Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses

• US 6,316,457 B1
• Filed: 02/10/1999
• Issued: 11/13/2001
• Est. Priority Date: 11/01/1996
• Status: Expired due to Fees

• Current Assignee: Nitromed, Inc. (Arbor Pharmaceuticals LLC)
• Original Assignee: Nitromed, Inc. (Arbor Pharmaceuticals LLC)
• Inventors: Garvey, David S., de Tejada, Inigo Saenz
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Rao, Deepak R.
• Application Number:
  US09/247,323
• Time in Patent Office: 1,007 Days
• Field of Search: 514/263, 544/272
• US Class Current: 514/263.34
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

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 NO₂ 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.

Claims

1. A compound having structure VI:

wherein

R₁₅ is a hydrogen, a lower alkyl, R₄, or —

(CH₂)₄—

C(CH₃)₂—

O—

D₁;

R₁₆ is a lower alkyl; and

R₁₇ is a hydrogen, a lower alkyl, CH₃—

C(O)—

CH₂—

, CH₃—

O—

CH₂—

, or D, with the proviso that either R₁₅ or R₁₇ must contain D;

D is

(i) —

NO,

(ii) —

NO₂,

(iii) —

CH(R_d)—

O—

C(O)—

Y—

Z—

(C(R_e)(R_f))_p—

T—

Q,

wherein R_d is a hydrogen, a lower alkyl, a cycloalkyl, an aryl, an arylalkyl, or a heteroaryl;

Y is oxygen, sulfur, CH₂ 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;

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 —

NO₂;

(iv) —

C(O)—

Y—

Z—

(G—

(C(R_e)(R_f))_q—

T—

Q)_p,

wherein G is a covalent bond, —

T—

C(O)—

, —

C(O)—

T—

or T, wherein q is an integer from 0 to 5, and Y, Z, R_e, R_f, p, T and Q are as defined above;

or

(v) —

P—

Z—

(G—

(C(R_e)(R_f))_q—

T—

Q)_p,

wherein P is a carbonyl, a phosphoryl or a silyl, and Z, G, p, q, T, Q, R_e and R_f are as defined above;

R₄ is (i) hydrogen, (ii) —

CH(R_d)—

O—

C(O)—

Y—

Z—

(C(R_e)(R_f))_pT—

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, Y, Z, R_e, R_f, p, T, Q, Z and G are as defined above; and

D₁ is D or a hydrogen.

2. The compound of claim 1, wherein the compound having structure VI is a nitrosated denbufylline, a nitrosylated denbufylline, a nitrosated and nitrosylated denbufylline, a nitrosated albifylline, a nitrosylated albifylline, a nitrosated and nitrosylated albifylline, a nitrosated torbafylline, a nitrosylated torbafylline, a nitrosated and nitrosylated torbafylline, a nitrosated doxofylline, a nitrosylated doxofylline, a nitrosated and nitrosylated doxofylline, a nitrosated theophylline, a nitrosylated theophylline, a nitrosated and nitrosylated theophylline, a nitrosated propentofylline, a nitrosylated propentofylline, a nitrosated and nitrosylated propentofylline, a nitrosated pentoxifylline, a nitrosylated pentoxifylline, or a nitrosated and nitrosylated pentoxifylline.

3. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

4. 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 3 to treat the sexual dysfunction.

5. The method of claim 4, wherein the individual is female.

6. The method of claim 4, wherein the individual is male.

7. 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 3 and a therapeutically effective amount of 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.

8. The method of claim 7, wherein the composition and the compound are administered separately or in the form of a composition.

9. The method of claim 7, wherein the individual is male.

10. The method of claim 7, wherein the individual is female.

11. A composition comprising the compound of claim 1 and 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.

12. The composition of claim 11, wherein the 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 is present in a one to ten fold molar excess with respect to the compound of structure VI.

13. The composition of claim 11, wherein the compound that donates, transfers or releases nitrogen monoxide releases nitrogen monoxide as at least one of NO⁺, NO⁻

or NO·

.

14. The composition of claim 11, wherein the 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 is an S-nitrosothiol.

15. The composition of claim 14, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione.

16. The composition of claim 14, wherein the S-nitrosothiol is:

(i) CH₃(C(R_e)(R_f))_xSNO;

(ii) HS(C((R_e)(R_f))_xSNO;

(iii) ONS(C(R_e)(R_f))_xB;

or

(iv) H₂N—

CH(CO₂H)—

(CH₂)_x—

C(O)NH—

CH(CH₂SNO)—

C(O)NH—

CH₂—

CO₂H;

wherein x equals 2 to 20;

R_e and R_f are each 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 with the carbon atoms to which they are attached 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 NO₂, and B is a fluoro, an alkoxy, a cyano, a carboxamido, a cycloalkyl, an 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.

17. The composition of claim 11, wherein the 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 is L-arginine or OH-arginine.

18. The composition of claim 11, wherein the 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 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 R₆₁R₆₂—

N—

(O—

M⁺)—

NO, wherein R₆₁, and R₆₂ 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 R₆₁—

S—

NO₂, wherein R₆₁ is as defined above.

19. The composition of claim 18, 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, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—

N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—

C-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic ON—

O-hydrocarbon, an ON—

N-heterocyclic compound, or an ON—

C-heterocyclic compound.

20. The composition of claim 11, wherein the 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 is a compound comprising at least one O₂N—

O—

, O₂N—

N—

, O₂N—

S—

or O₂N—

C—

group.

21. The composition of claim 20, wherein the compound comprising at least one O₂N—

O—

, O₂N—

N—

, O₂N—

S—

or O₂N—

C—

group is an O₂N—

O-polypeptide, an O₂N—

N-polypeptide, an O₂N—

S-polypeptide, an O₂N—

C-polypeptide, an O₂N—

O-amino acid, an O₂N—

N-amino acid, an O₂N—

S-amino acid, an O₂N—

C-amino acid, an O₂N—

O-sugar, an O₂N—

N-sugar, an O₂N—

S-sugar, an O₂N—

C-sugar, an O₂N—

O-oligonucleotide, an O₂N—

N-oligonucleotide, an O₂N—

S-oligonucleotide, an O₂N—

C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O₂N—

O-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O₂N—

N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O₂N—

S-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O₂N—

C-hydrocarbon, an O₂N—

O-heterocyclic compound, an O₂N—

N-heterocyclic compound, an O₂N—

S-heterocyclic compound or an O₂N—

C-heterocyclic compound.

22. 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 11 to treat the sexual dysfunction.

23. The method of claim 22, wherein the individual is female.

24. The method of claim 22, wherein the individual is male.

39. The method of claim 4, 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.

40. A kit comprising the composition of claim 3.

41. The kit of claim 40, 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.

42. A kit comprising the composition of claim 11.

25. A method for treating a sexual dysfunction in an individual in need thereof comprising administering a therapeutically effective amount of a phosphodiesterase inhibitor, wherein the phosphodiesterase inhibitor is denbufylline, albifylline, torbafylline, doxofylline, theophylline, propentofylline or pentoxifyllin, and 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.

26. The method of claim 25, wherein the phosphodiesterase inhibitor and the compound that donates, transfers or releases nitrogen monoxide or induces the production of endogenous endothelium-derived relaxing factor or stimulates endogenous synthesis of nitrogen monoxide or is a substrate for nitric oxide synthase are administered separately or in the form of a composition.

27. The method of claim 25, wherein the individual is female.

28. The method of claim 25, wherein the individual is male.

29. The method of claim 25, wherein the 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 is present in a one to ten fold molar excess with respect to the phosphodiesterase inhibitor.

30. The method of claim 25, wherein the compound that donates, transfers or releases nitrogen monoxide donates, transfers or releases nitrogen monoxide as at least one of NO⁺, NO⁻

or NO·

.

31. The method of claim 25, wherein the 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 is an S-nitrosothiol.

32. The method of claim 31, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione.

33. The method of claim 31, wherein the S-nitrosothiol is:

(i) CH₃(C(R_e)(R_f))_xSNO;

(ii) HS(C((R_e)(R_f))_xSNO;

(iii) ONS(C(R_e)(R_f))_xB;

or

(iv) H₂N—

CH(CO₂H)—

(CH₂)_x—

C(O)NH—

CH(CH₂SNO)—

C(O)NH—

CH₂—

CO₂H;

wherein x equals 2 to 20;

R_e and R_f are each 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 with the carbon atoms to which they are attached 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 NO₂, and B is a fluoro, an alkoxy, a cyano, a carboxarnido, a cycloalkyl, an 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.

34. The method of claim 25, wherein the 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 is L-arginine or OH-arginine.

35. The method of claim 25, wherein the 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 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 R₆₁R₆₂—

N—

(O—

M⁺)—

NO, wherein R₆₁ and R₆₂ 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 R₆₁—

S—

NO₂), wherein R₆₁ is a polypeptide, an ami no acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aiphatic or aromatic hydrocarbon, or a heterocyclic compound.

36. The method of claim 35, 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-oliconucleotide, an ON—

C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—

N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—

C-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic ON—

O-hydrocarbon, an ON—

N-heterocyclic compound, or an ON—

C-heterocyclic compound.

37. The method of claim 25, wherein the 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 is a compound comprising at least one O₂N—

O—

, O₂N—

N—

, O₂N—

S—

or O₂N—

C—

group.

38. The method of claim 37, wherein the compound comprising at least one O₂N—

O—

, O₂N—

N—

, O₂N—

S—

or O₂N—

C—

group is an O₂N—

O-polypeptide, O₂N—

N-polypeptide, an O₂N—

S-polypeptide, an O₂N—

C-polypeptide, an O₂N—

O-amino acid, an O₂N—

N-amino acid, an O₂N—

S-amino acid, an O₂N—

C-amino acid, an O₂N—

O-sugar, an O₂N—

N-sugar, an O₂N—

S-sugar, an O₂N—

C-sugar, an O₂N—

O-oligonucleotide, an O₂N—

N-oligonucleotide, an O₂N—

S-oligonucleotide, an O₂N—

C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O₂N—

O-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O₂N—

N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O₂N—

S-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic O₂N—

C-hydrocarbon, an O₂N—

O-heterocyclic compound, an O₂N—

N-heterocyclic compound, an O₂N—

S-heterocyclic compound or an O₂N—

C-heterocyclic compound.