Claims
- 1. A compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XII), formula (XIV), formula (XV), formula (XVI), formula (XVII), formula (XVIII) or formula (XIX):
wherein the compound of formula (I) is: 33wherein R1 is an alkoxy, a cycloalkoxy, a halogen, or 34R2 is a hydrogen, an alkoxy, or a haloalkoxy; and R3 is: 35wherein, D is:
(i) —NO, (ii) —NO2, (iii) —CH(Rd)—O—C(O)-Y-Z(C(Re)(Rf))p-T-Q, (iv) —C(O)-Y-Z-(G-(C(Re)(Rf))b-T-Q)p; (v) —P-Z-(G-(C(Re)(Rf))b-T-Q)p; (vi) —P1-B1-W-Bt-Lr-Es-[C(Re)(Rf)]w-Ec-[C(Re)(Rf)]x-Ld-[C(Re)(Rf)]y-Li-Ej-Lg-[C(Re)(Rf)]z-T-Q or (vii) —P1-F′n-Lr-Es-[C(Re)(Rf)]w-Ec-[C(Re)(Rf)]x-Ld-[C(Re)(Rf)]y-Li-Ei-Lg-[C(Re)(Rf)]z -T-Q wherein, Rd is a hydrogen, a lower alkyl, a cycloalkyl, an aryl or an arylalkyl; Y is oxygen, S(O)o, lower alkyl or NR1; o is an integer from 0 to 2; 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, —CH2—C(T-Q)(Re)(Rf), or —(N2O2—)−&Circlesolid;M+, wherein M+ in an organic or inorganic cation; 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, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a urea, a nitro, -T-Q , or [C(Re)(Rf)]k-T-Q, or Re and Rf taken together are a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; k is an integer from 1 to 3; p is an integer from 1 to 10; T is independently a covalent bond, oxygen, S(O)o or NR1; Z is a covalent bond, an alkyl, an aryl, an arylalkyl, an alkylaryl, a heteroalkyl, or (C(Re)(Rf))p; Q is —NO or —NO2; G is a covalent bond, -T-C(O)—, —C(O)-T- or T; b is an integer from 0 to 5; P is a carbonyl, a phosphoryl or a silyl; l and t are each independently an integer from 1 to 3; r, S, c, d, g, i and j are each independently an integer from 0 to 3; w, x, y and z are each independently an integer from 0 to 10; P1 is a covalent bond or P; B at each occurrence is independently an alkyl group, an aryl group, or [C(Re)(Rf)]p; E at each occurrence is independently -T-, an alkyl group, an aryl group, or —(CH2CH2O)q, q is an integer of from 1 to 5; L at each occurrence is independently —C(O)—, —C(S)—,-T-, a heterocyclic ring, an aryl group, an alkenyl group, an alkynyl group, an arylheterocyclic ring, or —(CH2CH2O)q; W is oxygen, S(O)o, or NRI; F′ at each occurrence is independently selected from B or carbonyl; n is an integer from 2 to 5; with the proviso that when R1 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 designated in D can be a hydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an aminoalkyl, a hydroxy, or an aryl. R4 is:
(i) hydrogen; (ii) —CH(Rd)—O—C(O)-Y-Z-(C(Ref)(Rf))p-T-Q, (iii) —C(O)-T-(C(Re)(Rf))p-T-Q; (iv) —C(O)-Z-(G-(C(Re)(Rf))p-T-Q)p or (v) —Wo-Lr-Es-[C(Re)(Rf)]w-Ec-[C(Re)(Rf)]x-Ld-[C(Re)(Rf)]y-Ll-Ej-Lg-[C(Re)(Rf)]z-T-Q wherein r, s, c, d, g, i, j, o, p, w, x, y, z, Rd, ReRf, E, L, G, T, Q, W, Y, and Z areas defined herein; R5 is a lone pair of electrons or —CH(Rd)—O—C(O)-Y-Z-(C(Re)(Rf))p-T-Q; R11 and R12 are independently selected from hydrogen or R4; wherein R4, Rd, ReRf, p, T, Q, Y, and Z are as defined herein; X is a halogen, and D1 is D or hydrogen, wherein D is as defined herein; and with the proviso that if the structure does not contain D, then at least one of the variables R4, R5, R11 or R12 must contain the element “-T-Q”; wherein the compound of formula (II) is: 36wherein, R4 is as defined herein; with the proviso that R4 cannot be hydrogen; R8 is a hydrogen, a lower alkyl group or a haloalkyl group; R9 is a hydrogen or a halogen; and R10 is:
(i) hydrogen, 37wherein R8 is as defined herein; wherein the compound of formula (III) is: 38wherein, E1 is nitrogen or —CH—; G1 is nitrogen or —C(R8)—; R21 is 39R22 is R12 or a lower alkyl; R33 is a lower alkyl or [C(Re)(Rf)]p-T-Q; and p, Re, Rf, R11, R12, T and Q are as defined herein; with the proviso that at least one of the variables R11, R12, R22 or R33 must contain the element “T-Q”; wherein the compound of formula (IV)− is: 40wherein, G2 is —CH2— or sulfur; R4 and R8 are each as defined herein; and R13 is: 41wherein, R6 and R7are independently selected from R4, wherein R4is as defined herein; with the proviso that at least one of the variables R4, R6 or R7 must contain the element “T-Q”; wherein the compound of formula (V) is: 42wherein, R4 is as defined herein; and R14 is: 43wherein R6 is as defined herein, with the proviso that at least one of the variables R4, or R6 must contain the element “T-Q”; wherein the compound of formula (VI) is: 44wherein, R15 is a hydrogen, a lower alkyl, R4, or —(CH2)4—C(CH3)2—O-D1; wherein R4 is as defined herein; 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, wherein D and D1 are as defined herein; wherein the compound of formula (VII) is: 45wherein, R4 and R8 are as defined herein; and R18 is: 46and wherein is as defined herein; with the proviso that R4 cannot be hydrogen; wherein the compound of formula (VIII) is: 47wherein, R19 is: 48and wherein R4, R11, and R12 are as defined herein; with the proviso that at least one of the variables R4, R11 or R12 must contain the element “T-Q”; wherein the compound of formula (IX) is: 49wherein, R20 is: 50or (iii) -D; wherein R4 is as defined herein; with the proviso that when R20 is not D, then R4 cannot be hydrogen; wherein the compound of formula (X) is: 51wherein, a is an integer from 2 to 3 and D and D1 are as defined herein; wherein the compound of formula (XI) is: 52wherein D2 is hydrogen, a lower alkyl or D; wherein D is as defined herein; with the proviso that at least one D2 must be D; wherein the compound of formula (XII) is: 53wherein, R8 is as defined herein; J is: 54R24 is hydrogen or K-G-D; wherein, K is: 55G3 is (CH), (CH2), oxygen, sulfur or nitrogen; V is carbon or nitrogen; A1, A2 and A3 comprise the other subunits of a 5- or 6-membered monocyclic aromatic ring and each is independently (i) C—R23 wherein R23 at each occurrence is independently D, a hydrogen, a halogen, an alkoxy, a nitrile, an alkyl, an arylalkyl, an alkylaryl, a carboxamido, a carboxyl, a haloalkyl, an alkoxyalkyl, an alkoxyaryl or a nitro; (ii) sulfur; (iii) oxygen; and (iv) Ba=Bb wherein Ba and Bb are each independently nitrogen or C—R23 wherein at each occurrence R23 is as defined herein; and wherein R26, R27, R28, R29, and R30 are independently a hydrogen, a halogen, a hydroxy, a haloalkyl, an alkoxy, an alkoxyalkyl, an alkoxyaryl, an alkoxyhaloalkyl, a nitrile, a nitro, an alkyl, an alkylaryl, an arylalkyl, a hydroxy alkyl, a carboxamido, or a carboxyl; and wherein d, g, p, E, L, G, T, Y and D are as defined herein; with the proviso that at least one of the variables A1, A2, A3, J or R24 must contain the element “-T-Q” or “D”; wherein the compound of formula (XIII) is: 56wherein, R31 is an alkyl, a halogen, a haloalkyl, or a haloalkoxy; R32 is D1 or —C(O)—R8; and D, D1 and R8 are as defined herein; wherein the compound of formula (XIV) is: 57wherein A is CH2, a carbonyl or a methanethial; G4 is oxygen or sulfur; R34 is hydrogen, lower alkyl, alkenyl, alkynyl or Lr-Es-[C(Re)(Rf)]w-Ec-[C(Re)(Rf)]x-Ld-[C(Re)(Rf)]y-Li-Ej-Lg-[C(Re)(Rf)]z-T-Q; R35 and R36 are independently a hydrogen, a lower alkyl, an arylalkyl, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, T-Q or [C(Re)(Rf)]k-T-Q, R3, and R36 taken together are a carbonyl group, a methanethial group, a heterocyclic group or a cycloalkyl group; R34 and R35 taken together are [C(Rg)(Rh)]u or —C(Rg)(Rh)-C(Rg)=C(Rg)-[C(Rg)(Rh)]v wherein u is an integer of 3 or 4, v is an integer of 1 or 2 and Rg and Rh at each occurrence is independently a hydrogen, an alkyl, T-Q or [C(Re)(Rf)]k-T-Q; R38 is a hydrogen, a halogen or a lower alkyl; and R37 is: 58wherein, c, d, g, i, j, k, r, s, w, x, y, z, D1, E, L, G3, T, Q, Re, Rf, R26, R27, R28, R29, R30 and R38 are as defined herein; with the proviso that D1 must be D if R34, R35 R36 or R37 do not contain the element “T-Q”; wherein the compound of formula (XV) is: 59wherein R25 at each occurrence is a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an amino an alkoxy, an aryl, an arylalkyl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a carboxamido, an alkylcarboxamido, an arylcarboxamido, a haloalkoxy, a sulfonamido, a urea, a nitro, or Lr-Es[C(Re)(Rf)]w-Ec-[C(Re)(Rf)]x-Ld-[C(Re)(Rf)]y-Ll-Ej-Lz-[C(Re)(Rf)]z-T-Q; and wherein c, d, g, i, j, k, r, s, w, x, y, z, G4, D1, E, L, T, Q, Re, Rf, R37 and R38 are as defined herein; and with the proviso that D1 must be D if Re or R25 do not contain the element “T-Q”; wherein the compound of formula (XVI) is: 60wherein R40 is a hydrogen, a lower alkyl, a haloalkyl, a halogen, an alkoxy, an alkenyl, an alkynyl, a carbamoyl, a sulfonamido or Lr-Es-[C(Re)(Rf)]w-Ec-[C(Re)(Rf)]x-Ld-[C(Re)(Rf)]y-Li-Ej-Lg-[C(Re)(Rf)]z-T-Q; and wherein c, d, g, i, j, k, r, s, w, x, y, z, D1, E, L, T, Q, Re and Rf are as defined herein; R41 is a lower alkyl, a hydroxyalkyl, an alkylcarboxylic acid, an alkylcarboxylic ester an alkylcarboxamido or Lr-Es-[C(Re)(Rf)]w-Ec-[C(Re)(Rf)]x-Ld-[C(Re)(Rf)]y-Ll-Ej-Lg-[C(Re)(Rf)]z-T-Q; and wherein c, d, g, i, j, k, r, s, w, x, y, z, E, L, T, Q, Re and Rf are as defined herein; R42 is: 61wherein R43 at each occurrence is independently an amino, a cyano, a halogen, a nitro group, a carboxyl, a carbamoyl, a sulfonic acid, a sulfonic ester, a sulfonamido, a heterocyclic ring, a carboxamido, a carboxylic cster, an ester, an amidyl, a phosphoryl or Lr-E2-[C(Re)(Rf)]w-Ec-[C(Re)(Rf)]x-Ld-[C(Re)(Rf)]y-Li-Ej-L6-[C(Rc)(Rf)]7-T-Q; and c, d, g, i, j, k, r, s, w, x, y, z, F, L, T, Q, Rc, and Rf are as defined herein; with the proviso that at least one of R40, R41, or R43 must contain the element “T-Q”; wherein the compound of formula (XVII) is: 62wherein R8, R23, R24, p and J are as defined herein and with the proviso that at least one R24 or J must contain the element “-T-Q” or “-D”; wherein the compound of formula (XVIII) is: 63wherein R44 is: 64wherein d, g, p, D, E, L, G3, G4, T, R8, R26, R27, R28, R29, and R30 are as defined herein; wherein the compound of formula (XIX) is: 65wherein, R46 and R47 are independently selected from lower alkyl, hydroxyalkyl or D, or R46 and R47 taken together are a heterocyclic ring, wherein G4, T, R8, and k are defined herein; with the proviso that at least one of the variables R46 or R47 must be D or when the variables taken together are a heterocyclic ring, the ring must contain NRi, wherein R1 must contain the element “T-Q”.
- 2. The compound of claim 1, wherein the compound is a nitrosated, nitrosylated or nitrosated and nitrosylated member selected from the group consisting of filaminast, piclamilast, rolipram, Org 20241, MCI-154, roflumilast, toborinone, posicar, lixazinone, zaprinast, sildenafil, pyrazolopyrimidinones, motapizone, pimobendan, zardaverine, siguazodan, CI 930, EMD 53998, imazodan, saterinone, loprinone hydrochloride, a 3-pyridinecarbonitrile derivative, denbufyllene, albifylline, torbafylline, doxofylline, theophylline, pentoxofylline, nanterinone, cilostazol, cilostamide, MS 857, piroximone, milrinone, amrinone, tolafentrine, dipyridamole, papaverine, E4021, triflusal, ICOS-351, a tetrahydropiperazino[1,2-b]beta-carboline-1,4-dione derivative, a carboline derivative, a 2-pyrazolin-5-one derivative, a fused pyridazine derivative, a quinazoline derivative, an anthranilic acid derivative or an imidazoquinazoline derivative.
- 3. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
- 4. 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 3.
- 5. The method of claim 4, wherein the patient is female.
- 6. The method of claim 4, wherein the patient is male.
- 7. The method of claim 4, wherein the composition is administered orally, by intracavernosal injection, by transurethral application, or by transdermal application.
- 8. A method for treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 3.
- 9. The method of claim 8, wherein the disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.
- 10. The composition of claim 3, further comprising at least one vasoactive agent.
- 11. The composition of claim 10, wherein the vasoactive agent is a potassium channel activator, a calcium blocker, an α-blocker, a β-blocker, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a dopamine agonist, an opioid antagonist, a prostaglandin, an endothelin antagonist or a mixture thereof.
- 12. 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 10.
- 13. The method of claim 12, wherein the patient is female.
- 14. The method of claim 12, wherein the patient is male.
- 15. The method of claim 12, wherein the composition is administered orally, by intracavernosal injection, by transurethral application or by transdermal application.
- 16. A method for treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 10.
- 17. A method of claim 16, wherein the disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.
- 18. A composition comprising at least one compound of claim 1 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.
- 19. The composition of claim 18, wherein 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 is an S-nitrosothiol.
- 20. The composition of claim 19, 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.
- 21. The composition of claim 19, wherein the S-nitrosothiol is:
(i) HS(C(Re)(Rf))mSNO; (ii) ONS(C(Re)(Rf))mRe; or (iii) H2N—CH(CO2H)—(CH2)m—C(O)NH—CH(CH2SNO)—C(O)NH—CH2—CO2H; wherein m is an integer of 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, am alkoxy, a haloalkoxy, an amino, an alkyiamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a urea, a nitro, or -T-Q; or Re and Rf taken together are 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, an oxygen, S(O)o or NRi, wherein o is an integer from 0 to 2, and 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, carboxamido, —CH2—C(T-Q)(Re)(Rf), or —(N2O2—)M+, wherein M+ in 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.
- 22. The composition of claim 18, wherein 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 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 or glutamine.
- 23. The composition of claim 18, wherein 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 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; or (iv) a thionitrate having the formula: R1—(S)—NO2, wherein R1 is 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.
- 24. The composition of claim 23, 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.
- 25. The composition of claim 23, 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.
- 26. 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 18.
- 27. The method of claim 26, wherein the patient is female.
- 28. The method of claim 26, wherein the patient is male.
- 29. The method of claim 26, wherein the composition is administered orally, by intracavernosal injection, by transurethral application or by transdermal application.
- 30. A method for treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 26.
- 31. A method of claim 30, wherein the disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.
- 32. The composition of claim 18, further comprising at least one vasoactive agent.
- 33. The composition of claim 32, wherein the vasoactive agent is a potassium channel activator, a calcium blocker, an α-blocker, a β-blocker, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a dopamine agonist, an opioid antagonist, a prostaglandin, an endothelin antagonist or a mixture thereof.
- 34. 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 32.
- 35. The method of claim 34, wherein the patient is female.
- 36. The method of claim 34, wherein the patient is male.
- 37. The method of claim 34, wherein the composition is administered orally, by intracavernosal injection, by transurethral application or by transdermal application.
- 38. A method of treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 32.
- 39. A method of claim 38, wherein the disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.
- 40. A composition comprising at least one phosphodiesterase inhibitor 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.
- 41. The composition of claim 40, wherein the phosphodiesterase inhibitor is filaminast, piclamilast, rolipram, Org 20241, MCI-154, roflumilast, toborinone, posicar, lixazinone, zaprinast, sildenafil, a pyrazolopyrimidinone, motapizone, pimobendan, zardaverine, siguazodan, CI 930, EMD 53998, imazodan, saterinone, loprinone hydrochloride, a 3-pyridinecarbonitrile derivative, denbufyllene, albifylline, torbafylline, doxofylline, theophylline, pentoxofylline, nanterinone, cilostazol, cilostamide, MS 857, piroximone, milrinone, amrinone, tolafentrine, dipyridamole, papaverine, E4021, triflusal, ICOS-351, a tetrahydropiperazino[1,2-b]beta-carboline-1,4-dione derivative, a carboline derivative, a 2-pyrazolin-5-one derivative, a fused pyridazine derivative, a quinazoline derivative, an anthranilic acid derivative or an imidazoquinazoline derivative.
- 42. The composition of claim 40, wherein 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 is an S-nitrosothiol.
- 43. The composition of claim 42, 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.
- 44. The composition of claim 42, wherein the S-nitrosothiol is:
(i) HS(C(Re)(Rf))mSNO; (ii) ONS(C(Re)(Rf))mRe; or (iii) H2N—CH(CO2H)—(CH2)m—C(O)NH—CH(CH2SNO)—C(O)NH—CH2—CO2H; wherein m is an integer of 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, am alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a urea, a nitro, or -T-Q; or Re and Rf taken together are 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, an oxygen, S(O)o or NRi, wherein o is an integer from 0 to 2, and R1 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, carboxamido, —CH2—C(T-Q)(Re)(Rf), or —(N2O2—)M+, wherein M+ in 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.
- 45. The composition of claim 40, wherein 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 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 or glutamine.
- 46. The composition of claim 40, wherein 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 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; or (v) a thionitrate having the formula: R1—(S)—NO2, wherein R1 is 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.
- 47. The composition of claim 46, 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.
- 48. The composition of claim 46, 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.
- 49. 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 40.
- 50. The method of claim 49, wherein the patient is female.
- 51. The method of claim 49, wherein the patient is male.
- 52. The method of claim 49, wherein the composition is administered orally, by intracavernosal injection, by transurethral application or by transdermal application.
- 53. A method for treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 40.
- 54. A method of claim 53, wherein the disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.
- 55. The composition of claim 40, further comprising at least one vasoactive agent.
- 56. The composition of claim 55, wherein the vasoactive agent is a potassium channel activator, a calcium blocker, a β-blocker, an α-blocker, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a dopamine agonist, an opioid antagonist, a prostaglandin, an endothelin antagonist or a mixture thereof.
- 57. 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 55.
- 58. The method of claim 57, wherein the patient is female.
- 59. The method of claim 57, wherein the patient is male.
- 60. The method of claim 57, wherein the composition is administered orally, by intracavernosal injection, by transurethral application or by transdermal application.
- 61. A method for treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 55.
- 62. A method of claim 61, wherein the disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.
- 63. A composition comprising at least one phosphodiesterase inhibitor and at least one vasoactive agent.
- 64. The composition of claim 63, wherein the vasoactive agent is a potassium channel activator, a calcium blocker, a β-blocker, an α-blocker, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a dopamine agonist, an opioid antagonist, a prostaglandin, an endothelin antagonist or a mixture thereof.
- 65. The composition of claim 63, wherein the phosphodiesterase inhibitor is filaminast, piclamilast, rolipram, Org 20241, MCI-154, roflumilast, toborinone, posicar, lixazinone, zaprinast, sildenafil, a pyrazolopyrimidinone, motapizone, pimobendan, zardaverine, siguazodan, CI 930, EMD 53998, imazodan, saterinone, loprinone hydrochloride, a 3-pyridinecarbonitrile derivative, denbufyllene, albifylline, torbafylline, doxofylline, theophylline, pentoxofylline, nanterinone, cilostazol, cilostamide, MS 857, piroximone, milrinone, amrinone, tolafentrine, dipyridamole, papaverine, E4021, triflusal, ICOS-351, a tetrahydropiperazino[1,2-b]beta-carboline-1,4-dione derivative, a carboline derivative, a 2-pyrazolin-5-one derivative, a fused pyridazine derivative, a quinazoline derivative, an anthranilic acid derivative or an imidazoquinazoline derivative.
- 66. 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 63.
- 67. The method of claim 66, wherein the patient is female.
- 68. The method of claim 66, wherein the patient is male.
- 69. The method of claim 66, wherein the composition is administered by intracavernosal injection, by transurethral application or by transdermal application.
- 70. A method for treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 63.
- 71. A method of claim 70, wherein the disease induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.
RELATED APPLICATIONS
[0001] This is a continuation-in-part of U.S. application Ser. No. 09/145,142, filed Sep. 1, 1998, allowed, which is a continuation-in-part of U.S. application Ser. No. 08/740,764, filed Nov. 1, 1996, issued as U.S. Pat. No. 5,874,437; and is a continuation-in-part of PCT/US97/19870, filed Oct. 31, 1997, which claims priority to U.S. application Ser. No. 08/740,764, filed Nov. 1, 1996, issued as U.S. Pat. No. 5,874,437.
Continuations (1)
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Number |
Date |
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| Parent |
09387727 |
Sep 1999 |
US |
| Child |
09941691 |
Aug 2001 |
US |
Continuation in Parts (3)
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Number |
Date |
Country |
| Parent |
09145142 |
Sep 1998 |
US |
| Child |
09387727 |
Sep 1999 |
US |
| Parent |
08740764 |
Nov 1996 |
US |
| Child |
09145142 |
Sep 1998 |
US |
| Parent |
PCT/US97/19870 |
Oct 1997 |
US |
| Child |
09145142 |
Sep 1998 |
US |
Patent Application
20020019405
