Compounds, their preparation and use
AssigneeNovo Nordisk A/S
InventorsJohn Patrick Mogensen, Per Sauerberg, Paul Stanley Bury, Lone Jeppesen, Ingrid Pettersson
Life of this patent
Estimating the term…
Abstract
The present invention relates to compounds of the general formula (I) 1 The compounds are useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).
Claims89
A compound of formula (I)
- 180
- 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, C1-6-alkylamino, C1-6-dialkylamino, methylenedioxy, aralkenyl, aralkynyl, heteroaryloxy, heteroaralkoxy, aralkyl, heteroaralkyl, arylamino, or
- A is optionally substituted with C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl each of which is optionally substituted with one or more substituents selected from C1-6-alkoxycarbonyl or carboxy, or
- A is optionally substituted with C1-6-alkoxy, C1-6-alkylthio or C2-6-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 C1-6-alkoxy, nitro, carboxy or C1-6-alkoxycarbonyl;
- and
- X1 and X2 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, C1-6-alkoxy, C1-6-alkylthio, halogen, perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, amino, C1-6-alkylamino, C1-6-dialkylamino, arylamino or methylenedioxy, or aryl or heteroaryl each of which is optionally substituted with one or more substituents selected from C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl each of which is optionally substituted with hydroxy;
- or
- A is selected from the ring systems consisting of
- 181
- wherein the attachment point of A to the remaining part of the structure of formula (I) is as indicated on the chemical structures in FIG. 1, and wherein A is optionally substituted with one or more substituents selected from C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C1-6-alkoxy, C1-6-alkylthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino, C1-6-alkylamino, C1-6-dialkylamino, arylamino or methylenedioxy;
- and
- wherein X1 and X2 are hydrogen;
- and
- R5 is hydrogen or C1-6-alkyl;
- and
- Y is hydrogen, or
- Y is C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl, C4-12-alkenynyl, aralkyl or heteroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, C1-6-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino;
- and
- Z is hydrogen, halogen, hydroxy, or
- Z is C1-6-alkyl or C1-6-alkoxy each of which is optionally substituted with one or more substituents selected from halogen, hydroxy, carboxy, amino, cyano or C1-6-alkoxy;
- and
- Q is O, S or NR6, wherein R6 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C4-6-alkenynyl, aralkyl, heteroaralkyl and wherein R6 is optionally substituted with one or more substituents selected from halogen, hydroxy, C1-6-alkoxy, amino or carboxy;
- and
- Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally substituted with one or more substituents selected from C1-6-alkyl, aryl or C1-6-alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy, cyano or heterocyclyl;
- and
- R1 is hydrogen, hydroxy or halogen;
- or R1 forms a bond together with R2;
- and
- R2 is hydrogen or C1-6-alkyl;
- or R2 forms a bond together with R1;
- and
- R3 is hydrogen, or
- R3 is C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C4-6-alkenynyl, aryl, aralkyl, C1-6-alkoxyC1-6-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
- R4 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C4-6-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 including a racemic mixture, or polymorphs.
A compound according to any one of the preceding claims of formula (I)
- 186
- wherein A is aryl or heteroaryl and wherein A is optionally substituted with one or more substituents selected from C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C1-6-alkoxy, C1-6-alkylthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino, C1-6-alkylamino, C1-6-dialkylamino, arylamino or methylenedioxy;
- or
- provided X1 and X2 is hydrogen, A is selected from the ring systems consisting of
- 187
- wherein A is optionally substituted with one or more substituents selected from C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, C1-6-alkoxy, C1-6-alkylthio, heteroaryloxy, heteroaralkoxy, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl, heteroaralkyl, cyano, amino, C1-6-alkylamino, C1-6-dialkylamino, arylamino or methylenedioxy;
- and
- R5 is hydrogen or C1-6-alkyl;
- and
- X1 and X2 independently are hydrogen, aryl or heteroaryl optionally substituted with one or more substituents selected from C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, hydroxy, aryloxy, arylthio, aralkoxy, heteroaryloxy, aralkoxy, C1-6-alkoxy, C1-6-alkylthio, halogen, perhalomethyl, perhalomethoxy, acyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, amino, C1-6-alkylamino, C1-6-dialkylamino, arylamino or methylenedioxy;
- and
- Y is hydrogen, C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl, C4-12-alkenynyl, aralkyl or heteroaralkyl optionally substituted with one or more substituents selected from halogen, C1-6-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, carboxy or amino;
- and
- Z is hydrogen, halogen, hydroxy, C1-6-alkyl or C1-6-alkoxy optionally substituted with one or more substituents selected from halogen, hydroxy, carboxy, amino, cyano or C1-6-alkoxy;
- and
- Q is O, S or NR6, wherein R6 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C4-6-alkenynyl, aralkyl, heteroaralkyl and wherein R6 is optionally substituted with one or more substituents selected from halogen, hydroxy, C1-6-alkoxy, amino or carboxy;
- and
- Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally substituted with one or more substituents selected from C1-6-alkyl, aryl or C1-6-alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy, cyano or heterocyclyl;
- and
- R1 is hydrogen, hydroxy or halogen;
- or R1 forms a bond together with R2;
- and
- R2 is hydrogen or C1-6-alkyl;
- or R2 forms a bond together with R1;
- and
- R3 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C4-6-alkenynyl, aryl, aralkyl, C1-6-alkoxyC1-6-alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy or cyano;
- and
- R4 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C4-6-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 including a racemic mixture, or polymorphs.
A compound according to any one of the preceding claims wherein A is aryl or heteroaryl optionally substituted with one or more substituents selected from from C1-6-alkyl, C2-6-alkenyl each of which is optionally substituted with one or more substituents selected from C1-6-alkoxycarbonyl or carboxy, or
- A is optionally substituted with aryloxy optionally substituted with one or more C1-6-alkoxy, or
- A is optionally substituted with aralkoxy optionally substituted with one or more substituents selected from C1-6-alkoxy, nitro, carboxy or C1-6-alkoxycarbonyl, or
- A is optionally substituted with C1-6-alkoxy optionally substituted with one or more halogens, or
- A is optionally substituted with aralkenyl, C2-6-alkenyloxy, aralkynyl, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl or methylenedioxy.
A compound according to any one of the preceding claims wherein A is aryl, heteroaryl or
- 188
- optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, C1-6-alkoxy, C1-6-alkylthio, halogen, perhalomethyl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
A compound according to any one of the preceding claims wherein A is aryl optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, C1-6-alkoxy, C1-6-alkylthio, halogen, perhalomethyl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
A compound according to any one of the preceding claims wherein A is aryl optionally substituted with one or more substituents selected from from C1-6-alkyl, C2-6-alkenyl each of which is optionally substituted with one or more substituents selected from C1-6-alkoxycarbonyl or carboxy, or
- A is optionally substituted with aryloxy optionally substituted with one or more C1-6-alkoxy, or
- A is optionally substituted with aralkoxy optionally substituted with one or more substituents selected from C1-6-alkoxy, nitro, carboxy or C1-6-alkoxycarbonyl, or
- A is optionally substituted with C1-6-alkoxy optionally substituted with one or more halogens or
- A is optionally substituted with aralkenyl, C2-6-alkenyloxy, aralkynyl, halogen, perhalomethyl, perhalomethoxy, acyl, aralkyl or methylenedioxy.
A compound according to any one of the preceding claims wherein A is aryl optionally substituted with one or more substituents selected from from C1-6-alkyl, or
- A is optionally substituted with aryloxy optionally substituted with one or more C1-6-alkoxy,
- A is optionally substituted with aralkoxy optionally substituted with one or more substituents selected from C1-6-alkoxy, or
- A is optionally substituted with C1-6-alkoxy optionally substituted with one or more halogens, or
- A is optionally substituted with aralkenyl, aralkynyl, halogen, perhalomethyl, perhalomethoxy or aralkyl.
A compound according to any one of the preceding claims wherein A is heteroaryl optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, C1-6-alkoxy, C1-6-alkylthio, halogen, perhalomethyl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
A compound according to any one of the preceding claims wherein A is heteroaryl.
A compound according to any one of the preceding claims wherein A is
- 189
- optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, C1-6-alkoxy, C1-6-alkylthio, halogen, perhalomethyl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
A compound according to any one of the preceding claims wherein A is
- 190
- optionally substituted with one or more substituents selected from C1-6-alkyl, and wherein R5 is hydrogen or C1-6-alkyl.
A compound according to any one of the preceding claims wherein X1 and X2 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.
A compound according to any one of the preceding claims wherein X1 and X2 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 C1-6-alkyl, C2-6-alkynyl each of which is optionally substituted with hydroxy.
A compound according to any one of the preceding claims wherein X1 and X2 independently are
- hydrogen, or
- aryl optionally substituted with one or more substituents selected from halogen.
A compound according to any one of the preceding claims wherein X1 and X2 independently are hydrogen or aryl optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, halogen, perhalomethyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
A compound according to any one of the preceding claims wherein X1 and X2 independently are
- hydrogen,
- aryl optionally substituted with one or more substituents selected from halogen, acyl, aryl, or
- aryl optionally substituted with one or more substituents selected from C1-6-alkyl, C2-6-alkynyl each of which is optionally substituted with hydroxy.
A compound according to any one of the preceding claims wherein X1 and X2 independently are
- hydrogen, or
- phenyl optionally substituted with one or more substituents selected from halogen.
A compound according to any one of the preceding claims wherein X1 and X2 independently are hydrogen or heteroaryl optionally substituted with one or more substituents selected from aryloxy, arylthio, aralkoxy, halogen, perhalomethyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
A compound according to any one of the preceding claims wherein X1 and X2 independently are hydrogen or heteroaryl.
A compound according to any one of the preceding claims wherein X1 and X2 is hydrogen.
A compound according to any one of the preceding claims wherein Y is hydrogen or C1-12-alkyl.
A compound according to any one of the preceding claims wherein Y is hydrogen or methyl.
A compound according to any one of the preceding claims wherein Z is hydrogen or C1-6-alkoxy.
A compound according to any one of the preceding claims wherein Z is hydrogen or C1-6-alkyl.
A compound according to any one of the preceding claims wherein Z is hydrogen.
A compound according to any one of the preceding claims wherein Q is O.
A compound according to any one of the preceding claims wherein Ar is arylene optionally substituted with one or more substituents selected from C1-6-alkyl or C1-6-alkoxy each of which can be optionally substituted with carboxy.
A compound according to any one of the preceding claims wherein Ar is arylene.
A compound according to any one of the preceding claims wherein R1 is hydrogen or R1 forms a bond together with R2.
A compound according to any one of the preceding claims wherein R1 is hydrogen.
A compound according to any one of the preceding claims wherein R2 is hydrogen or R2 forms a bond together with R1.
A compound according to any one of the preceding claims wherein R2 is hydrogen.
A compound according to any one of the preceding claims wherein R3 is C1-6-alkyl or aralkyl.
A compound according to any one of the preceding claims wherein R3 is C1-6-alkyl.
A compound according to any one of the preceding claims wherein R4 is hydrogen, C1-3-alkyl.
A compound according to any one of the preceding claims wherein R4 is hydrogen.
A compound according to any one of the preceding claims wherein n is 1.
A compound according to any one of the preceding claims wherein m is 1.
A compound according to any one of the preceding claims wherein alkyl is methyl, ethyl, n-propyl, iso-propyl, butyl, tert-butyl, pentyl, hexyl, cyclopropyl or cyclopentyl.
A compound according to any one of the preceding claims wherein alkenyl is vinyl or 1-propenyl.
A compound according to any one of the preceding claims wherein alkynyl is ethynyl, 1-propynyl and 2-propynyl.
A compound according to any one of the preceding claims wherein alkoxy is methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isopropoxy or cyclopentyloxy.
A compound according to any one of the preceding claims wherein alkylthio is methylthio, ethylthio, propylthio or cyclopentylthio.
A compound according to any one of the preceding claims wherein aryl is phenyl optionally substituted with halogen.
A compound according to any one of the preceding claims wherein arylene is phenylene optionally substituted with halogen.
A compound according to any one of the preceding claims wherein halogen is fluorine or chlorine.
A compound according to any one of the preceding claims wherein perhalomethyl is trifluoromethyl.
A compound according to any one of the preceding claims wherein acyl is acetyl.
A compound according to any one of the preceding claims wherein heteroaryl is furan, thiophene, pyrrole, imidazole, pyrazole, pyridine, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole or benzofuran.
A compound according to any one of the preceding claims wherein heteroaryl is furan, pyrrole, indole or benzofuran.
A compound according to any one of the preceding claims wherein heteroarylene is furan, thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine or pyridazine.
A compound according to any one of the preceding claims wherein aralkyl is benzyl or phenethyl.
A compound according to any one of the preceding claims wherein aryloxy is phenoxy.
A compound according to any one of the preceding claims wherein aralkoxy is benzyloxy.
A compound according to any one of the preceding claims wherein n is an integer ranging from 1 to 3 and m is 1.
A compound according to any of the preceding claims wherein the substituents Z and Y are arranged in a trans-configuration.
A compound according to any of the preceding claims wherein the substituents Z and Y are arranged in a cis-configuration.
A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
A pharmaceutical composition useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR), the composition comprising, as an active ingredient, a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
A pharmaceutical composition useful in the treatment and/or prevention of diabetes and/or obesity, the composition comprising, as an active ingredient, a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
Use of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a medicament.
Use of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a medicament useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).
Use of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treatment and/or prevention of diabetes and/or obesity.
Dependencies are inferred from the claim text.