Claims
- 1. A compound of Formula (I), (II), (III) or a pharmaceutically acceptable salt thereof;
wherein the compound of Formula (I) is: 4wherein: R1 is —S(O)2—CH3 or —S(O)2—NH2; R1 at each occurrence is independently a hydrogen, a halogen, a methyl or CH2OH; R2 is a substituted lower alkyl group, a cycloalkyl group, an aryl group or a heterocyclic ring; R3 is:
(a) —(C(R4)(R′4))k—Y—(C(R4)(R′4))n—O—V; (b) —C(Z)-(C(R4)(R′4))k—O—V; (c) —C(Z)-(C(R4)(R′4))k—Y—(C(R4)(R′4))n—O—V; (d) —(C(R4)(R′4))k—Y—(C(R4)(R′4))n—C(Z)-(C(R4)(R′4))n—O—V; (e) —(C(R4)(R′4))k—CH═CH—(C(R4)(R′4))p—O—V; (f) —(C(R4)(R′4))n—O—V; (g) —(C(R4)(R′4))n—W-Q-(C(R4)(R′4))k—O—V; (h) —C(Z)-W-Q-(C(R4)(R′4))k—O—V; (i) —C(O)—N(Ri)—O—(C(R4)(R′4)n—O—V; (j) —(C(R4)(R′4))k—C≡C—(C(R4)(R′4))p—O—V; (k) —(C(R4)(R′4))k—Y—(C(R4)(R′4))k—Y—(C(R4)(R′4))k—O—V; (l) —(C(R4)(R′4))p-E-N(Ri)—O—W-Q-(C(R4)(R′4)k—O—V; (m) —(C(R4)(R′4))p-E-N(Ri)—O—(C(R4)(R′4)k—O—V; (n) —(C(R4)(R′4))p—N(Ri)—O—(C(R4)(R′4)k—O—V; (o) —(C(R4)(R′4))p—O—N(Ri)—(C(R4)(R′4)k—O—V; (p) —(C(R4)(R′4))p—O—N(Ri)-E-(C(R4)(R′4)k—O—V; (q) —(C(R4)(R′4))p—O—N(Ri)-E-W-Q-(C(R4)(R′4)k—O—V; (r) —(C(R4)(R′4))p—C(Z)-Y—(C(R4)(R′4)k—O—V; (s) —(C(R4)(R′4))p—Y—C(Z)-(C(R4)(R′4)k—O—V; or (t) —(C(R4)(R′4))p—Y—C(Z)-Y—(C(R4)(R′4)k—O—V; R4 and R′4 at each occurrence are independently a hydrogen, a halogen, a lower alkyl group, an alkoxy group; or R4 and R′4 taken together with the carbon atom to which they are attached are a substituted lower alkyl, a cycloalkyl group, an aryl group or a heterocyclic ring; V is —NO, —NO2, or a hydrogen; Y at each occurrence is independently an oxygen, —S(O)o— or —N(Ra)Ri—; Z is an oxo, a thial, an oxime or a hydrazone; Q is Y or a covalent bond; W at each occurrence is independently an aryl group, an alkylaryl group, a heterocyclic ring or an alkylheterocyclic ring; E is —C(O) or —S(O)o; Ra is a lone pair of electron a hydrogen or a lower 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 alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, arylsulphonyloxy, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —(C(R4)(R′4))n—O—V, a bond to an adjacent atom creating a double bond to that atom, —(N2O2—)−.M+, wherein M+ is an organic or inorganic cation; o is an integer from 0 to 2; k is an integer from 1 to 6; p at each occurrence is independently an integer from 0 to 10; n at each occurrence is independently an integer from 2 to 10; and with the proviso that when R2 is cycloalkyl, aryl or a heterocyclic ring, R3 cannot be —(C(R4)(R′4))n—O—V, where R4 and R′4 at each occurrence are independently a hydrogen, a halogen, a lower alkyl group, an alkoxy group and V is hydrogen; wherein the compound of Formula (II) is: 5wherein R1, R1′, R2 and R3 are as defined herein; and with the proviso that when R2 is cycloalkyl, aryl or a heterocyclic ring, R3 cannot be —(C(R4)(R′4))n—O—V, where R4 and R′4 at each occurrence are independently a hydrogen, a halogen, a lower alkyl group, an alkoxy group and V is hydrogen; wherein the compound of Formula (III) is: 6wherein: R5 is:
(a) —(C(R4)(R′4))k—Y—(C(R4)(R′4))k—B—(C(R4)(R′4))k—O—V; (b) —(C(R4)(R′4))k—Y—(C(R4)(R4))k-D-(C(R4)(R′4))k—O—V; (c) —C(Z)-(C(R4)(R′4))k—Y—(C(R4)(R′4))k—O—V; (d) —(C(R4)(R′4))k—Y—W-Q-C(R4)(R′4))k—O—V; (e) —C(Z)-W-Q-(C(R4)(R′4))k—O—V; (f) —(C(R4)(R′4))p-E-N(Ri)—O—W-Q-(C(R4)(R′4)k—O—V; (g) —(C(R4)(R′4))p-E-N(Ri)—O—(C(R4)(R′4)k—O—V; (h) —(C(R4)(R′4))p—N(Ri)—O—(C(R4)(R′4)k—O—V; (i) —(C(R4)(R′4))p—O—N(Ri)—(C(R4)(R′4)k—O—V; (j) —(C(R4)(R′4))p—O—N(Ri)-E-(C(R4)(R′4)k—O—V; or (k) —(C(R4)(R′4))p—O—N(Ri)-E-W-Q-(C(R4)(R′4)k—O—V; B is —C(Z)-, —Y— or a covalent bond; D is —S(O)o or —N(Ra)(Ri); and R1, R1′, R2, R4, R′4, Ra, Ri, E, Y, V, Z, W, Q, o and k are as defined herein.
- 2. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
- 3. A method for treating or reducing inflammation, pain or fever in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
- 4. A method for treating a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
- 5. The method of claim 4, wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterial infection, short-bowel (anastomosis) syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.
- 6. A method for facilitating wound healing in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
- 7. The method of claim 6, wherein the wound is an ulcer.
- 8. A method for treating or reversing renal and/or respiratory toxicity in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
- 9. A method for treating a disorder resulting from elevated levels of COX-2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
- 10. The method of claim 9, wherein the disorder resulting from elevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, a skin-related condition, neoplasia, an inflammatory process in a disease, an ophthalmic disorder, pulmonary inflammation, a central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, a microbial infection, a cardiovascular disorder, a urinary disorder, a urological disorder, endothelial dysfunction, organ deterioration, tissue deterioration, or activation, adhesion and infiltration of neutrophils at the site of inflammation.
- 11. The method of claim 10, wherein the neoplasia is a brain cancer, a bone cancer, an epithelial cell-derived neoplasia (epithelial carcinoma), a basal cell carcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, a mouth cancer, an esophageal cancer, a small bowel cancer, a stomach cancer, a colon cancer, a liver cancer, a bladder cancer, a pancreas cancer, an ovary cancer, a cervical cancer, a lung cancer, a breast cancer, a skin cancer, a squamus cell cancer, a basal cell cancer, a prostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, a polyp, an adenomatous polyp, a familial adenomatous polyposis or a fibrosis resulting from radiation therapy.
- 12. The method of claim 10, wherein the central nervous system disorder is cortical dementia, Alzheimer's disease, vascular dementia, multi-infarct dementia, pre-senile dementia, alcoholic dementia, senile dementia, or central nervous system damage resulting from stroke, ischemia or trauma.
- 13. A method for inhibiting platelet aggregation in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
- 14. The composition of claim 2, further comprising at least one therapeutic agent.
- 15. The composition of claim 14, wherein the therapeutic agent is a steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase (5-LO) inhibitor, a leukotriene B4 receptor antagonist, a leukotriene A4 hydrolase inhibitor, a 5-HT agonist, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, a H2 antagonist, an antineoplastic agent, an antiplatelet agent, a thrombin inhibitor, a thromboxane inhibitor, a decongestant, a diuretic, a sedating or non-sedating anti-histamine, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, a Helicobacter pylori inhibitor, a proton pump inhibitor, an isoprostane inhibitor, or a mixture of two or more thereof.
- 16. The composition of claim 15, wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen or naproxen.
- 17. A method for treating or reducing inflammation, pain or fever in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 14.
- 18. A method for treating a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 14.
- 19. The method of claim 18, wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterial infection, short-bowel (anastomosis) syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.
- 20. A method for facilitating wound healing in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 14.
- 21. The method of claim 20, wherein the wound is an ulcer.
- 22. A method for treating or reversing renal and/or respiratory toxicity in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 14.
- 23. A method for treating a disorder resulting from elevated levels of COX-2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 14.
- 24. The method of claim 23, wherein the disorder resulting from elevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, a skin-related condition, neoplasia, an inflammatory process in a disease, an ophthalmic disorder, pulmonary inflammation, a central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, a microbial infection, a cardiovascular disorder, a urinary disorder, a urological disorder, endothelial dysfunction, organ deterioration, tissue deterioration, or activation, adhesion and infiltration of neutrophils at the site of inflammation.
- 25. The method of claim 24, wherein the neoplasia is a brain cancer, a bone cancer, an epithelial cell-derived neoplasia (epithelial carcinoma), a basal cell carcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, a mouth cancer, an esophageal cancer, a small bowel cancer, a stomach cancer, a colon cancer, a liver cancer, a bladder cancer, a pancreas cancer, an ovary cancer, a cervical cancer, a lung cancer, a breast cancer, a skin cancer, a squamus cell cancer, a basal cell cancer, a prostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, a polyp, an adenomatous polyp, a familial adenomatous polyposis or a fibrosis resulting from radiation therapy.
- 26. The method of claim 24, wherein the central nervous system disorder is cortical dementia, Alzheimer's disease, vascular dementia, multi-infarct dementia, pre-senile dementia, alcoholic dementia, senile dementia, or central nervous system damage resulting from stroke, ischemia or trauma.
- 27. A method for inhibiting platelet aggregation in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 14.
- 28. 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.
- 29. The composition of claim 28, further comprising a pharmaceutically acceptable carrier.
- 30. The composition of claim 28, 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.
- 31. The composition of claim 30, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione, or S-nitroso-cysteinyl-glycine.
- 32. The composition of claim 30, 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 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, 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 cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, 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, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a urea, a nitro, -T-Q-, or —(C(Rg)(Rh))k-T-Q or Re and Rf taken together are an oxo, a thial, a heterocyclic ring, a cycloalkyl group, an oxime, a hydrazone 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 arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —CH2—C(T-Q)(Rg)(Rh), or —(N2O2—)−.M+, wherein M+ is an organic or inorganic cation; with the proviso that when Ri is —CH2—C(T-Q)(Rg)(Rh) 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; and Rg and Rh at each occurrence are independently Re.
- 33. The composition of claim 28, 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, nitrosated L-homoarginine, nitrosylated L-homoarginine), citrulline, ornithine, glutamine, lysine, an arginase inhibitor or a nitric oxide mediator.
- 34. The composition of claim 28, 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— or ON—N— group; (ii) a compound that comprises at least one O2N—O—, O2N—N— or O2N—S— or group; (iii) a N-oxo-N-nitrosoamine having the formula: R1″ R2″N—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.
- 35. The composition of claim 34, wherein the compound comprising at least one ON—O— or ON—N— group is an ON—O-polypeptide, an ON—N-polypeptide, an ON—O-amino acid, an ON—N-amino acid, an ON—O-sugar, an ON—N-sugar, an ON—O-oligonucleotide, an ON—N-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, an ON—O-heterocyclic compound or an ON—N-heterocyclic compound.
- 36. The composition of claim 34, wherein compound comprising at least one O2N—O—, O2N—N— or O2N—S— group is an O2N—O-polypeptide, an O2N—N-polypeptide, an O2N—S-polypeptide, an O2N—O-amino acid, O2N—N-amino acid, O2N—S-aamino acid, an O2N—O-sugar, an O2N—N-sugar, O2N—S-sugar, an O2N—O-oligonucleotide, an O2N—N-oligonucleotide, an O2N—S-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, an O2N—O-heterocyclic compound, an O2N—N-heterocyclic compound or an O2N—S-heterocyclic compound.
- 37. The composition of claim 28, further comprising at least one therapeutic agent.
- 38. The composition of claim 37, wherein the therapeutic agent is a steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase (5-LO) inhibitor, a leukotriene B4 receptor antagonist, a leukotriene A4 hydrolase inhibitor, a 5-HT agonist, a HMG CoA inhibitor, a H2 antagonist, an antineoplastic agent, an antiplatelet agent, a thrombin inhibitor, a thromboxane inhibitor, a decongestant, a diuretic, a sedating or non-sedating anti-histamine, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, a Helicobacter pylori inhibitor, a proton pump inhibitor, an isoprostane inhibitor, or a mixture of two or more thereof.
- 39. The composition of claim 38, wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen or naproxen.
- 40. A method for treating or reducing inflammation, pain or fever in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 29 or 37.
- 41. A method for treating a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 29 or 37.
- 42. The method of claim 41, wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterial infection, short-bowel (anastomosis) syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminenia.
- 43. A method for facilitating wound healing in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 29 or 37.
- 44. The method of claim 43, wherein the wound is an ulcer.
- 45. A method for treating or reversing renal and/or respiratory toxicity in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 29 or 37.
- 46. A method for treating a disorder resulting from elevated levels of COX-2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 29 or 37.
- 47. The method of claim 46, wherein the disorder resulting from elevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, a skin-related condition, neoplasia, an inflammatory process in a disease, an ophthalmic disorder, pulmonary inflammation, a central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, a microbial infection, a cardiovascular disorder, a urinary disorder, a urological disorder, endothelial dysfunction, organ deterioration, tissue deterioration, or activation, adhesion and infiltration of neutrophils at the site of inflammation.
- 48. The method of claim 47, wherein the neoplasia is a brain cancer, a bone cancer, an epithelial cell-derived neoplasia (epithelial carcinoma), a basal cell carcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, a mouth cancer, an esophageal cancer, a small bowel cancer, a stomach cancer, a colon cancer, a liver cancer, a bladder cancer, a pancreas cancer, an ovary cancer, a cervical cancer, a lung cancer, a breast cancer, a skin cancer, a squamus cell cancer, a basal cell cancer, a prostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, a polyp, an adenomatous polyp, a familial adenomatous polyposis or a fibrosis resulting from radiation therapy.
- 49. The method of claim 47, wherein the central nervous system disorder is cortical dementia, Alzheimer's disease, vascular dementia, multi-infarct dementia, pre-senile dementia, alcoholic dementia, senile dementia, or central nervous system damage resulting from stroke, ischemia or trauma.
- 50. A method for inhibiting platelet aggregation in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 29 or 37.
- 51. A kit comprising at least one compound of claim 1.
- 52. The kit of claim 51, further comprising (i) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase; (ii) at least one therapeutic agent; or (iii) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase and at least one therapeutic agent.
- 53. The kit of claim 52, wherein the at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase; the at least one therapeutic agent; or the at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase and at least one therapeutic agent; are in the form of separate components in the kit
- 54. A kit comprising the composition of claim 14, 29 or 37.
- 55. A compound selected from the group consisting of
1-(1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one; 1-(3-((1Z)-4-(hydroxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl-4-methylsulfonyl)benzene; 4-(3-((3-hydroxypropoxy)methyl)-1-phenylpyrazol-5-yl)-1-(methylsulfonyl)benzene; 1-(3-(difluoro(3-hydroxypropoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(1-(4-chlorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(3-((3-hydroxypropoxy)methyl)-1-(4-methylphenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(3-((3-hydroxypropoxy)methyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(3-((3-hydroxypropoxy)methyl)-1-(4-methoxyphenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(3-((1Z)-4-(hydroxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-methylsulfonyl)benzene; 4-hydroxy-1-(1-(4-methylphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)butan-1-one; 1-(1-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one; 1-(1-(4-bromophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one; 1-(1-cyclohexyl-3-((2-hydroxyethoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(1-cyclohexyl-3-((3-hydroxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(1-cyclohexyl-3-((3-(hydroxymethyl)phenoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(1-(4-fluorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(3-((3-hydroxybutoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(3-((1E)-4-(hydroxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-methylsulfonyl)benzene; 1-(1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)-pyrazol-3-yl)-6-hydroxyhexan-1-one; 4-hydroxy-1-(5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)-phenyl)pyrazol-3-yl)butan-1-one 4-hydroxy-1-(1-(4-methoxyphenyl)-5-(4-(methylsulfonyl)phenyl)-pyrazol-3-yl)butan-1-one; 4-(3-((1E)-3-hydroxyprop-1-enyl)-1-cyclohexylpyrazol-5-yl)-1(methylsulfonyl)benzene; 1-(1-cyclohexyl-3-(((2-hydroxyethyl)amino)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 4-(3-(4-hydroxybutanoyl)-5-(4-(methylsulfonyl)phenyl)pyrazolyl)benzenecarbonitrile; 4-(1-cyclohexyl-3-(4-hydroxybutanoyl)pyrazol-5-yl)benzenesulfonamide; 1-(1-(4-chlorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one; (1-cyclohexyl-5-(4-(methylsulfonylphenyl)pyrazol-3-yl)-N-(2-hydroxyethyl)carboxamide; (1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(3-hydroxypropyl)carboxamide; 1-(1-cyclooctyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-methylsulfonyl)benzene; 1-(1-cycloheptyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one 1-(3-((1Z)-4-(nitrooxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene; 4-(3-((3-(nitrooxy)propoxy)methyl)-1-phenylpyrazol-5-yl)-1-(methylsulfonyl)benzene; 1-(3-(difluoro(3-(nitrooxy)propoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(1-(4-chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(1-(4-methylphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 4-(methylsulfonyl)-1-(3-((3-(nitrooxy)propoxy)methyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-5-yl)benzene; 1-(1-(4-methoxy-3-nitrophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(3-((1Z)-4-(nitrooxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(3-((1E)-4-(nitrooxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-1-(4-methylphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one; 1-(1-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one; 1-(1-(4-bromophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one; 1-(1-cyclohexyl-3-((2-(nitrooxy)ethoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(1-cyclohexyl-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methysulfonyl)benzene; 1-(1-cyclohexyl-3-((3-((nitrooxy)methyl)phenoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(1-(4-fluorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 4-(methylsulfonyl)-1-(3-((3-(nitrooxy)butoxy)methyl)-1-phenylpyrazol-5-yl)benzene; 1-(3-((1E)-4-(nitrooxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene; 1-(1-cyclohexyl-5-(4-(methylsulfonyl)pyrazol-3-yl)-6-(nitrooxy)hexan-1-one; 1-(5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one; 1-(1-(4-methoxyphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl-4-(nitrooxy)butan-1-one; 4-(1-cyclohexyl-3-(2-(nitrooxy)ethyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene; 4-(1-cyclohexyl-3-(3-(nitrooxy)propyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene; 1-(5-(4-(methysulfonyl)phenyl)-1-(2-pyridyl)pyrazol-3-yl)-2-(nitrooxy)ethan-1-one; 4-(1-(4-methoxyphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene; 4-(1-(4-methyl-3-nitrophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene; 1-(3-((1E)-3-(nitrooxy)prop-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene; 4-(5-(4-(methylsulfonyl)phenyl)-3-(4-(nitrooxy)butanoyl)pyrazolyl)benzenecarbonitrile; 4-(1-cyclohexyl-3-(4-(nitrooxy)butanoyl)pyrazol-5-yl)benzenesulfonamide; 1-(1-(4-chlorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one; (1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(2-(nitrooxy)ethyl)carboxamide; (1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(3(nitrooxy)propyl)carboxamide; 3-(nitrooxy)propyl 4-(5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)-phenyl)pyrazol-3-yl)butanoate; 4-(3-((3-hydroxypropoxy)methyl)-5-(4-methylphenyl)pyrazolyl)benzenesulfonamide; 1-(3-((1Z)-4-hydroxybut-1-enyl)-5-(3-pyridnyl)pyrazolyl)-4-(methylsulfonyl)benzene; 4-(5-(4-chlorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazolyl)benzenesulfonamide; 4-(3-((3-hydroxypropoxy)methyl)-5-phenylpyrazolyl)benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazolyl)-benzenesulfonamide; 4-(5-(4-methylphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazolyl)benzenesulfonamide; 1-(3-((1Z)-4-(nitrooxy)but-1-enyl)-5-(3-pyridyl)pyrazolyl)-4-(methylsulfonyl)benznene; 4-(5-(4-chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazolyl)benzenesulfonamide; 4-(3-((3-(nitrooxy)propoxy)methyl)-5-phenylpyrazolyl)benzenesulfonamide; 4-(5-(chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)benzene-sulfonamide; 4-(5-(3-hydroxypropoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-(5-(2-hydroxyethoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-(5-((2,2-difluoro-3-hydroxypropoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-(3-phenyl-5-(2,2,3,3-tetrafluoro-4-hydroxy)methyl)isoxazol-4-yl)benzenesulfonamide; 4-(5-((2,2,3,3,4,4-hexafluoro-5-hydroxypentyloxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-(5-((2-((2-hydroxyethyl)sulfonyl)ethoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-(5-(3-nitrooxy)propoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-(5-(2-nitrooxy)ethoxy)methyl-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-(5-((2,2-difuoro-3-(nitrooxy)propoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-(3-phenyl-5-(2,2,3,3-tetrafluoro-4-hydroxy)methyl)isoxazol-4-yl)benzenesulfonamide; and 4-(5-((2,2,3,3,4,4-hexafluoro-5-(nitrooxy)pentyloxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-(5-((2-(nitrooxy)ethyl)sulfonyl)ethoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide; or a pharmaceutically acceptable salt thereof.
- 56. A composition comprising at least one compound of claim 55 and a pharmaceutically acceptable carrier.
- 57. The composition of claim 56, further comprising (i) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase; (ii) at least one therapeutic agent; or (iii) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase and at least one therapeutic agent.
- 58. A kit comprising at least one compound of claim 55.
RELATED APPLICATIONS
[0001] This application claims priority to U.S. application Ser. No. 60/391,769, filed Jun. 27, 2002, and U.S. application Ser. No. 60/454,307, filed Mar. 14, 2003, both of which are incorporated herein by reference.
Provisional Applications (2)
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Number |
Date |
Country |
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60391769 |
Jun 2002 |
US |
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60454307 |
Mar 2003 |
US |
Patent Application
20040053985
