IP Library › Granted Patent US 7,390,814
Granted Patent B2
US 7,390,814 · App. 10/778,554 · Granted Jun 24, 2008

Substituted hexahydropyrazino [1,2-a] pyrimidine-4,7-dione derivatives, process for their preparation and their use as medicaments

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Quick Facts
Patent No.
US 7,390,814
App. No.
10/778,554
Granted
Jun 24, 2008
Kind
B2
Abstract

Substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives, processes for their preparation and their use as medicaments The invention relates to substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives and to the physiologically tolerated salts and physiologically functional derivatives thereof. Compounds of the formula I in which the radicals have the stated meanings, and the physiologically tolerated salts thereof and processes for preparing them are described. The compounds are suitable for example as anorectic agents.

Claims (48)

1. A compound of the formula I,

wherein

A is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-membered mono-, bi- or spirobicyclic ring containing one or more heteroatoms selected from the group of N, O and S, and is optionally substituted with F, Cl, Br, NO 2 , CF 3 , OCF 3 , CN, (C 1 -C 6 )-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, N(R15)CO(C 1 -C 6 )-alkyl or COO—(C 1 -C 6 )-alkyl;

R11, R12, R13, R14, R15 are each independently H, (C 1 -C 6 )-alkyl or a heterocycle;

n is 1;

m is 0, 1, 2, 3, 4, 5 or 6;

R1 is R8, (C 1 -C 6 )-alkylene-R8, (C 2 -C 6 )-alkenylene-R9, (SO 2 )—R8, (SO 2 )—(C 1 -C 6 )-alkylene-R8, (SO 2 )—(C 2 -C 6 )-alkenylene-R9, (C═O)—R8, (C═O)—(C 1 -C 6 )-alkylene-R8, (C═O)NH—R8, (C═O)—(C 2 -C 6 )-alkenylene-R9, (C═O)—NH—(C 1 -C 6 )-alkylene-R8, (C═O)—NH—(C 2 -C 6 )-alkenylene-R9, COO—R8, COO—(C 1 -C 6 )-alkylene-R8, COO—(C 2 -C 6 )-alkenylene-R9, alkynylene-R9 or (C 1 -C 4 -alkyl)-heterocycle, wherein the alkylene component of said (C 1 -C 6 )-alkylene-R8, (C 2 -C 6 )-alkenylene-R9, (SO 2 )—(C 1 -C 6 )-alkylene-R8, (SO 2 )—(C 2 -C 6 )-alkenylene-R9, (C═O)—(C 1 -C 6 )-alkylene-R8, (C═O)—(C 2 -C 6 )-alkenylene-R9, (C═O)—NH—(C 1 -C 6 )-alkylene-R8, (C═O)—NH—(C 2 -C 6 )-alkenylene-R9, COO—(C 1 -C 6 )-alkylene-R8, COO—(C 2 -C 6 )-alkenylene-R9 and alkynylene-R9 groups is optionally substituted by F;

R8, R9 are each independently H, F, Cl, Br, I, OH, CF 3 , aryl, heterocycle or (C 3 -C 8 )-cycloalkyl, wherein said aryl, heterocycle and (C 3 -C 8 )-cycloalkyl groups are optionally mono-, di- or tri-substituted by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , CON(R11)(R12), N(R13)(R14), SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ;

R2 is H, F, Cl, Br, I, OH, CF 3 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, O—(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, aryl, O-aryl, (C 1 -C 8 )-alkylene-aryl, O—(C 1 -C 8 )-alkylene-aryl, S-aryl, CON(R11)(R12), (C 1 -C 6 )-alkyl-N(R13)(R14), COOH, COO—(C 1 -C 6 )-alkyl, COO—(C 2 -C 6 )-alkenyl, CO—N((C 1 -C 6 )-alkyl) 2 or heterocycle, with the proviso that said heterocycle may not be bonded via a nitrogen atom;

R3, R4, R5 are each independently H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, O—(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, aryl, O-aryl (C 1 -C 8 )-alkylene-aryl, O—(C 1 -C 8 )-alkylene-aryl, S-aryl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CO—N((C 1 -C 6 )-alkyl) 2 ;

R6 is H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, O—(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, (C 0 -C 8 )-alkylene-aryl, O—(C 0 -C 8 )-alkylene-aryl, S-aryl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CO—N((C 1 -C 6 )-alkyl) 2 ;

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein

A is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-membered mono-, bi- or spirobicyclic ring containing one or more heteroatoms selected from the group of N, O and S, and is optionally substituted with F, Cl, Br, NO 2 , CF 3 , OCF 3 , CN, (C 1 -C 6 )-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, N(R15)CO(C 1 -C 6 )-alkyl or COO—(C 1 -C 6 )-alkyl;

R11, R12, R13, R14, R15 are each independently H, (C 1 -C 6 )-alkyl or a heterocycle;

m is 1;

n is 1;

R1 is R8, (C 1 -C 6 )-alkylene-R8, (C 2 -C 6 )-alkenylene-R9, (SO 2 )—R8, (SO 2 )—(C 1 -C 6 )-alkylene-R8, (SO 2 )—(C 2 -C 6 )-alkenylene-R9, (C═O)—R8, (C═O)—(C 1 -C 6 )-alkylene-R8, (C═O)NH—R8, (C═O)—(C 2 -C 6 )-alkenylene-R9, (C═O)—NH—(C 1 -C 6 )-alkylene-R8, (C═O)—NH—(C 2 -C 6 )-alkenylene-R9, COO—R8, COO—(C 1 -C 6 )-alkylene-R8, COO—(C 2 -C 6 )-alkenylene-R9, alkynylene-R9 or (C 1 -C 4 -alkyl)-heterocycle;

R8, R9 are each independently H, F, Cl, Br, I, OH, CF 3 , aryl, heterocycle or (C 3 -C 8 )-cycloalkyl, wherein said aryl, heterocycle and (C 3 -C 8 )-cycloalkyl groups are optionally mono-, di- or tri-substituted by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , CON(R11)(R12), N(R13)(R14), SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ;

R2 is H, F, Cl, Br, I, OH, CF 3 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, O—(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, aryl, O-aryl, (C 1 -C 8 )-alkylene-aryl, O—(C 1 -C 8 )-alkylene-aryl, S-aryl, CON(R11)(R12), (C 1 -C 6 )-alkyl-N(R13)(R14), COOH, COO—(C 1 -C 6 )-alkyl, COO—(C 2 -C 6 )-alkenyl, CO—N((C 1 -C 6 )-alkyl) 2 or heterocycle, with the proviso that said heterocycle may not be bonded via a nitrogen atom;

R3, R4, R5 are each independently H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, O—(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, aryl, O-aryl (C 1 -C 8 )-alkylene-aryl, O—(C 1 -C 8 )-alkylene-aryl, S-aryl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CO—N((C 1 -C 6 )-alkyl) 2 ;

R6 is H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, O—(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, aryl, O-aryl, (C 1 -C 8 )-alkylene-aryl, O—(C 1 -C 8 )-alkylene-aryl, S-aryl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CO—N((C 1 -C 6 )-alkyl) 2 ;

and pharmaceutically acceptable salts thereof.

3. The compound of claim 2 wherein

A is aryl wherein said aryl is optionally substituted by F, Cl, Br, NO 2 , CF 3 , OCF 3 , CN, (C 1 -C 6 )-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, N(R15)CO(C 1 -C 6 )-alkyl or COO—(C 1 -C 6 )-alkyl;

R11, R12, R13, R14, R15 are each independently H or (C 1 -C 6 )-alkyl;

m is 1;

R1 is (C 1 -C 6 )-alkylene-R8 or (C 2 -C 6 )-alkenylene-R9;

R8, R9 are each independently H, F, Cl, Br, I, OH, CF 3 , aryl, heterocycle or (C 3 -C 8 )-cycloalkyl, wherein said aryl, heterocycle and (C 3 -C 8 )-cycloalkyl groups are optionally mono-, di-, or tri-substituted by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , CON(R11)(R12), N(R13)(R14), SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ;

R2 is H, F, Cl, Br, I, OH, CF 3 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-N(R13)(R14) or COO—(C 2 -C 6 )-alkenyl,

R3 is H

R4, R5 are each independently H, F, Cl, Br, OH, CF 3 , OCF 3 , O—(C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl;

R6 is H;

and pharmaceutically acceptable salts thereof.

4. The compound of claim 3 wherein

A is aryl wherein said aryl is optionally substituted by F, Cl, Br, NO 2 , CF 3 , OCF 3 , CN, (C 1 -C 6 )-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, N(R15)CO(C 1 -C 6 )-alkyl or COO—(C 1 -C 6 )-alkyl;

R11, R12, R13, R14, R15 are each independently H or (C 1 -C 6 )-alkyl;

m is 1;

n is 1;

R1 is (C 1 -C 6 )-alkyl or (C 2 -C 6 )-alkenyl;

R2 is H, OH, (C 1 -C 6 )-alkyl, COO—(C 2 -C 6 )-alkenyl or (C 1 -C 6 )-alkyl-N(R13)(R14);

R3 is H

R4 is F, Cl, Br, OH, CF 3 , OCF 3 , O—(C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl;

R5 is H, F, Cl, Br, OH, CF 3 , OCF 3 , O—(C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl;

R6 is H;

and pharmaceutically acceptable salts thereof.

5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

6. A method of treating type II diabetes comprising administering to a patient in need thereof a compound of claim 1 .