, Atenolol, Bendroflu This list is not exhaustive and additional inotropes known in azide, Saralasin. This list is not exhaustive and additional the art are also contemplated. angiotensin II antagonists known in the art are also contem 0561. In one example, COMPOUND A is used in com plated. bination with one or more of the above listed inotropes. The 0568. In one example, COMPOUND A is used in com COMPOUND A and an inotrope may be administered at the bination with one or more of the above listed angiotensin II same time, or at different times. COMPOUND A and an antagonists. The COMPOUND A and an angiotensin II inotrope may be administered via the same route or by antagonist may be administered at the same time, or at different routes of administration. COMPOUND A and an different times. COMPOUND A and an angiotensin II inotrope may be administered in one formulation or in antagonist may be administered via the same route or by different formulations. different routes of administration. COMPOUND A and an 0562) Examples of calcium sensitizers which may be angiotensin II antagonist may be administered in one for provided in combination with the ion channel modulating mulation or in different formulations. compounds described herein include, but are not limited to 0569. Examples of Xanthine oxidase inhibitors which Levosimendan, thiadiazinone derivatives such as EMD may be provided in combination with the ion channel 53998, CGP 48506. This list is not exhaustive and additional modulating compounds described herein include, but are not calcium Sensitizers known in the art are also contemplated. limited to oxypurinol, allopurinol (Zyloprim, Purinol), 0563. In one example, COMPOUND A is used in com febuxostat (TEI-6720; TMX-67). Furthermore, any pharma bination with one or more of the above listed calcium ceutically acceptable XOI may be provided in combination. sensitizers. The COMPOUND A and a calcium sensitizer Examples of Suitable classes of compounds from which a may be administered at the same time, or at different times. XO inhibitor may be selected may be found in the patent COMPOUND A and a calcium sensitizer may be adminis documents listed below and the patents and publications tered via the same route or by different routes of adminis referenced therein, all of which are incorporated by refer tration. COMPOUND A and a calcium sensitizer may be ence herein. The nature and Synthesis of the compounds administered in one formulation or in different formulations. referenced are taught in those patents. 0564) Examples of calcium channel blockers which may 0570) Examples of suitable classes of compounds from be provided in combination with the ion channel modulating which a XOI may be selected include: U.S. Pat. No. 5,674, compounds described herein include, but are not limited to 887, U.S. Pat. No. 5,272,151, U.S. Pat. No. 5,212,201, U.S. Nitrendipine, Nifedipine (Procardia, Procardia XL, Adalat, Pat No. 4,495,195, U.S. Pat No. 4,346,094, U.S. Pat No. Adalat CC), Diltiazem (Cardizem), and Verapamil (Calan, 4,281,005, U.S. Pat No. 4,241,064, U.S. Pat No. 4,179,512, Isoptin), Nicardipine, Bepridil (Vascor), Mibefradil (Posi U.S. Pat No. 4,058,614, U.S. Pat No. 4,024,253, U.S. Pat cor), Felodipine (Plendil, Renedil), Flunarizine (Sibelium), No. 4,021,556, U.S. Pat No. 3,920,652, U.S. Pat No. 3,907, Isradipine (DynaCirc), Nimodipine (Nimotop), Amlodipine 799, U.S. Pat No. 3,892,858, U.S. Pat No. 3,892,738, U.S. (Norvasc). This list is not exhaustive and additional calcium Pat No. 3,890,313, U.S. Pat No. 3,624,205, U.S. Pat No. channel blockers known in the art are also contemplated. 3,474,098, U.S. Pat No. 2,868,803, U.S. Pat No. 6,191,136, 0565. In one example, COMPOUND A is used in com U.S. Pat No. 6.569,862, WO0200210 (PCT/US01/20457), bination with one or more of the above listed calcium European 429,038, phenylethenyl esters of phenylpropenoic channel blockers. The COMPOUND A and a calcium chan acid; PCT Publication WO9113623, C5-monosubstituted nel blocker may be administered at the same time, or at barbiturates, Czechoslovakia 264505, salts of N-acetyl-p- different times. COMPOUND A and a calcium channel aminosalicylic acid; German 3912092, heterocyclic com blocker may be administered via the same route or by pounds with more than one hetero atom, Such as aminotria different routes of administration. COMPOUND A and a Zolopyridoquinazolinone; Japanese 0224.5198, phenyl calcium channel blocker may be administered in one for compounds Such as Sodium Salicylate; European 269859, mulation or in different formulations. pyrazolotriazines, European 274654, heterocylotriazinones such as 7-phenylisothiazolo 4,5-d-1,2,3-triazin-4(3H)-one; 0566. Examples of adrenergic blocking agents which Netherlands 8602382, catechol derivatives such as 4-(+)- may be provided in combination with the ion channel methylthiocatechol; German 3632841, similar to the above; modulating compounds described herein include, but are not German 3632824, bicyclic catechol derivatives; Japanese limited to reserpine, guanethidine, Alpha 1-Adrenergic 592 19229, indoles, such as 1-formyl-4-hydroxy-9H-pyrido antagonists (prazosin) In one example, COMPOUND A is 3,4-bindole; U.S. Pat. No. 4,336,257.2-(4-pyridyl)-5-chlo used in combination with one or more of the above listed robenzimidazole, 1H-imidazo4,5-b]pyridines, and imidazo adrenergic blocking agents. The COMPOUND A and an 4.5-cpyridines; European 28660, pyrazolobenzotriazine adrenergic blocking agent may be administered at the same derivatives; Japanese 55055185, compounds derived from time, or at different times. COMPOUND A and an adren extraction of picrasma quassioides; German 2941449, pyri ergic blocking agent may be administered via the same route dolindoles isolated according to the above patent; U.S. Pat. or by different routes of administration. COMPOUNDA and No. 4,110,456, imidazoles, including Sulfamoylimidazoles, an adrenergic blocking agent may be administered in one U.S. Pat. No. 4,021,556, pyrazolopyrimidines, pyrazolopy formulation or in different formulations. rimidinols and pyrazolopyrimidinediols; U.S. Pat. No. 0567 Examples of angiotensin II antagonists which may 4,032,522, trifluoromethylimidazoles; U.S. Pat. No. 3,988, be provided in combination with the ion channel modulating 324, heterocyclobenzo-thiadiazineSulfonamides, Japanese US 2005/01 19315 A1 Jun. 2, 2005 45
51054576, hydroxy or acyloxyalkylaminobenzothiadi inhibitor may be administered at the same time, or at azines; U.S. Pat. No. 3,960,854.7-mercapto (or thio) ben different times. COMPOUND A and a Xanthine oxidase Zothiadiazine-1,1-dioxides; U.S. Pat. No. 3,969,518,3-ha inhibitor may be administered via the same route or by loalkylbenzothiadiazine-1,1-dioxides; U.S. Pat. No. 3,951, different routes of administration. COMPOUND A and a 966, heterocycle-Substituted benzothiodiazines, Japanese Xanthine oxidase inhibitor may be administered in one 51006992, dihydrothiazoloadenines; Japanese 51006993, formulation or in different formulations. imidazoadenines and pyrimidinoadenines; French 2262977, formylaminoallylidenehydrazines, substituted with aryl 0572 The natriuretic peptide system includes A-type or groups; French 2262976, formamidrazones, substituted with atrial natriuretic peptide (ANP), B-type or brain natriuretic aryl groups, German 2410650, formamidraZones, isonicoti peptide (BNP), C-type natriuretic peptide (CNP) and D-type nyl pyrimidinones and the like; German 2410579, orotic natriuretic peptide (DNP). These similarly-structured pep acid hydrazide, and the corresponding nicotinic and isoni tides exert a wide range of effects on the kidney, heart and cotinic acid derivative; German 2509130, acryloylforma central nervous System. The A- and B-type natriuretic pep midrazones, pyririnidinones and the like; German 2410653, tides are Secreted predominantly from Storage granules in acylpyrazolocarboxamides; German 2508934, formylcar the myocardium of the atria and Ventricles of the human bamoylpyrazoles Substituted with heterocyclic and carbocy heart, respectively, and the main trigger for their Secretion is clic aryl groups, German 2410611, nicotinic acid hydrazide, the Stretching of the cardiac chambers regulated by Ven azapentadienylidene; German 2509094, aminoazapentadi tricular wall tension. Both ANP and BNP have profound enylidene hydrazine; German 2509049, morpholinoacry natriuretic, diuretic and vasodilatory effects on the body. An loyl-formamidraZones Substituted with various aryl groups, important feature of these natriuretic peptides is their inter German 2509175, Substituted 2-hydrazonomethyl-3-hy action with other neurohormonal Systems. In contrast with droxy-4-aza-2,4-pentadiene-nitriles; U.S. Pat. No. 3,892, loop diuretics and many vasodilators, natriuretic peptides 858,7-alkylsulfonyl-substituted-benzothiadiazine 1,1-diox cause inhibition rather than Stimulation of the renin-angio ides; German 2410614, heterocyclic N-acyl-N'-3-amino-2- tensin-aldosterone system. For example, ANP directly cyanoacryloyl) formamidrazones; U.S. Pat. No. 3,907,799, antagonizes the renin-angiotensin-aldosterone System by imidazopyrimidinediols; Japanese 50004039, salicylanil inhibiting renin Secretion, reducing ACE activity, and inhib ides; British 1403974, dioxo-6,6-azopurine; Japanese iting aldosterone release from the adrenal glands. Both ANP 49072298, 9-substituted palmatine derivatives; German and BNP also inhibit the release of endothelins, which are 2457127, haloimidazoles substituted with pyridyl and the potent vasoconstrictors that originate in the vascular endot like; Japanese 49127943, 4-(2-hydroxybenzamido)-salicylic helium, while ANP appears to reduce the levels of circulat acids, German 2418467, hydroxybenzanilides, Japanese ing catecholamines. They may also be able to reduce cardiac 49048664, hydroxyalkyl imidazoles; U.S. Pat. No. 3,816, ischemia and modulate vascular growth. 625,7-alkylsulfonyl-substituted benzothiadiazine-1,1-diox 0573. Examples of natriuretic peptides which may be ides; U.S. Pat. No. 3,816,626,3-pyridyl-1,2,4-benzothiadi provided in combination with the ion channel modulating azine-1,1-dioxides; U.S. Pat. No. 3,816,631,6-sulfamoyl-7- compounds described herein include, but are not limited to substituted-(3H)quinazolinones; German 2356690, pyrazolo ANP and BNP such as Nesiritide (Natrecor, recombinant 3,4-dpyrimidine N-oxides; German 234.4757, B-type brain natriuretic peptide). This list is not exhaustive, 2-cyanopyrimidine-4(1H)ones; German 2351126, 6-sulfa and additional natriuretic peptides known in the art are also moyl-4(3H)-quinazolinones; German 2343702, 4-mercapto contemplated. 1H-pyrazolo 3,4-dpyrimidine; German 2344733, 3-chloro 2-(hydrazonomethyl)-4-aza-2,4-pentadienenitriles; German 0574) In one example, COMPOUND A is used in com 234.4738, 2-hydrazonomethyl-3-hydroxy-aza-2,4-pentadi bination with one or more of the above listed natriuretic enenitriles; German 2224379, 7-3D-ribofuranosyl-4,6-dihy peptides. COMPOUND A and a natriuretic peptide may be droxypyrazolo 3,4-dipyrimidine; German 2318784, N-(2,4- administered at the same time, or at different times. COM dihydroxybenzoyl)-4-aminosalicylic acids, Japanese POUNDA and a natriuretic peptide may be administered via 48067491, formyluracils; German 2313573, 7-mercapto-1, the same route or by different routes of administration. 2,4-benzothiadiazine 1,1-dioxide; German 2313636, ben COMPOUND A and a natriuretic peptide may be adminis Zothiadiazines Substituted with heterocyclic groups, German tered in one formulation or in different formulations. 1966640, 4-hydroxypyrazolo 3,4-dpyrimidines; French 0575 Examples of metabolic modulators, which may be 2143577, 3-(2-chlorobenzoylamino)-benzoic acid deriva provided in combination with the ion channel modulating tives; German 2255247, 5-(5-indanyloxy)tetrazoles; Ger compounds described herein include, but are not limited to man 2236987, pyrazolo 1,5-apyrimidines; French partial fatty acid beta-oxidation (pFOX) inhibitors such as 2109005, 4-(2-quinoxalinyl)-phenoxyacetic acid deriva trimetazidine and ranolazine, inhibitors of the mitochondrial tives, French 2081360, 2,5-disubstituted imidazoles; Ger carnitine palmitoyltransferase-1 (CPT-1) Such as etomoxir, man 2147794, 1,2,4-triazoles substituted with heterocyclic Oxfenicine and perhexyline, pyruvate dehydrogenase (PDH) and other aryl groups, German 1814082, allopurinol and activatorS Such as dichloroacetate and carnitine. This list is oxypurinol; German 1927136, 1-D-ribosylallopurinol; not exhaustive and additional metabolic modulators known French 4777, 4-mercaptopyrazolo 3,4-dpyrimidine; French in the art are also contemplated. 1480652, 4-oxo-5-alkylpyrazolo 3,4-dipyrimidines. This list is not exhaustive and additional XOIs known in the art 0576. In one example, COMPOUND A is used in com are also contemplated. bination with one or more of the above listed metabolic modulators. COMPOUND A and a metabolic modulator 0571. In one example, COMPOUND A is used in com may be administered at the same time, or at different times. bination with one or more of the above listed Xanthine COMPOUND A and a metabolic modulator may be admin oxidase inhibitors. COMPOUND A and a Xanthine oxidase istered via the same route or by different routes of admin US 2005/01 19315 A1 Jun. 2, 2005 46 istration. COMPOUND A and a metabolic modulator may tone, triamterine), Indacrinone, Muzolimine. This list is not be administered in one formulation or in different formula exhaustive and additional diuretics known in the art are also tions. contemplated. 0577 Examples of lipid/cholesterol modulating agents 0584) In one example, COMPOUND A is used in com which may be provided in combination with the ion channel bination with one or more of the above listed diuretics. modulating compounds described herein include, but are not COMPOUND A and a diuretic may be administered at the limited to Statins (atorvastatin, pravastatin, Simvastatin, lov same time, or at different times. COMPOUND A and a astatin), hypercholesterolemia-treating agents. This list is diuretic may be administered via the Same route or by not exhaustive and additional lipid?cholesterol modulating different routes of administration. COMPOUND A and a agents known in the art are also contemplated. diuretic may be administered in one formulation or in 0578. In one example, COMPOUND A is used in com different formulations. bination with one or more of the above listed lipid/choles 0585 Examples of additional sympatholytic agents terol modulating agents. COMPOUND A and a lipid/cho which may be provided in combination with the ion channel lesterol modulating agent may be administered at the same modulating compounds described herein include, but are not time, or at different times. COMPOUND A and a lipid/ limited to clonidine, methyldopa(Aldomet), Guanabenz cholesterol modulating agent may be administered via the (Wytensin), Guanfacine (Tenex), Dihydroergotamine Mesy same route or by different routes of administration. COM late, Ergotamine Tartrate, Caffine, reserpine, Propranolol POUND A and a lipid/cholesterol modulating agent may be (Inderal), Labetalol (Normodyne, Trandate). This list is not administered in one formulation or in different formulations. exhaustive and additional Sympatholytic agents known in 0579. Examples of anti-inflammatory agents which may the art are also contemplated. be provided in combination with the ion channel modulating 0586. In one example, COMPOUND A is used in com compounds described herein include, but are not limited to bination with one or more of the above listed sympatholytic glucocorticoids (GCs), non-steroidal anti-inflammatory agents. COMPOUND A and a sympatholytic agent may be drugs (NSAIDs) Such as aspirin, diclofenac, naproxen, administered at the same time, or at different times. COM indomethacin and ibuprofen, selective COX-2 inhibitors POUND A and a sympatholytic agent may be administered Such as celecoxib, rofecoxib, etoricoxib. This list is not via the Same route or by different routes of administration. exhaustive and additional anti-inflammatory agents known COMPOUND A and a sympatholytic agent may be admin in the art are also contemplated. istered in one formulation or in different formulations. 0580. In one example, COMPOUND A is used in com 0587. Other examples of antiarrhythmic agents which bination with one or more of the above listed anti-inflam may be provided in combination with the ion channel matory agents. COMPOUND A and an anti-inflammatory modulating compounds described herein include, but are not agent may be administered at the same time, or at different limited to ANP, Adenosine (Adenosine triphosphate, times. COMPOUND A and a anti-inflammatory agent may Adenosine, Adenocard, Adenosine Phosphate), Amiodarone be administered via the same route or by different routes of HCl (Amiodarone, Cordarone, Pacerone), Azimilide, Brety administration. COMPOUND A and an anti-inflammatory lium (Bretylium Tosylate, Bretylol, Bretylium Tosylate/ agent may be administered in one formulation or in different Dextrose), Diisopyramide (Norpace, Diisopyramide Phos formulations. phate), Encainide HCl (Enkaid, Encainide), Esmolol HCl 0581 Examples of vasodilators which may be provided (Brevibloc), Propranolol (Inderide, Propranolol HCl), in combination with the ion channel modulating compounds Flecainide (Tambocor, Flecainide Acetate), Lidocaine (Nuli described herein include, but are not limited to Hydralazine caine, Lidocaine HCl Viscous, Lidocaine HC/Dextrose, (Apresoline), Diazoxide, Minoxidil (Loniten), Sodium Xylocalne), Mexilitine (Mexitil, Mexilitine HCl), Mori Nitroprusside, Nitroprusside, Diazozide, Ifenprodil Tartrate, cizine (Ethmozine, Moricizine HCl), Procainamide (Pro-2, Dilazep Dihydrochloride, Cilostazol, Dipyridamole, Isosor Procan SR, Procan, Procanbid, Pronestyl), Propanfenone bide Dinitrate, Isosorbide Mononitrate, Nitroglycerin, (Rythinol, Propafenone), Proparacaine (Kainair), Tocain Sildenafil, Vardenafil, tadalafil (Cialis), alprostadil, Papav inde (Tonocard), Quinidine (Cardioquin, Quinagulate, Qui erine. This list is not exhaustive and additional vasodilators nideX, Cin-Quin, Duracquin, Quinora, Sk-Quinidine Sulfate, known in the art are also contemplated. Quinatime, Quinalan, Quinaglute, QuinideX Extentab, Qui nidine Sulfate, Quinidine Gluconate), Dofetilide (Tikosyn), 0582. In one example, COMPOUND A is used in com Ibutilide (Corvert), Sotolol (Betapace). This list is not bination with one or more of the above listed vasodilators. exhaustive and additional antiarrhythmic agents known in COMPOUND A and a vasodilator may be administered at the art are also contemplated. the same time, or at different times. COMPOUND A and a vasodilator may be administered via the same route or by 0588. The ion channel modulating compounds described different routes of administration. COMPOUND A and a herein (including COMPOUNDA) can be combined with vasodilator may be administered in one formulation or in one or more class III antiarrhythmic drugs. Class III anti different formulations. arrhythmics may include: amiodarone, Sotalol, ibutilide, azimilide, clofilium, dolfetilide, Sematilide, and d.l-Sotalol. 0583. Examples of diuretics which may be provided in These class III antiarrhythmics prolong QT interval. combination with the ion channel modulating compounds described herein include, but are not limited to thiazides and 0589. In one example, COMPOUND A is used in com related agents (hydrochlorothiazide, chlorthalindone, bination with one or more of the above listed antiarrhythmic methyclothiazide, hydroflumethiazide, metolaZone, chlo agents. The COMPOUND A and an antiarrhythmic agent rothiazide, methyclothiazide, quinethaZone, chlorthalidone, may be administered at the same time, or at different times. trichlormethiazide, bendroflumethiazide, polythiazide), loop COMPOUNDA and an antiarrhythmic agent may be admin agents (bumetanide, torSemide, ethacrynic acid, furo istered via the same route or by different routes of admin Semide), potassium-sparing agents (amiloride, Spironolac istration. COMPOUND A and an antiarrhythmic agent may US 2005/01 19315 A1 Jun. 2, 2005 47 be administered in one formulation or in different formula Surgery from hearts of patients undergoing cardiopulmonary tions. AS described, the ion channel modulating compounds bypass. Cells were isolated and whole-cell Voltage-clamped. described herein may be combined with other drugs, includ Experiments were performed at 22t1 C. IN was elicited by ing other antiarrhythmic drugs. Such as Class III antiarrhyth a pulse to -20 mV from a holding potential of -70 mV mic drugs. In one version, the ion channel modulating (pulse duration was 40 ms. Peak inward current was mea compounds (for example, COMPOUND A) may be safely sured in control and in the presence of 0.1, 1, 10, and 100 uM coadministered with Class III antiarrhythmic drugs. Example 19 illustrates co-administration of COMPOUNDA COMPOUND B. Symbols are meaniSE (n=4) and data was with a Class III antiarrhythmic drug. fit with a Hill equation. 0593. A second example used HEK293 cells stably EXAMPLES expressing human heart (hh1) Sodium channels that were whole-cell patch clamped to measure currents. Concentra 0590. In the examples below, ion channel modulating tion and rate-dependent inhibition of hH1 channels by compounds used are designated COMPOUND A, COM COMPOUND A was tested by applying depolarizing pulses POUND B and COMPOUND C, and ion channel modulat at 0.25, 1, 10, or 20 Hz in control or in the presence of 10, ing compounds may be referred to as "Atrial Selective 50, or 100 uM (FIG. 2). Antiarrhythmic Agents." Atrial Selective Agents,” or other 0594) Inhibition by COMPOUND A was found to be Similar terms. COMPOUND A is: concentration- and rate-dependent When pulse trains were applied at 20 and 10 Hz, the ICs values were 9+0.7 uM (Hill
coefficient=0.92+0.06) and 11+1.1 uM (Hill coefficient= OCH3 0.91+0.08) respectively. At reduced rates, 1 and 0.25 Hz, COMPOUND A was a less potent inhibiter producing half maximal current inhibition at 19+2.3 uM (Hill coefficient= % N OCH3 0.81+0.10) and 42+2.8 uM (Hill coefficient=0.70+0.05) II iOH respectively. Rate-independent hH1 channel inhibition was OHC determined by measuring the peak Sodium current for the first depolarization after a 1 minute rest in COMPOUND A Compound: COMPOUNDA and dividing by the control peak current. COMPOUND A Chemical name: (1R,2R)-2-(3R)-hydroxypyrrollidinyl-1 (3,4- produced tonic inhibition of hEI1 channels with an ICso dimethoxyphenethoxy)cyclohexane monohydrochloride value of 800+24 uM (Hill coefficient=0.42+0.004). Molecular formula: CH31NOHCI 0595 FIG. 2 shows a concentration- and frequency FW: 385.93 g/mol dependent inhibition of hH1 Sodium channels by COM POUND A. Cells were depolarized from -100 mV to -30 mV for 10 ms at rates of 0.25 HZ, 1 Hz, 10 Hz or 20 Hz. 0591 COMPOUND A refers to the R.R.R diastereomer Pulses were performed in control or in the presence of of 2-hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy COMPOUND A. Steady-state current traces were Superim )cyclohexane monohydrochloride. COMPOUNDB refers to posed in FIG. 2A (control) and 2B (10 uM COMPOUND a mixture of the R.R.R and S.S.R diastereomers of 2 A). Reduction in peak current at the test potential of -30 mV hydroxypyrrolidinyl-1-(3,4-dimethoxyphenethoxy)cyclo was normalized to control current at each frequency and hexane monohydrochloride, and COMPOUND C refers to a then plotted against the concentration of COMPOUND A as mixture of the R,R,R, S.S.R., R.R.S, and S.S.S diastereomers shown in FIG. 2C (filled symbols). To measure the tonic of 2-hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy inhibition, peak Sodium current for the first depolarization )cyclohexane monohydrochloride. after rest in COMPOUND A for 1 minute was divided by the control peak Sodium current, and this value was plotted Example 1 against the concentrations of COMPOUND A (open sym bols). Data were averaged from 4-6 cells for each point. An Example of a Compound Showing a Rate-Dependent Inhibition of INA Example 2 0592 FIG. 1 shows a rate- and concentration-dependent An Example Showing a Minimal Effect on Cardiac inhibition of Sodium current (IN) in human atrial myocytes QRS Duration in Human Volunteers is shown by by COMPOUND B. Human myocytes were obtained from the table below: Specimens of human right atrial appendage obtained during 0596)
EFFECT OF COMPOUND AON ORS DURATION IN HUMAN VOLUNTEERS (10 MIN AFTER INFUSION) Summary Measurement Statistic 0.1 mg/kg 0.25 mg/kg 0.5 mg/kg 1.0 mg/kg 2.0 mg/kg 4.0 mg/kg 5.0 mg/kg Placebo
QRS (ms) Mean 89.0 89.O 85.3 89.8 93.8 97.5 94.3 91.O S.D. 4.2 5.2 9.8 1.7 6.3 5.1 US 2005/01 19315 A1 Jun. 2, 2005 48
Example 3 obtained by averaging data from 6 Separate experiments. IC=13+1.0 uM and Hill coefficient=0.92+0.05. An Example Showing a Voltage-Dependent Inhibition of Sodium Channels Example 6 0597 FIG.3 shows a voltage-dependent block of hH1 by An example showing an inhibition of hERG COMPOUND A. Panel A shows a single experiment for channels at concentrations Greater than 1, 10, 20 which hH1 current amplitude is plotted for each recorded mM trace in response to escalating concentrations of Compound A when pulsed from a holding potential of -100 mV. 0602 HEK 293 cells stably expressing hERG channels Dose-response curves (FIG.3, panel B) show that at holding were whole-cell patch clamped to measure currents. Peak potentials of -60 mV, -80 mV, -100 mV, and -120 mV the hERG tail-current amplitude was measured in control and in ICs values were 31+1 uM (Hill coefficient=0.92+0.06; 3, 10,30, 100, and 300 uM COMPOUNDA (FIG. 6A) using n=5), 43+8 uM (Hill coefficient=0.98+0.03; n=5), 60+4 uM the voltage protocol illustrated in FIG. 6B every 15 seconds. (Hill coefficient=0.85+0.06; n=3) and 107+11 uM (Hill Cells were held at -80 mV and stepped to +20 mV for 4s coefficient=0.89+0.03; n=3). Cells were held at either -120 followed by a step to -50 mV for 4s. mV, -100 mV, -80 mV, and -60 mV and stepped to -30 mV 0603 FIG. 6 shows a concentration-dependent inhibition for 6 ms (1 Hz). Cells held at -60, -80 and -100 mV of hERG channels. In FIG. 6A, the decline in peak hERG received a 2 ms pulse to -120 mV to relieve channel tail current amplitude in the presence of escalating concen inactivation prior to the -30 mV step. trations of COMPOUND A. Data are from a single experi ment and are not leak Subtracted. In FIG. 6B, full current Example 4 traces (leak subtracted) in the presence of 1, 3, 10, 30, 100, 300 uM (same cell as A). Cells were depolarized from a An Example Showing an Inhibition of Potassium holding potential of -80 mV to +20 mV for 4 S and stepped Channels at Micromolar Concentrations back to -50 mV for 5s, with an inter-pulse interval of 15 S. FIG. 6C shows a dose-response curve obtained by averag 0598 FIG. 4 shows a concentration-dependent inhibition ing data from 6 Separate experiments. ICso=21+3 and Hill of Kv4.2 at 1 Hz. Currents were recorded at 1 Hz with coefficient=0.96-0.04. depolarizations of 40 ms duration from -80 mV to +60 mV. Panel A shows Kv4.2 currents, after reaching the steady Example 7 State, from a single cell in control and in the presence of 1, 3, 10, 30, 100 and 300 uM COMPOUND A. Reduction in An example of preferential block of hERG and/or Steady-state current integral (relative to control) at the test Kv1.5 over Kv4.3 in HEK Cells potential of +60 mV was plotted against the concentration of 0604 HEK cells stably expressing Kv4.3 channels were COMPOUND A (panel B). Data were averaged from 6 cells. whole-cell patch clamped to measure currents. Current inhi Solid lines were fitted to the data using a Hill equation. The bition was tested at a range from 3-300 uM COMPOUNDA ICso value was 38+4 uM, and the Hill coefficient was (FIG. 7). The decline in steady-state integrated current was O840.06. measured at each concentration. Example 5 0605 COMPOUNDA is approximately 1.5-3 times more potent for hERG and/or Kv1.5 channels than for Kv4.3 An example showing an open-channel inhibition of channels. Kv1.5 0606 FIG. 7 shows a concentration-dependent inhibition of Kv4.3 channels at 1 Hz. Currents were recorded at 1 Hz 0599 HEK 293 cells stably expressing Kv1.5 channels with depolarizations of 40 ms duration from -80 mV to +60 were whole-cell patch clamped to measure currents. Inhibi mV. Panel Ashows Kv4.3 currents, after reaching the steady tion of KV1 0.5 channels was tested using a range of state, in a single cell (control) and at 1, 3, 10, 30 and 100 uM concentrations of COMPOUND A from 3 to a maximum of COMPOUND A. Reduction in steady-state current integral 300 uM (FIG. 5). Cells were held at -80 mV and pulsed to (relative to control) at the test potential of +60 mV was +60 mV for 200 ms at 1 Hz. plotted against the concentration of COMPOUND A (panel 0600 The presence of COMPOUND A caused a more B). Data were averaged from 6 cells. The ICso value was pronounced decline in the Steady-state current amplitude 30+5 uM. than the early current (FIG. 5B) indicating that the channel is preferentially inhibited in the open state. Inhibition of Example 8 Kv1.5 channels with COMPOUNDA occurred with an ICso value of 13+1.0 uM (Hill coefficient=0.92+0.05; n=6). An Example of Prolonged Atrial Refractoriness, Atrial Selectivity, and Neutral Ventricular Effect in 0601 FIG. 5 shows the concentration-dependent inhibi Humans tion of Kv1.5 channels by COMPOUNDA at 1 Hz. FIG. 5A illustrates the decline in Steady-state current amplitude in the 0607 All currently available antiarrhythmic drugs used presence of escalating concentrations of COMPOUND A. for atrial arrhythmias act on Ventricular, as well as atrial FIG. 5B shows full current traces (leak subtracted) recorded tissues, thus predisposing to proarrhythmia. Atrial Selective in the presence of 3, 10, 30, 100, and 300 uM (same cell as agents mainly affect atrial action potential repolarization in A). Cells were held at -80 mV and stepped at 1 Hz to +60 only; COMPOUNDA is an investigational drug that inhibits mV for 200 ms. FIG. 5C shows a dose-response curve K" channels important in human atrial repolarization and US 2005/01 19315 A1 Jun. 2, 2005 49 can terminate acute atrial fibrillation in humans (at cumu is ramped back to -100 mV, a late inward current, I, lative doses of 5 mg/kg). COMPOUND A had a neutral develops. I reaches its peak at voltages within the range effect on Ventricular repolarization. of half repolarization, between -20 mV and -40 mV. A 0608 Two (2) mg/kg iv COMPOUND A was adminis Sustained current (I) can be measured from the current tered over 10 min, followed by 0.5 mg/kg/h for 35 min, to during the constant portion of the Voltage Step. In 6 experi 10 patients following electrophysiologic study (8 also had ments, 30 uM COMPOUND A inhibited I, 61+4% and RF ablation). At baseline and 25 min after the start of drug I, 70+4%. COMPOUND A inhibits the late component of infusion, atrial, Ventricular and AV nodal refractory periods Sodium current active during depolarization approximately at various cycle lengths (AERP600, 400, 300 msec and equipotently to (or slightly more than) the early Sodium VERP600, 400 msec and WCL, respectively) and conduc Current. tion times in the atrium, AV node, and Ventricle were 0614 FIG. 8 shows an example of the TTX- and COM measured. All patients had normal hearts and were free of POUND A-sensitive components of the early and late cardioactive drugs. Sodium current observed during a step/ramp protocol. In 0609 Subjects were 52+12 years of age, 60% male. Heart FIG. 8A, COMPOUND A- and TTX-sensitive currents rate and blood pressure were unaffected. obtained by digitally Subtracting the current obtained in the
TABLE 2
RESULTS
AERP600 AERP4OO AERP3OO VERP6OO VERP4OO WCL
Baseline 2O6 32 1.88 - 31 180 - 31 251 - 19 224 20 396 - 113 COMPOUNDA 22O 34* 195 24 181 16 248 - 22 227 16 388-94
All measures are in msec. *P & O.O2
0610 AH intervals were prolonged from 115+42 to presence of either 30 uM COMPOUNDA or COMPOUND 161+144 msec (p<0.05); QT intervals did not change sig A plus 30 uM TTX respectively from the current obtained nificantly at 600 msec (365+27 to 361+26 msec) or 400 pre-drug. In FIG. 8B, the COMPOUND A- and TTX msec atrial pacing (328+29 to 325+9 msec). Intraatrial, sensitive I current traces that are off-scale in A. Current His-Purkinje and intraventricular conduction (QRS dura traces in A and B are averages of 45 raw traces. tion) intervals were unaffected by COMPOUND A. Five patients had a total of 9 episodes of transient atrial tachy Example 10 cardia (CL 272+48.9 msec) at baseline, lasting 26.1+19.0 Sec, induced with AA- or A burst pacing; after COM An Example Showing a State-Dependent Inhibition POUNDA, 3 patients had 1 episode each (4.4+4.3 sec). No of Sodium Channels (FIG.9) patient had any adverse effect. 0615. HEK cells stably expressing hH1 channels were 0611) At the relatively low dose studied, COMPOUNDA whole-cell patch clamped to measure currents. Inactivated prolongs atrial refractorineSS and AV nodal conduction and state inhibition of hH1 Sodium channel current by COM Suppresses inducible atrial tachycardia, without effect on POUND C (50 uM), lidocaine (50 uM) and flecainide (5 Ventricular tissue or AV nodal refractoriness. AlM) was examined by delivering depolarizing prepulses from -100 mV to -30 mV for varying durations (10, 100, Example 9 500 ms) followed by a single test pulse to the same voltage at varying time intervals. An Example Showing Inhibition of Early and Sustained Sodium Currents 0616) Lidocaine, a predominantly inactivated-state blocker, produced enhanced inhibition when prepulses of 0612 hH1 Sodium channels were stably expressed in longer duration were applied. Such maneuvers increase HEK cells. K" in internal and external physiological solu channel inactivation and enhanced hEI1 inhibition by tions were replaced with Cs to eliminate endogenous K' lidocaine. By comparison, COMPOUND C did not inhibit current and to maximize Sodium current (IN) measure hH1 channels to a greater extent when longer prepulses were ments. In whole-cell configuration, cells were Voltage applied. Similar results were obtained with flecainide, an clamped using the protocol illustrated in FIG. 8. Total IN activated-state blocker (FIG. 9D), suggesting that COM (TTX-sensitive current) was measured by Subtracting the POUND C preferentially inhibits the activated channel. current recorded in the presence of 30 uM TTX from the 0617 FIG. 9 illustrates a protocol to test level of inac control current (absence of drug). COMPOUND A-sensitive tivated state inhibition by COMPOUND C, flecainide, and currents were measured by Subtracting the current recorded lidocaine. In the presence of 50 uM COMPOUND C, 50 uM in the presence of 30 uM COMPOUND A from the control lidocaine, or 5 uM flecainide, pre-pulses of varying length Current. (-100 mV to -30 mV) were applied: 10, 100, or 500 ms. 0613 Components of the TTX-sensitive current are evi Following a prepulse, a Single test pulse was applied at dent in FIG.8. An early inward current, Isay, results from varying time intervals. Peak current amplitude resulting stepping the cell from -100 mV to +20 mV. As the voltage from the test pulse is plotted as a function of interval US 2005/01 19315 A1 Jun. 2, 2005 50 between prepulse and test pulse. Inhibition by COMPOUND goats, and then the effects of COMPOUND A (0.2 mg/kg/h C is not enhanced by longer prepulses indicating that it does i.v.), were evaluated on atrial refractory period (RP), win not inhibit hI1 channels in the inactivated State. dow of inducibility (WOI) and AF duration. In a separate series of 6 goats, the effects of COMPOUNDA on persistent Example 11 AF (2-16 weeks) were evaluated. An example showing rapid association and 0623 COMPOUND A reversed ER in remodeled atria dissociation from Sodium Channels (48 h AF): COMPOUND A prolonged left atrial RPat 300 ms CL from 110+14 to 136+27 ms. Similar effects were seen 0618 FIG. 10 shows that hH1 sodium current traces at the right atrium and Bachmann's bundle. COMPOUNDA exemplify minor changes in waveform kinetics in the pres decreased the median AF duration from 120 to 70S. Lower ence of COMPOUND A. Steady-state current traces were and upper limits of vulnerability increased similar to RP, recorded in control (trace 1) and in the presence of 30 uM thus WOI remained unchanged (39+9 ms at baseline and COMPOUNDA (trace 2). Currents were generated using the 44+29 ms after drug). same protocol as in FIG. 9. To compare the time to peak and current relaxation kinetics under each condition, trace 2 was 0624. In the goats with persistent AF, COMPOUND A normalized to trace 1. The resulting normalized waveform is prolonged atrial fibrillation cycle length (AFCL) from trace 3. Note the time to peak and relaxation kinetics in trace 107+4 to 156+10 ms (p<0.001) and slowed the ventricular 3 are largely unchanged from trace 1 and therefore trace 2 response rate from 327+30 to 539-114 ms (p<0.01). In Simply represents a Scaling down of the control current keeping with the slowed Ventricular rate, QT-time was waveform. 176+12 ms at baseline and 190+16 ms (p=N.S.) at cardio version. ORS increased 14.9% at this time. COMPOUND Example 12 A cardioverted AF in all 6 goats after 62+16 min infusion. 0625 FIG. 39 shows the effect of persistent AF (2-16 Inhibition of Acetyl Choline Dependent or weeks) in goats in tabular form. COMPOUND A terminated Adenosine Dependent Potassium Channels (Kir3) at AF and increased atrial fibrillation cycle length (AFCL) in Micromolar Concentrations goats (n=6). COMPOUND A prolonged AFCL from 105+4 to 156+10 ms and slowed the ventricular response rate from 0619) Kir3 or I was inhibited by COMPOUND A 3.04+28 to 525-96 ms. In keeping with the slowed ventricu with an ICso of between 1 and 50 uM (at 0.1 Hz). Ikach in lar rate, OT-time was 163-19 ms at baseline and 189-16 ms guinea pig atrial cells was inhibited by COMPOUND A with at cardioversion. QRS increased 15+10% at this time. COM an ICso of approximately 10 uM (at 0.1 Hz, FIG. 11). POUND A cardioverted AF in all 6 goats after 62+6 min 0620 FIG. 11 illustrates a concentration-dependent infusion. block of Ik by COMPOUND A in isolated guinea pig 0626. As a comparison, FIGS. 33 to 38 show the effect of atrial myocytes at 0.1 Hz. FIG. 11A shows current traces COMPOUND A on dog, primate and rabbit. For example, from one cell before ACh perfusion, after 100 nM ACh FIG. 33 shows that COMPOUND A slows atrial conduction perfusion, application of increasing concentrations of COM only at fibrilatory cycle lengths. The percent change in POUND A (3, 10, 30, 100 uM), washout of all compounds, conduction time is shown for different basic cycle lengths and application of 100 uM BaCl plus 100 nM ACh. Ven (BCL). FIG. 34 shows that COMPOUNDA has a substan tricular myocytes were depolarized at 0.1 Hz from a holding tial dose-dependent effect on rabbit Purkinje fiber APD, potential of -80 mV to -40 mV for 100 ms followed by a particularly compared to dofetilide. Similarly, FIG. 35 voltage ramp from -20 mV to -120 mV over 1s. FIG. 11B shows that COMPOUNDA reverses the effect of the dofetil shows reduction in peak Iki, current (relative to control ide widening of Purkinje fiber APD compared to vehicle current in the presence and absence of ACh) at the end of the (DMSO). FIG. 36 shows that COMPOUND A prolongs ramp was plotted against the concentration of COMPOUND APD in the ratby, in part, blocking I and I. This Species A. Solid lines were fit to the data using a Hill equation. The is relevant to human atrial action potentials and is not meant ICs for inward current (measured at -120 mV) was 10 uM to be representative in any form of effects on human or and the Hill coefficient was 1.3. Data shown are meantSEM primate ventricular repolarization. FIGS. 37 and 38 show (n=6). the atrial selectivity of COMPOUND A in both primates (FIG. 37) and dogs (FIG. 38). At 300 ms. BCL, increasing Example 13 doses of COMPOUND A resulted in increasing atrial, but not ventricular, effects. COMPOUND A reversed electrical An Example Showing an Acute Reversal of remodeling as evidenced by Selective increases in ER atria Electrical Remodeling and Cardioversion of RP and prolonged AFCL in persistent AF. These effects Persistent AF in the Goat resulted in cardioversion of persistent AF (2-16 weeks) in 0621. Inhibition of I and I can prolong the atrial goats. refractory period (RP) after electrical remodeling (ER). The aminocyclohexyl ether antiarrhythmic, COMPOUNDA, is a Example 14 mixed IN/I/I blocker. An investigation of the in vivo electrophysiological mechanisms of COMPOUND A in ER An Example Showing a Lack of Rate and atria and its efficacy for cardioversion in a persistent AF Use-Dependence on Kv1.5 model was carried out. 0627 HEK 293 cells stably expressing Kv1.5 channels 0622 Electrical remodeling (ER) was induced by repeti were whole-cell patch clamped to measure currents. Rate tive induction of AF over 48 h in 6 instrumented, conscious and use-dependent inhibition of Kv10.5 channels by COM US 2005/01 19315 A1 Jun. 2, 2005
POUND A was tested by applying depolarizing pulses at p=0.0014), and 4) median time to achieve conversion (14 vs. 0.25, 1, 10, or 20 Hz in control or in the presence of 5 uM 162 min; p=0.016). COMPOUND A converted acute atrial COMPOUND A (FIG. 13). fibrillation to sinus rhythm. 0628. As illustrated in FIG. 12, little resting inhibition was apparent with COMPOUND A. When the rate was then 0632 COMPOUND A is a mixed frequency-dependent increased in a stepwise fashion to 0.25, 1, 10 and 20 Hz, little Na" and atria-preferential K" channel blocker. In animal Steady-state rate-dependent current reduction could be models of AF, COMPOUND A is effective in terminating observed (grey bars). To test the use-dependence of COM and preventing relapse of AF. COMPOUND A selectively POUND A on Kv1.5, the current traces during changes of prolongs atrial refractory periods without significant effects rate were examined and Steady-state current amplitude was on ventricular refractoriness or OT intervals. plotted as a function of time (FIG. 13). Here currents can be Seen when the pulse rate was changed from rest to 0.25 Hz, 0633 Patients in this study had to have a rhythm of then to 1, 10 and 20 Hz. Note that there was no excess sustained atrial fibrillation (AF) with a duration of 3 to 72 h current reduction in the presence of COMPOUND A (open at the time of randomization. Patients were randomized to circles) over that seen in control (filled circles) when the one of three groups and in each group received up to two rates were changed. This suggests that COMPOUND A is 10-min intravenous infusions, separated by 30 min. Infu not use-dependent on Kv1.5. sions were placebo followed by placebo, 0.5 mg/kg followed 0629 FIG. 12 shows a lack of rate-dependent inhibition by 1.0 mg/kg COMPOUND A, or 2.0 mg followed by 3.0 of Kv1.5 by COMPOUND A. Pulse trains consisted of mg COMPOUND A. The second dose in each group was depolarizations of 40 ms duration from -80 mV to +60 mV administered only if AF was present 30 min after completion applied at 0.25 HZ, 1 Hz, 10 Hz or 20 Hz in the presence of of the first dose. Doses for patients weighing >113 kg were 5uM COMPOUNDA. Pulses were applied until the current capped as if the patient weight was 113 kg. levels reached Steady-State. Reduction in peak current at the test potential of +60 mV was normalized to control current 0634. A Holter rhythm strip continuously monitored at each frequency. To measure resting inhibition, the peak ECG, vital signs (blood pressure and heart rate, BP and HR, KV1.5 current during the first depolarization after rest in respectively) and O Saturation were recorded every 2 min drug was divided by the control peak Kv1.5 current. from the start of infusion to 5 min after, as well as at 15, 30, 0630 FIG. 13 shows a lack of use-dependent inhibition 60, 120, 240, 360, and 480 min and at discharge and of Kv1.5 by COMPOUND A. In each experiment, Kv1.5- one-week follow-up. Twelve-lead ECGs were obtained expressing HEK 293 cells were stimulated from rest in before dosing and every minute during infusion to 5 min control solutions (closed circles) at 0.25 Hz (A). Subse after, as well as at 15, 30, 60, 120,240,360, and 480 min and quently, the rate was increased to 1 Hz (B), then 10 Hz (C), at discharge, 24 h and one-week follow-up, and at the time and lastly 20 Hz (D). The stimulation sequence was then of arrhythmia termination or significant rhythm changes. repeated in the presence of 5 uM COMPOUND A (open Venous blood samples were drawn for COMPOUND A circles). Steady-state current amplitude was normalized to plasma concentrations at 0, 15, 30, 120, 240, 480 min that in the first pulse and data from 4 Separate cells were averaged. Most often error bars fell within the points. No discharge and at AF termination or Significant adverse Significant differences were found between currents in the eVentS. steady-state at the different rates. Thus, COMPOUND A is 0635 Fifty-five patients were evaluated for efficacy. Data not rate- or use-dependent on Kv1.5 channels. are presented as meantSD, median with interquartile range Example 15 (IQR), all tests were performed as two sided and 95% confidence interval (CI) were produced; p<0.05 was con Treatment of Acute Atrial Fibrillation sidered Statistically Significant unless Stated otherwise. 06.31 This was a randomized, double-blind, step-dose, Analysis of the relationship between termination of AF and placebo-controlled, parallel group Study. Fifty-six patients treatment was performed using a chi-square analysis. In with atrial fibrillation of 3 to 72 h duration were randomized cases of Small cell frequencies, the Fisher's exact test was to one of two COMPOUND A dose groups or to placebo. used. A Cochran-Armitage test Statistic with table Scores The two COMPOUND A groups were RSD-1 (0.5 mg/kg was used to test the ascending dose evaluation of efficacy. followed by 1.0 mg/kg) or RSD-2 (2.0 mg/kg followed by 3.0 mg/kg), doses given by intravenous infusion over 10 0636. The time to conversion from the start of the first min. The primary endpoint was termination of atrial fibril infusion was analyzed by the Cox regression method of lation during a 10-min infusion or the Subsequent 30-min. event time analysis and one-way ANOVA. Assessment of Secondary endpoints included the number of patients in the Significance of time point values and mean change from sinus rhythm at 0.5, 1 and 24 h post-infusion and time to baseline to each follow-up reading of ECG intervals (QRS, conversion to sinus rhythm. RSD-2 dose showed significant QT, QTc), BP, and HR were made within dose groups using differences over placebo in: 1) termination of atrial fibril paired t tests, and comparisons among dose groups were lation within 30-min 61% vs. 5%; p=0.0003); 2) patients in made using a one-way ANOVA. sinus rhythm at 30 min post-dose (56% vs. 5%; p=0.0008); 0637 Demographic characteristics for all patients in the 3) patients in sinus rhythm 1 h post-dose (53% vs. 5%; study are shown in table 3. US 2005/01 19315 A1 Jun. 2, 2005 52
TABLE 3
DEMOGRAPHIC CHARACTERISTICS FOR PATIENTS IN EACH STUDY GROUP
COMPOUNDA COMPOUND A Placebo (0.5 and 1.0 mg/kg) (2.0 and 3.0 mg/kg) (n = 20) (n = 18) (n = 18) Gender, n (%) Male 14 (70.0) 10 (56) 10 (56) Age (yrs) Median 64.0 (35–83) 67.4 (24–85) 60.8 (25–88) (range) Duration of AF (h) Median 13.3 (5.1-59.4) 11.5 (5.7–67.2) 19.5 (5.1-70.4) (range) Previous AF history, 75% 61% 44% n (%) Lone AF (%) 35% 28% 39% Hypertension (%) 45% 72% 56% Diabetes (%) 25% 28% 17% Concomitant - 75% 61% 67% blocker (%) Concomitant ACE-I 30% 28% 22% (%) Concomitant 30%b 22% 33% Dilt?verap (%) Concomitant digitalis 30% 22% 11% (%) ACE-I = angiotensin converting enzyme-I; Dilt?verap = diltiazem?verapamil.
0638 Baseline clinical characteristics were similar across 0642. The median time to conversion to sinus rhythm groups except that patients in the placebo group tended to from the start of the first infusion in the eleven responders more frequently report AF in the past than in the COM in the RSD-2 group was 14 min (range, 3 to 871 min; POUND A dosed groups. p=0.016) compared to the five spontaneous responders in the 0639 FIG. 15 shows conversion efficacy, including placebo group with a median time of 162 min (range, 58 to cumulative percentage of patients terminating atrial fibril 1119 min). The median time to conversion to sinus rhythm lation (AF) after infusions of placebo, 0.5 and 1 mg/kg from the start of the first infusion in the five eventual COMPOUND A or 2.0 and 3.0 mg/kg COMPOUND A, in responders in the RSD-1 group was 166 min (range, 1 to 332 patients with recent onset AF. Efficacy was significantly min; p=0.886 vs. placebo). higher after 2+3 mg/kg COMPOUND A than after placebo 0.643. The median time to termination of AF was 11 min (p=0.0003) and was significantly different between the two after start of the first infusion (range, 3 to 58 min) in the COMPOUND A (p=0.0018) dosing regimens. The median RSD-2 group. In fact, all the responders in this group time for termination of AF was 11 min from the start of the reached primary end-point during drug infusion or within 10 first infusion in the COMPOUND A treatment groups. min of the last infusion. One of the eleven responders in this 0640 The cumulative AF termination within 30 min of group converted from AF into atrial flutter and Subsequently infusion was 61% (11 of 18 patients) after 2+3 mg/kg converted to sinus rhythm 14.5 h later. COMPOUND A infusion, 11% (2 of 18 patients) after 0.5+1.0 mg/kg COMPOUND A and 5% (I of 19 patients) 0644) Table 4 shows the ECG effects of COMPOUNDA. after placebo-placebo. Paired comparisons indicated a Sta Infusion of COMPOUND A did not significantly prolong tistically significant difference (p=0.0003) between placebo QTc or QRS intervals compared to placebo. There was no and the RSD-2 group. There was no significant difference in difference in QT and QTc intervals between placebo the Success rates between the RSD-1 group and placebo. Of (389-31 ms and 414+16 ms) and RSD-2 treatment (366+28 the 11 AF terminations in the RSD-2 group, eight terminated ms and 427+19 ms) using the first available ECG records on the first infusion. after conversion to Sinus rhythm. 0641. The number of patients in sinus rhythm at 30-min TABLE 4 post-infusion was 56% (10 of 18 patients) in the RSD-2 group, 11% (2 of 18 patients) in the RSD-1 group and 5% OTC AND ORS INTERVALS AND HR VALUES FOR PATIENTS (I of 19 patients) in the placebo group. The number of INEACH STUDY GROUP patients in sinus rhythm at 1 h post infusion was 53% (9 of COMPOUND A COMPOUND A 17 patients) in the RSD-2 group, 11% (2 of 18 patients) in (0.5 and (2.0 and P the RSD-1 group, and 5% (I of 19 patients) in the placebo Time Period Placebo 1.0 mg/kg) 3.0 mg/kg) Value group. Patients in sinus rhythm (excluding those electrically QTC (MSEC) cardioverted) at 24 h post infusion was 79% (11 of 14 patients) in the RSD-2, 56% (5 of 9 patients) in the RSD-1 Predrug baseline 2O 16 17 (n) compared to 50% (5 of 10 patients) in the placebo group. meant SD 424 - 6 417 6 434 7 O.233 Only the difference between RSD-2 and placebo was sta End infusion 1 (n) 19 17 17 tistically significant at 30 min (p=0.008) and at 1 h meant SD 430 - 5 419 6 449 9 O.O66 (p=0.0014). US 2005/01 19315 A1 Jun. 2, 2005 53
premature beats were Seen in two patients and Sinus brady TABLE 4-continued cardia in another patient in the RSD-2 group. Other adverse events occurring with a similar frequency among treatment OTC AND ORS INTERVALS AND HR VALUES FOR PATIENTS groups were nervous System disorders, general disorders and INEACH STUDY GROUP infections. COMPOUND A COMPOUND A 0649 Serious adverse events were reported in five (0.5 and (2.0 and P patients (four in the placebo group and one in the RSD-1 Time Period Placebo 1.0 mg/kg) 3.0 mg/kg) Value group). A transient cerebral ischemic attack occurred 1 day End 16 7 11 after conversion in a placebo treated patient with a thera infusion 2 (n) peutic international normalized ratio (INR) at the time of meant SD 436 - 8 414 + 11 447 - 17 O.691 conversion. Severe bradycardia and hypotension immedi QRS (MSEC) ately following conversion occurred in one patient, pulmo Predrug baseline 2O 7 18 nary edema in another patient and recurrent AF in the fourth (n) meant SD 87 - 2 83 3 86 3 O.823 placebo patient. One patient in the RSD-1 group experi End infusion 1 (n) 19 7 17 enced ventricular fibrillation, which was attributed to an meant SD 89 2 86 3 95 3 O.150 asynchronous discharge during an electrical cardioversion End infusion 2 (n) 16 7 11 attempt performed 1 h after receiving the Second infusion. meant SD 88 2 90 - 6 99 - 5 O.12O HEART RATE (BPM) 0650. Within the study period (24 h) electrical cardiover sion was attempted in nine of 19 (47%) placebo treated, nine Predrug baseline 2O 6 17 (n) of 18 (50%) RSD-1 treated and four of 18 (22%) RSD-2 meant SD 112 - 6 101 6 108 6 0.585 treated patients and was Successful in eight (89%), nine End infusion 1 (n) 19 7 17 (100%) and four (100%) patients, respectively. meant SD 115 - 6 104 - 7 985 O.O45 0651 FIG. 16 shows a pharmacokinetic analysis of the End infusion 2 (n) 16 7 11 meant SD 109 6 107 6 104 6 O.6O1 data for COMPOUNDA, and shows plasma concentrations of COMPOUND A after infusion in patients dosed at 2 mg/kg i.v. (filled inverted triangles) and those additionally 0645. There were no statistically significant differences dosed at 3 mg/kg i.v. (filled circles). COMPOUND A doses in ECG intervals after infusion between groups. Heart rate were infused over 10 min as indicated in the text. Initially a was decreased after 2 mg/kg COMPOUND A (p<0.05), 2 mg/kg infusion was given and if required an additional 3 reflecting the number of patients who converted to Sinus mg/kg was infused 30 min later in the RSD-2 group. Time rhythm in this group. is shown relative to the end of the first infusion (T1). 0652) Mean peak COMPOUND Aplasma levels were 5.8 0646 There were no clinically significant changes from Aug/mL (range: 4.0 to 8.6 ug/mL) in the patients that received baseline in Systolic blood preSSure, and there were no both the 2.0 and 3.0 mg/kg infusions of COMPOUNDA and changes in blood preSSures that were Substantially different 1.9 tug/mL (range: 0.1 to 3.4 ug/mL) in those that received from those Seen in the placebo group. There were two both 0.5 and 1.0 mg/kg COMPOUNDA. Maximum plasma Significant cases of hypotension reported in the placebo levels were seen at the end of the second infusion. Plasma group and one mild case of transient hypotension in the drug levels at 24 h post-infusion were below the limit of RSD-2 group. Clinically Significant treatment-related detection (5 ng/mL) in the majority of patients who received decreases in mean heart rate from baseline (mean: 106 beats RSD-1. Similarly, negligible plasma levels were seen at 24 per min) occurred in patients administered the RSD-2 dose, h in the RSD-2 group; mean plasma levels were 0.017 starting at T=15 min (mean: 90 beats per min). This likely ug/mL (range: <0.005 to 0.028 ug/mL). In those patients that reflected the conversion of Several patients to normal sinus received only the 2 mg/kg infusion, mean peak plasma levels rhythm. at the end of infusion were 2.6 ug/mL (range: 1.4 to 4.5 0647. A total of thirty-nine patients experienced 122 Aug/mL). The median plasma level at the time of AF con adverse events over the course of the Study, with a similar version in these patients was 1.3 ug/mL (range: 1.1 to 3.5 incidence of events among the three treatment groups. The Aug/mL). The mean terminal elimination half life in these majority of adverse events were of mild or moderate inten patients was 3.1 h (range: 1.7 to 5.4 h). sity. There were four mild adverse events that occurred in 0653. This study demonstrated that the upper dose of two patients considered either definitely or probably related COMPOUND A (2+3 mg/kg) rapidly and effectively termi to study drug. Both patients were in the RSD-2 dose group: nated AF compared to lower dose COMPOUND A and one patient reported paraesthesia, and one patient reported placebo. There were no Serious adverse events associated paraesthesia, nausea, and hypotension. with COMPOUNDA, and observed SAEs were more com 0648. The most common adverse events experienced in mon in the placebo group. In contrast to other antiarrhythmic this Study were cardiac disorders, reported by Seven patients drugs used for conversion of acute AF, there were no (35.0%) in the placebo group, four patients (22.2%) in the instances of drug related proarrhythmia. While these initial RSD-1 group, and three patients (16.7%) in the RSD-2 findings will require confirmation in larger Scale clinical group. In addition to the Serious adverse events discussed trials, this Safety profile coupled with an efficacious and below, the cardiac disorders in the placebo group included rapid onset confirms that COMPOUND A is a promising two patients with non-Sustained Ventricular tachycardia and new agent for the medical conversion of acute AF. a patient with Ventricular premature beats. Ventricular pre 0654) COMPOUND A shows a higher net efficacy (61% mature beats were also seen in two patients and Sinus to 5%=56%) for conversion of recent onset AF within 2 h of bradycardia in one patient of the low dose group. Ventricular eXposure. US 2005/01 19315 A1 Jun. 2, 2005 54
0655 This randomized controlled trial provides evidence 0659 Intracellular Voltage recordings were determined as for the efficacy of this atrial specific, Na"/K"channel block follows: ing agent for the treatment of AF. Intravenous COMPOUND A (2+3 mg/kg) was effective in rapidly terminating AF and 0660 hearts were excised from female New Zealand was not associated with any drug induced proarrhythmia or white rabbits 2-2.5 kg any Serious adverse event. 0661 a single cut was made along the Septum to expose the endocardial Surface of the left ventricle Example 16 and the intervening Purkinje fibers 0662 a strand of Purkinje fibers was selected and Termination of EADS and Prevention of TDP in a excised from the Ventricular tissue and placed in a Rabbit Model tissue bath, bubbled with 95% O/5% CO 0656) COMPOUND A is an atrial fibrillation converting 0663 stable impalements were made with a floating agent that exhibited mixed Sodium and potassium channel sharp electrode (10-20 Mohms) blocking activity (Nav1.5, Kv1.5, Kv4.3, hERGICso values: 33, 9, 30, 20 uM). COMPOUND A (30 uM) attenuated the 0664 stock solutions of dolfetilide, lidocaine and action potential duration (APD) prolonging effects induced COMPOUND A were dissolved in DMSO by dofetilide (300 nM) in rabbit Purkinje fibers, while 0665 Current recordings were determined as follows: COMPOUND A alone had no significant effect on APD. Class III agents induce EADS. However, COMPOUND A 0666 hH1 (Na") were stably expressed in HEK cells terminated EADS due to Class III agents in an in vivo rabbit 0667 in physiological Solutions K" was replaced model of drug-induced TaP EADS were induced in isolated with Cs" rabbit Purkinje fibers and in all experiments (n=7), 30 uM COMPOUND A terminated EADS induced with 300 nM 0668 in whole-cell configuration, cells were voltage dofetilide, as did 100 uM lidocaine (n=2). COMPOUND A clamped using the illustrated protocol was tested and found to Suppress drug-induced TaP in an in 0669 total INa (TTX-sensitive current) was mea vivo rabbit model. In 7 of 9 control animals TodP was induced Sured by Subtracting the current recorded in the by a 25 min infusion of the alpha-adrenergic agonist meth presence of 30 uM TTX from the control current oxamine (20 ug/kg/min), to which the Class III antiarrhyth mic agent clofilium (300 nmol/kg/min) was added after 10 0670 COMPOUND A and lidocaine-sensitive cur min. COMPOUNDA, infused at 0.1, 0.3, or 1 umol/kg/min rent was measured by Subtracting the current for 5 min before starting methoxamine and continued recorded in the presence of 30 uM COMPOUND A throughout the study period reduced TaPincidence from 7/9 or 30 M lidocaine from the control current animals at 0.1, to 6/9 at 0.3, and to 1/9 at 1 tumol/kg/min 0671 stock solutions of lidocaine and COM COMPOUND A (p<0.05 at this dose compared to controls). POUND A were dissolved in de-ionized H2O Duration of TdP was also reduced in a dose-related fashion. The suppression of both EADS and TcP in the rabbit models 0672 FIG. 17 shows action potentials and EADS induced illustrates that COMPOUND A may be safely coadminis in an isolated rabbit Purkinje fiber preparation. COM tered with Class III antiarrhythmic drugs and that COM POUND A (30 uM) terminates EADS induced by dofetilide POUND A may suppress the ventricular arrhythmias (300 nM) (n=7). induced by these drugs. 0673 Stable EADs in isolated rabbit Purkinje fibers were induced in the presence of 300 nM dofetilide 0657 Further examples of the effect of ion-channel modulating compounds on TcP are included in U.S. provi 0674) Superfusion of 30 uM COMPOUND A+300 sional application 60/544.941, titled MIXED ION CHAN nM dofetilide terminated all EADS in 7 of 7 experi NEL BLOCKADE FOR THERAPEUTIC USE, filed Feb. mentS 13, 2004 and incorporated by reference herein in its entirety. 0675 Mean time to EAD termination after addition of in the presence of COMPOUND A to dofetilide Example 17 containing perfusate was 35-7.8 minutes Block of a Late Component of the Human Heart 0676 Addition of 100 uM lidocaine also terminated (hH1) Na Current Active During Repolarization dofetilide-induced (300 nM) EADs 0658 COMPOUND A exhibits frequency-dependent 0677 FIG. 18 shows late stage EAD suppression by blockade of IN critical to its antiarrhythmic actions. In COMPOUNDA. EADs were induced in the presence of 300 rabbit Purkinje fibers, in vitro tissue sensitive to agents that nM dofetilide and suppressed with the addition of 30 uM prolong repolarization, 30 uM COMPOUND A only mini COMPOUND A to 300 nM dofetilide solution. Trace begins mally prolonged AP duration. In fact, COMPOUND A 10 mins after COMPOUND A addition. PF was stimulated Significantly attenuated the AP prolongation induced by the every 8 S (arrows). In this experiment, complete EAD class III agent, dofetilide (300 nM). COMPOUND A lacks termination occurred in 16.8 minutes. I blockade at this concentration, and has little effect on AP 0678 FIG. 19 shows the fraction of each component of shape. The present study tested termination of EADS the TTX-sensitive current blocked by 30 uM lidocaine and induced by dofetilide in isolated rabbit Purkinje fibers using 30 uM COMPOUND A. Asterisks denote statistical signifi COMPOUND A. COMPOUND A blocks a late component cance (p<0.05) (n=6 for top graph). Top graph is the effect of IN that likely contributes to EAD genesis. of 30 uM COMPOUNDA and the bottom graph is the effect US 2005/01 19315 A1 Jun. 2, 2005 55 of 30 uM lidocine. The bottom graph shows the fraction of the early, Sustained, and late TTX-sensitive currents blocked TABLE 5-continued by 30 M lidocaine. In 4 experiments, 30 uM lidocaine blocked 41+2.7% of the TTX-sensitive early transient cur CONSTITUENTS OF CS-CONTAINING EXTERNAL rent (Irrs) & 70+2.5% of the TTX-sensitive Sustained SOLUTION (10 L current (Irix, and 73+2.8% of the TTX-sensitive late Reagent Concentration Supplier Cat. # Lotif current (laterix) The observation that lidocaine blocks MgCl2 1 mM Sigma M9272 129HOO36 TTX) and late(TTX) more than learlyrtko is statistically sig CsCl 5 nM Sigma C3011 11KO316 nificant (paired t-test; * p=0.00014, ** p=0.000037, respec CaCl2 (anhydrous) 1 mM Sigma C2661 99HOO57 tively). Results are expressed as the meantS.E.M. (n=4). pH corrected to 7.4 with NaOH 0679) COMPOUND A (30 uM) terminates EADs induced by dofetilide (300 nM) in rabbit Purkinje fibers. Further, COMPOUND Ablocks a late component Of IN that 0684) may participate in EAD initiation. TABLE 6
Example 18 CONSTITUENTS OF CS-CONTAINING INTERNAL SOLUTION (SOOML Block of Early, Sustained and Late Sodium Current 1N HEK-293 Cells Expressing the Human Heart Reagent Concentration Supplier Cat. # Lotif Sodium Channel (hH1) CsCl 130 mM Sigma C3011 11KO316 DiNa ATP 4 nM Fischer A3377 12K1163 0680 The sustained and late tetrodotoxin (TTX)-sensi MgCl, 6H,0 1 mM Sigma M9272 129HOO36 HEPES 5 nM Sigma H3375 O32K5464 tive Na" current were measured using whole-cell patch EGTA 10 mM Sigma E3889 58HS434 clamp of HEK cells expressing human heart Sodium chan nels (hH1). Cells were stimulated with a step/ramp voltage pH corrected to 7.2 with NaOH protocol that approximated the Voltages reached during the plateau and repolarizing phases of the action potential in 0685 Stock Solution Vehicle was de-ionized water. A 10 order to measure the early, Sustained and late Sodium current mM stock solution of COMPOUND A was prepared by the dissolution of 22.4 mg of compound in 5.8 mL of de-ionized components. Thirty (30) 1M of COMPOUNDA inhibited all water. Stock solution was stored at -20° C. 10 mM stock components of the TTX-sensitive current: early (Isarro), solutions of tetrodotoxin (Calbiochem) were prepared by Sustained (Isuscrix), and late (laterix). dissolving 1 mg in 313 it of de-ionized water. Stock 0681 COMPOUND A significantly attenuates dofetilide Solutions were stored-20 C. Lidocaine was stored as a 10 induced prolongation of the rabbit Purkinje fiber action mM stock solution at -20° C. Stock solutions were prepared potential at Voltages halfway to complete repolarization by dissolving 13.54 mg in 5 mL de-ionized water. (APDs). Block of L-type calcium current in guinea pig 0686. The recordings were obtained by whole-cell patch atrial myocytes is minimal at 30 uM of COMPOUND A. clamp from HEK-293 cells expressing hH1Na. Constituents Lidocaine (a Na" channel blocker) also reverses dofetilide of internal solution were: CsCl (130 mM), DiNa"ATP (4 induced APDso prolongation. In addition to attenuating mM), MgCl2.6HO (1 mM), HEPES (5 mM), EGTA (10 dofetilide-induced APDso prolongation, 30 uM COM mM). Constituents of external solution were: NaCl (130 mM), Dextrose (10 mM), HEPES (10 mM), MgCl, (1 mM), POUND A also terminates dofetilide-induced early afterde CsCl (5 mM), CaCl (anhydrous) (1 mM). Recordings wer polarizations (EADs) in isolated rabbit Purkinje fibers. taken by: 0682. The effect of COMPOUNDA and lidocaine on the 0687] 1. After achieving whole-cell configuration early, Sustained, and late components of Na' current using a with a series resistance of <10 MG2 (preferably Step/ramp protocol to generate the currents in HEK cells <6MS2), the cell was held at -80 mV for 5-10 expressing the hH1 Na channel were examined. COM minutes (up to 30 minutes) to achieve a stable leak POUNDA was able to effectively block the late components and allow for sufficient dialysis of the intracellular of IN, which occur at Voltages approximating APDso. pipette Solution. During this time the Solution flow 0683 Drugs used. TTX was purchased from Calbiochem was kept off; and lidocaine (lot #116H0611) from Sigma. Tables 5 and 6 0688 2. Clampex 8.2 software was configured to show components of experimental Solutions. allow viewing of the Sustained and late currents while also recording and plotting, in real-time, the TABLE 5 peak of the early transient current that will be off CONSTITUENTS OF CS-CONTAINING EXTERNAL Scale on the Signal display. Following equilibration, SOLUTION (10 L Solution was allowed to flow and 50-100 traces of control recordings were obtained during which time Reagent Concentration Supplier Cat. # Lotif the peak of the early transient current were kept NaCl 130 mM Sigma S9888 O32K1230 stable. The voltage protocol used was: hold 25 ms Dextrose 10 mM Sigma BP350-1 000199A (a)-100 mV, step from -100 mV to +20 mV, hold 100 HEPES 10 mM Sigma H3375 O32K5464 ms (G+20 mV, ramp from +20 mV to -100 mV over 100 ms: US 2005/01 19315 A1 Jun. 2, 2005 56
0689) 3. When the early current peak amplitude has Voltage-gated potassium currents were blocked during these been stable for 100-150 traces, add COMPOUND A recordings by replacing K with Cs" in both internal and at the concentration desired. Again, when the early external solutions. 30 uM COMPOUND A reliably blocked current amplitude has shown stability for 100-150 the unsubtracted I, by approximately half and 30 uM traces add 30 uMTTX. Washout after 100-150 traces TTX blocked this current completely (FIG. 20O). During in which the early current is stable. the negative ramp that Simulates the repolarization phase, this protocol reliably caused a "sag" in the current trace 0690 Exclusion/Inclusion Criteria were: only cells in (FIG.20A). Addition of 30 uM COMPOUNDA caused this which the unaveraged leak does not vary more than 20 pA “Sag to partly diminish. were accepted, experiments in which the current is not stable were excluded, experiments in which there is little or no 0694 FIG. 20 shows unsubtracted current traces obvious inward current (sag) during the negative ramp were obtained from HEK293 cells expressing hH1 Na channels excluded, Series resistance had to be <10 MS2, experiments before and during exposure to 30 uM COMPOUND A and that do not subtract correctly (likely a result of unstable COMPOUND A plus 30 uM TTX. FIG. 20A (upper trace) current or leak) were excluded (i.e., experiments where shows the Voltage protocol involves a 100 ms Step depolar capacitance or resistance artifacts changed, resulting in ization from -100 mV to +20 mV and is followed by a 100 Significant artifacts post-Subtraction that varied in magni ms ramp from +20 mV back down to -100 mV. The lower tude, causeing artifacts that did not Subtract and adversely trace shows averaged current traces following leak Subtrac altered current Subtraction were excluded). tion. FIG.20B shows the early transient current (I, that is off-scale in 20A. FIG. 20O shows a plot of the unsub 0691 After achieving the whole-cell configuration, the tracted peak amplitude of 1.30 uM COMPOUND A was cell was left to equilibrate for 5 to 10 minutes at a holding followed by 30 uM TTX plus 30 uM COMPOUND A and potential of -80 mV. This equilibration period allowed complete washout. complete dialysis of the intracellular solution with the internal pipette Solution and was critical to achieve Stable 0695) Additional perfusion of 30 uMTTXalmost entirely electrophysiological Signals. Since the Sustained and late removed the non-linearity in the current trace. FIG. 8 shows currents were Small (<60 pA), changes in leak current during examples of TTX- and COMPOUND A-sensitive current the recording could distort our measurements and the Sub traces obtained by digital Subtraction. sequent digital Subtraction. Holding the cell at -80 mV for 0696 Three components of the TTX-sensitive current are 5-10 minutes before running the voltage protocol resulted in evident. An early inward current, ITTX, results from recordings with Stable leak current and undistorted currents stepping the cell from -100 mV to +20 mV. During the of interest. 30-150 control traces (1 Hz) were obtained using plateau phase of the protocol, a Sustained inward current, the step/ramp voltage clamp protocol illustrated in FIG. 20. Irro, is present. As the Voltage is ramped back to -100 Trace averaging occurred post hoc. Cells were then perfused mV, a late inward current, laterix develops. Ilaterix with a Na" channel blocking drug, either 30 uM COM reaches its peak at Voltages within the range of half repo POUND A or 30 uM lidocaine. 30 uM TTX was applied larization, between -20 mV and -40 mV. when the amplitude of the peak early current had become 0697. In 6 experiments, 30 uM COMPOUND A blocked stable for approximately 30-150 traces. Following 30-150 61+4% of Isaro. 50+9% of Isrts, and 70+4% of traces of complete block, both drugs were washed out. By erro (FIGS. 8 & 19 top graph). 30 uM COMPOUND A using ClampeX 8.2 acquisition Software, the peak early proportionately blocked ~9% more of the late TTX-sensitive current amplitude (-2000 to -8000 pA) was plotted while current than Isrtc and this is statistically significant allowing the experimenter to Simultaneously observe the (paired t-test, p=0.005). The difference between the propor raw traces of Sustained and late current portions (-50 to tion of Isrix and Isacrix blocked is not statistically -150 pA). Significant (paired t-test; p>0.1). 0692 Analysis involved digital subtraction to identify the 0698. The ability of another Na" channel blocker that COMPOUND A-, lidocaine- and TTX-sensitive currents. reverses dofetilide-induced EADS, lidocaine, to block the 30-150 consecutive traces were averaged before drug addi components of Na' current during a Step/ramp protocol was tion, following perfusion with either COMPOUND A or also examined. 30 uM lidocaine blocked Isarts lidocaine and following 30 uM TTX perfusion. Trace aver 41+2.7%, Irix 70+2.5% and Iris 73+2.8% (FIGS. aging Significantly improved the Signal-to-noise ratio. Thus, 21 & 19 bottom graph). Block of both Iuscrix and laterix each analysis file contained 3 current traces: pre-drug, after was significantly greater than block Of Isarts (paired perfusion with either COMPOUND A or lidocaine, and t-test, p=0.00014 and p=0.000037 respectively). FIG. 21 current in the presence of TTX (see FIG. 20). The COM shows an example of the TTX- and lidocaine-sensitive POUND A-, lidocaine-, and TTX-sensitive traces were components of the early, Sustained, and late Sodium current obtained by digitally Subtracting the averaged trace in the observed during a step/ramp protocol. In FIG. 21A, presence of drug from the pre-drug averaged trace (FIGS. lidocaine- and TTX-sensitive currents are obtained by digi 20 and 21). tally Subtracting the current obtained in the presence of 0693) A step/ramp voltage protocol (FIG. 20) similar to either 30 M lidocaine or lidocaine plus 30 uM TTX Clancy et al. (Clancy CE, Tateyama M, Liu H, Wehrens X respectively from the current obtained pre-drug. FIG. 21B H, Kass R S., Non-equilibrium gating in cardiac Na chan shows the lidocaine- and TTX-sensitive I current traces nels: an original mechanism of arrhythmia. Circulation. that are off-scale in 21A. Current traces in 21A and 21B are 2003 May 6;107(17):2233-7, herein incorporated by refer averages of 30 raw traces. ence in its entirity) was used to uncover the Sustained and 0699 COMPOUND A does not prolong QT-interval in non-equilibrium portion of the hH1Na current. Resting and man. To investigate IN activity during phases 2 and 3, a US 2005/01 19315 A1 Jun. 2, 2005 57 protocol that approximated the time-course and Voltages of electrode was pulled from thin-walled filamented borosili the action potential during these phases was used. Using this cate glass capillary tubes having a resistance of 10 to 30 protocol, 3 TTX-sensitive components of IN were identi megaohms when filled with 3 M KCl. The electrode was fied: a fast early current (learly crux) occurring rapidly after attached to headstage mounted on an AXoclamp 2A amplifier depolarization, a Sustained current (Irrx) active during (or a similar amplifier known to those skilled in the art). The the plateau, and a late current (laterix) that occurred microelectrode was brought down upon an exposed Purkinje during repolarization. Ilaterix occurred near APDso poten fiber using a micromanipulator and the position was adjusted tials. until the electrode penetrated a single Purkinje cell. The 0700 30 uM COMPOUND A or 30 uM lidocaine sig Purkinje fiber network was stimulated using a biphasic nificantly inhibited Iris COMPOUND A, like Stimulation pulse and Subsequent action potentials were lidocaine, is particularly effective at promoting repolariza recorded for analysis. Extracellular Solutions containing tion at the time and potentials near APDso. aminocyclohexyl ether compounds (e.g., COMPOUNDA) and/or proarrhythmic agents (e.g., dofetilide or other class 0701. In HEK-293 cells expressing hH1Na channels, 30 III agents) were then perfused to discern changes in action uM COMPOUND A or 30 uM lidocaine reduced all TTX potential duration. A dose response relationship was Sensitive current components present during a Step/ramp obtained using ascending concentrations of aminocyclo voltage protocol. The results also indicate that COM hexyl ether compounds (e.g., COMPOUND A) (0.3 to 30 POUNDA and lidocaine reduce the late current component, uM) and this treatment was then followed by concomitant and that this inhibition occurs at Voltages near APDso. perfusion with 300 nM proarrhythmic agents (e.g., dofetilide or other class III agents) and 30 uM aminocyclohexyl ether Example 19 compounds (e.g., COMPOUND A). In a separate prepara tion, a dose-response relationship was obtained using Use of Rabbit Purkinje Fibers to Screen for ascending concentrations of proarrhythmic agents (e.g., Proarrhythmic Activity dofetilide or other class III agents) (10 nM to 300 nM) and 0702. This example relates to the use of aminocyclohexyl this treatment was followed by concomitant perfusion with ether compounds to modulate class III-induced action poten 300 nM proarrhythmic agents (e.g., dofetilide or other class tial prolongation and generation of triggered activity (EADS III agents) and 30 uM aminocyclohexyl ether compounds and TaP). Class III agents are proarrhythmic. Combination (e.g., COMPOUND A). A final study was undertaken in therapy with quinidine (a class III agent) and mexiletine (a which ascending concentrations of proarrhythmic agents class I agent and Sodium channel blocker) is more effective (e.g., dolfetilide or other class III agents) were paired with in the prevention of ventricular tachycardia (VT) and ven DMSO vehicle control, 30 uMaminocyclohexyl ether com tricular fibrillation (VF) in animal models and in humans. pounds (e.g., COMPOUND A) or 100 uM lidocaine, the EAD generation is thought to be a major cause of TdP in identity of which was blinded to the experimenter. humans. 0705 Effective Refractory Period (ERP) measurements: 0703. The present example concerns the perfusion of in the same preparations as described above, ERP was aminocyclohexyl ether compounds (e.g., COMPOUNDA) determined following each treatment arm. An S1-S2 proto at concentrations Sufficient to block Sodium current either col was used as known by those skilled in the art. Briefly, 15 before or during perfusion with proarrhythmic agents (e.g., S1 pulses were delivered at a frequency of 1 Hz and this train dofetilide or other class III agents) in order to attenuate was followed by an S2 pulse following a variable interval. action potential prolongation and/or EAD generation which The interval was Set to be greater than the refractory period are known to have proarrhythmic consequences. Sodium and it was reduced in 10 ms increments until an S2 response channel blockade by aminocyclohexyl ether compounds could no longer by elicited. The shortest duration which (e.g., COMPOUNDA) can prevent induction of AF or VF could generate an S2 response was termed the ERP. as well as terminate triggered activity which is thought to lead to fatal VF. The example herein relates to the effects of 0706 Early-after-depolarization (EAD) measurements: aminocyclohexyl ether compounds (e.g., COMPOUNDA) the left ventricle of a rabbit heart was exposed as described in rabbit Purkinje fibers, but the principles and methods can previously. A Purkinje fiber was located within the Purkinje likely be extended to treatment of acquired long-QT Syn fiber network having dimensions of approximately 2 mm drome, muti-focal ventricular arrhythmias (TdP) or preven length and 0.5 mm width. The fiber was excised from the tion of AF induction in humans. heart using fine cutting tools along with a Small amount of ventricular tissue attached at either end of the fiber. The fiber 0704 Action Potential duration measurements: female, was transferred to a 5 mL tissue bath and perfused and white New Zealand rabbits weighing between 2.5 and 3.5 kg penetrated as described above. Stable action potentials were were anaesthetized with a sufficient dose of pentobarbital to obtained for a period not less than 30 minutes and then 300 create a stuporous State and the animals were Sacrificed with nM proarrhythmic agent (e.g., dolfetilide or other class III a blow to the head. A midline thoracotomy was performed agents) was perfused in order to generate EADS. EADS were and the heart was excised as practised by those skilled in the characterized as depolarizations which disrupt the normal art. The right and left atrium were removed and the heart was course of Purkinje fiber repolarization. Stable EADS were opened through an incision along the left Side of the Septum obtained for a period of not less than 30 minutes and then 30 in order to expose the endocardial Surface of the left ven uMaminocyclohexyl ether compounds (e.g., COMPOUND tricle. The heart was transferred to a 10 mL tissue bath and A) was perfused concomitantly with 300 nM proarrhythmic Purkinje fibers exposed for microelectrode recording. The agent (e.g., dolfetilide or other class III agents). EADS were heart was perfused with standard bicarbonate buffered monitored for termination over a period not exceeding 60 Krebs' solution known to those skilled in the art. An minutes. US 2005/01 19315 A1 Jun. 2, 2005 58
0707. The initial experiments explored the effect of a induced by 300 nM dofetilide in the presence of DMSO or single concentration of COMPOUND A (30 uM) following 30 uM COMPOUND A was 86 and 37% respectively while ascending concentrations of dolfetilide and Vice versa (single the increase in APD90 was 92% and 61% respectively. concentration of dofetilide was 300 nM). FIG.22 illustrates There was no significant depression of Vmax in the presence the changes in action potential duration following these of dolfetilide and COMPOUND A relative to dofetilide and various treatments. The change in APD50 during COM DMSO (205+37 V/s and 253+48 V/s respectively, n=10, POUND A treatment was not significant (pa0.05), however p=0.44). immediately following perfusion with 30 uM COMPOUND A, concomitant perfusion of 30 uM COMPOUNDA and 300 0711 FIG. 25 shows the percent increases in APD50 nM dofetilide induced a 20% increase in APD50 (p<0.01) when Purkinje fibers were co-treated with dofetilide and (FIG.22A). This effect of the combination of COMPOUND either 30 uM COMPOUND A or DMSO control. The A and dofetilide was much less than the increase observed Stimulation frequency was 1 Hz. Results are expressed as the with 300 nM dofetilide alone which produced approximately meani-S.E.M. (n=10). * * p-0.01, it p-0.001 and it a 100% increase in APD50 (p<0.01) (FIG. 22B). Subse p-0.0001 for COMPOUND A cotreatment relative to quent treatment with 300 nM dofetilide and 30 uM COM vehicle control. FIG. 26 shows the percent increases in POUND A produced a reduction in APD50 to 70% of the APD90 when Purkinje fibers were co-treated with dofetilide APD50 for dofetilide alone (FIG. 22B). It appears that and either 30 uM COMPOUND A or DMSO control. The pretreatment with ascending concentrations of COM Stimulation frequency was 1 Hz. Results are expressed as the POUNDA (FIG.22A) reduced the effect of dofetilide more meani-S.E.M. (n=10). * p-0.05, ** p-0.01 for COM than acute treatment (FIG. 22B). Similar, but less pro POUND A cotreatment relative to vehicle control. nounced effects upon APD90 were observed (FIGS. 22C & 0712. The reduction in dofetilide-induced APD50 pro 22D). COMPOUNDA alone produced only mild increases longation in the presence of 30 uM COMPOUND A Sug in the PFAPD90 at concentrations up to 30 uM (FIG.22C). gests that 30 uM COMPOUND A may be effective in the Concomitant treatment with 300 nM dofetilide and 30 uM termination of dolfetilide-induced early-after-depolarizations COMPOUND A induced a 60% increase in APD90 (FIG. (EADs) in isolated rabbit Purkinje fibers. Preliminary data 22C) which was less than the 105% increase in APD90 (FIG. 27) show dofetilide induced EADS (27B & 27C) in an caused by 300 nM dofetilide alone (FIG. 22D). Similar to isolated Purkinje fiber preparation. Stable EADS are the effects observed on APD50, COMPOUND A treatment obtained after approximately 30 minutes of perfusion with following dofetilide pretreatment did not reduce the effects 300 nM dofetilide. Subsequent perfusion with 30 uM COM of dofetilide upon APD90 (105% increase) as much as POUND A and 300 nM dofetilide produces a time-depen dofetilide treatment following COMPOUND A pretreatment dent reduction in the number of early-depolarizations (27D (60% increase) (FIG. 22D). In FIG. 22, the stimulation & 27E) and after approximately 10 minutes of COM frequency was 1 Hz and results are expressed as the POUND A perfusion, complete abolishment of any EAD meani-S.E.M., (n=4). * p-0.05, ** p<0.01, it p-0.001, i. activity (27F). The termination of EADs by 30 uM COM p<0.0001 relative to predrug values. POUNDA was seen in 4 of 4 preparations studied. FIG. 27 0708. Whereas COMPOUND A tended to mildly attenu shows the termination of dofetilide-induced EADs by COM ate the prolongation of APD50 and APD90 induced by POUND A in isolated Purkinje fibers. Cycle length and dofetilide (FIGS. 22B & 22D), COMPOUND A tended to treatment conditions are indicated in the text of each panel. prolong the PF ERP produced by dofetilide (FIG. 23). In Panels 27A, 27B and 27F are on a more expanded time base addition, whereas pretreatment with COMPOUND A sig than panels 27C, 27D and 27E (see scale bars). Zero nificantly reduced the Subsequent effect of dolfetilide upon millivolts is indicated by the dotted line in each panel. APD90 and APD50, COMPOUND A pretreatment did not attenuate ERP prolongation induced by dofetilide (FIGS. 23 Example 20 and 24). FIG. 23 shows ERP values obtained in the pres ence of dolfetilide or a combination of dolfetilide and COM Antiarrhythmic Actions Against POUND A. The S1-S 1 interval was 1 Second and 8 S1 Chemically-Induced TDP (Carlsson Model) in pulses preceded the S2 pulse. Data are expressed as mean Anaesthetized Rabbits values+S.E.M., n=4. * p-0.05 and ** p<0.01 relative to 0713) The effect of pretreatment with COMPOUNDA on predrug. prevention of chemically-induced arrhythmias in a rabbit 0709 FIG. 24 shows ERP values obtained in the pres TdP model and to determine the effect of acute infusions of ence of COMPOUNDA or a combination of COMPOUND COMPOUND A on termination of chemically-induced A and dofetilide. The S1-S1 interval was 1 second and 8 S1 arrhythmias was determined. TodP is induced by infusion of pulses preceded the S2 pulse. Data are expressed as mean the class III drug clofilium in conjunction with methoxamine values+S.E.M., n=4. * p-0.05 relative to predrug. (Carlsson Model). 0710. The second set of experiments illustrated in FIGS. 0714 TcP is chemically induced in anaesthetised rabbits 25 & 26 explored the effects of concomitant COMPOUND (Carlsson Model). Briefly, continuous infusion of COM A/dofetilide treatment over the entire dose range of dolfetil POUNDA was administered prior to continuous infusion of ide (10 to 300 nM). Blinded to the experimenter, either 30 methoxamine and followed by clofilium. The incidence of uM COMPOUNDA or DMSO was perfused with dofetilide. TdP (the number of animals in which TcP occurred) was Concomitant treatment with 30 uM COMPOUND A signifi compared to experiments in which COMPOUND A was not cantly blunted the effects of dofetilide upon APD50 (FIG. infused. 25) and APD90 (FIG. 26) when compared to the vehicle 0715 The following procedure was used: (1) Female control (DMSO). The percentage increase in APD50 NZW rabbits were weighed and anaesthetised initially with US 2005/01 19315 A1 Jun. 2, 2005 59
35 mg/kg Sodium pentobarbital via ear vein (60 mg/mL) 3.3+0.5 min after starting clofilium infusion and no arrhyth using a sterile 23G 34 needle. Additional doses (in incre mias were observed with infusion of methoxamine alone. ments of 0.2-0.3 mL) were used if required to attain and maintain Sufficient anaesthesia as determined by abolish 0719. When continuous infusion of COMPOUND A was ment of eyelid refleX. Care was taken not to over anaesthe started before methoxamine and clofilium were added to the tize as this could cause respiratory and cardiac arrest. (2) The infusion regimen, the time to first PVC increased slightly anaesthetised rabbit was placed on a rabbit restraining board and TcP inducibility declined in a dose-dependent fashion in the Supine position and limbs were tied down. (3) The fur (FIG. 30). In addition, the overall severity and frequency of in the neck and inguinal region were wetted with water and arrhythmias was reduced in these pre-treated animals. DOSes trimmed down to the Skin with Scissors to facilitate dissec of 1 umol/kg/min COMPOUND A reduced the incidence of tion. Fur was placed in a water-filled beaker to prevent fur TdP to 1 of 9 animals (p<0.05). Lower dose pretreatment from becoming airborne. (4) The left or right femoral artery with COMPOUND A (0.1 and 0.3 umol/kg/min) did not was cannulated with PE 50 tubing and attached to a pressure significantly affect the incidence of TdP. Time to first PVC transducer to monitor blood pressure. (5) The right and left was delayed with escalating doses from 3.0+0.9 min at 0.1 jugular veins were cannulated using PE-90 tubing for drug tumol/kg/min, to 5.5-2.1 min 0.3 tumol/kg/min, but delivery via an infusion pump. (6) The left or right femoral decreased slightly at 1 umol/kg/min to 4.30.8 min. Since vein was cannulated using PE-50 tubing for drug delivery TdPoccurred in runs that often self-terminated, the effects of via an infusion pump. (7) ECG leads were attached as COMPOUND A on the duration of the episodes of TdP follows: the ground lead was inserted Subcutaneously into during 15 min of clofilium infusion were also examined. In the femoral vein region; one lead was inserted Subcutane control and COMPOUND A pretreated animals the mean ously near the apex of the heart and the third lead was placed Summed duration of TdP episodes per animal was signifi in the open Surgical area near the right jugular vein. (8) cantly reduced from 64+28 s in controls (n=9) to 14+0s Control recordings of ECG and blood pressure were taken (n=9; p<0.001) at a dose of 1 tumol/kg/min COMPOUNDA for 5 minutes to observe pre-drug effects. Recordings were (FIG. 30B). At 0.3 umol/kg/min COMPOUND A, a dose continued throughout the entire experiment. (9) Arterial K" that did not reduce the overall incidence of clofilium concentration was measured with the hand-held I-STAT induced TaP, the duration was reduced to 25+8 s (n=9; blood-gas analyzer prior to infusion of arrhythmogenic p<0.05). The effect of 0.1 umol/kg/min, was not significantly agent and at the end of the experiment. (10) After 5 minutes, different from control (98+24 s, n=9; pr0.1). It is also the COMPOUND A was infused at the desired rate and noteworthy that COMPOUND A and methoxamine, co concentration. Infusion was continued throughout the administered for 5 min, induced no arrhythmias, further experiment. (11) After a further 5 minutes, methoxamine supporting the hypothesis that COMPOUND A does not was administered at 20 tug/kg/min via the femoral vein. induce TdP in this model. Methoxamine infusion was also continued throughout the 0720 AS prolongation of QTc interval by clofilium is the experiment. (12) 10 minutes following the start of methox trigger for TcP, a potential mechanism for TcP prevention is amine infusion, clofilium was infused via a jugular vein. Suppression of QTc prolongation. QTc was measured 2.5 (13) In COMPOUND A-pretreated animals and controls, minutes after Starting clofilium infusion in rabbits receiving recording continued for 15 minutes regardless of whether methoxamine and clofilium and in rabbits pre-treated with TdP is seen or not. (14) Ablood sample was collected when COMPOUND A (0.3 and 1 umol/kg/min). In controls, an the experimental endpoint was reached, immediately after increase in arrhythmias after this time prevented accurate the infusion pumps were stopped. (15) To test the effect of ECG interval measurement. Rabbits pretreated with 1 umol/ acute infusion of COMPOUND A, immediately following kg/min COMPOUND A exhibited a 7+6% increase in QTc first bout of TdP (characterized by the classic polymorphic interval (from that measured just before clofilium infusion) VT with clear twisting about the isoelectric point), animals compared to a 20t11% increase without any pretreatment were infused continuously with COMPOUND A. All other (FIG. 31). This trend suggests that COMPOUND A may infusions continued concomitantly with COMPOUND A for reduce the QTc prolongation induced by class III drugs. 5 minutes at which time the experimental endpoint was reached. 0721 Acute Termination of TdP by COMPOUND A. 0716 FIG. 28 shows an outline of the method used in 0722. In animals treated with only methoxamine and these experiments, as outlined above. COMPOUND A was clofilium, acute infusions of COMPOUND A reduced the applied and examined as described. To analyze the data, the overall duration of TdP in a dose-dependent manner. Doses parameters measured are (1) incidence of TdP (2) duration of 1 or 3 umol/kg/min COMPOUND A were infused over 5 of TdP episodes (3) arterial K" concentration, (4) PR, QRS min (corresponding to cumulative doses of 1.2 or 5.8 mg/kg) and QTc intervals during normal sinus rhythm (until arrhyth immediately after the first episode of TdP.3 mg/kg COM mias begin and determination is no longer possible), (5) BP, POUND A reduced overall duration of TdP from 8121 S in and (6) HR. control (n=10) to 17+9 s (p<0.05) and restored normal sinus rhythm in all animals by the end of the 5 min infusion (n=9) 07.17 Prevention of TdP by COMPOUND A. as exemplified by the ECG tracings in FIG. 32A. The lower 0718 Rabbits treated with the alpha 1-adrenergic agonist dose of COMPOUND A, 1.2 mg/kg, reduced TaP duration methoxamine and the class III agent clofilium consistently to 35+15 s and restored normal sinus rhythm in 2 of 9 experienced QT prolongation, bradycardia, pre-Ventricular animals. The decline in TcP duration after COMPOUND A contractions (PVCs) (FIG. 29) and, in 7 of 9 animals, TdP. infusion began was dependent on infusion duration (FIG. In these control animals, TcP occurred on average 7.0+1.3 32B). With cumulative doses of 1.2 or 5.8 mg/kg COM min after Starting clofilium infusion, at a cumulative dose of POUND A, there was no effect on TcP duration in the first 1.4+0.2 mg/kg clofilium. The first PVC was observed minute of infusion. However, in the 3rd to 5th minute, TodP US 2005/01 19315 A1 Jun. 2, 2005 60 duration significantly declined at the higher dose, while at These data suggest that COMPOUND A may be safely the lower dose TdP decreased only in the 5th minute co-administered with class III antiarrhythmicS and indeed compared to control at the same infusion duration. The effect that COMPOUND A may be an effective treatment for TdP of acute infusions of COMPOUNDA on OTC was examined. induced by drugs that prolong ventricular repolarization. QTc was measured 2 min after Starting clofilium infusion These data also Suggest that human polymorphisms that and at the end of the 5 min infusion of COMPOUND A and result in long QT (LQT) syndromes, such as LQT2 (hERG no difference was observed (pd0.05, data not shown). polymorphism) and LOT3 (Na" channel polymorphism), in 0723 With continuous background infusions of COM which patients experience greatly increased Susceptibility to POUNDA, TaPinducibility, the duration of runs of TdP, and TdP, may also be effectively treated with COMPOUND A. the overall Severity of arrhythmias decreased in a dose dependent fashion. Continuous infusions of COMPOUNDA Appendix I administered after TaP induction Suppressed TcP and restored normal Sinus rhythm in a dose-dependent fashion. 0724)
TABLE 7 Drugs that prolong the QT interval and/or induce TdP Generic Name (Brand Name) Drug Class/Clinical Usage Comments List Albuterol (Ventolin (R) Bronchodilatorf Asthma 3 Albuterol (Proventil (R) Bronchodilatorf Asthma 3 Alfuzosin (Uroxatral (R) Alphal-blocker/Benign prostatic 2 hyperplasia Amantadine (Symmetrel (R) Dopaminergic/Anti-viral/Anti- 2 infective/Parkinson's Disease Amiodarone (Pacerone (R) Anti-arrhythmic/abnormal heart Females > Males, TodP rhythm risk regarded as low Amiodarone (Cordarone (R) Anti-arrhythmic/abnormal heart Females > Males, TodP rhythm risk regarded as low Amitriptyline (Elavil (R) Tricyclic 4. Antidepressant/depression Amoxapine (Asendin (E)) Tricyclic 4 Antidepressant/depression Ampicillin (Omnipen (R) Antibioticinfection 4 Ampicillin (Principen (R) Antibioticinfection 4 Amphetamine? Attention Deficite Disorder dextroamphetamine (Adderall (R) Arsenic trioxide (Trisenox (R) Anti-cancer/Leukemia Atomoxetine (Strattera (R) norepinephrine reuptake inhibitor? 3 ADHD Azithromycin (Zithromax (R) Antibioticfbacterial infection 2 Bepridil (Vascor (R) Anti-anginal/heart pain Females > Males Chloral hydrate (Noctec (R) Sedativefsedation/insomnia 2 Chloroquine (Arelan (R) Anti-malarial/malaria infection Chlorpromazine (Thorazine (R)) Anti-psychotic/Anti emetic/schizophrenia/nausea Ciprofloxacin (Cipro (R) Antibioticfbacterial infection 4 Cisapride (Propulsid (R) GI stimulant?heartburn Restricted availability; Females > Males. Clarithromycin (Biaxin (R) Antibioticfbacterial infection Clomipramine (Anafranil (R) Tricyclic 4 Antidepressant/depression Cocaine (Cocaine) Local anesthetic? 3 Desipramine (Pertofrane (R) Tricyclic 4 Antidepressant/depression Disopyramide (Norpace (R) Anti-arrhythmic/abnormal heart Females > Males rhythm Dobutamine (Dobutrex (R) Catecholaminefheart failure and 3 shock Dofetilide (Tikosyn (R) Anti-arrhythmic/abnormal heart rhythm Dolasetron (Anzemet (R) Anti-nausea?nausea, vomiting 2 Domperidone (Motilium (E)) Anti-nauseafnausea Dopamine (Intropine (R) Anti-arrhythmic/abnormal heart 3 rhythm Doxepin (Sinequan (R) Tricyclic 4 Antidepressant/depression Droperidol (Inapsine (R) Sedative; Anti-nauseafanesthesia adjunct, nausea