Xanthine phosphodiesterase V inhibitors

Abstract

A xanthine phosphodiesterase V inhibitor having the formula (I), with the variables defined herein, which is especially useful for treating male (erectile) and female sexual dysfunction and other physiological disorders: For example, a representative compound of the invention is:

1 . A compound of Formula (1), an enantiomer, stereoisomer, rotomer, tautomer or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 (a) R 1  and R 2  are, independently of one another, each a C 1-15  alkyl group, branched or straight chain, unsubstituted or substituted with one or more substituents, a C 2-15  alkenyl group, branched or straight chain, unsubstituted or substituted with one or more substituents, a C 2-15  alkynyl group, branched or straight chain, unsubstituted or substituted with one or more substituents, or one of R 1  and R 2  is a hydrogen atom and the other one of R 1  and R 2  is defined the same as above;  
 (b) R 3  is an aryl group, unsubstituted or substituted with one or more substituents, a heteroaryl group, unsubstituted or substituted with one or more substituents, or a heterocyclic group having 1 to 3 heteroatoms fused to a 5- or 6-membered aryl ring, unsubstituted or substituted with one or more substituents, with the proviso that R 3  is not an aryl group substituted at its para position with a —Y-aryl group, where, Y is a carbon-carbon single bond, —C(O)—, —O—, —S—, —N(R 21 )—, —C(O)N(R 22 )—, —N(R 22 )C(O)—, —OCH 2 —, —CH 2 O—, —SCH 2 —, —CH 2 S—, —N(H)C(R 23 )(R 24 )—, —N(R 23 )S(O 2 )—, —S(O 2 )N(R 23 )—,  
 (c) —(R 23 )(R 24 )N(H)—, —CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—, —CH 2 CH 2 —, —CF 2 CF 2 —,  
                     
 where, 
 R 21  is a hydrogen atom or a —CO(C 1-4  alkyl), C 1-6  alkyl, allyl, C 3-6  cycloalkyl, phenyl or benzyl group;  
 R 22  is a hydrogen atom or a C 1-6  alkyl group;  
 R 23  is a hydrogen atom or a C 1-5  alkyl, aryl or —CH 2 -aryl group;  
 R 24  is a hydrogen atom or a C 1-4  alkyl group;  
 R 25  is a hydrogen atom or a C 1-8  alkyl, C 1-8  perfluoroalkyl, C 3-6  cycloalkyl, phenyl or benzyl group;  
 R 26  is a hydrogen atom or a C 1-6  alkyl, C 3-6  cycloalkyl, phenyl or benzyl group;  
 R 27  is —NR 23 R 24 —R 24 , —NHCONH 2 , —NHCSNH 2 ,  
                     
 
 and 
 R 28  and R 29  are, independently of one another, each a C 1-4  alkyl group or, taken together with each other, a —(CH 2 ) q  group, where q is 2 or 3; and  
 
 (d) R 4  is a C 3-15  cycloalkyl group, unsubstituted or substituted with one or more substituents, or a C 3-15  cycloalkenyl group, unsubstituted or substituted with one or more substituents;  
 wherein, the one or more substituents for all the groups are chemically-compatible and are, independently of one another, each an: alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl, heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di- and trihaloalkyl, mono-, di- and trihaloalkoxy, amino, alkylamino, dialkylamino, alkoxy, hydroxy, halo, nitro, oximino, —COOR 50 , —COR 50 , —SO 2 R 50 , —SO 2 NR 50 R 51 , NR 52 SO 2 R 50 , ═C(R 50 R 51 ), ═N—OR 50 , ═N—CN, ═C(halo) 2 , ═S, ═O, —CON(R 50 R 51 ), —OCOR 50 , —OCON(R 50 R 51 ), —N(R 52 )CO(R 50 ), —N(R 52 )COOR 50  or —N(R 52 )CON(R 50 R 51 ) group, where: 
 R 50 , R 51  and R 52  are, independently of one another, each a hydrogen atom or a branched or straight-chain, optionally substituted, C 1-6  alkyl, C 3-6  cycloalkyl, C 4-6  heterocycloalkyl, heteroaryl or aryl group, or R 50  and R 51  are joined together to form a carbocyclic or heterocyclic ring system, or R 50 , R 51  and R 52  are, independently of one another, each:  
                     
 
 where, 
 R 40  and R 41  are, independently of one another, each a hydrogen atom or a branched or straight-chain, optionally substituted, alkyl, cycloalkyl, heterocycloalkyl, halo, aryl, imidazolylalkyl, indolylalkyl, heteroaryl, arylalkyl, arylalkoxy, heteroarylalkyl, heteroarylalkoxy, aminoalkyl, haloalkyl, mono-, di- or trihaloalkyl, mono-, di- or trihaloalkoxy, nitro, cyano, alkoxy, hydroxy, amino, phosphino, phosphate, alkylamino, dialkylamino, formyl, alkylthio, trialkylsilyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, morpholino, thioalkyl, alkylthioalkyl, carboxyalkyl, oximino, —COOR 50 , —COR 50 , —SO 0-2 R 5 °, —SO 2 N R 50 R 51 , —N R 52 SO 2 R 50 , —CON(R 50 R 51 ), —OCON(R 50 R 51 ), —N(R 52 )CO(R 50 ), —N(R 52 )COOR 50 , —N(R 52 )CON(R 50 R 51 ) or —OCONR 50  group, where, R 50 , R 51  and R 52  are defined the same as above;  
 R 42  is a hydrogen atom or a branched or straight-chain, optionally substituted, alkyl, alkenyl, arylalkyl or acyl group; and  
 R 43  is a hydrogen atom or a branched or straight-chain, optionally substituted, alkyl or aryl group;  
 wherein, the optional substituents are defined the same as above for the one or more substituents.  
 
 
     
     
         2 . The compound according to  claim 1 , wherein R 1  is a methyl or ethyl group, with or without the one or more substituents.  
     
     
         3 . The compound according to  claim 1 , wherein R 2  is a methyl, ethyl, iso-butyl or hydroxyethyl group, with or without the one or more substituents.  
     
     
         4 . The compound according to  claim 1 , wherein R 3  is a phenyl group, with or without the one or more substituents.  
     
     
         5 . The compound according to  claim 4 , wherein the phenyl group for R 3  is substituted with at least one halogen atom.  
     
     
         6 . The compound according to  claim 1 , wherein R 4  is a cyclohexyl, hydroxycyclopentyl or tetrahydropyranyl group, with or without the one or more substituents.  
     
     
         7 . A compound selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . A compound of the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         9 . A method for treating a physiological disorder, symptom or disease in a patient in need of the treatment, comprising administering to the patient an effective amount of the compound according to  claim 1 , wherein the physiological disorder, symptom or disease is hypertension, pulmonary hypertension, ischemic heart, impaired glucose tolerance, diabetes, insulin resistance syndrome or erectile dysfunction.  
     
     
         10 . The method according to  claim 9 , wherein the physiological disorder is pulmonary hypertension.  
     
     
         11 . The method according to  claim 9 , wherein the physiological disorder is ischemic heart.  
     
     
         12 . The method according to  claim 9 , wherein the physiological disorder is diabetes.  
     
     
         13 . The method according to  claim 9 , wherein the physiological disorder is erectile dysfunction.  
     
     
         14 . A method for treating a physiological disorder, symptom or disease in a patient in need of the treatment, comprising administering to the patient an effective amount of the compound according to  claim 7 , wherein the physiological disorder, symptom or disease is hypertension, pulmonary hypertension, ischemic heart, impaired glucose tolerance, diabetes, insulin resistance syndrome or erectile dysfunction.  
     
     
         15 . The method according to  claim 14 , wherein the physiological disorder is pulmonary hypertension.  
     
     
         16 . The method according to  claim 14 , wherein the physiological disorder is ischemic heart.  
     
     
         17 . The method according to  claim 14 , wherein the physiological disorder is diabetes.  
     
     
         18 . The method according to  claim 14 , wherein the physiological disorder is erectile dysfunction.  
     
     
         19 . A method for treating a physiological disorder, symptom or disease in a patient in need of the treatment, comprising administering to the patient an effective amount of the compound according to  claim 8 , wherein the physiological disorder, symptom or disease is hypertension, pulmonary hypertension, ischemic heart, impaired glucose tolerance, diabetes, insulin resistance syndrome or erectile dysfunction.  
     
     
         20 . The method according to  claim 19 , wherein the physiological disorder is pulmonary hypertension.  
     
     
         21 . The method according to  claim 19 , wherein the physiological disorder is ischemic heart.  
     
     
         22 . The method according to  claim 19 , wherein the physiological disorder is diabetes.  
     
     
         23 . The method according to  claim 19 , wherein the physiological disorder is erectile dysfunction.