Claims
- 1. A method for treating, preventing and/or reducing inflammation, pain, and fever; for decreasing or reversing the gastrointestinal, renal and other toxicities resulting from the use of nonsteroidal antiinflammatory compounds; for treating and/or preventing gastrointestinal disorders; for facilitating wound healing; for treating inflammatory disease states and/or disorders; for treating and/or preventing ophthalmic diseases and/or disorders; for treating and/or improving gastrointestinal properties of COX-2 selective inhibitors; for treating and/or preventing renal toxicity; for treating and/or preventing COX-2 mediated disorders; for decreasing the recurrence of ulcers; for improving gastroprotective properties, anti-Helicobacter pylori properties or antacid properties of proton pump inhibitors; for treating and/or preventing bacterial infections, microbial infections, multiple sclerosis, and/or viral infections; for improving gastroprotective properties of H2 receptor antagonists; for treating and/or preventing restenosis, autoimmune diseases, pathological conditions resulting from abnormal cell proliferation, polycystic kidney disease, inflammatory diseases or to inhibit wound contraction; for treating or preventing sexual dysfunctions in males and females, for enhancing sexual responses in males and females; for treating or preventing benign prostatic hyperplasia, hypertension, neurodegenerative disorders, vasospastic diseases, cognitive disorders, urge incontinence, or an overactive bladder; for reversing the state of anesthesia; for treating or preventing diseases induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate (cGMP) or for treating respiratory disorders, in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one compound of Formula I or II, or a pharmaceutically acceptable salts thereof,
wherein the compound of Formula (I) is: 5R11 is hydrogen, an alkyl group having 1 to 6 carbon atoms, a substituted lower alkyl wherein the substituent is halogen, hydroxyl, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio or arylthio, R12 is R11 hydrogen or a lower alkyl group; R13 is a nitratoalkyl group having 1 to 6 carbon atoms; r is an integer from 0 to 10; R1 and R1′ are each independently hydrogen or lower alkyl; R2 and R2′ are each independently hydrogen, lower alkyl, phenyl, methoxyphenyl, phenyl-lower-alkyl, methoxyphenyl-lower-alkyl, hydroxyphenyl-lower-alkyl, hydroxy-lower-alkyl, alkoxy-lower-alkyl, amino-lower-alkyl, acylamino-lower-alkyl, mercapto-lower-alkyl or lower alkylthio-lower-alkyl; R3 and R3′ are each independently hydroxyl, lower alkoxy, lower alkenoxy, di-lower-alkylamino-lower-alkoxy, acylamino-lower-alkoxy, acyloxy-lower-alkoxy, aryloxy, aryl-lower-alkoxy, substituted aryloxy or substituted aryl-lower-alkoxy, in which the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower-alkylamino, aryl-lower-alkylamino, hydroxy-lower-alkyl-amino, pyrrolidine, piperidine, morpholine, piperazine or amino-acid residues via peptide linkage; R4 and R4′ are each independently hydrogen or lower alkyl; R5 and R5′ are each independently R4, R4′ hydrogen or lower alkyl; R2 and R3, and R2′ and R3′, can be linked together to form an ester or an amide; R1 and R2, and R1′ and R2′, can be linked together to form an alkylene bridge having 2 to 4 carbon atoms, an alkylene bridge having 2 to 3 carbon atoms and a sulfur atom, an alkylene bridge having 3 to 4 carbon atoms, which contains a double bond or an alkylene bridge, optionally substituted by hydroxyl, lower alkoxy, lower alkyl or di-lower-alkyl; m, n, o, p, q, m′, n′, o′, p′ and q′ are each independently integers from 0 to 10; wherein the compound of Formula (II) is: 6wherein: R20 and R21 are each independently a hydrogen, an alkyl having 1 to 6 carbon atoms, a substituted lower alkyl in which the substituent is a halogen, groups defined by R3 containing hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio or arylthio; R22 is hydrogen or lower alkyl; R23 is hydrogen, lower alkyl, phenyl, methoxy phenyl, phenyl-lower alkyl, methoxyphenyl-lower alkyl, hydroxyphenyl-lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, amino-lower alkyl, acylamino-lower alkyl, mercapto-lower alkyl or lower alkylthio-lower alkyl; R24 is lower alkyl thiol, —SH, S-acyl compound of lower alkylthiol, preferably —S-acetyl, —S-propionyl, —S-butyryl, —S-isobutyryl, —S-capryl, —S-pivaloyl, —S-benzoyl; 7and lower alkylthio-lower alkanoic acid and esters and amides thereof, and lower alkylthio-lower alkyl; R25 is hydrogen and lower alkyl groups in which R3 and R24 are bonded together and form part of a thiolactone group, groups in which R3 and R23 are bonded together in the form of an ester or amide, groups in which R22 and R23 are bonded together in the form of an alkylene bridge with 2 to 4 carbon atoms, an alkylene bridge with 2 to 3 carbon atoms and a sulfur atom, an alkylene bridge with 3 to 4 carbon atoms, which contains a double bond or an alkylene bridge as above, which can be substituted by one or more hydroxy, lower alkoxy, lower alkyl or di-lower alkyl groups; and R3, m, n, and o are as defined herein.
- 2. The method of claim 1, further comprising administering a pharmaceutically acceptable carrier.
- 3. The method of claim 1, further comprising administering at least one NSAID, COX-2 inhibitor, H2 receptor antagonist, proton pump inhibitor, vasoactive agent, steroid, β-agonist, anticholinergic, mast cell stabilizer, PDE inhibitor, taxane, rapamycin, tranilast, or mixture of two or more thereof.
- 4. The method of claim 1, wherein the compound of Formula (I) is:
N′-3-nitratopivaloyl-L-cysteinamide-glutathione mixed disulphide, N′-3-nitratopivaloyl-L-cysteine ethyl ester-glutathione mixed disulphide; N′-3-nitratopivaloyl-L-cysteine ethyl ester-N′-acetyl-L-cysteine mixed disulphide; N-(3-nitratopivaloyl)-L-cysteine ethyl ester-D,L-penicillamine mixed disulphide; 2-acetylamino-3-(2-(2,2-dimethyl-3-nitrooxy-propionylamino)-2-ethoxycarbon ylethyl disulphanyl)-3-methylbutyric acid; N,N′-di(3-nitratopivaloyl)-L-cystine; N,N′-di(3-nitratopivaloyl)-D,L-homocystine; N,N′-di(3-nitratopivaloyl)-L-cystine diethyl ester; N,N′-di(3-nitratopivaloyl)-D,L-homocystine diethyl ester; N,N′-di(3-nitratopivaloyl)-L-cystine di-tertiary-butyl ester; N,N′-di(4-nitratomethylbenzoyl)-L-cystine dimethyl ester; N,N′-di(3-nitratomethylbenzoyl)-L-cystine dimethyl ester; N,N′-di(4-nitratomethylbenzoyl)-L-cystine-di(N,N′-butylamide); N,N′-di(3-nitratomethylbenzoyl)-L-cystine-di(N,N′-butylamide); N,N′-di(4-nitratomethylbenzoyl)-L-cystinediamide; N,N′-di(3-nitratomethylbenzoyl)-L-cystinediamide; N,N′-di(3-nitratopivaloyl)-L-penicillamine disulphidediamide; N,N′-di(3-nitratopivaloyl)-L-cystinediamide; N,N′-di(3-nitratopivaloyl)-L-cystine-di(N,N′-methylamide); N,N′-di(3-nitratopivaloyl)-L-cystine-di(N,N′-butylamide); N,N′-di(3-nitratopivaloyl)-L-cystine-di(N,N′-tertiary-butylamide); N,N′-di(3-nitratopivaloyl)-L-cystine-dimorpholide; N,N′-di(3-nitratopivaloyl)-L-cystinediisopropyl ester, or a pharmaceutically acceptable salts thereof.
- 5. The method of claim 1, wherein the compound of Formula (II) is N-nitrato-pivaloyl-S-(N-acetyl-glycyl)-L-cysteine ethyl ester (compound SPM 5186);
N-nitrato-pivaloyl-S-(N-acetyl-alanyl)-L-cysteine ethyl ester (compound SPM 5185); N-nitrato-pivaloyl-S-(N-acetyl-leucyl)-L-cysteine ethyl ester. N-(2-nitratoacetyl)-cysteine ethyl ester; N-(2-nitratoacetyl)-S-acetyl-cysteine ethyl ester; N-(2-nitratoacetyl)-S-propionyl-cysteine ethyl ester; N-(2-nitratoacetyl)-S-pivaloyl-cysteine ethyl ester; N-(2-nitratoacetyl)-methionine methyl ester; N-(2-nitratopropionyl)-cysteine; N-(2-nitratopropionyl)-cysteine ethyl ester; N-(2-nitratopropionyl)-methionine ethyl ester; N-(2-nitratobutyryl)-cysteine; N-(2-nitratobutyryl)-cysteine ethyl ester; N-(2-nitratobutyryl)-S-acetyl-cysteine ethyl ester; N-(2-nitratobutyryl)-S-butyryl-cysteine ethyl ester; N-(2-nitratobutyryl)-methionine ethyl ester; N-(2-nitratoisobutyryl)-cysteine; N-(2-nitratoisobutyryl)-cysteine ethyl ester; N-(2-nitratoisobutyryl)-S-benzoyl-cysteine ethyl ester; N-(2-nitratoisobutyryl)-S-acetyl-cysteine ethyl ester; N-(2-nitratoisobutyryl)-S-pivaloyl-cysteine ethyl ester; N-(2-nitratoisobutyryl)-methionine ethyl ester; N-(3-nitratobutyryl)-cysteine; N-(3-nitratobutyryl)-cysteine ethyl ester; N-(3-nitratobutyryl)-S-acetyl-cysteine ethyl ester; N-(3-nitratobutyryl)-S-propionyl-cysteine ethyl ester; N-(3-nitratobutyryl)-methionine ethyl ester; N-(3-nitratobutyryl)-homocysteine thiolactone; N-(3-nitratopivaloyl)-cysteine; N-(3-nitratopivaloyl)-cysteine ethyl ester; N-(3-nitratopivaloyl)-cysteine ethyl ester-S-ethyl carbonate; N-(3-nitratopivaloyl)-S-acetyl-cysteine ethyl ester; N-(3-nitratopivaloyl)-S-propionyl-cysteine ethyl ester; N-(3-nitratopivaloyl)-S-butyryl-cysteine ethyl ester; N-(3-nitratopivaloyl)-S-isobutyryl-cysteine ethyl ester; N-(3-nitratopivaloyl)-S-pivaloyl-cysteine ethyl ester; N-(3-nitratopivaloyl)-S-benzoyl-cysteine ethyl ester; N-(3-nitratopivaloyl)-methionine ethyl ester; N-(3-nitratopivaloyl)-methionine; N-(3-nitratopivaloyl)-homocysteine thiolactone; N-(2-nitratohexanoyl)-cysteine ethyl ester; N-(2-nitratohexanoyl)-S-propionyl-cysteine ethyl ester; N-(3-nitratohexanoyl)-cysteine ethyl ester; N-(3-nitratohexanoyl)-methionine methyl ester; N-(12-nitratolauroyl)-cysteine; N-(12-nitratolauroyl)-cysteine ethyl ester; N-(12-nitratolauroyl)-S-acetyl-cysteine; N-(12-nitratolauroyl)-S-pivaloyl-cysteine; compound SPM 3672; compound SPM 6373; or a pharmaceutically acceptable salts thereof.
RELATED APPLICATIONS
[0001] This application is a continuation of PCT/US02/24923 filed Aug. 7, 2002, which claims priority to U.S. Application No. 60/311,715 filed Aug. 10, 2001.
Provisional Applications (1)
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Number |
Date |
Country |
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60311715 |
Aug 2001 |
US |
Continuations (1)
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Number |
Date |
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| Parent |
PCT/US02/24923 |
Aug 2002 |
US |
| Child |
10760672 |
Jan 2004 |
US |
Patent Application
20040152753
