US 20040072883A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0072883 A1 Garvey et al. (43) Pub. Date: Apr. 15, 2004

(54) CYCLOOXYGENASE-2 SELECTIVE (52) U.S. Cl...... 514/365; 514/374; 514/397; INHIBITORS, COMPOSITIONS AND 514/424; 514/461 METHODS OF USE (75) Inventors: David S. Garvey, Dover, MA (US); Subhash P. Khanapure, Clinton, MA (57) ABSTRACT (US); Ramani R. Ranatunge, Lexington, MA (US); Stewart K. Richardson, Tolland, CT (US); Joseph The invention describes novel cyclooxygenase 2 (COX-2) D. Schroeder, Minneapolis, MN (US) Selective inhibitors and novel compositions comprising at Correspondence Address: least one cyclooxygenase 2 (COX-2) Selective inhibitor, EDWARD ID GRIEFF and, optionally, at least one compound that donates, transfers HALE & DORR LLP or releases nitric oxide, Stimulates endogenous Synthesis of 1455 PENNSYLVANIAAVE, NW nitric oxide, elevates endogenous levels of endothelium WASHINGTON, DC 20004 (US) derived relaxing factor or is a Substrate for nitric oxide Synthase, and/or at least one therapeutic agent. The inven (73) Assignee: NitroMed, Inc., Bedford, MA tion also provides novel kits comprising at least one COX-2 Selective inhibitor, optionally nitroSated and/or nitrosylated, (21) Appl. No.: 10/628,375 and, optionally, at least one nitric oxide donor, and/or, (22) Filed: Jul. 29, 2003 optionally, at least one therapeutic agent. The novel cyclooxygenase 2 Selective inhibitors of the invention can be Related U.S. Application Data optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever, (60) Provisional application No. 60/398.829, filed on Jul. for treating and/or improving the gastrointestinal properties 29, 2002. of COX-2 selective inhibitors; for facilitating wound heal ing; for treating and/or preventing renal and/or respiratory Publication Classification toxicity; for treating and/or preventing other disorders 51) Int.nt. Cl.C.7 ...... A61K 31/427; A61K 31/422 resulting from elevated levels of cyclooxygenase-2, and for A61K 31/4015; CO7D 417/02; improving the cardiovascular profile of COX-2 selective CO7D 413/02 inhibitors. US 2004/0072883 A1 Apr. 15, 2004

CYCLOOXYGENASE-2 SELECTIVE INHIBITORS, selectivity for either isoform or are COX-1 selective. COMPOSITIONS AND METHODS OF USE Recently compounds that are COX-2 selective inhibitors have been developed and marketed. These COX-2 selective RELATED APPLICATIONS inhibitors have the desired therapeutic profile of an antiin flammatory drug without the adverse effects commonly 0001. This application claims priority to U.S. Application associated with the inhibition of COX-1. However, these No. 60/398,829 filed Jul. 29, 2002. compounds can result in dyspepsia and can cause gastropa thy (Mohammed et al., N. Engl. J. Med., 340(25) 2005 FIELD OF THE INVENTION (1999)). Additionally the COX-2 selective inhibitors can 0002 The invention describes novel nitrosated and/or increase the risk of cardiovascular events in a patient nitrosylated cyclooxygenase 2 (COX-2) selective inhibitors (Mukherjee et al., JAMA 286(8) 954-959 (2001)); Hennan et and novel compositions comprising at least one nitroSated al., Circulation, 104.820–825 (2001)). and/or nitrosylated cyclooxygenase 2 (COX-2) Selective 0005. There is still a need in the art for novel COX-2 inhibitor, and, optionally, at least one compound that Selective inhibitor compounds that have gastroprotective donates, transferS or releases nitric oxide, Stimulates endog properties, facilitate wound healing, decreased renal toxicity enous Synthesis of nitric oxide, elevates endogenous levels and dyspepsia, improved cardiovascular profile and that can of endothelium-derived relaxing factor or is a Substrate for be used at low dosages. The invention is directed to these, nitric oxide Synthase, and/or at least one therapeutic agent. as well as other, important ends. The invention also provides novel compositions comprising at least one COX-2 selective inhibitor, that is optionally SUMMARY OF THE INVENTION nitrosated and/or nitrosylated, and at least one compound that donates, transferS or releases nitric oxide, elevates 0006. The invention provides novel COX-2 selective endogenous levels of endothelium-derived relaxing factor, inhibitors, or a pharmaceutically acceptable Salt thereof. Stimulates endogenous Synthesis of nitric oxide or is a These compounds are potent analgesics, have antiinflam Substrate for nitric oxide Synthase and/or at least one thera matory properties and have an unexpected potential for peutic agent. The invention also provides novel kits com facilitating wound healing. The novel compounds also have prising at least one COX-2 Selective inhibitor, that is option unexpected properties in the treatment and/or prevention of ally nitrosated and/or nitrosylated, and, optionally, at least renal and/or respiratory toxicity and for improving the one nitric oxide donor and/or at least one therapeutic agent. cardiovascular profile of COX-2 selective inhibitors. The The invention also provides methods for treating inflamma COX-2 selective inhibitor, or a pharmaceutically acceptable tion, pain and fever, for treating gastrointestinal disorders Salt thereof, can be nitroSated and/or nitrosylated through and/or improving the gastrointestinal properties of COX-2 one or more sites, Such as oxygen (hydroxyl condensation), Selective inhibitors, for facilitating wound healing, for treat Sulfur (Sulfhydryl condensation) and/or nitrogen. The inven ing and/or preventing renal and/or respiratory toxicities; for tion also provides compositions comprising the novel com treating and/or preventing other disorders resulting from pounds described herein in a pharmaceutically acceptable elevated levels of cyclooxygenase-2, and for improving the carrier. cardiovascular profile of COX-2 selective inhibitors. 0007. The invention is also based on the discovery that administering at least one COX-2 selective inhibitor and at BACKGROUND OF THE INVENTION least one nitric oxide donor or administering at least one 0003) Nonsteroidal anti-inflammatory compounds nitrosated and/or nitrosylated COX-2 selective inhibitor, (NSAIDs) are widely used for the treatment of pain, inflam and, optionally, at least one nitric oxide donor reduces the mation, and acute and chronic inflammatory disorderS Such gastrointestinal toxicity induced by COX-2 selective inhibi as osteoarthritis and rheumatoid arthritis. These compounds tors. Nitric oxide donors include, for example, S-nitroSothi inhibit the activity of the enzyme cyclooxygenase (COX), ols, nitrites, nitrates, N-oxo-N-nitrosamines, SPM 3672, also known as prostaglandin G/H Synthase, which is the SPM5185, SPM 5186 and analogues thereof, and substrates enzyme that converts arachidonic acid into prostanoids. The of the various isozymes of nitric oxide Synthase. Thus, NSAIDs also inhibit the production of other prostaglandins, another aspect of the invention provides compositions com especially prostaglandin G, prostaglandin H and prostag prising at least one COX-2 Selective inhibitor, that is option landin E, thereby reducing the prostaglandin-induced pain ally substituted with at least one NO and/or NO group (i.e., and Swelling associated with the inflammation process. The nitrosylated and/or nitrosated), and at least one compound chronic use of NSAIDs has been associated with adverse that donates, transferS or releases nitric oxide as a charged effects, Such as gastrointestinal ulceration and renal toxicity. species, i.e., nitrosonium (NO") or nitroxyl (NO-), or as the The undesirable side effects are also due to the inhibition of neutral species, nitric oxide (NO.), and/or Stimulates endog prostaglandin in the affected organ. enous production of nitric oxide or EDRF in vivo and/or is a Substrate for nitric oxide Synthase. The invention also 0004 Recently two isoforms of cyclooxygenase, provides for Such compositions in a pharmaceutically encoded by two distinct genes (Kujubu et al., J. Biol. Chem., acceptable carrier. 266, 12866-12872 (1991)), have been identified-a consti tutive form, cyclooxygenase-1 (COX-1), and an inductive 0008. Yet another aspect of the invention provides com form, cyclooxygenase-2 (COX-2). It is thought that the positions comprising at least one COX-2 Selective inhibitor, antiinflammatory effects of NSAIDs are mediated by the that is optionally Substituted with at least one NO group inhibition of COX-2, whereas the side effects seem to be and/or at least one NO group (i.e., nitrosated and/or nitrosy caused by the inhibition of COX-1. The NSAIDs currently lated respectively), and, optionally, at least one compound on the market either inhibit both isoforms of COX with little that donates, transferS or releases nitric oxide as a charged US 2004/0072883 A1 Apr. 15, 2004

species, i.e., nitrosonium (NO") or nitroxyl (NO-), or as the effective amount of at least one COX-2 selective inhibitor, neutral species, nitric oxide (NO.), and/or Stimulates endog optionally substituted with at least one NO and/or NO enous production of nitric oxide or EDRF in vivo and/or is group (i.e. nitrosated and/or nitrosylated), and, optionally, at a Substrate for nitric oxide Synthase, and/or, optionally, at least one compound that donates, transferS or releases nitric least one therapeutic agent, including but not limited to, oxide as a charged species, i.e., nitroSonium (NO") or Steroids, nonsteroidal antiinflammatory compounds nitroxyl (NO-), or as the neutral species, nitric oxide (NO.), (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B. and/or Stimulates endogenous production of nitric oxide or (LTB) receptor antagonists, leukotriene A (LTA) hydro EDRF in vivo and/or is a substrate for nitric oxide synthase lase inhibitors, 5-HT agonists, HMG CoA inhibitors, H. (i.e. NO donor). The methods can optionally further com antagonists, antineoplastic agents, antiplatelet agents, prise the administration of at least one of 3-hydroxy-3- thrombin inhibitors, thromboxane inhibitors, decongestants, methylglutaryl coenzyme A (HMG-CoA) inhibitors, anti diuretics, Sedating or non-Sedating anti-histamines, induc platelet agents, thrombin inhibitors, thromboxane inhibitors, ible nitric oxide Synthase inhibitors, opioids, analgesics, and mixtures of two or more thereof. In this aspect of the Helicobacter pylori inhibitors, proton pump inhibitors, iso invention, the methods can involve administering the nitro prostane inhibitors, and the like. The invention also provides sated and/or nitrosylated COX-2 selective inhibitors, admin for Such compositions in a pharmaceutically acceptable istering the COX-2 selective inhibitors, that are optionally carrier. nitrosated and/or nitrosylated, and NO donors, administer 0009. Yet another aspect of the present invention pro ing the COX-2 selective inhibitors, that are optionally nit vides methods for treating and/or preventing inflammation, rosated and/or nitrosylated, and at least one of 3-hydroxy pain and fever, for treating gastrointestinal disorders and/or 3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, improving gastrointestinal properties of COX-2 inhibitors, antiplatelet agents, thrombin inhibitors or thromboxane for facilitating wound healing; for treating and/or preventing inhibitors, or administering the COX-2 selective inhibitors, renal and/or respiratory toxicity; and for treating and/or that are optionally nitrosated and/or nitrosylated, NO preventing COX-2 mediated disorders (i.e., disorders result donors, and at least one of 3-hydroxy-3-methylglutaryl ing from elevated levels of COX-2) in a patient in need coenzyme A (HMG-CoA) inhibitors, antiplatelet agents, thereof which comprises administering to the patient a thrombin inhibitors or thromboxane inhibitors. The COX-2 therapeutically effective amount of at least one COX-2 inhibitors, nitric oxide donors, and/or 3-hydroxy-3-methyl selective inhibitor, that is optionally substituted with at least glutaryl coenzyme A (HMG-CoA) inhibitors, antiplatelet one NO group and/or at least one NO group (i.e., nitrosated agents, thrombin inhibitors or thromboxane inhibitors can be and/or nitrosylated respectively), and, optionally, at least administered Separately or as components of the same one compound that donates, transferS or releases nitric oxide composition in one or more pharmaceutically acceptable as a charged species, i.e., nitroSonium (NO) or nitroxyl carriers. (NO-), or as the neutral species, nitric oxide (NO.), and/or 0011. In yet another aspect the invention provides kits stimulates endogenous production of nitric oxide or EDRF comprising at least one COX-2 Selective inhibitor, that is in Vivo and/or is a Substrate for nitric oxide Synthase (i.e., optionally Substituted with at least one NO group and/or at NO donors). The methods can optionally further comprise least one NO group (i.e., nitrosated and/or nitrosylated the administration of at least one therapeutic agent, Such as, respectively), and, optionally, at least one compound that for example, Steroids, nonsteroidal antiinflammatory com donates, transferS or releases nitric oxide as a charged pounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukot species, i.e., nitrosonium (NO") or nitroxyl (NO-), or as the riene B (ITB) receptor antagonists, leukotriene A (LTA) neutral species, nitric oxide (NO.), and/or Stimulates endog hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, enous production of nitric oxide or EDRF in vivo and/or is H, antagonists, antineoplastic agents, antiplatelet agents, a substrate for nitric oxide synthase. The kit can further thrombin inhibitors, thromboxane inhibitors, decongestants, comprise at least one therapeutic agent, Such as, for diuretics, Sedating or non-Sedating anti-histamines, induc example, Steroids, nonsteroidal antiinflammatory com ible nitric oxide Synthase inhibitors, opioids, analgesics, pounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukot Helicobacter pylori inhibitors, proton pump inhibitors, iso riene B (ITB) receptor antagonists, leukotriene A (LTA) prostane inhibitors, and mixtures of two or more thereof. In hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methyl this aspect of the invention, the methods can involve admin glutaryl coenzyme A (HMG-CoA) inhibitors, H antago istering the COX-2 selective inhibitors, that are optionally nists, antineoplastic agents, antiplatelet agents, thrombin nitrosated and/or nitrosylated, administering the COX-2 inhibitors, thromboxane inhibitors, decongestants, diuretics, Selective inhibitors, that are optionally nitrosated and/or Sedating or non-Sedating anti-histamines, inducible nitric nitrosylated and NO donors, administering the COX-2 selec oxide Synthase inhibitors, opioids, analgesics, Helicobacter tive inhibitors, that are optionally nitroSated and/or nitrosy pylori inhibitors, proton pump inhibitors, isoprostane inhibi lated, and therapeutic agents, or administering the COX-2 tors, and mixtures of two or more thereof. The COX-2 Selective inhibitors, that are optionally nitrosated and/or Selective inhibitor, the nitric oxide donor and/or therapeutic nitrosylated, NO donors and therapeutic agents. The Selec agent, can be separate components in the kit or can be in the tive COX-2 inhibitors, nitric oxide donors, and/or therapeu form of a composition in the kit in one or more pharma tic agents can be administered Separately or as components ceutically acceptable carriers. of the same composition in one or more pharmaceutically acceptable carriers. DETAILED DESCRIPTION OF THE 0.010 Yet another aspect of the invention provides meth INVENTION ods for improving the cardiovascular profile of COX-2 0012. As used throughout the disclosure, the following selective inhibitors in a patient in need thereof which terms, unless otherwise indicated, shall be understood to comprises administering to the patient a therapeutically have the following meanings. US 2004/0072883 A1 Apr. 15, 2004

0013 “NSAID” refers to a nonsteroidal anti-inflamma result of increased platelet deposition, activation, thrombus tory compound or a nonsteroidal antiinflammatory drug. formation or consumption of platelets and coagulation pro NSAIDs inhibit cyclooxygenase, the enzyme responsible for teins. Such complications, which are within the definition of the biosyntheses of the prostaglandins and certain autocoid “cardiovascular disease or disorder, include, for example, inhibitors, including inhibitors of the various isozymes of myocardial infarction, ischemic Stroke, transient ischemic cyclooxygenase (including but not limited to cyclooxyge Stroke, thromboembolic events, pulmonary thromboembo nase-1 and -2), and as inhibitors of both cyclooxygenase and lism, cerebral thromboembolism, thrombophlebitis, throm lipoxygenase. bocytopenia, bleeding disorders and/or any other complica tions which occur either directly or indirectly as a result of 0014) “Cyclooxygenase-2 (COX-2) selective inhibitor” the foregoing disorders. refers to a compound that Selectively inhibits the cyclooxy genase-2 enzyme over the cyclooxygenase-1 enzyme. In one 0018 “Restenosis” is a cardiovascular disease or disorder embodiment, the compound has a cyclooxygenase-2 ICso of that refers to the closure of a peripheral or coronary artery less than about 2 uM and a cyclooxygenase-1 ICso of greater following trauma to the artery caused by an injury Such as, than about 5uM, in the human whole blood COX-2 assay (as for example, angioplasty, balloon dilation, atherectomy, described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) laser ablation treatment or Stent insertion. Restenosis can and also has a Selectivity ratio of cyclooxygenase-2 inhibi also occur following a number of invasive Surgical tech tion over cyclooxygenase-1 inhibition of at least 10, and niques, Such as, for example, transplant Surgery, vein graft preferably of at least 40. In another embodiment, the com ing, coronary artery bypass Surgery, endarterectomy, heart pound has a cyclooxygenase-1 ICso of greater than about 1 transplantation, balloon angioplasty, atherectomy, laser abla LiM, and preferably of greater than 20 uM. The compound tion, endovascular Stenting, and the like. can also inhibit the enzyme, lipoxygenase. Such Selectivity 0019 “Atheroslcerosis” is form of chronic vascular may indicate an ability to reduce the incidence of common injury in which Some of the normal vascular Smooth muscle NSAID-induced side effects. cells in the artery wall, which ordinarily control vascular 0015 “Parent COX-2 inhibitor” refers to a non-nitrosated tone regulating blood flow, change their nature and develop and/or non-nitrosylated COX-2 inhibitor, or pharmaceuti “cancer-like' behavior. These vascular Smooth muscle cells cally acceptable Salts thereof or pharmaceutically acceptable become abnormally proliferative, Secreting Substances Such esters thereof. "Parent COX-2 inhibitor” includes the com as growth factors, tissue-degradation enzymes and other pounds of Formulas (I), (II) and (III) before they are proteins, which enable them to invade and Spread into the nitrosated and/or nitrosylated by the methods described inner vessel lining, blocking blood flow and making that herein. vessel abnormally Susceptible to being completely blocked by local blood clotting, resulting in the death of the tissue 0016 “Therapeutic agent” includes any therapeutic agent Served by that artery. Atherosclerotic cardiovascular disease, that can be used to treat or prevent the diseases described coronary heart disease (also known as coronary artery herein. “Therapeutic agents' include, for example, Steroids, disease or ischemic heart disease), cerebrovascular disease nonsteroidal antiinflammatory compounds, 5-lipoxygenase and peripheral vessel disease are all common manifestations inhibitors, leukotriene B receptor antagonists, leukotriene of atherosclerosis and are therefore encompassed by the A hydrolase inhibitors, 3-hydroxy-3-methylglutaryl coen terms “atherosclerosis” and “atherosclerotic disease'. Zyme A inhibitors, H antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibi 0020 “Improving the cardiovascular profile” refers to tors, decongestants, diuretics, Sedating or non-Sedating anti and includes reducing the risk of thromboembolic events, histamines, inducible nitric oxide Synthase inhibitors, opio reducing the risk of developing atherosclerosis and athero ids, analgesics, Helicobacter pylori inhibitors, proton pump Sclerotic diseases, and inhibiting platelet aggregation of the inhibitors, isoprostane inhibitors, and the like. Therapeutic parent COX-2 inhibitor. agent includes the pro-drugs and pharmaceutical derivatives 0021 “Thromboembolic events” includes, but is not lim thereof including but not limited to the corresponding nit ited to, ischemic Stroke, transient ischemic Stroke, myocar rosated and/or nitrosylated derivatives. Although nitric dial infarction, angina pectoris, thrombosis, thromboembo oxide donors have therapeutic activity, the term “therapeutic lism, thrombotic occlusion and reocclusion, acute vascular agent” does not include the nitric oxide donors described events, restenosis, transient ischemic attacks, and first and herein, Since nitric oxide donors are separately defined. Subsequent thrombotic stroke. Patients who are at risk of developing thromboembolic events, may include those with 0017 “Cardiovascular disease or disorder” refers to any a familial history of, or genetically predisposed to, throm cardiovascular disease or disorder known in the art, includ ing, but not limited to, restenosis, atherosclerosis, athero boembolic disorders, who have had ischemic Stroke, tran genesis, angina, (particularly chronic, stable angina pecto Sient ischemic Stroke, myocardial infarction, and those with ris), ischemic disease, congestive heart failure or pulmonary unstable angina pectoris or chronic Stable angina pectoris edema associated with acute myocardial infarction, throm and patients with altered prostacyclin/thromboxane A bosis, controlling blood pressure in hypertension (especially homeostasis or higher than normal thromboxane A levels hypertension associated with cardiovascular Surgical proce leading to increase risk for thromboembolism, including dures), thromboembolic events, platelet aggregation, plate patients with diabetes and rheumatoid arthritis. let adhesion, Smooth muscle cell proliferation, Vascular 0022 “Thromboxane inhibitor” refers to any compound complications associated with the use of medical devices, that reversibly or irreversibly inhibits thromboxane synthe wounds associated with the use of medical devices, cere sis, and includes compounds which are the So-called throm brovascular ischemic events, and the like. Complications boxane A receptor antagonists, thromboxane A antago asSociated with the use of medical devices may occur as a nists, thromboxane A/prostaglandin endoperoxide US 2004/0072883 A1 Apr. 15, 2004 antagonists, thromboxane receptor (TP) antagonists, throm 0032 “Transmucosal” refers to delivery of a compound boxane antagonists, thromboxane Synthase inhibitors, and by passage of the compound through the mucosal tissue and dual acting thromboxane Synthase inhibitors and thrombox into the blood stream. ane receptor antagonists. The characteristics of the preferred thromboxane inhibitor should include the suppression of 0033 “Penetration enhancement” or “permeation thromboxane A formation (thromboxane Synthase inhibi enhancement” refers to an increase in the permeability of the tors) and/or blockade of thromboxane A and prostaglandin skin or mucosal tissue to a Selected pharmacologically active He platelet and vessel wall (thromboxane receptor antago compound Such that the rate at which the compound per nists). The effects should block platelet activation and there meates through the Skin or mucosal tissue is increased. fore platelet function. 0034). “Carriers” or “vehicles” refers to carrier materials Suitable for compound administration and include any Such 0023 “Thromboxane A receptor antagonist” refers to material known in the art Such as, for example, any liquid, any compound that reversibly or irreversibly blocks the gel, Solvent, liquid diluent, Solubilizer, or the like, which is activation of any thromboxane A receptor. non-toxic and which does not interact with any components 0024 “Thromboxane synthase inhibitor” refers to any of the composition in a deleterious manner. compound that reversibly or irreversibly inhibits the enzyme 0035) “Nitric oxide adduct” or “NO adduct” refers to thromboxane Synthesis thereby reducing the formation of compounds and functional groups which, under physiologi thromboxane A. Thromboxane Synthase inhibitors may also cal conditions, can donate, release and/or directly or indi increase the Synthesis of antiaggregatory prostaglandins rectly transfer any of the three redox forms of nitrogen including prostacyclin and prostaglandin D. Thromboxane monoxide (NO+, NO-, NO.), such that the biological activ A receptor antagonists and thromboxane Synthase inhibi ity of the nitrogen monoxide Species is expressed at the tors and can be identified using the assays described in Tai, intended Site of action. Methods of Enzymology, Vol. 86, 110-113 (1982); Hall, 0036 “Nitric oxide releasing” or “nitric oxide donating” Medicinal Research Reviews, 11:503–579 (1991) and Cole refers to methods of donating, releasing and/or directly or man et al., Pharmacol Rev., 46: 205-229 (1994) and refer indirectly transferring any of the three redox forms of ences therein, the disclosures of which are incorporated nitrogen monoxide (NO", NO-, NO.), such that the biologi herein by reference in its entirety. cal activity of the nitrogen monoxide Species is expressed at 0.025 “Dual acting thromboxane receptor antagonist and the intended site of action. thromboxane Synthase inhibitor” refers to any compound 0037 “Nitric oxide donor” or “NO donor” refers to that Simultaneously acts as a thromboxane A receptor compounds that donate, release and/or directly or indirectly antagonist and a thromboxane Synthase inhibitor. transfer a nitrogen monoxide Species, and/or Stimulate the 0.026 “Thrombin inhibitors' refers to and includes com endogenous production of nitric oxide or endothelium pounds that inhibit hydrolytic activity of thrombin, includ derived relaxing factor (EDRF) in vivo and/or elevate ing the catalytic conversion of fibrinogen to fibrin, activation endogenous levels of nitric oxide or EDRF in vivo. “NO of Factor V to Va., Factor VIII to VIIIa, Factor XIII to XIIIa donor” also includes compounds that are Substrates for nitric and platelet activation. Thrombin inhibitors may be identi oxide Synthase. fied using assays described in Lewis et at., Thrombosis 0038 “Alkyl” refers to a lower alkyl group, a haloalkyl Research. 70: 173-190 (1993). group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a 0.027 “Platelet aggregation” refers to the binding of one heterocyclic ring, as defined herein. An alkyl group may also or more platelets to each other. Platelet aggregation is comprise one or more radical Species, Such as, for example commonly referred to in the context of generalized athero a cycloalkylalkyl group or a heterocyclicalkyl group. Sclerosis, not with respect to platelet adhesion on Vascula ture damaged as a result of physical injury during a medical 0039) “Lower alkyl refers to branched or straight chain procedure. Platelet aggregation requires platelet activation acyclic alkyl group comprising one to about ten carbon which depends on the interaction between the ligand and its atoms (preferably one to about eight carbon atoms, more Specific platelet Surface receptor. preferably one to about six carbon atoms). Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, 0028 “Platelet activation” refers either to the change in n-butyl, isobutyl, Sec-butyl, t-butyl, pentyl, neopentyl, iso conformation (shape) of a cell, expression of cell Surface amyl, hexyl, octyl, and the like. proteins (e.g., the IIb/IIIa receptor complex, loss of GPIb 0040 “Substituted lower alkyl” refers to a lower alkyl Surface protein), and Secretion of platelet derived factors group, as defined herein, wherein one or more of the (e.g., Serotonin, growth factors). hydrogen atoms have been replaced with one or more R' 0029. “Patient” refers to animals, preferably mammals, groups, wherein each R" is independently a hydroxy, an most preferably humans, and includes males and females, OXO, a carboxyl, a carboxamido, a halo, a cyano or an amino and children and adults. group, as defined herein. 0030) “Therapeutically effective amount” refers to the 0041) “Haloalkyl” refers to a lower alkyl group, an alk amount of the compound and/or composition that is effective enyl group, an alkynyl group, a bridged cycloalkyl group, a to achieve its intended purpose. cycloalkyl group or a heterocyclic ring, as defined herein, to which is appended one or more halogens, as defined herein. 0031) “Transdermal” refers to the delivery of a com Exemplary haloalkyl groups include trifluoromethyl, chlo pound by passage through the skin and into the blood romethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the Stream. like. US 2004/0072883 A1 Apr. 15, 2004

0.042 “Alkenyl' refers to a branched or straight chain alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamido, C-Co hydrocarbon (preferably a C-C hydrocarbon, more alkylcarboxamido, arylcarboxamido, Sulfonic acid, Sulfonic preferably2 a C-C hydrocarbon) that can comprise one or ester, Sulfonamido and nitro. Exemplary heterocyclic groups more carbon-carbon double bonds. Exemplary alkenyl include pyrrolyl, furyl, thienyl, 3-pyrrolinyl, 4,5,6-trihydro groups include propylenyl, buten-1-yl, isobutenyl, penten 2H-pyranyl, pyridinyl, 1,4-dihydropyridinyl, pyrazolyl, tria 1-yl, 2.2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl, Zolyl, pyrimidinyl, pyridaZinyl, oxazolyl, thiazolyl, imida hepten-1-yl, octen-1-yl, and the like. Zolyl, indolyl, thiophenyl, furanyl, tetrhydrofuranyl, tetrazolyl, pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-diox 0.043 “Lower alkenyl” refers to a branched or straight olanyl, imidazolinyl, imidazolindinyl, pyrazolinyl, pyrazo chain C-C hydrocarbon that can comprise one or two lidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3- carbon-carbon double bonds. triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, 0044) “Substituted alkenyl' refers to a branched or piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thio Straight chain C-Co hydrocarbon (preferably a C-Cs morpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5- hydrocarbon, more preferably a C-C hydrocarbon) which trithianyl, benzo(b)thiophenyl, benzimidazolyl, benzothiaz can comprise one or more carbon-carbon double bonds, olinyl, quinolinyl, and the like. wherein one or more of the hydrogen atoms have been 0049) “Heterocyclic compounds” refer to mono- and replaced with one or more R' groups, wherein each R' polycyclic compounds comprising at least one aryl or het is independently a hydroxy, an OXO, a carboxyl, a carboxa erocyclic ring. mido, a halo, a cyano or an amino group, as defined herein. 0.045 “Alkynyl refers to an unsaturated acyclic C-Co 0050 “Aryl” refers to a monocyclic, bicyclic, carbocy hydrocarbon (preferably a C-C hydrocarbon, more prefer clic or heterocyclic ring System comprising one or two ably a C-C hydrocarbon) that can comprise one or more aromatic rings. Exemplary aryl groups include phenyl, carbon-carbon triple bonds. Exemplary alkynyl groups pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl, inda include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1- nyl, indenyl, indoyl, and the like. Aryl groups (including yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl, bicyclic aryl groups) can be unsubstituted or Substituted with one, two or three Substituents independently Selected from hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like. alkyl, alkoxy, alkylthio, amino, alkylamino, dialkylamino, 0046) “Bridged cycloalkyl” refers to two or more arylamino, diarylamino, alkylarylamino, halo, cyano, alkyl cycloalkyl groups, heterocyclic groups, or a combination Sulfinyl, hydroxy, carboxyl, carboxylic ester, alkylcarboxy thereof fused via adjacent or non-adjacent atoms. Bridged lic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, cycloalkyl groups can be unsubstituted or Substituted with arylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, one, two or three Substituents independently Selected from ester, carboxamido, alkylcarboxamido, carbomyl, Sulfonic alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, acid, Sulfonic ester, Sulfonamido and nitro. Exemplary Sub halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, Stituted aryl groups include tetrafluorophenyl, pentafluo alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo rophenyl, Sulfonamide, alkylsulfonyl, arylsulfonyl, and the and nitro. Exemplary bridged cycloalkyl groups include like. adamantyl, decahydronapthyl, quinuclidyl, 2,6- dioxabicyclo(3.3.0)octane, 7-Oxabycyclo(2.2.1)heptyl, 0051) “Cycloalkenyl” refers to an unsaturated cyclic 8-azabicyclo(3,2,1)Oct-2-enyl and the like. C-Clio hydrocarbon (preferably a C-Cs hydrocarbon, more preferably a C-C hydrocarbon) which can comprise one or 0047 “Cycloalkyl” refers to a saturated or unsaturated more carbon-carbon triple bonds. cyclic hydrocarbon comprising from about 3 to about 10 carbon atoms. Cycloalkyl groups can be unsubstituted or 0052 “Alkylaryl” refers to an alkyl group, as defined substituted with one, two or three substituents independently herein, to which is appended an aryl group, as defined Selected from alkyl, alkoxy, amino, alkylamino, dialky herein. Exemplary alkylaryl groups include benzyl, phenyl lamino, arylamino, diarylamino, alkylarylamino, aryl, ethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, the like. alkylcarboxylic ester, carboxamido, alkylcarboxamido, OXO, alkylsulfinyl, and nitro. Exemplary cycloalkyl groups 0053 “Arylalkyl” refers to an aryl radical, as defined herein, attached to an alkyl radical, as defined herein. include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Exemplary arylalkyl groups include benzyl, phenylethyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. 4-hydroxybenzyl, 3-fluorobenzyl, 2-fluorophenylethyl, and 0.048 “Heterocyclic ring or group” refers to a saturated or the like. unsaturated cyclic hydrocarbon group having about 2 to about 10 carbon atoms (preferably about 4 to about 6 carbon 0054 “Arylalkenyl' refers to an aryl radical, as defined atoms) where 1 to about 4 carbon atoms are replaced by one herein, attached to an alkenyl radical, as defined herein. or more nitrogen, oxygen and/or Sulfur atoms. Sulfur maybe Exemplary arylalkenyl groups include Styryl, propenylphe in the thio, sulfinyl or sulfonyl oxidation state. The hetero nyl, and the like. cyclic ring or group can be fused to an aromatic hydrocarbon 0055 “Cycloalkylalkyl” refers to a cycloalkyl radical, as group. Heterocyclic groups can be unsubstituted or Substi defined herein, attached to an alkyl radical, as defined tuted with one, two or three Substituents independently herein. Selected from alkyl, alkoxy, amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, OXO, thial, halo, carboxyl, car 0056 “Cycloalkylalkoxy' refers to a cycloalkyl radical, boxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, as defined herein, attached to an alkoxy radical, as defined aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester, herein. US 2004/0072883 A1 Apr. 15, 2004

0057 “Cycloalkylalkylthio” refers to a cycloalkyl radi 0.071) “Hydroxy” refers to -OH. cal, as defined herein, attached to an alkylthio radical, as defined herein. 0.072 “Oxo” refers to =O. 0.073 “Oxy” refers to -OR," wherein R, is an 0.058 “Heterocyclicalkyl” refers to a heterocyclic ring organic or inorganic cation. radical, as defined herein, attached to an alkyl radical, as 0.074) “Oxime” refers to =N-OR wherein Rs is a defined herein. hydrogen, an alkyl group, an aryl group, an alkylsulfonyl 0059) “Arylheterocyclic ring” refers to a bi- or tricyclic group, an arylsulfonyl group, a carboxylic ester, an alkyl ring comprised of an aryl ring, as defined herein, appended carbonyl group, an arylcarbonyl group, a carboxamido via two adjacent carbon atoms of the aryl ring to a hetero group, an alkoxyalkyl group or an alkoxyaryl group. cyclic ring, as defined herein. Exemplary arylheterocyclic 0075) “Hydrazone refers to =N-N(Rs)(R's) wherein rings include dihydroindole, 1,2,3,4-tetrahydroquinoline, Risindependently selected from Rs, and Rs is as defined and the like. herein. 0060 “Alkylheterocyclic ring” refers to a heterocyclic 0076 “Organic cation” refers to a positively charged ring radical, as defined herein, attached to an alkyl radical, organic ion. Exemplary organic cations include alkyl Sub as defined herein. Exemplary alkylheterocyclic rings include Stituted ammonium cations, and the like. 2-pyridylmethyl, 1-methylpiperidin-2-one-3-methyl, and 0077. “Inorganic cation” refers to a positively charged the like. metal ion. Exemplary inorganic cations include Group I 0061 “Alkoxy' refers to RO-, wherein Rs is an alkyl metal cations Such as for example, Sodium, potassium, and group, as defined herein (preferably a lower alkyl group or the like. a haloalkyl group, as defined herein). Exemplary alkoxy 0078 “Hydroxyalkyl refers to a hydroxy group, as groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, defined herein, appended to an alkyl group, as defined trifluoromethoxy, and the like. herein. 0.062 “Aryloxy' refers to RO-, wherein Rss is an aryl 0079) “Nitrate” refers to -O-NO. group, as defined herein. Exemplary arylkoxy groups include napthyloxy, quinolyloxy, isoquinolizinyloxy, and the 0080 “Nitrite” refers to -O-NO. like. 0081) “Thionitrate” refers to -S-NO. 0063 “Alkylthio" refers to RS -, wherein Rso is an 0082) “Thionitrite” and “nitrosothiol” refer to -S-NO. alkyl group, as defined herein. 0083) “Nitro” refers to the group-NO and “nitrosated” 0.064 “Lower alkylthio” refers to a lower alkyl group, as refers to compounds that have been substituted therewith. defined herein, appended to a thio group, as defined herein. 0084) “Nitroso" refers to the group -NO and “nitrosy 0065 “Arylalkoxy” or “alkoxyaryl” refers to an alkoxy lated” refers to compounds that have been substituted there group, as defined herein, to which is appended an aryl group, with. as defined herein. Exemplary arylalkoxy groups include 0085 “Nitrile” and “cyano” refer to -CN. benzyloxy, phenylethoxy, chlorophenylethoxy, and the like. 0086) “Halogen” or “halo” refers to iodine (I), bromine 0.066 “Alkoxyalkyl” refers to an alkoxy group, as (Br), chlorine (Cl), and/or fluorine (F). defined herein, appended to an alkyl group, as defined 0087 “Amino” refers to -NH2, an alkylamino group, a herein. Exemplary alkoxyalkyl groups include methoxym dialkylamino group, an arylamino group, a diarylamino ethyl, methoxyethyl, isopropoxymethyl, and the like. group, an alkylarylamino group or a heterocyclic ring, as 0067 “Alkoxyhaloalkyl” refers to an alkoxy group, as defined herein. defined herein, appended to a haloalkyl group, as defined 0088 “Alkylamino” refers to RONH-, wherein Rs is herein. Exemplary alkoxyhaloalkyl groups include 4-meth an alkyl group, as defined herein. Exemplary alkylamino oxy-2-chlorobutyl and the like. groups include methylamino, ethylamino, butylamino, cyclohexylamino, and the like. 0068 “Cycloalkoxy” refers to RO-, wherein Rs is a cycloalkyl group or a bridged cycloalkyl group, as defined 0089) “Arylamino” refers to RsNH-, wherein Rss is an herein. Exemplary cycloalkoxy groups include cyclopropy aryl group, as defined herein. loxy, cyclopentyloxy, cyclohexyloxy, and the like. 0090 “Dialkylamino” refers to RsRN-, wherein Rs. 0069. “Cycloalkylthio’ refers to RS-, wherein Rs is and Rs are each independently an alkyl group, as defined a cycloalkyl group or a bridged cycloalkyl group, as defined herein. Exemplary dialkylamino groups include dimethy herein. Exemplary cycloalkylthio groups include cyclopro lamino, diethylamino, methyl propargylamino, and the like. pylthio, cyclopentylthio, cyclohexylthio, and the like. 0091 “Diarylamino” refers to RssRN-, wherein Rss 0070 "Haloalkoxy' refers to an alkoxy group, as defined and Reo are each independently an aryl group, as defined herein, in which one or more of the hydrogen atoms on the herein. alkoxy group are Substituted with halogens, as defined 0092 “Alkylarylamino or arylalkylamino” refers to herein. Exemplary haloalkoxy groups include 1,1,1-trichlo RRsN-, wherein Rs is an alkyl group, as defined herein, roethoxy, 2-bromobutuoxy, and the like. and Rss is an aryl group, as defined herein. US 2004/0072883 A1 Apr. 15, 2004

0.093 “Alkylarylalkylamino” refers to RsRN-, 0113 “Alkylsulfonyl” refers to Rso S(O), wherein wherein Rs is an alkyl group, as defined herein, and Rio is R is an alkyl group, as defined herein. an arylalkyl group, as defined herein. 0114) “Alkylsulfonyloxy” refers to Rso S(O)-O-, 0094) “Alkylcycloalkylamino” refers to Rs.RON wherein Rso is an alkyl group, as defined herein. wherein Rs is an alkyl group, as defined herein, and Rs is an cycloalkyl group, as defined herein. 0115 “Arylsulfinyl" refers to Rss-S(O), wherein Rss is an aryl group, as defined herein. 0.095 “Aminoalkyl” refers to an amino group, an alky lamino group, a dialkylamino group, an arylamino group, a 0116 “Arylsulfonyl” refers to Rss-S(O), wherein diarylamino group, an alkylarylamino group or a heterocy R is an aryl group, as defined herein. clic ring, as defined herein, to which is appended an alkyl 0117 “Arylsulfonyloxy” refers to Rss-S(O)-O-, group, as defined herein. Exemplary aminoalkyl groups wherein Rss is an aryl group, as defined herein. include dimethylaminopropyl, diphenylaminocyclopentyl, methylaminomethyl, and the like. 0118 “Amidyl” refers to RC(O)N(Rs.)- wherein Rs and Rs, are each independently a hydrogen atom, an alkyl 0.096 “Aminoaryl” refers to an aryl group to which is group, an aryl group or an arylheterocyclic ring, as defined appended an alkylamino group, a arylamino group or an herein. arylalkylamino group. Exemplary aminoaryl groups include anilino, N-methylanilino, N-benzylanilino, and the like. 0119) “Ester” refers to RC(O)O- wherein Rs is a hydrogen atom, an alkyl group, an aryl group or an arylhet 0097. “Thio” refers to -S- erocyclic ring, as defined herein. 0098 “Sulfinyl” refers to -S(O)-. 0120 “Carbamoyl” refers to -O-C(O)N(Rs.)(Rs), 0099 “Methanthial” refers to -C(S)-. wherein Rs and Rs 7 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic 01.00 “Thial” refers to =S. ring, as defined herein, or Rs and Rs 7 taken together are a 0101) “Sulfonyl” refers to -S(O). heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein. 0102 "Sulfonic acid” refers to -S(O), OR, wherein R is a hydrogen, an organic cation or an inorganic cation, 0121 “Carboxyl” refers to -C(O)OR7, wherein R is as defined herein. a hydrogen, an organic cation or an inorganic cation, as 0103 “Alkylsulfonic acid” refers to a sulfonic acid defined herein. group, as defined herein, appended to an alkyl group, as 0122 Carbonyl” refers to -C(O)-. defined herein. 0123 “Alkylcarbonyl” refers to Rs-C(O), wherein 0104 " Arylsulfonic acid” refers to a sulfonic acid group, R is an alkyl group, as defined herein. as defined herein, appended to an aryl group, as defined 012.4 "Arylcarbonyl” refers to Rss-C(O), wherein herein R is an aryl group, as defined herein. 0105 "Sulfonic ester” refers to -S(O)ORss, wherein R is an alkyl group, an aryl group, or an aryl heterocyclic 0125 "Arylalkylcarbonyl” refers to Rss-Rs-C(O), wherein Rss is an aryl group, as defined herein, and Rs is ring, as defined herein. an alkyl group, as defined herein. 0106 “Sulfonamido” refers to -S(O)-N(Rs.)(Rs), wherein Rs and Rs 7 are each independently a hydrogen 0126 “Alkylarylcarbonyl” refers to R-R-C(O), atom, an alkyl group, an aryl group or an arylheterocyclic wherein Rss is an aryl group, as defined herein, and Rs is ring, as defined herein, or Rs and Rs7 when taken together an alkyl group, as defined herein. are a heterocyclic ring, a cycloalkyl group or a bridged 0127) “Heterocyclicalkylcarbonyl” refer to RC(O)- cycloalkyl group, as defined herein. wherein Rs is a heterocyclicalkyl group, as defined herein. 0107 “Alkylsulfonamido” refers to a sulfonamido group, 0128 “Carboxylic ester” refers to -C(O)ORss, wherein as defined herein, appended to an alkyl group, as defined Rss is an alkyl group, an aryl group or an arylheterocyclic herein. ring, as defined herein. 0108 “Arylsulfonamido” refers to a sulfonamido group, 0129. “Alkylcarboxylic acid” and “alkylcarboxyl” refer as defined herein, appended to an aryl group, as defined to an alkyl group, as defined herein, appended to a carboxyl herein. group, as defined herein. 0109) “Alkylthio” refers to ROS-, wherein Rs is an 0.130 “Alkylcarboxylic ester” refers to an alkyl group, as alkyl group, as defined herein (preferably a lower alkyl defined herein, appended to a carboxylic ester group, as group, as defined herein). defined herein. 0110 "Arylthio” refers to RS-, wherein Rs is an aryl 0131 “Arylcarboxylic acid” refers to an aryl group, as group, as defined herein. defined herein, appended to a carboxyl group, as defined 0111 “Arylalkylthio’ refers to an aryl group, as defined herein. herein, appended to an alkylthio group, as defined herein. 0132) “Arylcarboxylic ester” and “arylcarboxyl” refer to 0112 “Alkylsulfinyl” refers to Rso-S(O), wherein an aryl group, as defined herein, appended to a carboxylic R is an alkyl group, as defined herein. ester group, as defined herein. US 2004/0072883 A1 Apr. 15, 2004

0133) “Carboxamido” refers to -C(O)N(Rs)(Rs), These novel compounds and novel compositions of the wherein Rs and Rs 7 are each independently a hydrogen present invention are described in more detail herein. atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or Rs and Rs, when taken together 0.141. In one embodiment, the invention describes are a heterocyclic ring, a cycloalkyl group or a bridged COX-2 inhibitors of Formula (I), and pharmaceutically cycloalkyl group, as defined herein. acceptable Salts thereof: 0134) “Alkylcarboxamido” refers to an alkyl group, as defined herein, appended to a carboxamido group, as defined herein. 0135 “Arylcarboxamido” refers to an aryl group, as defined herein, appended to a carboxamido group, as defined herein. 0136 “Urea” refers to -N(Rs.)-C(O)N(Rs)(Rs.) wherein Rs, Rs7, and Rso are each independently a hydro gen atom, an alkyl group, an aryl group or an arylhetero cyclic ring, as defined herein, or Rs and Rs, taken together are a heterocyclic ring, a cycloalkyl group or a bridged 0142 wherein: cycloalkyl group, as defined herein. 0.143 when side b is a double bond, and sides a and care single bonds, -X-Y-Z'- is: 0137) “Phosphoryl” refers to -P(R)(R)(R), wherein Rio is a lone pair of electrons, thial or OXO, and R7 and R7 are each independently a covalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, a hydroxy, an oxy or an aryl, as defined herein. 0138 “Silyl” refers to -Si(R)(R)(Rs), wherein Rz, R7 and R7s are each independently a covalent bond, a lower alkyl, an alkoxy, an aryl or an arylalkoxy, as defined herein. 013:9 Compounds that donate, transfer or release nitric oxide Species in Vivo have been recognized as having a wide Spectrum of advantages and applications. The invention is based on the unexpected discovery of the effects of Such compounds alone and together with one or more COX-2 inhibitors. Treatment or prevention of inflammation, pain and fever, treatment of gastrointestinal disorders and/or improvement of the gastrointestinal properties of COX-2 inhibitors, facilitation of wound healing, and treatment and/or prevention of renal and/or respiratory toxicity and cyclooxygenase-2 mediated disorders can be obtained by the use of COX-2 inhibitors of the invention; or by the use of COX-2 inhibitors in conjunction with one or more com pounds that donate, release or transfer nitric oxide and/or stimulate endogenous production of NO and/or EDRF in Vivo and/or is a Substrate for nitric oxide Synthase, and, optionally, with one or more therapeutic agents. 0140. The COX-2 selective inhibitors, that are optionally nitrosated and/or nitrosylated, can be used alone or in conjunction with one or more compounds that donate, release or transfer nitric oxide and/or Stimulate endogenous production of NO and/or EDRF in vivo and/or is a substrate for nitric oxide Synthase, and/or with one or more therapeu tic agents, Such as for example, Steroids, nonsterodal anti inflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B (LTB) receptor antagonists, leu kotriene A (LTA) hydrolase inhibitors, 3-hydroxy-3-me thylglutaryl coenzyme A(HMG-CoA) inhibitors, Hantago nists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, Sedating or non-Sedating anti-histamines, inducible nitric oxide Synthase inhibitors, opioids, analgesics, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, iso prostane inhibitors, and mixtures of two or more thereof. US 2004/0072883 A1 Apr. 15, 2004

0173 0215) 0174) 0216) 0175) 0217) 0176) 0218) 0.177 0219) 0178) O220) 0179 0221) 0180) 0222 0181) 0223) R' at each occurrence is independently: 0182 0224 (a) hydrogen; 0183) 0225 (b) halogen; 0226 (c) methyl; or 0185 0227 (d) CH-OH: 0186 0228) R is: 0187. 0229 (a) lower alkyl; 0188) 0230 (b) cycloalkyl; 0189) 0231 (c) mono-, di- or tri-substituted phenyl or 0.190) naphthyl, wherein the Substituents are each inde 0191) pendently: 0.192 0232) (1) hydrogen; 0193) 0233 (2) halo; 0.194 0234) (3) alkoxy; 0195 0235) (4) alkylthio; 0196) 0236 (5) CN: 0197) when Sides a and c are double bonds and 0237) (6) haloalkyl, preferably CF; side b is a single bond, -X-Y-Z'- is: 0238) (7) lower alkyl; 0198) 0239) (8) Na; 0.199) 0240 (9) -COD'; 0200) 0241) (10) -CO-lower alkyl; 0201) 0242 (11)–(C(R)(R))-OD'; 0202) 0243) (12) -(C(R)(R)), O-lower alkyl; 0203) 0244) (13) lower alkyl-CO-R; 0204) 0245) 0205) (14) —OD'; (15) haloalkoxy; 0206 0246 0207 0247 (16) amino; 0208) 0248 (17) nitro; 0209) 0249) (18) alkylsulfinyl; or 0210) 0250) (19) heteroaryl; 0251 (d) mono-, di- or tri-substituted heteroaryl, 0211) R' is: wherein the heteroaryl is a monocyclic aromatic 0212 (a) -S(O)-CH; ring of 5 atoms, Said ring having one heteroatom which is S, O, or N, and, optionally, 1, 2, or 3 0213) (b) -S(O)-NR(D"); additional N atoms, or the heteroaryl is a mono 0214) (c) -S(O)-N(D)-C(O)-CF; cyclic ring of 6 atoms, said ring having one US 2004/0072883 A1 Apr. 15, 2004 10

heteroatom which is N, and, optionally, 1, 2, 3, or a carbonyl group or a Sulfonyl group, and wherein 4 additional Natoms; wherein the Substituents are Said Substituents are each independently: each independently: 0288 (1) halo; 0252 (1) hydrogen; 0289 (2) lower alkyl; 0253) (2) halo; 0290 (3) alkoxy; 0254 (3) lower alkyl; 0291 (4) alkylthio; 0255 (4) alkoxy; 0292 (5) CN: 0256 (5) alkylthio; 0293 (6) haloalkyl, preferably CF; 0257 (6) CN: 0294 (7) N.; 0258 (7) haloalkyl, preferably CF; 0295 (8)-C(R)(R)-OD'; 0259 (8) N.; 0296 (9) –C(R')(R)-O-lower alkyl; or 0260 (9) –C(R)(R)-OD'; 0297 (10) alkylsulfinyl; 0261 (10) –C(R)(R)-O-lower alkyl; or 0298 (n) styryl, mono or di-substituted styryl, 0262 (11) alkylsulfinyl; wherein the Substituent are each independently: 0263 (e) benzoheteroaryl which includes the 0299 (1) halo; benzo fused analogs of (d); 0300 (2) alkoxy; 0264 (f) -NR'OR'; 0301 (3) alkylthio; 0265 (g) –SR'; 0302) (4) CN: 0266 (h)-OR'; 0303 (5) haloalkyl, preferably CF; 0267 (i) -R'; 0304 (6) lower alkyl; 0268) () alkenyl; O305 (7) N.; 0269 (k) alkynyl; 0306 (8) –COD'; 0270 (I) unsubstituted, mono-, di-, tri- or tetra Substituted cycloalkenyl, wherein the Substituents 0307 (9) -CO-lower alkyl; are each independently: 0308 (10) -C(R)(R)-OD'; 0271 (1) halo; 0309 (11) –C(R)(R)-O-lower alkyl; 0272 (2) alkoxy; 0310 (12) lower alkyl-CO-R'; 0273 (3) alkylthio; 0311 (13) benzyloxy; 0274 (4) CN: 0312 (14) -O-(lower alkyl)-COR'; or 0275 (5) haloalkyl, preferably CF; 0313 (15) -O-(lower alkyl)-NR'R'; 0276 (6) lower alkyl; 0314 (o) phenylacetylene, mono- or di-substi 0277 (7) N.; tuted phenylacetylene, wherein the Substituents are each independently: 0278 (8) –COD'; 0279 (9) -CO-lower alkyl; 0315 (1) halo; 0316 (2) alkoxy; 0280 (10) –C(R)(R)-OD'; 0281 (11) –C(R')(R)-O-lower alkyl; 0317 (3) alkylthio; 0282 (12) lower alkyl-CO-R'; 0318 (4) CN: 0319 (5) haloalkyl, preferably CF; 0283 (13) benzyloxy; 0284 (14) -O-(lower alkyl)-COR; 0320 (6) lower alkyl; 0285) (15) -O-(lower alkyl)-NR'R'; or 0321 (7) N.; 0286 (16) alkylsulfinyl; 0322 (8) –COD'; 0323 (9) -CO-lower alkyl; 0287) (m) mono-, di-, tri- or tetra-substituted het erocycloalkyl group of 5, 6 or 7 members, or a 0324 (10) –C(R)(R')–OD'; benzoheterocycle, wherein Said heterocycloalkyl or benzoheterocycle contains 1 or 2 heteroatoms 0325 (11) –C(R)(R)-O-lower alkyl; Selected from O, S, or N and, optionally, contains 0326 (12) lower alkyl-CO-R'; US 2004/0072883 A1 Apr. 15, 2004 11

0327 (13) benzyloxy; 0367) (3) lower alkyl-S-lower alkyl-Q; 0328) (14)14) -O-(lower( alkvl)-COR':yl)-COR'; or 0368) (4) lower alkyl-O-Q; 0329 (15) -O-(lower alkyl)-NR'R'; 0369) (5) lower alkyl-S-Q; 0330 (p) fluoroalkenyl; 0370 (6) lower alkyl-O-V; 0331 (q) mono- or di-substituted bicyclic het 0371) (7) lower alkyl-S-V; eroaryl of 8, 9 or 10 members, containing 2, 3, 4 or 5 heteroatoms, wherein at least one heteroatom 0372) (8) lower alkyl-O-K; or resides on each ring of Said bicyclic heteroaryl, 0373) (9) lower alkyl-S-K; Said heteroatoms are each independently O, S and 0374) wherein the substituent(s) reside on the N and Said Substituents are each independently: lower alkyl group; (1) hydrogen; 0332) 0375) (h) Q; 0333) (2) halo; 0376) (i) alkylcarbonyl, 0334) (3) lower alkyl; 0377) (j) arylcarbonyl, 0335) (4) alkoxy, 0378) (k) alkylarylcarbonyl, 0336) (5) alkylthio; 0379) (l) arylalkylcarbonyl; 0337) (6) CN: 0380 (m) carboxylic ester; 0338) (7) haloalkyl, preferably CF; 0381) (n) carboxamido; 0339 (8) Na; 0382) (o) cycloalkyl, 0340) (9) –C(R)(R)-OD'; or 0383) (p) mono-, di- or tri-Substituted phenyl or 0341 (10) -C(R)(R)-O-lower alkyl; naphthyl, wherein the Substituents are each inde pendently: 0342 (r) K; 0343) (s) aryl; 0384) (1) hydrogen; 0344) (t) arylalkyl, 0385) (2) halo; 0345) (u) cycloalkylalkyl, 0386) (3) alkoxy; 0346) (v) –C(O)R'; 0387) (4) alkylthio; 0347) (u) hydrogen; 0388 (5) CN: 0348 (V) arylalkenyl; 0389) (6) haloalkyl, preferably CF; 0349) (w) arylalkoxy, 0390) (7) lower alkyl; 0350 (x) alkoxy; 0391) (8) Na; 0351) (y) aryloxy; 0392) (9) -COD'; O352 (Z) cycloalkoxy; 0393) (10) -CO-lower alkyl; 0353) (aa) arylthio; 0394) (11)–(C(R)(R))-OD'; 0354) (bb) alkylthio; 0395) (12) -(C(R)(R))-O-lower alkyl; 0355) (cc) arylalkylthio; or 0396) (13) lower alkyl-CO-R; 0356) (dd) cycloalkylthio; 0397) (14) —OD'; 0357 R is: 0398) (15) haloalkoxy; 0358) (a) hydrogen; 0399) (16) amino; 0359 (b) haloalkyl, preferably CF; 04.00 (17) nitro; or 0360) (c) CN; 0401) (18) alkylsulfinyl; 0361) (d) lower alkyl; 0402 (q) alkenyl; 0362 (e) -(C(R)(R))-U-V; 0403) (r) alkynyl; 0363) (f) K; 04.04 (S) arylalkyl, 0364 (g) unsubstituted or Substituted: 0405 (t) lower alkyl-OD'; 0365) (1) lower alkyl-Q; 0406) (u) alkoxyalkyl, 0366) (2) lower alkyl-O- lower alkyl-Q; 0407 (v) aminoalkyl, US 2004/0072883 A1 Apr. 15, 2004 12

0408 (w) lower alkyl-COR'; 0443) (6) haloalkyl, preferably CF; 0409 (x) lower alkyl-C(O)NR'(R'); 0444 (7) N.; 0410 (y) heterocyclicalkyl; or 0445) (8) –C(R)(R7)–OD'; 0411 (z) heterocyclic ring-C(O)-; 0446) (9)-C(R)(R)-O-lower alkyl; or 0412 R", R", R and R are each independently: 0447) (10) alkylsulfinyl 0413 (a) hydrogen; 0448 (p) –CON(R)(R); 0414 (b) amino; 0449) (q)-CHOR; 0415 (c) CN: 0450 (r) -CHOCN; 0416) (d) lower alkyl; 0451) (s) unsubstituted or substituted: 0417 (e) haloalkyl; 0452) (1) lower alkyl-Q; 0418 (f) alkoxy; 0453 (2) -O-lower alkyl-Q; 0419 (g) alkylthio; 0454) (3) -S-lower alkyl-Q; 0420 (h) Q; 0455) (4) lower alkyl-O-lower alkyl-Q; 0421 (i) -O-Q; 0456) (5) lower alkyl-S-lower alkyl-Q; 0422 () -S-Q; 0457) (6) lower alkyl-O-Q; 0423) (k) K; 0458) (7) lower alkyl-S-Q; 0424 (l) cycloalkoxy; 0459) (8) lower alkyl-O-K; 0425 (m) cycloalkylthio; 0460) (9) lower alkyl-S-K; 0426 (n) unsubstituted, mono-, or di-substituted 0461) (10) lower alkyl-O-V; or phenyl or unsubstituted, mono-, or disubstituted benzyl, wherein the Substituents are each indepen 0462) (11) lower alkyl-S-V; dently: 0463 wherein the substituent(s) resides on the 0427 (1) halo; lower alkyl; 0428 (2) lower alkyl; 0464) (t) cycloalkyl, 0429 (3) alkoxy; 0465 (u) aryl; 0430 (4) alkylthio; 0466) (v) arylalkyl; 0431 (5) CN: 0467) (w) cycloalkylalkyl, 0432 (6) haloalkyl, preferably CF; 0468 (x) aryloxy; 0433 (7) N.; 0469 (y) arylalkoxy; 0434 (8) Q; 0470) (Z) arylalkylthio; 0435 (9) nitro; or 0471) (aa) cycloalkylalkoxy, 0436 (10) amino; 0472) (bb) heterocycloalkyl; 0437 (o) unsubstituted, mono-, or di-substituted 0473) (cc) alkylsulfonyloxy; heteroaryl or unsubstituted, mono-, or di-Substi 0474) (dd) alkylsulfonyl; tuted heteroarylmethyl, wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, Said ring 0475 (ee) arylsulfonyl, having one heteroatom which is S, O, or N, and, (f) arylsulfonyloxy; optionally, 1, 2, or 3 additional N atoms, or the 0476) heteroaryl is a monocyclic ring of 6 atoms, said 0477) (gg) -C(O)R'; ring having one heteroatom which is N, and, optionally, 1, 2, 3, or 4 additional N atoms, said 0478) (hh) nitro; Substituents are each independently: 0479) (ii) amino; 0438 (1) halo; 0480 (ii) aminoalkyl, 0439 (2) lower alkyl; 0481) (kk) -C(O)-alkyl-heterocyclic ring; 0440 (3) alkoxy; 0482 (l) halo; 0441 (4) alkylthio; 0483) (mm) heterocyclic ring; 0442 (5) CN: 0484) (nn) -COD'; US 2004/0072883 A1 Apr. 15, 2004 13

0485 (oo) carboxyl; 0519 R is: 0486 (pp) amidyl; or 0520 (a) hydrogen; 0487 (qq) alkoxyalkyl; 0521 (b) K; or 0488 alternatively, R" and R together with the 0522 (c) R; carbons to which they are attached are: 0523 alternatively, R and R, R and R7 or R' and R together with the carbon to which they are 0489 (a) cycloalkyl; attached form a Saturated monocyclic ring of 3, 4, 5, 0490 (b) aryl; or 6 or 7 atoms, optionally containing up to two het 0491 (c) heterocyclic ring; eroatoms Selected from Oxygen, S(O) or NR; 0492) alternatively, R' and R' or RandR taken 0524) R is: together with the carbon to which they are attached 0525) (a) lower alkyl; C. 0526 (b) lower alkyl-COD'; 0493 (a) cycloalkyl; or 0527 (c) lower alkyl-NHD; 0494 (b) heterocyclic ring; 0528) (d) phenylenyl or mono-, di-di or tri-Substitutei-Substituted 0495) alternatively, R' and R,R" and R,R" and phenyl, wherein the Substituents are each indepen R", or R" and R when substituents on adjacent dently: carbon atoms taken together with the carbons to 0529 (1) halo; which they are attached are: 0530 (2) lower alkyl; 0496 (a) cycloalkyl; 0531 (3) alkoxy; 0497 (b) heterocyclic ring; or 0532 (4) alkylthio; 0498 (c) aryl; 0533 (5) lower alkyl-COD'; 0499 R and R7 are each independently: 0534 (6) lower alkyl-NHD'; 0500 (a) hydrogen; 0535 (7) CN: 0501 (b) unsubstituted, mono- or di-substituted 0536 (8) COD'; or phenyl; unsubstituted, mono- or disubstituted ben Zyl; unsubstituted, mono- or di-Substituted het 0537) (9) haloalkyl, preferably fluoroalkyl; eroaryl; mono- or di-Substituted heteroarylmethyl, 0538 (e) benzyl, mono-, di- or tri-substituted wherein Said Substituents are each independently: benzyl, wherein the Substituents are each indepen 0502 (1) halo; dently: 0503) (2) lower alkyl; 0539 (1) halo; 0504 (3) alkoxy; 0540 (2) lower alkyl; 0541 (3) alkoxy; 0505) (4) alkylthio; 0542 (4) alkylthio; 0506 (5) CN: 0543 (5) lower alkyl-COD'; 0507 (6) haloalkyl, preferably CF; 0544 (6) lower alkyl-NHD; 0508) (7) N.; 0545 (7) CN: 0509 (8)-C(R')(R)-OD'; or 0546) (8) -COD'; or 0510 (9) –C(R')(R')–O-lower alkyl; 0547 (9) haloalkyl, preferably CF; 0511 (c) lower alkyl; 0548 (f) cycloalkyl; 0512 (d) –CHOR; 0549 (g) K; or 0513 (e) CN: 0550 (h) benzoyl, mono-, di-, or trisubstituted benzoyl, wherein the Substituents are each inde 0514) (f) –CHCN: pendently: 0515 (g) haloalkyl, preferably fluoroalkyl; 0551 (1) halo; 0516 (h)-CON(R)(R); 0552) (2) lower alkyl; 0517 (i) halo; or 0553 (3) alkoxy; 0518) () –OR; 0554 (4) alkylthio; US 2004/0072883 A1 Apr. 15, 2004

0555 (5) lower alkyl-COD'; 0591 (7) N.; 0556 (6) lower alkyl-NHD'; 0592 (8) –C(R)(R')–OD'; or 0557 (7) CN: 0593 (9) –C(R)(R)-O-lower alkyl; 0558 (8) –COD'; or 0594 (e) unsubstituted, mono- or di-substituted benzoheterocycle, wherein the benzoheterocycle 0559) (9) haloalkyl, preferably CF; is a 5, 6, or 7-membered ring which contains 1 or 0560) R' and R'' are each independently: 2 heteroatoms independently Selected from O, S, or N, and, optionally, a carbonyl group or a 0561 (a) hydrogen; or Sulfonyl group, wherein Said Substituents are each 0562 (b) R'; independently: 0563) R' is: 0595 (1) halo; 0564 (a) lower alkyl; 0596) (2) lower alkyl; 0565 (b) cycloalkyl; 0597 (3) alkoxy; 0566 (c) unsubstituted, mono-, di- or tri-substi 0598 (4) alkylthio; tuted phenyl or naphthyl, wherein the Substituents are each independently: 0599 (5) CN: 0567 (1) halo; 0600 (6) haloalkyl, preferably CF; 0568 (2) alkoxy; 0601 (7) N.; 0569 (3) alkylthio; 0602 (8) –C(R)(R')–OD'; or 0570) (4) CN: 0603 (9) –C(R')(R)-O-lower alkyl; 0604 (f) unsubstituted, mono- or di-substituted 0571 (5) haloalkyl, preferably CF; benzocarbocycle, wherein the carbocycle is a 5, 6, 0572 (6) lower alkyl; or 7-membered ring which optionally contains a carbonyl group, wherein Said Substituents are each 0573 (7) N.; independently: 0574 (8) –COD'; 0605 (1) halo; 0575 (9) -CO-lower alkyl; 0606 (2) lower alkyl; 0576 (10) -C(R)(R)-OD; 0607 (3) alkoxy; 0577 (11) –C(R)(R)-O-lower alkyl; 0608 (4) alkylthio; 0578 (12) lower alkyl-COD'; 0609 (5) CN: 0579 (13) lower alkyl-COR; 0610 (6) haloalkyl, preferably CF; 0580 (14) benzyloxy; 0611 (7) N.; 0581) (15) -O-(lower alkyl)-COD'; 0612 (8) –C(R)(R')–OD'; or 0582 (16) -O-(lower alkyl)-COR'; or 0613) (9) –C(R')(R)-O-lower alkyl; 0583 (17) -O-(lower alkyl)-NR'R'; 0614 (g) hydrogen; or 0584) (d) unsubstituted, mono-, di- or tri-substi 0615 (h) K tuted heteroaryl, wherein the heteroaryl is a mono 0616) R' and R' are each independently: cyclic aromatic ring of 5 atoms, Said ring having one heteroatom which is S, O, or N, and, option 0617 (a) hydrogen; ally, 1, 2, or 3 additional N atoms, or Said het 0618) (b) lower alkyl; or eroaryl is a monocyclic ring of 6 atoms, Said ring having one heteroatom which is N, and, optionally 0619) (c) aryl; or 1, 2, or 3 additional N atoms, and wherein said 0620) R' and R' together with the atom to which Substituents are each independently: they are attached form a Saturated monocyclic ring of 0585 (1) halo; 3, 4, 5, 6 or 7 atoms; 0586 (2) lower alkyl; 0621) R' and R' are each independently: 0587 (3) alkoxy; 0622 (a) hydrogen; or 0588 (4) alkylthio; 0623) (b) lower alkyl; or 0624) R' and R together with the atom to which 0589 (5) CN: they are attached form a carbonyl, a thial, or a 0590 (6) haloalkyl, preferably CF; Saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms, US 2004/0072883 A1 Apr. 15, 2004 15

0625) Q is: 0666 D is: 0626 (a) –C(O)-U-D; 0667) (a) V; or 0627 (b) -CO-lower alkyl; 0668 (b) K; 0628 (c) tetrazolyl-5-yl; 0669 U is: 0629) (d) –C(R7)(R)(S-D); 0670 (a) oxygen; 0630 (e) –C(R)(R)(O-D); or 0671 (b) sulfur; or 0631 (f) –C(R)(R)(O-lower alkyl); 0672 (c) -N(R)(R)-; 0632 X is: 0673 V is: 0633 (a)-(CRR)-; 0674) (a) -NO; 0634 (b) –(CRR)-A"; 0675 (b) -NO; or 0635 (c) –A-(CRR)-; 0676 (c) hydrogen 0636) (d) - CRR2-ACR'R''. 0637 (e) –CR'=; or 0638 (f) -A; 0678 wherein aa, b, c, d, g, i and j are each 0639 A' is: independently an integer from 0 to 3; 0640 (a) oxygen; 0679 p. x, y and Z are each independently an integer from 0 to 10; 0641 (b) thio; 0680 W at each occurrence is independently: 0642 (c) sulfinyl; 0643 (d) sulfonyl; or 0681 (a) –C(O)-; 0644 (c) —N(R)-; 0682 (b) –C(S)-; 0645) R' and Rare each independently: 0683 (c) -T-; 0646 (a) hydrogen; 0684 (d) -(C(R)(R)) ; 0647 (b) lower alkyl; 0685 (e) alkyl; 0648 (c) substituted lower alkyl; 0686) (f) aryl; 0649) (d) lower alkoxy; 0687 (g) heterocyclic ring; 0650 (e) lower haloalkyl; or 0688 (h) arylheterocyclic ring, or 0651) (f) halo; or 0689) ()-(CH2CH2O). ; 0652) R' and R' taken together are; 0690 E at each occurrence is independently a -T- group, an alkyl group, an aryl group, a heterocyclic 0653 (a) oxo; ring, -(C(R)(R)) , an arylheterocyclic ring or 0654 (b) thial; -(CH2CH2O). ; 0655 (c) oxime; or 0691 h is an integer form 1 to 10; 0656 (d) hydrazone; 0692 q is an integer from 1 to 5; 0693 R and Rare each independently a hydrogen, 0657 R’ is: an alkyl, a cycloalkoxy, a halogen, a hydroxy, an 0658) (a) lower alkyl; hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring. a cycloalkylalkyl, a heterocyclicalkyl, an 0659 (b) hydrogen; or alkoxy, a haloalkoxy, an amino, an alkylamino, a 0660 (c) –C(O)H; dialkylamino, an arylamino, a diarylamino, an alky larylamino, an alkoxyhaloalkyl, a haloalkoxy, a Sul 0661 a is an integer equal to 1 or 3; fonic acid, a Sulfonic ester, an alkylsulfonic acid, an 0662 bb is an integer equal to 2 or 3; arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an 0663 D is: aryl, an arylalkyl, a carboxamido, a alkylcarboxa mido, an arylcarboxamido, an amidyl, a carboxyl, a 0664 (a) hydrogen or carbamoyl, an alkylcarboxylic acid, an arylcarboxy 0665 (b) D; lic acid, an alkylcarbonyl, an arylcarbonyl, an ester, US 2004/0072883 A1 Apr. 15, 2004

a carboxylic ester, an alkylcarboxylic ester, an aryl 0705 wherein: carboxylic ester, a haloalkoxy, a Sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsul 0706 A-B is: fonyl, an alkylsulfonyloxy, an arylsulfonyl, an aryl 0707) (a) N-C; Sulfonyloxy, a urea, a nitro, -T-Q'-, or -(C(R- )(R))-T-Q' or R and R taken together are an OXO, 0708 (b) C-N; or a thial, a heterocyclic ring, a cycloalkyl group, an 0709) (c) N-N; Oxime, a hydraZone or a bridged cycloalkyl group; 0710 when A-B is N-C, sides d and fare double 0694 Q' is -NO or -NO; bonds, and sides e and g are single bonds, X-Y- 0695 k is an integer from 1 to 3; Z - is: 0696 T is independently a covalent bond, a carbo 0711) (a) =CR-CR'—CR-; nyl, an oxygen, -SO)- or -N(R)R-, 0712) (b) =N-CR'=CR"; 0697) o is an integer from 0 to 2, 0713) (c) =N-CR'=N-; 0698 R is a lone pair of electrons, a hydrogen or an alkyl group; 0714) (d) =CR-N=CR" -: 0715 (e)=CR-N=N-; 0699 R, is a hydrogen, an alkyl, an aryl, an alkyl carboxylic acid, an arylcarboxylic acid, an alkylcar 0716) (f) =N-N=CR-; boxylic ester, an arylcarboxylic ester, an alkylcar boxamido, an arylcarboxamido, an alkylsulfinyl, an 0717 (g) =N-N=N-; or alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, 0718 (h) =CR-CR=N-; an arylsulfonyloxy, an arylsulfonyl, a Sulfonamido, a 0719 when A-B is C-N, sides e and g are double carboxamido, a carboxylic ester, an aminoalkyl, an bonds, and sides d and fare single bonds, -X- aminoaryl, -OR', -CH-C(T-Q')(R)(R), a Y-Z - is: bond to an adjacent atom creating a double bond to that atom or -(N2O).M", wherein M" is an 0720 (a) -CR'=N-N=; organic or inorganic cation; with the proviso that when R, is -CH-C(T-Q')(R)(R) or -(N.O.- 0721 (b) -N=N-CR'=; ).M"; then “-T-Q" can be a hydrogen, an alkyl group, 0722 (c)-CR'=N-CR'—; an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group; 0723) (d)-N=CR-N=; (0700 R and R, at each occurrence are indepen 0724) (e) -CR'=CR-N=; dently R; 0725 (f) -N=CR-CR=; 0701) R' is independently selected from R. 0726 (g) –CR'—CR-CR=; or 0702. In cases where R and Rare a heterocyclic ring or 0727 (h)-N=N-N=; R and R taken together with the carbon atom to which they are attached are a heterocyclic ring, then R can be a 0728 when A-B is C-N, side g is a double bond, Substituent on any disubstituted nitrogen contained within and sides d, e and fare single bonds, -X-Y-Z'- the radical where R is as defined herein. is: 0703. In cases where multiple designations of variables that reside in Sequence are chosen as a “covalent bond' or the integer chosen is 0, the intent is to denote a single covalent bond connecting one radical to another. For example, E would denote a covalent bond, while E denotes (E-E) and (C(R)(R)) denotes-C(R)(R)-C(R)(R)-. 0733 when A-B is N-C, sides d is a double bond, 0704. Another embodiment of the invention describes and sides e. f and g are single bonds, -X-Y-Z'- compounds of Formula (II) and pharmaceutically acceptable is: salts thereof:

II R S/S

2 A. S-Z?\ 0738 when sides f is a double bond, and sides d, e. 2 Y and g are single bonds, -X-Y-Z'- is: RS-Nx3 US 2004/0072883 A1 Apr. 15, 2004 17

0741 when sides e is a double bond, and sides d, f 0771) (h)-C(O)R'; or and g are single bonds, -X-Y-Z - is: 0772 (i) -OC(O)R; 0742 (a) -N=CR-CH(R)-; or 0773) R is: 0743) (b) –CR'=CR-C(O)–: 0774 (a) hydrogen; (0744), when sides d, e, f and g are Single bonds, 0775) (b) lower alkyl; or -X-Y-Z - is: 0745) (a) –C(O)-CR'(R)-C(O)-; and 0776 (c) alkoxy; 0777 RSS is: 0746 with the proviso that when A-B is C-N, then X must be —(CRR), or—(CRR)-A"; and 0778 (a) lower alkyl; 0747 wherein R,R,R,R,R,R,R,R, XA', 0779) (b) alkoxy R, R', a and bb are as defined herein 0780 (c) unsubstituted, mono-, di- or tri-substi 0748. Another embodiment of the invention describes tuted phenyl or pyridyl, wherein the Substituents compounds of Formula (III) and pharmaceutically accept- are each independently: able salts thereof: 0781 (1) halo; 0782) (2) alkoxy;

III 0783 (3) haloalkyl; 0784 (4) CN: 0785 (5)-C(O)R'; 0786 (6) lower alkyl; 0787 (7) –S(O)-lower alkyl; or 0788 (8) -OD'; 0749 wherein: (or,slatively. RandR or RandR taken 0750 X is: 0790 (a) oxo; 0751 (a) –C(O)-U-D'; 0791) (b) thial; 0752 (b) –CH-U-D'; 0792) (c) =CRR7; or 0753 (c) —CH-C(O)-CH; 0793) (d) =NR; 0754) (d) -CH-CH-C(O)-U-D'; 0794) R and R7 are each independently: 0755 (e) –CH-O-D; 0795) (a) hydrogen; 0756) (f) –C(O)H or 0796) (b) lower alkyl; 0757 (g) c(O)-U-R'; 0797 (c) lower alkyl-OD'; 0758) Y is: 0798) (d) CN; or 0759 (a)-(CR(R))-U-D'; 0799 (e) -C(O)R'; 0760) (b) -CH: 0800 R is: 0761 (c) –CHOC(O)R; or 0801) (a) OD'; 0762) (d) –C(O)H; 0802 (b) alkoxy; 0763) R, R, R and R are each indepen- 0803 (c) lower alkyl; or dently: 0804 (d) unsubstituted, mono-, di- or tri-substi 0764 (a) hydrogen; SEE E. wherein the Substituents 0765) (b) hydroxy; 0805) (1) halo; 0766 (c) alkyl; 0806) (2) alkoxy; 0767 (d) alkoxy; 0807 (3) haloalkyl; 0768 (e) lower alkyl-OD'; 0808 (4) CN: 0769 (f) alkylthio; 0809 (5)-C(O)R'; 0770 (g) CN: 0810 (6) lower alkyl; US 2004/0072883 A1 Apr. 15, 2004 18

0811 (7) -S(O)O-lower alkyl; or O845) 08.12 (8) –OD'; 0846) 0813 X is: O847) (t) aryl; 0814) (a)-(CRR)-; O848) (u) arylalkylthio; 0815) (b) –(CRR)-A-; or 0849) (v) arylalkoxy; 0816 (e) –CR'=; and 0850 (w) alkylamino; 0817 wherein R,R,R,R,R,R,R,R,R, (x) aryloxy; A, U, D', a, bb, o and k are as defined herein. 0851) O852) (y) alkylarylalkylamino; 0818. Another embodiment of the invention describes compounds of Formula (IV) and pharmaceutically accept O853) (Z) cycloalkylalkylamino; or able salts thereof: 0854) (aa) cycloalkylalkoxy, 0855) R' is: IV O856) (a) mono-, di- or tri-Substituted phenyl or pyridinyl (or the N-oxide thereof), wherein the Substituent are each independently: O857) (1) hydrogen; 0858) (2) halo; O859) (3) alkoxy; 0819 wherein: 0860) (4) alkylthio; 0820) X" and Z' are each independently: 0861) (5) CN: 0821 (a) N; or 0862) (6) lower alkyl; 0822) (b) CR; O863) (7) haloalkyl, preferably fluoroalkyl; 0823 R is: 0864) (8) Na; 0824 (a) -S(O)-CH; 0865) (9) -COD'; 0825 (b) –S(O)-NR(D"); or 0866) (10) -CO-lower alkyl; 0826 (c) -S(O)-N(D)-C(O)—CF; 0867) 0827) R' and R'' are each independently: 0868) (12) —OD'; 0828) (a) hydrogen; 0869) (13) lower alkyl-CO-R'"; or 0829) (b) lower alkyl; O870) (14) lower alkyl-CO-D'; 0830) (c) alkoxy; O871) (b) -T-C(R)(R')–(C(R)(R))- 0831) (d) alkylthio; 0832) (e) haloalkyl, preferably fluoroalkyl; 0833) (f) haloalkoxy, preferably fluoroalkoxy; 0834) (g) CN; 0835) (h) -COD'; 0836) (i) -COR'; / (CH2)-Ys 0837 (j) lower alkyl-O-D; 0838) (k) lower alkyl-COD'; 0839) (1) lower alkyl-COR'; O872) (d) arylalkyl, or 0840) (m) halo, 0873) (e) cycloalkylalkyl, 0841 0874) wherein: 0842) (o) -N, O875) R' and R' are each independently: 0843) (p) -NO; O876) (a) hydrogen; or 0844) (q)-NR'D'; 0877) (b) lower alkyl; US 2004/0072883 A1 Apr. 15, 2004 19

0878) R, R', R, R, R-7, R are each inde- 0908), Z7 is: pendentlydentlv: 0909 (a)-(CRR-)-; 0879 (a) hydrogen; or 0910) R' is: 0880 (b) lower alkyl; or 0881) R' and R-7, or R-7 and R together with the 0911) (a) Ri;3. or atoms to which they are attached form a carbocyclic 0912 (b) R"; ring of 3,4,5,6 or 7 atoms, or R and Rare joined to form a covalent bond; 0913) R' and R'' are each independently: 0882) Y is: 0914 (a) hydrogen; 0883) (a) CRR, 0915) (b) halo; 0884 (b) oxygen; or 0916 (c) lower alkyl; 0885) (c) sulfur; 0917 (d) aryl; 0886) R'29 and R''3O are each independently: 0918 (e) arylalkyl; O887 (a) hydrogenhvd 0919) (f) cycloalkyl; 0888 (b) lower alkyl; 1. 0920 (g) cycloalkylalkyl; 0889) (c) (CH), OD"; 0890) (d) halo; or O921) (h)-OD';1. 0891) R' and R' taken together are an oxo group; 0922 (i) lower alkyl-OD'; 0892 s is an integer from 2 to 4; and 0923) () carboxamido; 0893 wherein R, R, X, D', T, U, Kando are as 0924) (k) amidyl; or defined herein. 0925) (1) K; 0894. Another embodiment of the invention describes compounds of Formula (V) and pharmaceutically acceptable 0926 R is: salts thereof: 0927) (a) lower alkyl;

V 0928 (b) alkenyl;

0929) (c) cycloalkyl; 0930 (d) cycloalkylalkyl; 0931) (e) aryl; 0932 (f) arylalkyl; 0933) (g) heterocyclic ring; or 0934. (h) lower alkyl-heterocyclic ring; 0895 wherein: 0935 R and Rare each independently: 0896) X7 is: 0936 (a) lower alkyl; 0897) (a) oxygen; 0937) (b) cycloalkyl; C s "N, 0938 (c) cycloalkylalkyl; 0900) (d)-N-O-R; or 0939) (d) aryl; 0901) (e) -N-NR'R'; 0940 (e) arylalkyl; 0902 Y7 at each occurrence is independently: 0941 (f) heterocyclic ring; or 0903 (a) hydrogen; 0942 (g) heterocyclicalkyl; and 0904 (b) halo; 0943 wherein R,R,R,R,R, K, D and a are 0905 (c) lower alkyl; as defined herein. 0906) (d) alkenyl; or 0944. Another embodiment of the invention describes compounds of the Formula (VI) and pharmaceutically 0907) (e) alkynyl; acceptable Salts thereof: US 2004/0072883 A1 Apr. 15, 2004 20

-continued VI

0959 when sides i, k and l are single bonds, and 0945) wherein: sides handjare double bonds, -X'. Y'-Z'- is: 0946 X is –C(O)—U-D and Y is —CH CR(R)-U-D'; or

0947 X is –CH-CR (R)-U-D and Y is -C(O)-U-D'; or 0948) X and Y taken together are: 0949 (a) –C(O)-O-CR'(R")–CR(R)-; 0950 (b) —(CR"(R"))-CR (R)- CR(R)–: 0960 when side h and j are single bonds, 1 is a double bond, and Side k and i is a Single or a double bond, - X9 Y9-Z'9- is:

(a) 0954) wherein X is the first carbon atom of a, b, c, d and e, and 0955) wherein R,R,R,R,R,R,R, X, U, D' and k are as defined herein. 0956. Another embodiment of the invention describes (b) compounds of the Formula (VII) and pharmaceutically acceptable Salts thereof:

VII

0961) p" is: 0962) (a)-N=; 0963) (b) -NR-; 0964) (c) -O-, or 0957) wherein: 0965 (d) -S-; 0958 when side h, k, and are single bonds, and side 0966 Q' and Q' are each independently: i and 1 are a double bond, -X'. Y'-Z'- is: 0967) (a) CR; or 0968) (b) nitrogen; (a) 0969 A-B-C-D- is: 0970) (a) -CR'=CR" CR=CR-; N A. Q o O RošV AYR61

US 2004/0072883 A1 Apr. 15, 2004 22

that each must contain at least one NO and/or NO group (i.e., nitrosylated and/or nitrosated) wherein the one NO

VIII and/or NO group is linked to the compounds of Formula (I) to (VIII) through one or more sites, Such as oxygen (hydroxyl condensation), Sulfur (Sulfhydryl condensation) and/or nitrogen. 1087 Another embodiment of the invention describes the metabolites of the compounds of Formulas (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), and pharmaceutically acceptable Salts thereof. These metabolites, include but are not limited to, the non-nitroSated and/or normitrosylated 1054 wherein: derivatives, degradation products, hydrolysis products, and the like, of the compounds of Formulas (I), (II), (III), (IV), 1055) X* is: (V), (VI), (VII), and (VIII), and pharmaceutically acceptable 1056 (a) –C(O)-; or salts thereof. 1057) (b) –C(S)-; 1088. In other embodiments of the invention, the COX-2 Selective inhibitors of Formula II are: 1058) Yi* is: 1089) 1-(1-(cyclohexylmethyl)-3-(hydroxymeth 1059 (a) -O-, or yl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1060 (b) -S-; 1090 4-(1-(cyclohexylmethyl)-3-((2-hydroxy ethoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)ben Zene, 1091 1-(3-(hydroxymethyl)-1-benzylpyrazol-5-yl)-4- (methylsulfonyl)benzene; 1092] 1-(3-((1E)-3-Hydroxyprop-1-enyl)-1-(cyclo hexylmethyl)pyrazol-5-yl)-4-(methylsulfonyl) ben Zene, 1093) 1-(1-(cyclohexylmethyl)-3-(3-hydroxypropy l)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1094) 1-(1-(cyclohexylmethyl)-3-vinylpyrazol-5-yl)- 4-(methylsulfonyl)benzene; 1095 methyl (2E)-3-(1-(cyclohexylmethyl)-5-(4-(me thylsulfonyl)phenyl)pyrazol-3-yl) prop-2-enoate; 1096 methyl 5-(4-(methylsulfonyl)phenyl)-1-ben Zylpyrazole-3-carboxylate; and pharmaceutically acceptable Salts thereof. 1097. In other embodiments of the invention, the nitro Sated COX-2 selective inhibitors of Formula II are: 1098 1-(1-(cyclohexylmethyl)-3-((nitrooxy)meth yl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; 1099) 4-(1-(cyclohexylmethyl)-3-((2-(nitrooxy )ethoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl) ben Zene, 1100 4-(methylsulfonyl)-1-(3-((nitrooxyl)methyl)-1- benzylpyrazol-5-yl)benzene, 1101 1-(3-((1E)-3-nitrooxyprop-1-enyl)-1-(cyclo hexylmethyl)pyrazol-5-yl)-4-(methylsulfonyl) ben Zene, 1102 1-(1-(cyclohexylmethyl)-3-(3-(nitrooxy)propy l)pyrazol-5-yl)-4-(methylsulfonyl) benzene, and phar (1085) wherein R', R", R. R. R", R", R, R and maceutically acceptable Salts thereof. X are as defined herein. 1103 In other embodiments of the invention, the COX-2 1086. In another embodiment of the invention describes Selective inhibitors of Formula IV are: compounds of Formulas (I), (II), (III), (IV), (V), (VI), (VII) 1104) 3-(4-(methylsulfonyl)phenyl)-5-(trifluorom and (VIII), and pharmaceutically acceptable Salts thereof, ethyl)(2-pyridyl) phenyl ketone; US 2004/0072883 A1 Apr. 15, 2004 23

1105 2-(3-(4-(methylsulfonyl)phenyl)-5-(trifluorom 5,474,995, 5,486,534, 5,504,215, 5,508,426, 5,510,496, ethyl)(2-pyridyl)-2-phenylethanenitrile; 5,516,907, 5,521,207, 5,536,752, 5,550,142, 5,563,165, 5,616,601, 5,620,999, 5,677,318, 5,668,161, 5,691,374, 1106 3-fluorophenyl 2-(4-methylsulfonylphenyl)(3- 5,698,584, 5,710,140, 5,753,688, 5,859,257, 5,908.858, pyridyl) ketone; 5,945,539, 5,994,381, 6,080,876, 6,083,969 and 6,071,954 1107 2-(4-(methylsulfonyl)phenyl)(3-pyridyl) 2-py and in WO 91/19708, WO 94/15932, WO 94/26731, WO ridyl ketone; 94/27980, WO 95/00501, WO 95/11883, WO95/15315, WO 95/15316, WO 95/15317, WO 95/15318, WO 1108) ethyl 3-((2-(4-(methylsulfonyl)phenyl)-3-py 95/18799, WO 95/21817, WO 95/30652, WO 96/30656, ridyl)carbonyl)benzoate, and pharmaceutically accept WO 96/03387, WO 96/03392, WO 96/03385, WO able salts thereof. 96/03387, WO 96/03388, WO 96/09293, WO 96/09304, 1109 Compounds of the invention that have one or more WO 96/16934, WO 96/19462, WO 96/19463, WO asymmetric carbon atoms may exist as the optically pure 96/19469, WO 96/25405, WO 96/36617, WO 96/36623, enantiomers, pure diastereomers, mixtures of enantiomers, WO 97/11704, WO 97/13755, WO 97/27181, WO mixtures of diastereomers, racemic mixtures of enantiomers, 97/14691, WO 97/16435, WO 97/34882, WO 97/36863, diastereomeric racemates or mixtures of diastereomeric WO 97/40012, WO 97/45420, WO 98/00416, WO racemates. The invention includes within its Scope all Such 98/11080, WO 98/22422, WO 98/41516, WO 98/46594, isomers and mixtures thereof. WO 98/52937, WO 99/15531, WO 99/23087, WO 99/33796, WO 99/25695, WO 99/61016, WO 99/62884 and 1110 Another embodiment of the invention provides WO 99/64415 and in EP 0 745 596 A1, EP0087 629B1, processes for making the novel compounds of the invention EP0418 845B1, EP0554829A2, EP0863 134A1, EP 1 006 and to the intermediates useful in Such processes. The 114A1 for the intermediate of Formulas (I) and (II); and in reactions are performed in Solvents appropriate to the U.S. Pat. Nos. 5,733,909, 5,789,413 and 5,849,943 and in reagents and materials used are Suitable for the transforma WO 96/13483, WO 97/28120 and WO 97/28121 for the tions being effected. It is understood by one skilled in the art intermediates of Formula (III); and in U.S. Pat. No. 5,861, of organic Synthesis that the functionality present in the 419 and 6,001,843 and in WO96/10012, WO 96/16934, WO molecule must be consistent with the chemical transforma 96/24585, WO 98/03484, WO 98/24584, WO 98/47871, tion proposed. This will, on occasion, necessitate judgment WO 99/14194 and WO 99/14195 for the intermediates of by the routineer as to the order of Synthetic Steps, protecting Formula (IV); and in WO 98/41511, WO 99/10331, WO groups required, and deprotection conditions. Substituents 99/10332 and WO OO/24719 for the intermediates of For on the starting materials may be incompatible with Some of mula (V); and in U.S. Pat. No. 5,807.873 and WO 98/43966 the reaction conditions required in Some of the methods for the intermediates of Formula (VI); and in U.S. Pat. Nos. described, but alternative methods and Substituents compat 5,521,213 and 5,552,422 and in WO 96/06840, WO ible with the reaction conditions will be readily apparent to 96/21667, WO 96/31509, WO 99/12930, WO 00/08024 and one skilled in the art. The use of Sulfur and oxygen protect WO 00/26216 for the intermediates of Formula (VII); and in ing groups is well known for protecting thiol and alcohol WO 00/10993 for the intermediates of Formula (XIV); and groups against undesirable reactions during a Synthetic in WO 98/32732 for the intermediates of Formula (VII); the procedure and many Such protecting groups are known and disclosures of each of which are incorporated by reference described by, for example, Greene and Wuts, Protective herein in their entirety. The COX-2 inhibitor compounds can Groups in Organic Synthesis, Third Edition, John Wiley & then be nitroSated and/or nitrosylated through one or more Sons, New York (1999). Sites Such as oxygen, Sulfur and/or nitrogen using the 1111. The chemical reactions described herein are gener methods described in the examples herein and using con ally disclosed in terms of their broadest application to the ventional methods known to one skilled in the art. For preparation of the compounds of this invention. Occasion example, known methods for nitroSating and/or nitrosylating ally, the reactions may not be applicable as described to each compounds are described in U.S. Pat. Nos. 5,380,758 and compound included within the disclosed Scope. The com 5,703,073; WO 94/03421, WO 94/04484, WO 94/12463, pounds for which this occurs will be readily recognized by WO 95/09831, WO 95/30641, WO 97/27749, WO one skilled in the art. In all Such cases, either the reactions 98/19672, WO 00/25776, WO 01/00563 and WO 01/04082, can be Successfully performed by conventional modifica WO 01/10814, WO 01/45703 and Oae etal, Org. Prep. Proc. tions known to one skilled in the art, e.g., by appropriate Int., 15(3):165-198 (1983), the disclosures of each of which protection of interfering groups, by changing to alternative are incorporated by reference herein in their entirety. The conventional reagents, by routine modification of reaction methods of nitroSating and/or nitrosylating the compounds conditions, and the like, or other reactions disclosed herein described in the examples herein and in these references can or otherwise conventional, will be applicable to the prepa be applied by one skilled in the art to produce any of the ration of the corresponding compounds of this invention. In nitrosated and/or nitrosylated COX-2 inhibitors described all preparative methods, all Starting materials are known or herein. readily prepared from known starting materials. 1113) The compounds of the invention include the 1112) The intermediates for the compounds of Formulas COX-2 inhibitors, which have been nitrosated and/or (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) can be nitrosylated through one or more Sites Such as oxygen synthesized by one skilled in the art following the methods (hydroxyl condensation), Sulfur (Sulfhydryl condensation) and examples described herein. The Synthesis of the inter and/or nitrogen. The nitrosated and/or nitrosylated COX-2 mediates for the COX-2 inhibitors (i.e. non-nitrosated and/or inhibitors of the invention donate, transfer or release a non-nitrosylated COX-2 inhibitors) are disclosed in, for biologically active form of nitrogen monoxide (i.e., nitric example, U.S. Pat. Nos. 5,344.991, 5,393,790, 5,466,823, oxide). US 2004/0072883 A1 Apr. 15, 2004 24

1114) Nitrogen monoxide can exist in three forms: NO and derivatives thereof), S-nitrosylated amino acids (includ (nitroxyl), NO. (uncharged nitric oxide) and NO" (nitroso ing natural and Synthetic amino acids and their Stereoiso nium). NO. is a highly reactive short-lived species that is mers and racemic mixtures and derivatives thereof), S-ni potentially toxic to cells. This is critical because the phar trosylated Sugars, S-nitrosylated, modified and unmodified, macological efficacy of NO depends upon the form in which oligonucleotides (preferably of at least 5, and more prefer it is delivered. In contrast to the nitric oxide radical (NO.), ably 5-200 nucleotides); straight or branched, saturated or nitrosonium (NO") does not react with O. or O species, unsaturated, aliphatic or aromatic, Substituted or unsubsti and functionalities capable of transferring and/or releasing tuted S-nitrosylated hydrocarbons; and S-nitroso heterocy NO" and NO- are also resistant to decomposition in the clic compounds. S-nitroSothiols and methods for preparing presence of many redox metals. Consequently, administra them are described in U.S. Pat. Nos. 5,380,758 and 5,703, tion of charged NO equivalents (positive and/or negative) is 073; WO 97/27749; WO 98/19672; and Oae etal, Org. Prep. a more effective means of delivering a biologically active Proc. Int., 15(3):165-198 (1983), the disclosures of each of NO to the desired site of action. which are incorporated by reference herein in their entirety. 1115 Compounds contemplated for use in the invention, 1118) Another embodiment of the invention is S-nitroso e.g., COX-2 Selective inhibitor, that can be optionally nit amino acids where the nitroSo group is linked to a Sulfur rosated and/or nitrosylated, through one or more Sites Such group of a Sulfur-containing amino acid or derivative as oxygen (hydroxyl condensation), Sulfur (Sulfhydryl con thereof. Such compounds include, for example, S-nitroSo densation) and/or nitrogen, are, optionally, used in combi N-acetylcysteine, S-nitroSo-captopril, S-nitroso-N-acetyl nation with nitric oxide and compounds that release nitric penicillamine, S-nitroSo-homocysteine, S-nitroSo-cysteine, oxide or otherwise directly or indirectly deliver or transfer a S-nitroSO-glutathione, S-nitroSo-cysteinyl-glycine, and the biologically active form of nitrogen monoxide to a Site of its like. intended activity, Such as on a cell membrane in Vivo. 1119 Suitable S-nitrosylated proteins include thiol-con 1116. The term “nitric oxide' encompasses uncharged taining proteins (where the NO group is attached to one or nitric oxide (NO.) and charged nitrogen monoxide species, more Sulfur groups on an amino acid or amino acid deriva preferably charged nitrogen monoxide Species, Such as tive thereof) from various functional classes including nitrosonium ion (NO") and nitroxyl ion (NO-). The reactive enzymes, Such as tissue-type plasminogen activator (TPA) form of nitric oxide can be provided by gaseous nitric oxide. and cathepsin B; transport proteins, Such as lipoproteins, The nitrogen monoxide releasing, delivering or transferring heme proteins, Such as hemoglobin and Serum albumin; and compounds have the structure F-NO, wherein F is a nitrogen biologically protective proteins, Such as immunoglobulins, monoxide releasing, delivering or transferring moiety, and antibodies and cytokines. Such nitrosylated proteins are include any and all Such compounds which provide nitrogen described in WO 93/09806, the disclosure of which is monoxide to its intended site of action in a form active for incorporated by reference herein in its entirety. Examples its intended purpose. The term “NO adducts' encompasses include polynitrosylated albumin where one or more thiol or any nitrogen monoxide releasing, delivering or transferring other nucleophilic centers in the protein are modified. compounds, including, for example, S-nitroSothiols, nitrites, nitrates, S-nitrothiols, Sydnonimines, 2-hydroxy-2-nitroSo 1120. Other examples of Suitable S-nitrosothiols include: hydrazines, (NONOates), (E)-alkyl-2-(E)-hydroxyimino)- 1121 (i) HS(C(R)(R)), SNO; 5-nitro-3-hexeneamide (FK-409), (E)-alkyl-2-((E)-hydroxy imino)-5-nitro-3-hexeneamines, N-((2Z, 3E)-4-ethyl-2- 1122 (ii) ONS(C(R)(R)), R.; or (hydroxyimino)-6-methyl-5-nitro-3-heptenyl)-3- 1123 (iii) HN-CH(COH)-(CH), pyridinecarboxamide (FR 146801), nitroSoamines, furoxans C(O)NH-CH(CHSNO)–C(O)NH-CH as well as Substrates for the endogenous enzymes which COH: synthesize nitric oxide. NONOates include, but are not 1124 wherein m is an integer from 2 to 20; R and Rare limited to, (Z)-1-(N-methyl-N-(6-(N-methyl-ammoniohexy each independently a hydrogen, an alkyl, a cycloalkoxy, a l)amino))diazen-1-ium-1,2-diolate (“MAHMA/NO”), (Z)- halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an 1-(N-(3-ammoniopropyl)-N-(n-propyl)amino)diazen-1- arylheterocyclic ring. a cycloalkylalkyl, a heterocyclicalkyl, ium-1,2-diolate (“PAPA/NO”), (Z)-1-(N-(3-aminopropyl)- an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky N-(4-(3-aminopropylammonio)butyl)-amino) diazen-1- lamino, an arylamino, a diarylamino, an alkylarylamino, an ium-1,2-diolate (spermine NONOate or “SPER/NO”) and alkoxyhaloalkyl, a haloalkoxy, a Sulfonic acid, a Sulfonic sodium(Z)-1-(N,N-diethylamino)diazenium-1,2-diolate ester, an alkylsulfonic acid, an arylsulfonic acid, an aryla (diethylamine NONOate or “DEA/NO”) and derivatives lkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an thereof. NONOates are also described in U.S. Pat. Nos. aminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcar 6,232,336, 5,910,316 and 5,650,447, the disclosures of boxamido, an arylcarboxamido, an amidyl, a carboxyl, a which are incorporated herein by reference in their entirety. carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, The “NO adducts' can be mono-nitrosylated, poly-nitrosy an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic lated, mono-nitrosated and/or poly-nitroSated at a variety of ester, an alkylcarboxylic ester, an arylcarboxylic ester, a naturally Susceptible or artificially provided binding sites for haloalkoxy, a Sulfonamido, an alkylsulfonamido, an arylsul biologically active forms of nitrogen monoxide. fonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsul 1117. One group of NO adducts is the S-nitrosothiols, fonyl, an arylsulfonyloxy, a urea, a nitro, -T-Q'-, or -(C(R- which are compounds that include at least one -S-NO )(R))-T-Q' or R, and R taken together are an oxo, a group. These compounds include S-nitroSo-polypeptides methanthial, a heterocyclic ring, a cycloalkyl group, an (the term “polypeptide' includes proteins and polyamino Oxime, a hydrazone or a bridged cycloalkyl group; Q' is acids that do not possess an ascertained biological function, -NO or -NO, and T is independently a covalent bond, a US 2004/0072883 A1 Apr. 15, 2004

carbonyl, an oxygen, -SO)- or -N(R)R-, wherein o urated, aliphatic or aromatic, Substituted or unsubstituted is an integer from 0 to 2, R is a lone pair of electrons, a hydrocarbons; and ON-O-, ON-N- or ON-S- hydrogen or an alkyl group; R is a hydrogen, an alkyl, an heterocyclic compounds. Preferred examples of compounds aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an comprising at least one ON-O-, ON-N- or ON alkylcarboxylic ester, an arylcarboxylic ester, an alkylcar S-group include isosorbide dinitrate, isosorbide mononi boxamido, an arylcarboxamido, an alkylsulfinyl, an alkyl trate, clonitrate, erythrityl tetranitrate, mannitol heXanitrate, Sulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfo nitroglycerin, pentaerythritoltetranitrate, pentrinitrol, pro nyloxy, an arylsulfonyl, a Sulfonamido, a carboxamido, a patylnitrate and organic nitrates with a Sulfhydryl-contain carboxylic ester, an aminoalkyl, an aminoaryl, -CH ing amino acid such as, for example SPM 3672, SPM 5185, C(T-Q')(R)(Ri), or -(NO-)-.M", wherein M' is an SPM 5186 and those disclosed in U.S. Pat. Nos. 5,284,872, organic or inorganic cation; with the proviso that when R is 5,428,061, 5,661,129, 5,807,847 and 5,883,122 and in WO -CH-C(T-Q')(R)(R) or -(NO-).M"; then “-T-Q" 97/46521, WOOO/54756 and in WO 03/013432, the disclo can be a hydrogen, an alkyl group, an alkoxyalkyl group, an Sures of each of which are incorporated by reference herein aminoalkyl group, a hydroxy group or an aryl group; and in their entirety. 1125) R, and R, at each occurrence are indepen 1130. Another group of NO adducts are N-oxo-N-ni dently R; troSoamines that donate, transfer or release nitric oxide and are represented by the formula: R'R''N-N(O-M")-NO, 1126. In cases where R and RF are a heterocyclic ring or where R'' and R are each independently a polypeptide, an taken together R and Rf are a heterocyclic ring, then Rican amino acid, a Sugar, a modified or unmodified oligonucle be a Substituent on any disubstituted nitrogen contained otide, a Straight or branched, Saturated or unsaturated, ali within the radical wherein R, is as defined herein. phatic or aromatic, Substituted or unsubstituted hydrocar 1127 Nitrosothiols can be prepared by various methods bon, or a heterocyclic group, and where M is an organic or of Synthesis. In general, the thiol precursor is prepared first, inorganic cation, Such as, for example, an alkyl Substituted then converted to the S-nitrosothiol derivative by nitrosation ammonium cation or a Group I metal cation. of the thiol group with NaNO under acidic conditions (pH 1131 The invention is also directed to compounds that is about 2.5) which yields the S-nitroso derivative. Acids Stimulate endogenous NO or elevate levels of endogenous which can be used for this purpose include acqueous Sulfuric, endothelium-derived relaxing factor (EDRF) in vivo or are acetic and hydrochloric acids. The thiol precursor can also Substrates for nitric oxide Synthase. Such compounds be nitrosylated by reaction with an organic nitrite Such as include, for example, L-arginine, L-homoarginine, and tert-butyl nitrite, or a nitroSonium Salt Such as nitroSonium N-hydroxy-L-arginine, including their nitrosated and tetrafluoroborate in an inert Solvent. nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated 1128) Another group of NO adducts for use in the inven L-arginine, nitrosated N-hydroxy-L-arginine, nitroSylated tion, where the NO adduct is a compound that donates, N-hydroxy-L-arginine, nitroSated L-homoarginine and transferS or releases nitric oxide, include compounds com nitrosylated L-homoarginine), precursors of L-arginine and/ prising at least one ON-O- or ON-N- group. The or physiologically acceptable Salts thereof, including, for compounds that include at least one ON-O- or ON-N- example, citrulline, omithine, glutamine, lysine, polypep group are preferably ON-O- or ON-N-polypeptides tides comprising at least one of these amino acids, inhibitors (the term “polypeptide' includes proteins and polyamino of the enzyme arginase (e.g., N-hydroxy-L-arginine and acids that do not possess an ascertained biological function, 2(S)-amino-6-boronohexanoic acid), nitric oxide mediators and derivatives thereof); ON-O- or ON-N-amino acids and/or physiologically acceptable Salts thereof, including, (including natural and Synthetic amino acids and their Ste for example, pyruvate, pyruvate precursors, C.-keto acids reoisomers and racemic mixtures); ON-O- or ON-N- having four or more carbon atoms, precursors of C-keto Sugars; ON-O- or -ON-N- modified or unmodified acids having four or more carbon atoms (as disclosed in WO oligonucleotides (comprising at least 5 nucleotides, prefer 03/017996, the disclosure of which is incorporated herein in ably 5-200 nucleotides); ON-O- or ON-N-straight or its entirety), and the Substrates for nitric oxide synthase, branched, Saturated or unsaturated, aliphatic or aromatic, cytokines, adenosin, bradykinin, calreticulin, bisacodyl, and substituted or unsubstituted hydrocarbons; and ON-O-, phenolphthalein. EDRF is a vascular relaxing factor Secreted ON-N- or ON-C-heterocyclic compounds. by the endothelium, and has been identified as nitric oxide 1129. Another group of NO adducts for use in the inven (NO) or a closely related derivative thereof (Palmer et al., tion include nitrates that donate, transfer or release nitric Nature, 327:524-526 (1987); Ignarro et al., Proc. Natl. Acad. oxide, Such as compounds comprising at least one ON Sci. USA, 84:9265-9269 (1987)). O-, ON-N- or ON-S- group. Preferred among 1132) The invention is also based on the discovery that these compounds are ON-O-, ON-N- or ON-S- compounds and compositions of the invention may be used polypeptides (the term “polypeptide' includes proteins and in conjunction with other therapeutic agents for co-thera also polyamino acids that do not possess an ascertained pies, partially or completely, in place of other conventional biological function, and derivatives thereof); ON-O-, antiinflammatory compounds, Such as, for example, together ON-N- or ON-S-amino acids (including natural and with steroids, NSA/Ds, 5-lipoxygenase (5-LO) inhibitors, Synthetic amino acids and their Stereoisomers and racemic leukotriene B (LTB) receptor antagonists, leukotriene A mixtures); ON-O-, ON-N- or ON-S- sugars; (LTA) hydrolase inhibitors, 5-HT agonists, HMG-CoA ON-O-, ON-N- or ON-S- modified and inhibitors, H2 receptor antagonists, antineoplastic agents, unmodified oligonucleotides (comprising at least 5 nucle antiplatelet agents, thrombin inhibitors, thromboxane inhibi otides, preferably 5-200 nucleotides); ON-O-, ON tors, decongestants, diuretics, Sedating or non-Sedating anti N- or ON-S-straight or branched, Saturated or unsat histamines, inducible nitric oxide Synthase inhibitors, opi US 2004/0072883 A1 Apr. 15, 2004 26 ods, analgesics, Helicobacter pylori inhibitors, proton pump 1139 Suitable NSAIDs, include, but are not limited to, inhibitors, isoproStane inhibitors, and mixtures of two or acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen, more thereof. naproxen, indomethacin, including but not limited to pro 1133) Leukotriene A (LTA) hydrolase inhibitors refer to drugs thereof, and the like. Suitable NSAIDs are described compounds that Selectively inhibit leukotriene A hydrolase more fully in the literature, Such as in Goodman and Gilman, with an ICs of less than about 10 uM, and preferably with The Pharmacological Basis of Therapeutics (9th Edition), an ICs of less than about 1 uM. Suitable LTA hydrolase McGraw-Hill, 1995, Pgs. 617-657; the Merck Index on inhibitors include, but are not limited to, RP-64966, (S,S)- CD-ROM, 13" Edition; and in U.S. Pat. Nos. 6,057,347 and 3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric acid 6,297.260 assigned to NitroMed Inc., the disclosures of benzyl ester, N-(2(R)-(cyclohexylmethyl)-3-(hydroxycar which are incorporated herein by reference in their entirety. bamoyl)propionyl)-L-alanine, 7-(4-(4-ureidobenzyl)phenyl) 1140) Suitable H receptor anatgonists, include, but are heptanoic acid and 3 (3-(1E,3E-tetradecadienyl)-2-oxiranyl not limited to, cimetidine, roXatidine, rantidine and the like. )benzoic acid lithium salt, and mixtures of two or more Suitable H receptor antagonists are described more fully in thereof. the literature, Such as in Goodman and Gilman, The Phar 1134) Suitable LTB receptor antagonists include, but are macological Basis of Therapeutics (9th Edition), McGraw not limited to, ebSelen, linazolast, ontazolast; WAY 121006; Hill, 1995, Pgs. 901-915; the Merck Index on CD-ROM, Bay-X-1005; BI-RM-270; CGS-25019C; ETH-615; MAFP; 13 Edition; and in WO 00/28988 assigned to NitroMed Inc., TMK-688; T-0757; LY 213024, LY 210073, LY223982, LY the disclosures of which are incorporated herein by refer 233469, LY255283, LY264086, LY 292728 and LY 293111; ence in their entirety. ONO-LB457, ONO-4057, and ONO-LB-448, S-2474, cal 1141 Suitable antineoplastic agents, include but are not citrol; PF 10042; Pfizer 105696; RP 66153; SC-53228, limited to, 5-FU-fibrinogen, acanthifolic acid, aminothiadia SC-41930, SC-50605, SC-51146 and SC-53228; SB-2011.46 Zole, altretamine, anaXirone, aclarubicin and the like. Suit and SB-209247; SKF-104493; SM 15178; TMK-688; BPC able antineoplastic agents are also described in U.S. Pat. No. 15, and mixtures of two or more thereof. The preferred LTB 6,025,353 and WO 00/38730, the 25 disclosures of which receptor antagonists are calcitrol, ebSelen, Bay-X-1005, are incorporated herein by reference in their entirety. CGS-25019C, ETH-615, LY-293111, ONO-4057 and TMK 1142 Suitable antiplatelet agents, include but are not 688, and mixtures of two or more thereof. limited to, aspirin, ticlopidine, dipyridamole, clopidogrel, 1135 Suitable 5-LO inhibitors include, but are not lim glycoprotein IIb/IIIa receptor antagonists, and the like. Suit ited to, A-76745, 78773 and ABT761; Bay-X-1005; CMI able antineoplastic agents are also described in WO 392; E-3040; EF-40; F-1322; ML-3000; PF-5901; R-840; 99/45913, the disclosure of which is incorporated herein by rilopiroX, flobufen, linasolast, lonapolene, masoprocol, Onta reference in its entirety. In a preferred embodiment of the Solast, tenidap, Zileuton, pranlukast, tepoxalin, rilopirox, invention, the antiplatelet agent is aspirin, more preferably, fleZelastine hydrochloride, enaZadrem phosphate, and low-dose aspirin (i.e. 75 mg-100 mg/day). bunaprolast, and mixtures of two or more thereof. Suitable 5-LO inhibitors are also described more fully in WO 1143) Suitable thrombin inhibitors, include but are not 97/29776, the disclosure of which is incorporated herein by limited to, N'-(1-(aminoiminomethyl)-4-piperidinyl)m- reference in its entirety ethyl)-N-(3,3-diphenylpropinyl)-L-proline amide), 3-(2- phenylethylamino)-6-methyl-1-(2-amino-6-methyl-5-meth 1136 Suitable 5-HT agonists, include, but are not limited ylene-carboxamidomethylpyridinyl)-2-pyrazinone, 3-(2- to, rizatriptan, Sumatriptan, naratriptan, Zoimitroptan, eiep phenethylamino)-6-methyl-1-(2-amino-6-methyl-5- triptan, aimotriptan, ergot alkaloids. ALX 1323, Merck L methylenecarboxamidomethylpyridinyl)-2-pyridinone, and 741604 SB 220453 and LAS 31416. Suitable 5-HTagonists the like. Suitable thrombin inhibitors are also described in are described more fully in WO 0025779, and in WO 00/48583. 5-HT agonists refers to a compound that is an WO 00/18352, the disclosure of which is incorporated agonist to any 5-HT receptor, including but not limited to, herein by reference in its entirety. 5-HT, agonists, 5-HT1B agonists and 5-HT1D agonists, and 1144 Suitable thromboxane inhibitors, include but are the like. not limited to thromboxane synthase inhibitors, thrombox 1137 Suitable steroids, include, but are not limited to, ane receptor antagonists, and the like. Suitable thromboxane budeSonide, dexamethasone, corticosterone, prednisolone, inhibitors, are also described in WO 01/87343, the disclo and the like. Suitable steroids are described more fully in the Sure of which is incorporated herein by reference in its literature, such as in the Merck Index on CD-ROM, 13" entirety. Edition. 1145 Suitable decongestants include, but are not limited 1138 Suitable HMG CoA inhibitors, include, but are not to, phenylephrine, phenylpropanolamine, pseudophedrine, limited to, reductase and Synthase inhibitors, Such as, for oxymetazoline, ephinephrine, naphazoline, Xylometazoline, example, Squalene Synthetase inhibitors, benzodiazepine propylhexedrine, levo-desoxyephedrine, and the like. Squalene Synthase inhibitors, Squalene epoxidase inhibitors, 1146 Suitable antitussives include, but are not limited to, acyl-coenzyme A, bile acid Sequestrants, cholesterol absorp codeine, hydrocodone, caramiphen, carbetapentane, dex tion inhibitors, and the like. Suitable HMG CoA inhibitors tramethorphan, and the like. include Simvastatin, pravastatin, lovastatin, mevastatin, flu vastatin, atorvastatin, cerivastatin, and the like, and are 1147 Suitable proton pump inhibitors, include, but are described more fully in U.S. Pat. No. 6,245,797 and WO not limited to, omeprazole, esomeprazole, lanSoprazole, 99/20110, the disclosures of which are incorporated herein rabeprazole, pantoprazole, and the like. Suitable proton by reference in their entirety. pump inhibitors are described more fully in the literature, US 2004/0072883 A1 Apr. 15, 2004 27

Such as in Goodman and Gilman, The Pharmacological flammatory compounds (NSAID), 5-lipoxygenase (5-LO) Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, inhibitors, leukotriene B (LTB) receptor antagonists, leu Pgs. 901-915; the Merck Index on CD-ROM, 13" Edition; kotriene A (LTA) hydrolase inhibitors, 5-HT agonists, and in WO 00/50037 assigned to NitroMed Inc., the disclo 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) Sures of which are incorporated herein by reference in their inhibitors, Hantagonists, antineoplastic agents, antiplatelet entirety. agents, thrombin inhibitors, thromboxane inhibitors, decon 1148. The compounds and compositions of the invention, gestants, diuretics, Sedating or non-Sedating anti-histamines, may also be used in combination therapies with opioids and inducible nitric oxide Synthase inhibitors, opioids, analge other analgesics, including, but not limited to, narcotic Sics, Helicobacter pylori inhibitors, proton pump inhibitors, analgesics, Mu receptor antagonists, Kappa receptor antago isoproStane inhibitors, and, optionally, at least one com nists, non-narcotic (i.e. non-addictive) analgesics, monoam pound that donates, transferS or releases nitric oxide, or ine uptake inhibitors, adenosine regulating agents, cannab elevates levels of endogenous EDRF or nitric oxide, or is a inoid derivatives, neurokinin 1 receptor antagonists, Substrate for nitric oxide Synthase. The compounds can be Substance Pantagonists, neurokinin-1 receptor antagonists, administered Separately or in the form of a composition. Sodium channel blockers, N-methyl-D-aspartate receptor 1151) Another embodiment of the invention provides antagonists, and mixtures of two or more thereof. Preferred methods for treating gastrointestinal disorders and/or combination therapies would be with morphine, meperidine, improving the gastrointestinal properties of the COX-2 codeine, pentazocine, buprenorphine, butorphanol, dezo Selective inhibitor by administering to the patient in need cine, meptazinol, hydrocodone, oxycodone, methadone, thereof a therapeutically effective amount of the compounds Tramadol ((+) enantiomer), DuP 747, Dynorphine A, Ena and/or compositions described herein. Such gastrointestinal doline, RP-6O180, HN-11608, E-2078, ICI-204448, disorders refer to any disease or disorder of the upper acetominophen (paracetamol), propoxyphene, nalbuphine, gastrointestinal tract (e.g., eSophagus, the Stomach, the E-4018, filenadol, mirtentanil, amitriptyline, DuP631, Tra duodenum, jejunum) including, for example, inflammatory madol ((-) enantiomer), GP-531, acadesine, AKI-1, AKI-2, bowel disease, Crohn's disease, gastritis, irritable bowel GP-1683, GP-3269, 4030W92, tramadol racemate, Dynor Syndrome, ulcerative colitis, peptic ulcers, StreSS ulcers, phine A, E-2078, AXC3742, SNX-111, ADL2-1294, ICI gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-El 204448, CT-3, CP-99,994, CP-99,994, and mixtures of two lison Syndrome, gastroesophageal reflux disease, bacterial or more thereof. infections (including, for example, a Helicobacter Pylori associated disease), short-bowel (anastomosis) Syndrome, 1149. The compounds and compositions of the invention hyperSecretory States associated with Systemic mastocytosis can also be used in combination with inducible nitric oxide or basophilic leukemia and hyperhistaminemia, and bleed synthase (iNOS) inhibitors. Suitable iNOS inhibitors are ing peptic ulcers that result, for example, from neuroSurgery, disclosed in U.S. Pat. Nos. 5,132,453 and 5,273,875, and in head injury, Severe body trauma or burns. For example, the WO 97/38977 and WO 99/18960, the disclosures of each of patient can be administered a therapeutically effective which are incorporated by reference herein in their entirety. amount of at least one COX-2 selective inhibitor, that is 1150. The invention is also based on the discovery that optionally nitrosated and/or nitrosylated In another embodi the administration of a therapeutically effective amount of ment, the patient can be administered a therapeutically the compounds and compositions described herein is effec effective amount of at least one COX-2 selective inhibitor, tive for treating inflammation, pain (both chronic and acute), that is optionally nitrosated and/or nitrosylated, and at least and fever, Such as, for example, analgesic in the treatment of one compound that donates, transferS or releases nitric pain, including, but not limited to headaches, migraines, oxide, or elevates levels of endogenous EDRF or nitric postoperative pain, dental pain, muscular pain, and pain oxide, or is a Substrate for nitric oxide Synthase. In yet resulting from cancer; as an antipyretic for the treatment of another embodiment, the patient can be administered a fever, including but not limited to, rheumatic fever, Symp therapeutically effective amount of at least one COX-2 toms associated with influenza or other viral infections, Selective inhibitor, that is optionally nitrosated and/or common cold, low back and neck pain, dySmenorrhea, nitrosylated, and, at least one therapeutic agent, including headache, toothache, Sprains, Strains, myositis, neuralgia, but not limited to, including but not limited to, Steroids, Synovitis, arthritis, including but not limited to rheumatoid nonsteroidal antiinflammatory compounds (NSAID), 5-li arthritis, degenerative joint disease (osteoarthritis), spondy poxygenase (5-LO) inhibitors, leukotriene B (LTB) recep loarthropathies, gouty arthritis, Systemic lupus erythemato tor antagonists, leukotriene A (LTA) hydrolase inhibitors, SuS and juvenile arthritis. For example, the patient can be 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A administered a therapeutically effective amount of at least (HMG-CoA) inhibitors, H antagonists, antineoplastic one COX-2 selective inhibitor, that is optionally nitrosated agents, antiplatelet agents, thrombin inhibitors, thrombox and/or nitrosylated. In another embodiment, the patient can ane inhibitors, decongestants, diuretics, Sedating or non be administered a therapeutically effective amount of at least Sedating anti-histamines, inducible nitric oxide Synthase one COX-2 selective inhibitor, that is optionally nitrosated inhibitors, opioids, analgesics, Helicobacter pylori inhibi and/or nitrosylated, and at least one compound that donates, tors, proton pump inhibitors, isoproStane inhibitors, and, transferS or releases nitric oxide, or elevates levels of optionally, at least one compound that donates, transferS or endogenous EDRF or nitric oxide, or is a substrate for nitric releases nitric oxide, or elevates levels of endogenous EDRF oxide Synthase. In yet another embodiment, the patient can or nitric oxide, or is a Substrate for nitric oxide Synthase. The be administered a therapeutically effective amount of at least compounds can be administered Separately or in the form of one COX-2 selective inhibitor, that is optionally nitrosated a composition. and/or nitrosylated, and, at least one therapeutic agent, 1152 Yet another embodiment of the invention provides including but not limited to, Steroids, nonsteroidal antiin methods for facilitating wound healing (Such as, for US 2004/0072883 A1 Apr. 15, 2004 28 example, ulcer healing, bone healing including osteoporo leukotriene B (LTB) receptor antagonists, leukotriene A sis) by administering to the patient in need thereof a thera (LTA) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3- peutically effective amount of the compounds and/or com methylglutaryl coenzyme A (HMG-CoA) inhibitors, H. positions described herein. Wound refers to, and includes, antagonists, antineoplastic agents, antiplatelet agents, any lesion that is characterized by loSS of tissue, and, thrombin inhibitors, thromboxane inhibitors, decongestants, includes, but is not limited to, ulcers, cuts, bums, bone diuretics, Sedating or non-Sedating anti-histamines, induc fractures, orthopedic procedure, wound infliction, and the ible nitric oxide Synthase inhibitors, opioids, analgesics, like. Ulcers refers to lesions of the upper gastrointestinal Helicobacter pylori inhibitors, proton pump inhibitors, iso tract lining that are characterized by loSS of tissue, and, prostane inhibitors, and, optionally, at least one compound include, but are not limited to, gastric ulcers, duodenal that donates, transferS or releases nitric oxide, or elevates ulcers, gastritis, and the like. For example, the patient can be levels of endogenous EDRF or nitric oxide, or is a substrate administered a therapeutically effective amount of at least for nitric oxide Synthase. The compounds can be adminis one COX-2 selective inhibitor, that is optionally nitrosated tered Separately or in the form of a composition. and/or nitrosylated In another embodiment, the patient can be administered a therapeutically effective amount of at least 1155 Disorders resulting from elevated levels of COX-2 one COX-2 selective inhibitor, that is optionally nitrosated (e.g., COX-2 mediated disorders) include, but are not lim and/or nitrosylated, and at least one compound that donates, ited to, for example, angiogenisis, arthritis, asthma, bron transferS or releases nitric oxide, or elevates levels of chitis, menstrual cramps, premature labor, tendinitis, bursi endogenous EDRF or nitric oxide, or is a substrate for nitric tis, skin-related conditions, Such as, for example, psoriasis, oxide Synthase. In yet another embodiment, the patient can eczema, Surface wounds, burns and dermatitis, post-opera be administered a therapeutically effective amount of at least tive inflammation including from ophthalmic Surgery, Such one COX-2 selective inhibitor, that is optionally nitrosated as, for example, cataract Surgery and refractive Surgery, and and/or nitrosylated, and, at least one therapeutic agent, and, the like; treatment of neoplasia, Such as, for example, brain optionally, at least one nitric oxide donor. The compounds cancer, bone cancer, epithelial cell-derived neoplasia (epi can be administered Separately or in the form of a compo thelial carcinoma), Such as, for example, basal cell carci Sition. noma, adenocarcinoma, gastrointestinal cancer, Such as, for example, lip cancer, mouth cancer, esophageal cancer, Small 1153) Another embodiment of the invention provides bowel cancer and Stomach cancer, colon cancer, liver cancer, methods to decrease or reverse renal and/or other toxicities bladder cancer, pancreas cancer, ovary cancer, cervical can (Such as, for example, kidney toxicity, respiratory toxicity) cer, lung cancer, breast cancer and skin cancer, Such as by administering to a patient in need thereof a therapeuti Squamus cell and basal cell cancers, prostate cancer, renal cally effective amount of the compounds and/or composi cell carcinoma, and other known cancers that effect epithe tions described herein. For example, the patient can be lial cells throughout the body, benign and cancerous tumors, administered a therapeutically effective amount of at least growths, polyps, adenomatous polyps, including, but not one COX-2 selective inhibitor, that is optionally nitrosated limited to, familial adenomatous polyposis, fibrosis resulting and/or nitrosylated In another embodiment, the patient can from radiation therapy, and the like, treatment of inflamma be administered a therapeutically effective amount of at least tory processes in diseases, Such as, for example, Vascular one COX-2 selective inhibitor, that is optionally nitrosated diseases, migraine headaches, periarteritis nodosa, thyroidi and/or nitrosylated, and at least one nitric oxide donor. In yet tis, aplastic anemia, Hodgkin's disease, Sclerodoma, rheu another embodiment, the patient can be administered a matic fever, type I diabetes, neuromuscular junction disease therapeutically effective amount of at least one COX-2 including myasthenia gravis, white matter disease including Selective inhibitor, that is optionally nitrosated and/or multiple Sclerosis, Sarcoidosis, nephrotic Syndrome, Beh nitrosylated, and at least one therapeutic agent, and, option cet's Syndrome, polymyositis, gingivitis, nephritis, hyper ally, at least one nitric oxide donor. The compounds can be Sensitivity, Swelling occurring after injury, myocardial administered Separately or in the form of a composition. ischemia, and the like, treatment of ophthalmic diseases and 1154. Another embodiment of the invention provides disorders, Such as, for example, retinitis, retinopathies, uvei methods to treat or prevent disorders resulting from elevated tis, ocular photophobia, acute injury to the eye tissue, levels of COX-2 by administering to a patient in need glaucoma, inflammation of the eye and elevation of thereof a therapeutically effective amount of the compounds intraocular pressure and the like; treatment of pulmonary and/or compositions described herein. For example, the inflammation, Such as, for example, those associated with patient can be administered a therapeutically effective Viral infections and cystic fibrosis, and the like; treatment of amount of at least one COX-2 selective inhibitor, that is central nervous System disorders, Such as, for example, optionally nitrosated and/or nitrosylated. In another embodi cortical dementia including Alzheimer's disease, Vascular ment, the patient can be administered a therapeutically dementia, multi-infarct dementia, pre-Senile dementia, alco effective amount of at least one COX-2 selective inhibitor, holic dementia, Senile dementia, and central nervous System that is optionally nitrosated and/or nitrosylated, and at least damage resulting from Stroke, ischemia and trauma, and the one compound that donates, transferS or releases nitric like; treatment of allergic rhinitis, respiratory distreSS Syn oxide, or elevates levels of endogenous EDRF or nitric drome, endotoxin Shock Syndrome, atherOSclerosis, treat oxide, or is a Substrate for nitric oxide Synthase. In yet ment of inflammations and/or microbial infections includ another embodiment, the patient can be administered a ing, for example, inflammations and/or infections of the therapeutically effective amount of at least one COX-2 eyes, ears, nose, throat, and/or skin; treatment and/or pre Selective inhibitor, that is optionally nitrosated and/or vention of cardiovascular disorders, Such as, for example, nitrosylated, and at least one therapeutic agent, including but coronary artery disease, aneurysm, arterioSclerosis, athero not limited to, Steroids, a nonsteroidal antiinflammatory Sclerosis, including, but not limited to, cardiac transplant compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, atherOSclerosis, myocardial infarction, hypertension, US 2004/0072883 A1 Apr. 15, 2004 29 ischemia, embolism, Stroke, thrombosis, Venous thrombosis, 1158 When administered in vivo, the compounds and thromboembolism, thrombotic occlusion and reclusion, res compositions of the invention can be administered in com tenosis, angina, unstable angina, shock, heart failure, coro bination with pharmaceutically acceptable carriers and in nary plaque inflammation, bacterial-induced inflammation, dosages described herein. When the compounds and com Such as, for example, Chlamydia-induced inflammation, positions of the invention are administered as a combination Viral induced inflammation, inflammation associated with of at least one COX-2 selective inhibitor and/or at least one Surgical procedures, Such as, for example, Vascular grafting, nitrosated and/or nitrosylated COX-2 selective inhibitor coronary artery bypass Surgery, revascularization proce and/or at least one nitric oxide donor and/or therapeutic dures, Such as, for example, angioplasty, Stent placement, agent, they can also be used in combination with one or more endarterectomy, vascular procedures involving arteries, additional compounds which are known to be effective veins, capillaries, and the like; treatment and/or prevention against the Specific disease State targeted for treatment. The of urinary and/or urological disorders, Such as, for example, nitric oxide donors, therapeutic agents and/or other addi incontinence and the like, treatment and/or prevention of tional compounds can be administered Simultaneously with, endothelial dysfunctions, Such as, for example, diseases Subsequently to, or prior to administration of the COX-2 accompanying these dysfunctions, endothelial damage from Selective inhibitor and/or nitrosated and/or nitrosylated hypercholesterolemia, endothelial damage from hypoxia, COX-2 selective inhibitor. endothelial damage from mechanical and chemical noxae, 1159 The compounds and compositions of the invention especially during and after drug, and mechanical reopening can be administered by any available and effective delivery of Stenosed vessels, for example, following percutaneous System including, but not limited to, orally, bucally, transluminal angiography (PTA) and percuntaneous trans parenterally, by inhalation Spray, by topical application, by luminal coronary angiography (PTCA), endothelial damage injection, transdermally, or rectally (e.g., by the use of in postinfarction phase, endothelium-mediated reocculusion Suppositories) in dosage unit formulations containing con following bypass Surgery, blood Supply disturbances in ventional nontoxic pharmaceutically acceptable carriers, peripheral arteries, as well as, cardiovascular diseases, and adjuvants, and Vehicles, as desired. Parenteral includes Sub the like; methods for treating and/or preventing tissue dete cutaneous injections, intravenous, intramuscular, intraster rioration, Such as, for example, for organ transplants, and the nal injection, or infusion techniques. like; disorders treated by the inhibition and/or prevention of activation, adhesion and infiltration of neutrophils at the Site 1160 Transdermal compound administration, which is of inflammation; and disorders treated by the inhibition known to one skilled in the art, involves the delivery of and/or prevention of platelet aggregation. The compounds pharmaceutical compounds via percutaneous passage of the and compositions of the invention can also be used as a compound into the Systemic circulation of the patient. Topi pre-anesthetic medication in emergency operations to reduce cal administration can also involve the use of transdermal the danger of aspiration of acidic gastric contents. administration Such as transdermal patches or iontophoresis devices. Other components can be incorporated into the 1156. Another embodiment of the invention provides transdermal patches as well. For example, compositions methods for improving the cardiovascular profile of COX-2 and/or transdermal patches can be formulated with one or Selective inhibitors by administering to a patient in need more preservatives or bacterioStatic agents including, but thereof a therapeutically effective amount of the compounds not limited to, methyl hydroxybenzoate, propyl hydroxy and/or compositions described herein. For example, the benzoate, chlorocreSol, benzalkonium chloride, and the like. patient can be administered a therapeutically effective Dosage forms for topical administration of the compounds amount of at least one nitrosated and/or nitrosylated COX-2 and compositions can include creams, Sprays, lotions, gels, Selective inhibitor of the invention. In another embodiment, ointments, eye drops, nose drops, ear drops, and the like. In the patient can be administered a therapeutically effective Such dosage forms, the compositions of the invention can be amount of at least one COX-2 selective inhibitor, that is mixed to form white, Smooth, homogeneous, opaque cream optionally nitroSated and/or nitrosylated, and at least one or lotion with, for example, benzyl alcohol 1% or 2% nitric oxide donor. In yet another embodiment, the patient (wt/wt) as a preservative, emulsifying wax, glycerin, iso can be administered a therapeutically effective amount of at propyl palmitate, lactic acid, purified water and Sorbitol least one COX-2 selective inhibitor, that is optionally nit Solution. In addition, the compositions can contain polyeth rosated and/or nitrosylated, at least one of 3-hydroxy-3- ylene glycol 400. They can be mixed to form ointments with, methylglutaryl coenzyme A (HMG-CoA) inhibitors, anti for example, benzyl alcohol 2% (wit/wt) as preservative, platelet agents, thrombin inhibitors, thromboxane inhibitors, white petrolatum, emulsifying wax, and tenox II (butylated and, optionally, at least one nitric oxide donor. The com hydroxyanisole, propyl gallate, citric acid, propylene gly pounds can be administered Separately or in the form of a col). Woven pads or rolls of bandaging material, e.g., gauze, composition. can be impregnated with the compositions in Solution, lotion, cream, ointment or other Such form can also be used 1157. When administered separately, the COX-2 selec for topical application. The compositions can also be applied tive inhibitor, that is optionally nitrosated and/or nitrosy topically using a transdermal System, Such as one of an lated, can be administered about the same time as part of the acrylic-based polymer adhesive with a resinous crosslinking overall treatment regimen, i.e., as a combination therapy. agent impregnated with the composition and laminated to an “About the same time' includes administering the COX-2 impermeable backing. Selective inhibitor, that is optionally nitrosated and/or nitrosylated, Simultaneously, Sequentially, at the Same time, 1161 Solid dosage forms for oral administration can at different times on the same day, or on different days, as include capsules, tablets, effervescent tablets, chewable tab long as they are administered as part of an overall treatment lets, pills, powders, Sachets, granules and gels. In Such Solid regimen, i.e., combination therapy or a therapeutic cocktail. dosage forms, the active compounds can be admixed with at US 2004/0072883 A1 Apr. 15, 2004 30 least one inert diluent Such as Sucrose, lactose or Starch. 1166 The composition, if desired, can also contain minor Such dosage forms can also comprise, as in normal practice, amounts of wetting agents, emulsifying agents and/or pH additional Substances other than inert diluents, e.g., lubri buffering agents. The composition can be a liquid Solution, cating agents Such as magnesium Stearate. In the case of Suspension, emulsion, tablet, pill, capsule, Sustained release capsules, tablets, effervescent tablets, and pills, the dosage formulation, or powder. The composition can be formulated forms can also comprise buffering agents. Soft gelatin as a Suppository, with traditional binders and carrierS Such as capsules can be prepared to contain a mixture of the active triglycerides. Oral formulations can include Standard carri compounds or compositions of the invention and vegetable erS Such as pharmaceutical grades of mannitol, lactose, oil. Hard gelatin capsules can contain granules of the active Starch, magnesium Stearate, Sodium Saccharine, cellulose, compound in combination with a Solid, pulverulent carrier magnesium carbonate, and the like. Such as lactose, Saccharose, Sorbitol, mannitol, potato Starch, 1167 Various delivery systems are known and can be corn Starch, amylopectin, cellulose derivatives of gelatin. used to administer the compounds or compositions of the Tablets and pills can be prepared with enteric coatings. invention, including, for example, encapsulation in lipo 1162 Liquid dosage forms for oral administration can Somes, microbubbles, emulsions, microparticles, microcap include pharmaceutically acceptable emulsions, Solutions, Sules and the like. The required dosage can be administered Suspensions, Syrups, and elixirs containing inert diluents as a Single unit or in a Sustained release form. commonly used in the art, Such as water. Such compositions can also comprise adjuvants, Such as wetting agents, emul 1168. The bioavailability of the compositions can be Sifying and Suspending agents, and Sweetening, flavoring, enhanced by micronization of the formulations using con and perfuming agents. ventional techniques Such as grinding, milling, Spray drying and the like in the presence of Suitable excipients or agents 1163 Suppositories for vaginal or rectal administration Such as phospholipids or Surfactants. of the compounds and compositions of the invention, Such as for treating pediatric fever and the like, can be prepared 1169 The preferred methods of administration of the by mixing the compounds or compositions with a Suitable COX-2 selective inhibitors and compositions for the treat nonirritating excipient Such as cocoa butter and polyethylene ment of gastrointestinal disorders are orally, bucally or by glycols which are Solid at room temperature but liquid at inhalation. The preferred methods of administration for the rectal temperature, Such that they will melt in the rectum and treatment of inflammation and microbial infections are release the drug. orally, bucally, topically, transdermally or by inhalation. 1164) Injectable preparations, for example, Sterile inject 1170 The compounds and compositions of the invention able aqueous or oleaginous Suspensions can be formulated can be formulated as pharmaceutically acceptable Salt according to the known art using Suitable dispersing agents, forms. Pharmaceutically acceptable Salts include, for wetting agents and/or Suspending agents. The Sterile inject example, alkali metal Salts and addition Salts of free acids or able preparation can also be a Sterile injectable Solution or free bases. The nature of the salt is not critical, provided that Suspension in a nontoxic parenterally acceptable diluent or it is pharmaceutically-acceptable. Suitable pharmaceuti Solvent, for example, as a Solution in 1,3-butanediol. Among cally-acceptable acid addition Salts may be prepared from an the acceptable vehicles and Solvents that can be used are inorganic acid or from an organic acid. Examples of Such water, Ringer's Solution, and isotonic Sodium chloride Solu inorganic acids include, but are not limited to, hydrochloric, tion. Sterile fixed oils are also conventionally used as a hydrobromic, hydroiodic, nitric, carbonic, Sulfuric and phos Solvent or Suspending medium. phoric acid and the like. Appropriate organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, 1165. The compositions of this invention can further heterocyclic, carboxylic and Sulfonic classes of organic include conventional excipients, i.e., pharmaceutically acids, Such as, for example, formic, acetic, propionic, Suc acceptable organic or inorganic carrier Substances Suitable cinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascor for parenteral application which do not deleteriously react bic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, with the active compounds. Suitable pharmaceutically benzoic, anthranilic, meSylic, Salicylic, p-hydroxybenzoic, acceptable carriers include, for example, water, Salt Solu phenylacetic, mandelic, embonic (pamoic), methane tions, alcohol, vegetable oils, polyethylene glycols, gelatin, Sulfonic, ethaneSulfonic, benzeneSulfonic, pantothenic, tolu lactose, amylose, magnesium Stearate, talc, Surfactants, eneSulfonic, 2-hydroxyethaneSuifonic, Sulfanilic, Stearic, Silicic acid, Viscous paraffin, perfume oil, fatty acid algenic, B-hydroxybutyric, cyclohexylaminoSulfonic, galac monoglycerides and diglycerides, petroethral fatty acid taric and galacturonic acid and the like. Suitable pharma esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and ceutically-acceptable base addition Salts include, but are not the like. The pharmaceutical preparations can be Sterilized limited to, metallic Salts made from aluminum, calcium, and if desired, mixed with auxiliary agents, e.g., lubricants, lithium, magnesium, potassium, Sodium and Zinc or organic preservatives, Stabilizers, wetting agents, emulsifiers, Salts Salts made from primary, Secondary and tertiary amines, for influencing osmotic pressure, buffers, colorings, flavor cyclic amines, N,N'-dibenzylethylenediamine, chlorop ing and/or aromatic Substances and the like which do not deleteriously react with the active compounds. For rocaine, choline, diethanolamine, ethylenediamine, meglu parenteral application, particularly Suitable vehicles consist mine (N-methylglucamine) and procaine and the like. All of of Solutions, preferably oily or aqueous Solutions, as well as these Salts may be prepared by conventional means from the Suspensions, emulsions, or implants. Aqueous Suspensions corresponding compound by reacting, for example, the may contain Substances which increase the Viscosity of the appropriate acid or base with the compound. Suspension and include, for example, Sodium carboxymethyl 1171 While individual needs may vary, determination of cellulose, Sorbitol and/or dextran. Optionally, the Suspension optimal ranges for effective amounts of the compounds may also contain Stabilizers. and/or compositions is within the skill of the art. Generally, US 2004/0072883 A1 Apr. 15, 2004 the dosage required to provide an effective amount of the Sale of pharmaceuticals or biological products which reflects compounds and compositions, which can be adjusted by one approval by the agency of manufacture, use or Sale for of ordinary skill in the art, will vary depending on the age, humans. health, physical condition, Sex, diet, weight, extent of the dysfunction of the recipient, frequency of treatment and the EXAMPLES nature and Scope of the dysfunction or disease, medical 1175. The following non-limiting examples further condition of the patient, the route of administration, phar describe and enable one of ordinary skill in the art to make macological considerations Such as the activity, efficacy, and use the invention. In each of the examples, flash pharmacokinetic and toxicology profiles of the particular chromatography was performed on 40 micron Silica gel compound used, whether a drug delivery System is used, and (Baker). whether the compound is administered as part of a drug combination. Example 1 1172. The amount of a given COX-2 selective inhibitor of 1-(1-Cyclohexylmethyl-3-((nitrooxy)methyl)pyra the invention that will be effective in the treatment of a zol-5-yl)-4-(methylsulfonyl) Benzene particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by Standard 1176) 1a. N-((1Z)-1-Aza-2-cyclohexylvinyl)(tert-butoxy clinical techniques, including reference to Goodman and )carboxamide Gilman, Supra; The Physician's Desk Reference, Medical 1177 Cyclohexane carboxaldehyde (5.0 g, 44.5 mmol) Economics Company, Inc., Oradell, N.J., 1995; and Drug and t-butyl carbazate (5.89 g, 44.5 mmol) in methanol (140 Facts and Comparisons, Inc., St. Louis, Mo., 1993. The mL) was stirred at room temperature for 1 hour. The solvent precise dose to be used in the formulation will also depend was evaporated and the resulting Solid dried under vacuo to on the route of administration, and the Seriousness of the give a white solid in quantitative yield; mp 123-125° C. "H disease or disorder, and should be decided by the physician NMR (300 MHz, CDC1) & 7.61 (bs, 1H), 7.02 (d, J-5.9 Hz, and the patient's circumstances. 1H), 2.22-2.39 (m, 1H), 1.60-1.89 (m, 5H), 1.49 (s, 9H), 1.19-147 (m, 5H); C NMR (75 MHz, CDC1) & 152.5, 1173) The amount of nitric oxide donor in a pharmaceu 151.5, 81.0, 40.7, 30.4, 28.5, 26.0, 25.6; mass spectrum tical composition can be in amounts of about 0.1 to about 10 (API-TIS) m/z 227 (MH"), 249 (MNa"). Anal. calcd for times the molar equivalent of the COX-2 selective inhibitor. CHNO: C, 63.69; H, 9.80; N, 12.38. Found: C, 63.97; The usual daily doses of the COX-2 selective inhibitors are H, 9.76; N, 12.26. about 0.001 mg to about 140 mg/kg of body weight per day, 1178) 1b. (tert-Butoxy)-N-((cyclohexylmethyl)ami preferably 0.005 mg to 30 mg/kg per day, or alternatively no)carboxamide about 0.5 mg to about 7 g per patient per day. For example, inflammations may be effectively treated by the administra 1179 Sodium cyanoborohydride (2.8 g., 44.6 mmol) was tion of from about 0.01 mg to 50 mg of the compound per added portionwise to a Suspension of the product of kilogram of body weight per day, or alternatively about 0.5 Example 1a (10.1 g, 44.6 mmol) in 50% acetic acid (125 mg to about 3.5g per patient per day. The compounds may mL) at room temperature. The resultant clear Solution was be administered on a regimen of up to 6 times per day, Stirred at room temperature for 2 hours. The reaction mixture preferably 1 to 4 times per day, and most preferably once per was neutralized with 1N NaOH, extracted with CHCl, day. Effective doses may be extrapolated from dose-re washed with Saturated NaHCO, dried, filtered and evapo Sponse curves derived from in Vitro or animal model test rated to give the title compound as a colorless oil in Systems and are in the same ranges or less than as described quantitative yield. "H NMR (300 MHz, CDC1) & 6.90 (bs, for the commercially available compounds in the Physi 1H), 6.15 (bs, 1H), 2.68 (d, J=6.7 Hz, 2H), 2.25-2.50 (m, cian's Desk Reference, Supra. 1H), 1.60- 1.87 (m, 5H), 1.46 (s, 9H), 1.12-1.33 (m, 3H), 0.80-1.08 (m, 2H); mass spectrum (API-TIS) m/z 129 (MH" 1174. The invention also provides pharmaceutical kits ). comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compounds and/or 1180 1c. Cyclohexylmethylhydrazine Trifluoroacetate compositions of the invention, including, at least, one or 1181 Trifluoroacetic acid (20 mL) was added dropwise more of the novel COX-2 selective inhibitors, that is option to a solution of the product of Example 1b (6.4 g, 28.1 ally nitrosated and/or nitrosylated, and one or more of the mmol) in CHCl (20 mL). The reaction mixture was stirred NO donors described herein. ASSociated with Such kits can at room temperature for 1 hour. The Solvent was evaporated be additional therapeutic agents or compositions (e.g., Ste to give the trifluoroacetate Salt of the title compound as a roids, NSAIDs, 5-lipoxygenase (5-LO) inhibitors, leukot colorless oil in quantitative yield. H NMR (300 MHz, riene B (LTB) receptor antagonists and leukotriene A CDC1) & 8.80 (bs, 5H), 2.98-3.08 (m, 2H), 1.64-1.92 (m, (LTA) hydrolase inhibitors, 5-HT agonists, HMG-CoA 6H), 1.12-1.47 (m, 3H), 0.90-1.10 (m, 2H); mass spectrum inhibitors, Hantagonists, antineoplastic agents, antiplatelet (API-TIS) m/z 129 (MH"). agents, thrombin inhibitors, thromboxane inhibitors, decon gestants, diuretics, Sedating or non-Sedating anti-histamines, 1182 1d. Methyl (2Z)-2-hydroxy-4-(4-methylthiophe inducible nitric oxide Synthase inhibitors, opioids, analge nyl)-4-oxobut-2-enoate Sics, Helicobacter pylori inhibitors, proton pump inhibitors, 1183 Dimethyloxalate (26 g., 180.7 mmol) was added to isoprostane inhibitors, and the like), devices for administer a stirred suspension of sodium methoxide (9.75 g, 180.7 ing the compositions, and notices in the form prescribed by mmol) in dry toluene (200 mL) at 0°C. The white suspen a governmental agency regulating the manufacture, use or sion was stirred for 15 minutes at 0° C. A solution of US 2004/0072883 A1 Apr. 15, 2004 32

4'-(methylthio)acetophenone (15g, 90.4 mmol) in dry tolu in water (7 mL) was added at room temperature. The ene (150 mL) was then added dropwise over 15 minutes reaction mixture was Stirred for 1 hour and the resulting giving a yellow Suspension which was Stirred for 2 hours at solid was removed by filtration. CHCl was added to the room temperature. The thick yellow Suspension was trans filtrate, and then the organic layer was washed with Saturated ferred to a 2 liter flask and stirred vigorously with 10% HCl NaHCO, water, dried over Na-SO, and filtered. The resi (250 mL) and EtOAc (200 mL) to dissolve all the solids due after evaporation of the Solvent was recrystallized from present. The organic layer was separated and the aqueous CHCl2/EtOAc/Hexane to give the title compound (0.33 g, layer was extracted with EtOAc (100 mL). The combined 59%) as a white solid; mp 104° C. "H NMR (300 MHz, organic extracts were washed with water (250 mL), dried CDC1) & 8.04 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.1 Hz, 2H), over NaSO and the Solvent was evaporated under reduced 6.32 (s, 1H), 4.74 (d, J=5.8 Hz, 2H), 3.92 (d, J=7.3 Hz, 2H), pressure to give thick brown oil. The brown oil was dis 3.13 (s, 3H), 1.98 (t, J=5.9 Hz, 1H), 1.801.94 (m, 1H), solved in CHCl (25 mL) and hexane (125 mL) and left in 1.40-1.70 (m, 5H), 0.98-1.25 (m, 3H), 0.65-0.82 (m, 2H); a freezer at -20° C. for 16 hours to give the title compound 'C NMR (75 MHz, CDC1) & 1518, 143.3, 140.6, 136.7, (18 g, 79%) as orange color solid; mp 81° C. "H NMR (300 130.0, 128.0, 105.4, 59.2, 56.0, 44.6, 39.0, 30.7, 26.3, 25.7; MHz, CDC1) & 7.83 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, mass spectrum (API-TIS) m/z 349 (MH), 331 (M-OH). 2H), 6.97 (s, 1H), 3.89 (s.3H), 2.47 (s, 3H); C NMR (75 Anal. Calcd for C.H.N.O.S: C, 62.04; H, 6.94; N, 8.04; MHz, CDC1); mass spectrum (API-TIS) m/z 253 (MH"). S, 9.20. Found: C, 61.88; H, 6.91; N, 7.84; S, 9.09. Anal. calcd for CHOS: C, 57.13; H, 4.79; S, 12.71. 1190) 1h. 1-(1-(Cyclohexylmethyl)-3-((nitrooxy)meth Found: C, 56.85; H, 4.76; S, 12.43. yl)pyrazol-5-yl)-4-(methylsulfonyl)benzene 1184) 1e. Methyl 1-(cyclohexylmethyl)-5-(4-methylth 1191. The product of Example 1 g (0.22g, 0.62 mmol) in iophenyl)pyrazole-3-carboxylate CHCl (2.6 mL) was added to a mixture of fuming HNO 1185. A mixture of the product of Example 1d (2 g, 7.9 (130 ul, 0.19 g, 3.1 mmol) and AcO (0.47 mL, 0.5g, 4.96 mmol) and the product of Example 1c (3.5g, 10.3 mmol) in mmol) at -10°C. and stirred at -10°C. for 20 minutes. The methanol (40 mL) was heated at 70° C. for 2 hours and reaction mixture was quenched with ice-cold water and cooled to room temperature. The mixture was made basic extracted with CHCl2. The extracts were washed with with 5% NaCO and extracted with EtOAc which was then ice-cold saturated NaHCO, water, dried over NaSO, washed with saturated NaHCO and water. The organic filtered and the Solvent evaporated under reduced pressure. extracts were dried over Na2SO and the Solvent was evapo The residue obtained was recrystallized from CHCl2/ rated under reduced pressure to give a thick oil, which was EtOAc/Hex to give the title compound as a white solid (0.17 purified by chromatography over Silica gel eluting with 1:2 g, 70%); mp 98-99° C. "H NMR (300 MHz, CDC1) & 8.05 EtOAc: Hex to give the title compound as a pale yellow solid (d, J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 6.41 (s, 1H), 5.50 (1.55 g, 57%); mp 92° C. "H NMR (300 MHz, CDC1) & (s, 2H), 3.93 (d, J=7.3 Hz, 2H), 3.13 (s, 3H), 1.80-1.97 (m, 7.15-7.30 (m, 4H), 6.76 (s, 1H), 3.99 (d, J–74 Hz, 2H), 3.94 1H), 1.40-1.68 (m, 5H), 1.00-1.28 (m, 3H), 0.67-0.82 (m, (s, 3H), 2.54 (s, 3H), 1.82-2.00 (m, 1H), 1.35-1.63 (m, 5H), 2H); C NMR (75 MHz, CDC1) & 138.31, 138.27, 135.6, 0.97-1.18 (m, 3H), 0.67-084 (m, 2H). 'C NMR (75 MHz, 130.7, 124.7, 122.7, 102.2, 63.2, 50.9, 39.2, 33.6, 25.3, 20.9, CDC1) & 163.1, 145.2, 142.6, 140.2, 129.6, 126.5, 126.3, 20.3; mass spectrum (API-TIS) m/z 394 (MH"). Anal. calcd 108.9, 56.4,52.1, 38.7, 30.5, 26.3, 25.6, 15.4; mass spectrum for C.H.N.O.S: C, 54.95; H, 5.89; N, 10.68; S, 8.15. (API-TIS) m/z 345 (MH"). Anal. calcd for CHNOS: C, Found: C, 54.96; H, 5.94; N, 10.49; S, 8.31. 66.25; H, 7.02; N, 8.13. Found: C, 66.31; H, 7.20; N, 8.15. 1186 1f. (1-(Cyclohexylmethyl)-5-(4-methylthiophe Example 2 nyl)pyrazol-3-yl)methan-1-ol 1-(1-Cyclohexylmethyl-3-((nitrooxy)methyl)pyra 1187 Lithium aluminum hydride (2.0 mL of 1M solution zol-5-yl)-4-(methylsulfonyl) Benzene in THF, 79.0 mg, 2.09 mmol) was added dropwise to a solution of the product of Example 1e (0.72 g, 2.09 mmol) 1192) 2a. Methyl (2Z)-2-hydroxy-4-(4-(methylsulfo in THF (14 mL) at 0°C. The yellow solution was stirred at nyl)phenyl)-4-oxobut-2-enoate room temperature for 1 hour. Solid NaSO.10HO was 1193 Sodium methoxide was prepared by dissolving Na added portionwise to the reaction mixture at 0°C., followed (6.9 g, 30 mmol) in MeOH (400 mL). The solution was by few drops of water and 0.1 N NaOH. The solid was cooled to 0° C. Dimethyl oxalate (33 g, 280 mmol) was filtered and washed with EtOAc. The solvent was evapo added followed by 1-(4-(methylsulfonyl)phenyl)ethan-1- rated to give the title compound (0.5 g, 76%) as a white one (28 g., 140 mmol). The reaction mixture was allowed to foam. H NMR (300 MHz, CDC1) & 7.13-7.30 (m, 4H), warm to room temperature and stirred for 18 hours. The 6.22 (s, 1H), 4.70 (s, 2H), 3.88 (d, J=7.3 Hz, 2H), 3.65 (bs, MeOH was evaporated and the residue triturated with 1N 1H), 2.53 (s, 3H), 1.75-1.83 (m, 1H), 1.40-1.68 (m, 5H), HCl (600 mL). The solid was collected on filter paper, 0.92-1.28 (m, 3H), 0.60-082 (m, 2H); C NMR (75 MHz, washed with HO (2x250), and dried in vacuo. This gave the CDC1) & 1515, 1448, 139.5, 129.3, 127.2, 126.1, 104.6, title compound (39 g, 100%) as a tan solid. 'H-NMR (300 58.0, 55.3, 38.7, 30.3, 26.0, 25.5, 15.1; mass spectrum MHz, CDC1) & 8.17 (d, J=6.9 Hz, 2H), 8.09 (d, J=6.9 Hz, (API-TIS) m/z. 317 (MH), 299 (M-OH). 2H), 7.10 (s, 1H), 3.97 (s, 3H), 3.10 (s, 3H). 1188) 19. 1-(1-(Cyclohexylmethyl)-3-(hydroxymeth 1194) 2b. Methyl 1-(cyclohexylmethyl)-5-(4-(methylsul yl)pyrazol-5-yl)-4-(methylsulfonyl)benzene fonyl)phenyl)pyrazole-3-carboxylate 1189 The product of Example 1 f(0.5g, 1.58 mmol) was 1195 The product of Example 1c (8 mL, 23 mmol) and dissolved in MeOH (32 mL). OXONE(E) (1.94g, 3.16 mmol) the product of Example 2a (4.5 g, 16 mmol) were added to US 2004/0072883 A1 Apr. 15, 2004

MeOH and heated at reflux for 3 hours. The reaction mixture the residue on Silica gel eluting with Hex:EtOAC 1:2 gave was cooled to room temperature and diluted with H2O (150 the title compound (200 mg, 51%) as a white solid, mp mL). The aqueous MeOH solution was extracted with 73-75° C. "H-NMR (300 MHz, CDC1) & 8.03 (d, J=8.2 Hz, CHCl (3x50). The combined organic extracts were washed 2H), 7.58 (d, J=8.2 Hz, 2H), 6.33 (s, 1H4.64 (t, J=4.1 Hz, with 1N NaCO (2x50) and 1N HCl (1x50), dried over 2H), 4.62 (s, 2H), 3.92 (d, J=7.3 Hz, 2H), 3.77 (brmult, 2H), NaSO, concentrated. The residue was crystallized from 3.67-3.69 (Mult 2H), 3.12 (s, 3H), 0.73-191 (mult, 10H); MeOH (15 mL) to give the title compound (3.5g, 58%) as a white solid. 'H-NMR (300 MHz, CDC1) & 8.06 (d, J=8.4 mass spectrum (API-TIS) m/z 393 (MH"). Anal calcd for Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 6.87 (s, 1H), 4.02 (d, J=7.5 C.H.N.O.S: C, 61.20; H, 7.19; N, 7.14. Found C, 60.97; Hz, 2H), 3.96 (s, 3H), 3.13 (s, 3H), 0.73-1.94 (mult, 11H). H, 6.99; N, 7.02. 1196 2c. 4-(1-(Cyclohexylmethyl)-3-(hydroxymeth 1202) 2f. 4-(1-(Cyclohexylmethyl)-3-((2-(nitrooxy yl)pyrazol-5-yl)-1-(methylsulfonyl)benzene )ethoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene 1197 A flask was charged with lithium aluminum 1203) Fuming 90% HNO (0.5 mL, 12 mmol) was cooled hydride (125 mg, 3.3 mmol) in THF (5 mL) and cooled to to 0°C. The product of Example 2e (200 mg, 0.5 mmol) was 0° C. The product of Example 2b (750 mg, 2 mmol) in THF added and allowed to stir at 0° C. for 45 minutes. The (5 mL) was added dropwise. The resulting mixture was reaction mixture was poured in to 0.5 N NaCO (20 mL). stirred at 0° C. for 15 minutes then warmed to room The aqueous mixture was extracted with EtOAc (2x15). The temperature with stirring for 1.5 hours. The excess lithium combined extracts were washed with brine, dried over aluminum hydride was destroyed by adding Sequentially NaSO, and concentrated. The residue was triturated with HO (150 ul), 15% NaOH (150 uL), HO (450 uL). The Hex:EtOAc 2:1 (2 ml). The solid was isolated by filtration precipitate that formed was removed by filtration through to give the title compound (100 mg, 50%) as a pale yellow Celite, the filter cake was washed with EtOAc (2x10). The solid. mp 98-100° C. H-NMR (300 MHz, CDC1) & 8.04 (d. combined filtrates were dried over NaSO and concentrated J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 6.36 (s, 1H), 4.64 (t, to give the title compound (790 mg, 100%) as a white solid. J=4.1 Hz, 2H), 4.60 (s, 2H), 3.92 (d, J=7.3 Hz, 2H), 3.83 (t, H-NMR (300 MHz, CDC1) & 8.04 (d, J-84 Hz, 2H), 7.58 J=44 Hz, 2H), 3.13 (s, 3H), 0.70-1.87 (nult, 11H); mass (d, J=8.4 Hz, 2H), 6.33 (s, 1H), 4.73 (d, J=5.1 Hz, 2H), 3.91 spectrum (API-TIS) m/z 348 (MH"). Anal calcd for (d, J=7.2 Hz, 2H), 3.13 (s, 3H), 0.73-2.09 (mult, 11H). C.H.N.O.S: C, 54.91; H, 6.22; N, 9.60. Found C, 54.17; 1198) 2d. 4-(3-(Bromomethyl)-1-(cyclohexylmeth H, 6.38; N, 9.24. yl)pyrazol-5-yl)-1-(methylsulfonyl)benzene Example 3 1199 The product of Example 2c (790 mg, 2 mmol) was dissolved in CHCl (5 ML). Phosphorous tribromide (100 4-(Methylsulfonyl)-1-(3-((nitrooxy)methyl)-1-ben AiL, 1 mmol) was added and the mixture was stirred at room Zylpyrazol-5-yl)benzene temperature for 18 hours. The reaction mixture was trans ferred to a separation funnel with CHCl (40 mL) and 1204 3a. Methyl 5-(4-(methylthiophenyl)-1-benzylpyra washed with HO (1x10) and dried over NaSO. Evapo Zole-3-carboxylate ration of the Solvent gave a residue that was filtered through silica gel eluting with Hex:EtOAc 1:1 to give the title 1205) A mixture of the product Example 1d (2 g, 7.9 compound (440 mg, 53%) as a white solid, mp 141-143° C. mmol) and benzylhydrazine hydrochloride (1.64 g, 10.3 H-NMR (300 MHz, CDC1) & 8.04 (d, J-8.2 Hz, 2H), 7.59 mmol) in methanol (40 mL) and trifluoroacetic acid (0.5 (d, J=8.2 Hz, 2H), 6.39 (s, 1H), 4.53 (s, 2H), 3.91 (d, J=7.3 mL) was heated at 70° C. for 2 hours and cooled to room Hz, 2H), 3.13 (s, 3H), 0.73-1.88 (mult, 1H); mass spectrum temperature. The mixture was made basic with 5% NaCO (API-TIS) m/z 411 (MH"). Anal calcd for C.HBrNOS: and extracted with EtOAc which was then washed with C, 52.56; H, 5.64; N, 6.81. Found C, 52.47; H, 5.67; N, 6.65. saturated NaHCO and water. The organic extracts were dried over NaSO and the solvent was evaporated. The 1200) 2e. 4-(1-(Cyclohexylmethyl)-3-((2-hydroxy residue was recrystallized from CHCl/EtOAc/Hex to give ethoxy)methyl)pyrazol-5-yl)-1 (methylsulfonyl)benzene the title compound as a white solid (1.88 g., 70%); mp. 94-96 1201) To a slurry of 95% NaH (75 mg, 3 mmol) in THF C. "H NMR (300 MHz, CDC1) & 7.12-7.30 (m, 7H), (5 mL) was added 2-benzyloxyethanol (275 uL, 2 mmol). 7.00-7.08 (m, 2H), 6.87 (s, 1H), 5.41 (s, 2H), 3.95 (s, 3H), The mixture was stirred at room temperature for 15 minutes 2.50 (s, 3H). 'C NMR (75 MHz, CDC1) & 1630, 145.2, by which time effervescence had ceased. The product of 143.1, 140.6, 136.7, 129.4, 128.8, 127.9, 126.9, 126.3, Example 2d (410 mg, 1 mmol) in THF (2 mL) was added 126.0, 109.4, 54.2, 52.2, 15.4; mass spectrum (API-TIS) m/z. and the reaction mixture was Stirred at room temperature for 339 (MH), 307 (M-OCH); Anal. Calcd for CHNOS: 18 hours. Excess NaH was quenched with saturated NHCl C, 67.43; H, 5.36; N, 8.28; S, 9.47. Found: C, 67.56; H, 5.39; (20 mL). The aqueous THF was extracted with EtOAc N, 8.29; S, 9.39. (3x20). The combined extracts were washed with HO, 1206 3b. (5-(4-(Methylthiophenyl)-1-benzylpyrazol-3- brine, dried over NaSO, and concentrated. The residue was yl)methan-1-ol taken up in EtOAc (30 mL), 10% Pd/C (300 mg) was added and the mixture was shaken under 50 psi of hydrogen for 18 1207 The title compound was prepared as a white foam hours. The reaction mixture was filtered through Celite and in quantitative yield from the product of Example 3a by the filter cake was washed with EtOAc (2x25). The com following the procedure for Example 1.f. "H NMR (300 bined filtrate was washed with HO (2x25) and brine (1x25), MHz, CDC1) & 7.19-7.28 (m, 7H), 7.02-7.04 (m, 2H), 6.32 dried over NaSO, and concentrated. Chromatography of (s, 1H), 5.28 (s, 2H), 4.70 (s, 2H), 2.49 (s.3H). 'C NMR US 2004/0072883 A1 Apr. 15, 2004 34

(75 MHz, CDC1) & 152.1,144.9, 139.9,137.6, 129.3,128.8, 1214) 4b. Methyl (2E)-3-(1-(cyclohexylmethyl)-5-(4- 127.7, 127.1, 126.8, 126.4, 104.9, 59.1, 53.2, 15.5; mass methylthiophenyl)pyrazol-3-yl)prop-2-enoate spectrum (API-TIS) m/z. 311 (MH"), 293 (M-OH). 1215 n-Butyl lithium (2.5 M solution in hexane, 1.65 1208 3c. 1-(3-(Hydroxymethyl)-1-benzylpyrazol-5-yl)- mL, 0.27g, 4.14 mmol) was added dropwise to a Solution of 4-(methylsulfonyl)benzene trimethylphosphonoacetate (0.70 g, 3.82 mmol) in THF (7 mL) at -78°C. The resultant solution was stirred at -78°C. 1209 The title compound was prepared as a white solid for 1 hour. To this solution the product from Example 4a (1.0 (0.55g, 66%) from the product of Example 3b by following g, 3.18 mmol) in THF (7 mL) was added dropwise. The the procedure for Example 1g. mp 155° C.; H NMR (300 reaction mixture was stirred at -78 C. for 1 hour. The MHz, CDC1) & 7.96 (d, J=8.4 Hz, 2H), 7.51 (dd, J=1.7 and reaction mixture was gradually allowed to warm to room 6.9 Hz, 2H), 7.27-7.30 (m, 3H), 7.02-7.05 (m, 2H), 6.45 (s, temperature and stirred for 24 hours. Water was added and 1H), 5.33 (s, 2H), 4.76 (d, J=5.8 Hz, 2H), 3.08 (s, 3H), 2.26 extracted with EtOAc, which was then washed with water, (t, J-5.9 Hz, 1H). C NMR (75 MHz, CDC1) & 1524, dried over NaSO and filtered. The residue obtained after 143.2, 140.6, 137.0, 136.0, 129.7, 129.0, 127.9, 126.6, evaporation of the Solvent was purified by chromatography 106.0, 59.0, 53.6, 44.6. Mass spectrum (API-TIS) m/z 343 over silica gel eluting with 1:9 to 2:8 EtOAc: Hexane to give (MH"). Anal. Calcd for CHNOS: C, 63.14; H, 5.30; N, the pure E-isomer (1.04g, 88%) as a colorless oil. "H NMR 8.18; S, 9.36. Found: C, 62.97; H, 5.23; N, 8.03; S, 9.16. (300 MHz, CDC1) & 7.69 (d, J=16.0 Hz, 1H), 7.20-7.34 (m, 1210 3d. 4-(Methylsulfonyl)-1-(3-((nitrooxyl)methyl)- 4H), 6.45 (s, 1H), 6.40 (d. J=16.2 Hz, 1H), 3.92 (d. J=7.3 Hz, 1-benzylpyrazol-5-yl)benzene 2H), 3.79 (s.3H), 2.53 (s.3H), 1.80-198 (m, 1H), 1.37-170 1211. The title compound was prepared as a white solid (m, 5H), 0.92-122 (m, 3H), 0.62-082 (m, 2H); C NMR (0.22 g, 57%) from the product of Example 3c by following (75 MHz, CDC1) & 1676, 147.2, 145.4,140.0, 137.3, 129.6, the procedure for Example 1 h; mp 93-94 C.; H NMR (300 127.0, 126.3, 118.5, 105.1, 56.0, 51.7, 38.9, 30.6, 26.3, 25.7, MHz, CDC1) & 7.97 (dd, J=1.6 and 6.8 Hz, 2H), 7.49 (dd. 15.5; mass spectrum (API-TIS) m/z. 371 (MH"); Anal. Calcd J=1.7 and 6.7 Hz, 2H), 7.26-7.33 (m, 3H), 7.01-703 (m, for CHNOS: C, 68.08; H, 7.07; N, 7.56. Found: C, 2H), 6.53 (s, 1H), 5.54 (s, 2H), 5.35 (s, 2H), 3.08 (s.3H). 'C 67.77; H, 6.76; N, 7.39. NMR (75 MHz, CDC1) & 1443,143.6, 141.1,136.6, 135.4, 1216 4c. (2E)-3-(1-(Cyclohexylmethyl)-5-(4-methylth 129.8, 129.0, 128.2, 128.0, 126.7, 108.1, 68.4, 53.9, 44.5; iophenyl)pyrazol-3-yl)prop-2-en-1-ol mass spectrum (API-TIS) m/z 388 (MH"). Anal. Calcd for 1217 Lithium aluminum hydride (2.0 mL of 1M solution CH-NOS: C, 55.81; H, 4.42; N, 10.85; S, 8.28. Found: in THF, 75.9 mg, 2.0 mmol) was added dropwise to a C, 55.57; H, 4.37; N, 10.78; S, 8.50. solution of the product of Example 4b (0.74g, 2.0 mmol) in Example 4 THF (11 mL) at 0°C. The yellow solution was stirred for 30 min at 0° C. and at room temperature for 30 min. Solid 1-(3-(1E)-3-(nitrooxy)prop-1-enyl)-1-(cyclohexyl NaSO.10HO was added portionwise to the reaction mix methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene ture at 0° C., followed by few drops of water and 0.1 N NaOH. The Solid was filtered and washed with EtOAc. The 1212) 4a. 1-(Cyclohexylmethyl)-5-(4-methylthiophe Solvent was evaporated and the product was purified by nyl)pyrazole-3-carbaldehyde column chromatograpy to give the title compound (0.44 g, 1213) To a stirred solution of oxalyl chloride (0.60 mL, 64%) as an oil and 3-(1-(cyclohexylmethyl)-5-(4-methylth 0.87 g., 6.8 mmol) in CHCl (2.3 mL) at -78° C. under iophenyl)pyrazol-3-yl) propan-1-ol (0.21 g, 31%) as a minor nitrogen was added DMSO (0.97 mL, 1.06 g., 13.7 mmol) in product. H NMR (300 MHz, CDC1) & 7.24-7.33 (m, 4H), CHCl (1.8 mL) dropwise over a period of 20 min. To this 6.66 (dt, J=1.2 and 16.0 Hz, 1H), 6.32-6.42 (m, 1H), 6.32 (s, solution the product of Example 1f (1.73 g, 5.47 mmol) in 1H), 4.31 (dd, J=1.3 and 5.7 Hz, 2H), 3.88 (d, J=7.4 Hz, 2H), CHCl (10 mL) was added dropwise over a period of 40 2.53 (s, 3H), 1.75-193 (m, 1H), 1.40-1.84 (m, 5H), 0.98 minutes at -78 C. The mixture was stirred at -78 C. for 1.5 1.28 (m, 3H), 0.64–0.83 (m, 2H); 'C NMR (75 MHz, hours. Triethylamine (3.8 mL, 2.77g, 27.3 mmol) in CHCl CDC1) & 149.1, 1448, 139.5, 130.2, 129.5, 127.5, 126.3, (2.3 mL) was then added dropwise over a period of 45 123.4, 103.0, 63.5, 55.6, 38.9, 30.6, 26.3, 25.7, 15.5; mass minutes at -78°C. The resultant mixture was stirred at 0°C. spectrum (API-TIS) m/z 343 (MH); Anal. Calcd for for 20 minutes. To this mixture, water (2 mL) was added CHNOS: C, 70.14; H, 7.65; N, 8.18. Found: C, 70.13; dropwise followed by CHCl (50 mL). The organic layer H, 7.72; N, 8.18. was separated and the aqueous layer was extracted with 1218 4d. 1-(3-(1E)-3-Hydroxyprop-1-enyl)-1-(cyclo CHCl2. The combined organic extracts were washed with hexylmethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene 5% HCl, dried over NaSO and filtered. The residue after evaporation of the Solvent was chromatographed on Silica 1219. The product of Example 4c (0.44 g, 1.29 mmol) gel eluting with 1:9 EtOAC/Hexane to give the title com was dissolved in MeOH (16 mL). OXONE(R) (1.58 g, 2.57 pound (1.6 g., 93%) as a clear oil. H NMR (300 MHz, mmol) in water (3 mL) was added at room temperature. The CDC1) & 9.99 (s, 1H), 7.22-7.37 (m, 4H), 6.75 (s, 1H), 4.01 reaction mixture was stirred for 1 hour and then filtered to (d, J=7.4 Hz, 2H), 2.54 (s.3H), 1.83-2.00 (m, 1H), 1.42-1.69 remove the solid. CHCl was added to the filtrate which (m, 5H), 1.00-1.25 (m, 3H), 0.73-089 (m, 2H). 'C NMR was washed with Saturated NaHCO, water, dried over (75 MHz, CDC1) & 1817, 145.3, 145.2, 1406,135.2, 1242, NaSO, and filtered. The solvent was evaporated to give the 120.9, 100.4, 51.2, 33.5, 25.2, 20.9, 20.3, 10.1; mass spec product (0.23g, 48%) as a white foam; mp 49-52 C.; H trum (API-TIS) m/z. 315 (MH"); Anal. Calcd for NMR (300 MHz, CDC1) & 8.03 (d, J–8.1 Hz, 2H), 7.59 (d. CHNOS: C, 68.75; H, 7.05; N, 8.91. Found: C, 68.48; J=8.2 Hz, 2H), 6.66 (d, J=16.1 Hz, 1H), 6.41 (s, 1H), H, 6.82; N, 8.88. 6.32-6.47 (m, 1H), 4.32 (bd, J=5.2 Hz, 2H), 3.91 (d, J=7.3

US 2004/0072883 A1 Apr. 15, 2004 36

Example 7 residue was treated with water and then extracted with ethyl acetate (1X250 mL). The combined organic extracts were Methyl (2E)-3-(1-(cyclohexylmethyl)-5-(4-(methyl washed with water (4x250 mL), brine (1x250 mL), dried Sulfonyl)phenyl) pyrazol-3-yl)prop-2-enoate over Sodium Sulfate, treated with charcoal, filtered and 1232 7a. Methyl (2E)-3-(1-(cyclohexylmethyl)-5-(4- concentrated to give the crude product. Purification by (methylsulfonyl)phenyl)pyrazol-3-yl) prop-2-enoate column chromatography over Silica gel using 5% ethyl acetate in hexane gave a thick oil (1.3 g) that was a mixture 1233. The title compound was prepared as a white foam (85:15) of 2-(3-(4-methylthiophenyl)-5-(trifluoromethyl)(2- (0.24g, 74%) from the product of Example 4b by following pyridyl)-2-phenylethanenitrile and 3-(4-methylthiophenyl)- the procedure for Example 4d; mp 48-50° C.; H NMR (300 5-(trifluoromethyl)(2-pyridyl) phenyl ketone. This mixture MHz, CDC1) & 8.06 (d, J=8.3 Hz, 2H), 7.70 (d, J=16.0 Hz, was dissolved in methanol (60 mL) and OXONE(R) (4.35 g, 1H), 7.60 (d, J=8.2 Hz, 2H), 6.54 (s, 1H), 6.44 (d, J=16.0 Hz, 7.1 mmol) in water (15 mL) was added, and then stirred at 1H), 3.95 (d, J=7.3 Hz, 2H), 3.81 (s, 3H), 3.13 (s, 3H), room temperature for 1.5 hours. The resulting mixture was 1.80-1.95 (m, 1H), 1.38-1.70 (m, 5H), 0.98-1.27 (m, 3H), neutralized with ammonium hydroxide, the Solvent was 0.62-0.87 (n, 2H); C NMR (75 MHz, CDC1) & 1674, evaporated and the residue extracted with ethyl acetate 147.5, 143.7, 140.9, 136.7, 136.1, 130.1, 128.1, 119.1, (2x50 mL). The combined organic extracts were washed 106.0, 56.3, 51.8, 44.6, 39.0, 30.6, 26.2, 25.7; mass spectrum with water (2x50 mL), brine (1x25 mL), dried over sodium (API-TIS) m/z 403 (MH); Anal. calcd for C. H.N.O.S: Sulfate, filtered and Solvent was evaporated to give the crude C, 62.66; H, 6.51; N, 6.96. Found: C, 62.40; H, 6.49; N, product. Purification by column chromatography over Silica 6.84. gel using a gradient of 20 to 40% ethyl acetate in hexane gave the less polar compound, 3-(4-(methylsulfonyl)phe Example 8 nyl)-5-(trifluoromethyl)(2-pyridyl) phenyl ketone, as a white crystalline product (85 mg), mp 141-142 C. "H NMR Methyl (CDC1) & 9.03 (s, 1H), 8.14 (d, J=1.3 Hz, 1H), 7.96 (d. 5-(4-(methylsulfonyl)phenyl)-1-benzylpyrazole-3- J=8.3 Hz, 2H), 7.85 (dd, J=7.2 and 1.0 Hz, 2H), 7.66 (t, carboxylate J=7.6 Hz, 1H), 7.58 (d. J=8.3 Hz, 2H), 7.51 (t, J-7.5 Hz, 1234 8a. Methyl 5-(4-(methylsulfonyl)phenyl)-1-ben 2H), 3.03 (s.3H); 'CNMR (CDC1) & 193.1, 158.2, 145.05, Zylpyrazole-3-carboxylate 1415, 140.7, 135.3, 134.3, 130.3 (2C), 129.7 (2C), 128.2 1235. The title compound was prepared from the product (2C), 127.8, (2C), 127.0 (q, J=33 Hz, CFs), 124.6, 121.0, of Example 3a by following the procedure for Example 4d 44.3; LRMS (APIMS) m/z 406 (M+H)". to give a white solid (0.23g, 63% yield); mp 142-143° C. "H 1238 9b. 2-(3-(4-(methylsulfonyl)phenyl)-5-(trifluorom NMR (300 MHz, CDC1) & 7.96 (d, J=8.1 Hz, 2H), 7.48 (d. ethyl)(2-pyridyl)-2-phenylethanenitrile J=8.1 Hz, 2H), 7.27-7.28 (m, 3H), 6.98-7.02 (m, 2H), 6.98 1239 Purification of the more polar fractions of the (s, 1H), 5.45 (s, 2H), 3.98 (s, 3H), 3.08 (s, 3H). 'C NMR product of Example 9a by column chromatography over (75 MHz, CDC1) & 1626, 143.5, 143.4,141.3, 136.1,135.0, Silica gel using a gradient of 20 to 40% ethyl acetate in 129.9, 129.0, 128.2, 128.0, 126.8, 110.4, 54.7, 52.4, 44.6; hexane gave the title compound, 2-(3-(4-(methylsulfo mass spectrum (API-TIS) m/z. 371 (MH), 387 (MNH); nyl)phenyl)-5-(trifluoromethyl)(2-pyridyl))-2phenyle Anal. Calcd for ClHisN.O.S: C, 61.61; H, 4.90; N, 7.56, S, thanenitrile, 490 mg, as a light yellow solid; mp 78° C.; H 8.65. Found: C, 61.36; H, 4.85; N, 7.46; S, 8.95. NMR (CDC1) & 9.05 (s, 1H), 8.10 (d, J=1.6 Hz, 2H), 7.80 (s, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.33 (m, 3H), 7.16 (m, 2H), Example 9 5.42(s, 1H), 3.18 (s.3H); CNMR (CDC1) & 155.0, 146.6, 3-(4-(Methylsulfonyl)phenyl)-5-(trifluoromethyl)(2- 1416, 1414, 135.5, 135.1, 133.6, 130.1 (2C), 129.2 (2C), pyridyl) Phenyl Ketone and 2-(3-(4-(methylsulfo 128.1, 127.8, (2C), 127.0 (2xC), 126.3 (q, J=33 Hz, CF), nyl)phenyl)-5-(trifluoromethyl)(2-pyridyl))-2-phe 124.6, 121.0, 118.1, 44.4, 42.3; LRMS (APIMS) m/z. 417 nylethanenitrile (M+H)". 1236 9a. 3-(4-(Methylsulfonyl)phenyl)-5-(trifluorom Example 10 ethyl)(2-pyridyl) Phenyl Ketone 3-Fluorophenyl 1237 To 2-(3-Chloro-5-(trifluoromethyl)(2-pyridyl)-2- 2-(4-(methylsulfonyl)phenyl)(3-pyridyl) ketone phenylethanenitrile (Ryan Scientific Inc., South Carolina, U.S., 4.8 g., 16.17 mmol) and 4-(methylthio)benzeneboronic 1240) 10a, 2-Chloro(3-pyridyl) 3-fluorophenyl Ketone acid (4.15g, 25 mmol) dissolved in anhydrous dioxane (80 1241 The Grignard reagent was prepared by refluxing mL) were added Successively, tris(dibenzylideneacetone)di 1-bromo-3-fluorobenzene (1.75 g, 10 mmol) and magne palladium (0.58 g., 0.633 mmol), tri-tert-butylphosphine sium metal (267 mg, 11 mmol) and a few crystals of iodine (150 mg, 0.724 mmol) followed by cesium carbonate (6.5g, in anhydrous THF (40 mL) under nitrogen atmosphere until 20 mmol). The resulting mixture was heated at reflux most of the magnesium metal was consumed. The reagent overnight under a nitrogen atmosphere. Additional 4-(me was cooled to room temperature and 2-chloro-3-nicotinoyl thylthio)benzeneboronic acid (4.15g, 25 mmol), tris(diben chloride (1.76 g, 10 mmol) in anhydrous THF (20 mL) was Zylideneacetone)dipalladium(0) (0.58 g., 0.633 mmol), tri added and the resulting mixture was stirred at room tem tert-butylphosphine (150 mg, 0.724 mmol) and cesium perature for 15 minutes and then quenched with Saturated carbonate (6.5 g, 20 mmol) were added and the reaction aqueous ammonium chloride Solution. The organic layer mixture was heated at reflux for another 24 hours, then was separated and the aqueous layer was extracted with cooled to room temperature and Solvent was evaporated. The ethyl acetate (1x50 mL). The combined organic layers were US 2004/0072883 A1 Apr. 15, 2004 37 dried over anhydrous sodium sulfate, filtered and the filtrate 4-(methylthio)benzeneboronic acid (830 mg, 5 mmol) were concentrated to give the crude product. Purification by flash dissolved in toluene (50 mL) and ethanol (5 mL). To this column chromatography using 20% ethyl acetate in hexane solution was added 2 MNaCO (6 mL, 12 mmol) followed gave the title compound (2.35 g) in nearly quantitative yield, by tetrakis (triphenylphosphine)palladium (250 mg, 0.2 as a colorless thick oil. "H NMR (CDC1) & 8.54 (dd, J=5.0, mmol) and the resulting mixture was refluxed overnight 3.0 Hz, 1H), 7.73 (dd, J-7.5, 1.9 Hz, 1H), 7.5-7.2 (m, 5H); under nitrogen atmosphere. The mixture was then cooled to 'C NMR (CDC1) & 1920, 1644, 161.1, 1511, 147.6, room temperature and diluted with water (25 mL), stirred 139.9, 134.3, 130.4, (d, J-7.5 Hz), 125.8, 122.3, 121.2 (d. and the aqueous layer was separated and extracted with ethyl J=22 Hz), 116.2 (d, J =22 Hz); LRMS (APIMS) m/z. acetate (1x75 mL). The combined organic layers were 236 (M+H)". washed with water (2x50 mL), brine (1x50 mL), dried over Sodium Sulfate, filtered and concentrated at reduced preSSure 1242 10b. 3-Fluorophenyl 2-(4-methylthiophenyl)(3-py to give the crude product. Purification by column chroma ridyl) Ketone tography over Silica gel using 40% ethyl acetate in hexane 1243 The product of Example 10a (1.41 g, 6 mmol) and gave the title compound (770 mg, 68% yield) as a white 4-(methylthio)benzeneboronic acid (1.66 g, 10 mmol) were solid; mp 122-123° C.; H NMR (CDC1) & 8.87 (dd, J=4.8 dissolved in toluene (125 mL) and 2 M NaCO (6 mL, 12 and 1.7 Hz, 1H), 8.45 (d, J=4.7 Hz, 1H), 8.0 (dd, J=7.7 and mmol) was added. To this mixture was added ethanol (10 1.4 Hz, 2H), 7.75 (m, 1H), 7.45-7.3 (m, 4H), 7.12 (d. J=8.4 mL) followed by tetrakis (triphenylphosphine) palladium Hz, 2H), 2.44 (s, 3H); C NMR (CDC1) & 1960, 1576, (450 mg, 0.4 mmol) and the mixture was refluxed overnight 153.5, 150.7, 148.8, 139.3, 137.4, 136.6, 136.5, 133.6, 129.4 under nitrogen atmosphere. The mixture was then cooled to (2C), 126.5, 125.7 (2C), 123.5, 121.1, 15.3; LRMS (APIMS) room temperature and diluted with water (25 mL), stirred, m/z 307 (M+H)". and the aqueous layer was separated and extracted with ethyl 1248) 11b. 2-(4-(Methylsulfonyl)phenyl)(3-pyridyl) acetate (1x75 mL). The combined organic layers were 2-pyridyl Ketone washed with water (4x50 mL), brine (1x50 mL), dried over Sodium Sulfate, filtered and concentrated at reduced pressure 1249. The product of Example 11a (670 mg, 2.2 mmol) to give the crude product. Purification by column chroma was dissolved in MeOH (50 mL). To this solution, tography over Silica gel using 20% ethyl acetate in hexane OXONE(E) (3.07 g., 5 mmol) dissolved in HO (20 mL) was gave the title compound (900 mg, 46% yield) as a white added. The reaction mixture was stirred at room temperature solid; mp 91-92 C.; H NMR (CDC1) 88.88 (dd, J=4.8, 1.7 overnight, it was then diluted with water, ammonium HZ, 1H), 7.88 (dd, J=7.6, 1.6 Hz, 1H), 7.5-7.35 (m, 5H), hydroxide added until the solution became basic and the 7.3-7.25 (m, 1H), 7.2-7.15 (m, 3H), 2.51 (s, 3H); LRMS Solvent was evaporated. The product was extracted with (APIMS) m/z 324 (M+H)". ethyl acetate (2x75 mL), washed with brine (1x50 mL), dried over anhydrous sodium sulfate, filtered and solvent 1244 10c. 3-Fluorophenyl 2-(4-methylsulfonylphe evaporated at reduced pressure to give an oil which upon nyl)(3-pyridyl) ketone trituration with hexane:ethyl acetate (80:20) gave the title 1245) The product of Example 10b (650 mg, 1.857 compound (670 mg, 99%) as a white solid; mp 143-147 C.; mmol) was dissolved in MeOH (40 mL). To this solution, H NMR (CDC1) & 8.90 (dd, J=4.8 and 1.6 Hz, 1H), 8.43 OXONE(E) (2.848g, 4.64 mmol) dissolved in HO (10 mL) (d, J=4.3 Hz, 1H), 8.06 (d, J=7.7, 2H), 7.80 (m,3H), 7.71 (d. was added. The mixture was stirred at room temperature for J=8.4 Hz, 2H), 7.52 (dd, J=7.7 and 4.8 Hz, 1H), 7.3 (m, 1H), 1.5 hours, then diluted with water, and ammonium hydrox 3.0 (s, 3H); 'CNMR (CDC1) & 196.2, 1564, 153.1, 150.9, ide added until the Solution became basic. The solvent was 148.9, 145.5, 140.1, 137.7, 136.9, 134.3, 130.1 (2C), 127.1 evaporated and the product was extracted with ethyl acetate (2C), 127.0, 123.7, 122.4, 44.4; LRMS (APIMS) m/z 339 (2x75 mL), washed with brine (1x50 mL), dried over (M+H)". anhydrous Sodium Sulfate, filtered and Solvent evaporated at reduced pressure to give an oil which upon trituration with Example 12 hexane/ethyl acetate gave the title compound (650 mg, 99% yield); mp 157-159° C.; H NMR (CDC1) & 8.92 (d. J=4.7 Ethyl Hz, 1H), 7.94 (d, J-7.7 Hz, 1H), 7.88 (d, J-7.6 Hz, 2H), 7.74 3-((2-(4-(methylsulfonyl)phenyl)-3-pyridyl)carbonyl) (d, J=7.8 Hz, 2H), 7.53 (dd, J=7.7, 4.8 Hz, 1H), 7.47-7.3 (m, benzoate 3H), 7.2 (m, 1H), 3.18 (s, 3H); 'C NMR (CDC1) & 195.1, 1250 12a. Ethyl 3-((2-(4-methylthiophenyl)-3-pyridyl 1641, 160.8, 155.4, 151.3, 144.3, 140.5, 138.3, (d. J=6.4 )carbonyl)benzoate Hz), 137.1, 134.1, 130.1 (2C), 128.1 (2C), 125.7., (d, J=3 1251) To ethyl 3-((2-chloro-3-pyridyl)carbonyl)benzoate Hz), 122.5, 120.8 (d, J=21.5 Hz), 116.2 (d, J=22 Hz), 44.4; (Ryan Scientific Inc., South Carolina, U.S., 950 mg, 3.3 LRMS (APIMS) m/z. 356 (M+H)". mmol) in ethanol (5 mL) was added 2 MNaCO (3.3 mL, 6.6 mmol) followed by tetrakis (triphenylphosphine)palla Example 11 dium (250 mg, 0.2 mmol) and the resulting mixture was refluxed overnight under nitrogen atmosphere. The mixture 2-(4-(Methylsulfonyl)phenyl)(3-pyridyl) 2-pyridyl was then cooled to room temperature and diluted with water Ketone (25 mL), Stirred and the aqueous layer was separated and 1246 11a. 2-(4-Methylthiophenyl)(3-pyridyl) 2-pyridyl extracted with ethyl acetate (1x75 mL). The combined organic layers were washed with water (2x50 mL), brine Ketone (1x50 mL), dried over sodium sulfate, filtered and evapo 1247 2-Chloro(3-pyridyl) 2-pyridyl ketone (Ryan Scien rated to give the crude product. Purification by column tific Inc., South Carolina, U.S.) (810 mg, 3.7 mmol) and chromatography over Silica gel using 10% ethyl acetate in US 2004/0072883 A1 Apr. 15, 2004 38 hexane gave the title compound (1.24 g) as a thick oil in wells not incubated with LPS received 2 ul of DMSO.) For nearly quantitative yield. H NMR (CDC1) & 8.9 (dd, J=7.8, the stimulation of COX-1, the calcium ionophore, A23 187 1.8 Hz, 1H), 8.31 (s, 1H), 8.16 (dt, J=7.9, 1.4 Hz, 1H), 7.91 (free acid from Sigma Chemical Co., St. Louis, Mo., Cata (dd, J=7.7, 1.8 Hz, 1H), 7.88 (dt, J=7.9 and 1.4 Hz, 1H), logue No. C7522) was added at 25uM (1 uL of 25 mM stock 7.5-7.4 (m, 4H), 7.15 (d, J=7.7 Hz, 2H), 4.40 (q, J=7.1 Hz, in DMSO) to separate wells 4.5 hours after the addition of 2H), 2.43 (s.3H), 1.42 (t, J=7.1 Hz, 3H); C NMR (CDC1) the test compound. (Again, basal, background or control & 196.4, 165.4, 156.9, 151.1, 140.1, 137.2, 136.7, 135.7, wells not stimulated with A23.187 received 1 uL of DMSO.) 1340,133.6, 130.8, 129.5 (2xC), 128.6, 125.9, (2C), 121.5, At 5 hours after the addition of the test compound, all 61.3, 15.3 14.2; LRMS (APIMS) m/z. 378 (M+H)". incubations were terminated by placement on ice and the addition of 2 mM EGTA (100 ul of 20 mM EGTA, 1252) 12b. Ethyl 3-((2-(4-(methylsulfonyl)phenyl)-3-py tetrasodium, in PBS (phosphate buffered saline) without ridyl)carbonyl)benzoate Ca" and Mg", pH 7.2)). The resulting solutions, were 1253) To the product of Example 12a (1.3g, 3.44 mmol) transferred by polyethylene transfer pipettes to 15 mL in MeOH (180 mL) was added OXONE(R) (6.14g, 10 mmol) polypropylene centrifuge tubes and centrifuged at 1200 g for dissolved in H2O (50 mL). The resulting mixture was stirred 10 minutes at 4 C. One hundred lull of plasma was removed at room temperature for 1 hour, then diluted with water, and from each blood sample and added to 1 mL of methanol in ammonium hydroxide was added until the Solution became new 15 mL polypropylene centrifuge tubes, Vortexed, and basic and the Solvent was evaporated. The product was stored overnight at -20° C. The next day, the samples were extracted with ethyl acetate (2x75 mL), washed with brine centrifuged at 2000 g for 10 minutes at 4 C. and the (1x50 mL), dried over anhydrous sodium sulfate, filtered Supernatants transferred to glass tubes and evaporated to and Solvent evaporated to give an oil which upon trituration dryneSS. The Samples were assayed for thromboxane B. with hexane:ethyl acetate (90:10) gave the title compound using EIA kits Supplied by Cayman Chemical Co. (Ann (1.34g, 95% yield) as a white solid; mp 125-132° C.; H Arbor, Mich., Catalogue No. 519031) in duplicate wells NMR (CDC1) & 8.92 (dd, J=4.5, 1.1 Hz, 1H), 8.30 (s, 1H), after reconstitution with EIA Buffer and appropriate dilution 8.16 (d, J-7.7 Hz, 1H), 7.96 (dd, J-7.7, 1.41 Hz, 1H), 7.90 (2000 fold for COX-1 and 500 fold for Cox-2 samples). (d, J=7.9 Hz, 1H), 7.84 (d, J=8.3 Hz, 2H), 7.75 (d, J=8.3 Hz, 2H), 7.54 (dd, J=7.7, 4.9 Hz, 1H), 7.46 (t, J=7.2 Hz, 1H), 1256). The % inhibition for COX-1 and COX-2 enzyme 4.39 (q, J=7.2 Hz, 2H), 2.97 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); activity in human whole blood by the test compounds, at the 'C NMR (CDC1) & 195.5, 165. 1, 155.5, 151.3, 1444, indicated concentrations, are given in Table 1. 140.4, 137.3, 136.4, 134.3, 134.1, 133.5, 131.0, 130.9, 130.1 (2C), 128.9, 127.3 (2C), 122.7, 61.4, 44.3, 14.2; LRMS TABLE 1. (APIMS) m/z 410 (M+H)". % INHIBITION OF COX-1 AND COX-2 ENZYME ACTIVITY IN HUMAN WEHOLE BLOOD Example 13 Test COX-1 Inhibition COX-2 Inhibition COX-2 Inhibition Compound (% at 100 uM) (% at 10 uM) (% at 1 uM) Assay for Human COX-1 and COX-2 Enzyme Example 1g 65 45 O Activity in Human Whole Blood Example 1h. 25 65 1O Example 2e 65 65 25 1254. The assay for COX-1 and COX-2 enzyme activity, Example 2f 70 75 2O in the human whole blood was performed as described in Example 3c 25 15 1O Brideau et al., Inflamm Res., 45: 68-74 (1996)). Human Example 3d 55 40 2O Example 4d 50 45 25 blood (s.50 mL) from male or female donors who had not Example 4e 40 75 35 received any aspirin or NSAIDs for 14 days was collected at Example Sb 90 90 45 two local area blood donor centers and placed in polypro Example 5c 90 1OO 75 pylene Syringes containing Sodium heparin (20 units per mL Example 6b 3O 1OO 70 Example 7 5 3O 15 blood, final concentration). The blood was transported to the Example 8 55 25 15 laboratory on ice packs and used within 1.5 hours of Example 9a 90 90 60 collection. Upon receipt in the laboratory, the blood was Example 9b -10 55 35 allowed to come to room temperature for 15 minutes prior Example 10c 5 50 55 to distribution in 1 mL aliquots per well of 24 well tissue Example 11b O 15 O culture plates. The plates were then placed on a gently Example 12b 25 2O 1O rotating platform shaker in a 5% CO incubator at 37 C. for 15 minutes. Test compounds were dissolved in DMSO, at 1000 fold the final desired concentration, and further diluted, 1257. The results show that the compounds in Table 1 as indicated, in DMSO. One till of each dilution of the test have COX-2 selectivity. compound was added per well, in duplicate wells, wells not receiving test compound (e.g., basal, background or control Example 10 wells) received 1 uL DMSO. Rat Carrageenan Air-Pouch 1255) To induce COX-2, lipopolysaccharide (LPS) from E. coli (LPS, serotype 026:B6 or serotype 0127:B8, Sigma 1258. The carrageenan air pouch model was performed as Chemical Co., St. Louis, Mo., Catalogue No. L3755 or described by Sedgwick, A. D., et al., Agents Actions 18, L3129, respectively) was added at 10 ug/mL (2 uL of 5 429-438, (1986) and Masferrer et al., Proc. Natl. Acad. Sci. mg/mLLPS in DMSO) to appropriate wells 15 minutes after 91, 3228-3232 (1994). Air pouches were produced by Sub the addition of the test compound. (Basal or background cutaneous injection of 20 ml of Sterile air on day (-6) into US 2004/0072883 A1 Apr. 15, 2004 39 the intrascapular area of the back of the anesthesia rat (male CD, Charles River, 175-200 g). An additional 10 mL of Sterile air was injected into the pouch 3 days later to keep the Space open and to assist in the development of the interior membrane. Six days after the initial air injection, 1 mL of a 1% Solution of carrageenan (Sigma, lambda fraction) dis Solved in pyrogen-free Saline was injected directly into the pouch to produce an inflammatory response. The test com pound in vehicle (3 mL/rat, 0.5% Methocel) was adminis tered by oral intubation 1 hour prior to carrageenan injection into the inflammatory pouch. After 4 hours the exudate was removed by pipette into a calibrated centrifuge tube and the Volume measured. The number of leukocytes in the exudate was determined by cell counting with a Beckman Coulter Particle Counter with the lower threshold set to exclude red blood cells. The exudate Samples were assayed without further processing for PGE (prostaglandin E) using PGE EIA kit-Monoclonal, friom Cayman Chemical Co. (Ann Arbor, Mich., Catalogue No. 514010). 1259. The % inhibition for the cell infiltration and the % inhibition for PGE by the test compounds, at the indicated concentrations, are given in Table 2.

TABLE 2 Test Cell Infiltration (% PGE-2 Compound inhibition (a 45 umol/kg) (%. Inhibition at (Q) 45 umol/kg) Example 2f 42 85

1260. The compound in Table 2 inhibited cell infiltration with an accompanying decrease in PGE levels. 1261 The disclosure of each patent, patent application and publication cited or described in the present specifica tion is hereby incorporated by reference herein in its entirety. 1262 Although the invention has been set forth in detail, one skilled in the art will appreciate that numerous changes and modifications can be made to the invention, and that Such changes and modifications can be made without depart ing from the Spirit and Scope of the invention. What is claimed is: 1. A compound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), or a pharmaceutically acceptable salt thereof; wherein the compound of Formula (I) is:

R1 SAS 2 l Z' N b Y1 2 M RS 51 Nx!

wherein: when Side b is a double bond, and Sides a and c are Single bonds, -X-Y-Z'- is:

US 2004/0072883 A1 Apr. 15, 2004 41

(j) alkenyl, (7) N.; (k) alkynyl; (8) -COD'; (l) unsubstituted, mono-, di-, tri- or tetra-Substituted (9) -CO-lower alkyl; cycloalkenyl, wherein the Substituents are each 12Y-3 1. independently: (10) –C(R')(R)-OD'; (1) halo; (11) -C(R 2)(R)-O-lower alkyl; (2) alkoxy, (12) lower alkyl-CO-R'; (3) alkylthio; (13) benzyloxy; (4) CN: (14) -O-(lower alkyl)-COR'; or (5) haloalkyl, preferably CF; (15) -O-(lower alkyl)-NR'R'; (6) lower alkyl; (o) phenylacetylene, mono- or di-Substituted pheny (7) N.; lacetylene, wherein the Substituents are each inde pendently: (8) -COD';1. (1) halo; (9) coast ally (2) alkoxy, (10)10) -CR(R')(R') (R-OD: s (3) alkylthio; (11) –C(R')(R)-O-lower alkyl; (4) CN: (12) lower alkyl-CO-R'; (5) haloalkyl, preferably CF; (13) benzyloxy; (14) -O-(lower alkyl)-COR'; (6) lower alkyl; (15) -O-(lower alkyl)-NR'R'; or (7) N.; (16) alkylsulfinyl; (8) -COD'; (m) mono-, di-, tri- or tetra-Substituted heterocy- (9)9) -CO-l-lower alIkvl: Kyl; cloalkyl group of 5, 6 or 7 members, or a benzohet- (10) –C(R)(R)-OD'; erocycle, wherein Said heterocycloalkyl or benzohet- ?(R 12YR 13Y. erocycle contains 1 or 2 heteroatoms Selected from (11) -C(R')(R')-O-lower alkyl; O, S, or N and, optionally, contains a carbonyl group (12) lower alkyl-CO-R'; or a Sulfonyl group, and wherein Said Substituents are each independently: (13) benzyloxy; (1) halo; (14) -O-(lower alkyl)-COR'; or (2) lower alkyl; (15) -O-(lower alkyl)-NR'R'; (3) alkoxy; (p) fluoroalkenyl; (4) alkylthio; (q) mono- or di-substituted bicyclic heteroaryl of 8, 9 (5) CN: or 10 members, containing 2, 3, 4 or 5 heteroatoms, s wherein at least one heteroatom resides on each ring (6) haloalkyl, preferably CF; of Said bicyclic heteroaryl, Said heteroatoms are each (7) N.; independently O, S and N and said substituents are 33 each independently: (8) –C(R)(R)-OD'; (1) hydrogen; (9) –C(R')(R)-O-lower alkyl; or (2) halo; (10) alkylsulfinyl; (3) lower alkyl; (n) Styryl, mono or di-Substituted Styryl, wherein the Substituent are each independently: (4) alkoxy, (1) halo; (5) alkylthio; (2) alkoxy, (6) CN: (3) alkylthio; (7) haloalkyl, preferably CF; (4) CN: (8) Na; (5) haloalkyl, preferably CF; (9) –C(R)(R)-OD'; or (6) lower alkyl; (10) -C(R)(R)-O-lower alkyl; US 2004/0072883 A1 Apr. 15, 2004 42

(r) K; (p) mono-, di- or tri-Substituted phenyl or naphthyl, (s) aryl; wherein the Substituents are each independently: (t) arylalkyl, (1) hydrogen; (u) cycloalkylalkyl, (2) halo; (3) alkoxy; (4) alkylthio; (u) hydrogen; (V) arylalkenyl; (5) CN: (6) haloalkyl, preferably CF; (w) arylalkoxy; (7) lower alkyl; (x) alkoxy, (8) Na; (y) aryloxy; (9) -COD'; (Z) cycloalkoxy; (10) -CO-lower alkyl; (aa) arylthio; (11) -(C(R)(R))-OD'; (bb) alkylthio; (12) -(C(R)(R))-O-lower alkyl; (cc) arylalkylthio; or (13) lower alkyl-CO-R; (dd) cycloalkylthio; (14) —OD'; R is: (15) haloalkoxy; (a) hydrogen; (16) amino; (b) haloalkyl, preferably CF; (17) nitro; or (c) CN; (18) alkylsulfinyl; (d) lower alkyl; (q) alkenyl; (r) alkynyl, (s) arylalkyl, (f) K; (t) lower alkyl-OD'; (g) unsubstituted or Substituted: (u) alkoxyalkyl, (1) lower alkyl-Q; (v) aminoalkyl, (2) lower alkyl-O-lower alkyl-Q; (w) lower alkyl-COR'; (3) lower alkyl-S-lower alkyl-Q; (x) lower alkyl-C(O)NR'(R'); (4) lower alkyl-O-Q; (y) heterocyclicalkyl, or (5) lower alkyl-S-Q; (z) heterocyclic ring-C(O)-; (6) lower alkyl-O-V; R", R", R and R are each independently: (7) lower alkyl-S-V; (a) hydrogen; (8) lower alkyl-O-K; or (b) amino; (9) lower alkyl-S-K; (c) CN; wherein the Substituent(s) reside on the lower alkyl group; (d) lower alkyl; (h) Q; (e) haloalkyl, (i) alkylcarbonyl, (f) alkoxy; (j) arylcarbonyl, (g) alkylthio; (k) alkylarylcarbonyl, (h) Q; (l) arylalkylcarbonyl; (i) -O-Q; (m) carboxylic ester; (j) -S-Q; (n) carboxamido; (k) K; (o) cycloalkyl, (l) cycloalkoxy; US 2004/0072883 A1 Apr. 15, 2004 43

(m) cycloalkylthio; (10) lower alkyl-O-V; or (n) unsubstituted, mono-, or di-Substituted phenyl or (11) lower alkyl-S-V; unsubstituted, mono-, or disubstituted benzyl, wherein the Substituents are each independently: wherein the Substituent(s) resides on the lower alkyl; (1) halo; (t) cycloalkyl, (2) lower alkyl; (u) aryl; (3) alkoxy; (v) arylalkyl; (4) alkylthio; (w) cycloalkylalkyl, (5) CN: (x) aryloxy; (6) haloalkyl, preferably CF; (y) arylalkoxy, (7) N.; (Z) arylalkylthio; 8) O; aa) cycloalkylalkoxy,y y y (9) nitro; or (bb) heterocycloalkyl; (10) amino; cc) alkylsulfonyloxy,y yloxy (o) unsubstituted, mono-, or di-Substituted heteroaryl or (dd) alkylsulfonyl; unsubstituted, mono-, or di-Substituted heteroarylm ethyl, wherein the heteroaryl is a monocyclic aro- (ee) arylsulfonyl, matic ring of 5 atoms, Said ring having one heteroa (f) arylsulfonyloxy; tom which is S, O, or N, and, optionally, 1, 2, or 3 additional Natoms, or the heteroaryl is a monocyclic (gg) -C(O)R'; ring of 6 atoms, Said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or 4 additional N (hh) nitro; atoms, Said Substituents are each independently: (ii) amino; (1) halo; (ii) aminoalkyl, (2) lower alkyl; (kk) -C(O)-alkyl-heterocyclic ring; (3) alkoxy; (l) halo; (4) alkylthio; (mm) heterocyclic ring; (5) CN: (nn)-COD'; (6) haloalkyl, preferably CF; (oo) carboxyl, (7) N.; (pp) amidyl, or (8) –C(R)(R7)–OD'; (qq) alkoxyalkyl, (9)9) -C(R)(R)-O-lower(R)(R) alkyl;y or alternatively, R" and R together with the carbons to (10) alkylsulfinyl which they are attached are: (p) –CON(R)(R); (a) cycloalkyl, (q)-CHOR; (b) aryl; or (r) —CHOCN; (c) heterocyclic ring; (s) unsubstituted or substituted: alternatively, R' and R' or R and R taken together with (1) lower alkyl-Q; the carbon to which they are attached are: (2) -O-lower alkyl-Q; (a) cycloalkyl, or (3) -S-lower alkyl-Q; (b) heterocyclic ring; (4) lower alkyl-O-lower alkyl-Q; alternatively, RandR, R" and R,R and R, or R" and R when Substituents on adjacent carbon atoms taken (5) lower alkyl-S-lower alkyl-Q; together with the carbons to which they are attached (6) lower alkyl-O-Q; C. (7) lower alkyl-S-Q; (a) cycloalkyl, (8) lower alkyl-O-K; (b) heterocyclic ring; or (9) lower alkyl-S-K; (c) aryl; US 2004/0072883 A1 Apr. 15, 2004 44

R and R7 are each independently: (8) COD'; or (a) hydrogen; (9) haloalkyl, preferably fluoroalkyl; (b) unsubstituted, mono- or di-Substituted phenyl; (e) benzyl, mono-, di- or tri-Substituted benzyl, wherein unsubstituted, mono- or disubstituted benzyl, unsub- the Substituents are each independently: Stituted, mono- or di-Substituted heteroaryl; mono- (1) halo; or di-substituted heteroarylmethyl, wherein said Sub- s Stituents are each independently: (2) lower alkyl; ( 1) halo; 3) alkoxy;y 2) lower alkyl;y 4) alkylthio;y (3) alkoxy; (5) lower alkyl-COD'; (4) alkylthio; (6) lower alkyl-NHD"; (5) CN: (7) CN: 6) haloalkyl,y1, preferablyp y U2CF, 8) -COD';2 or (7) N.; (9) haloalkyl, preferably CF; 8) –C(R')(R)-OD'; or cycloalkyl,y y (9) –C(R')(R)-O-lower alkyl; (g) K, or c) 1IOWer alIkvl Kyl, h) benzoyl, 1 mono-, di-,di or triSubstituteisubstituted b enZOyl,1 (d) —CHOR;8 Whereherein in the SubStituentSSubsti are eachh independentlyIndependentTV: 2 s (e) CN; (1) halo; (f) -CHCN; (2) lower alkyl; (g) haloalkyl, preferably fluoroalkyl, (3) alkoxy;

(i) halo; or (5) lower alkyl-COD'; Y ?nR8. OWC KWI R is: (7) CN: (a) hydrogen; (8) -COD'; or (b)b) KiK; or 9) haloalkvlaloalkyl, pre?erablyferably UF,CF (c) R'; R" and R" are each independently: alternatively, RandR ', Rand R7 or RandR together (a) hydrogen; or with the carbon to which they are attached form a (b) R'; Saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms, s optionally containing up to two heteroatoms selected R is: from oxygen, S(O)o or NR'; (a) lower alkyl, R is: (b) cycloalkyl; (a) lower alkyl, (c) unsubstituted, mono-, di- or tri-Substituted phenyl or (b) lower alkyl-COD'; naphthyl, wherein the Substituents are each indepen (c) lower alkyl-NHD"; dently: (d) phenyl or mono-, di- or tri-Substituted phenyl, (1) halo; wherein the Substituents are each independently: (2) alkoxy, (1) halo; (3) alkylthio; (2) lower alkyl; (4) CN: (3) alkoxy; (5) haloalkyl, preferably CF; (4) alkylthio; (6) lower alkyl; (5) lower alkyl-COD'; (7) N.; (6) lower alkyl-NHD; (8) -COD'; (7) CN: (9) -CO-lower alkyl; US 2004/0072883 A1 Apr. 15, 2004 45

(10) –C(R 2)(R')–OD'; (4) alkylthio; (11) -C(R 2)(R3)-O-lower alkyl; (5) CN: (12) lower alkyl-COD'; (6) haloalkyl, preferably CF; (13) lower alkyl-COR'; (7) N.; (14) benzyloxy; (8) –C(R)(R')–OD'; or (15) -O-(lower alkyl)-COD'; (9) –C(R)(R)-O-lower alkyl; (16) -O-(lower alkyl)-COR'; or (g) hydrogen; or (17) -O-(lower alkyl)-NR'R'; (h) K (d) unsubstituted, mono-, di- or tri-Substituted het- R'' and R' are each independently: eroaryl, wherein the heteroaryl is a monocyclic aro matic ring of 5 atoms, Said ring having one heteroa (a) hydrogen; tom which is S, O, or N, and, optionally, 1, 2, or 3 (b) lower alkyl; or additional Natoms, or Said heteroaryl is a monocy clic ring of 6 atoms, Said ring having one heteroatom (c) aryl; or which is N, and, optionally 1, 2, or 3 additional N R'' and R' together with the atom to which they are atoms, and wherein Said Substituents are each inde- attached form a Saturated monocyclic ring of 3, 4, 5, 6 pendently: or 7 atoms, (1) halo; R'' and R are each independently: (2) lower alkyl; (a) hydrogen; or (3) alkoxy; (b) lower alkyl; or (4) alkylthio; R'' and R together with the atom to which they are attached form a carbonyl, a thial, or a Saturated mono (5) CN: cyclic ring of 3, 4, 5, 6 or 7 atoms, (6) haloalkyl, preferably CF; Q is: (7) N; (a) -C(O)-U-D; (8) –C(R)(R')–OD'; or (b) -CO-lower alkyl; (9) –C(R)(R)-O-lower alkyl; (c) tetrazolyl-5-yl; (e) unsubstituted, mono- or di-Substituted benzohetero cycle, wherein the benzoheterocycle is a 5, 6, or (d) –C(R)(R)(S-D"); 7-membered ring which contains 1 or 2 heteroatoms (e) –C(R)(R)(O-D); or independently Selected from O, S, or N, and, option ally, a carbonyl group or a Sulfonyl group, wherein (f) –C(R)(R)(O-lower alkyl); Said Substituents are each independently: X is: (1) halo, (a) –(CRR)-; (2) lower alkyl; (b) —(CRR-)-A-; ()3) alkoxy;alloy. (c) -A-(CR'R'') ; (4) alkylthio; (d) - CRR2-A-CRR, (5) CN: (e) –CR'=; or (6) haloalkyl, preferably CF; (f) -A"; (7)7) N. A' is: s (9) –C(R)(R)-O-lower alkyl; (a)a) oxygOXygen, (f) unsubstituted, mono- or di-Substituted- benzocar (b) thio; bocycle, wherein the carbocycle is a 5, 6, or 7-mem- (c) Sulfinyl; bered ring which optionally contains a carbonyl (d) sulfonyl; or group, wherein Said Substituents are each indepen dently: (c) -N(R)-; (1) halo; R" and R are each independently: (2) lower alkyl; (a) hydrogen; (3) alkoxy; (b) lower alkyl; US 2004/0072883 A1 Apr. 15, 2004 46

(c) substituted lower alkyl; (h) arylheterocyclic ring, or (d) lower alkoxy, (i) -(CH2CH2O), ; (e) lower haloalkyl; or E at each occurrence is independently a -T group, an (f) halo; or alkyl group, an aryl group, a heterocyclic ring, -(C(R- R and R' taken together are; )(R))-, arylheterocyclic ring O -(CH2CH2O), ; (a) oxo; h is an integer form 1 to 10; (b) thial; (c) oxime; or q is an integer from 1 to 5; (d) hydrazone; R and R are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an R is: alkoxyalkyl, an arylheterocyclic ring. a cycloalkyla (a) lower alkyl, lkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an (b) hydrogen; or amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a (c) -C(O)H; haloalkoxy, a Sulfonic acid, a Sulfonic ester, an alkyl a is an integer equal to 1 or 3; Sulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an bb is an integer equal to 2 or 3; aminoaryl, an aryl, an arylalkyl, a carboxamido, a D is: alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an (a) hydrogen or arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, (b) D; an ester, a carboxylic ester, an alkylcarboxylic ester, an D is: arylcarboxylic ester, a haloalkoxy, a Sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfo (a) V, or nyl, an alkylsulfonyloxy, an arylsulfonyl, an arylsulfo (b) K; nyloxy, a urea, a nitro, -T-Q'-, or -(C(R)(R))-T-Q' or R and R taken together are an OXO, a thial, a U is: heterocyclic ring, a cycloalkyl group, an OXime, a (a) oxygen; hydraZone or a bridged cycloalkyl group; (b) sulfur; or Q' is -NO or -NO; (c) -N(R)(R)-; k is an integer from 1 to 3, V is: T is independently a covalent bond, a carbonyl, an oxy (a) -NO; gen, -S(O)O- or -N(R)R , (b) -NO; or o is an integer from 0 to 2, (c) hydrogen R is a lone pair of electrons, a hydrogen or an alkyl grOup, R is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, wherein aa, b, c, d, g, i and j are each independently an an arylcarboxylic acid, an alkylcarboxylic ester, an integer from 0 to 3; arylcarboxylic ester, an alkylcarboxamido, an arylcar boxamido, an alkylsulfinyl, an alkylsulfonyl, an alkyl p, x, y and Z are each independently an integer from 0 to Sulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an 10; arylsulfonyl, a Sulfonamido, a carboxamido, a carboxy W at each occurrence is independently: lic ester, an aminoalkyl, an aminoaryl, -OR', (a) -C(O)-; —CH2—C(T-Q')(R)(R), a bond to an adjacent atom creating a double bond to that atom or -(NO-) (b) -C(S)-; M", wherein M is an organic or inorganic cation; with (c) -T-; the proviso that when R, is-CH-C(T-Q')(R)(R) or -(N2O).M"; then “-T-Q" can be a hydrogen, an (d) -(C(R)(R)) ; alkyl group, an alkoxyalkyl group, an aminoalkyl (e) alkyl, group, a hydroxy group or an aryl group; (f) aryl; R and R, at each occurrence are independently Re; (g) heterocyclic ring; R" is independently Selected from R, US 2004/0072883 A1 Apr. 15, 2004 47

wherein the compound of Formula (II) is:

II when Sides f is a double bond, and Sides d, e and g are R single bonds, -X-Y-Z - is:

r:21 A. 7& 2 Y when Sides e is a double bond, and Sides d, f and g are R N51 BN3 e single bonds, -X-Y-Z - is:

wherein: A-B is: when sides d, e, fand g are single bonds, -X-Y-Z'- is: (a) N-C; (b) C-N; or with the proviso that when A-B is C-N, then X must be (c) N-N; –(CRR), or -(CRR)-A"; and when A-B is N-C, Sides d and fare double bonds, and wherein R,R,R,R,R,R,R,R, X A', R, R, sides e and g are single bonds, -X-Y-Z - is: a and bb are as defined herein; wherein the compound of Formula (III) is:

III

when A-B is C-N, sides e and g are double bonds, and wherein: sides d and fare single bonds, -X-Y-Z - is: X is: (a) -C(O)-U-D; (b) -CH-U-D'; (c) -CH-C(O)-CH; (d) -CH-CH-C(O)-U-D; (e) -CH-O-D';

Y is: when A-B is C-N, side g is a double bond, and sides d, e and fare single bonds, -X-Y-Z - is: (a) —(CR(R))-U-D'; (b) -CH; (c) —CHOC(O)R; or (d) -C(O)H; R°, R, R and R are each independently: when A-B is N-C, Sides d is a double bond, and sides e, (a) hydrogen; f and g are single bonds, -X-Y-Z - is: (b) hydroxy; (c) alkyl, (d) alkoxy, US 2004/0072883 A1 Apr. 15, 2004 48

(e) lower alkyl-OD'; (4) CN: (f) alkylthio; (5) –C(O)R'; (g) CN; (6) lower alkyl; (h) –C(O)R'; or (7) -S(O)-lower alkyl; or (i) –OC(O)R; (8) —OD'; R is: X is: (a) hydrogen; (a) —(CRR-)-; (b) lower alkyl; or (b) —(CRR)-A-; or (c) alkoxy; (e) –CR'=; and R is: wherein R,R,R,R,R,R,R,R,R, A, U, D', (a) lower alkyl, a, bb, o and k are as defined herein; (b) alkoxy wherein the compound of Formula (IV) is: (c) unsubstituted, mono-, di- or tri-Substituted phenyl or IV pyridyl, wherein the Substituents are each indepen dently: (1) halo; (2) alkoxy, (3) haloalkyl; (4) CN:

(5) –C(O)R'; wherein: (6) lower alkyl; X" and Z are each independently: (7) -S(O)o-lower alkyl; or (a) N; or (8) —OD'; alternatively, R and R or R'' and R taken together (b) CR; C. R9 is: (a) oxo; (a) -S(O)-CH; (b) thial; (b) -S(O)-NR(D"); or (c) =CRR7; or (c) -S(O)N(D)-C(O)-CF; (d) =NR; R° and R'' are each independently: R and R7 are each independently: (a) hydrogen; (a) hydrogen; (b) lower alkyl; (b) lower alkyl; (c) alkoxy; (c) lower alkyl-OD'; (d) alkylthio; (d) CN; or (e) haloalkyl, preferably fluoroalkyl; (f) haloalkoxy, preferably fluoroalkoxy; (g) CN; (a) OD'; (h) -COD'; (b) alkoxy; (i) -COR'; (c) lower alkyl, or (i) lower alkyl-O-D'; (d) unsubstituted, mono-, di- or tri-Substituted phenyl (k) lower alkyl-COD'; or pyridyl, wherein the Substituents are each inde pendently: (1) lower alkyl-COR'"; (1) halo; (m) halo, (2) alkoxy, (n)-O-D'; (3) haloalkyl; (o) -N, US 2004/0072883 A1 Apr. 15, 2004 49

R. R', R’, R, R-7, Rare each independently: (a) hydrogen; or (b) lower alkyl; or R° and R', or R7 and R together with the atoms to which they are attached form a carbocyclic ring of 3, 4, (t) aryl; 5, 6 or 7 atoms, or R* and R are joined to form a (u) arylalkylthio; covalent bond; (V) arylalkoxy, Y is: (w) alkylamino; (a) CR2R39; (x) aryloxy; (b) oxygen; or (y) alkylarylalkylamino; (c) Sulfur, (Z) cycloalkylalkylamino; or R” and Rare each independently: (aa) cycloalkylalkoxy; (a) hydrogen; (b) lower alkyl; (a) mono-, di- or tri-Substituted phenyl or pyridinyl (or the N-oxide thereof), wherein the substituent are (c) (CH)-OD'; each independently: (d) halo; or (1) hydrogen; R” and R' taken together are an oxo group; (2) halo; S is an integer from 2 to 4, and (3) alkoxy; wherein R, R, X, D, T, U, K and o are as defined (4) alkylthio; herein; (5) CN: wherein the compound of Formula (V) is: (6) lower alkyl; (7) haloalkyl, preferably fluoroalkyl; (8) Na; (9) -COD'; (10) -CO-lower alkyl; (11) –C(R')(R')–OD'; (12) —OD'; (13) lower alkyl-CO-R'"; or (14) lower alkyl-CO-D;

D s

(c) wherein: X7 is: ^ (CH2)s (a) oxygen; (CH2). YS (b) sulfur, (c)-NR; (d) arylalkyl, or (d)-N-O-R; or (e) cycloalkylalkyl, (e)-N-NR'R''. wherein: Y7 at each occurrence is independently: R'' and R' are each independently: (a) hydrogen; (a) hydrogen; or (b) halo; (b) lower alkyl; (c) lower alkyl, US 2004/0072883 A1 Apr. 15, 2004 50

(d) alkenyl; or wherein R', R, R", R, R°, K, D and a are as defined herein; (e) alkynyl; wherein the compound of Formula (VI) is: Z7 is:

(a) —(CRR)-; VI R' is: (a) R; or (b) R'; R9 and R are each independently: (a) hydrogen; (b) halo; wherein: (c) lower alkyl, X is –C(O)-U-D and Y is —CH-CR (R)-U-D; O (d) aryl; X is —CH-CR(R)-U-D and Y is –C(O)-U-D; (e) arylalkyl, O (f) cycloalkyl, X and Y taken together are: (g) cycloalkylalkyl, (a) –C(O)-O-CR (R")—CR(R)-; (h) —OD'; (b) –(CR'(R"))-CR(R)-CR(R)-; (i) lower alkyl-OD'; (c) –C(O)–(CR'(R"))-CR (R)-; (d) -(CR'(R"))-CR (R)-C(O)-; or (j) carboxamido; (e) –C(O)—CR'(R")—CR(R)-; (k) amidyl; or wherein X is the first carbon atom of a, b, c, d and e, and (l) K; wherein R,R,R,R, R", R, R, X, U, D and k are R is: as defined herein; (a) lower alkyl, wherein the compound of Formula (VII) is: (b) alkenyl;

VII (c) cycloalkyl, (d) cycloalkylalkyl, (e) aryl; (f) arylalkyl; (g) heterocyclic ring; or (h) lower alkyl-heterocyclic ring; wherein: R° and Rare each independently: when Side h, k, and j are single bonds, and Side i and l are a double bond, -X'. Y'-Z'- is: (a) lower alkyl, (b) cycloalkyl; (c) cycloalkylalkyl, (d) aryl; (e) arylalkyl, Q10 olo O (f) heterocyclic ring; or (g) heterocyclicalkyl, and US 2004/0072883 A1 Apr. 15, 2004 51

-continued (b)

when Sides i, k and l are single bonds, and SideS h and are double bonds, -X'. Y'-Z'- is:

when Side hand are Single bonds, l is a double bond, and side k and i is a single or a double bond, -X'Y'- Z9- is:

(a)

(b) R61 J Alli 1.

Plo is:

(a) -N=; A10-B10-D10 is: (b) -NR-; (c) -O-, or (d) -S-;

US 2004/0072883 A1 Apr. 15, 2004

3. A method for treating or reducing inflammation, pain or 13. A method for inhibiting platelet aggregation in a fever in a patient in need thereof comprising administering patient in need thereof comprising administering to the to the patient a therapeutically effective amount of the patient a therapeutically effective amount of the composition composition of claim 2. of claim 2. 4. A method for treating a gastrointestinal disorder, or 14. The composition of claim 2, further comprising at improving the gastrointestinal properties of a COX-2 inhibi least one therapeutic agent. tor in a patient in need thereof comprising administering to 15. The composition of claim 14, wherein the therapeutic agent is a Steroid, a nonsteroidal antiinflammatory com the patient a therapeutically effective amount of the com pound, a 5-lipoxygenase (5-LO) inhibitor, a leukotriene B. position of claim 2. receptor antagonist, a leukotriene A hydrolase inhibitor, a 5. The method of claim 4, wherein the gastrointestinal 5-HT agonist, a 3-hydroxy-3-methylglutaryl coenzyme A disorder is an inflammatory bowel disease, Crohn's disease, inhibitor, a Hantagonist, an antineoplastic agent, an anti gastritis, irritable bowel Syndrome, ulcerative colitis, a pep platelet agent, a thrombin inhibitor, a thromboxane inhibitor, tic ulcer, a StreSS ulcer, a bleeding ulcer, gastric hyperacidity, a decongestant, a diuretic, a Sedating or non-Sedating anti dyspepsia, gastroparesis, Zollinger-Ellison Syndrome, gas histamine, an inducible nitric oxide Synthase inhibitor, an troesophageal reflux disease, a bacterial infection, short opioid, an analgesic, a Helicobacter pylori inhibitor, a bowel (anastomosis) Syndrome, or a hyperSecretory State proton pump inhibitor, an isoproStane inhibitor, or a mixture asSociated with Systemic mastocytosis or basophilic leuke of two or more thereof. mia and hyperhistaminemia 16. The composition of claim 15, wherein the nonsteroi 6. A method for facilitating wound healing in a patient in dal antiinflammatory compound is acetaminophen, aspirin, need thereof comprising administering to the patient a diclofenac, ibuprofen, ketoprofen, indomethacin or naproXen. therapeutically effective amount of the composition of claim 17. A method for treating or reducing inflammation, pain 2. or fever in a patient in need thereof comprising administer 7. The method of claim 6, wherein the wound is an ulcer. ing to the patient a therapeutically effective amount of the 8. A method for treating or reversing renal and/or respi composition of claim 14. ratory toxicity in a patient in need thereof comprising 18. A method for treating a gastrointestinal disorder, or administering to the patient a therapeutically effective improving the gastrointestinal properties of a COX-2 inhibi amount of the composition of claim 2. tor in a patient in need thereof comprising administering to 9. A method for treating a disorder resulting from elevated the patient a therapeutically effective amount of the com levels of COX-2 in a patient in need thereof comprising position of claim 14. administering to the patient a therapeutically effective 19. The method of claim 18, wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, amount of the composition of claim 2. gastritis, irritable bowel Syndrome, ulcerative colitis, a pep 10. The method of claim 9, wherein the disorder resulting tic ulcer, a StreSS ulcer, a bleeding ulcer, gastric hyperacidity, from elevated levels of COX-2 is angiogenesis, arthritis, dyspepsia, gastroparesis, Zollinger-Ellison Syndrome, gas asthma, bronchitis, menstrual cramps, premature labor, ten troesophageal reflux disease, a bacterial infection, short dinitis, burSitis, a skin-related condition, neoplasia, an bowel (anastomosis) Syndrome, or a hyperSecretory State inflammatory process in a disease, an ophthalmic disorder, asSociated with Systemic mastocytosis or basophilic leuke pulmonary inflammation, a central nervous System disorder, mia and hyperhistaminemia. allergic rhinitis, respiratory distress Syndrome, endotoxin 20. A method for facilitating wound healing in a patient in Shock Syndrome, atherOSclerosis, a microbial infection, a need thereof comprising administering to the patient a cardiovascular disorder, a urinary disorder, a urological therapeutically effective amount of the composition of claim disorder, endothelial dysfunction, organ deterioration, tissue 14. deterioration, or activation, adhesion and infiltration of 21. The method of claim 20, wherein the wound is an neutrophils at the Site of inflammation. ulcer. 11. The method of claim 10, wherein the neoplasia is a 22. A method for treating or reversing renal and/or res brain cancer, a bone cancer, an epithelial cell-derived neo piratory toxicity in a patient in need thereof comprising plasia (epithelial carcinoma), a basal cell carcinoma, an administering to the patient a therapeutically effective adenocarcinoma, a gastrointestinal cancer, a lip cancer, a amount of the composition of claim 14. mouth cancer, an esophageal cancer, a Small bowel cancer, 23. A method for treating a disorder resulting from a stomach cancer, a colon cancer, a liver cancer, a bladder elevated levels of COX-2 in a patient in need thereof cancer, a pancreas cancer, an OVary cancer, a cerVical cancer, comprising administering to the patient a therapeutically a lung cancer, a breast cancer, a skin cancer, a Squamus cell effective amount of the composition of claim 14. cancer, a basal cell cancer, a prostate cancer, a renal cell 24. The method of claim 23, wherein the disorder result carcinoma, a cancerous tumor, a growth, a polyp, an ing from elevated levels of COX-2 is angiogenesis, arthritis, adenomatous polyp, a familial adenomatous polyposis or a asthma, bronchitis, menstrual cramps, premature labor, ten fibrosis resulting from radiation therapy. dinitis, burSitis, a skin-related condition, neoplasia, an 12. The method of claim 10, wherein the central nervous inflammatory process in a disease, an ophthalmic disorder, System disorder is cortical dementia, Alzheimer's disease, pulmonary inflammation, a central nervous System disorder, vascular dementia, multi-infarct dementia, pre-Senile allergic rhinitis, respiratory distreSS Syndrome, endotoxin dementia, alcoholic dementia, Senile dementia, or central Shock Syndrome, atherosclerosis, a microbial infection, a nervous System damage resulting from Stroke, ischemia or cardiovascular disorder, a urinary disorder, a urological trauma. disorder, endothelial dysfunction, organ deterioration, tissue US 2004/0072883 A1 Apr. 15, 2004 54 deterioration, or activation, adhesion and infiltration of a haloalkoxy, a Sulfonamido, an alkylsulfonamido, an neutrophils at the Site of inflammation. arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, 25. The method of claim 24, wherein the neoplasia is a an arylsulfonyl, an arylsulfonyloxy, a urea, a nitro, brain cancer, a bone cancer, an epithelial cell-derived neo -T-Q'-, or -(C(R)(R))-T-Q' or R, and R taken plasia (epithelial carcinoma), a basal cell carcinoma, an together are an OXO, a methanthial, a heterocyclic ring, adenocarcinoma, a gastrointestinal cancer, a lip cancer, a a cycloalkyl group, an oxime, a hydrazone or a bridged mouth cancer, an esophageal cancer, a Small bowel cancer, cycloalkyl group; Q' is -NO or -NO; and T is a stomach cancer, a colon cancer, a liver cancer, a bladder independently a covalent bond, a carbonyl, an oxygen, cancer, a pancreas cancer, an OVary cancer, a cerVical cancer, -S(O) or -N(R)R-, wherein o is an integer a lung cancer, a breast cancer, a skin cancer, a Squamus cell from 0 to 2, R is a lone pair of electrons, a hydrogen cancer, a basal cell cancer, a prostate cancer, a renal cell or an alkyl group; R is a hydrogen, an alkyl, an aryl, carcinoma, a cancerous tumor, a growth, a polyp, an an alkylcarboxylic acid, an arylcarboxylic acid, an adenomatous polyp, a familial adenomatous polyposis or a alkylcarboxylic ester, an arylcarboxylic ester, an alky fibrosis resulting from radiation therapy. lcarboxamido, an arylcarboxamido, an alkylsulfinyl, an 26. The method of claim 24, wherein the central nervous alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an System disorder is cortical dementia, Alzheimer's disease, arylsulfonyloxy, an arylsulfonyl, a Sulfonamido, a car vascular dementia, multi-infarct dementia, pre-Senile boxamido, a carboxylic ester, an aminoalkyl, an ami dementia, alcoholic dementia, Senile dementia, or central noaryl, -CH-COT-Q')(R)(R), or -(N.O.-). M", nervous System damage resulting from Stroke, ischemia or wherein M is an organic or inorganic cation; with the trauma. proviso that when R, is -CH2-C(T-Q')(R)(R) or 27. A method for inhibiting platelet aggregation in a -(N2O).M"; then “-T-Q" can be a hydrogen, an patient in need thereof comprising administering to the alkyl group, an alkoxyalkyl group, an aminoalkyl patient a therapeutically effective amount of the composition group, a hydroxy group or an aryl group; and RandR, of claim 14. at each occurrence are independently R. 28. A composition comprising at least one compound of 33. The composition of claim 28, wherein the compound claim 1 and at least one compound that donates, transferS or that donates, transfers, or releases nitric oxide, or induces the releases nitric oxide, or induces the production of endog production of endogenous nitric oxide or endothelium enous nitric oxide or endothelium-derived relaxing factor, or derived relaxing factor, or is a Substrate for nitric oxide is a Substrate for nitric oxide Synthase. Synthase is L-arginine, L-homoarginine, N-hydroxy-L-argi 29. The composition of claim 28, further comprising a nine, nitrosated L-arginine, nitrosylated L-arginine, nitro pharmaceutically acceptable carrier. sated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L- 30. The composition of claim 28, wherein the compound arginine, nitroSated L-homoarginine, nitrosylated that donates, transfers, or releases nitric oxide, or induces the L-homoarginine), citrulline, ornithine, glutamine, lysine, an production of endogenous nitric oxide or endothelium arginase inhibitor or a nitric oxide mediator. derived relaxing factor or is a Substrate for nitric oxide 34. The composition of claim 28, wherein the compound Synthase is an S-nitroSothiol. that donates, transfers, or releases nitric oxide, or induces the 31. The composition of claim 30, wherein the S-nitro production of endogenous nitric oxide or endothelium Sothiol is S-nitroso-N-acetylcysteine, S-nitroSo-captopril, derived relaxing factor, or is a Substrate for nitric oxide S-nitroso-N-acetylpenicillamine, S-nitroSo-homocysteine, Synthase is: S-nitroSo-cysteine, S-nitroSO-glutathione, or S-nitroSo-cyS (i) a compound that comprises at least one ON-O- or teinyl-glycine. ON-N-group; 32. The composition of claim 30, wherein the S-nitro Sothiol is: (ii) a compound that comprises at least one O-N-O-, ON-N- or ON-S- or group; (i) HS(C(R)(R)), SNO; (iii) a N-oxo-N-nitroSoamine having the formula: (ii) ONS(C(R)(R)), R.; or R"R"N-N(O-M')-NO, wherein R'" and R" are each independently a polypeptide, an amino acid, a (iii) HN-CH(COH)-(CH), C(O)NH Sugar, an oligonucleotide, a Straight or branched, Satu CH(CHSNO)-C(O)NH-CH-COH: rated or unsaturated, aliphatic or aromatic, Substituted wherein m is an integer from 2 to 20; R and R are each or unsubstituted hydrocarbon, or a heterocyclic group, independently a hydrogen, an alkyl, a cycloalkoxy, a and M is an organic or inorganic cation. halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, 35. The composition of claim 34, wherein the compound an arylheterocyclic ring. a cycloalkylalkyl, a heterocy comprising at least one ON-O- or ON-N-group is an clicalkyl, an alkoxy, a haloalkoxy, an amino, an alky ON-O-polypeptide, an ON-N-polypeptide, an ON-O- lamino, a dialkylamino, an arylamino, a diarylamino, amino acid, an ON-N-amino acid, an ON-O-Sugar, an an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a ON-N-sugar, an ON-O-oligonucleotide, an ON-N-oligo Sulfonic acid, a Sulfonic ester, an alkylsulfonic acid, an nucleotide, a Straight or branched, Saturated or unsaturated, arylsulfonic acid, an arylalkoxy, an alkylthio, an substituted or unsubstituted, aliphatic or aromatic ON-O- arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, hydrocarbon, a Straight or branched, Saturated or unsatur an arylalkyl, a carboxamido, a alkylcarboxamido, an ated, Substituted or unsubstituted, aliphatic or aromatic arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, ON-N-hydrocarbon, an ON-O-heterocyclic compound or an alkylcarboxylic acid, an arylcarboxylic acid, an an ON-N-heterocyclic compound. alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic 36. The composition of claim 34, wherein compound ester, an alkylcarboxylic ester, an arylcarboxylic ester, comprising at least one ON-O-, ON-N- or ON US 2004/0072883 A1 Apr. 15, 2004

S-group is an ON-O-polypeptide, an ON-N-polypep 47. The method of claim 46, wherein the disorder result tide, an ON-S-polypeptide, an ON-O-amino acid, ON ing from elevated levels of COX-2 is angiogenesis, arthritis, N-amino acid, ON-S-amino acid, an ON-O-Sugar, an asthma, bronchitis, menstrual cramps, premature labor, ten ON-N-sugar, ON-S-Sugar, an ON-O-oligonucle dinitis, burSitis, a skin-related condition, neoplasia, an otide, an ON-N-oligonucleotide, an ON-S-oligonucle inflammatory process in a disease, an ophthalmic disorder, otide, a Straight or branched, Saturated or unsaturated, ali pulmonary inflammation, a central nervous System disorder, phatic or aromatic, substituted or unsubstituted ON-O- allergic rhinitis, respiratory distreSS Syndrome, endotoxin hydrocarbon, a Straight or branched, Saturated or Shock Syndrome, atherosclerosis, a microbial infection, a unsaturated, aliphatic or aromatic, Substituted or unsubsti cardiovascular disorder, a urinary disorder, a urological tuted ON-N-hydrocarbon, a straight or branched, satu disorder, endothelial dysfunction, organ deterioration, tissue rated or unsaturated, aliphatic or aromatic, Substituted or deterioration, or activation, adhesion and infiltration of unsubstituted ON-S-hydrocarbon, an ON-O-heterocy neutrophils at the Site of inflammation. clic compound, an ON-N-heterocyclic compound or an 48. The method of claim 47, wherein the neoplasia is a ON-S-heterocyclic compound. brain cancer, a bone cancer, an epithelial cell-derived neo 37. The composition of claim 28, further comprising at plasia (epithelial carcinoma), a basal cell carcinoma, an least one therapeutic agent. adenocarcinoma, a gastrointestinal cancer, a lip cancer, a 38. The composition of claim 37, wherein the therapeutic mouth cancer, an esophageal cancer, a Small bowel cancer, agent is a Steroid, a nonsteroidal antiinflammatory com a stomach cancer, a colon cancer, a liver cancer, a bladder pound, a 5-lipoxygenase (5-LO) inhibitor, a leukotriene B. cancer, a pancreas cancer, an OVary cancer, a cerVical cancer, receptor antagonist, a leukotriene A4 hydrolase inhibitor, a a lung cancer, a breast cancer, a skin cancer, a Squamus cell 5-HT agonist, a HMG CoA inhibitor, a H. antagonist, an cancer, a basal cell cancer, a prostate cancer, a renal cell antineoplastic agent, an antiplatelet agent, a thrombin inhibi carcinoma, a cancerous tumor, a growth, a polyp, an tor, a thromboxane inhibitor, a decongestant, a diuretic, a adenomatous polyp, a familial adenomatous polyposis or a Sedating or non-Sedating anti-histamine, an inducible nitric fibrosis resulting from radiation therapy. oxide Synthase inhibitor, an opioid, an analgesic, a Helico 49. The method of claim 47, wherein the central nervous bacter pylori inhibitor, a proton pump inhibitor, an isoproS System disorder is cortical dementia, Alzheimer's disease, tane inhibitor, or a mixture of two or more thereof. vascular dementia, multi-infarct dementia, pre-Senile 39. The composition of claim 38, wherein the nonsteroi dementia, alcoholic dementia, Senile dementia, or central dal antiinflammatory compound is acetaminophen, aspirin, nervous System damage resulting from Stroke, ischemia or trauma. diclofenac, ibuprofen, ketoprofen, indomethacin or 50. A method for inhibiting platelet aggregation in a naproXen. patient in need thereof comprising administering to the 40. A method for treating or reducing inflammation, pain patient a therapeutically effective amount of the composition or fever in a patient in need thereof comprising administer of claim 29 or 37. ing to the patient a therapeutically effective amount of the 51. A kit comprising at least one compound of claim 1. composition of claim 29 or 37. 52. The kit of claim 51, further comprising (i) at least one 41. A method for treating a gastrointestinal disorder, or compound that donates, transferS or releases nitric oxide, improving the gastrointestinal properties of a COX-2 inhibi induces the production of endogenous nitric oxide or endot tor in a patient in need thereof comprising administering to helium-derived relaxing factor, or is a Substrate for nitric the patient a therapeutically effective amount of the com oxide Synthase; (ii) at least one therapeutic agent; or (iii) at position of claim 29 or 37. least one compound that donates, transferS or releases nitric 42 The method of claim 41, wherein the gastrointestinal oxide, induces the production of endogenous nitric oxide or disorder is an inflammatory bowel disease, Crohn's disease, endothelium-derived relaxing factor, or is a Substrate for gastritis, irritable bowel Syndrome, ulcerative colitis, a pep nitric oxide Synthase and at least one therapeutic agent. tic ulcer, a StreSS ulcer, a bleeding ulcer, gastric hyperacidity, 53. The kit of claim 52, wherein the at least one com dyspepsia, gastroparesis, Zollinger-Ellison Syndrome, gas pound that donates, transferS or releases nitric oxide, induces troesophageal reflux disease, a bacterial infection, short the production of endogenous nitric oxide or endothelium bowel (anastomosis) Syndrome, or a hyperSecretory State derived relaxing factor, or is a Substrate for nitric oxide asSociated with Systemic mastocytosis or basophilic leuke Synthase; the at least one therapeutic agent, or the at least mia and hyperhistaminemia. one compound that donates, transferS or releases nitric 43. A method for facilitating wound healing in a patient in oxide, induces the production of endogenous nitric oxide or need thereof comprising administering to the patient a endothelium-derived relaxing factor, or is a Substrate for therapeutically effective amount of the composition of claim nitric oxide Synthase and at least one therapeutic agent, are 29 or 37. in the form of Separate components in the kit 44. The method of claim 43, wherein the wound is an 54. A kit comprising the composition of claim 14, 29 or ulcer. 37. 45. A method for treating or reversing renal and/or res 55. A compound Selected from the group consisting of: piratory toxicity in a patient in need thereof comprising 1-(1-(cyclohexylmethyl)-3-(hydroxymethyl)pyrazol-5- administering to the patient a therapeutically effective yl)-4-(methylsulfonyl) benzene; amount of the composition of claim 29 or 37. 4-(1-(cyclohexylmethyl)-3-((2-hydroxyethoxy)meth 46. A method for treating a disorder resulting from yl)pyrazol-5-yl)-1-(methylsulfonyl)benzene; elevated levels of COX-2 in a patient in need thereof comprising administering to the patient a therapeutically 1-(3-(hydroxymethyl)-1-benzylpyrazol-5-yl)-4-(methyl effective amount of the composition of claim 29 or 37. Sulfonyl)benzene,