초록 ▼

The invention is directed to thiocarbonate compounds of Formula (I)-(III) and methods of treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, COPD, cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, LADA, Wolfram Synd

The invention is directed to thiocarbonate compounds of Formula (I)-(III) and methods of treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, COPD, cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, LADA, Wolfram Syndrome 1, Wolcott-Rallison syndrome, metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance. The compounds of the invention are also useful for protecting pancreatic beta-cells and for reducing free fatty acids, triglycerides, advanced glycated end products, ROS, lipid peroxidation, tissue and plasma TNFalpha and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis.

대표청구항 ▼

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2;R1 is OR6 or NR6R7;R2 is H or 2,4-difluorophenyl;R3 is H or (C1-C6)alkyl;R4 is H or acetyl;R5 is H or trifluoromethyl;R6 and R7 are independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2;R1 is OR6 or NR6R7;R2 is H or 2,4-difluorophenyl;R3 is H or (C1-C6)alkyl;R4 is H or acetyl;R5 is H or trifluoromethyl;R6 and R7 are independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein the (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl are independently optionally substituted with 1, 2, 3, or 4 substituents that are independently (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ1Z2, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens and each Z1 and Z2 is independently H or (C1-C6)alkyl; or R6 and R7 together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane. 2. The compound of claim 1, wherein R6 is H or (C1-C6)alkyl. 3. The compound of claim 1, wherein R6 is (C3-C6) alkyl or optionally-substituted benzyl. 4. The compound of claim 1, wherein R1 is methoxy, ethoxy or hydroxy. 5. The compound of claim 1, wherein R1 is amino, methylamino, or dimethylamino. 6. The compound of claim 1, wherein R2 is 2,4-difluorophenyl. 7. The compound of claim 1, wherein R3 is hydrogen or methyl. 8. The compound of claim 1, wherein R4 is acetyl. 9. The compound of claim 1, wherein R5 is hydrogen. 10. A compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein R9 is OR3 or NR10R11;R3 is H, (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein the (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl are independently optionally substituted with 1, 2, 3, or 4 substituents that are independently (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ1Z2, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens;R10 and R11 are independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl, wherein the (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl are independently optionally substituted with 1, 2, 3, or 4 substituents that are independently (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ1Z2, or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R4 and R5 together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane;in which each Z1 and Z2 is independently H or (C1-C6)alkyl. 11. The compound of claim 10, wherein R9 is NR10R11, R10 is (C2-C6)alkyl and R11 is H or (C1-C6)alkyl. 12. A compound of claim 1 that is (R)-2-Acetamido-3-((2′,4′-difluoro-3-(methoxycarbonyl)biphenyl-4-yloxy)carbonylthio)propanoic acid,(R)-2-Acetamido-3-((2-(methoxycarbonyl)phenoxy)carbonylthio)propanoic acid,(R)-2-Acetamido-3-((2′,4′-difluoro-3-(benzyloxycarbonyl)biphenyl-4-yloxy)carbonylthio)propanoic acid,(R)-2-Acetamido-3-((2-(benzyloxycarbonyl)phenoxy)carbonylthio)propanoic acid,(+/−)-2-Acetamido-4-((2′,4′-difluoro-3-(methoxycarbonyl)biphenyl-4-yloxy)carbonylthio)butanoic acid,(+/−)-2-Acetamido-4-((2-(methoxycarbonyl)phenoxy)carbonylthio)butanoic acid,(R)-2-Acetamido-3-((2′,4′-difluoro-3-(ethoxycarbonyl)biphenyl-4-yloxy)carbonylthio)propanoic acid,(R)-2-Acetamido-3-((2′,4′-difluoro-3-(propoxycarbonyl)biphenyl-4-yloxy)carbonylthio) propanoic acid,(R)-2-Acetamido-3-((2′,4′-difluoro-3-(isopropoxycarbonyl)biphenyl-4-yloxy)carbonylthio)propanoic acid,(R)-2-Acetamido-3-((2-(ethoxycarbonyl)phenoxy)carbonylthio)propanoic acid,(R)-2-Acetamido-3-((2-(propoxycarbonyl)phenoxy)carbonylthio)propanoic acid,(R)-2-Acetamido-3-((2-(isopropoxycarbonyl)phenoxy)carbonylthio)propanoic acid,(R)-2-Acetamido-3-((2-(tert-butoxycarbonyl)phenoxy)carbonylthio)propanoic acid,(R)-2-Acetamido-3-((3-(tert-butoxycarbonyl)-2′,4′-difluorobiphenyl-4-yloxy)carbonylthio)propanoic acid,(R)-Benzyl 4-((2-acetamido-3-methoxy-3-oxopropylthio)carbonyloxy)-2′,4′-difluoro biphenyl-3-carboxylate,(R)-tert-Butyl 4-((2-acetamido-3-methoxy-3-oxopropylthio)carbonyloxy)-2′,4′-difluoro biphenyl-3-carboxylate,(R)-2-Acetamido-3-((2-(benzyloxycarbonyl)-5-(trifluoromethyl)phenoxy)carbonylthio)propanoic acid,or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable excipient, adjuvant, or carrier. 14. A method of treating metabolic disorders selected from the group consisting of type I diabetes, type II diabetes, Latent Autoimmune Diabetes of Adulthood (LADA), Wolfram Syndrome 1, Wolcott-Rallison syndrome, hyperglycemia, elevated free fatty acids, elevated triglycerides, insulin resistance, and beta cell protection in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a compound according to claim 1. 15. A method of treating metabolic disorders selected from the group consisting of type I diabetes, type II diabetes, Latent Autoimmune Diabetes of Adulthood (LADA), Wolfram Syndrome 1, Wolcott-Rallison syndrome, hyperglycemia, elevated free fatty acids, elevated triglycerides, insulin resistance, and beta cell protection in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to claim 13. 16. A pharmaceutical composition comprising a compound according to claim 10 and at least one pharmaceutically acceptable excipient, adjuvant, or carrier. 17. A method of treating metabolic disorders selected from the group consisting of type I diabetes, type II diabetes, Latent Autoimmune Diabetes of Adulthood (LADA), Wolfram Syndrome 1, Wolcott-Rallison syndrome, hyperglycemia, elevated free fatty acids, elevated triglycerides, insulin resistance, and beta cell protection in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a compound according to claim 10. 18. A method of treating metabolic disorders selected from the group consisting of type I diabetes, type II diabetes, Latent Autoimmune Diabetes of Adulthood (LADA), Wolfram Syndrome 1, Wolcott-Rallison syndrome, hyperglycemia, elevated free fatty acids, elevated triglycerides, insulin resistance, and beta cell protection in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to claim 16. 19. The compound of claim 2, wherein R1 is methoxy, ethoxy, hydroxy, amino, methylamino, or dimethylamino. 20. The compound of claim 2, wherein R2 is 2,4-difluorophenyl. 21. The compound of claim 2, wherein R3 is hydrogen or methyl. 22. The compound of claim 2, wherein R4 is acetyl. 23. The compound of claim 2, wherein R5 is hydrogen. 24. The compound of claim 19, wherein R2 is 2,4-difluorophenyl. 25. The compound of claim 19, wherein R3 is hydrogen or methyl. 26. The compound of claim 19, wherein R4 is acetyl. 27. The compound of claim 19, wherein R5 is hydrogen. 28. The compound of claim 24, wherein R3 is hydrogen or methyl. 29. The compound of claim 24, wherein R4 is acetyl. 30. The compound of claim 24, wherein R5 is hydrogen. 31. The compound of claim 28, wherein R4 is acetyl. 32. The compound of claim 28, wherein R5 is hydrogen. 33. The compound of claim 31, wherein R5 is hydrogen. 34. A method of treating type II diabetes in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a compound according to claim 1. 35. A method of treating type II diabetes in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a compound according to claim 10. 36. A method of treating hyperglycemia in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a compound according to claim 1. 37. A method of treating hyperglycemia in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a compound according to claim 10. 38. A method of treating elevated triglycerides in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a compound according to claim 1. 39. A method of treating elevated triglycerides in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a compound according to claim 10. 40. A method of treating insulin resistance in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a compound according to claim 1. 41. A method of treating insulin resistance in a mammal or patient comprising administering to the mammal or patient in need of such treatment a therapeutically effective amount of a compound according to claim 10.