Tetrazole derivatives of bile acids as fxr/tgr5 agonists and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016145295-A1
Application number	US-201514951736-A
Country	US
Kind code	A1
Filing date	Nov 25, 2015
Priority date	Nov 26, 2014
Publication date	May 26, 2016
Grant date	—

Abstract

The present invention provides compounds of Formula I:

pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent a disease or disorder mediated by FXR and/or TGR5.

First claim

1 . A compound represented by Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, or combination thereof:

wherein:
X is absent, —C(O)NH— or —NH—;
R 1 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted arylalkyl; and
6) Substituted or unsubstituted aryl;
m is 0, 1, 2 or 3;
R 2 is hydrogen, hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 or —OPO 3 2− ; preferably R 2 is hydrogen or hydroxyl;
R 3 is hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 , —OPO 3 2− , —SR 1 or —NHR 1 , wherein R 1 is as defined previously;
Or R 2 and R 3 are taken together with the carbon atoms to which they are attached to form —CH═CH— or cycloalkyl ring or heterocycloalkyl ring such as, but not limited to cyclopropyl, or epoxide;
R 4 and R 5 are independently selected from hydrogen or hydroxyl protecting group; and
R 6 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Substituted or unsubstituted —C 1 -C 8 alkyl;
4) Substituted or unsubstituted —C 2 -C 8 alkenyl;
5) Substituted or unsubstituted —C 2 -C 8 alkynyl; and
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl.

2 . The compound of claim 1 , represented by Formula II or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, or combination thereof:

wherein R 1 , R 2 , R 3 , R 6 , X and m are as defined in claim 1 .

3 . The compound of claim 1 , represented by Formula III or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, or combination thereof:

wherein R 1 , R 2 , R 6 , X and m are as defined in claim 1 .

4 . The compound of claim 1 , represented by formula (III-1˜III-18), where R 6 and m are as defined in claim 1 :

5 . The compound of claim 1 , represented by Formula IV or a pharmaceutically acceptable salt thereof:

wherein m is as defined in claim 1 .

6 . The compound of claim 1 , represented by Formula V or a pharmaceutically acceptable salt thereof:

wherein m is as defined in claim 1 .

7 . The compound of claim 1 , represented by Formula VI or a pharmaceutically acceptable salt thereof:

wherein m is as defined in claim 1 .

8 . A method for the prevention or treatment of an FXR-mediated disease or condition in a mammal comprising administering to the mammal suffering from an FXR-mediated disease or condition a therapeutically effective amount of a compound of formula (I) according to claim 1 .

9 . The method according to claim 8 , wherein the FXR-mediated disease or condition is selected from the group consisting of chronic liver disease, gastrointestinal disease, renal disease, cardiovascular disease, and metabolic disease.

10 . The method according to claim 9 , wherein the chronic liver disease is selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1-antitrypsin deficiency.

11 . The method according to claim 9 , wherein the renal disease is selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease.

12 . The method according to claim 9 , wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia.

13 . The method according to claim 9 , wherein the metabolic disease is selected from the group consisting of insulin resistance, Type I and Type II diabetes, and obesity.

14 . A method for the prevention or treatment of an TGR5-mediated disease or condition in a mammal comprising administering to the mammal suffering from an TGR5-mediated disease or condition a therapeutically effective amount of a compound of formula (I) according to claim 1 .

15 . A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.

16 . Use of a compound of claim 1 for the preparation of pharmaceutical compositions for the prevention or treatment of FXR-mediated or TGR5-mediated diseases or conditions.

Assignees

• Enanta Pharm Inc

Inventors

• Or Yat Sun
• He Jin
• Wang Guoqiang

Classifications

• C07J43/003 Primary

  not condensed · CPC title

• C07J41/0061 Primary

  one of the carbon atoms being part of an amide group · CPC title

• C07J41/0055

  the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives · CPC title

• C07J9/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane · CPC title

• C07J31/006

  not covered by C07J31/003 · CPC title