RU2001133004A - The use of selective alpha1b-adrenergic receptor antagonists to improve sexual dysfunction - Google Patents

Claims (24)

1. The compound of General formula

where A is 2-tetrahydrofuryl, substituted 2-furyl, substituted alkoxy or substituted phenoxyalkyl group, or the enantiomer, diastereoisomer or pharmaceutically acceptable salt of such a compound. 2. The compound according to claim 1, where the octahydroquinoxaline ring has the configuration (4aR, 8aS). 3. The compound according to claim 1 or 2, where a represents a group of the formula

where R ₁ represents a linear or branched alkyl chain containing from 1 to 5 carbon atoms, and R ₂ represents an alkoxy group containing from 1 to 4 carbon atoms. 4. The compound according to claim 1, which is 4-amino-6,7-dimethoxy-2 - [(±) -4- (2-methoxy-6-isopropylphenoxyacetyl) -cis-octahydro-1-quinoxalinyl] quinazoline, 4-amino-6,7-dimethoxy-2 - [(±) -4- (5-methyl-2-furoyl) -cis-octahydro-1-quinoxalinyl] quinazoline, 4-amino-6,7-dimethoxy-2 - [(±) -4- (2-tetrahydrofuroyl) -cis-octahydro-1-quinoxalinyl] quinazoline, 4-amino-6,7-dimethoxy-2 - [(±) -4-benzyloxycarbonyl-cis-octahydro-1-quinoxalinyl] quinazoline or an enantiomer, diastereoisomer or pharmaceutically acceptable salt of such a compound. 5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or an enantiomer, diastereoisomer or a pharmaceutically acceptable salt of such a compound in admixture with a pharmaceutically acceptable diluent or carrier. 6. The pharmaceutical composition according to claim 5, additionally containing prostaglandin, a direct vasodilator or an inhibitor of 5 cGMP-phosphodiesterase. 7. The pharmaceutical composition according to claim 6, containing sildenafil. 8. The pharmaceutical composition according to claims 5-7, formulated for intravaginal administration in the form of a gel, shower, cream or suppository. 9. The use of compounds of General formula I

where A represents 2-furyl, substituted 2-furyl, 2-tetrahydrofuryl, substituted alkoxy or substituted phenoxyalkyl group, and B represents one of the following groups of formula B ₁ , B ₂ or B ₃ :

provided that (i) if B is a group B ₁ , then A is a substituted phenoxyalkyl group, and (ii) if B represents a group B ₃ , then A represents a 2-furyl group, or enantiomer, diastereoisomer or pharmaceutically acceptable salt of such a compound to obtain a drug for the treatment of sexual dysfunction. 10. The use according to claim 9 of a compound in which B represents one of the groups

11. The use according to claim 9 or 10 of the compound in which A represents a group of the formula

where R ₁ represents a linear or branched alkyl group containing from 1 to 5 carbon atoms, and R ₂ represents an alkoxy group containing from 1 to 4 carbon atoms. 12. The use according to claim 9 or claim 10 of a compound in which A represents a 2-furyl or 6-isopropyl-2-methoxyphenoxymethyl group. 13. The use according to claim 9 of any of the following compounds: - 4-amino-6,7-dimethoxy-2- [4- (2-methoxy-6-isopropylphenoxyacetyl) -1-piperazinyl] quinazoline - 4-amino-6,7-dimethoxy-2 - [(4aR, 8aS) -4- (2-furoyl) -cis-octahydro-1-quinoxalinyl] quinazoline and - 4-amino-6,7-dimethoxy-2 - [(3S) -3- (tert-butylcarbamoyl) -4- (2-furoyl) -1-piperazinyl] quinazoline or an enantiomer, diastereoisomer or pharmaceutically acceptable salt of such a compound. 14. The use according to any one of claims 5 to 10 for the manufacture of a medicament further comprising prostaglandin, a direct vasodilator or an inhibitor of 5 cGMP-phosphodiesterase. 15. The use of claim 14 for the manufacture of a medicament containing sildenafil. 16. The use according to any one of paragraphs.9-15 for the manufacture of a medicament formulated for intravaginal administration in the form of a gel, shower, cream or suppository. 17. A pharmaceutical composition comprising (a) a compound of general formula I, as defined in claim 9, or an enantiomer, diastereoisomer or pharmaceutically acceptable salt of such a compound, (b) prostaglandin, a direct vasodilator or an inhibitor of 5 cGMP phosphodiesterase, and (c) a pharmaceutically acceptable diluent or carrier. 18. The pharmaceutical composition according to 17, containing sildenafil. 19. The pharmaceutical composition according to claim 17 or claim 18, formulated for intravaginal administration in the form of a gel, shower, cream or suppository. 20. Use of a compound that (a) binds to the α _1b -adrenergic receptors of a mammal with an affinity of at least about 10 ⁻⁸ M, and (b) binds to α _1b -adrenergic receptors of a mammal with an affinity that is at least 10 times higher than the affinity of this compound for α _1a - or α _1d - or α _1L- adrenergic receptors of a mammal to obtain a drug for the treatment of sexual dysfunction. 21. The use according to claim 20 for the manufacture of a medicament further comprising prostaglandin, a direct vasodilator or an inhibitor of 5 cGMP-phosphodiesterase. 22. The use according to item 21 to obtain a medicinal product containing sildenafil. 23. The use according to claims 20-22 for the manufacture of a medicament formulated for intravaginal administration in the form of a gel, shower, cream or suppository. 24. A method for identifying a compound useful for treating sexual dysfunction in patients suffering from this disorder, the method comprising the steps of (a) individually measuring the binding affinity of the test compounds to a mammalian α _1b adrenergic receptor and a mammalian α _1a or α _1d adrenergic receptor using radioactive receptor binding methods, (b) measuring affinity for the α _1L adrenergic receptor of a mammal by antagonizing the effect of contraction on α ₁ adrenergic receptors on selected mammalian tissue, and (c) the identification of such compounds that (1) bind to the α _1b adrenergic receptor with an affinity of at least about 10 ⁻⁸ M, and (2) bind to the α _1b adrenergic receptor with an affinity that is at least 10 times higher than the affinity of this compound for α _1a - or α _1d -, or α _1L - adrenergic receptors.