Analogs of fexaramine and methods of making and using

Patent metadata

Field	Value
Publication number	US-11440889-B2
Application number	US-202017008866-A
Country	US
Kind code	B2
Filing date	Sep 1, 2020
Priority date	Mar 13, 2014
Publication date	Sep 13, 2022
Grant date	Sep 13, 2022

Abstract

Novel compounds having a formulaembodiments 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 method of treating a disorder or disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to a formula

or a pharmaceutically acceptable salt thereof, wherein
R is selected from

R a is selected from aryl, heteroaryl, alkenyl, cycloalkyl, heterocyclic, or polycyclic;
R b is selected from hydrogen, alkyl, alkenyl, or cycloalkyl;
Y is CR g , N or N—O (N-oxide);
R c , R d , R e and R g are each independently selected from hydrogen, deuterium, halide, alkyl, alkenyl, alkoxy, alkylthio, amino, sulfonyl, aminosulfonyl, aminocarbonyl, acyl, hydroxyl or nitro;
R fa and R fb are each independently selected from hydrogen, deuterium, halide or alkyl;
L a and L b are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl, or together form a pi-bond;
L c and L d are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl;
W is selected from O or —(C(L c )(L d )) s- ;
s is 1, 2, 3, 4, 5 or 6;
n is 0 or 1;
X is heterocyclic or heteroaryl; and

wherein
if W is CH 2 and L c and L d are both H, then X is not a benzopyran;
if R is

L c and L d are both H, and L a and L b are both H or together form a pi-bond, then X is not a benzopyran;
X is not substituted with —R x -L x -R x2 , where
R x is selected from O, NR x3 , sulfonyl or S;
R x3 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl;
L x is selected from a bond, alkylene, alkenylene, alkynylene, cycloalkyl, cycloalkenyl, heterocyclic, aryl, heteroaryl or CR x4 R x5 ;
R x4 and R x5 are each independently selected from H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —C(O)OR x6 , or —C(O)NR x6 R x7 ;
R x6 and R x7 are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl;
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, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —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, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl.

2. The method of claim 1 , wherein the polycyclic is selected from

or adamantane.

3. The method of claim 1 , wherein R is selected from

4. The method of claim 3 , wherein L a and L b together form a pi-bond.

5. The method of claim 1 , where the compound has a formula

6. The method of claim 1 , wherein X is pyridine or piperidine.

7. The method of claim 1 , wherein R fa is deuterium.

8. The method of claim 5 , wherein:
the polycyclic is selected from

or adamantane;
X is pyridine or piperidine; and
R fa is deuterium.

9. The method of claim 1 , wherein the disorder or disease is 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.

10. The method of claim 1 , 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.

11. A compound having a formula

or a pharmaceutically acceptable salt thereof, wherein:
Y is CR g , N or N—O (N-oxide);
R is selected from

R a is selected from aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, heterocyclic, or polycyclic;
R b is selected from alkyl, alkenyl, or cycloalkyl;
R c , R d , R e and R g are each independently selected from hydrogen, deuterium, halide, alkyl, alkenyl, alkoxy, alkylthio, amino, sulfonyl, aminosulfonyl, aminocarbonyl, cycloalkyl, heterocyclic, acyl, hydroxyl or nitro;
R fa and R fb are each independently selected from hydrogen, deuterium, halide or alkyl;
X is aryl, heterocyclic or heteroaryl;
L a and L b are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl, or together form a pi-bond;
L c and L d are each independently selected from hydrogen, deuterium, alkyl or cycloalkyl;
W is selected from O or —(C(L c )(L d )) s- ;
s is 1, 2, 3, 4, 5 or 6;
n is 0 or 1; and
wherein X is not substituted with —R x -L x -R x2 , where
R x is selected from O, NR x3 , sulfonyl or S;
R x3 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl;
L x is selected from a bond, alkylene, alkenylene, alkynylene, cycloalkyl, cycloalkenyl, heterocyclic, aryl, heteroaryl or CR x4 R x5 ;
R x4 and R x5 are each independently selected from H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —C(O)OR x6 , or —C(O)NR x6 R x7 ;
R x6 and R x7 are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl;
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, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —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 o

Assignees

• Salk Inst For Biological Studi
• Univ Sydney
• Salk Inst Biological Studies

Inventors

• Evans Ronald M
• Downes Michael
• Atkins Annette
• Fang Sungsoon
• Suh Jae Myoung
• Baiga Thomas J
• Yu Ruth T
• Keana John F W
• Liddle Christopher

Classifications

• C07C2602/42

  the bicyclo ring system containing seven carbon atoms · CPC title

• C07C233/63

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07B59/001

  Acyclic or carbocyclic compounds · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title