Substituted N-phenyl-pyrrolidinylmethylpyrrolidine amides and therapeutic use thereof

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Quick Facts

Patent No.: US 8,227,504
App. No.: 12/724,044
Granted: Jul 24, 2012
Kind: B2

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Abstract

The present invention discloses and claims a series of substituted N-phenyl-pyrrolidinylmethylpyrrolidine amides of formula (I). Wherein R, R 1 , R 2 , R 3 and R 4 are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, this invention also discloses methods of preparation of substituted pyrrolidinylmethylpyrrolidine amides and intermediates therefor.

Claims (202)

1. A compound of formula (I):

wherein

R, R 1 , R 2 and R 3 are the same or different and independently of each other chosen from hydrogen, (C 1 -C 4 )alkyl or CF 3 ;

R 4 is selected from the group consisting of phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydro-benzofuranyl, benzo[1,3]dioxolyl and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl; wherein said R 4 is optionally substituted one or more times with a substituent selected from halogen, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, CF 3 , hydroxymethyl, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl, N-acetyl-piperidinyl, pyrrolyl, imidazolyl and 5-oxo-4,5-dihydro-pyrazolyl; or

a salt thereof or an enantiomer or a diastereomer thereof.

2. The compound according to claim 1 , wherein R and R 2 are methyl; and R 1 and R 3 are hydrogen.

3. The compound according to claim 1 , wherein R 4 is phenyl, wherein phenyl is optionally substituted with one or more groups selected from fluorine, methyl, hydroxymethyl, N-acetyl-piperidinyl, imidazolyl or 5-oxo-4,5-dihydro-pyrazolyl.

4. The compound according to claim 1 , wherein R 4 is pyridinyl which is optionally substituted one or more times with chlorine, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl or pyrrolyl.

5. The compound according to claim 1 , wherein R 4 is quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl or benzofuranyl, and wherein said R 4 is optionally substituted one or more times with chlorine, hydroxy, methyl or methoxy.

6. The compound according to claim 1 , wherein R 4 is chromanyl, 4-oxo-4H-chromenyl or 2,3-dihydro-benzofuranyl, wherein said R 4 is optionally substituted one or more times with hydroxy or methyl.

7. The compound according to claim 1 , wherein R 4 is benzo[1,3]dioxolyl or 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl.

8. The compound of claim 1 selected from the group consisting of:

(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;

(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;

4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;

4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;

4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;

N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;

(2S,3R)-cyclohexanecarboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;

5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;

pyridine-2,5-dicarboxylic acid 2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);

N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;

6-benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;

(2S,3R)-furan-3-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;

(2S,3R)-3,5-dimethyl-isoxazole-4-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;

7-chloro-4-hydroxy-quinoline-3-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;

4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;

1H-indole-6-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;

5-methoxy-1H-indole-2-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;

2-methyl-1H-benzoimidazole-5-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;

6-methoxy-benzofuran-2-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;

3,4-dihydroxy-2,2-dimethyl-chroman-6-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;

6-methyl-4-oxo-4H-chromene-2-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;

2,3-dihydro-benzofuran-5-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;

benzo[1,3]dioxole-5-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide; and

2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylic acid {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 selected from the group consisting of:

(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide