Nitrosated and nitrosylated phosphodiestrase inhibitor compounds, compositions and their uses

Abstract

Disclosed are nitrosated and/or nitrosylated phosphodiesterase inhibitors having the formula NO n -PDE inhibitor where n is 1 or 2. The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier. The invention also provides a composition comprising a therapeutically effective amount of an phosphodiesterase inhibitor (PDE inhibitor), which can optionally be substituted with at least one NO or NO 2 moiety, and one to ten fold molar excess of a compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO + ) or nitroxyl (NO − ), or as the neutral species, nitric oxide (NO•) or which stimulates endogenous EDRF production. The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier. The invention also provides methods for treating sexual dysfunctions in males and females.

What is claimed is:  
     
       1. A nitrosated or nitrosylated phosphodiesterase inhibitor  compound of structure III:                    
       wherein E is nitrogen or —CH—; 
       M is nitrogen or —C(R 8 )—;  
       R 21  is:                    
       R 22  is R 12  or a lower alkyl, with the proviso that when R 12  is a lower alkyl, then R 11  cannot be hydrogen;  
       R 11  and R 12  are each independently a hydrogen or R 4 , with the proviso that R 11  and R 12  are not both hydrogen;  
       R 8  is a hydrogen or a lower alkyl; and  
       R 4  is  
       (i) hydrogen,  
       (ii) —CH(R d )—O—C(O)—Y—Z—(C(R e )(R f )) p T—Q,  
       (iii) —C(O)—T—(C(R e )(R f )) p —T—Q, or  
       (iv) —C(O)—Z—(G—(C(R e )(R f )) p —T—Q) p ;  
       wherein R d  is a hydrogen, a lower alkyl, a cycloalkyl, an aryl, an arylalkyl, or a heteroaryl; Y is oxygen, sulfur, CH 2  or NR i , wherein R i  is a hydrogen or a lower alkyl; R e  and R f  are each independently a hydrogen, a lower alkyl, a haloalkyl, an alkoxy, a cycloalkyl, an aryl, a heteroaryl, an arylalkyl, an amino, an alkylamino, an amido, an alkylamido, a dialkylamino, a carboxylic acid, a carboxylic ester, a carboxamido or —T—Q, or R e  and R f  taken together are a carbonyl, a cycloalkyl, a heterocyclic ring or a bridged cycloalkyl; p is an integer from 1 to 10; T is independently a covalent bond, oxygen, sulfur or NH; G is a covalent bond, —T—C(O)—, —C(O)—T— or T; Z is a covalent bond, a lower alkyl, a haloalkyl, a cycloalkyl, an aryl, a heteroaryl, an arylalkyl, a heteroalkyl, an arylheterocyclic ring or (C(R e )(R f )) p ; and Q is —NO or —NO 2 . 
     
     
       2. The compound of claim  1 , wherein the nitrosated or nitrosylated phosphodiesterase inhibitor  compound of structure III is a nitrosated zaprinast, a nitrosylated zaprinast, or a nitrosated and nitrosylated zaprinast. 
     
     
       3. The compound of claim  1   24 , wherein the nitrosated or nitrosylated phosphodiesterase inhibitorcompound of structure III is a nitrosated sildenafil, a nitrosylated sildenafil, or a nitrosated and nitrosylated sildenafil. 
     
     
       4. A composition comprising the nitrosated or nitrosylated phosphodiesterase inhibitor  compound of claim  1   24 and a pharmaceutically acceptable carrier. 
     
     
       5. A composition comprising the nitrosated or nitrosylated phosphodiesterase inhibitor  compound of claim  1  and a composition that donates, transfers or releases nitrogen monoxideor , induces the production of endogenous endothelium-derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or a substrate for nitric oxide synthase. 
     
     
       6. The composition of claim  5 , wherein the compound that donates, transfers or releases nitrogen monoxideor , induces the production of endogenous endothelium-derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase is present in a one to ten fold molar excess. 
     
     
       7. The composition of claim  5  wherein the compound that donates, transfers or releases nitrogen monoxidedonates, transfers or release nitrogen monoxide as at least one of NO + , NO −  or NO•. 
     
     
       8. The composition of claim  5 , wherein the compound that donates, transfers or releases nitrogen monoxideor , induces the production of endogenous endothelium-derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase is an S-nitrosothiol. 
     
     
       9. The composition of claim  8 , wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione. 
     
     
       10. The composition of claim  8 , wherein the S-nitrosothiol is: 
       (i) CH 3 (C(R e )(R f )) x SNO;  
       (ii) HS(C((R e )(R f )) x SNO:  
       (iii) ONS(C(R e )(R f )) x B; or  
       (iv) H 2 N—CH(CO 2 H)—(CH 2 ) x —C(O)NH—C(CH 2 SNO)—C(O)NH—CH 2 —CO 2 H  
       ( iv )  H   2   N—CH ( CO   2   H )—( CH   2 ) x   —C ( O ) NH—CH ( CH   2   SNO )— C ( O ) NH—CH   2   —CO   2   H;    
       wherein x equals 2 to 20; R e  and R f  are independently a hydrogen, a lower alkyl, a haloalkyl, an alkoxy, a carboxylic acid, a carboxylic ester, a cycloalkyl, an aryl, a heteroaryl, an arylalkyl, an alkylamino, a dialkylamino, or —T—Q, or R e  and R f  taken together are a carbonyl, a heterocyclic ring, a cycloalkyl or a bridged cycloalkyl; T is a covalent bond, oxygen, sulfur or nitrogen, Q is NO or NO 2 , and B is a fluoro, an alkoxy, a cyano, a carboxamido, a cycloalkyl, an arylakoxy  arylalkoxy, an alkylsulfinyl, an arylthio, an alkylamino, a dialkylamino, a hydroxy, a carbamoyl, an N-alkylcarbamoyl, an N,N-dialkylcarbamoyl, an amino, a hydroxyl, a carboxyl, a hydrogen, a nitro or an aryl. 
     
     
       11. The composition of claim  5 , wherein the compound that donates, transfers or releases nitrogen monoxideor , induces the production of endogenous endothelium-derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase is L-arginine or OH-arginine. 
     
     
       12. The composition of claim  5 , wherein the compound that donates, transfers or releases nitrogen monoxideor , induces the production of endogenous endothelium-derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase is: 
       (i) a compound comprising at least one ON—O—, ON—N— or ON—C-group;  
       (ii) a nitroso-metal compound having the structure (R) u —A—M—(NO) v , wherein R is a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic hydrocarbon, or a heterocyclic compound; A is S, O or N; u and v are each independently an integer of 1, 2 or 3; and M is a transition metal;  
       (iii) a compound having the structure R 61 R 62 —N—(O—M + )—NO, wherein R 61  and R 62  are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic hydrocarbon, or a heterocyclic compound; and M +  is a metal cation; or  
       (iv) a thionitrate having the structure R 61 —S—NO 2 , wherein R 61  is as defined above.  
     
     
       13. The composition of claim  12 , wherein the compound comprising at least one ON—O—, ON—N— or ON—C-group is an ON—N-polypeptide, an ON—C-polypeptide, an ON—N-amino acid, an ON—C-amino acid, an ON—C-sugar, an ON—N-sugar, an ON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched, a saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—N-hydrocarbon, a straight or branched, a saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—C-hydrocarbon, a straight or branched, a saturated or unsaturated, aliphatic or aromatic ON—O-hydrocarbon, an ON—N-heterocyclic compound, or a ON—C-heterocyclic compound. 
     
     
       14. The composition of claim  5 , wherein the compound that donates, transfers or releases nitrogen monoxideor , induces the production of endogenous endothelium-derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase is a compound comprising at least one O 2 N—O—, O 2 N—N—, O 2 N—S— or O 2 N—C-group. 
     
     
       15. The composition of claim  14 , wherein the compound comprising at least one O 2 N—O—, O 2 N—N—, O 2 N—S— or O 2 N—C-group is an O 2 N—O-polypeptide, an O 2 N—N-polypeptide, an O 2 N—S-polypeptide, an O 2 N—C-polypeptide, an O 2 N—O-amino acid, an O 2 N—N-amino acid, an O 2 N—S-amino acid, an O 2 N—C-amino acid, an O 2 N—O-sugar, an O 2 N—N-sugar, an O 2 N—sugar, an O 2 N—C-sugar, an O 2 N-O-oligonucleotide, an O 2 N—N-oligonucleotide, an O 2 N—S-oligonucleotide, an O 2 N—C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O 2 N—O-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O 2 N—N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O 2 N—S-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O 2 N—C-hydrocarbon, an O 2 N—O-heterocyclic compound, an O 2 N—N-heterocyclic compound, an O 2 N—S-heterocyclic compound or an O 2 N—C-heterocyclic compound. 
     
     
       16. A method for treating a sexual dysfunction in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the composition of claim  5  to treat the sexual dysfunction. 
     
     
       17. The method of claim  16 , wherein the individual is female. 
     
     
       18. The method of claim  16 , wherein the individual is male. 
     
     
       19. A method for treating sexual dysfunction in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the composition of claim  4  to treat the sexual dysfunction. 
     
     
       20. The method of claim  19 , wherein the individual is female. 
     
     
       21. The method of claim  19 , wherein the individual is male. 
     
     
       22. The method of claim  19 , further comprising administering a compound that donates, transfers or releases nitrogen monoxide, induces the production of endogenous endothelium- derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase.    
     
     
       23. A kit comprising the composition of claim  4 .  
     
     
       24. The kit of claim  23 , further comprising a compound that donates, transfers or releases nitrogen monoxide, induces the production of endogenous endothelium- derived relaxing factor, stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase.    
     
     
       25. A kit comprising the composition of claim  5 .