Claims
- 1. A compound selected from the group consisting of 4-aza-4-(2-methyl-2-(nitrosothio)propyl)tricyclo(5.2.1.0<2,6>)dec-8-ene-3,5-dione or a pharmaceutically acceptable salt thereof; and 4-(1-methyl-1-(nitrosothio)ethyl)-1,3-oxazolidin-2-one or a pharmaceutically acceptable salt thereof.
- 2. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
- 3. The composition of claim 3, further comprising at least one penetration enhancer, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, or a pharmaceutically acceptable salt thereof and/or at least one vasoactive agent or a pharmaceutically acceptable salt thereof.
- 4. The composition of claim 3, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is an S-nitrosothiol.
- 5. The composition of claim 4, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione or S-nitroso-cysteinyl-glycine.
- 6. The composition of claim 5, wherein the S-nitrosothiol is S-nitroso-glutathione.
- 7. The composition of claim 4, wherein the S-nitrosothiol is:
(i) HS(C(Re)(Rf))mSNO; (ii) ONS(C(Re)(Rf))mRe; and (iii) H2N—CH(CO2H)—(CH2)m—C(O)NH—CH(CH2SNO)—C(O)NH—CH2—CO2H; wherein m is an integer from 2 to 20; Re and Rf are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cycloalkylthio, a cycloalkenyl, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, a carbamate, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a sulfonic ester, a urea, a phosphoryl, a nitro, -T-Q, or —(C(Re)(Rf))k-T-Q, or Re and Rf taken together with the carbon atom to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; Q is —NO or —NO2; and T is independently a covalent bond, a carbonyl, an oxygen, —S(O)o— or —N(Ra)Ri—, wherein o is an integer from 0 to 2, Ra is a lone pair of electrons, a hydrogen or an alkyl group; Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an amino alkyl, an amino aryl, —CH2—C(T-Q)(Re)(Rf), or —(N2O2—).M+, wherein M+ is an organic or inorganic cation; with the proviso that when Ri is —CH2—C(T-Q)(Re)(Rf) or —(N2O2—).M+; then “-T-Q” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.
- 8. The composition of claim 3, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is:
(i) a compound that comprises at least one ON—O—, ON—N— or ON—C— group; (ii) a compound that comprises at least one O2N—O—, O2N—N—, O2N—S— or —O2N—C— group; (iii) a N-oxo-N-nitrosoamine having the formula: R1R2N—N(O-M+)—NO, wherein R1 and R2 are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M+is an organic or inorganic cation.
- 9. The composition of claim 8, wherein the compound comprising at least one ON—O—, ON—N— or ON—C— group is an ON—O-polypeptide, an ON—N-polypepetide, an ON—C-polypeptide, an ON—O-amino acid, an ON—N-amino acid, an ON—C-amino acid, an ON—O-sugar, an ON—N-sugar, an ON—C-sugar, an ON—O-oligonucleotide, an ON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—O-hydrocarbon, 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, an ON—O-heterocyclic compound, an ON—N-heterocyclic compound or a ON—C-heterocyclic compound.
- 10. The composition of claim 8, wherein 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, O2N—N-amino acid, O2N—S-amino acid, an O2N—C-amino acid, an O2N—O-sugar, an O2N—N-sugar, 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, aliphatic or aromatic, substituted or unsubstituted O2N—O-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—S-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—C-hydrocarbon, an O2N—O-heterocyclic compound, an O2N—N-heterocyclic compound, an O2N—S-heterocyclic compound or an O2N—C-heterocyclic compound.
- 11. The composition of claim 3, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine, glutamine, lysine, polypeptides comprising at least one of these amino acids or inhibitors of the enzyme arginase.
- 12. The composition of claim 3, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is a NONOate.
- 13. The composition of claim 3, wherein the vasoactive agent is a potassium channel activator, a calcium channel blocker, an α-adrenergic receptor antagonist, a β-blocker, a phosphodiesterase inhibitor, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a prostaglandin, a dopamine agonist, an opioid antagonist, an endothelin antagonist, a thromboxane inhibitor or a mixture thereof.
- 14. The composition of claim 3, wherein the penetration enhancer is dimethylsulfoxide, dimethyl formamide, N,N-dimethylacetamide, decylmethylsulfoxide, polyethylene glycol monolaurate, polyethyleneglycol, glycerol monolaurate, lecithin, a 1-substituted azacycloheptan-2-one, a lower alkanol, a C6 to C20-hydrocarbyl substituted 1,3-dioxane, a C6 to C20-hydrocarbyl substituted 1,3-dioxolane or a C6 to C20-hydrocarbyl substituted acetal, an alkonate, a glyceride, a surfactant, or a mixture thereof.
- 15. The composition of claim 14, wherein the glyceride is a mono glyceride, a diglyceride, a triglycerides, a polyglycolyzed glyceride or a mixture thereof.
- 16. The composition of claim 15, wherein the glyceride is a mixture of caprylic triglycerides and capric triglycerides, a decanoly triglyceride, an octanoyl triglyceride, a C8-C12 triglyceride, a saturated polyglycolyzed glyceride, a glyceryl caprylate/caprate and PEG-8 (polyethylene glycol) caprylate/caprate complex, a unsaturated polyglycolyzed glyceride, an apricot kernel oil PEG-6 complex, an almond oil PEG-6 complex, a peanut oil PEG-6 complex, an olive oil PEG-6 complex, a corn oil PEG-6 complex, an ethoxylated glyceride, a glyceryl caprylate/caprate PEG-4 complex, or a mixture thereof.
- 17. A method for treating a sexual dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
- 18. The method of claim 17, wherein the patient is female.
- 19. The method of claim 17, wherein the patient is male.
- 20. The method of claim 17, wherein the composition is administered orally, bucally, topically, by injection, by inhalation or by transurethral application.
- 21. The method of claim 20, wherein the composition is administered orally as a solid or liquid dose.
- 22. The method of claim 17, further comprising administering at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or the at least one vasoactive agent
- 23. The method of claim 22, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and the at least one vasoactive agent are administered separately.
- 24. The method of claim 22, wherein the at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and the at least one vasoactive agent are administered in the form of a composition.
- 25. A kit comprising at least one compound of claim 1.
- 26. The kit of claim 25, further comprising at least one penetration enhancer, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one vasoactive agent.
- 27. A compound selected from the group consisting of 4-aza4-(2-methyl-2-sulfanylpropyl)tricyclo(5.2.1.0<2,6>)dec-8-ene-3,5-dione or a pharmaceutically acceptable salt thereof; 4-1{1-methyl-1-((2,4,6-trimethoxyphenyl)methylthio)ethyl}-1,3-oxazolidin-2-one or a pharmaceutically acceptable salt thereof; and 2-amino-3-methyl-3-((2,4,6-trimethoxyphenyl)methylthio)butan-1-ol or a pharmaceutically acceptable salt thereof.
- 28. 4-aza-4-(2-methyl-2-(nitrosothio)propyl)tricyclo(5.2.1.0<2,6>)dec-8-ene-3,5-dione or a pharmaceutically acceptable salt thereof.
- 29. 4-(1-methyl-1-(nitrosothio)ethyl)-1,3-oxazolidin-2-one or a pharmaceutically acceptable salt thereof.
RELATED APPLICATIONS
[0001] This application is a continuation under 35 USC § 120 of U.S. application Ser. No. 09/850,081 filed May 8, 2001, now allowed, which claims priority under 35 USC § 119 to U.S. Application No. No. 60/202,935 filed May 9, 2000.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60202935 |
May 2000 |
US |
Continuations (1)
|
Number |
Date |
Country |
| Parent |
09850081 |
May 2001 |
US |
| Child |
10781705 |
Feb 2004 |
US |
Patent Application
20040162243
