Substituted 3,3-diamino-2-propenenitriles, their preparation and use

Abstract

Substituted cyanoenamines of the general formula I wherein Z, R 1 , R 2 and R 3 are defined in the description, compositions thereof and methods for preparing the compounds are described. The compounds are useful in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.

1 . A compound of the general formula I  
                   
       wherein 
 R 1  is alkyl optionally substituted with halogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; or aralkyl optionally substituted with alkyl, trifluoromethyl, aryl, a 5-, 6- or 7-membered heterocyclic system, halogen, alkoxy, methylenedioxo, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or aryl optionally substituted with alkyl, trifluoromethyl, aryl, a 5-, 6- or 7-membered heterocyclic system, halogen, alkoxy, methylenedioxo, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or a 5-, 6- or 7-membered heterocyclic system optionally substituted with alkyl, aryl, a 5-, 6- or 7-membered heterocyclic system, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl;  
 R 2  and R 3  are independently hydrogen; or alkyl optionally substituted with aryl, a 5-, 6- or 7-membered heterocyclic system, halogen, hydroxy, alkoxy, aralkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; or aryl optionally substituted with alkyl, aryl, a 5-, 6- or 7-membered heterocyclic system, halogen, trifluoromethyl, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or  
 a 5-, 6- or 7-membered heterocyclic system optionally substituted with alkyl, aryl, a 5-, 6- or 7-membered heterocyclic system, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or R 2  and R 3  are linked together by —(CH 2 ) n —, n being 4-7, provided that R 2  and R 3  cannot be hydrogen at the same time;  
 Z is hydrogen, cyano, carbonylalkyl, alkoxycarbonyl, optionally substituted aminocarbonyl, alkylsulfonyl optionally substituted with alkyl, aryl, a 5-, 6- or 7-membered heterocyclic system, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or arylsulfonyl optionally substituted with alkyl, aryl, a 5-, 6- or 7-membered heterocyclic system, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form as well as metabolites or prodrugs.  
 
     
     
         2 . A compound according to    claim 1    wherein Z is alkylsulfonyl or arylsulfonyl substituted with halogen.  
     
     
         3 . A compound according to    claim 1    or    2    wherein R 1  is optionally substituted aryl.  
     
     
         4 . A compound according to    claim 3    wherein R 1  is optionally substituted phenyl.  
     
     
         5 . A compound according to    claim 4    wherein R 1  is phenyl substituted by one or two perhalomethyl groups.  
     
     
         6 . A compound according to    claim 4    wherein R 1  is phenyl substituted by one or two alkoxy groups.  
     
     
         7 . A compound according to    claim 4    wherein R 1  is phenyl substituted by one or two halogen groups.  
     
     
         8 . A compound according to    claim 4    wherein R 1  is phenyl substituted by one or two cyano groups.  
     
     
         9 . A compound according to    claim 5   ,    6   ,  7  or  8  wherein R 2  is cyclic alkyl, preferably cyclobutyl.  
     
     
         10 . A compound according to    claim 5   ,    6   ,  7  or  8  wherein R 2  is alkyl, preferably 1,1-dimethylpropyl.  
     
     
         11 . A compound selected from the group consisting of: 
 3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile    3-[3,5-bis(trifluaromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-cyclopentylamino-2-propenenitrile    3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4chlorophenylsulfonyl)-3-isopropylamino-2-propenenitrile    3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-cyclobutylamino-2-propenenitrile    3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-propylamino-2-propenenitrile    2-(4-Chlorophenylsulfonyl)-3-(pyridin-3-ylamino)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile    2-(4-Chlorophenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile    3-(Benzo[1,3]dioxol-5-ylamino)-2-(4-chloro-phenylsulfonyl)-3-(1,2,2-trimethyl-propylamino)-propenenitrile    3-(3,5-Bis(trifluoromethyl)phenylamino)-2-methylsulfonyl-3-(1,2,2-trimethylpropylamino)-propenenitrile    2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile    3-[N-(3,5-bis(trifluoromethyl)phenyl)-N-methylamino]-2-(4-chlorophenylsulfonyl)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile    (1′S,2′S)-3-[2-Benzyloxycyclopentylamino]-3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-2-propenenitrile    (1′R,2′R)-3-[2-Benzyloxycyclopentylamino]-3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-2-propenenitrile    (S)-3-[3,5-Bis(trfluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile    (S)-3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-(1,2-dimethylpropylamino)-2-propenenitrile    (R)-3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-(1,2-dimethylpropylamino)-2-propenenitrile    3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-(1,1-dimethylpropylamino)-2-propenenitrile    3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4chlorophenylsulfonyl)-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-ylamino)-2-propenenitrile    (R)-3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile    3-(3,5-Bis(trifluoromethyl)phenylamino)-3-isopropylamino-2-methylsulfonyl-propenenitrile    (R)-3-[3,5-bis(trifluoromethyl)phenylamino]-2-methanesulfonyl-3-(1,2,2-trimethylpropylamino)-2-propenenitrile    (S)-3-[3,5-bis(trifluoromethyl)phenylamino]-2-methanesulfonyl-3-(1,2,2-trimethylpropylamino)-2-propenenitrile    2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-(1,1dimethylpropylamino)-2-propenenitrile    2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-cyclobutylamino-2-propenenitrile    3-(3,5-dimethoxyphenylamino)-2-methanesulfonyl-3-(1,2,2-trimethylpropylamino)-propenenitrile    3-(3,5-dimethoxyphenylamino)-3-isopropyl-2-methanesulfonyl-propenenitrile    3-(Benzo[1,3]dioxol-5-ylamino)-3-(1,1 -dimethyl-propylamino)-2-(4-chloro-phenylsulfonyl)-propenenitrile    3-(Benzo[1,3]dioxol-5-ylamino)-3-cyclobutylamino-2-(4-chloro-phenylsulfonyl)-propenenitrile    2-(4-Chlorophenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-(1,1 -dimethylpropylamino)-2-propenenitrile    2-(4-Chlorophenylsulfonyl)-3-cyclobutylamino-3-(3,5-dichlorophenylamino)-2-propenenitrile    3-sec-Butylamino-2-(4-chlorophenylsulfonyl)-3-(3,5-dichlorophenylamino)-2-propenenitrile    2-Methylsulfonyl-3-(3-methoxy-5-trifluoromethyl-phenylamino)-3-(1,2,2-trimethylpropylamino)-propenenitrile    3-(3-Fluoro-5-trifluoromethyl-phenylamino)-2-methylsulfonyl-3-(1,2,2-trimethylpropylamino)-propenenitrile    3-(4-Chlorophenylamino)-2-methylsulfonyl-3-(1,2,2-trimethylpropylamino)-acrylonitrile    3-(Benzothiazol-6-ylamino)-3-(1,1-dimethyl-propylamino)-2-methylsulfonyl-propenenitrile    3-(Benzo(1,3]dioxol-5-ylamino)-2-(2,2dimethyl-propionyl)-3-(1,1-dimethyl-propylamino) propenenitrile    2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-(1,2,2-trimethylpropylamino)-2propenenitrile    2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-cyclopentylamino-2-propenenitrile    2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino-3-(1,2-dimethylpropylamino)-2-propenenitrile    3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-(1,2,2-trimethylpropylamino)-propenenitrile    3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-cyclopentylamino-2-propenenitrile    3-(3,5-Bis(trifluoromethyl)phenylamino)-3-cyclobutylamino-2-isopropylsulfonyl-2-propenenitrile    3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-(2-methyl)propylamino)-2-propenenitrile    2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile    3-Cyclopentylamino-2-isopropylsulfonyl-3-(3-methoxy)phenylamino-2-propenenitrile    3-Cyclobutylamino-2-isopropylsulfonylamino-3-(3-methoxy)phenylamino-2-propenenitrile    2-Isopropylsulfonyl-3-(3-methoxy)phenylamino-3-(2-methyl)propylamino)-2-propenenitrile    3-(1,1-Dimethyl)propylamino)-2-isopropylsulfonyl-3-(3-methoxy)phenylamino-2-propenenitrile    2-Isopropylsulfonyl-3-(3-methoxy)phenylamino-3-tert.-butylamino-2-propenenitrile    3-(Benzo[1,3]dioxol-5-ylamino)-3-(1,1-dimethylpropylamino)-2-methanesulfonyl-2-propenenitrile    and pharmaceutically acceptable salts thereof.    
     
     
         12 . Compounds according to any one of the preceding claims which are active as potassium channel openers.  
     
     
         13 . A pharmaceutical composition comprising a compound according to any of the    claim 1   - 11  or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.  
     
     
         14 . A pharmaceutical composition for use in the treatment of diseases of the endocrinological system such as diabetes comprising a compound according to any of the claims  1 - 11  or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.  
     
     
         15 . The pharmaceutical composition according to    claim 13    or    14    in the form of an oral dosage unit or parenteral dosage unit.  
     
     
         16 . A pharmaceutical composition according to    claim 13    or    14    wherein said compound is administered as a dose in a range from about 0.05 mg to 1000 mg, preferably from about 0.1 mg to 500 mg and especially in the range from 50 mg to 200 mg per day.  
     
     
         17 . A compound according to any one of the claims  1 - 11  or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use.  
     
     
         18 . A compound according to any one of the claims  1 - 11  or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use in the treatment or prevention of diseases of the endocrinological system, such as diabetes.  
     
     
         19 . The use of a compound according to any one of the claims  1 - 11  or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form as a medicament.  
     
     
         20 . The use of a compound according to any of the claims  1 - 11  for preparing a medicament.  
     
     
         21 . The use of a compound according to any one of the claims  1 - 11  or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment or prevention of diseases of the endocrinological system, such as diabetes.  
     
     
         22 . A method of treating or preventing diseases of the endocrinological system, such as diabetes in a subject in need thereof comprising administering an effective amount of a compound according to any of the claims  1 - 11  to said subject.  
     
     
         23 . A process for the manufacture of a medicament to be used in the treatment or prevention of diseases of the endocrinological system, such as diabetes which process comprising bringing a compound of formula I according to any of the claims  1 - 11  or a pharmaceutically acceptable salt thereof into a galenic dosage form.  
     
     
         24 . A method of preparing a compound of formula I, comprising the following steps of reaction:  
                   
       wherein acceptor substituted acetonitriles are reacted with isothiocyanates in the presence of a base and the resulting salts of the adducts are treated with alkyl halide to give the corresponding alkylsulfanyl propenenitriles, which are then reacted with primary and secondary amines to give cyanoenamines of formula I.  
     
     
         25 . Any novel feature or combination of features as described herein.