- Patent Number:
11312,709
- Appl. No:
16/967262
- Application Filed:
February 05, 2019
- نبذة مختصرة :
This invention relates to novel compounds according to Formula (I) which are inhibitors of ghrelin O-acyltransferase (GOAT), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of metabolic disorders (e.g. Prader-Willi syndrome, metabolic syndrome, insulin resistance, impaired glucose tolerance, prediabetes, diabetes mellitus (e.g., type II diabetes mellitus), dysglycemia (e.g., hyperglycemia), obesity (e.g., obesity caused by Prader-Willi syndrome), increased adiposity, poor glycemic control, hyperphagia, impaired satiety, dyslipidemia (e.g., atherogenic dyslipidemia), hepatic steatosis (e.g., non-alcoholic fatty liver disease (e.g., non-alcoholic steatohepatitis))), psychiatric disorders (e.g., eating disorders (e.g., bulimia nervosa, binge eating disorder, night-time eating syndrome), substance related disorders (e.g., addiction disorders (e.g., alcohol, smoking, overeating, or use of illicit drugs))), as well as disorders related to or complications of metabolic or psychiatric disorders (e.g., cardiovascular diseases (e.g., diabetic heart disease (e.g., diabetic cardiomyopathy), heart failure, or hypertension), ischemia (e.g., myocardial ischemia, cerebral ischemia, ischemic stroke), or BMI-related cancers (e.g., pancreatic cancer, gallbladder cancer, esophageal cancer, colorectal cancer, breast cancer etc.). [chemical expression included]
- Inventors:
Glaxosmithkline Intellectual Property Development Limited (Brentford, GB)
- Assignees:
Glaxosmithkline Intellectual Property Development Limited (Brentford, GB)
- Claim:
1. A compound according to Formula (I) or a pharmaceutically acceptable salt thereof: [chemical expression included] wherein: R 1 is hydrogen, halogen, cyano, (C 1 -C 4)alkyl, halo(C 1 -C 4)alkyl, or C(═O)NH 2 ; X is CH 2 or O; R 2 is halogen; and R 3 is hydrogen or halogen.
- Claim:
2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , represented by Formula (II): [chemical expression included] wherein: R 1 is hydrogen, halogen, cyano, (C 1 -C 4)alkyl, halo(C 1 -C 4)alkyl, or C(═O)NH 2 ; X is CH 2 or O; R 2 is halogen; and R 3 is hydrogen or halogen.
- Claim:
3. The compound or pharmaceutically acceptable salt thereof according to claim 1 , represented by Formula (III): [chemical expression included] wherein: R 1 is hydrogen, halogen, cyano, (C 1 -C 4)alkyl, halo(C 1 -C 4)alkyl, or —C(═O)NH 2 ; X is CH 2 or O; R 2 is halogen; and R 3 is hydrogen or halogen.
- Claim:
4. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is hydrogen, chloro, cyano, methyl, —CF 3 , or —C(═O)NH 2 .
- Claim:
5. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is hydrogen.
- Claim:
6. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X is CH 2 .
- Claim:
7. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X is O.
- Claim:
8. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is chloro.
- Claim:
9. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is hydrogen, chloro, or fluoro.
- Claim:
10. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is hydrogen.
- Claim:
11. The compound according to claim 1 which is: 2-(4-chloro-6-((6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (R)-2-(4-chloro-6-((6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (S)-2-(4-chloro-6-((6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; 2-(4-chloro-6-((2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (R)-2-(4-chloro-6-((2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (S)-2-(4-chloro-6-((2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; 2-(4,7-dichloro-6-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (R)-2-(4,7-dichloro-6-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (S)-2-(4,7-dichloro-6-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; 2-(4,7-dichloro-6-((2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (R)-2-(4,7-dichloro-6-((2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (S)-2-(4,7-dichloro-6-((2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; 2-(4-chloro-7-fluoro-6-((6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (R)-2-(4-chloro-7-fluoro-6-((6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (S)-2-(4-chloro-7-fluoro-6-((6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; 2-(4-chloro-6-((2,3-dihydrofuro[2,3-b]pyridin-3-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (R)-2-(4-chloro-6-((2,3-dihydrofuro[2,3-b]pyridin-3-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (S)-2-(4-chloro-6-((2,3-dihydrofuro[2,3-b]pyridin-3-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; 2-(4,7-dichloro-6-((2,3-dihydrofuro[2,3-b]pyridin-3-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (R)-2-(4,7-dichloro-6-((2,3-dihydrofuro[2,3-b]pyridin-3-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (S)-2-(4,7-dichloro-6-((2,3-dihydrofuro[2,3-b]pyridin-3-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; 2-(4-chloro-6-((2-cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (R)-2-(4-chloro-6-((2-cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; (S)-2-(4-chloro-6-((2-cyano-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)benzo[b]thiophen-3-yl)acetic acid; 2-(6-((2-carbamoyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-4-chlorobenzo[b]thiophen-3-yl)acetic acid; (R)-2-(6-((2-carbamoyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-4-chlorobenzo[b]thiophen-3-yl)acetic acid; or (S)-2-(6-((2-carbamoyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)oxy)-4-chlorobenzo[b]thiophen-3-yl)acetic acid; or a pharmaceutically acceptable salt thereof.
- Claim:
12. The compound according to claim 1 which is: [chemical expression included] or a pharmaceutically acceptable salt thereof.
- Claim:
13. The compound according to claim 1 which is: [chemical expression included] or a pharmaceutically acceptable salt thereof.
- Claim:
14. The compound according to claim 13 which is: [chemical expression included]
- Claim:
15. A combination of a compound or pharmaceutically acceptable salt thereof according claim 1 and at least one anti-adiposity agent or anti-adiposity therapy.
- Claim:
16. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.
- Claim:
17. The pharmaceutical composition of claim 16 , further comprising an additional pharmaceutical agent.
- Claim:
18. A method of treating Prader-Willi syndrome, metabolic syndrome, insulin resistance, impaired glucose tolerance, prediabetes, diabetes mellitus, type 2 diabetes mellitus, dysglycemia, hyperglycemia, obesity, increased adiposity, poor glycemic control, hyperphagia, impaired satiety, dyslipidemia, atherogenic dyslipidemia, hepatic steatosis, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
- Claim:
19. A method of treating obesity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
- Claim:
20. A method of treating Prader-Willi syndrome in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
- Patent References Cited:
WO 2013/125732 August 2013
WO 2010/143733 December 2010
WO 2013/125732 August 2013
WO 2013/144097 October 2013
WO 2015/024526 February 2015
- Other References:
Cummings, D.E. Physiology and Behavior, 89(1):71-84 (2006) (Year: 2006). cited by examiner
Barnett et al., Science 2010, 330 (6011), 1689-1692 (Year: 2010). cited by examiner
PCT/EP2019/052770, May 15, 2019, International Search Report and Written Opinion. cited by applicant
PCT/EP2019/052770, Aug. 20, 2020, International Preliminary Report on Patentability. cited by applicant
- Primary Examiner:
Heyer, Dennis
- Attorney, Agent or Firm:
Wolf, Greenfield & Sacks, P.C.
- الرقم المعرف:
edspgr.11312709
Processing Request
No Comments.