Piperazine derivatives and methods of use

Abstract

The invention provides 2-carboxamide piperazine compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful for the treatment of mammalian infertility.

1 . A method for treating infertility in a mammal, comprising administering to a mammal suspected of infertility a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are independently selected from the group comprising or consisting of hydrogen, C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl, wherein said alkyl, alkenyl, alkynyl chains may be interrupted by a heteroatom selected from N, O or S, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, heterocycloalkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, an acyl moiety, C 1 -C 12 -alkyl aryl, C 1 -C 12 -alkyl heteroaryl, C 2 -C 12 -alkenyl aryl, C 2 -C 12 -alkenyl heteroaryl, C 2 -C 12 -alkynyl aryl, C 2 -C 12 -alkynyl heteroaryl, C 1 -C 12 -alkyl cycloalkyl, C 1 -C 12 -alkyl heterocycloalkyl, C 2 -C 12 -alkenyl cycloalkyl, C 2 -C 12 -alkenyl heterocycloalkyl, C 2 -C 12 -alkynyl cycloalkyl, C 2 -C 12 -alkynyl heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, C 1 -C 12 -alkyl carboxy, alkyl acyl, aryl acyl, heteroaryl acyl, C 3 -C 8 -(hetero)cycloalkyl acyl, C 1 -C 12 -alkyl acyloxy, C 1 -C 12 -alkyl alkoxy, C 1 -C 12 -alkyl alkoxycarbonyl, C 1 -C 12 -alkyl aminocarbonyl, C 1 -C 12 -alkyl acylamino, acylamino, C 1 -C 12 -alkyl ureido, C 1 -C 12 -alkyl carbamate, C 1 -C 12 -alkyl amino, C 1 -C 12 -alkyl ammonium, C 1 -C 12 -alkyl sulfonyloxy, C 1 -C 12 -alkyl sulfonyl, C 1 -C 12 -alkyl sulfinyl, C 1 -C 12 -alkyl sulfanyl, C 1 -C 12 -alkyl sulfonylamino, or C 1 -C 12 -alkyl aminosulfonyl;
 R 3  is C 1 -C 16 -alkyl, C 2 -C 16 -alkenyl, C 2 -C 16 -alkynyl, wherein said alkyl, alkenyl, alkynyl chains may be interrupted by a heteroatom selected from N, O or S, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, heterocycloalkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, an acyl moiety, C 1 -C 16 -alkyl aryl, C 1 -C 16 -alkyl heteroaryl, C 2 -C 16 -alkenyl aryl, C 2 -C 16 -alkenyl heteroaryl, C 2 -C 16 -alkynyl aryl, C 2 -C 16 -alkynyl heteroaryl, C 1 -C 16 -alkyl cycloalkyl, C 1 -C 16 -alkyl heterocycloalkyl, C 2 -C 16 -alkenyl cycloalkyl, C 2 -C 16 -alkenyl heterocycloalkyl, C 2 -C 16 -alkynyl cycloalkyl, C 2 -C 16 -alkynyl heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, C 1 -C 16 -alkyl carboxy, C 1 -C 16 -alkyl acyl, aryl acyl, heteroaryl acyl, C 3 -C 8 -(hetero)cycloalkyl acyl, C 1 -C 16 -alkyl acyloxy, C 1 -C 16 -alkyl alkoxy, C 1 -C 16 -alkyl alkoxycarbonyl, C 1 -C 16 -alkyl aminocarbonyl, C 1 -C 16 -alkyl acylamino, acylamino, C 1 -C 16 -alkyl ureido, C 1 -C 16 -alkyl carbamate, C 1 -C 16 -alkyl amino, C 1 -C 16 -alkyl ammonium, C 1 -C 16 -alkyl sulfonyloxy, C 1 -C 16 -alkyl sulfonyl, C 1 -C 16 -alkyl sulfinyl, C 1 -C 16 -alkyl sulfanyl, C 1 -C 16 -alkyl sulfonylamino, or C 1 -C 16 -alkyl aminosulfonyl; 
 R 4  is C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl, wherein said alkyl, alkenyl, alkynyl chains may be interrupted by a heteroatom selected from N, O or S, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, heterocycloalkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, or amino; and pharmaceutically acceptable salts thereof. 
 
     
     
         2 . The method of  claim 1 , wherein R 1  is H. 
     
     
         3 . The method of  claim 1 , wherein R 2  is selected from aryl, heteroaryl, 3-8 membered cycloalkyl and heterocycloalkyl. 
     
     
         4 . The method of  claim 1 , wherein R 4  is selected from C 1 -C 6 -alkyl, amino, aryl, heteroaryl, 3-8-membered cycloalkyl and heterocycloalkyl. 
     
     
         5 . The method of treatment of  claim 1 , wherein R′ is H; R 2  is aryl; R 3  is selected from C 1 -C 8 -alkyl, C 1 -C 8 -acyl amino and C 1 -C 8 -alkyl acyl and R 4  is selected from C 1 -C 6 -alkyl, amino, aryl and heteroaryl. 
     
     
         6 . The method of  claim 1  wherein the compound has the following Formula II: 
       
         
           
           
               
               
           
         
       
       wherein R 5  is independently halogen, hydroxy or the same as defined for R′; m is an integer of from 0 to 4; and pharmaceutically acceptable salts thereof. 
     
     
         7 . The method of  claim 1  wherein the compound has the following Formula III: 
       
         
           
           
               
               
           
         
       
       wherein R 5  is independently halogen, hydroxy or the same as defined for R′; m is an integer of from 0 to 4; and pharmaceutically acceptable salts thereof. 
     
     
         8 . The method of  claim 7  wherein R 1  is hydrogen and R 2  is other than hydrogen. 
     
     
         9 . The method of  claim 7  wherein R 2  is aryl or heteroaryl. 
     
     
         10 . The method of  claim 7  wherein R 3  is an n-alkyl group. 
     
     
         11 . The method of  claim 10  wherein R 3  is an alkyl having five or more carbon atoms. 
     
     
         12 . The method of  claim 1  wherein R 4  is optionally substituted alkyl, aryl, or heteroaryl. 
     
     
         13 . The method of  claim 1  wherein R 2  comprises a carbazolyl, tetrahydro-beta-carbolinyl or benzimidazolyl moiety. 
     
     
         14 . The method of  claim 1  wherein the compound of formula I is selected from the following group:
 4-hexyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridinyl-3-yl-1H-benzoimidazol-5-yl)-amide);   4-(thiophene-2-sulfonyl)-piperazine-1,3-dicarboxylic acid 3-[(9-ethyl-9H-carbazol-3-yl)amide]-1-pentylamide;   4-(thiophene-2-sulfonyl)-piperazine-1,3-dicarboxylic acid 1-ethylamide 3-[(9-ethyl-9H-carbazol-3-yl)amide];   {[3-(9-ethyl-9H-carbazol-3-ylcarbamoyl)-4-(thiophene-2-sulfonyl)-piperazine-1-carbonyl]-amino}acetic acid ethyl ester;   4-pentanoyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide;   4-hexyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide;   4-dimethylsulfamoyl-piperazine-1,3-dicarboxylic acid 3-[(9-ethyl-9H-carbazol-3-yl)amide]1-pentylamide;   4-(1-methyl-1H-imidazole-4-sulfonyl)-piperazine-1,3-dicarboxylic acid 3-[(9-ethyl-9H-carbazol-3-yl)-amide]1-pentylamide;   4-(thiophene-2-sulfonyl)-piperazine-1,3-dicarboxyclic acid 1-pentylamide 3-[(3-pyridin-4-yl-phenyl)-amide];   4-(thiophene-2-sulfonyl)-piperazine-1,3-dicarboxylic acid 3-[(9-ethyl-9H-carbazol-3-yl)-amide]1-{[2-(1H-imidazol-4-yl)-ethyl]-amide};   4-hexyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-oxo-2,3,4,9-tetrahydro-1H-beta-carbolin-6-yl)-amide;   4-heptyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl)-amide;   4-(thiophene-2-sulfonyl)-piperazine-1,3-dicarboxylic acid 3-[(9-ethyl-9H-carbazol-3-yl)-amide]1-[(3-imidazol-1-yl-propyl)-amide]);   4-pentyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-oxo-2,3,4,9-tetrahydro-1H-beta-carbolin-6-yl)amide;   4-heptyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-oxo-2,3,4,9-tetrahydro-1H-beta-carbolin-6-yl)amide;   4-(3-methylsulfanyl-propyl)-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide;   4-(4-ethyl-furan-3-ylmethyl)-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide;   3-(9-ethyl-9H-carbazol-3-ylcarbamoyl)-4-(thiophene-2-sulfonyl)-piperazin-1-yl]acetic acid ethyl ester;   1-benzenesulfonyl-4-hexyl-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl) amide;   4-pentyl-1-thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl) amide;   4-hexyl-1-thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl) amide;   1-(4-fluoro-benzenesulfonyl)-4-hexyl-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl) amide;   1-(2-fluoro-benzenesulfonyl)-4-hexyl-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl) amide;   4-octyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-4-yl-1H-benzoimidazol-5-yl) amide;   4-heptyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-4-yl-1H-benzoimidazol-5-yl) amide;   1-dimethylsulfamoyl-4-hexyl-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl) amide;   1-(butane-1-sulfonyl)-4-hexyl-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl) amide;   4-hexyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-4-yl-1′-1-benzoimidazol-5-yl) amide;   4-(3-methylsulfanyl-propyl)-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-4-yl-1H-benzoimidazol-5-yl) amide;   4-(thiophene-2-sulfonyl)-piperazine-1,3-dicarboxylic acid 3-[(9-ethyl-9H-carbazol-3-yl)-amide]1-[(2-methoxy-ethyl)-amide];   4-octyl-1-(thiophene-2-sulfonyl)-piperazine-2-carboxylic acid (1-ethyl-2-pyridin-3-yl-1H-benzoimidazol-5-yl) amide; and pharmaceutically acceptable salts thereof.   
     
     
         15 . A method for treatment of a subject suffering from or susceptible to a disease or disorder associated with phosphodiesterase PDE4, adenosine transporters, or prostanoid receptors, comprising administering to the mammal a therapeutically effective amount of a compound of  claim 1 . 
     
     
         16 . The method of  claim 15  wherein the mammal is a human. 
     
     
         17 . The method of  claim 16  wherein the mammal is a female. 
     
     
         18 . The method of  claim 17  wherein the mammal is suffering from an ovulatory disorder. 
     
     
         19 . The method of  claim 17  wherein the mammal is being treated with an assisted reproduction procedure. 
     
     
         20 . The method of  claim 17  wherein the mammal is undergoing in-vitro fertilization. 
     
     
         21 - 34 . (canceled)