Claims
- 1. A potassium channel activator compound comprising at least one NO group, or at least one NO and NO2 group, or a pharmaceutically acceptable salt thereof.
- 2. A compound of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI), or a pharmaceutically acceptable salt thereof:
wherein the compound of formula (I) is: 19wherein R1 is: 20wherein R2 is a hydrogen atom or a halogen atom; B is oxygen or —N—CN; D2 is Q or K; Q is —NO or —NO2; K is —Wa—Eb—(C(Re)(Rf))p—Ec—(C(Re)(Rf))x—Wd—(C(Re)(Rf))y—Wi—Ej—Wg(C(Re)(Rf))z—T—Q; a, b, C, d, g, i and j are each independently an integer from 0 to 3; p, x, y and z are each independently an integer from 0 to 10; W at each occurrence is independently —C(O)—, —C(S)—, —T—, —(C(Re)(Rf))h—, an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, or —(CH2CH2O)q—; E at each occurrence is independently —T—, an alkyl group, an aryl group, —(C(Re)(Rf))h—, a heterocyclic ring, an arylheterocyclic ring, or —(CH2CH2O)q—; h is an integer from 1 to 10; q is an integer from 1 to 5; 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, 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 carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; k is an integer from 1 to 3; T at each occurrence is independently a covalent bond, a carbonyl, an oxygen, —S(O)o— or —N(Ra)Ri—; 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 arylcarboxylic 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+, or Re or Rf are T—Q or (C(Re)(Rf))k—T—Q, then the “—T—Q” subgroup can be a hydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an aminoalkyl, a hydroxy, a heterocyclic ring or an aryl group; with the proviso that when the T in “—T—Q” is oxygen then Q is not —NO2; and provided that the compound contains at least one nitrite, nitrate, thionitrite or thionitrate group; provided that the “—T—D2” group is not N′-(2-nitroxyethyl), N′-(3-nitroxypropyl), N′-(4-nitrobenzyl), N′-(2-(4-nitrophenyl)-2-nitroxyethyl) or N′-(1-methyl-2-(4-nitrophenyl)-2-nitroxyethyl); wherein the compound of Formula (II) is: 21wherein R3 is a hydrogen, an alkyl, an aryl, an alkylaryl or K; D3 is a hydrogen or D2, with the proviso that at least one D3 must be designated as D2 if R3 is not K; G is: 22R4, R5, and R6 are each independently a hydrogen, a halogen, a hydroxy, a lower alkyl, an alkoxy, a nitrite, a nitrite, a carboxyamido, a carboxylic ester, an alkylsulfinyl, an arylsulfinyl, an aminoalkyl, an alkylthio, or an arylthio; or R5 and R6 taken together are a group which forms a ring with the two carbon atoms to which they are attached, wherein the group is —S(O),—(CH2)r—CH2—, —C(O)Z—(CH2)o—CH2, or —C(O)—CH2—(CH2)0—Z—; t is an integer of 1 or 2; r is an integer from 1 to 3; Z is oxygen, NR7 or CH2; R7 is hydrogen or R3; and o and D2 are as defined herein; wherein the compound of Formula (III) is: 23wherein X —(CH2)a— or oxygen; Y is: 24R7 and R8 are each independently a hydrogen, an alkylcarbonyl, an alkoxycarbonyl, a heterocyclic ring, an ester, a nitro, a cyano, a halo, a haloalkyl, an alkylsulphinyl, an alkylsulphonyl, a sulfonic ester, an amidyl, a carbamate, a formyl, a sulfonamido, or a carboxamido; R9 is an aryl or a heterocyclic ring; R10 is a carboxylic ester, a carboxylic acid, a carboxamido, a urea, a thiourea, an amidyl, a sulfamoyl, a hydroxyalkyl, —C(O)OD, —N(R59)(C═NCN)NR51R57, —N(R59)(C═NCN)SR12, —N(R59)(C═NCN)OR12, —P(O)(OR50)2, —P(O)(O(CH2)k′O), —SR11, —S(O)R11, —S(O)2R11, —OR11, a cyano, a heterocyclic ring, a pyridine N-oxide or —C(NR51R57)═CH—C(O)R59; R11 is a hydrogen, an alkyl, an aryl, an arylalkyl, a cycloalkyl, or cycloalkylalkyl; R12 is an alkyl, an aryl, an alkylaryl, or an arylheterocyclic ring; R13 is aryl, a heterocyclic ring, a cycloalkyl X1 is an oxygen, a sulfur, or —NH—; X2 is a hydrogen or an alkyl group; X3 is oxygen or sulfur; k′ is an interger from 2 to 4; a′ and b′ are each independently an integer from 0 to 3; and a, D, D2, R50, R51, R57 and R59 are as defined herein; wherein the compound of Formula (IV) is: 25wherein D3is hydrogen or D2 with the proviso that at least one D3 must be D2; and D2 is as defined herein; wherein the compound of Formula (V) is: 26wherein, R14 and R15 are independently selected from a lower alkyl, a lower haloalkyl or R14 and R15 together with the carbon to which they are attached form a cyclic haloalkyl group; A1—B1 is —NHC(O)—, —OCH2—, —SCH2—NHCH2, —CH═CH—, or —CH═CH—; and Y1 is an aryl group; and D2 is as defined herein; wherein the compound of Formula (VI) is: 27wherein, R16 and R17 are each independently a lower alkyl, a lower haloalkyl or R16 and R17together with the carbon to which they are attached form a cyclic haloalkyl group; Y3 is an sp2-hybridized atom and Y2, Y3, and Y4 together with the carbon atoms to which they are attached form a 5- or 6-membered heterocyclic ring; R18 and R19 are each independently a hydrogen, a nitro, a cyano, a halo, a haloalkyl, an alkylsulfonyl, or an aryl, with the proviso that either R18 or R19 must be a hydrogen but that both R18 and R19 cannot be a hydrogen; and D2 is as defined herein.
- 3. The compound of claim 2, wherein the compound of Formula (I) is a nitrosated nicorandil, a nitrosylated nicorandil or a nitrosated and nitrosylated nicorandil.
- 4. The compound of claim 2, wherein the compound of Formula (II) is a nitrosated pinacidil, a nitrosylated pinacidil or a nitrosated and nitrosylated pinacidil.
- 5. The compound of claim 2, wherein the compound of Formula (III) is a nitrosated cromakalim, a nitrosylated cromakalim, a nitrosated and nitrosylated cromakalim, nitrosated lemakalim, a nitrosylated lemakalim, or a nitrosated and nitrosylated lemakalim.
- 6. The compound of claim 2, wherein the compound of Formula (IV) is a nitrosated minoxidil, a nitrosylated minoxidil or a nitrosated and nitrosylated minoxidil.
- 7. The compound of claim 2, wherein the compound of Formula (V) is a nitrosated ZD 6169, a nitrosylated ZD 6169 or a nitrosated and nitrosylated ZD 6169.
- 8. A composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier.
- 9. 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 8.
- 10. The method of claim 9, wherein the patient is female.
- 11. The method of claim 9, wherein the patient is male.
- 12. The method of claim 9, wherein the composition is administered by intracavernosal injection, by transurethral application or topically.
- 13. The method of claim 12, wherein the composition is administered topically in the form of a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 14. A method for treating a cardiovascular disorder, a cerebrovascular disorder, hypertension, asthma, baldness, urinary incontinence, epilepsy, a sleep disorder, a gastrointestinal disorder, a migraine, an irritable bowel syndrome or sensitive skin in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 8.
- 15. The composition of claim 8, further comprising at least one vasoactive agent.
- 16. The composition of claim 15, wherein the vasoactive agent is 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.
- 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 15.
- 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 by intracavernosal injection, by transurethral application or topically.
- 21. The method of claim 20, wherein the composition is administered topically in the form of a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 22. A method for treating a cardiovascular disorder, a cerebrovascular disorder, hypertension, asthma, baldness, urinary incontinence, epilepsy, a sleep disorder, a gastrointestinal disorder, a migraine, an irritable bowel syndrome or sensitive skin in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 15.
- 23. A composition comprising at least one compound of claim 2 and at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase or a pharmaceutically acceptable salt thereof.
- 24. The composition of claim 23, wherein the at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase is an S-nitrosothiol.
- 25. The composition of claim 24, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione.
- 26. The composition of claim 24, 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 carbons 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 R1 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.
- 27. The composition of claim 23, wherein the at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, 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: R1R2—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.
- 28. The composition of claim 27, 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.
- 29. The composition of claim 27, 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.
- 30. The composition of claim 23, wherein the at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, 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.
- 31. 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 23.
- 32. The method of claim 31, wherein the patient is female.
- 33. The method of claim 31, wherein the patient is male.
- 34. The method of claim 31, wherein the composition is administered by intracavernosal injection, by transurethral application or topically.
- 35. The method of claim 34, wherein the composition is administered topically in the form of a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 36. A method for treating a cardiovascular disorder, a cerebrovascular disorder, hypertension, asthma, baldness, urinary incontinence, epilepsy, a sleep disorder, a gastrointestinal disorder, a migraine, an irritable bowel syndrome or sensitive skin in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 23.
- 37. The composition of claim 23, further comprising at least one vasoactive agent.
- 38. The composition of claim 37, wherein the vasoactive agent is a 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, a prostaglandin, an opioid antagonist, an endothelin antagonist, a thromboxane inhibitor or a mixture thereof.
- 39. 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 37.
- 40. The method of claim 39, wherein the patient is female.
- 41. The method of claim 39, wherein the patient is male.
- 42. The method of claim 39, wherein the composition is administered by intracavernosal injection, by transurethral application or topically.
- 43. The method of claim 42, wherein the composition is administered topically in the form of a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 44. A method for treating a cardiovascular disorder, a cerebrovascular disorder, hypertension, asthma, baldness, urinary incontinence, epilepsy, a sleep disorder, a gastrointestinal disorder, a migraine, an irritable bowel syndrome or sensitive skin in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 37.
- 45. A composition comprising at least one potassium channel activator or a pharmaceutically acceptable salt thereof and at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase or a pharmaceutically acceptable salt thereof.
- 46. The composition of claim 45, wherein the potassium channel activator is nicorandil, pinacidil, cromakalim, aprikalim, bimakalim, emakalim, lemakalim, minoxidil, diazoxide, 9-chloro-7-(2-chlorophenyl)-5H-pyrimido(5,4,-d)(2)-benzazepine, Ribi, CPG-11952, CGS-9896, ZD 6169, diazixide, Bay X 9227, P1075, Bay X 9228, SDZ PCO 400, WAY-120,491, WAY-120,129, Ro 31-6930, SR 44869, BRL 38226, S 0121, SR 46142A, CGP 42500, SR 44994, artilide fumarate, lorazepam, temazepam, rilmazafone, nimetazepam, midazolam, lormetazepam, loprazolam, ibutilide fumarate, haloxazolam, flunitrazepam, estazolam, doxefazepam, clonazepam, cinolazepa, brotizolam or a pharmaceutically acceptable salt thereof.
- 47. The composition of claim 46, wherein the potassium channel activator is nicorandil, pinacidil, cromakalim or minoxidil.
- 48. The composition of claim 45, wherein the potassium channel activator is a compound of Formula (A) or Formula (B), or a pharmaceutically acceptable salt thereof, wherein the compound of Formual (A) is:
- 49. The composition of claim 45, wherein the at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase is an S-nitrosothiol.
- 50. The composition of claim 46, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione.
- 51. The composition of claim 49, 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 carbons 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)n— 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 R1 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.
- 52. The composition of claim 45, wherein the at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, 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—, 02N—N—, O2N—S— or —O2N—C— group; (iii) a N-oxo-N-nitrosoamine having the formula: R1R2—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.
- 53. The composition of claim 52, 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.
- 54. The composition of claim 52, 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.
- 55. The composition of claim 45, wherein the at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, 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.
- 56. 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 45.
- 57. The method of claim 56, wherein the patient is female.
- 58. The method of claim 56, wherein the patient is male.
- 59. The method of claim 56, wherein the composition is administered by intracavernosal injection, by transurethral application or topically.
- 60. The method of claim 59, wherein the composition is administered topically in the form of a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 61. A method for treating a cardiovascular disorder, a cerebrovascular disorder, hypertension, asthma, baldness, urinary incontinence, epilepsy, a sleep disorder, a gastrointestinal disorder, a migraine, an irritable bowel syndrome or sensitive skin in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 45.
- 62. The composition of claim 45, further comprising at least one vasoactive agent.
- 63. The composition of claim 62, wherein the vasoactive agent is a a calcium channel blocker, an α-adrenergic receptor antagonist, 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.
- 64. 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 62.
- 65. The method of claim 62, wherein the patient is female.
- 66. The method of claim 62, wherein the patient is male.
- 67. The method of claim 62, wherein the composition is administered by intracavernosal injection, by transurethral application or topically.
- 68. The method of claim 67, wherein the composition is administered topically in the form of a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 69. A method for treating a cardiovascular disorder, a cerebrovascular disorder, hypertension, asthma, baldness, urinary incontinence, epilepsy, a sleep disorder, a gastrointestinal disorder, a migraine, an irritable bowel syndrome or sensitive skin in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 62.
- 70. A composition comprising a potassium channel activator and a vasoactive agent.
- 71. The composition of claim 70, the potassium channel activator is nicorandil, pinacidil, cromakalim, aprikalim, bimakalim, emakalim, lemakalim, minoxidil, diazoxide, 9-chloro-7-(2-chlorophenyl)-5H-pyrimido(5,4,-d)(2)-benzazepine, Ribi, CPG-11952, CGS-9896, ZD 6169, diazixide, Bay X 9227, P1075, Bay X 9228, SDZ PCO 400, WAY-120,491, WAY-120,129, Ro 31-6930, SR 44869, BRL 38226, S 0121, SR 46142A, CGP 42500, SR 44994, artilide fumarate, lorazepam, temazepam, rilmazafone, nimetazepam, midazolam, lormetazepam, loprazolam, ibutilide fumarate, haloxazolam, flunitrazepam, estazolam, doxefazepam, clonazepam, cinolazepam, brotizolam or a pharmaceutically acceptable salt thereof.
- 72. The composition of claim 70, wherein the potassium channel activator is a compound of Formula (A), Formula (B), Formula (C), Formula (D), Formula (E), or Formula (F), wherein the compound of Formual (A) is:
- 73. The composition of claim 69, wherein the potassium channel activator is nicorandil, pinacidil, cromakalim or minoxidil.
- 74. The composition of claim 68, wherein the vasoactive agent is a 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.
- 75. 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 70.
- 76. The method of claim 75, wherein the patient is female.
- 77. The method of claim 75, wherein the patient is male.
- 78. The method of claim 75, wherein the composition is administered by intracavernosal injection, by transurethral application or topically.
- 79. The method of claim 78, wherein the composition is administered topically in the form of a cream, a spray, a lotion, a gel, an ointment, an emulsion, a foam, a coating for a condom, or a liposome composition.
- 80. A method for treating a cardiovascular disorder, a cerebrovascular disorder, hypertension, asthma, baldness, urinary incontinence, epilepsy, a sleep disorder, a gastrointestinal disorder, a migraine, an irritable bowel syndrome or sensitive skin in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 70.
- 81. A kit comprising at least one compound of claim 2 and at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, or a pharmaceutically acceptable salt thereof.
- 82. The kit of claim 81, further comprising at least one vasoactive agent.
- 83. The kit of claim 81, wherein the compound of claim 2 and the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase are separate components in the kit.
- 84. The kit of claim 81, wherein the compound of claim 2 and the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase are in the form of a composition in the kit.
- 85. A kit comprising at least one potassium channel activator and at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, or a pharmaceutically acceptable salt thereof.
- 86. The kit of claim 85, further comprising at least one vasoactive agent.
- 87. The kit of claim 85, wherein the potassium channel activator and the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase are separate components in the kit.
- 88. The kit of claim 85, wherein the potassium channel activator and the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase are in the form of a composition in the kit.
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 60/133,888 filed May 12, 1999.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60133888 |
May 1999 |
US |
Divisions (1)
|
Number |
Date |
Country |
| Parent |
09570727 |
May 2000 |
US |
| Child |
10154916 |
May 2002 |
US |
Patent Application
20020143188
