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( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2020/0017460 A1 US 20200017460A1 IN (19 ) United States ( 12 ) Patent Application Publication (10 ) Pub. No.: US 2020/0017460 A1 STIERLE et al. (43 ) Pub . Date : Jan. 16 , 2020 (54 ) 16 -METHYL -OXACYCLOHEXADECAN - 2 - ONE Related U.S. Application Data AND 16 -METHYL - AZACYCLOHEXADECAN - 2 -ONE (60 ) Provisional application No. 62 /473,910 , filed on Mar. DERIVATIVES AS ANTIMICROBIAL 20 , 2017 . AGENTS (71 ) Applicant: THE UNIVERSITY OF MONTANA , Publication Classification Missoula , MT (US ) (51 ) Int. Ci. CO7D 313/00 (2006.01 ) (72 ) Inventors : Andrea STIERLE , Missoula , MT A61P 31/04 (2006.01 ) (US ) ; Donald STIERLE , Missoula , MT C07D 405/04 (2006.01 ) (US ) ; Nigel PRIESTLEY , Alberton , C07D 491/044 ( 2006.01 ) MT (US ) (52 ) U.S. CI. CPC C07D 313/00 ( 2013.01) ; C07D 491/044 (73 ) Assignee : THE UNIVERSITY OF MONTANA , ( 2013.01) ; CO7D 405/04 ( 2013.01) ; A61P Missoula , MT (US ) 31/04 ( 2018.01 ) ( 21 ) Appl. No .: 16 /495,312 (57 ) ABSTRACT (22 ) PCT Filed : Mar. 20 , 2018 16 -membered macrolide compounds inhibit growth of vari (86 ) PCT No.: PCT /US2018 /023332 ous microbial species and have utility in the treatment of $ 371 ( c ) ( 1 ) , systemic or topical microbial infections, including methicil ( 2 ) Date : Sep. 18 , 2019 lin -resistant strains (Formula I) . CO2H ?? , O: Din -CO2H -CO2H BPL 76 ?? BPL 88 .CO2H CO2H CO2H -?? "OH BPL 81/ A26771B BPL 77 BPL 78 COZH ?? , ?? HO "OH BPL 84 BPL 79 CO2H CO2H HO "" OH HO CH2OH BPL 86 BPL 98 Patent Application Publication Jan. 16 , 2020 Sheet 1 of 12 US 2020/0017460 A1 6 FIG . 1A similiki : ????** ??????? FIG . 1B i enester reggaet **** 075 adecan withhandelt FIG . 1C Patent Application Publication Jan. 16 , 2020 Sheet 2 of 12 US 2020/0017460 A1 CO2H ?? , -CO2H CO2H HO BPL 76 HO BPL 88 CO2H CO2H CO2H OH " OH BPL 81/ A26771B BPL 77 BPL 78 CO2H ?? , HO ?? 'OH BPL 84 BPL 79 CO2H CO2H ?? " OH HO CH2OH BPL 86 BPL 98 FIG . 2A Patent Application Publication Jan. 16 , 2020 Sheet 3 of 12 US 2020/0017460 A1 R110 5 CO2H 0 15 2 Ri Disse O CO2R8 " R ? R ? BPL76 R7, R8 , R11 = H BPL81 R2 = H , R3 = H Methylated BPL76 R7, R11 = H , R8 = CH3 BPL77 R2 = OH , R3 = H Acetylated BPL76 R ?,R11 = Ac, R ' = CH3 BPL78 R2 = H , R3 = OH BPL88 R ?, R8 = H ,R11 = COCH2CH2CO2H R110 R120 "R ? O R1 BPL84 R ' = CH3, R², R12 = H , R11 = COCH2CH2CO2H BPL79 R1 = CH3, R2 = OH , R11,1 R12 = H Acetylated BPL79 R ' = CH3, R2 = OAC, R11, R12 = Ac Chiral BPL79 R1 = CH3, R2 = Ror S OMTPA, R11 , R12 = Ror SMTPA BPL86 R ' = CH3, R2 = OH , R11 = COCH2CH2CO2H , R 12 = H BPL 98 R1 = CH2OH , R2 = H , R11 = COCH2CH2CO2H , R 12 = OH , FIG . 2B Patent Application Publication Jan. 16 , 2020 Sheet 4 of 12 US 2020/0017460 A1 un HY H I H OR HO 4 A H S H B I. x 1' OH H R102C FIG . 2C Patent Application Publication Jan. 16 , 2020 Sheet 5 of 12 US 2020/0017460 A1 cz FIG . 2D MTPA - O H -0.05 ? + 0.23 +I -0.07 H + 0.9 MTPA - O ? O - APTM H - 1.17 +0.15 + 0.7 + 0.49 FIG . 2E Patent Application Publication Jan. 16 , 2020 Sheet 6 of 12 US 2020/0017460 A1 220 *** ci FIG . 2F ?? , HOC. ?? , HO HO Loy BPL 94 BPL 95 BPL 96 FIG . 2G Patent Application Publication Jan. 16 , 2020 Sheet 7 of 12 US 2020/0017460 A1 Meo ACO Meo BPL 81 Butyl - succinate BPL 81 5 -MeO BPL 81 5 - OAC BPL 81 2,3 - Cycloprop , 5 -MeO Meo ?? , Meo Me , N BPL 81 lactam , b - 5 -MeO BPL 81 lactam , a - 5 -MeO BPL 81 , 2 -Me , 5 -MeO Fac BPL 81 2 - trifluoroethylthioether Meo dihydro - BPL81, 5 -MeO Ph . NAC .N Meo BPL 81 Butyl est , 2 -phen - ox -ethylamine ' N Meo BPL 81 Butyl est , 2 -piperazine BPL 81,2,3 - epoxide , 5 -MeO SO2 Meo ?? . dh - BPL 81, 2 - phenylsulfonether BPL 81 5 - OH dh -BPL 81 , 2 - phenylthioether BPL 81 4,5 - imidazole BPL 81 Butyl est , 2,3 -pyrazole FIG . 3 Patent Application Publication Jan. 16 , 2020 Sheet 8 of 12 US 2020/0017460 A1 BPL76(50uM) BPL76(250uM) 06300992769 FIG . 4A Patent Application Publication Jan. 16 , 2020 Sheet 9 of 12 US 2020/0017460 A1 Www BPL 76 (50PM ) Fluorescence Aux BPL 76 (250pm ) LaFIG . 4B Patent Application Publication Jan. 16 , 2020 Sheet 10 of 12 US 2020/0017460 A1 8 6 26 B.anthracis UM 64 250 26 >400 50> C,albicans 250 125 250>> 13 UM 32 FIG.5 16 125 3 26 UMug/mL 250 Wwe? ??? 3 6 13709aureus( Staphylococcus 8 8 125 BPL88 BPL81 Patent Application Publication Jan. 16 , 2020 Sheet 11 of 12 US 2020/0017460 A1 CefazoliaDoxycycline Levofloxacia ErythromyciaClindamycin MCJamh) VancomycinErythromycia FIG.6 wy 3 2 6 BPL81BPL76Description www 2 ww HA-MRSA Patent Application Publication Jan. 16 , 2020 Sheet 12 of 12 US 2020/0017460 A1 32 22 532 > 32 $13:48 68 > >63 338 00 fagratis 16.30 2.00 180 2.00 230 *30 200 200 64.30 STANICE 16:00 200 4130 200 2:00 200 200 00* 18:00 Este 2013 200 50 5.50 203 10 3290 08 35393ãos 732 22:00 3836 16:00 16:00 $63 FIG.7 239 30 8.00 30 2.00 1.30 100 100 360 100 22.00 60 230 2.00 2:03 081 14083 1.00 10 200 30 00 0 09 St 200 1.00 OS0 100 OSO VO 2013 3200 OPU81Butylest,2. Datube 921Butyest,20 NeoVer581,2BP: 5.MenCyclapos, BP:81,23*oxicke BYL81,2,5xxide 3981Butyk. 28de 30803a5 BE81Dutyust, BPL814,5midazole ploetasnë B2B3.0 BBP31 (3881 sulfonetherahenyi 1881.nodihydro- 388033 HPL81 SU008ate plentylingelser DB22 deBar Veo Neo US 2020/0017460 A1 Jan. 16 , 2020 1 16 -METHYL -OXACYCLOHEXADECAN - 2 - ONE [0007 ] Compounds described herein may represent a new AND class of macrolide antibiotics useful for treating microbial 16 -METHYL - AZACYCLOHEXADECAN - 2 -ONE infections and inhibiting microbial growth . Conventional DERIVATIVES AS ANTIMICROBIAL macrolide antibiotics produced by bacterial species are AGENTS polypropionate in nature . BPL 76 and related compounds are polyacetate derived . Conventional bacterially derived CROSS - REFERENCE TO RELATED macrolides are active because of specific sugar moieties that APPLICATION ( S ) interact within the ribosome to block bacterial protein syn [ 0001 ] This application claims the benefit of U.S. Provi thesis . BPL 76 and analogs lack all sugar moieties and do not sional Patent Application No. 62/ 473,910 , filed on Mar. 20 , interfere with bacterial protein synthesis . 2017 , the entire contents of which are fully incorporated [ 0008 ] In one aspect, the invention provides a compound herein by reference . of formula ( I ) , or pharmaceutically acceptable salt thereof, TECHNICAL FIELD [0002 ] The invention relates to novel 16 -membered macrolide compounds and pharmaceutically acceptable salts thereof, their use in the treatment of systemic or topical R3 microbial infections, and methods of inhibiting microbial growth . X ! R2 BACKGROUND R1 [ 0003 ] Macrolide antibiotics are important therapeutic agents and are considered to be one of the safest antibiotic treatments available . Macrolide compounds are character wherein ized by the presence of a macrocyclic lactone ring, which [0009 ] Xl is O or NH ; can vary from 12 to 16 atoms, known as a macrolide ring, [ 0010 ] Riis C - alkyl, C -- haloalkyl, -C -zalkylene -OH , and usually one or more sugar chains is attached to the ring . or Cj- zalkylene- OC1- alkyl ; Generally , macrolides inhibit protein synthesis in bacteria by [ 0011 ] R² is hydrogen , OH , OC1- alkyl, OC (O )C reversibly binding to the P site of the 50S unit of the 4alkyl, -OC (O ) C ( CF3 ) (OCH ) Ph , NH , NHC -alkyl , ribosome, thereby interrupting the growth of polypeptides. -N ( C - alkyl ) 2, - NHC( O ) C - alkyl , N ( C -alkyl ) C [0004 ] Macrolide antibiotics such as erythromycin , ( 0 ) C1-4alkyl, SH , SC1- alkyl , or SC ( O )C1 - alkyl; clarithromycin , and azithromycin have been used widely to [ 0012] R is hydrogen , OH , OC1_4alkylOC -alkyl, OC ( O )C1 combat diseases caused by gram -positive pathogens and 4alkyl , NH2, -NHC1-4alkyl, N (C1-4alkyl ) 2 , NHC fastidious gram -negative pathogens . The popularity of this ( 0 ) C1-4alkyl, -N (C1 1 - alkyl) C ( O )C1 - alkyl, SH , SC1 class of antibiotics is largely due to their spectrum of 4alkyl, or SC ( O )C1-4alkyl ; activity . Macrolide antibiotics generally share a similar [0013 ] L ' is range of activities against many strains of streptococci, staphylococci , clostridia , corynebacteria , listeria , haemo philus sp ., moxicella , and Neisseria meningitidis . Clarithro mycin and azithromycin are more active than erythromycin against several gram negative bacteria as well as Myco plasma pneumonia , Helicobacter pylori , Toxoplasma gon dii , cryptosporidia and several atypical mycobacteria . Minund [ 0005 ] Unfortunately , the widespread use and misuse of macrolides , and many other types of antibiotics , catalyzed the emergence of antimicrobial resistant strains . Among gram - positive bacteria , antibiotic resistant Staphylococcus and Enterococcus species pose the biggest threat . Certain gram -negative bacteria are becoming increasingly resistant ht to nearly all of the antibiotic drug options available , creating situations reminiscent of the pre -antibiotic era . Although [0014 ] X7 is H2 or 0 ; overall antifungal resistance is still fairly low , many infec [0015 ] R4 is hydrogen or methyl ; tions caused by the fungus Candida no longer respond to [0016 ] R?is hydrogen , SC1- alkyl, -SC1-4haloalkyl, or common antifungal medications . It is of critical importance S_C alkylene -CH ( R ) X to develop and provide new drugs with broad -spectrum [0017 ] R? is - SC - alkyl, SC )-- haloalkyl, -S ( O ) , - G !, activity , particularly against the ever increasing list of drug -NR - C1- zalkylene - O - G ' , or G ?; resistant microbial species.
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