IP Library › Granted Patent US 7,008,957

Granted Patent B2

US 7,008,957 · App. 10/898,751 · Granted Mar 7, 2006

Bicyclic cyanoheterocycles, process for their preparation and their use as medicaments

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Quick Facts

Patent No.: US 7,008,957
App. No.: 10/898,751
Granted: Mar 7, 2006
Kind: B2

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Abstract

The invention relates to compounds of the formula I in which the radicals have the stated meanings, their stereoisomeric forms and their physiologically tolerated salts and process for their preparation. The compounds are suitable for the treatment of metabohlic disorders such as type 2 diabetes.

Claims (54)

1. A compound of the formula I,

wherein

R1 is H, (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 6 –C 10 )-aryl or heterocyclyl,

wherein said (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 6 –C 10 )-aryl and heterocyclyl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, —CF 3 , (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, OR3, NR3R4, COR3, CO2R3, CONR3R4, (C 1 –C 6 )-alkylene-OR3, (C 1 –C 6 )-alkylene-NR3R4, (C 1 –C 6 )-alkylene-SR3, alkylene-SOR3, alkylene-SO 2 R3, (C 1 –C 6 )-alkylene-COR3, (C 1 –C 6 )-alkylene-COOR3, (C 1 –C 6 )-alkylene-CONR3R4, (C 1 –C 6 )-alkylene-O—P(O)(OR3) 2 , SR3, SOR3, SO 2 NR3R4, SO 2 R3, (C 1 –C 6 )-alkylene-(C 3 –C 10 )-cycloalkyl, (C 1 –C 6 )-alkylene-(C 6 –C 10 )-aryl, (C 1 –C 6 )-alkylene-heterocyclyl, (C 3 –C 10 )-cycloalkyl, (C 6 –C 10 )-aryl or heterocyclyl,

wherein said (C 6 –C 10 )-aryl is optionally substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, —CF 3 , (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, OR3, NR3R4, COR3, CO 2 R3 or CONR3R4,

and wherein said heterocyclyl is optionally substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, —CF 3 , (C 1 –C 6 )-alkyl, OR3, NR3R4, COR3, CO 2 R3 or CONR3R4;

R2 is H, (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 6 –C 10 )-aryl, heterocyclyl, COR3, COOR3, CONR3R4 or CN,

wherein said (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 6 –C 10 )-aryl and heterocyclyl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO 2 , SH, SF 5 , OH, (C 1 –C 6 )-alkyl, —CF 3 , (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, OR3, OP(O)(OR3) 2 , NR3R4, NR3CONR3R4, COR3, OCOR3, OCOOR3, COOR3, CONR3R4, OCONR3R4, (C 1 –C 6 )-alkylene-OR3, (C 1 –C 6 )-alkylene-NR3R4, (C 1 –C 6 )-alkylene-NR3SO 2 R4, (C 1 –C 6 )-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O) 2 R3, alkylene-S(O) 2 NR3R4, (C 1 –C 6 )-alkylene-COR3, (C 1 –C 6 )-alkylene-COOR3, (C 1 –C 6 )-alkylene-CONR3R4, SR3, SOR3, SO 2 R3, SO 2 NR3R4, NR3SO 2 R4, (C 1 –C 6 )-alkylene-(C 3 –C 10 )-cycloalkyl, (C 1 –C 6 )-alkylene-(C 6 –C 10 )-aryl, (C 1 –C 6 )-alkylene-heterocyclyl, (C 3 –C 10 )-cycloalkyl, (C 6 –C 10 )-aryl or heterocyclyl;

R3, R4 are each, independently of one another, H, (C 1 –C 6 )-alkyl, —CF 3 , (C 3 –C 10 )-cycloalkyl, (C 6 –C 10 )-aryl, heterocyclyl, (C 1 –C 6 )-alkylene-CONR5R6, CONR5R6, (C 1 –C 6 )-alkylene-COOR5, COOR5, COR5, (C 1 –C 6 )-alkylene-COR5, (C 1 –C 6 )-alkylene-OR5, (C 1 –C 6 )-alkylene-NR5R6, (C 1 –C 6 )-alkylene-SR5, (C 1 –C 6 )-alkylene-S(O)R5, (C 1 –C 6 )-alkylenee-S(O) 2 R5, S(O)R5, S(O) 2 R5, (C 1 –C 4 )-alkylene-(C 6 –C 10 )-aryl or (C 1 –C 4 )-alkylene-heterocyclyl;

R5, R6 are each, independently of one another, H, (C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene-(C 6 –C 10 )-aryl, —(C 6 –C 10 )-aryl, heterocyclyl or (C 1 –C 6 )-alkylene-heterocyclyl;

X is S, SO or SO 2 ;

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein:

R1 is H, (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl or (C 6 –C 10 )-aryl,

wherein said (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl and (C 6 –C 10 )-aryl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, —CF 3 , (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, OR3, NR3R4, COR3, CO 2 R3, CONR3R4, (C 1 –C 6 )-alkylene-OR3, (C 1 –C 6 )-alkylene-NR3R4, (C 1 –C 6 )-alkylene-SR3, alkylene-SOR3, alkylene-SO 2 R3, (C 1 –C 6 )-alkylene-COR3, (C 1 –C 6 )-alkylene-CO 2 R3, (C 1 –C 6 )-alkylene-CONR3R4, (C1–C6)-alkylene-O—P(O)(OR3) 2 , SR3, SOR3, SO 2 NR3R4, SO 2 R3, (C 1 –C 6 )-alkylene-(C 3 –C 10 )-cycloalkyl, (C 1 –C 6 )-alkylene-(C 6 –C 10 )-aryl, (C 1 –C 6 )-alkylene-heterocyclyl, (C 3 –C 10 )-cycloalkyl or (C 6 –C 10 )-aryl,

R2 is H, (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 6 –C 10 )-aryl, heterocyclyl, COR3, CO2R3, CONR3R4 or CN,

wherein said (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 6 –C 10 )-aryl and heterocyclyl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO 2 , SH, SF 5 , OH, (C 1 –C 6 )-alkyl, —CF 3 , (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, OR3, OP(O)(OR3) 2 , NR3R4, NR3CONR3R4, COR3, OCOR3, CO 2 R3, CONR3R4, OCONR3R4, (C 1 –C 6 )-alkylene-OR3, (C 1 –C 6 )-alkylene-NR3R4, (C 1 –C 6 )-alkylene-NR3SO 2 R4, (C 1 –C 6 )-alkylene-SR3, alkylene-SOR3, alkylene-SO 2 R3, alkylene-SO 2 NR3R4, (C 1 –C 6 )-alkylene-COR3, (C 1 –C 6 )-alkylene-CO 2 R3, (C 1 –C 6 )-alkylene-CONR3R4, SR3, SOR3, SO 2 R3, SO 2 NR3R4, NR3SO 2 R4, (C 1 –C 6 )-alkylene-(C 3 –C 10 )-cycloalkyl, (C 1 –C 6 )-alkylene-(C 6 –C 10 )-aryl, (C 1 –C 6 )-alkylene-heterocyclyl, (C 3 –C 10 )-cycloalkyl, (C 6 –C 10 )-aryl or heterocyclyl,

and wherein said heterocyclyl is optionally substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, —CF 3 , (C 1 –C 6 )-alkyl, OR3, NR3R4, COR3, CO 2 R3 or CONR3R4;

R3, R4 are each, independently of one another, H, (C 1 –C 6 )-alkyl, —CF 3 , (C 3 –C 10 )-cycloalkyl, (C 6 –C 10 )-aryl, heterocyclyl, (C 1 –C 6 )-alkylene-CONR5R6, (C 1 –C 6 )-alkylene-CO 2 R5, (C 1 –C 6 )-alkylene-COR5, (C 1 –C 6 )-alkylene-OR5, (C 1 –C 6 )-alkylene-NR5R6, (C 1 –C 6 )-alkylene-SR5, (C 1 –C 6 )-alkylene-SOR5, (C 1 –C 6 )-alkylene-SO 2 R5, (C 1 –C 4 )-alkylene-(C 6 –C 10 )-aryl or (C 1 –C 4 )-alkylene-heterocyclyl;

R5, R6 are each, independently of one another, H, (C 1 –C 6 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 1 –C 6 )-alkylene-(C 6 –C 10 )-aryl, —(C 6 –C 10 )-aryl, heterocyclyl or (C 1 –C 6 )-alkylene-(C 3 –C 10 )-heterocyclyl;

X is S;

and pharmaceutically acceptable salts thereof.

3. The compound of claim 2 wherein:

R1 is H;

R2 is H, (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 6 –C 10 )-aryl, heterocyclyl, COR3, CO 2 R3, CONR3R4 or CN,

wherein said (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 6 –C 10 )-aryl and heterocyclyl radicals are optionally substituted one or more times by F, Cl, Br, I, CN, NO 2 , SH, SF 5 , OH, (C 1 –C 6 )-alkyl, —CF 3 , (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, OR3, OP(O)(OR3)2, NR3R4, NR3CONR3R4, COR3, OCOR3, CO 2 R3, CONR3R4, OCONR3R4, (C 1 –C 6 )-alkylene-OR3, (C 1 –C 6 )-alkylene-NR3R4, (C 1 –C 6 )-alkylene-NR3SO 2 R4, (C 1 –C 6 )-alkylene-SR3, alkylene-SOR3, alkylene-SO 2 R3, alkylene-S(O) 2 NR3R4, (C 1 –C 6 )-alkylene-COR3, (C 1 –C 6 )-alkylene-CO 2 R3, (C 1 –C 6 )-alkylene-CONR3R4, SR3, SOR3, SO 2 R3, SO 2 NR3R4, NR3SO 2 R4, (C 1 –C 6 )-alkylene-(C 3 –C 10 )-cycloalkyl, (C 1 –C 6 )-alkylene-(C 6 –C 10 )-aryl, (C 1 –C 6 )-alkylene-heterocyclyl, (C 3 –C 10 )-cycloalkyl, (C 6 –C 10 )-aryl or heterocyclyl,

and wherein said heterocyclyl is optionally substituted one or more times by F, Cl, Br, I, CN, NO 2 , OH, —CF 3 , (C 1 –C 6 )-alkyl, OR3, NR3R4, COR3, CO 2 R3 or CONR3R4;

R3, R4 are each, independently of one another, H, (C 1 –C 6 )-alkyl, —CF 3 , (C 3 –C 10 )-cycloalkyl, (C 6 –C 10 )-aryl, heterocyclyl, (C 1 –C 6 )-alkylene-CONR5R6, (C 1 –C 6 )-alkylene-CO 2 R 5 , (C 1 –C 6 )-alkylene-COR5, (C 1 –C 6 )-alkylene-OR5, (C 1 –C 6 )-alkylene-NR5R6, (C 1 –C 6 )-alkylene-SR5, (C 1 –C 6 )-alkylene-SOR5, (C 1 –C 6 )-alkylene-SO 2 R5, (C 1 –C 4 )-alkylene-(C 6 –C 10 )-aryl or (C 1 –C 4 )-alkylene-heterocyclyl;

X is S;

and pharmaceutically acceptable salts thereof.

4. The compound of claim 3 wherein

R1 is H;

R2 is H, (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 6 –C 10 )-aryl, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino or homopiperazino radical,

wherein said (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 6 –C 10 )-aryl, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino and homopiperazino radicals are optionally substituted one or more times by F, Cl, Br, CN, SF 5 , OH, (C 1 –C 6 )-alkyl, —CF 3 , (C 2 –C 6 )-alkenyl, OR3, NR3R4, NR3CONR3R4, COR3, OCOR3, CO 2 R3, CONR3R4, OCONR3R4, (C 1 –C 6 )-alkylene-OR3, (C 1 –C 6 )-alkylene-NR3R4, (C 1 –C 6 )-alkylene-NR3SO 2 R4, (C 1 –C 6 )-alkylene-SR3, alkylene-S(O)R3, alkylene-S(O) 2 R3, alkylene-S(O) 2 NR3R4, (C 1 –C 6 )-alkylene-COR3, (C 1 –C 6 )-alkylene-CO 2 R3, (C 1 –C 6 )-alkylene-CONR3R4, SR3, SOR3, SO 2 R3, SO 2 NR3R4, NR3SO 2 R4, (C 1 –C 6 )-alkylene-(C 3 –C 10 )-cycloalkyl, (C 1 –C 6 )-alkylene-(C 6 –C 10 )-aryl, (C 1 –C 6 )-alkylene-heterocyclyl, (C 3 –C 10 )-cycloalkyl, (C 6 –C 10 )-aryl or heterocyclyl,

wherein said (C 6 –C 10 )-aryl is optionally substituted one or more times by F, Cl, Br, I, CN, OH, —CF 3 , (C 1 –C 6 )-alkyl, OR3, NR3R4, COR3, CO2R3 or CONR3R4,

and wherein said heterocyclyl is optionally substituted one or more times by F, Cl, Br, CN, NO 2 , OH, —CF 3 , (C 1 –C 6 )-alkyl, OR3, NR3R4, COR3, CO2R3 or CONR3R4;

R3, R4 are each, independently of one another, H, (C 1 –C 6 )-alkyl, —CF 3 , (C 3 –C 10 )-cycloalkyl, (C 6 –C 10 )-aryl, heterocyclyl, (C 1 –C 6 )-alkylene-CONR5R6, (C 1 –C 6 )-alkylene-COOR5, (C 1 –C 6 )-alkylene-COR5, (C 1 –C 6 )-alkylene-OR5, (C 1 –C 6 )-alkylene-NR5R6, (C1–C 6 )-alkylene-SR5, (C 1 –C 6 )-alkylene-S(O)R5, (C 1 –C 6 )-alkylene-S(O) 2 R5, (C 1 –C 4 )-alkylene-(C 6 –C 10 )-aryl or (C 1 –C 4 )-alkylene-heterocyclyl;

X is S;

and pharmaceutically acceptable salts thereof.

5. The compound of claim 4 wherein

R1 is H;

R2 is (C 1 –C 10 )-alkyl, (C 3 –C 10 )-cycloalkyl, phenyl, (C 1 –C 6 )-alkylene-phenyl, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, thiomorpholino or homopiperazino radical;

X is S;

and pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6 further comprising at least one other active ingredient.

8. A method of reducing blood sugar comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .

9. A method of treating type 2 diabetes comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .

10. A method of treating insulin resistance comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .