Methods for modulating FXR receptor activity

1. A method of treating an FXR-mediated pathological condition selected from hypercholesterolemia and hyperlipoproteinemia in a mammal comprising the step of administering to a mammal in need thereof a pharmaceutically acceptable composition comprising a compound of the formula:

wherein the dashed line represents a bond or absence of a bond;

X is S, O, NR′ where R′ is H or alkyl of 1 to 6 carbons, or X is (C(R 1 ) 2 ) n where R 1 is H or alkyl of 1 to 6 carbons, and n is an integer having the value of 0 to 1;

R 2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, 1, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 12 carbons, or alkylthio of to 12 carbons, benzyloxy or C 1 -C 12 alkylbenzyloxy;

R 3 is hydrogen, lower alkyl of 1 to 6 carbons or F;

m is an integer having the value of 0-3;

o is an integer having the value of 0-4 when the dashed line represents absence of a bond, and 0-3 when the dashed line represents a bond;

R′ 3 is hydrogen, lower alky of 1 to 6 carbons, F or (R 15 ) r -phenyl, (R 15 ) r -naphthyl, or (R 15 ) r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and H, r is an integer having the values of 0-5;

R 4 is alkyl of 1 to 8 carbons, or phenyl;

s is an integer having the value of 0-2;

Y is phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinly, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups;

R 15 is independently H, F, Cl, Br, I, NO 2 , N(R 8 ) 2 , NH(R 8 ), COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons;

A is (CH) q where q is 0-5, lower branched chain alkyl having 3-6 carbons cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH, NO 2 , P(O)(OH) 2 , P(O)(OH)OR 8 , P(O)(OR 8 ) 2 , SO 2 OH, SO 2 (OR 8 ), COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.

2. A method in accordance with claim 1 where X is (C(R 1 ) 2 ) n and n is 1.

3. A method in accordance with claim 1 where X is S.

4. A method in accordance with claim 1 where X is 0.

5. A method in accordance with claim 1 where X is NR′.

6. A method in accordance with claim 1 where Y is phenyl.

7. A method in accordance with claim 1 where Y is thienyl.

8. A method in accordance with claim 1 wherein said compound has a structure of formula (3) where the dashed line represents a bond.

9. A method in accordance with claim 1 wherein said compound has a structure of formula (3) where the dashed line represents a bond.

10. A method of treating a hypercholesterolemic mammal comprising the steps: administering to a mammal in need thereof a pharmaceutically acceptable composition comprising an FXR antagonist having the following formula

wherein the dashed line represents a bond or absence of a bond;

X is S, O, NR′ where R′ is H or alkyl of 1 to 6 carbons, or X is (C(R 1 ) 2 ) n where R 1 is H or alkyl of 1 to 6 carbons, and n is an integer having the value of 0 to 1;

R 2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 12 carbons, or alkylthio of 1 to 12 carbons, benzyloxy or C 1 -C 12 alkylbenxyloxy;

R 3 is hydrogen, lower alkyl of 1 to 6 carbons or F;

m is an integer having the value of 0-3;

o is an integer having the value of 04 when the dashed line represents absence of a bond, and 0-3 when the dashed line represents a bond;

R′ 3 is hydrogen, lower alky of 1 to 6 carbons, F or (R 15 ) r -phenyl, (R 15 )r-naphthyl, or (R 15 ) r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and H, r is an integer having the values of 0-5;

R 4 is alkyl of 1 to 8 carbons, or phenyl;

Y is phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinly, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups;

s is an integer having the value of 0-2;

R 15 , is independently H, F, Cl, Br, I, NO 2 , N(R 8 ) 2 , NH(R 8 ), COR 8 , NR 8 CON(RB) 2 , OH, OCOR 8 , OR 8 , CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons;

A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 carbons cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH, NO 2 , P(O)(OH) 2 , P(O)(OH)OR 8 , P(O)(OR 8 ) 2 , SO 2 OH, SO 2 (OR 8 ), COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 21 CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of S-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.

11. A method in accordance with claim 1 where R 2 is H and R 4 is ethyl.

12. A method in accordance with claim 11 where B is CH 2 OH.

13. A method in accordance with claim 11 where B is COOR 8 .

14. A method in accordance with claim 1 where the compound of formula (3) is

or a pharmaceutically acceptable salt thereof.

15. The method in accordance with claim 1 where the compound of formula (3) is

or a pharmaceutically acceptable salt thereof.

16. The method in accordance with claim 1 where the compound of formula (3) is

or a pharmaceutically acceptable salt thereof.

17. A method in accordance with claim 10 where R 2 is H and R 4 is ethyl.

18. A method in accordance with claim 17 where B is CH 2 OH.

19. A method in accordance with claim 17 where B is COOR 8 .

20. A method in accordance with claim 10 where X is (C(R 1 ) 2 ) n and n is 1.

21. A method in accordance with claim 10 where X is S.

22. A method in accordance with claim 10 where X is O.

23. A method in accordance with claim 10 where X is NR′.

24. A method in accordance with claim 10 where Y is phenyl.

25. A method in accordance with claim 10 where Y is thienyl.

26. A method in accordance with claim 10 where the compound of formula (3) is

or a pharmaceutically acceptable salt thereof.

27. The method in accordance with claim 10 where the compound of formula (3) is

or a pharmaceutically acceptable salt thereof.

28. The method in accordance with claim 10 where the compound of formula (3) is

or a pharmaceutically acceptable salt thereof.

29. A method of treating an FXR-mediated pathological condition selected from hypercholesterolemia and hyperlipoproteinemia in a mammal comprising the step of administering to a mammal in need thereof a pharmaceutically acceptable composition comprising (Z)-5-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronapthalen-2-yl)-2-(trimethylsilyl)vinyl]thiophene-2-carboxylic acid.

30. A method of treating a hypercholesterolemic mammal comprising the steps: administering to a mammal in need thereof a pharmaceutically acceptable composition comprising an FXR antagonist (Z)-5-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronapthalen-2-yl)-2-(trimethylsilyl)vinyl]thiophene-2-carboxylic acid.