Fxr agonists and methods for making and using

Patent metadata

Field	Value
Publication number	US-2016376279-A1
Application number	US-201615263048-A
Country	US
Kind code	A1
Filing date	Sep 12, 2016
Priority date	Mar 13, 2014
Publication date	Dec 29, 2016
Grant date	—

Abstract

Novel FXR agonists are disclosed, embodiments of a method of making the same, and of a composition comprising them are disclosed herein. Also disclosed are embodiments of a method of treating or preventing a metabolic disorder in a subject, comprising administering to a subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and treating or preventing a metabolic disorder in the subject. Additionally disclosed are embodiments of a method of treating or preventing inflammation in an intestinal region of a subject, comprising administering to the subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and thereby treating or preventing inflammation in the intestinal region of the subject.

First claim

We claim:

1 . A compound, having a formula

or a pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof, wherein
R 1 -R 6 and R 8 -R 15 independently are selected from hydrogen, deuterium, halogen, CF 3 , NO 2 , OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl, aminosulfonyl, aliphatic, D-aliphatic, heteroaliphatic, D-heteroaliphatic, or —(CH 2 ) n1 —R 150 —(CH 2 ) n2 —R 151 , wherein n1 and n2 are independently selected from the group consisting of 0, 1, 2, 3, and 4, R 150 is O, NR 16 , or absent, and R 151 is carboxyl ester or amino;
R 7 is H, aliphatic, heteroaliphatic or D-heteroaliphatic;
R 16 is selected from hydrogen, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic; and
R a and R b are independently hydrogen, deuterium, aliphatic or D-aliphatic, or together form a pi-bond;
wherein if R a and R b together form a pi-bond, then at least one of R 1 -R 15 is or comprises deuterium; and
none of R 1 -R 16 is —R x L x -R x2 , where R x is selected from O, NR x3 , sulfonyl or S;
R x3 is selected from H, aliphatic, or aryl;
L x is selected from a bond, aliphatic, heteroaliphatic, aryl, heteroaryl or CR x4 R x5 ;
R x4 and R x5 are each independently selected from H, D, halogen, aliphatic, —C(O)OR x6 , or —C(O)NR x6 R x7 ;
R x6 and R x7 are each independently selected from H, aliphatic;
R x2 is selected from —C(O)L x2 R x8 or a carboxyl bioisostere;
L x2 is a bond or NR x3 ;
R x8 is H, aliphatic, —OR x9 , N(R x9 ) 2 , —C(O)R x9 , —S(O) 2 R x9 , —C(O)OR x9 , —S(O) 2 N(R x9 ) 2 or —C(O)N(R x9 ) 2 ; and
each R x9 is independently selected from H, aliphatic.

2 . The compound of claim 1 , wherein the compound has a formula selected from

wherein if the compound has Formula II then at least one of R 1 -R 15 is or comprises deuterium.

3 . The compound of claim 1 , wherein R 7 is alkyl, deuterated alkyl, or comprises from 1 to 7 deuterium atoms.

4 . The compound of claim 1 , wherein R 10 and R 11 independently are alkyl, deuterated alkyl, or comprise from 1 to 3 deuterium atoms.

5 . The compound of claim 1 , wherein the compound is selected from

6 . A composition, comprising:
at least a first compound of claim 1 ; and an additional component.

7 . A method of treating or preventing a disorder or disease selected from a metabolic disorder, inflammation in an intestinal region, a cell proliferation disease, alcoholic liver disease, non-alcoholic liver disease, a cholestatic disorder, an intestinal permeability disorder, a disease that causes or results from an altered intestinal microbiome, an inborn error of metabolism, a bile disorder, or an intestinal malabsorption disorder, the method comprising administering to a subject a therapeutically effective amount of a compound of claim 1 .

8 . The method of claim 7 , wherein the disorder or disease is selected from obesity, diabetes, insulin resistance, dyslipidemia, necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation induced enteritis, pseudomembranous colitis, chemotherapy induced enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, colon cancer, post-surgical inflammation, gastric carcinogenesis, fatty liver (steatosis), cirrhosis, alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholestasis resulting from a drug, overlap syndrome (PBC plus autoimmune hepatitis), drug-induced cholestatic hepatitis, total parenteral nutrition (TPN)-induced cholestasis, ICU/sepsis-related cholestasis, obstetric cholestasis, graft vs. host disease, prolonged cholestasis due to hepatitis A, B or C infection, cholestasis due to cystic fibrosis, alcoholic hepatitis, progressive familial intrahepatic cholestasis (PFIC) syndromes, Alagille syndrome, biliary atresia, infectious colitis, type 1 diabetes, an intestinal permeability condition, an intestinal inflammation disorder, intestinal lesions, cirrhosis, cerebrotendinous xanthomatosis (CTX), benign biliary stricture, malignant biliary obstruction, bile acid diarrhea, short bowel syndrome, tropical sprue, environmental enteropathy, or volvulus.

9 . A compound, having a formula

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein
R 21 -R 34 independently are selected from hydrogen, deuterium, halogen, CF 3 , NO 2 , OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl, aminosulfonyl, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic;
R 35 is aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic;
R 36 is hydrogen, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic;
X is N or CR 37 ; and
R 37 is hydrogen, deuterium, halogen, CF 3 , NO 2 , OH, amino, acyl, carboxyl, carboxyl ester, cyano, aminocarbonyl, aminosulfonyl, aliphatic, D-aliphatic, heteroaliphatic or D-heteroaliphatic;
wherein if X is N, then at least one of R 21 -R 35 is or comprises deuterium; and
none of R 21 -R 37 is —R x -L x -R x2 , where R x is selected from O, NR x3 , sulfonyl or S;
R x3 is selected from H, aliphatic, or aryl;
L x is selected from a bond, aliphatic, heteroaliphatic, aryl, heteroaryl or CR x4 R x5 ;
R x4 and R x5 are each independently selected from H, D, halogen, aliphatic, —C(O)OR x6 , or —C(O)NR x6 R x7 ;
R x6 and R x7 are each independently selected from H, aliphatic;
R x2 is selected from —C(O)L x2 R x8 or a carboxyl bioisostere;
L x2 is a bond or NR x3 ;
R x8 is H, aliphatic, —OR x9 , N(R x9 ) 2 , —C(O)R x9 , —S(O) 2 R x9 , —C(O)OR x9 , —S(O) 2 N(R x9 ) 2 or —C(O)N(R x9 ) 2 ; and
each R x9 is independently selected from H, aliphatic.

10 . The compound of claim 9 , wherein the compound has a formula selected from

11 . The compound of claim 9 , wherein the compound is chiral; R 35 is alkyl, cycloalkyl, deuterated alkyl or deuterated cycloalkyl; or a combination thereof.

12 . The compound of claim 9 , wherein the compound is selected from

wherein x is 0 to 4;
y is 0 to 11; and
z is 0 to 3.

13 . A composition, comprising:
at least a first compound of claim 9 ; and an additional component.

14 . A method of treating or preventing a disease or disorder selected from a metabolic disorder, inflam

Assignees

• Salk Inst For Biological Studi
• Univ Sydney

Inventors

• Evans Ronald M
• Downes Michael
• Baiga Thomas J
• Keana John F W
• Liddle Christopher

Classifications

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D209/18

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D235/18

  with aryl radicals directly attached in position 2 · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title