Substituted pyrrolopyridinone derivatives useful as phosphodiesterase inhibitors

Abstract

The invention relates to novel pyrrolopyridinone derivatives of the formula (I) or (II): pharmaceutical compositions containing the compounds and their use for the treatment of sexual dysfunction.

1 . A compound of formula (I) or (II):  
       
         
           
           
               
               
           
         
         wherein  
         R 1  is selected from the group consisting of hydrogen, carboxy, —C(O)—C 1 -C 6 alkyl, —C(O)—C 1 -C 6 alkoxy, —C(O)—NH—C 1 -C 6 alkyl-NH 2 , —C(O)—NH—C 1 -C 6 alkyl-NHR A , NH—C 1 -C 6 alkyl-N(R A ) 2 , —C(O)—NH 2 , —C(O)—NHR A , —C(O)—N(R A ) 2 , —C 1 -C 6 alkyl-NH 2 , —C 1 -C 6 alkyl-NHR A , —C 1 -C 6 alkyl-N(R A ) 2 , —NH—C 1 -C 6 alkyl-N(R A ) 2 ;  
         where each R A  is independently selected from the group consisting of C 1 -C 6 alkyl, aryl, C 1 -C 6 aralkyl and heteroaryl, where the aryl, aralkyl or heteroaryl may be optionally substituted with one to three R B ;  
         where each R B  is independently selected from the group consisting of halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylcarbonyl, carboxyC 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, trifluoromethyl, amino, di(C 1 -C 6 alkyl)amino, acetylamino, carboxyC 1 -C 6 alkylcarbonylamino, hydroxyC 1 -C 6 alkylamino, NHR A  and N(R A ) 2 ;  
         R 2  is selected from the group consisting of C 5 -C 10 alkyl (optionally substituted with one to three substituents independently selected from halogen, hydroxy, nitro, amino, NHR A  or N(R A ) 2 ), aryl (optionally substituted with one to three substituents independently selected from R C ), cycloalkyl (optionally substituted with one to three substituents independently selected from R A ), heteroaryl (optionally substituted with one to three substituents independently selected from R C ), and heterocycloalkyl (optionally substituted with one to three substituents independently selected from R C );  
         where R C  is selected from the group consisting of halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, NH 2 , NH(C 1 -C 6 alkyl) and N(C 1 -C 6 alkyl) 2 ;  
         R 3  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 2 -C 6 alkenylcarbonyl and C 2 -C 6 alkynylcarbonyl;  
         b is an integer from 0 to 4;  
         R 4  is independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, trifluoromethyl, phenyl (wherein the phenyl group may be optionally substituted with one to three substituents independently selected from R D ), phenylsulfonyl, naphthyl, C 1 -C 6 aralkyl, —O-aralkyl, (wherein the aralkyl group may be optionally substituted with one to three substituents independently selected from R D ), heteroaryl (wherein the heteroaryl may be optionally substituted with one to three substituents independently selected from R D ), heterocycloalkyl, NH 2 , NHR A , N(R A ) 2 ,  
         
           
             
             
                 
                 
             
           
         
         where each R D  is independently selected from halogen, hydroxy, carboxy, oxo, C 1 -C 4 alkyl, C 1-4 alkylthio, hydroxyC 1-4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyoxycarbonyl, C 1 -C 4 alkylcarbonyl, trifluoromethyl, trifluoromethoxy, NH 2 , NHR A , N(R A ) 2 , C(O)N(R A ) 2 , SO 2 N(R A ) 2 , acetylamino, nitro, cyano, formyl, C 1 -C 6 alkylsulfonyl, carboxyC 1 -C 6 alkyl and aralkyl;  
         c is an integer from 0 to 4;  
         R 5  is independently selected from the group consisting of halogen, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —NHR A , —N(R A ) 2 , —OR A , —C(O)NH 2 , —C(O)NHR A , —C(O)N(R A ) 2 , —NHC(O)R A , —SO 2 NHR A , —SO 2 N(R A ) 2 , where R A  is as defined above, phenyl (optionally substituted with one to three substituents independently selected from R B ), heteroaryl (optionally substituted with one to three substituents independently selected from R B ) and heterocycloalkyl (optionally substituted with one to three substituents independently selected from R B );  
         a is an integer from 0 to 1;  
         Y selected from the group consisting of —C 1 -C 6 alkyl-, —C(O)—, —(C 1 -C 6 alkyl)carbonyl-, —(C 2 -C 6 alkenyl)carbonyl-, —(C 2 -C 6 alkynyl)carbonyl-, -carbonyl(C 1 -C 6 alkyl)-, -carbonyl(C 2 -C 6 alkenyl)-, —C(O)O—(C 1 -C 6 alkyl)-, —C(S)—, —SO 2 —, —(C 1 -C 6 alkyl)sulfonyl-, -sulfonyl(C 1 -C 6 alkyl)-, —C(O)NH—, —C(O)NH—(C 1 -C 6 alkyl)-, C(O)(C 3 -C 7 cycloalkyl)- and —(C 3 -C 7 cycloalkyl)-C(O)—;  
         
           
             
             
                 
                 
             
           
         
         is selected from the group consisting phenyl, furyl, thienyl and pyrrolyl;  
         
           
             
             
                 
                 
             
           
         
         is cycloalkyl;  
         or a pharmaceutically acceptable salts thereof.  
       
     
     
         2 - 9 . (canceled)  
     
     
         10 . A compound of formula (I) or (II):  
       
         
           
           
               
               
           
         
         wherein  
         R 1  is selected from the group consisting of hydrogen, carboxy, —C(O)—C 1 -C 6 alkyl, —C(O)—C 1 -C 6 alkoxy, —C(O)—NH—C 1 -C 6 alkyl-NH 2 , —C(O)—NH—C 1 -C 6 alkyl-NHR A , —C(O)—NH—C 1 -C 6 alkyl-N(R A ) 2 , —C(O)—NH 2 , —C(O)—NHR A , —C(O)—N(R A ) 2 , —C 1 -C 6 alkyl-NH 2 , —C 1 -C 6 alkyl-NHR A , C 1 -C 6 alkyl-N(R A ) 2 , —NH-C 1 -C 6 alkyl-N(R A ) 2 ;  
         where each R A  is independently selected from the group consisting of C 1 -C 6 alkyl, aryl, C 1 -C 6 aralkyl and heteroaryl, where the aryl, aralkyl or heteroaryl may be optionally substituted with one to three R B ;  
         where each R B  is independently selected from the group consisting of halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylcarbonyl, carboxyC 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, trifluoromethyl, amino, di(C 1 -C 6 alkyl)amino, acetylamino, carboxyC 1 -C 6 alkylcarbonylamino, hydroxyC 1 -C 6 alkylamino, NHR A  and N(R A ) 2 ;  
         R 2  is selected from the group consisting of C 5 -C 10 alkyl (optionally substituted with one to three substituents independently selected from halogen, hydroxy, nitro, amino, NHR A  or N(R A ) 2 ), aryl (optionally substituted with one to three substituents independently selected from R C ), cycloalkyl (optionally substituted with one to three substituents independently selected from R A ), heteroaryl (optionally substituted with one to three substituents independently selected from R C ), and heterocycloalkyl (optionally substituted with one to three substituents independently selected from R C );  
         where R C  is selected from the group consisting of halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, NH 2 , NH(C 1 -C 6 alkyl) and N(C 1 -C 6 alkyl) 2 ;  
         R 3  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 2 -C 6 alkenylcarbonyl and C 2 -C 6 alkynylcarbonyl;  
         b is an integer from 0 to 4;  
         R 4  is independently selected from the group consisting of halogen, hydroxy, carboxy, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, trifluoromethyl, phenyl (wherein the phenyl group may be optionally substituted with one to three substituents independently selected from R D ), phenylsulfonyl, naphthyl, C 1 -C 6 aralkyl, —O-aralkyl, (wherein the aralkyl group may be optionally substituted with one to three substituents independently selected from R D ), heteroaryl (wherein the heteroaryl may be optionally substituted with one to three substituents independently selected from R D ), NH 2 , NHR A , N(R A ) 2 ,  
         
           
             
             
                 
                 
             
           
         
         where each R D  is independently selected from halogen, hydroxy, carboxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyoxycarbonyl, C 1 -C 4 alkylcarbonyl, trifluoromethyl, trifluoromethoxy, NH 2 , NHR A , N(R A ) 2 , C(O)N(R A ) 2 , SO 2 N(R A ) 2 , acetylamino, nitro, cyano, formyl, C 1 -C 6 alkylsulfonyl and carboxyC 1 -C 6 alkyl;  
         c is an integer from 0 to 4;  
         R 5  is independently selected from the group consisting of halogen, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —NHR A , —N(R A ) 2 , —OR A , —C(O)NH 2 , —C(O)NHR A , —C(O)N(R A ) 2 , —NHC(O)R A , —SO 2 NHR A , SO 2 N(R A ) 2 , where R A  is as defined above, phenyl (optionally substituted with one to three substituents independently selected from R B ), heteroaryl (optionally substituted with one to three substituents independently selected from R B ) and heterocycloalkyl (optionally substituted with one to three substituents independently selected from R B );  
         a is an integer from 0 to 1;  
         Y selected from the group consisting of —C 1 -C 6 alkyl-, —C(O)—, —(C 1 -C 6 alkyl)carbonyl-, —(C 2 -C 6 alkenyl)carbonyl-, —(C 2 -C 6 alkynyl)carbonyl-, -carbonyl(C 1 -C 6 alkyl)-, -carbonyl(C 2 -C 6 alkenyl)-, —C(O)O—(C 1 -C 6 alkyl)-, —C(S)—, —SO 2 —, —(C 1 -C 6 alkyl)sulfonyl-, -sulfonyl(C 1 -C 6 alkyl)-, —C(O)NH—, —C(O)NH—(C 1 -C 6 alkyl)-, C(O)(C 3 -C 7 cycloalkyl)- and —(C 3 -C 7 cycloalkyl)-C(O)—;  
         
           
             
             
                 
                 
             
           
         
         is selected from the group consisting phenyl, furyl, thienyl and pyrrolyl;  
         
           
             
             
                 
                 
             
           
         
         is cycloalkyl;  
         or a pharmaceutically acceptable salts thereof.  
       
     
     
         11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1 .  
     
     
         12 . A pharmaceutical composition made by mixing a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         13 . A process for making a pharmaceutical composition comprising mixing a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         14 . A method of treating sexual dysfunction in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 .  
     
     
         15 . A method of treating sexual dysfunction in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of  claim 11 .  
     
     
         16 . The method of treating sexual dysfunction of  claim 14 , wherein the sexual dysfunction is male sexual dysfunction, male erectile dysfunction, impotence, female sexual dysfunction, female sexual arousal dysfunction and female sexual dysfunction related to blood flow and nitric oxide production in the tissues of the vagina and clitoris.  
     
     
         17 . A method for increasing the concentration of cGMP in penile tissue in a male subject in need thereof comprising administering to the subject an effective amount of the compound of  claim 1 .  
     
     
         18 . A method of treating a condition selected from the group consisting of male erectile dysfunction (ED), impotence, female sexual arousal dysfunction, female sexual dysfunction related to blood flow and nitric oxide production in the tissues of the vagina and clitoris, premature labor, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 1.