Compounds, their preparation and use
View Patent ↗The present invention relates to compounds of the general formula (I) The compounds are useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).
1. A compound of formula (I)
wherein A is heteroaryl, a 5-10 membered ring system containing from 1-4 heteroatoms selected from O, N, and S, and wherein A is optionally substituted with one or more substituents selected from hydroxy, halogen, perhalomethyl, perhalomethoxy, acyl, cyano, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, methylenedioxy, aralkenyl, aralkynyl, heteroaryloxy, heteroaralkoxy, aralkyl, heteroaralkyl, a straight or branched saturated carbon chain containing from 1-6 carbons substituted with 1 heteroaryl group, arylamino, or
A is optionally substituted with C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl each of which is optionally substituted with one or more substituents selected from C 1-6 -alkoxycarbonyl or carboxy, or
A is optionally substituted with C 1-6 -alkoxy, C 1-6 -alkylthio or C 2-6 -alkenyloxy each of which is optionally substituted with one or more halogens, or
A is optionally substituted with aryloxy, arylthio or aralkoxy each of which is optionally substituted with one or more substituents selected from C 1-6 -alkoxy, nitro, carboxy or C 1-6 -alkoxycarbonyl; and
X 1 and X 2 independently are hydrogen,
aryl or heteroaryl, a 5-10 membered ring system containing from 1-4 heteroatoms selected from O, N, and S, each of which is optionally substituted with one or more substituents selected from hydroxy, aryloxy, arylthio, aralkoxy, heteroaryloxy, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, halogen, perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl, heteroaralkyl, a straight or branched saturated carbon chain containing from 1-6 carbons substituted with 1 heteroaryl group, cyano, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, arylamino or methylenedioxy, or
aryl or heteroaryl each of which is optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl each of which is optionally substituted with hydroxy; and
Y is hydrogen, or
Y is C 1-12 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 4-12 -alkenynyl, aralkyl or heteroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, C 1-6 -alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, a 5-10 membered ring system containing from 1-4 heteroatoms selected from O, N, and S, carboxy or amino; and
Z is hydrogen, halogen, hydroxy, or
Z is C 1-6 -alkyl or C 1-6 -alkoxy each of which is optionally substituted with one or more substituents selected from halogen, hydroxy, carboxy, amino, cyano or C 1-6 -alkoxy; and
Q is O, S or NR 6 , wherein R 6 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl, aralkyl, heteroaralkyl and wherein R 6 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 -alkoxy, amino or carboxy; and
Ar is arylene, which can be optionally substituted with one or more substituents selected from C 1-6 -alkyl, aryl or C 1-6 -alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy, cyano or heterocyclyl; and
R 1 is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and
R 2 is hydrogen or C 1-6 -alkyl; or R 2 forms a bond together with R 1 ; and
R 3 is hydrogen, or
R 3 is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl, aryl, aralkyl, C 1-6 -alkoxyC 1-6 -alkyl, acyl, heterocyclyl, a 5-10 membered ring system containing from 1-4 heteroatoms selected from O, N, and S, heteroaryl, a 5-10 membered ring system containing from 1-4 heteroatoms selected from O, N, and S, or heteroaralkyl, a straight or branched saturated carbon chain containing from 1-6 carbons substituted with 1 heteroaryl group, each of which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy or cyano; and
R 4 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl or aryl; and
n is an integer ranging from 0 to 3; and
m is an integer ranging from 0 to 1;
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers, or a racemic mixture.
2. A compound according to claim 1 of formula (I)
wherein A is aryl or heteroaryl and wherein A is optionally substituted with one or more substituents selected from hydroxy, halogen, perhalomethyl, perhalomethoxy, acyl, cyano, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, methylenedioxy, aralkenyl, aralkynyl, heteroaryloxy, heteroaralkoxy, aralkyl, heteroaralkyl, arylamino, or
A is optionally substituted with C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl each of which is optionally substituted with one or more substituents selected from C 1-6 -alkoxycarbonyl or carboxy, or
A is optionally substituted with C 1-6 -alkoxy, C 1-6 -alkylthio or C 2-6 -alkenyloxy each of which is optionally substituted with one or more halogens, or
A is optionally substituted with aryloxy, arylthio or aralkoxy each of which is optionally substituted with one or more substituents selected from C 1-6 -alkoxy, nitro, carboxy or C 1-6 -alkoxycarbonyl; and
X 1 and X 2 independently are hydrogen,
aryl or heteroaryl each of which is optionally substituted with one or more substituents selected from hydroxy, aryloxy, arylthio, aralkoxy, heteroaryloxy, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, halogen, perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, arylamino or methylenedioxy, or
aryl or heteroaryl each of which is optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl each of which is optionally substituted with hydroxy; and
Y is hydrogen, or
Y is C 1-12 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 4-12 -alkenynyl, aralkyl or heteroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, C 1-6 -alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino; and
Z is hydrogen, halogen, hydroxy, or
Z is C 1-6 -alkyl or C 1-6 -alkoxy each of which is optionally substituted with one or more substituents selected from halogen, hydroxy, carboxy, amino, cyano or C 1-6 -alkoxy; and
Q is O, S or NR 6 , wherein R 6 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl, aralkyl, heteroaralkyl and wherein R 6 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 -alkoxy, amino or carboxy; and
Ar is arylene, which can be optionally substituted with one or more substituents selected from C 1-6 -alkyl, aryl or C 1-6 -alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy, cyano or heterocyclyl; and
R 1 is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and
R 2 is hydrogen or C 1-6 -alkyl; or R 2 forms a bond together with R 1 ; and
R 3 is hydrogen, or
R 3 is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl, aryl, aralkyl, C 1-6 -alkoxyC 1-6 -alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy or cyano; and
R 4 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl or aryl; and
n is an integer ranging from 1 to 3; and
m is 1;
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers, or a racemic mixture.
3. A compound according to claim 1 of formula (I)
wherein A is heteroaryl and wherein A is optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, arylamino or methylenedioxy; and
X 1 and X 2 independently are hydrogen, aryl or heteroaryl optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, heteroaryloxy, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, halogen, perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, arylamino or methylenedioxy;
Y is hydrogen, C 1-12 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 4-12 -alkenynyl, aralkyl or heteroaralkyl optionally substituted with one or more substituents selected from halogen, C 1-6 -alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino; and
Z is hydrogen, halogen, hydroxy, C 1-6 -alkyl or C 1-6 -alkoxy optionally substituted with one or more substituents selected from halogen, hydroxy, carboxy, amino, cyano or C 1-6 -alkoxy; and
Q is O, S or NR 6 , wherein R 6 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl, aralkyl, heteroaralkyl and wherein R 6 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 -alkoxy, amino or carboxy; and
Ar is arylene, which can be optionally substituted with one or more substituents selected from C 1-6 -alkyl, aryl or C 1-6 -alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy, cyano or heterocyclyl; and
R 1 is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and
R 2 is hydrogen or C 1-6 -alkyl; or R 2 forms a bond together with R 1 ; and
R 3 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl, aryl, aralkyl, C 1-6 -alkoxyC 1-6 -alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy or cyano; and
R 4 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl or aryl; and
n is an integer ranging from 0 to 3; and
m is an integer ranging from 0 to 1;
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers, or a racemic mixture.
4. A compound according to claim 1 of formula (I)
wherein A is heteroaryl and wherein A is optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, arylamino or methylenedioxy; and
X 1 and X 2 independently are hydrogen, aryl or heteroaryl optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, heteroaryloxy, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, halogen, perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, amino, C 1-6 -alkylamino, C 1-6 -dialkylamino, arylamino or methylenedioxy; and
Y is hydrogen, C 1-12 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 4-12 -alkenynyl, aralkyl or heteroaralkyl optionally substituted with one or more substituents selected from halogen, C 1-6 -alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino; and
Z is hydrogen, halogen, hydroxy, C 1-6 -alkyl or C 1-6 -alkoxy optionally substituted with one or more substituents selected from halogen, hydroxy, carboxy, amino, cyano or C 1-6 -alkoxy; and
Q is O, S or NR 6 , wherein R 6 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl, aralkyl, heteroaralkyl and wherein R 6 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 -alkoxy, amino or carboxy; and
Ar is arylene, of which can be optionally substituted with one or more substituents selected from C 1-6 -alkyl, aryl or C 1-6 -alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy, cyano or heterocyclyl; and
R 1 is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and
R 2 is hydrogen or C 1-6 -alkyl; or R 2 forms a bond together with R 1 ; and
R 3 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl, aryl, aralkyl, C 1-6 -alkoxyC 1-6 -alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy or cyano; and
R 4 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 4-6 -alkenynyl or aryl; and
n is an integer ranging from 0 to 3; and
m is an integer ranging from 0 to 1;
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers, or a racemic mixture.
5. A compound according to claim 1 , wherein A is heteroaryl optionally substituted with one or more substituents selected from from C 1-6 -alkyl, C 2-6 -alkenyl each of which is optionally substituted with one or more substituents selected from C 1-6 -alkoxycarbonyl or carboxy, or
A is optionally substituted with aryloxy optionally substituted with one or more C 1-6 -alkoxy, or
A is optionally substituted with aralkoxy optionally substituted with one or more substituents selected from C 1-6 -alkoxy, nitro, carboxy or C 1-6 -alkoxycarbonyl, or
A is optionally substituted with C 1-6 -alkoxy optionally substituted with one or more halogens, or
A is optionally substituted with aralkenyl, C 2-6 -alkenyloxy, aralkynyl, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl or methylenedioxy.
6. A compound according to claim 1 , wherein A is heteroaryl optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, halogen, perhalomethyl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
7. A compound according to claim 1 , wherein A is heteroaryl optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, C 1-6 -alkoxy, C 1-6 -alkylthio, halogen, perhalomethyl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
8. A compound according to claim 1 , wherein A is heteroaryl.
9. A compound according to claim 1 , wherein X 1 and X 2 independently are hydrogen, aryl or heteroaryl optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, halogen, perhalomethyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
10. A compound according to claim 9 , wherein X 1 and X 2 independently are hydrogen,
aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, acyl, aryl, or
aryl or heteroaryl optionally substituted with one or more substituents selected from C 1-6 -alkyl, C 2-6 -alkynyl each of which is optionally substituted with hydroxy.
11. A compound according to claim 1 , wherein Y is hydrogen or C 1-12 -alkyl.
12. A compound according to claim 1 , wherein Z is hydrogen or C 1-6 -alkoxy.
13. A compound according to claim 1 , wherein Q is O.
14. A compound according to claim 1 , wherein Ar is arylene optionally substituted with one or more substituents selected from C 1-6 -alkyl or C 1-6 -alkoxy each of which can be optionally substituted with carboxy.
15. A compound according to claim 1 , wherein R 1 is hydrogen or R 1 forms a bond together with R 2 .
16. A compound according to claim 1 , wherein R 2 is hydrogen.
17. A compound according to claim 1 , wherein R 3 is C 1-6 -alkyl or aralkyl.
18. A compound according to claim 1 , wherein R 4 is hydrogen, or C 1-3 -alkyl.
19. A compound according to claim 1 , wherein alkyl is methyl, ethyl, n-propyl, iso-propyl, butyl, tert-butyl, pentyl, hexyl, cyclopropyl or cyclopentyl.
20. A compound according to claim 1 , wherein alkenyl is vinyl or 1-propenyl.
21. A compound according to claim 1 , wherein alkynyl is ethynyl, 1-propynyl and 2-propynyl.
22. A compound according to claim 1 , wherein alkoxy is methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isopropoxy or cyclopentyloxy.
23. A compound according to claim 1 , wherein alkylthio is methylthio, ethylthio, propylthio or cyclopentylthio.
24. A compound according to claim 1 , wherein aryl is phenyl optionally substituted with halogen.
25. A compound according to claim 1 , wherein arylene is phenylene optionally substituted with halogen.
26. A compound according to claim 1 , wherein halogen is fluorine or chlorine.
27. A compound according to claim 1 , wherein perhalomethyl is trifluoromethyl.
28. A compound according to claim 1 , wherein acyl is acetyl.
29. A compound according to claim 1 , wherein heteroaryl is furan, thiophene, pyrrole, imidazole, pyrazole, pyridine, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole or benzofuran.
30. A compound according to claim 1 , wherein aralkyl is benzyl or phenethyl.
31. A compound according to claim 1 , wherein aryloxy is phenoxy.
32. A compound according to claim 1 , wherein aralkoxy is benzyloxy.
33. A compound according to claim 1 , wherein n is an integer ranging from 1 to 3 and m is 1.
34. A compound according to claim 1 , wherein the substituents Z and Y are arranged in a trans-configuration.
35. A compound according to claim 1 , wherein the substituents Z and Y are arranged in a cis-configuration.
36. The compound according to claim 1 , which is:
(E)-(S)-2-Ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionic acid ethyl ester,
(E)-(S)-2-Ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionic acid,
(S)-3-[4-(2-Benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid ethyl ester,
(S)-3-[4-(2-Benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid;
or a pharmaceutically acceptable salt thereof.
37. The compound according to claim 4 which is:
(E)-(S)-2-Ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionic acid ethyl ester,
(E)-(S)-2-Ethoxy-3-[4-(3-pyridin-2-yl-but-2-enyloxy)-phenyl]-propionic acid,
(S)-3-[4-(2-Benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid ethyl ester,
(S)-3-[4-(2-Benzofuran-3-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid;
or a pharmaceutically acceptable salt thereof.
38. The compound according to claim 1 , which is:
(E)-(S)-3-[4-(3-Benzo[1,3]dioxol-5-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid ethyl ester,
(E)-(S)-3-[4-(3-Benzo[1,3]dioxol-5-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid,
(E)-(S)-3-[4-(3-Benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid ethyl ester,
(E)-(S)-3-[4-(3-Benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid,
(S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionic acid ethyl ester,
(S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionic acid,
or a pharmaceutically acceptable salt thereof.
39. The compound according to claim 4 which is:
(E)-(S)-3-[4-(3-Benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid ethyl ester,
(E)-(S)-3-[4-(3-Benzofuran-7-yl-allyloxy)-phenyl]-2-ethoxy-propionic acid,
(S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionic acid ethyl ester,
(S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionic acid,
or a pharmaceutically acceptable salt thereof.
40. The compound according to claim 1 , which is:
(E)-(S)-Ethyl 2-Ethoxy-3-{4-[3-(4-furan-2-yl-phenyl)-but-2-enyloxy]-phenyl}-propionate.
41. A composition comprising, as an active ingredient, a compound according to claim 1 , or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
42. A composition according to claim 41 in unit dosage form, comprising from about 0.05 to about 100 mg of the compound or a pharmaceutically acceptable salt thereof.
43. A composition according to claim 41 for oral, nasal, transdermal, pulmonal, or parenteral administration.
44. A method for the treatment of diabetes and/or obesity, the method comprising administering to a subject in need thereof an effective amount of a composition according to claim 41 .
45. The method according to claim 44 , wherein the effective amount of the compound in said composition is in the range of from about 0.05 to about 100 mg per day.
46. A composition suitable for treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers, or racemic mixture together with one or more pharmaceutically acceptable carriers or diluents and an ACE (angiotensin converting enzyme) inhibitor.
47. A method of treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers, or racemic mixture, together with one or more pharmaceutically acceptable carriers or diluents and an ACE (angiotensin converting enzyme) inhibitor to said subject.
48. A composition suitable for treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers, or racemic mixture together with one or more pharmaceutically acceptable carriers or diluents and an agent stimulating insulin release from β cells such as a meglitinide, like repaglinide or senaglinide.
49. A method of treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 and an agent stimulating insulin release from β cells such as a meglitinide, like repaglinide or senaglinide, to said subject.
50. A composition suitable for treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers, or racemic mixture together with one or more pharmaceutically acceptable carriers or diluents and a biguanide like metformin.
51. A method of treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers, or racemic mixture together with one or more pharmaceutically acceptable carriers or diluents and a biguanide, like metformin, to said subject.
52. A composition suitable for treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers, or racemic mixture together with one or more pharmaceutically acceptable carriers or diluents and a HMG CoA inhibitor.
53. A method of treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers, or racemic mixture together with one or more pharmaceutically acceptable carriers or diluents and a HMG CoA inhibitor to said subject.