Claims
- 1. A nitrosated or nitrosylated o-adrenergic receptor antagonist selected from the group consisting of:
(i) a compound having structure I: 37 wherein Ra is a hydrogen or an alkoxy; Rb is: 38 wherein a is an integer of 2 or 3; Rc is a heteroaryl, a heterocyclic ring, a lower alkyl, a hydroxyalkyl, or an arylheterocyclic ring; D is (i) —NO, (ii) —NO2, (iii) —C(Rd)—O—C(O)—Y-Z-(C(Re)(Rf))p-T-Q, wherein Rd is a hydrogen, a lower alkyl, a cycloalkyl, an aryl, an arylalkyl, or a heteroaryl; Y is oxygen, sulfur, carbon or NRi wherein Ri is a hydrogen or a lower alkyl; Re and Rf are each independently a hydrogen, a lower alkyl, a haloalkyl, a cycloalkyl, an alkoxy, an aryl, a heteroaryl, an arylalkyl, an amino, an alkylamino, a dialkylamino, an amido, an alkylamido, a carboxylic acid, a carboxylic ester, a carboxamido, a carboxy or -T-Q, or Re and Rf taken together are a carbonyl, a heterocyclic ring, a cycloalkyl or a bridged cycloalkyl; p is an integer from 1 to 10; T is independently a covalent bond, oxygen, sulfur or nitrogen; 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(Re)(Rf))p, and Q is —NO or —NO2; (iv) —C(O)—Y-Z-(G-(C(Re)(Rf))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 wherein Re, Rf, p, Q, Z, Y and T are as defined above, or (v) —P-Z-(G-(C(Re)(Rf))q-T-Q)q, wherein P is a carbonyl, a phosphoryl or a silyl, and wherein Re, Rf, p, q, Q, T, Z and G are as defined above. (ii) a compound having structure II: 39 wherein, Rg is: 40 wherein D1 is a hydrogen or D, wherein D is as defined above, with the proviso that D1 must be D if there is no other D in the compound; (iii) a compound having structure III: 41 wherein Rh is a hydrogen, —C(O)—ORd or —C(O)—X, wherein X is (1) —Y—(C(Re)(Rf))p-G-(C(Re(Rf))pT-Q, wherein G is a covalent bond, -T-C(O)—, C(O)-T-, or —C(Y—C(O)—Rm)—, wherein Rm is a heteroaryl or a heterocyclic ring; and wherein Y, Rd, Re, Rf, p, Q and T are as defined above; or 42 wherein W is a heterocyclic ring or NRiR′i, wherein Ri and R′i are independently a lower alkyl, an aryl, or an alkenyl; and wherein Rj is -D or —(O)CRd, wherein D and Rd are as defined above; (iv) a compound having structure IV: 43 wherein A, is an oxygen or a methylene, and X and Rj are as defined above; (v) a compound having structure V: 44 wherein Rk is independently a hydrogen or a lower alkyl; and Rl is: 45 wherein b is an integer of 0 or 1; D1 is as defined above; and Rn is: 46 wherein A2 is an oxygen or a sulfur: (vi) a compound having structure VI: 47 wherein Ro is: 48 and Rp is: 49 and Rk, D and D1 are as defined above; and (vii) a compound having structure VII: 50 wherein Rd, T and D are defined as above.
- 2. The nitrosated or nitrosylated α-adrenergic receptor antagonist of claim 1, wherein the nitrosated or nitrosylated α-adrenergic receptor antagonist is a nitrosated or nitrosylated member selected from the group consisting of a haloalkylamine, an imidazoline, a quinazoline, an indole derivative, a phenoxypropanolamine, an alcohol, an alkaloid, an amine, a piperazine and a piperidine.
- 3. The nitrosated or nitrosylated α-adrenergic receptor antagonist of claim 2, wherein the haloalkylamine is selected from the group consisting of phenoxybenzamine and dibenamine;
wherein the imidazoline is selected from the group consisting of phentolamine, tolazoline, idazoxan, deriglidole, RX 821002, BRL 44408 and BRL 4409; wherein the quinazoline is selected from the group consisting of prazosine, terazosin, doxazosin, alfuzosin, bunazosin, ketanserin, trimazosin and abanoquil; wherein the indole derivative is selected from the group consisting of carvedilol and BAM 1303; wherein the alcohol is selected from the group consisting of labetalol and ifenprodil; wherein the alkaloid is selected from the group consisting of ergotoxine, ergocornine, ergocristing, ergocryptine, rauwolscine, corynathine, raubascine, tetrahydroalstonine, apoyohimbine, akuammignie, O-yohimbine, yohimbol, pseudoyohimbine and epi-3α-yohimbine; wherein the amine is selected from the group consisting of tamsulosin, benoxathian, atipamezole, tedisamil, mirtazipine, setiptiline, reboxitine, delequamine, chlorpromazine, phenothiazine, BE 2254, WB 4101 and HU 723; wherein the amide is selected from the group consisting of indoramin and SB 216469; wherein the piperazine is selected from the group consisting of naftopil, saterinone urapidil, 5-methylurapidil, monatepil, SL 89.0591 and ARC 239; and wherein the piperidine is haloperidol.
- 4. A composition comprising the nitrosated or nitrosylated α-adrenergic receptor antagonist of claim 1 and a pharmaceutically acceptable carrier.
- 5. A method of treating a sexual dysfunction in an individual in need thereof comprising administering to the individual the composition of claim 4 to treat the sexual dysfunction.
- 6. The method of claim 5, wherein the individual is female.
- 7. The method of claim 5, wherein the individual is male.
- 8. A composition comprising (i) the nitrosated or nitrosylated α-adrenergic receptor antagonist of claim 1 and (ii) a compound that donates, transfers or releases nitric oxide or elevates levels of endogenous endothelium-derived relaxing factor.
- 9. The composition of claim 8, wherein the compound that donates, transfers or releases nitric oxide or elevates levels of endogenous endothelium-derived relaxing factor is an S-nitrosothiol.
- 10. The composition of claim 9, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroscysteine or S-nitroso-glutathione.
- 11. The composition of claim 9, wherein the S-nitrosothiol is:
(i) CH3(C(Re)(Rf))xSNO; (ii) HS(C(Re)(Rf))xSNO; (iii) ONS(C(Re)(Rf))xB; or (iv) H2N—(CO2 H)(CH2)—C(O)NH13 C(CH2SNO)—C(O)NH—CH2—CO2H wherein x equals 2 to 20; Re and Rf are independently a hydrogen, a lower alkyl, a haloalkyl, an alkoxy, a carboxylic acid, a carboxylic ester, a cycloalkyl, an aryl, a hereroaryl, an arylalkyl, an alkylamino, a dialkylamino, or -T-Q, or Re and Rf 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 NO2, and B is a fluoro, an alkoxy, a cyano, a carboxamido, a cycloalkyl, an arylkoxy, 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.
- 12. The composition of claim 8, wherein the compound that donates, transfers or releases nitric oxide or elevates levels of endogenous endothelium-derived relaxing factor is:
(i) a compound comprising at least one ON—O—, ON—N— or ON—C— group; (ii) a N-oxo-N-nitrosoamine comprising an R1 R2—N(O-M+)-NO group, wherein M+ is a metal cation; and R1 and R2 are 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; (iii) a thionitrate having the structure R10—S—NO2, wherein R10 is a polypeptide, an amino acid, a sugar, an oligonucleotide, or a straight or branched, saturated or unsaturaed, aliphatic or aromatic hydrocarbon; or (iv) a nitrate having the structure R10—O—NO2, wherein R10 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—N-sugar, an ON—C-sugar, an ON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic ON-O-hydrocarbon, a straight or branched, substituted or unsubstituted, saturated or unsaturated, aliphatic or aromatic ON—N-hydrocarbon, a straight or branched, substituted or unsubstituted, saturated or unsaturated, aliphatic or aromatic ON—C-hydrocarbon, an ON—N-heterocyclic compound or an ON—C-heterocyclic compound.
- 14. The composition of claim 8, wherein the compound that donates, transfers or releases nitric oxide or elevates levels of endogenous endothelium-derived relaxing factor is L-arginine or OH-arginine.
- 15. The composition of claim 8, wherein the compound that donates, transfers or releases nitric oxide or elevates levels of endogenous endothelium-derived relaxing factor is a compound comprising at least one O2N—O—, O2N—N—, O2N—S— or O2N—C— group.
- 16. The composition of claim 15, 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.
- 17. A method of treating a sexual dysfunction in an individual in need thereof comprising administering to the individual the composition of claim 8 in a pharmaceutically acceptable carrier to treat the sexual dysfunction.
- 18. The method of claim 17, wherein the individual is female.
- 19. The method of claim 17, wherein the individual is male.
- 20. A composition comprising (i) an α-adrenergic receptor antagonist and (ii) a compound that donates, transfers or releases nitric oxide or elevates endogenous levels of endothelium-derived relaxing factor.
- 21. The composition of claim 20, wherein the α- adrenergic receptor antagonist is a haloalkylamine, an imidazoline, a quinazoline, an indole derivative, a phenoxypropanolamine, an alcohol, an alkaloid, an amine, a piperazine or a piperidine.
- 22. The composition of claim 21, wherein the haloalkylamine is selected from the group consisting of phenoxybenzamine and dibenamine;
wherein the imidazoline is selected from the group consisting of phentolamine, tolazoline, idazoxan, deriglidole, RX 821002, BRL 44408 and BRL 4409; wherein the quinazoline is selected from the group consisting of prazosine, terazosin, doxazosin, alfuzosin, bunazosin, ketanserin, trimazosin and abanoquil; wherein the indole derivative is selected from the group consisting of carvedilol and BAM 1303; wherein the alcohol is selected from the group consisting of labetalol and ifenprodil; wherein the alkaloid is selected from the group consisting of ergotoxine, ergocornine, ergocristing, ergocryptine, rauwolscine, corynathine, raubascine, tetrahydroalstonine, apoyohimbine, akuammignie, ,α-yohimbine, yohimbol, pseudoyohimbine and epi-3α-yohimbine; wherein the amine is selected from the group consisting of tamsulosin, benoxathian, atipamezole, tedisamil, mirtazipine, setiptiline, reboxitine, delequamine, chlorpromazine, phenothiazine, BE 2254, WB 4101 and HU 723; wherein the amide is selected from the group consisting of indoramin and SB 216469; wherein the piperazine is selected from the group consisting of naftopil, saterinone urapidil, 5-methylurapidil, monatepil, SL 89.0591 and ARC 239; and wherein the piperidine is haloperidol.
- 23. The composition of claim 20, wherein the compound that donates, transfers or releases nitric oxide is an S-nitrosothiol.
- 24. The composition of claim 23, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione.
- 25. The composition of claim 23, wherein the S-nitrosothiol is:
(i) CH3(C(Re)(Rf))xSNO; (ii) HS(C(Re)(Rf))xSNO; (iii) ONS(C(Re)(Rf))xB; or (iv) H2N—(CO2 H)(CH2)—C(O)NH—C(CH2SNO)—C(O)NH—CH2 —CO2H wherein x equals 2 to 20; Re and Rf are independently a hydrogen, a lower alkyl, a haloalkyl, an alkoxy, a carboxylic acid, a carboxylic ester, a cycloalkyl, an aryl, a hereroaryl, an arylalkyl, an alkylamino, a dialkylamino, or -T-Q, or Re and Rf 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 NO2, and B is a fluoro, an alkoxy, a cyano, a carboxamido, a cycloalkyl, an arylkoxy, 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.
- 26. The composition of claim 20, wherein the compound that donates, transfers or releases nitric oxide is:
(i) a compound comprising at least one ON—O—, ON—N— or ON—C— group; (ii) a N-oxo-N-nitrosoamine comprising an R1R2—N(O-M+)-NO group, wherein M+is a metal cation; and R1 and R2 are 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; (iii) a thionitrate having the structure R10—S—NO2, wherein R10 is a polypeptide, an amino acid, a sugar, an oligonucleotide, or a straight or branched, saturated or unsaturaed, aliphatic or aromatic hydrocarbon; or (iv) a nitrate having the structure R10—O—NO2, wherein R10 is as defined above.
- 27. The composition of claim 26, 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—N-sugar, an ON—C-sugar, an ON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic ON—O-hydrocarbon, a straight or branched, substituted or unsubstituted, saturated or unsaturated, aliphatic or aromatic ON—N-hydrocarbon, a straight or branched, substituted or unsubstituted, saturated or unsaturated, aliphatic or aromatic ON—C-hydrocarbon, an ON—N-heterocyclic compound or an ON—C-heterocyclic compound.
- 28. The composition of claim 20, wherein the compound that elevates levels of endogenous endothelium-derived relaxing factor is L-arginine or OH-arginine.
- 29. The composition of claim 20, wherein the compound that donates, transfers or releases nitric oxide or elevates levels of endogenous endothelium-derived relaxing factor is a compound comprising at least one O2N—O—, O2N—N—, O2N—S- or O2N—C— group.
- 30. The composition of claim 29, 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.
- 31. A method of treating a sexual dysfunction in an individual in need thereof comprising administering to the individual the composition of claim 20 in a pharmaceutically acceptable carrier to treat the sexual dysfunction.
- 32. The method of claim 31, wherein the individual is female.
- 33. The method of claim 31, wherein the individual is male.
- 34. A compound comprising a nitrosated or nitrosylated α-adrenergic receptor antagonist.
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. application Ser. No. 08/714,313, filed Sep. 18, 1996, which is a continuation-in-part of U.S. application Ser. No. 08/595,732, filed Feb. 2, 1996.
Continuation in Parts (2)
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Number |
Date |
Country |
Parent |
08714313 |
Sep 1996 |
US |
Child |
10024550 |
Dec 2001 |
US |
Parent |
08595732 |
Feb 1996 |
US |
Child |
08714313 |
Sep 1996 |
US |