Farnesoid x receptor agonists
AssigneeSmithKline Beecham Corporation
InventorsRichard CALDWELL, David Norman Deaton, Robert Blount McFayden, Frank Navas, Paul Kenneth Spearing
Life of this patent
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Abstract
The present invention provides novel substituted isoxazole compounds, pharmaceutical compositions, therapeutic uses and processes for preparing the same.
Claims47
A compound of formula (I):
- wherein:
- a is 1, 2, 3, 4 or 5;
- each R1 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, —O—CF3, —OR6, —S(O)fR6, —NR6R7, —R5OR6, —R5S(O)fR6, —R5NR6R7 and cyano;
- b is 0, 1, 2 or 3;
- R2 is selected from the group consisting of alkyl, alkenyl, C3-6cycloalkyl, C3-6cycloalkenyl, —R5OR6, —R5NR6R7 and cyano;
- Y is —O—, —S— or —N(R5)—;
- R3 is an acid, amide, ester or acid-equivalent group;
- R4 is H, halo, alkyl or haloalkyl;
- each R5 is the same or different and is independently selected from the group consisting of alkylene and alkenylene;
- each R6 and R7 are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, C3-6cycloalkyl and C3-6cyclolalkenyl;
- and
- f is 0, 1 or 2;
- each R5 is the same or different and is independently H or alkyl;
- or a pharmaceutically acceptable salt or solvate thereof.
A compound selected from the group consisting of:
- 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthoic acid sodium salt;
- 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;
- 6-[2-Chloro-4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;
- 6-[4-({[5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;
- 6-[4-({[3-[(2,6-dichlorophenyl)methyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;
- 6-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;
- 6-(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}phenyl)-2-naphthoic acid;
- Methyl 6-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-naphthalenecarboxylate;
- 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-naphthalenecarboxylic acid;
- 7-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-naphthalenecarboxylic acid;
- 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;
- 7-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid;
- 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxamide;
- 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarbonitrile;
- 5-{6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenyl}-1H-tetrazole;
- and
- 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthoic acid tris(hydroxymethyl)aminomethane salt.
6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid or a pharmaceutically acceptable salt or solvate thereof.
6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthoic acid tris(hydroxymethyl)aminomethane salt.
A composition comprising 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid or a pharmaceutically acceptable salt or solvate thereof.
A composition comprising 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthoic acid tris(hydroxymethyl)aminomethane salt.
A method for the treatment of cholestatic liver disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid or a pharmaceutically acceptable salt or solvate thereof.
A method for the treatment of cholestatic liver disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthoic acid tris(hydroxymethyl)aminomethane salt.
A method for the treatment of diabetes mellitus in a subject in need thereof comprising administering to said subject a therapeutically effective amount of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid or a pharmaceutically acceptable salt or solvate thereof.
A method for the treatment of diabetes mellitus in a subject in need thereof comprising administering to said subject a therapeutically effective amount of 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthoic acid tris(hydroxymethyl)aminomethane salt.
Dependencies are inferred from the claim text.