WO2005041864A2

WO2005041864A2 - Combination of cyclooxygenase-2 inhibitor and phosphodiesterase 4 inhibitor and method

Info

Publication number: WO2005041864A2
Application number: PCT/US2004/034685
Authority: WO
Inventors: Walter G. Smith
Original assignee: Pharmacia Corporation
Priority date: 2003-10-21
Filing date: 2004-10-21
Publication date: 2005-05-12
Also published as: JP2007509154A; CA2542277A1; MXPA06004499A; BRPI0415753A; EP1691797A2; WO2005041864A3

Abstract

A method is described for the prevention and/or treatment of respiratory inflammation, and in particular asthma and COPD, in a subject in need of such prevention or treatment, the method comprising administering to the subject a cycloogenase-2 inhibitor in combination with a phosphodiesterase 4 inhibitor. Also described are therapeutic and pharmaceutical compositions and kits that are useful in the present invention.

Description

METHOD FOR THE TREATMENT OR PREVENTION OF RESPIRATORY INFLAMMATION WITH A CYCLOOXYGENASE-2 INHIBITOR IN COMBINATION WITH A PHOSPHODIESTERASE 4 INHIBITOR AND COMPOSITIONS THEREWITH

BACKGROUND OF THE INVENTION

(1) Field of the Invention

[0001] The present invention relates to the treatment and/or prevention of respiratory inflammation and, more particularly, to the treatment and/or prevention of respiratory inflammation in a subject in need of such treatment or prevention, by administration of a combination of two different enzyme inhibitors.

(2) Description of the Related Art

[0002] A broad spectrum of respiratory diseases and disorders has been recognized, many of which have overlapping and interacting etiologies. Two of the most widespread and prevalent of these diseases are asthma and chronic obstructive pulmonary disorder (COPD). [0003] Asthma is a pulmonary disease that is characterized by reversible airway obstruction, airway inflammation, and increased airway responsiveness (manifested as bronchoconstriction), due to a variety of irritating stimuli. The Merck Manual, 17^th edition, Sec. 6, Chapter 68, Chronic Obstructive Airway Disorders, Asthma (1999). Airway obstruction in asthma can result from a combination of factors including spasm of airway smooth muscle, edema of airway mucosa, increased mucus secretion, and cellular infiltration of the airway walls. Symptoms of asthma usually begin quite suddenly with wheezing episodes, coughing, and shortness of breath.

[0004] In the United States, an estimated 12 million people suffer from asthma. During the ten-year period from 1982 to 1992, the prevalence of asthma increased from 34.7 to 49.4 per 1000 and the death rate increased

40%, from 13.4 to 18.8 per million. See The Merck Manual of Diagnosis & Therapy, Beers & Brakow, 17^th edition, Published by Merck Research Labs, Sec. 6, Chapter 68, Chronic Obstructive Airway Disorders, COPD (1999). Asthma is now the leading cause of hospitalization for children. [0005] COPD is a chronic respiratory disorder characterized by airflow limitation, accompanied by shortness of breath, cough, wheezing, increased sputum production and occasionally fever. Id. Many factors contribute to the risk of developing COPD, including breathing heavy dust, air pollution, poor nutrition, childhood respiratory infections, chronic uncontrolled asthma, and even heredity. Nevertheless, almost 90% of COPD cases are caused by long-term cigarette smoking and/or passive exposure to cigarette smoke.

[0006] Cigarette smoke contains an abundance of toxic and irritating substances. Over time, cigarette smoke produces inflammation in both the bronchial tubes of the lungs and the walls of the alveoli. In the alveoli, smoke-induced inflammatory cells destroy the capillaries and air sacs, giving rise to permanent lung damage or emphysema. In addition, cigarette smoke induces inflammation in the airways and causes swelling which reduces trie diameter of these passages. The inflammation in the bronchi also produces large amounts of mucus. The swelling of the bronchial tubes, the increased mucus production, and bronchial muscle spasm can obstruct airflow into and out of the lungs; all leading to COPD.

[0007] The inflammatory responses characteristic of asthma and COPD result in infiltration of the respiratory tract with a variety of inflammatory cells, specifically eosinophils, mast cells, and CD4⁺ T-lymphocytes in asthma, and in COPD, primarily neutrophils, but also macrophages, and CD8+ T lymphocytes. See Bundschuh, D., etal., Pharm. Exper. Therap.,

297:280-290 (20O1). These inflammatory cells release a variety of mediators, including histamine and the products of arachidonic acid metabolism, such as leukotrienes and prostaglandins, cytokines, interleukins IL-1 to IL-12, alpha-, beta- and gamma-interferon, tumor necrosis factor (TNF) and proteases, all ultimately leading to the harmful symptoms and the> histopathology of asthma and COPD. [0008] The enzyme phosphodiesterase 4 (PDE 4) is the predominant phosphodiesterase expressed within these inflammatory cells. Representative inflammatory cell-types include eosinophils, T lymphocytes, macrophages, neutrophils, dendritic cells, mast cells, and structural cells. One of the primary activities of PDE 4 is to metabolize excess intracellular levels of the signal transduction molecule adenosine cyclic 3',5'-monophosphate (cAMP).

[0009] PDE 4 is responsible for the conversion of active intracellular cAMP to its inactive form. cAMP is a ubiquitous second messenger produced in cells in response to extracellular hormones and several neurotransmitters. cAMP is formed by the enzyme adenylyl cyclase. As levels of cAMP rise, the enzyme protein kinase A becomes activated and triggers the phosphorylation of a multitude of cellular constituents. Phosphorylation of several inflammatory cell constituents results in lower airway edema, reduced airway constriction, reduced cellular infiltration to the inflammatory site, reduced chemotaxis, cellular adhesion and proliferation, reduced superoxide generation, and prevention of inflammatory mediator release (e.g. mast cell, neutrophils, and basophil degranulation). See Torphy, T., et al., Am. J. Respir. Crit. Care Med., 757:351-370 (1998) and see U.S. Patent No. 6,288,118 to Nieman, et al.

Overall, higher levels of intracellular cAMP result in improved asthma and inflammation symptoms, while a decrease in levels of cAMP in inflammatory cells triggers the release of the inflammatory cellular mediators mentioned previously, resulting in the symptoms characteristic of asthma and inflammation. See e.g. Giembycz, M., et al., Drugs 55:193-

212 (2000); Bundschuh, D.. et al., (2001), supra.

[00010] Eleven distinct classes of PDEs have been identified, each with unique catalytic properties, substrate specificities, and tissue expression patterns. See Uckert, S., et al., World J Urol, 19:14-22 (2001). Non- specific phosphodiesterase inhibitors are able to block the activity of more than one PDE isoform, often resulting in adverse side effects. Some of the adverse effects associated with, for example, the non-selective PDE inhibitor theophylline, include hypotension, tachycardia, headache, and emesis. In the course of the discovery of different classes of PDE enzymes, inhibitors with selectivity for specific PDE isoforms have been designed and synthesized. Of particular importance is that selective chemical inhibition of PDE 4 activity has been found to increase intracellular levels of cAMP, leading to the inhibition of synthesis and release of pro-inflammatory mediators by immunocompetent cells. See Torphy, T., et al., (1998), supra, and Dal Piaz, V. and Giovannoni, M.P., Eur. J. Med. Chem., 35:463-480 (2000). [00011 ] As a result, clinicians are actively searching for compounds that inhibit PDE 4 activity and thus, have efficacy against the inflammatory processes of asthma and COPD. See e.g. Bamette, M., Progress in Drug Research (Jucker, E., ed.), vol. 33, Birkhauser Verlag, Vasel, Switzerland (1999); Giembycz, M., Bioche . Pharmacol., 43:2041-2051 (1992); Bundschuh, D., etal., (2001), supra. Several PDE 4 inhibitors have been reported to improve the airflow obstruction seen in asthmatic patients by reversing or preventing bronchoconstriction, limiting airway edema (microvascular leakage), altering mucus secretion and clearance, relaxing airway smooth muscle, reducing secretion of pro-inflammatory mediators, blocking leukocyte adhesion to vascular endothelial cells, and blocking generation of oxygen-derived free radicals. See Giembycz, M., etal., ,

(2000), supra.

[00012] Although there are beneficial consequences to treatment with PDE 4 inhibitors, many of these agents are associated with unwanted central nervous system and gastrointestinal side effects. See Martin, C, et al., Naunyn Schmiedebergs Arch. Pharmacol., 355:284-289 (2002). Clinical use of the "first-generation" PDE 4 inhibitor rolipram, initially developed as an antidepressant, was limited by associated increase in gastric acid secretion, nausea, and vomiting. See Torphy, T.J. and Undem, B.J., Thorax, 45:512-523 (1991). Improved "second-generation"

PDE 4 inhibitors, such as cilomilast, lirimilast, and roflumilast, have been developed, and seem to maintain high anti-inflammatory activity while partially overcoming these side effects. See Bamette, M.S., et al., J. Pharmacol. Exp. Ther., 284:420-426 (1998); Giembycz, M.A., Expert Opin. Investig. Drugs, 70:1361 -1379 (2001); Sturton, G. and Fitzgerald, M., Chest, 121'Λ 92S-196S (2002); Bundschuh etal., supra. [00013] Many common anti-inflammatory agents, such as aspirin and ibuprofen, fall under the classification of non-steroidal anti-inflammatory drugs (NSAIDs). It is now widely recognized that many of the traditional NSAIDs are inhibitors of two cyclooxygenases, cyclooxygenase-1 (Cox-1) and cyclooxygenase-2 (Cox-2). These two enzymes are involved in the critical initiation step of prostaglandin synthesis - the addition of molecular oxygen to arachidonic acid in the cell membrane. See Needleman, P. et al., Annu. Rev. Biochem, 55:69-102 (1986). [00014] Cox-1 is constituitively active and is responsible for the synthesis of housekeeping prostaglandins critical to maintaining normal renal function, gastric mucosal integrity, and vascular homeostasis. Cox-2 expression is induced by cytokines and growth factors in inflammatory cells, leading to the release of prostanoids, for example, prostaglandin E2, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity, inflammation, and edema. See e.g. Samad, T.A. etal., Nature 470:471 -5 (2001 ). Because many common NSAIDs inhibit prostaglandin synthesis by blocking the activity of both Cox-1 and Cox-2 , side effects associated with long-term administration of these drugs such as gastrointestinal bleeding and ulcers are thought to be a result of inhibiting the homeostatic functions of Cox-1 , while the inhibiton of Cox-2 accounts for their analgesic properties.

[00015] Research into the area of arachidonic acid metabolism has resulted in the discovery of compounds that inhibit the Cox-2 enzyme to a greater extent than the activity of Cox-1. The Cox-2 selective inhibitors are believed to offer advantages that include the capacity to prevent or reduce inflammation while avoiding harmful side effects associated with the inhibition of Cox-1. Thus, Cox-2 selective inhibitors have shown great promise for use in therapies, especially in therapies that require maintenance administration.

[00016] Currently, the most prominent therapy for asthma, and for a percentage of COPD cases, includes orally inhaled and orally ingested corticosteroids, due to their efficacy, tolerance, and relatively rapid onset of action. See Barnes, P.J., J. Allergy Clin. Immunol., 707:S427-33 (1998); Ducharme, F., BMJ, 324:1545-1 552 (2002). Often, patients with chronic severe asthma are dependent upon the long-term prescription of corticosteroids for treatment. However, this mode of treatment can result in unintended and unwanted side effects. For inhaled corticosteroids, those side effects include fungal infections of the mouth and throat (thrush), hoarseness, cough, and, in some instances, delayed growth. For more severe or chronic forms of asthma, orally ingested corticosteroids are prescribed either as short-term burst therapies to treat acute severe episodes or as routine maintenance therapies. Orally prescribed steroids are known to cause severe side effects, especially with higher doses and during the course of long-term therapies. Resistance to corticosteroids may develop over time to maintenance therapies, thus requiring increasingly higher dosing and a corresponding increase in side effects. It has also been noted that sudden cessation of corticosteroid therapy can give rise to an apparent worsening of the original inflammatory symptoms (steroid-rebound effect).

[00017] Therefore, it would be useful to develop methods of treating respiratory diseases such as asthma and COPD that do not require administering corticosteroids, in order to avoid the side effects associated with this treatment regimen. Additionally, it would be desirable to reduce the dosage of PDE 4 inhibitors used to treat respiratory disorders such as asthma and COPD in order to avoid associated gastrointestinal side effects, by including an anti-inflammatory agent in the treatment protocol. SUMMARY OF THE INVENTION

[00018] Briefly, therefore, the present invention is directed toward a novel method for the treatment or prevention of respiratory inflammation in a subject in need of such prevention or treatment, the method comprising administering to the subject a phosphodiesterase 4 inhibitor in combination with a Cox-2 inhibitor.

[00019] The present invention is also directed to a novel therapeutic composition for the prevention or treatment of respiratory inflammation, the therapeutic composition comprising at least one Cox-2 inhibitor and at least one phosphodiesterase 4 inhibitor.

[00020] The present invention is also directed to a novel pharmaceutical composition for the prevention or treatment of respiratory inflammation, the pharmaceutical composition comprising at least one Cox-2 inhibitor, at least one phosphodiesterase 4 inhibitor and a pharmaceutically- acceptable excipient.

[00021] The present invention is also directed to a novel kit that is suitable for use in the prevention or treatment of respiratory inflammation, the kit comprising a first dosage form comprising a Cox-2 inhibitor and a second dosage comprising a phosphodiesterase 4 inhibitor, in amounts which comprise a therapeutically effective combination of the compounds for the prevention or treatment of the respiratory inflammation. [00022] Among the several advantages found to be achieved by the present invention, therefore, may be noted the provision of improved methods and therapeutic compositions for the prevention or treatment of respiratory inflammation, such as that associated with asthma and COPD, in a subject in need of such treatment or prevention. Other advantages achieved by the present invention include methods and compositions that improve patient airway responses following acute respiratory episodes. In addition, the present invention provides methods and compositions that reduce dosages or reduce unwanted side effects in conventional treatments for respiratory inflammation. Finally, the present invention provides methods and compositions that improve the efficacy of treating a respiratory disorder that is considered resistant or intractable to known methods of therapy alone. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [00023] In accordance with the present invention, it has been found that respiratory inflammation may be treated and/or prevented in a subject that is in need of such treatment or prevention by administering to the subject a Cox-2 inhibitor in combination with one or more phosphodiesterase 4 inhibitors.

[00024] In preferred embodiments, an amount of a Cox-2 inhibitor and an amount of a phosphodiesterase 4 inhibitor are administered to the subject wherein the amount of the Cox-2 inhibitor and the amount of the phosphodiesterase 4 inhibitor together comprise a therapeutic amount.

[00025] In preferred embodiments, the administration of a Cox-2 inhibitor in combination with a phosphodiesterase 4 inhibitor for the prevention or treatment of respiratory inflammation provides an effect that is unexpectedly superior to the effect that would be expected based on the use of either agent alone. The administration of a Cox-2 inhibitor in combination with a phosphodiesterase 4 inhibitor is effective for improving respiratory inflammation, and in preferred embodiments can avoid or reduce certain disadvantages of current treatments. The combination therapy of the present invention would also be useful to prevent the occurrence of other symptoms associated with respiratory disorders such as, for example, coughing, congestion, dyspnea, wheezing, hyperventilation, difficulty breathing, bronchospasm, and bronchoconstriction in a subject suffering from such symptoms. The combination therapy of the invention would be useful, for example, to reduce the death rate or the number of non-fatal hospitalizations, or to prevent or retard the development of COPD, which can arise from chronic cigarette smoking. The combination therapy of a Cox-2 inhibitor and a phosphodiesterase 4 inhibitor is also useful for decreasing the required number of separate dosages, thus, potentially improving patient compliance.

[00026] As used herein, the phrases "combination therapy", "co- administration", "co-administering", "administration with", "administering", "combination", or "co-therapy", when referring to use of a Cox-2 inhibitor in combination with a phosphodiesterase 4 inhibitor, are intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended to embrace co-administration of these agents in a substantially simultaneous manner as well. Thus, the Cox-2 inhibitor and phosphodiesterase 4 inhibitor may be administered in one therapeutic dosage form, such as in a single capsule, tablet, eye drop, aerosol, or injection, or in two separate therapeutic dosage forms, such as in separate capsules, tablets, eye drops, aerosols, or injections.

[00027] Sequential administration of such treatments encompasses both relatively short and relatively long periods between the administration of each of the drugs of the present method. However, for purposes of the present invention, the second drug is administered while the first drug is still having an efficacious effect on the subject. Thus, the present invention, in one embodiment, takes advantage of the fact that the simultaneous presence of the combination of a Cox-2 inhibitor and a phosphodiesterase 4 inhibitor in a subject has an unexpectedly greater efficacy than the administration of either agent alone. [00028] Preferably, the second of the two drugs is administered to the subject within the therapeutic response time of the first drug to be administered. For example, the present invention encompasses administration of a Cox-2 inhibitor to the subject and the later administration of a phosphodiesterase 4 inhibitor, as long as the phosphodiesterase 4 inhibitor is administered to the subject while the Cox-

2 inhibitor is still present in the subject at a level, which in combination with the level of the phosphodiesterase 4 inhibitor is therapeutically effective, and vice versa. [00029] In one embodiment, the present invention encompasses a method for preventing respiratory inflammation in a subject that is in need of such prevention, the method comprising administering to the subject a Cox-2 inhibitor and a phosphodiesterase 4 inhibitor. [00030] As used herein, the term "prevention" refers to any reduction, no matter how slight, of a subject's predisposition or risk for developing respiratory inflammation. For purposes of prevention, the subject is any subject, and preferably is a subject that is at risk for, or is predisposed to, developing respiratory inflammation.

[00031] As used herein, a subject that is "predisposed to" or "at risk for," both of which are used interchangeably herein, includes any subject with an increased chance for developing respiratory inflammation. The subject may be at risk due to genetic predisposition, diet, age, and the like. The subject may also be at risk due to physiological factors such as anatomical and biochemical abnormalities and certain autoimmune diseases. [00032] In another embodiment, the present invention encompasses a method for treating respiratory inflammation in a subject that is in need of such treatment, the method comprising administering to the subject a Cox- 2 inhibitor and a phosphodiesterase 4 inhibitor.

[00033] The terms "treating" or "to treat" mean to alleviate symptoms, eliminate the causation of symptoms, either on a temporary or permanent basis, or to alter or slow the appearance of symptoms. The term "treatment" includes alleviation of, or elimination of causation of, symptoms associated with any of the diseases or disorders described herein.

[00034] The term "subject" for purposes of treatment includes any vertebrate. The subject is typically a mammal. "Mammal", as that term is used herein, refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cattle, etc., Preferably, the mammal is a human. A subject "that is in need or prevention or treatment", is a subject who, by genetics, lifestyle, age, physical condition, accident, medical treatment, medical history, or otherwise, is at risk for contacting, or who has contacted, a disease or disorder. In the context of this application, the disease or disorder is respiratory inflammation.

[00035] As used herein, the term "respiratory inflammation" refers to any local response in the airway or lungs that is marked by capillary dilatation, leukocytic infiltration, and edema, and that serves as a mechanism initiating the elimination of noxious agents and of damaged tissue. The respiratory inflammation can be associated with a disease or disorder including, but not limited to, asthma, chronic obstructive airway disorder, pneumonia, respiratory syncytial viral infection, bronchitis, bronchiolitis, idiopathic pulmonary fibrosis, cystic fibrosis, acute respiratory distress syndrome, bronchopulmonary dysplasia, occupational respiratory disease, particulate exposure, pleurisy, emphysema, and pulmonary edema. [00036] A component of the present invention is a Cox-2 inhibitor. The terms "cyclooxygenase-2 inhibitor", or "Cox-2 inhibitor", which can be used interchangeably herein, embrace compounds which inhibit the Cox-2 enzyme regardless of the degree of inhibition of the Cox-1 enzyme, and include pharmaceutically acceptable salts of those compounds. Thus, for purposes of the present invention, a compound is considered a Cox-2 inhibitor irrespective of whether the compound inhibits the Cox-2 enzyme to an equal, greater, or lesser degree than the Cox-1 enzyme. [00037] In one embodiment of the present invention, it is preferred that the Cox-2 inhibitor compound is a non-steroidal anti-inflammatory drug (NSAID). Therefore, preferred materials that can serve as the Cox-2 inhibitor of the present invention include non-steroidal anti-inflammatory drug compounds, a pharmaceutically acceptable salt thereof, or a pure (-) or (+) optical isomeric form thereof. [00038] Examples of NSAID compounds that are useful in the present invention include acemetacin, acetyl salicylic acid, alclofenac, alminoprofen, azapropazone, benorylate, benoxaprofen, bucloxic acid, carprofen, choline magnesium trisalicylate, clidanac, clopinac, dapsone, diclofenac, diflunisal, droxicam, etodolac, fenoprofen, fenbufen, fenclofenec, fentiazac, floctafenine, flufenisal, flurbiprofen, (r)-flurbiprofen, (s)-flurbiprofen, furofenac, feprazone, flufenamic acid, fluprofen, ibufenac, ibuprofen, indometacin, indomethacin, indoprofen, isoxepac, isoxicam, ketoprofen, ketorolac, miroprofen, piroxicam, meloxicam, mefenamic, mefenamic acid, meclofenamic acid, meclofen, nabumetone, naproxen, niflumic acid, oxaprozin, oxipinac, oxyphenbutazone, phenylbutazone, podophyllotoxin derivatives, proglumetacin, piprofen, pirprofen, prapoprofen, salicylic acid, salicylate, sudoxicam, suprofen, sulindac, tenoxicam, tiaprofenic acid, tiopinac, tioxaprofen, tolfenamic acid, tolmetin, zidometacin, zomepirac, and 2-fluoro-a-methyl[1 ,1'-biphenyl]-4-acetic acid, 4-(nitrooxy)butyl ester.

[00039] In a preferred embodiment, the Cox-2 inhibitor is a Cox-2 selective inhibitor. The term "Cox-2 selective inhibitor" embraces compounds which selectively inhibit the Cox-2 enzyme over the Cox-1 enzyme, and also include pharmaceutically acceptable salts and prodrugs of those compounds.

[00040] In practice, the selectivity of a Cox-2 inhibitor varies depending upon the condition under which the test is performed and on the inhibitors being tested. However, for the purposes of this specification, the selectivity of a Cox-2 inhibitor can be measured as a ratio of the in vitro or in vivo IC50 value for inhibition of Cox-1, divided by the IC₅₀ value for inhibition of Cox-2 (Cox-1 ICso Cox-2 IC5₀). Cox-2 selective inhibitor is any inhibitor for which the ratio of Cox-1 IC₅₀ to Cox-2 IC₅₀ is greater than 1. In preferred embodiments, this ratio is greater than 2, more preferably greater than 5, yet more preferably greater than 10, still more preferably greater than 50, and more preferably still greater than 100. [00041] As used herein, the term "IC₅₀" refers to the concentration of a compound that is required to produce 50% inhibition of cyclooxygenase activity. Preferred Cox-2 selective inhibitors of the present invention have a Cox-2 IC50 of less than about 1 μM, more preferred of less than about 0.5 μM, and even more preferred of less than about 0.2 μM. [00042] Preferred Cox-2 selective inhibitors have a Cox-1 IC₅₀ of greater than about 1 μM, and more preferably of greater than 20 μM. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects. [00043] Also included within the scope of the present invention are compounds that act as prodrugs of Cox-2-selective inhibitors. As used herein in reference to Cox-2 selective inhibitors, the term "prodrug" refers to a chemical compound that can be converted into an active Cox-2 selective inhibitor by metabolic or simple chemical processes within the body of the subject. One example of a prodrug for a Cox-2 selective inhibitor is parecoxib, which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib. An example of a preferred Cox-2 selective inhibitor prodrug is sodium parecoxib. A class of prodrugs of Cox-2 inhibitors is described in U.S. Patent No. 5,932,598. [00044] The Cox-2 selective inhibitor of the present invention can be, for example, the Cox-2 selective inhibitor meloxicam, Formula B-1 (CAS registry number 71125-38-7), or a pharmaceutically acceptable salt or prodrug thereof.

[00045] In another embodiment of the invention the Cox-2 selective inhibitor can be the Cox-2 selective inhibitor RS 57067, 6-[[5-(4- chlorobenzoyl)-1 ,4-dimethyl-1 H-pyrrol-2-yl]methyl]-3(2H)-pyridazinone, Formula B-2 (CAS registry number 179382-91-3), or a pharmaceutically acceptable salt or prodrug thereof.

[00046] As used herein, the term "alkyl", either alone or within other terms such as "haloalkyl" and "alkylsulfonyl"; embraces linear or branched radicals having one to about twenty carbon atoms. Lower alkyl radicals have one to about ten carbon atoms. The number of carbon atoms can also be expressed as "C₁-C₅", for example. Examples of lower alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the, like. [00047] The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains at least one double bond. The alkenyl radicals may be optionally substituted with groups such as those defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropylenyl, buten-1yl, isobutenyl, penten-1yl, 2-methylbuten-1 -yl, 3-methylbuten-1-yl, hexen-1-yl, 3- hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl, and the like. [00048] The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds, such radicals preferably containing 2 to about 6 carbon atoms, more preferably from 2 to about 3 carbon atoms. The alkynyl radicals may be optionally substituted with groups such as described below. Examples of suitable alkynyl radicals include ethynyl, proynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3- methylbutyn-1-yl, hexyl-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1 -yl radicals, and the like. [00049] The term "oxo" means a single double-bonded oxygen. [00050] The terms "hydrido", "-H", or "hydrogen", denote a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical, or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH₂ -) radical. [00051] The term "halo" means halogens such as fluorine, chlorine, and bromine or iodine atoms. The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have a bromo, chloro, or a fluoro atom within the radical. Dihalo alkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.

[00052] The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. [00053] The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term "alkoxyalkyl" also embraces alkyl radicals having two or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and diaikoxyalkyl radicals. The "alkoxy" or "alkoxyalkyl" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide

"haloalkoxy" or "haloalkoxyalkyl" radicals. Examples of "alkoxy" radicals include methoxy, butoxy, and trifluoromethoxy.

[00054] The term "aryl", whether used alone or with other terms, means a carbocyclic aromatic system containing one, two, or three rings wherein such rings may be attached together in a pendent manner, or may be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronapthyl, indane, and biphenyl. The term "heterocyclyl" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms are replaced by N, S, P, or O. This includes, for example, structures such as:

where Z, Z¹, Z², or Z³ is C, S, P, O, or N, with the proviso that one of Z, Z¹, Z², or Z³ is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom. Furthermore, the optional substituents are understood to be attached to Z, Z¹, Z², or Z³ only when each is C. The term "heterocycle" also includes fully saturated ring structures, such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others. [00055] The term "heteroaryl" embraces unsaturated heterocyclic radicals. Examples of unsaturated heterocyclic radicals include thienyl, pyrryl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, and tetrazolyl. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.

[00056] The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO₂-. "Alkylsulfonyl", embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. The term "arylsulfonyl" embraces sulfonyl radicals substituted with an aryl radical. The term "aminosulfonyl"denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide

[00057] The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -C0₂-H. The term "carboxyalkyl" embraces radicals having a carboxyradical as defined above, attached to an alkyl radical. The term "carbonyl", whether used alone or with other terms, such as "alkylcarbonyl", denotes - (C=0) -. The term "alkylcarbonyl" embraces radicals having a carbonyl radical substituted with an alkyl radical. An example of an "alkylcarbonyl" radical is CH₃ - (CO) -. The term "alkoxycarbonyl" means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl (C=0) radical. Examples of such "alkoxycarbonyl" radicals include (CH₃)₃-C-0-C=0) - and - (0=)C- OCH₃. The term "amino", whether used alone or with other terms, such as "aminocarbonyl", denotes -NH .

[00058] The term "heterocycloalkyl" embraces heterocyclic-substituted alkyl radicals such as pyridylmethyl and thienylmethyl. The terms "aralkyl", or "arylalkyl" embrace aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable. The term "cycloalkyl" embraces radicals having three to ten carbon atoms, such as cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term

"cycloalkenyl" embraces unsaturated radicals having three to ten carbon atoms, such as cylopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. [00059] The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of "alkylthio" is methylthio, (CH₃ -S-). The term "alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent — S(-O) - atom. The term "acyl", whether used alone, or within a term such as "acylamino", denotes a radical provided by the residue after removal of hydroxyl from an organic acid.

[00060] The term "cyano", used either alone or with other terms, such as "cyanoalkyl", refers to C≡N. The term "nitro" denotes -N0₂. [00061] In one embodiment of the invention the Cox-2 selective inhibitor is of the chromene/chroman structural class, which encompasses substituted benzopyrans or substituted benzopyran analogs, as well as substituted benzothiopyrans, dihydroquinolines, or dihydronaphthalenes having the structure of any one of the general Formulas I, II, III, IV, V, and VI, shown below, and including, by way of non-limiting example, the structures disclosed in Table 1, and the diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof. [00062] Benzopyrans that can serve as a Cox-2 selective inhibitor of the present invention include substituted benzopyran derivatives that are described in U.S. Patent Nos. 6,271,253 and 6,492,390. One such class of compounds is defined by the general formula shown below in formula I:

wherein X¹ is selected from O, S, CR^C R^b and NR^a ; wherein R^a is selected from hydrido, Ci -C₃ -alkyl, (optionally substituted phenyl)-Cι -C₃ -alkyl, acyl and carboxy-Ci -Cβ -alkyl; wherein each of R^b and R^c is independently selected from hydrido, Ci -C₃

-alkyl, phenyl-C_! -C₃ -alkyl, Ci -C₃ -perfluoroalkyl, chloro, Ci -C₆ - alkylthio, Ci -Cβ -alkoxy, nitro, cyano and cyano-Ci -C₃ -alkyl; or wherein CR^b R^c forms a 3-6 membered cycloalkyl ring; wherein R¹ is selected from carboxyl, aminocarbonyl, Ci -Cβ - alkylsulfonylaminocarbonyl and Ci -C₆ -alkoxycarbonyl; wherein R² is selected from hydrido, phenyl, thienyl, Ci -C₆ -alkyl and C₂ -Cβ -alkenyl; wherein R³ is selected from Ci -C₃ -perfluoroalkyl, chloro, Ci -Cβ - alkylthio, Ci -Cβ -alkoxy, nitro, cyano and cyano-Ci -C₃ -alkyl; wherein R⁴ is one or more radicals independently selected from hydrido, halo, CT -C₆ -alkyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl, ha!o-C₂ -Cβ - alkynyl, aryl-C_! -C₃ -alkyl, aryl-C₂ -C₆ -alkynyl, aryl-C₂ -C₆ -alkenyl, Ci — Cβ -alkoxy, methylenedioxy, Ci -C₆ -alkylthio, Ci -Cβ -alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, d -Cβ -alkoxy-d -Cβ -alkyl, aryl-Cι -C₆ -alkyloxy, heteroaryl-C_! -C₆ -alkyloxy, aryl-Ci -C₆ -alkoxy-Ci

-C₆ -alkyl, Ci -C₆ -haloalkyl, Ci -C₆ -haloalkoxy, Ci -C₆ -haloalkylthio, Ci -C₆ -haloalkylsulfinyl, ^ -C₆ -haloalkylsulfonyl, Ci -C₃ -(haloalkyh - C₃ -hydroxyalkyl, Ci -C₆ -hydroxyalkyl, hydroxyimino-Ci -C₆ -alkyl, Ci -

Cβ -alkylamino, arylamino, aryl-Ci -C₆ -alkylamino, heteroarylamino, heteroaryl-Ci -C₆ -alkylamino, nitro, cyano, amino, aminosulfonyl, Ci -C₆

-alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-Ci -

Cβ -alkylaminosulfonyl, heteroaryl-Ci -Cβ -alkylaminosulfonyl, heterocyclylsulfonyl, Ci -C₆ -alkylsulfonyl, aryl-Ci -C₆ -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-Ci -Cβ - alkylcarbonyl, heteroaryl-Ci -Cβ -alkylcarbonyl, heteroaryicarbonyl, arylcarbonyl, aminocarbonyl, Ci -Ci -alkoxycarbonyl, formyl, Ci -Cβ — haloalkylcarbonyl and Ci -Cβ -alkylcarbonyl; and wherein the A ring atoms A¹, A², A³ and A⁴ are independently selected from carbon and nitrogen with the proviso that at least two of A¹, A², A³ and A⁴ are carbon; or wherein R⁴ together with ring A forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.

[00063] Another class of benzopyran derivatives that can serve as the

Cox-2 selective inhibitor of the present invention includes compounds having the structure of formula II:

wherein X² is selected from O, S, CR^C R^fa and NR^a ; wherein R^a is selected from hydrido, Ci -C₃ -alkyl, (optionally substituted phenyl)-Cι -C₃ -alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-Ci -Cβ -alkyl; wherein each of B^b and R^c is independently selected from hydrido, Ci -C₃ -alkyl, phenyl-Ci -Ca -alkyl, Ci -C₃ -perfluoroalkyl, chloro, Ci -C₆ - alkylthio, Ci -C₆ -alkoxy, nitro, cyano and cyano-Ci -C₃ -alkyl; or wherein CR^C R^b form a cyclopropyl ring; wherein R⁵ is selected from carboxyl, aminocarbonyl, Ci -Cβ - alkylsulfonylaminocarbonyl and Ci -C₆ -alkoxycarbonyl; wherein R⁶ is selected from hydrido, phenyl, thienyl, C₂ -C₆ -alkynyl and C₂ -C₆ -alkenyl; wherein R⁷ is selected from Ci -C₃ -perfluoroalkyl, chloro, Ci -Cβ - alkylthio, Ci -Cβ -alkoxy, nitro, cyano and cyano-Ci -C₃ -alkyl; wherein R⁸ is one or more radicals independently selected from hydrido, halo, Ci -C₆ -alkyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl, halo-C₂ -C₆ - alkynyl, aryl-Ci -C₃ -alkyl, aryl-C₂ -C₆ -alkynyl, aryl-C₂ -C₆ -alkenyl, Ci - C₆ -alkoxy, methylenedioxy, Ci -C₆ -alkylthio, Ci -C₆ -alkylsulfinyl, — 0(CF₂)₂ O — , aryloxy, arylthio, arylsulfinyl, heteroaryloxy, Ci -Cβ -alkoxy-

Ci -C₆ -alkyl, aryl-Ci -C_β -alkyloxy, heteroaryl-Ci -C₆ -alkyloxy, aryl-Ci - C₆ -alkoxy-d -C₆ -alkyl, Ci -C₆ -haloalkyl, Ci -C₆ -haloalkoxy, d -C₆ - haloalkylthio, Ci -C₆ -haloalkylsulfinyl, Ci -C₆ -haloalkylsulfonyl, Ci -C₃ - (haloalkyl-d -C₃ -hydroxyalkyl), Ci -Cβ -hydroxyalkyl, hydroxyimino-Ci - Cβ -alkyl, Ci -C₆ -alkylamino, arylamino, aryl-Ci -C₆ -alkylamino, heteroarylamino, heteroaryl-Ci -Cβ -alkylamino, nitro, cyano, amino, aminosulfonyl, C-i -Cβ -alkylaminosulfonyl, arylaminosulfonyl, , heteroarylaminosulfonyl, aryl-Ci -C₆ -alkylaminosulfonyl, heteroaryl-Ci - Cβ -alkylaminosulfonyl, heterocyclylsulfonyl, Ci -Cβ -alkylsulfonyl, aryl-Ci -Cβ -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-d -C₆ -alkylcarbonyl, heteroaryl-Ci -Cβ -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, Ci -Cβ -alkoxycarbonyl, formyl, Ci -Cβ -haloalkylcarbonyl and Ci -Cβ -alkylcarbonyl; and wherein the D ring atoms D¹ , D², D³ and D⁴ are independently selected from carbon and nitrogen with the proviso that at least two of D¹, D², D³ and D⁴ are carbon; or wherein R⁸ together with ring D forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.

[00064] Other benzopyran Cox-2 selective inhibitors useful in the practice of the present invention are described in U.S. Patent Nos.

6,034,256 and 6,077,850. The general formula for these compounds is shown in formula III:

wherein X³ is selected from the group consisting of O or S or NR^a; wherein R^a is alkyl; wherein R⁹ is selected from the group consisting of H and aryl; wherein R¹⁰ is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; wherein R¹ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and wherein R¹² is selected from the group consisting of one or more radicals selected from H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroaryialkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyciosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein R¹² together with ring E forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof; and including the diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof.

[00065] A related class of compounds useful as Cox-2 selective inhibitors in the present invention is described by Formulas IV and V below:

wherein X⁴ is selected from O or S or NR^a ; wherein R^a is alkyl; wherein R¹³ is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; wherein R¹⁴ is selected from haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and wherein R¹⁵ is one or more radicals selected from hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyciosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein R¹⁵ together with ring G forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof. [00066] Formula V is:

wherein:

X⁵ is selected from the group consisting of O or S or NR^b;

R^b is alkyl;

R¹⁶is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;

R¹⁷is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl each is independently optionally substituted with one or more radicals selected from the group consisting of alkylthio, nitro and alkylsulfonyl; and

R¹⁸ is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyciosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein R¹⁸ together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.

[00067] The Cox-2 selective inhibitor may also be a compound of

Formula V, wherein:

X⁵ is selected from the group consisting of oxygen and sulfur;

R¹⁶is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;

R¹⁷ is selected from the group consisting of lower haloalkyl, lower cycloalkyl and phenyl; and R¹⁸ is one or more radicals selected from the group of consisting of hydrido, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5- membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen-containing heterocyciosulfonyl, 6-membered nitrogen-containing heterocyciosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R¹⁸ together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.

[00068] The Cox-2 selective inhibitor may also be a compound of Formula V, wherein:

X⁵ is selected from the group consisting of oxygen and sulfur; R¹⁶ is carboxyl; R¹⁷ is lower haloalkyl; and

R¹⁸ is one or more radicals selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen- containing heterocyciosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R¹⁸ together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof. [00069] The Cox-2 selective inhibitor may also be a compound of

Formula V, wherein:

X⁵ is selected from the group consisting of oxygen and sulfur; R¹⁶ is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; R¹⁷ is selected from the group consisting of fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyl; and

R¹⁸ is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, fert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N,N- dimethylamino, N,N-diethylamino, N-phenylmethylaminosulfonyl, N- phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, nitro, N,N- dimethylaminosulfonyl, aminosulfonyl, N-methy!aminosulfonyl, N- ethylsulfonyl, 2,2-dimethylethylaminosulfonyl, N,N-dimethylaminosulfonyl,

N-(2-methylpropyl)aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl and phenyl; or wherein R² together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof. [00070] The Cox-2 selective inhibitor may also be a compound of

Formula V, wherein:

X⁵ is selected from the group consisting of oxygen and sulfur; R¹⁶ is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; R¹⁷ is selected from the group consisting trifluoromethyl and pentafluoroethyl; and

R¹⁸ is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, ført-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl, N- phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, N,N- dimethylaminosulfonyl, N-methylaminosulfonyl, N-(2,2- dimethylethyl)aminosulfonyl, dimethylaminosulfonyl, 2- methylpropylaminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, and phenyl; or wherein R¹⁸ together with ring A forms a naphthyl radical; or an isomer or prodrug thereof. [00071] The Cox-2 selective inhibitor of the present invention can also be a compound having the structure of Formula VI:

wherein: X⁶ is selected from the group consisting of O and S;

R¹⁹ is lower haloalkyl;

R²⁰ is selected from the group consisting of hydrido, and halo;

R²¹ is selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5-membered nitrogen-containing heterocyciosulfonyl, and 6- membered nitrogen-containing heterocyciosulfonyl;

R²² is selected from the group consisting of hydrido, lower alkyl, halo, lower alkoxy, and aryl; and

R²³ is selected from the group consisting of the group consisting of hydrido, halo, lower alkyl, lower alkoxy, and aryl; or an isomer or prodrug thereof.

[00072] The Cox-2 selective inhibitor can also be a compound of having the structure of Formula VI, wherein:

X⁶ is selected from the group consisting of O and S;

R¹⁹ is selected from the group consisting of trifluoromethyl and pentafluoroethyl;

R²⁰ is selected from the group consisting of hydrido, chloro, and fluoro; R²¹ is selected from the group consisting of hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl, and morpholinosulfonyl; R²² is selected from the group consisting of hydrido, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, and phenyl; and R²³ is selected from the group consisting of hydrido, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, and phenyl; or an isomer or prodrug thereof. Table 1. Examples of Chromene Cox-2 Selective Inhibitors

[00073] In preferred embodiments the chromene Cox-2 inhibitor is selected from (S)-6-chloro-7-(1 ,1 -dimethylethyl)-2-(trifluoromethyl)-2H-1 - benzopyran-3-carboxylic acid, (2S)-6,8-dimethyl-2-(trif!uoromethyl)-2H- chromene-3-carboxylic acid, (2S)-6-chloro-8-methyl-2-(trifluoromethyl)-2H- chromene-3-carboxylic acid, (2S)-8-ethyl-6-(trifluoromethoxy)-2- (trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6,8-dichloro-2- (trifluoromethyl)-2H-1 -benzopyran-3-carboxylic acid, (2S)-6-chloro-5,7- dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and mixtures thereof.

[00074] In a preferred embodiment of the invention the Cox-2 inhibitor can be selected from the class of tricyclic Cox-2 selective inhibitors represented by the general structure of formula VII:

wherein: Z¹ is selected rom the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings; 24 (

R is selected from the group consisting of heterocyclyl, cycloalkyl, 24 cycloalkenyl and aryl, wherein R is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; 25

R is selected from the group consisting of methyl or amino; and R is selected from the group consisting of a radical selected from H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N- arylaminocarbonyl, N-alkyl-N- arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N- arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl- N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N- arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl; or a prodrug thereof.

[00075] In a preferred embodiment of the invention the Cox-2 selective inhibitor represented by the above Formula VII is selected from the group of compounds, illustrated in Table 2, which includes celecoxib (B-21), valdecoxib (B-22), deracoxib (B-23), rofecoxib (B-24), etoricoxib (MK-663; B-25), JTE-522 (B-26), or prodrugs thereof.

[00076] Additional information about selected examples of the Cox-2 selective inhibitors discussed above can be found as follows: celecoxib (CAS RN 169590-42-5, C-2779, SC-58653, and in U.S. Patent No. 5,466,823); deracoxib (CAS RN 169590-41-4); rofecoxib (CAS RN 162011 -90-7); compound B-24 (U.S. Patent No. 5,840,924); compound B-

26 (WO 00/25779); and etoricoxib (CAS RN 202409-33-4, MK-663, SC- 86218, and in WO 98/03484).

Table 2. Examples of Tricyclic COX-2 Selective Inhibitors

[00077] In a more preferred embodiment of the invention, the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib.

[00078] In a preferred embodiment, parecoxib (See, U.S. Patent No. 5,932,598), having the structure shown in B-27, and which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib, B-22, (See, U.S. Patent No. 5,633,272), may be advantageously employed as the Cox-2 inhibitor of the present invention.

[00079] A preferred form of parecoxib is sodium parecoxib. [00080] Another tricyclic Cox-2 selective inhibitor useful in the present invention is the compound ABT-963, having the formula B-28 shown below, that has been previously described in International Publication Number WO 00/24719.

B-28

[00081] In a further embodiment of the invention, the Cox-2 inhibitor can be selected from the class of phenylacetic acid derivative Cox-2 selective inhibitors represented by the general structure of formula VIII:

wherein:

R²⁷ is methyl, ethyl, or propyl;

R²⁸ is chloro or fluoro;

R²⁹ is hydrogen, fluoro, or methyl;

R³⁰ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxyl;

R³¹ is hydrogen, fluoro, or methyl; and

R³² is chloro, fluoro, trifluoromethyl, methyl, or ethyl, provided that R²⁸, R²⁹, R³⁰ and R³¹ are not all fluoro when R²⁷ is ethyl and

R³⁰ is H.

[00082] An exemplary phenylacetic acid derivative Cox-2 selective inhibitor that is described in WO 99/11605 is a compound that has the structure shown in formula VIII, wherein:

R²⁷ is ethyl;

R²⁸ and R³⁰ are chloro;

R²⁹ and R³¹ are hydrogen; and

R³² is methyl.

[00083] Another phenylacetic acid derivative Cox-2 selective inhibitor is a compound that has the structure shown in formula VIII, wherein:

R²⁷ is propyl;

R²⁸ and R³⁰ are chloro; R²⁹ and R³¹ are methyl; and

R³² is ethyl.

[00084] Another phenylacetic acid derivative Cox-2 selective inhibitor that is disclosed in WO 02/20090 is a compound that is referred to as COX-189 (also termed lumiracoxib; CAS Reg. No. 220991-20-8), having the structure shown in formula VIII, wherein:

R²⁷ is methyl;

R²⁸ is fluoro; R³² is chloro; and

R²⁹, R³⁰, and R³¹ are hydrogen.

[00085] Compounds having a structure similar to that shown in formula

VIII, that can serve as the Cox-2 selective inhibitor of the present invention, are described in U.S. Patent Nos. 6,451 ,858, 6,310,099, 6,291 ,523, and 5,958,978.

[00086] Other Cox-2 selective inhibitors that can be used in the present invention have the general structure shown in formula IX, where the J group is a carbocycle or a heterocycle. Preferred embodiments have the structure:

wherein:

X⁷ is O; J is 1 -phenyl; R³³ is 2-NHS0₂CH₃; R³⁴ is 4-N0₂; and there is no

R³⁵ group, (nimesulide), or

X⁷ is O; J is 1-oxo-inden-5-yl; R³³ is 2-F; R³⁴ is 4-F; and R³⁵ is 6-

NHS0₂CH₃, (flosulide); or X⁷ is O; J is cyclohexyl; R³³ is 2-NHS0₂CH₃; R³⁴ is 5-N0₂; and there is no

R³⁵ group, (NS-398); or

X⁷ is S; J is 1 -oxo-inden-5-yl; R³³ is 2-F; R³⁴ is 4-F; and R³⁵ is 6-N-S0₂CH₃

• Na⁺, (L-745337); or

X⁷ is S; J is thiophen-2-yl; R³³ is 4-F; there is no R³⁴ group; and R³⁵ is 5-

NHSO₂CH3, (RWJ-63556); or

X⁷ is O; J is 2-oxo-5(R)-methyl-5-(2,2,2-trifluoroethyl)furan-(5H)-3-yl; R³³ is

3-F; R³⁴ is 4-F; and R³⁵ is 4-(p-S0₂CH₃)C₆H₄, (L-784512).

[00087] The Cox-2 selective inhibitor NS-398, also known as N-(2- cyclohexyloxynitrophenyl) methane sulfonamide (CAS RN 123653-11-2), having a structure as shown below in formula B-29, has been described in, for example, Yoshimi, N. et al., in Japanese J. Cancer Res., 90(4):406 -

412 (1999).

[00088] An evaluation of the anti-inflammatory activity of the Cox-2 selective inhibitor, RWJ 63556, in a canine model of inflammation, was described by Kirchner etal., in J Pharmacol Exp Ther282, 1094-1101 (1997).

[00089] Materials that can serve as the Cox-2 selective inhibitor of the present invention include diarylmethylidenefuran derivatives that are described in U.S. Patent No. 6,180,651. Such diarylmethylidenefuran derivatives have the general formula shown below in formula X:

wherein: the rings T and M independently are a phenyl radical, a naphthyl radical, a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms; at least one of the substituents Q¹, Q², L¹ or L² is an — S(0)_n — R group, in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having

1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an -S0₂NH₂ group; and is located in the para position, the others independently being a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a trifluoromethyl radical, or a lower O-alkyl radical having 1 to 6 carbon atoms, or Q¹ and Q² or L¹ and

L² are a methylenedioxy group; and

R³⁶, R³⁷, R³⁸ and R³⁹ independently are a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, fury! and pyridyl; or,

R³⁶, R³⁷ or R³⁸, R³⁹ are an oxygen atom; or

R³⁶, R³⁷ or R³⁸, R³⁹, together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms; or an isomer or prodrug thereof. [00090] Particular diarylmethylidenefuran derivatives that can serve as the Cox-2 selective inhibitor of the present invention include, for example, N-(2-cyclohexyloxynitrophenyl)methane sulfonamide, and (E)-4-[(4- methylphenyl)(tetrahydro-2-oxo-3-furanylidene) methyObenzenesulfonamide.

[00091 ] Other Cox-2 selective inhibitors that are useful in the present invention include darbufelone (Pfizer), CS-502 (Sankyo), LAS 34475 (Almirall Profesfarma), LAS 34555 (Almirall Profesfarma), S-33516 (Servier), SD 8381 (Pharmacia, described in U.S. Patent No. 6,034,256), BMS-347070 (Bristol Myers Squibb, described in U.S. Patent No.

6,180,651), MK-966 (Merck), L-783003 (Merck), T-614 (Toyama), D-1367 (Chiroscience), L-748731 (Merck), CT3 (Atlantic Pharmaceutical), CGP- 28238 (Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome), 6-dioxo-9H-purin-8-yl-cinnamic acid (Glaxo Wellcome), and S-2474 (Shionogi).

[00092] Compounds that may act as Cox-2 selective inhibitors of the present invention include multibinding compounds containing from 2 to 10 ligands covanlently attached to one or more linkers, as described in U.S. Patent No. 6,395,724. [00093] Conjugated linoleic, as described in U.S. Patent No. 6,077,868, is useful as a Cox-2 selective inhibitor in the present invention. [00094] Compounds that can serve as a Cox-2 selective inhibitor of the present invention include heterocyclic aromatic oxazole compounds that are described in U.S. Patents 5,994,381 and 6,362,209. Such heterocyclic aromatic oxazole compounds have the formula shown below in formula XI:

wherein:

Z² is an oxygen atom; one of R⁴⁰ and R⁴¹ is a group of the formula

wherein:

R⁴³ is lower alkyl, amino or lower alkylamino; and R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷ are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxyl or amino, provided that at least one of R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷ is not hydrogen atom, and the other is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group or an optionally substituted aryl; and R³⁰ is a lower alkyl or a halogenated lower alkyl, and a pharmaceutically acceptable salt thereof. [00095] Cox-2 selective inhibitors that are useful in the method and compositions of the present invention include compounds that are described in U.S. Patent Nos. 6,080,876 and 6,133,292, and described by formula XII:

wherein:

Z³ is selected from the group consisting of linear or branched Ci -Cβ alkyl, linear or branched Ci -Cβ alkoxy, unsubstituted, mono-, di- or tri- substituted phenyl or naphthyl wherein the substituents are selected from the group consisting of hydrogen, halo, Ci -C₃ alkoxy, CN, Ci -C fluoroalkyl Ci -C₃ alkyl, and -C0₂ H;

R⁴⁸ is selected from the group consisting of NH₂ and CH₃,

R⁴⁹ is selected from the group consisting of Ci -C₆ alkyl unsubstituted or substituted with C₃ -Cβ cycloalkyl, and C -Cβ cycloalkyl;

R⁵⁰ is selected from the group consisting of:

Ci -C₆ alkyl unsubstituted or substituted with one, two or three fluoro atoms, and C₃ -Ce cycloalkyl; with the proviso that R⁴⁹ and R⁵⁰ are not the same.

[00096] Pyridines that are described in U.S. Patent Nos. 6,596,736,

6,369,275, 6,127,545, 6,130,334, 6,204,387, 6,071 ,936, 6,001 ,843 and

6,040,450, and can seve as Cox-2 selective inhibitors of the present invention, have the general formula described by formula XIII:

wherein: "

R⁵¹ is selected from the group consisting of CH₃, NH₂, NHC(0)CF₃, and

NHCH₃;

Z⁴ is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-oxide thereof), wherein the substituents are chosen from the group consisting of hydrogen, halo, Ci -C₆ alkoxy, Ci -C₆ alkylthio, CN, Ci -C₆ alkyl, Ci ~C₆ fluoroalkyl, N₃, -C0₂R⁵³, hydroxyl, -C(R⁵⁴)(R⁵⁵)— OH, - C -C₆ alkyl-

C0₂— R⁵⁶, Ci -C₆ fluoroalkoxy;

R⁵² is chosen from the group consisting of: halo, Ci ~C₆ alkoxy, Ci -Cβ alkylthio, CN, C -C₆ alkyl, d -C₆ fluoroalkyl, N₃, — C0₂R⁵⁷, hydroxyl, —

C(R⁵⁸)(R⁵⁹)— OH, — Ci -C₆ alkyl-C0 — R⁶⁰, Ci -C₆ fluoroalkoxy, N0₂,

NR⁶¹R⁶², and NHCOR⁶³;

R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶ , R⁶², and R⁶³, are each independently chosen from the group consisting of hydrogen andOt -C₆ alkyl; or R⁵⁴ and R⁵⁵, R⁵⁸ and R⁵⁹, or R⁶¹ and R⁶² together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6, or 7 atoms.

[00097] Materials that can serve as the Cox-2 selective inhibitor of the present invention include diarylbenzopyran derivatives that are described in U.S. Patent No. 6,340,694. Such diarylbenzopyran derivatives have the general formula shown below in formula XIV:

wherein:

X⁸ is an oxygen atom or a sulfur atom;

R⁶⁴ and R⁶⁵, identical to or different from each other, are independently a hydrogen atom, a halogen atom, a Ci -Cβ lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a nitro group, a nitrile group, or a carboxyl group;

R⁶⁶ is a group of a formula: S(0)_nR⁶⁸ wherein n is an integer of 0-2, R⁶⁸ is a hydrogen atom, a Ci -C₆ lower alkyl group, or a group of a formula: NR⁶⁹

R⁷⁰ wherein R⁶⁹ and R⁷⁰, identical to or different from each other, are independently a hydrogen atom, or a Ci -C₆ lower alkyl group; and

R⁶⁷ is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a Ci -C₆ lower alkyl group, indanyl, pyrazinyl, or a substituted group represented by the following structures:

wherein:

R⁷¹ through R⁷⁵, identical to or different from one another, are independently a hydrogen atom, a halogen atom, a Ci -C₆ lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a group of a formula: S(0)_nR⁶⁸, a group of a formula: NR⁶⁹ R⁷⁰, a trifluoromethoxy group, a nitrile group a carboxyl group, an acetyl group, or a formyl group, wherein n, R⁶⁸, R⁶⁹ and R⁷⁰ have the same meaning as defined by R⁶⁶ above; and

R⁷⁶ is a hydrogen atom, a halogen atom, a C -C₆ lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a trifluoromethoxy group, a carboxyl group, or an acetyl group.

[00098] Materials that can serve as the Cox-2 selective inhibitor of the present invention include 1-(4-sulfamylaryl)-3-substituted-5-aryl-2- pyrazolines that are described in U.S. Patent No. 6,376,519. Such 1-(4- sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines have the formula shown below in formula XV:

wherein:

X⁹ is selected from the group consisting of Ci -C₆ trihalomethyl, preferably trifluoromethyl; Ci -C₆ alkyl; and an optionally substituted or di-substituted phenyl group of formula XVI:

wherein:

R⁷⁷ and R⁷⁸ are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl; nitro; Ci -C₆ alkyl, preferably C -C₃ alkyl; Ci -C₆ alkoxy, preferably Ci - C₃ alkoxy; carboxy; Ci -C₆ trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano; Z⁵ is selected from the group consisting of substituted and unsubstituted aryl.

[00099] Compounds useful as Cox-2 selective inhibitors of the present invention include heterocycles that are described in U.S. Patent No.

6,153,787. Such heterocycles have the general formulas shown below in formulas XVII and XVIII:

wherein:

R⁷⁹ is a mono-, di-, or tri-substituted Ci -Cι₂ alkyl, or a mono-, or an unsubstituted or mono-, di- or tri-substituted linear or branched C₂ -Cι₀ alkenyl, or an unsubstituted or mono-, di- or tri-substituted linear or branched C₂ -C10 alkynyl, or an unsubstituted or mono-, di- or tri- substituted C₃ -C₁₂ cycloalkenyl, or an unsubstituted or mono-, di- or tri- substituted C₅ -C12 cycloalkynyl, wherein the substituents are chosen from the group consisting of halo selected from F, CI, Br, and I, OH, CF₃, C₃ - Cβ cycloalkyl, =0,dioxolane, CN;

R⁸⁰ is selected from the group consisting of CH₃, NH₂, NHC(0)CF₃, and NHCH₃;

R⁸¹ and R⁸² are independently chosen from the group consisting of hydrogen and Ci -Cι₀ alkyl; or R⁸¹ and R⁸² together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms. [000100] Formula XVIII is: XVIII

wherein X¹⁰ is fluoro or chloro.

[000101] Materials that can serve as the Cox-2 selective inhibitor of the present invention include 2,3,5-trisubstituted pyridines that are described in U.S. Patent No. 6,046,217. Such pyridines have the general formula shown below in formula XIX:

or a pharmaceutically acceptable salt thereof, wherein:

X¹¹ is selected from the group consisting of O, S, and a bond; n is O or 1 ; R⁸³ is selected from the group consisting of CH₃, NH₂, and NHC(0)CF₃;

R⁸⁴ is chosen from the group consisting of halo, Ci -C₆ alkoxy, Ci -C₆ alkylthio, CN, Ci -C₆ alkyl, d -C₆ fluoroalkyl, N₃₎ — C0₂ R⁹², hydroxyl, —

C(R⁹³)(R⁹⁴)— OH, — Ci -C₆ alkyl-C0₂ — R⁹⁵, Ci -C₆ fluoroalkoxy, N0₂,

NR⁹⁶ R⁹⁷, and NHCOR⁹⁸;

R⁸⁵ to R⁸⁹ are independently chosen from the group consisting of hydrogen and Ci -C₆ alkyl; or R⁸⁵ and R⁸⁹, or R⁸⁹ and R⁹⁰ together with the atoms to which they are attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R⁸⁵ and R⁸⁷ are joined to form a bond.

[000102] Compounds that are useful as the Cox-2 selective inhibitor of the present invention include diaryl bicyclic heterocycles that are described in U.S. Patent No. 6,329,421. Such diaryl bicyclic heterocycles have the general formula shown below in formula XX:

and pharmaceutically acceptable salts thereof wherein: — A⁵=A⁶ — A⁷=A⁸ — is selected from the group consisting of:

(a) — CH=CH— CH=CH— ,

(b) — CH₂ — CH₂ — CH₂ — C(O)— , — CH₂ — CH₂ — C(O)— CH₂ — , — CH₂ — C(O)— CH₂ — CH₂, — C(O)— CH₂ — CH₂ — CH₂,

(c) — CH₂ — CH₂ — C(O)— , — CH₂ — C(O)— CH₂ — , — C(O)— CH₂ — CH₂

(d) — CH₂ — CH₂ — O— C(O)— , CH₂ — O— C(O)— CH₂ -O— C(O)— CH₂ — CH₂ — , (e) — CH₂ — CH₂ — C(O)— O— , — CH₂ — C(O)— OCH₂ — , — C(O)— 0—

(f) — C(R¹⁰⁵)₂ — O— C(O)— , — C(O)— O— C(R¹⁰⁵)₂ — , — O— C(O)— C(R¹⁰⁵)₂ — , — C(R¹⁰⁵)₂ — C(0)~0— , (g) — N=CH— CH=CH— ,

(h) — CH=N— CH=CH--,

(i) — CH=CH— N=CH— ,

(j) — CH=CH— CH=N— ,

(k) — N=CH— CH=N— , (I) — =CH— N=CH— ,

(m) — CH=N— CH=N— ,

(n) — S— CH=N— ,

(o) — S— N=CH— ,

(p) — N=N— NH— , (q) — CH=N— S— , and

(r) — N=CH— S— ;

R" is selected from the group consisting of S(0)₂CH₃, S(0)₂NH₂,

S(0)₂NHCOCF₃, S(0)(NH)CH₃, S(0)(NH)NH₂, S(0)(NH)NHCOCF₃,

P(0)(CH₃)OH, and P(0)(CH₃)NH₂; R¹⁰⁰ is selected from the group consisting of:

(a) Ci -C₆ alkyl,

(b) C₃ -C₇ cycloalkyl,

(c) mono- or di-substituted phenyl or naphthyl wherein the substituent is selected from the group consisting of: (1) hydrogen, (2) halo, including F, CI, Br, I, (3) Ci -C₆ alkoxy, (4) Ci -C₆ alkylthio, (5) CN, (6) CF₃, (7) Ci -C₆ alkyl, (8) N₃, (9) — C0₂ H, (10) — C0₂ — C1 -C4 alkyl, (11 ) — C(R¹⁰³)(R¹⁰⁴)— OH, (1 ) — C(R¹⁰³)(R¹⁰⁴)— O— Ci -C₄ alkyl, and (13) — d -C₆ alkyl-C0₂ — R¹⁰⁶;

(d) mono- or di-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1 , 2, or 3 additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of: (1) hydrogen, (2) halo, including fluoro, chloro, bromo and iodo, (3) Ci -C₆ alkyl, (4) Ci -C₆ alkoxy, (5) Ci -C₆ alkylthio, (6) CN, (7) CF₃, (8) N₃, (9) — C(R¹⁰³)(R¹⁰⁴)— OH, and (10) — C(R¹⁰³)(R¹⁰⁴)— O— Ci -C₄ alkyl;

(e) benzoheteroaryl which includes the benzo fused analogs of (d);

R >101⁷ and R >102 are the substituents residing on any position of -A =A — A⁷=A⁸ — and are selected independently from the group consisting of:

(a) hydrogen,

(b) CF₃,

(c) CN,

(d) Ci -C₆ alkyl,

(e) — Q³ wherein Q³ is Q⁴, C0₂ H, C(R¹⁰³)(R¹⁰ )OH,

(f) -O-Q⁴,

(g) — S— Q⁴, and

(h) optionally substituted: (1) — Ci -C₅ alkyl-Q³, (2) — O— Ci -C₅ alkyl-Q³, (3) _s— Ci -C₅ alkyl-Q³, (4) — Ci -C₃ alkyl-O— Ci.₃ alkyl-Q³, (5) — Ci -C₃ alkyl-S— Ci_-3 alkyl-Q³, (6) — d -C₅ alkyl-O— Q⁴, (7) — Ci -C₅ alkyl-S— Q⁴, wherein the substituent resides on the alkyl chain and the substituent is Ci

~C₃ alkyl, and Q³ is Q⁴, C0₂ H, C(R¹⁰³)(R¹⁰⁴)OH Q⁴ is C0₂ — Ci -C₄ alkyl, tetrazolyl-5-yl, or C(R¹⁰³)(R¹⁰⁴)O— Ci -C₄ alkyl;

R¹⁰³, R¹⁰⁴ and R¹⁰⁵ are each independently selected from the group consisting of hydrogen and Ci -C₆ alkyl; or

R¹⁰³ and R¹⁰⁴ together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms, or two R¹⁰⁵ groups on the same carbon form a saturated monocyclic carbon ring of 3,

4, 5, 6 or 7 atoms;

R¹⁰⁶ is hydrogen or Ci -C₆ alkyl;

R¹⁰⁷ is hydrogen, Ci -C₆ alkyl or aryl;

X⁷ is O, S, NR¹⁰⁷, CO, C(R¹⁰⁷)₂, C(R¹⁰⁷)(OH), — C(R ⁰⁷)=C(R¹⁰⁷)— ; — C(R¹⁰⁷)=N— ; or— N=C(R¹⁰⁷)— .

[000103] Compounds that may act as Cox-2 selective inhibitors include salts of 5-amino or a substituted amino 1 ,2,3-triazole compound that are described in U.S. Patent No. 6,239,137. The salts are of a class of compounds of formula XXI:

wherein: R¹⁰⁸ is:

wherein: p is 0 to 2; m is 0 to 4; and n is 0 to 5;

X¹³ is O, S, SO, S0₂, CO, CHCN, CH₂ or C=NR¹¹³ where R¹¹³ is hydrogen, loweralkyl, hydroxyl, loweralkoxy, amino, loweralkylamino, diloweralkylamino or cyano;

R¹¹ and R¹¹² are independently halogen, cyano, trifluoromethyl, loweralkanoyl, nitro, loweralkyl, loweralkoxy, carboxy, lowercarbalkoxy, trifuloromethoxy, acetamido, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfinyl, or trifluoromethylsulfonyl;

R¹⁰⁹ is amino, mono or diloweralkyl amino, acetamido, acetimido, ureido, formamido, or guanidino; and

R¹¹⁰ is carbamoyl, cyano, carbazoyl, amidino or N-hydroxycarbamoyl; wherein the loweralkyl, loweralkyl containing, loweralkoxy and loweralkanoyl groups contain from 1 to 3 carbon atoms.

[000104] Pyrazole derivatives such as those described in U.S. Patent 6,136,831 can serve as a Cox-2 selective inhibitor of the present invention. Such pyrazole derivatives have the formula shown below in formula XXII:

wherein:

R¹¹⁴ is hydrogen or halogen;

R¹¹⁵ and R¹¹⁶ are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl or lower alkanoyloxy;

R¹¹⁷ is lower haloalkyl or lower alkyl;

X¹⁴ is sulfur, oxygen or NH; and

Z⁶ is lower alkylthio, lower alkylsulfonyl or sulfamoyl; or a pharmaceutically acceptable salt thereof.

[000105] Materials that can serve as a Cox-2 selective inhibitor of the present invention include substituted derivatives of benzosulphonamides that are described in U.S. Patent 6,297,282. Such benzosulphonamide derivatives have the formula shown below in formula XXIII:

XXIII

wherein:

X ^15 denotes oxygen, sulphur or NH; R ¹⁸ is an optionally unsaturated alkyl or alkyloxyalkyl group, optionally mono- or polysubstituted or mixed substituted by halogen, alkoxy, oxo or cyano, a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted or mixed substituted by halogen, alkyl, CF₃, cyano or alkoxy;

R¹¹⁹ and R¹²⁰, independently from one another, denote hydrogen, an optionally polyfluorised alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH₂)_n -X¹⁶; or R¹¹⁹ and R¹²⁰, together with the N- atom, denote a 3 to 7-membered, saturated, partially or completely unsaturated heterocycle with one or more heteroatoms N, O or S, which can optionally be substituted by oxo, an alkyl, alkylaryl or aryl group, or a group (CH₂)_n — X¹⁶; X¹⁶ denotes halogen, N0₂, —OR¹²¹, —COR¹²¹, — C0₂ R¹²¹, — OC0₂ R¹²¹, — CN, — CONR¹²¹ OR¹²², — CONR¹²¹ R¹²², — SR¹²¹, — S(0)R¹²¹, — S(0)₂ R ²¹, — NR¹²¹ R¹²², — NHC(0)R¹²¹, — NHS(0)₂ R¹²¹; n denotes a whole number from 0 to 6;

R¹²³ denotes a straight-chained or branched alkyl group with 1-10 C- atoms, a cycloalkyl group, an alkylcarboxyl group, an aryl group, aralkyl group, a heteroaryl or heteroaralkyl group which can optionally be mono- or polysubstituted or mixed substituted by halogen or alkoxy;

R¹²⁴ denotes halogen, hydroxyl, a straight-chained or branched alkyl, alkoxy, acyloxy or alkyloxycarbonyl group with 1-6 C- atoms, which can optionally be mono- or polysubstituted by halogen, N0₂, — OR¹²¹, — COR¹²¹, — C0₂ R¹²¹, — OC0₂ R¹²¹, — CN, —CONR¹²¹ OR¹²², —CONR¹²¹ R¹²², — SR¹²¹, — S(0)R¹²¹, — S(0)₂ R¹² , -NR¹²¹ R¹²², -NHC(0)R¹²¹, —

NHS(0)₂ R¹²¹, or a polyfluoroalkyl group;

R¹²¹ and R¹²², independently from one another, denote hydrogen, alkyl, aralkyl or aryl; and m denotes a whole number from 0 to 2; and the pharmaceutically-acceptable salts thereof.

[000106] Compounds that are useful as Cox-2 selective inhibitors of the present invention include phenyl heterocycles that are described in U.S. Patent Nos.5,474,995 and 6,239,173. Such phenyl heterocyclic compounds have the formula shown below in formula XXIV:

or pharmaceutically acceptable salts thereof wherein: X¹⁷ — Y¹ — Z⁷-is selected from the group consisting of:

(a) — CH₂ CH₂ CH₂ — , (b)— C(0)CH₂CH₂— ,

(c) — CH₂ CH₂ C(O)— ,

(d) — CR¹²⁹ (R^129')— O— C(O)— , (e) — C(O)— O— CR¹²⁹ (R^129')— ,

(f) — CH₂ — NR¹²⁷ — CH₂ — ,

(g) — CR¹²⁹ (R^129')— NR¹²⁷ — C(O)— , (h)— CR¹²⁸=CR^128'-S-,

(i)_ S— CR¹²⁸=CR^128'-, (j)— S— N=CH— ,

(k) — CH=N— S— ,

(I) — N=CR¹²⁸ — O— ,

(m) — O— CR¹²⁸=N— ,

(n)— N=CR¹²⁸— NH— , (o) — N=CR¹²⁸ — S— , and

(p) — S— CR²⁸=N— ,

(q) — C(O)— NR¹²⁷-CR¹²⁹ (R^129')-, (r) — R¹²⁷ N— CH=CH— provided R¹²² is not — S(0)₂CH₃, (s) — CH=CH— NR¹²⁷ — provided R¹²⁵ is not — S(0)₂CH₃; when side b is a double bond, and sides a and c are single bonds; and X¹⁷ — Y¹ — Z⁷-is selected from the group consisting of: (a) =CH— O— CH=, and

(b) =CH— MR¹²⁷ — CH=,

(c) =N— S— CH=,

(d) =CH— S— N=,

(e) =N— O — CH=, (f) =CH— O— N=,

(g) =N-S— N=, (h) =N— O— N=, when sides a and c are double bonds and side b is a single bond; R¹²⁵ is selected from the group consisting of: (a) S(0)₂ CH₃,

(b) S(0)₂ NH₂,

(c) S(0)₂ NHC(0)CF₃,

(d) S(0)(NH)CH₃,

(e) S(0)(NH)NH₂, (f) S(0)(NH)NHC(0)CF₃,

(g) P(0)(CH₃)OH, and

(h) P(0)(CH₃)NH₂;

R¹²⁶ is selected from the group consisting of

(a) Ci -C₆ alkyl, (b) C₃, C₄, C₅, C₆, and C₇, cycloalkyl,

(c) mono-, dϊ- or tri-substituted phenyl or naphthyl, wherein the substituent is selected from the group consisting of: (1) hydrogen, (2) halo, (3) Ci -C₆ alkoxy, (4) Ci -C₆ alkylthio, (5) CN, (6) CF₃, (7) Ci -C₆ alkyl, (8) N₃, (9) — C0₂ H, (10) — C0₂ — Ci -C₄ alkyl, (11) — C(R¹²⁹)(R¹³⁰)— OH, (12) — C(R¹²⁹)(R¹³⁰)— O— d -C₄ alkyl, and (13) — Ci -C₆ alkyl-C0₂ — R¹²⁹ ;

(d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1 , 2, or 3 additionally N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1 , 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of: (1) hydrogen, (2) halo, including fluoro, chloro, bromo and iodo, (3) Ci -C₆ alkyl, (4) Ci -C₆ alkoxy, (5) Ci -C₆ alkylthio, (6) CN, (7) CF₃, (8) N₃, (9) — C(R¹²⁹)(R¹³⁰)— OH, and (10) — C(R¹²⁹)(R¹³⁰)— O— Ci -C₄ alkyl; (e) benzoheteroaryl which includes the benzo fused analogs of (d);

R¹²⁷ is selected from the group consisting of:

(a) hydrogen,

(b) CF₃,

(c) CN, (d) Ci -C₆ alkyl,

(e) hydroxyl Ci -C₆ alkyl, (f) -C(O)— Cι -C₆ alkyl, (g) optionally substituted: (1) — C₁ -C5 alkyl-Q⁵, (2) — Ci -C₅ alkyl-O— Ci -C₃ alkyl-Q⁵, (3) — Ci -C₃ alkyl-S— d -C₃ alkyl-Q⁵, (4) — Ci -C₅ alkyl-O— Q⁵, or (5) — Ci -C₅ alkyl-S— Q⁵, wherein the substituent resides on the alkyl and the substituent is Ci - C₃ alkyl;

(h) -Q⁵; R¹²⁸ and R^128' are each independently selected from the group consisting of:

(a) hydrogen,

(b) CF₃,

(c) CN, (d) Ci -C₆ alkyl,

(e) -Q⁵,

(f) -O-Q⁵;

(g) — S— Q⁵, and

(h) optionally substituted: (1) — Ci -C₅ alkyl-Q⁵, (2) — O— Ci -C₅ alkyl-Q⁵, (3) — S— Ci -C₅ alkyl-Q⁵, (4) — Ci -C₃ alkyl-O— Ci -C₃ alkyl-Q⁵, (5) — Ci -C₃ alkyl-S— Ci -C₃ alkyl-Q⁵, (6) — Ci -C₅ alkyl-O— Q⁵, (7) — Ci -C₅ alkyl-S— Q⁵, wherein the substituenf resides on the alkyl and the substituent is Ci - C₃ alkyl, and R¹²⁹, R^129', R¹³⁰, R¹³¹ and R¹³² are each independently selected from the group consisting of:

(a) hydrogen,

(b) Ci -C₆ alkyl; ^} or R¹²⁹ and R¹³⁰ or R¹³¹ and R¹³² together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;

Q⁵ is C0₂ H, C0₂ — Ci -C₄ alkyl, tetrazolyl-5-yl, C(R¹³¹)(R¹³²)(OH), or

C(R¹³¹)(R¹³²)(0— Ci -C₄ alkyl); provided that when X— Y— Z is — S— CR¹²⁸=CR^128', then R¹²⁸ and R^128' are other than CF₃.

[000107] An exemplary phenyl heterocycle that is disclosed in U.S.

Patent No. 6,239,173 is 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(2H)- furanone.

[000108] Bicycliccarbonyl indole compounds such as those described in

U.S. Patent No. 6,303,628 are useful as Cox-2 selective inhibitors of the present invention. Such bicycliccarbonyl indole compounds have the formula shown below in formula XXV:

or the pharmaceutically acceptable salts thereof wherein:

A⁹ is Ci -C₆ alkylene or — NR¹³³ — ;

Z⁸ is C(=L³)R¹³⁴, or S0₂ R¹³⁵ ;

Z⁹ is CH or N;

Z¹⁰ and Y² are independently selected from — CH₂ — , O, S and — N— R¹³³; m is 1 , 2 or 3; q and r are independently 0, 1 or 2; X¹⁸ is independently selected from halogen, Ci -C₄ alkyl, halo-substituted Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy, halo-substituted Ci -C₄ alkoxy, Ci - C₄ alkylthio, nitro, amino, mono- or di-(Cι -C₄ alkyl)amino and cyano; n is 0, 1, 2, 3 or 4; L³ is oxygen or sulfur;

R¹³³ is hydrogen or Ci -C₄ alkyl;

R¹³⁴ is hydroxyl, Ci -C₆ alkyl, halo-substituted Ci -C₆ alkyl, Ci -C₆ alkoxy, halo-substituted Ci -C₆ alkoxy, C₃ -C₇ cycloalkoxy, Ci -C₄ alkyl(C₃ -C₇ cycloalkoxy), — NR¹³⁶ R¹³⁷, Ci -C₄ alkylphenyl-O— or phenyl-O— , said phenyl being optionally substituted with one to five substituents independently selected from halogen, Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy and nitro;

R¹³⁵ is Ci — C₆ alkyl or halo-substituted Ci -C₆ alkyl; and

R¹³⁶ and R¹³⁷ are independently selected from hydrogen, Cι_-6 alkyl and halo-substituted Ci -C₆ alkyl.

[000109] Materials that can serve as a Cox-2 selective inhibitor of the present invention include benzimidazole compounds that are described in U.S. Patent No. 6,310,079. Such benzimidazole compounds have the formula shown below in formula XXVI:

or a pharmaceutically acceptable salt thereof, wherein: A¹⁰ is heteroaryl selected from a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring; X²⁰ is independently selected from halo, Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy, halo-substituted Ci -C₄ alkyl, hydroxyl-substituted Ci -C₄ alkyl, (Ci -C₄ alkoxy)Cι -C₄ alkyl, halo-substituted Ci -C₄ alkoxy, amino, N-(Cι -C₄ alkyl)amino, N, N-di(Cι -C₄ alkyl)amino, [N-(Cι -C₄ alkyl)amino]Cι -C₄ alkyl, [N, N-di(C-ι -C₄ alkyl)amino]Cι -C₄ alkyl, N-(Cι -C₄ alkanoyl)amonio, N-(Cι -C₄ alkyl) (Ci -C₄ alkanoyl)amino, N-[(Cι -C₄ alkyl)sulfonyl]amino,

N-[(halo-substituted Ci -C₄ alkyl)sulfonyl]amino, Ci -C₄ alkanoyl, carboxy, (Ci -C alkoxy)carbonyl, carbamoyl, [N-(Cι -C₄ alkyl)amino]carbonyl, [N, N-di(Cι -C alkyl)aminojcarbonyl, cyano, nitro, mercapto, (Ci -C₄ alkyl)thio, (Ci -C₄ alkyl)sulfinyl, (Ci -C₄ alkyl)sulfonyl, aminosulfonyl, [N- (Ci -C₄ alkyl)arnino]sulfonyl and [N, N-di(Cι -C₄ alkyl)amino]sulfonyl;

X²¹ is independently selected from halo, Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy, halo-substituted Ci -C₄ alkyl, hydroxyl-substituted Ci -C₄ alkyl, (Ci -C₄ alkoxy)Cι -C₄ alkyl, halo-substituted Ci -C₄ alkoxy, amino, N-(Cι -C₄ alkyl)amino, N, N-di(Cι -C₄ alkyl)amino, [N-(Cι -C₄ alkyl)amino]Cι -C₄ alkyl, [N, N-di(C-ι -C₄ alkyl)amino]Cι -C₄ alkyl, N-(Cι -C₄ alkanoyl)amino,

N-(Cι -C₄ alkyl)-N-(d -C₄ alkanoyl) amino, N-[(Cι -C₄ alkyl)sulfonyl]arnino, N-[(halo-substituted Ci -C₄ alkyl)sulfonyl]amino, Ci - C₄ alkanoyl, carboxy, (Ci -C₄ alkoxy)hydroxyl, cabamoyl, [N-(Cι -C₄ alkyl) aminojcarbonyl, [N, N-di(Cι -C₄ alkyl)amino]carbonyl, N-carbomoylamino, cyano, nitro, mercapto, (Ci -C alkyl)thio, (Ci -C₄ alkyl)sulfinyl, (Ci -C₄ alkyl)su!fonyl, aminosulfonyl, [N-(Cι -C₄ alkyl)amino]sulfonyl and [N, N- di(Cι -C₄ alkyl)amino]sulfonyl; R¹³⁸ is selected from: hydrogen; straight or branched Ci -C₄ alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxyl, Ci -C₄ alkoxy, amino, N-(Cι -C₄ alkyl)amino and N, N- di(Cι -C₄ alkyl)amino;

C₃ -C₈ cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are indepently selected from halo, Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy, amino, N-(Cι -C₄ alkyl)amino and N, N-di(Cι -C alkyl)amino;

C₄ -Ca cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, Ci -C₄ alkyl, hydroxyl, Ci -C alkoxy, amino, N-(Cι -C₄ alkyl)amino and N, N- di(Cι -C₄ alkyl)amino; phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy, halo-substituted Ci -C₄ alkyl, Dydroxyl-substituted Ci -C₄ alkyl, (Ci -C₄ alkoxy)Cι -C₄ alkyl, halo-substituted Ci -C alkoxy, amino, N-(Cι -C₄ alkyl)amino, N, N-di(Cι -C₄ alkyl)amino, [N-(Cι -C₄ alkyl)amino]d -C₄ alkyl, [N, N-di(Cι -C₄ alkyl)amino]d -C₄ alkyl, N-(Cι - C₄ alkanoyl)amino, N-[Cι -C₄ alkyl)(Cι -C₄ alkanoyl)]amino, N-[(Cι -C₄ alkyl)sulfonyjamino, N-[(halo-substituted Ci -C₄ alkyl)sulfonyl]amino, Ci - C alkanoyl, carboxy, (Ci -C alkoxy)carbonyl, carbomoyl, [N-(Cι -C₄ alky)amino]carbonyl, [N, N-di(Cι -C₄ alkyl)amino]carbonyl, cyano, nitro, mercapto, (Ci -C₄ alkyl)thio, (Ci -C₄ alkyl)sulfinyl, (Ci -C₄ alkyl)sulfonyl, aminosulfonyl, [N-(Cι -C₄ alkyl)amino]sulfonyl and [N, N-di(Cι -C₄ alkyl)amino]sulfonyl; and heteroaryl selected from: a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom; or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and said heteroaryl being optionally substituted with one to three substituent(s) selected from X²⁰ ; R¹³⁹ and R¹⁴⁰ are independently selected from: hydrogen; halo;

Ci -C₄ alkyl; phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, Ci -C₄ alkyl, hydroxyl,

Ci -C₄ alkoxy, amino, N-(Cι -C₄ alkyl)amino and N, N-di(Cι -C₄ alkyl)amino; or R¹³⁸ and R¹³⁹ can form, together with the carbon atom to which they are attached, a C₃ — C₇ cycloalkyl ring; m is 0, 1 , 2, 3, 4 or 5; and n is 0, 1 , 2, 3 or 4.

[000110] Compounds that may be employed as a Cox-2 selective inhibitor of the present invention include indole compounds that are described in U.S. Patent No. 6,300,363. Such indole compounds have the formula shown below in formula XXVII:

XXVII

and the pharmaceutically acceptable salts thereof, wherein: L⁴ is oxygen or sulfur; Y³ is a direct bond or Ci -C₄ alkylidene; Q⁶ is:

(a) Ci -C₆ alkyl or halosubstituted Ci -C₆ alkyl, said alkyl being optionally substituted with up to three substituents independently selected from hydroxyl, Ci -C alkoxy, amino and mono- or di-( Ci -C₄ alkyl)amino,

(b) C₃ -C₇ cycloalkyl optionally substituted with up to three substituents independently selected from hydroxyl, Ci -C₄ alkyl and Ci -C₄ alkoxy, (c) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to four substituents independently selected from: (c-1) halo, Ci -C₄ alkyl, halosubstituted Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy, halosubstituted Ci -C₄ alkoxy, S(0)_m R¹⁴³, S0₂ NH₂, S0₂ N(d -C₄ alkyl)₂, amino, mono- or di-( Ci -C₄ alkyl)amino, NHS0₂ R¹⁴³, NHC(0)R¹⁴³, CN, C0₂ H, C0₂ (d -C₄ alkyl), Ci -C₄ alkyl-OH, d -C₄ alkyl-OR¹⁴³, CONH₂, CONH(d -C₄ alkyl), CON(Cι -C₄ alkyl)₂ and — O— Y-phenyl, said phenyl being optionally substituted with one or two substituents independently selected from halo, Ci -C₄ alkyl, CF₃, hydroxyl, OR¹⁴³, S(0)_mR¹⁴³, amino, mono- or di-( Ci -C₄ alkyl)amino and CN;

(d) a monocyclic aromatic group of 5 atoms, said aromatic group having one heteroatom selected from O, S and N and optionally containing up to three N atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substitutents independently selected from: (d-1) halo, Ci — C₄ alkyl, halosubstituted Ci -C₄ alkyl, hydroxyl, Ci -C alkoxy, halosubstituted Ci -C₄ alkoxy, Ci -C₄ alkyl-OH, S(0)_m R¹⁴³, S0₂ NH₂, S0₂ N(Cι -C alkyl)₂, amino, mono- or di-( Ci -C alkyl)amino, NHSO_s R¹⁴³, NHC(0)R¹⁴³, CN, C0₂ H, C0₂ (Ci -C₄ alkyl), Ci -C₄ alkyl-OR¹⁴³, CONH₂, CONH(Cι -C₄ alkyl), CON(Cι -C₄ alkyl)₂, phenyl, and mono-, di- or tri-substituted phenyl wherein the substituent is independently selected from halo, CF₃, Ci -C₄ alkyl, hydroxyl, Ci - C₄ alkoxy, OCF₃, SR¹⁴³, S0₂ CH₃, S0₂ NH₂, amino, d_-4 alkylamino and NHS0₂ R¹⁴³;

(e) a monocyclic aromatic group of 6 atoms, said aromatic group having one heteroatom which is N and optionally containing up to three atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substituents independently selected from the above group (d-1);

R¹⁴¹ is hydrogen or Ci -Cβ alkyl optionally substituted with a substituent selected independently from hydroxyl, OR¹⁴³, nitro, amino, mono- or di-( Ci -C₄ alkyl)amino, C0₂ H, C0₂ (Ci -C₄ alkyl), CONH₂, CONH(Cι -C₄ alkyl) and CON(Cι -C₄ alkyl)₂ ; R¹⁴² is: (a) hydrogen, (b) Ci -C₄ alkyl,

(c) C(0)R¹⁴⁵, wherein R¹⁴⁵ is selected from: (c-1) Ci -C₂₂ alkyl or C₂ -C₂₂ alkenyl, said alkyl or alkenyl being optionally substituted with up to four substituents independently selected from: (c-1-1) halo, hydroxyl, OR¹⁴³, S(0)_m R¹⁴³, nitro, amino, mono- or di-( Ci -C₄ alkyOamino, NHS0₂ R¹⁴³, C0₂ H, C0₂ (Ci -C₄ alkyl), CONH₂, CONH(d -C₄ alkyl), CON(Cι -C₄ alkyl)₂, OC(0)R¹⁴³, thienyl, naphthyl and groups of the following formulas:

(c-2) Ci -C₂₂ alkyl or C₂ -C₂₂ alkenyl, said alkyl or alkenyl being optionally substituted with five to forty-five halogen atoms, (c-3) -Y⁵— C₃ -C₇ cycloalkyl or-Y⁵— C₃ -C₇ cycloalkenyl, said cycloalkyl or cycloalkenyl being optionally substituted with up to three substituent independently selected from: (c-3-1) Ci -C₄ alkyl, hydroxyl, OR¹⁴³, S(0)_m R¹⁴³, amino, mono- or di- ( Ci -C₄ alkyl)amino, CONH₂, CONH(Cι -C₄ alkyl) and CON(Cι -C₄ alkyl)₂, (c-4) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to seven (preferably up to seven) substituents independently selected from: (c-4-1) halo, Ci -C₈ alkyl, d -C₄ alkyl-OH, hydroxyl, Ci -C₈ alkoxy, halosubstituted Ci -C₈ alkyl, halosubstituted Ci -C₈ alkoxy, CN, nitro, S(0)_m R¹⁴³, S0₂ NH₂, S0₂ NH(Cι -C₄ alkyl), S0₂ N(Cι -C₄ alkyl)₂, amino, Ci -C₄ alkylamino, di-(Cι -C₄ alkyl)amino, CONH₂, CONH(Cι -C₄ alkyl), CON(Cι -C₄ alkyl)₂, OC(0)R¹⁴³, and phenyl optionally substituted with up to three substituents independently selected from halo, Ci -C₄ alkyl, hydroxyl, OCH₃, CF₃, OCF₃, CN, nitro, amino, mono- or di-(Cι — C₄ alkyl)amino, C0₂ H, C0₂ (Ci -C₄ alkyl) and CONH₂, (c-5) a monocyclic aromatic group as defined in (d) and (e) above, said aromatic group being optionally substituted with up to three substituents independently selected from: (c-5-1) halo, Ci -C₈ alkyl, Ci -C₄ alkyl-OH, hydroxyl, Ci -C₈ alkoxy, CF₃, OCF₃, CN, nitro, S(0)_m R¹⁴³, amino, mono- or di-( Ci -C₄ alkyOamino, CONH₂, CONH(d -C₄ alkyl), CON(Cι -C₄ alkyl)₂, C0₂ H and C0₂ (Ci — C alkyl), and — Y-phenyl, said phenyl being optionally substituted with up to three substituents independently selected halogen, Ci -C alkyl, hydroxyl, Ci -C₄ alkoxy, CF₃, OCF₃, CN, nitro, S(O) R¹⁴³, amino, mono- or di-( Ci -C₄ alkyl)amino, C0₂ H, C0₂ (Ci -C₄ alkyl), CONH₂, CONH(Cι -C₄ alkyl) and CON(Cι -C₄ alkyl)₂, (c-6) a group of the following formula:

X²² is halo, Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy, halosubstitutued Ci -C₄ alkoxy, S(0)_m R¹⁴³, amino, mono- or di-(Cι -C₄ alkyl)amino, NHS0₂ R¹⁴³, nitro, halosubstitutued Ci -C₄ alkyl, CN, C0₂ H, C0₂ (d -C₄ alkyl), Ci -C₄ alkyl-OH, d -C₄ alkylOR¹⁴³, CONH₂, CONH(Cι -C₄ alkyl) or CON(Cι -C₄ alkyl)₂ ; R¹⁴³ is d -C₄ alkyl or halosubstituted Ci -C₄ alkyl; m is 0, 1 or 2; n is 0, 1 , 2 or 3; p is 1 , 2, 3, 4 or 5; q is 2 or 3;

Z¹¹ is oxygen, sulfur or NR¹⁴⁴ ; and

R¹⁴⁴ is hydrogen, Ci -C₆ alkyl, halosubstitutued Ci -C₄ alkyl or-Y⁵- phenyl, said phenyl being optionally substituted with up to two substituents independently selected from halo, Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy,

S(0)_m R¹⁴³, amino, mono- or di-(Cι -C₄ alkyl)amino, CF₃, OCF₃, CN and nitro; with the proviso that a group of formula -Y⁵ — Q is not methyl or ethyl when

X²² is hydrogen;

L⁴ is oxygen;

R¹⁴¹ is hydrogen; and

R¹⁴² is acetyl.

[000111] Aryl phenylhydrazides that are described in U.S. Patent No.

6,077,869 can serve as Cox-2 selective inhibitors of the present invention.

Such aryl phenylhydrazides have the formula shown below in formula

XXVIII:

XXVIII

wherein:

X²³ and Y⁶ are selected from hydrogen, halogen, alkyl, nitro, amino, hydroxy, methoxy and methylsulfonyl; or a pharmaceutically acceptable salt thereof,.

[000112] Materials that can serve as a Cox-2 selective inhibitor of the present invention include 2-aryIoxy, 4-aryl furan-2-ones that are described in U.S. Patent No. 6,140,515. Such 2-aryloxy, 4-aryl furan-2-ones have the formula shown below in formula XXIX:

or a pharmaceutical salt thereof, wherein:

R¹⁴⁶ is selected from the group consisting of SCH₃, — S(0) CH₃ and —

S(0)₂ NH₂ ;

R¹⁴⁷ is selected from the group consisting of OR¹⁵⁰, mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;

R¹⁵⁰ is unsubstituted or mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;

R¹⁴⁸ is H, Ci -C₄ alkyl optionally substituted with 1 to 3 groups of F, CI or

Br; and

R¹⁴⁹ is H, Ci -C₄ alkyl optionally substituted with 1 to 3 groups of F, CI or

Br, with the proviso that R¹⁴⁸ and R¹⁴⁹ are not the same.

[000113] Materials that can serve as a Cox-2 selective inhibitor of the present invention include bisaryl compounds that are described in U.S.

Patent No. 5,994,379. Such bisaryl compounds have the formula shown below in formula XXX:

or a pharmaceutically acceptable salt, ester or tautomer thereof, wherein:

Z¹³ is C or N; when Z¹³ is N, R¹⁵¹ represents H or is absent, or is taken in conjunction with R¹⁵² as described below: when Z¹³ is C, R¹⁵¹ represents H and R¹⁵² is a moiety which has the following characteristics:

(a) it is a linear chain of 3-4 atoms containing 0-2 double bonds, which can adopt an energetically stable transoid configuration and if a double bond is present, the bond is in the trans configuration,

(b) it is lipophilic except for the atom bonded directly to ring A, which is either lipophilic or non-lipophilic, and

(c) there exists an energetically stable configuration planar with ring A to within about 15 degrees; or R¹⁵¹ and R¹⁵² are taken in combination and represent a 5- or 6- membered aromatic or non-aromatic ring D fused to ring A, said ring D containing 0-3 heteroatoms selected from O, S and N; said ring D being lipophilic except for the atoms attached directly to ring A, which are lipophilic or non-lipophilic, and said ring D having available an energetically stable configuration planar with ring A to within about 15 degrees; said ring D further being substituted with 1 R^a group selected from the group consisting of: Ci -C₂ alkyl, — OCι -C₂ alkyl, — NHCi -C₂ alkyl, — N(Cι -C₂ alkyl)₂, — C(O) Ci -C₂ alkyl, — S— d -C₂ alkyl and — C(S) Ci -

C₂ alkyl;

Y⁷ represents N, CH or C— OCι -C₃ alkyl, and when Z¹³ is N, Y⁷ can also represent a carbonyl group; R¹⁵³ represents H, Br, CI or F; and R¹⁵⁴ represents H or CH₃.

[000114] Compounds useful as Cox-2 selective inhibitors of the present invention include 1 ,5-diarylpyrazoles that are described in U.S. Patent No. 6,028,202. Such 1 ,5-diarylpyrazoles have the formula shown below in formula XXXI:

wherein:

R ⁵⁵, R¹⁵⁶, R¹⁵⁷, and R¹⁵⁸ are independently selected from the groups consisting of hydrogen, Ci -C₅ alkyl, C-j -C₅ alkoxy, phenyl, halo, hydroxyl, Ci -C₅ alkylsulfonyl, Ci -C₅ alkylthio, trihaloCi -C₅ alkyl, amino, nitro and

2-quinolinylmethoxy; R¹⁵⁹ is hydrogen, Ci -C₅ alkyl, trihaloCi -C₅ alkyl, phenyl, substituted phenyl where the phenyl substitutents are halogen, Ci -C₅ alkoxy, trihaloCi -C₅ alkyl or nitro or R¹⁵⁹ is heteroaryl of 5-7 ring members where at least one of the ring members is nitrogen, sulfur or oxygen; R¹⁶⁰ is hydrogen, Ci -C₅ alkyl, phenyl Ci -C₅ alkyl, substituted phenyl Ci -

C₅ alkyl where the phenyl substitutents are halogen, Ci -C₅ alkoxy, trihaloCi -C₅ alkyl or nitro, or R¹⁶⁰ is d -C₅ alkoxycarbonyl, phenoxycarbonyl, substituted phenoxycarbonyl where the phenyl substitutents are halogen, Ci -C₅ alkoxy, trihaloCi -C₅ alkyl or nitro; R¹⁶¹ is Ci -C1₀ alkyl, substituted Ci -Cι₀ alkyl where the substituents are halogen, trihaloCi -C₅ alkyl, Ci — C₅ alkoxy, carboxy, Ci -C₅ alkoxycarbonyl, amino, Ci -C₅ alkylamino, diCi -C₅ alkylamino, diCi -C₅ alkylaminoCi -C₅ alkylamino, Ci -Cs alkylaminoCi -C₅ alkylamino or a heterocycle containing 4-8 ring atoms where one more of the ring atoms is nitrogen, oxygen or sulfur, where said heterocycle may be optionally substituted with Ci -C₅ alkyl; or R ⁶¹ is phenyl, substituted phenyl (where the phenyl substitutents are one or more of Ci -C5 alkyl, halogen, Ci -C₅ alkoxy, trihaloCi -C₅ alkyl or nitro), or R¹⁶¹ is heteroaryl having 5-7 ring atoms where one or more atoms are nitrogen, oxygen or sulfur, fused heteroaryl where one or more 5-7 membered aromatic rings are fused to the heteroaryl; or

R¹⁶¹ is NR¹⁶³ R¹⁶⁴ where R¹⁶³ and R¹⁶⁴ are independently selected from hydrogen and C1.₅ alkyl or R¹⁶³ and R¹⁶⁴ may be taken together with the depicted nitrogen to form a heteroaryl ring of 5-7 ring members where one or more of the ring members is nitrogen, sulfur or oxygen where said heteroaryl ring may be optionally substituted with Ci -C₅ alkyl; R¹⁶² is hydrogen, Ci -C₅ alkyl, nitro, amino, and halogen; and pharmaceutically acceptable salts thereof. [000115] Materials that can serve as a Cox-2 selective inhibitor of the present invention include 2-substituted imidazoles that are described in

U.S. Patent No. 6,040,320. Such 2-substituted imidazoles have the formula shown below in formula XXXII:

wherein:

R¹⁶⁴ is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6 ring atoms, or substituted phenyl; wherein the substituents are independently selected from one or members of the group consisting of d-s alkyl, halogen, nitro, trifluoromethyl and nitrile;

R¹⁶⁵ is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6 ring atoms, substituted heteroaryl; wherein the substituents are independently selected from one or more members of the group consisting of Ci -C₅ alkyl and halogen, or substituted phenyl, wherein the substituents are independently selected from one or members of the group consisting of Ci -C₅ alkyl, halogen, nitro, trifluoromethyl and nitrile;

R¹⁶⁶ is hydrogen, 2-(trimethylsilyl)ethoxymethyl), Ci -C₅ alkoxycarbonyl, aryloxycarbonyl, arylCi -C5 alkyloxycarbonyl, arylCi -C₅ alkyl, phthalimidoCi -C₅ alkyl, aminoCi -C₅ alkyl, diaminoCi -C₅ alkyl, succinimidoCi -C₅ alkyl, Ci -C₅ alkylcarbonyl, arylcarbonyl, Ci -C₅ alkylcarbonylCi -C₅ alkyl, aryloxycarbonylC-i -C₅ alkyl, heteroarylCi -C₅ alkyl where the heteroaryl contains 5 to 6 ring atoms, or substituted arylCi -C₅ alkyl, wherein the aryl substituents are independently selected from one or more members of the group consisting of Ci — C₅ alkyl, Ci -C₅ alkoxy, halogen, amino, Ci -C₅ alkylamino, and diC -C₅ alkylamino;

R¹⁶⁷ is (A¹¹)„ -(CH¹⁶⁵)_q-X²⁴ wherein: A¹¹ is sulfur or carbonyl; n is 0 or 1 ; q is 0-9;

X²⁴ is selected from the group consisting of hydrogen, hydroxyl, halogen, vinyl, ethynyl, Ci -C₅ alkyl, C₃ -C₇ cycloalkyl, Ci -C₅ alkoxy, phenoxy, phenyl, arylCi -C₅ alkyl, amino, Ci -C5 alkylamino, nitrile, phthalimido, amido, phenylcarbonyl, Ci -C₅ alkylaminocarbonyl, phenylaminocarbonyl, arylCi -C₅ alkylaminocarbonyl, Ci -C₅ alkylthio, Ci -C₅ alkylsulfonyl, phenylsulfonyl, substituted sulfonamido, wherein the sulfonyl substituent is selected from the group consisting of Ci

-C₅ alkyl, phenyl, araCi -C₅ alkyl, thienyl, furanyl, and naphthyl; substituted vinyl, wherein the substituents are independently selected from one or members of the group consisting of fluorine, bromine, chlorine and iodine, substituted ethynyl, wherein the substituents are independently selected from one or more members of the group consisting of fluorine, bromine chlorine and iodine, substituted Ci -C₅ alkyl, wherein the substituents are selected from the group consisting of one or more Ci -C₅ alkoxy, trihaloalkyl, phthalimido and amino, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of Ci -C₅ alkyl, halogen and Ci -C₅ alkoxy, substituted phenoxy, wherein the phenyl substituents are independently selected from one or more members of the group consisting of Ci -C₅ alkyl, halogen and Ci -C₅ alkoxy, substituted Ci -C₅ alkoxy, wherein the alkyl substituent is selected from the group consisting of phthalimido and amino, substituted arylCi -C₅ alkyl, wherein the alkyl substituent is hydroxyl, substituted arylCi -C₅ alkyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of Ci -C₅ alkyl, halogen and Ci -C₅ alkoxy, substituted amido, wherein the carbonyl substituent is selected from the group consisting of Ci -C₅ alkyl, phenyl, arylCi -C₅ alkyl, thienyl, furanyl, and naphthyl, substituted phenylcarbonyl, wherein the phenyl substituents are independently selected from one or members of the group consisting of Ci -C₅ alkyl, halogen and Ci -C₅ alkoxy, substituted Ci -C₅ alkylthio, wherein the alkyl substituent is selected from the group consisting of hydroxyl and phthalimido, substituted Ci -C₅ alkylsulfonyl, wherein the alkyl substituent is selected from the group consisting of hydroxyl and phthalimido, substituted phenylsulfonyl, wherein the phenyl substituents are independently selected from one or members of the group consisting of bromine, fluorine, chlorine, C -C₅ alkoxy and trifluoromethyl, with the proviso: if A¹¹ is sulfur and X²⁴ is other than hydrogen, Ci -C₅ alkylaminocarbonyl, phenylaminocarbonyl, arylCi -C₅ alkylaminocarbonyl, d -C₅ alkylsulfonyl or phenylsulfonyl, then q must be equal to or greater than 1 ; if A¹¹ is sulfur and q is 1 , then X²⁴ cannot be Ci -C₂ alkyl; if A¹¹ is carbonyl and q is 0, then X²⁴ cannot be vinyl, ethynyl, Ci -C₅ alkylaminocarbonyl, phenylaminocarbonyl, arylCi -d alkylaminocarbonyl,

Ci -C₅ alkylsulfonyl or phenylsulfonyl; if A¹¹ is carbonyl, q is 0 and X²⁴ is H, then R¹⁶⁶ is not 2-

(trimethylsilyl)ethoxymethyl; if n is 0 and q is 0, then X²⁴ cannot be hydrogen; and pharmaceutically acceptable salts thereof.

[000116] Materials that can serve as a Cox-2 selective inhibitor of the present invention include 1,3- and 2,3-diarylcycloalkano and cycloalkeno pyrazoles that are described in U.S. Patent No. 6,083,969. Such 1 ,3- and

2,3-diarylpyrazole compounds have the general formulas shown below in formulas XXXIII and XXXIV:

XXXIII

XXXIV

wherein:

R¹⁶⁸ and R¹⁶⁹ are independently selected from the group consisting of hydrogen, halogen, (Ci -C₆)alkyl, (Ci -C₆)alkoxy, nitro, amino, Dydroxyl, trifluoro, — S(Cι -C₆)alkyl, — SO(d -C₆)alkyl and — S0₂ (Ci -C₆)alkyl; and the fused moiety M is a group selected from the group consisting of an optionally substituted cyclohexyl and cycloheptyl group having the formulae:

wherein:

R¹⁷⁰ is selected from the group consisting of hydrogen, halogen, hydroxyl and carbonyl; or R¹⁷⁰ and R¹⁷¹ taken together form a moiety selected from the group consisting of — OCOCH₂ — , — ONH(CH₃)COCH₂ — , — OCOCH= and — 0-;

R¹⁷¹ and R¹⁷² are independently selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (Ci -C₆)alkyl, (Ci -

C₆)alkoxy, =NOH, — NR¹⁷⁴ R¹⁷⁵, — OCH₃₎ — OCH₂ CH₃, — OS0₂ NHC0₂ CH₃, =CHC0₂ CH₂ CH₃, — CH₂ C0₂ H, — CH₂ C0₂ CH₃, — CH₂ C0₂ CH₂ CH₃, — CH₂ CON(CH₃)₂, — CH₂ C0₂ NHCH₃, — CHCHC0₂ CH₂ CH₃, — OCON(CH₃)OH, — C(COCH₃)₂, di(Cι -C₆)alkyl and di(Cι -C₆)alkoxy; R¹⁷³ is selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (Ci -C₆)alkyl, (Ci -Cβjalkoxy and optionally substituted carboxyphenyl, wherein substituents on the carboxyphenyl group are selected from the group consisting of halogen, hydroxyl, amino, (Ci - C₆)alkyl and (C -C₆)alkoxy; or R¹⁷² and R¹⁷³ taken together form a moiety selected from the group consisting of — O — and

R¹⁷⁴ is selected from the group consisting of hydrogen, OH, — OCOCH₃, — COCH₃ and (Ci -C₆)alkyl; and

R¹⁷⁵ is selected from the group consisting of hydrogen, OH, — OCOCH₃,

— COCH₃, (Ci -C₆)alkyl, — CONH₂ and — S0₂ CH₃ ; with the proviso that if M is a cyclohexyl group, then R¹⁷⁰ through R¹⁷³ may not all be hydrogen; and pharmaceutically acceptable salts, esters and pro-drug forms thereof. [000117] Esters derived from indolealkanols and novel amides derived from indolealkylamides that are described in U.S. Patent No. 6,306,890 can serve as Cox-2 selective inhibitors of the present invention. Such compounds have the general formula shown below in formula XXXV:

wherein:

R¹⁷⁶ is Ci -C₆ alkyl, Ci -C₆ branched alkyl, C₄ -C₈ cycloalkyl, Ci -C₆ hydroxyalkyl, branched Ci -C₆ hydroxyalkyl, hydroxyl substituted C -C₈ aryl, primary, secondary or tertiary Ci -C₆ alkylamino, primary, secondary or tertiary branched Ci -C₆ alkylamino, primary, secondary or tertiary C - C₈ arylamino, Ci -C₆ alkylcarboxylic acid, branched Ci -C₆ alkylcarboxylic acid, Ci -Cβ alkylester, branched Ci -Cβ alkylester, C -C₈ aryl, C₄ -Cs arylcarboxylic acid, C -C₈ arylester, C₄ -C₈ aryl substituted Ci -C₆ alkyl, C₄ -Cs heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-substituted or aryl-substituted C₄ -C₈ heterocyclic alkyl or aryl with O, N or S in the ring, or halo-substituted versions thereof, where halo is chloro, bromo, fluoro or iodo;

R¹⁷⁷ is Ci -C₆ alkyl, Ci -C₆ branched alkyl, C₄ -C_a cycloalkyl, C₄ -C₈ aryl, C -Ca aryl-substituted -C₆ alkyl, Ci -C₆ alkoxy, -C₆ branched alkoxy, C₄ -C₈ aryloxy, or halo-substituted versions thereof or R¹⁷⁷ is halo where halo is chloro, fluoro, bromo, or iodo; R¹⁷⁸ is hydrogen, Ci -Cβ alkyl or Ci -C₆ branched alkyl; R¹⁷⁹ is Ci -C₆ alkyl, d -C₈ aroyl, C₄ -C₈ aryl, C₄ -C₈ heterocyclic alkyl or aryl with O, N or S in the ring, C₄ ~C₈ aryl-substituted Ci -C₆ alkyl, alkyl- substituted or aryl-substituted C₄ -C₈ heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-substituted C₄ -C₈ aroyl, or alkyl-substituted C₄ -C₈ aryl, or halo-substituted versions thereof where halo is chloro, bromo, or iodo; n is 1, 2, 3, or 4; and

X²⁵ is O, NH, or N— R¹⁸⁰, where R¹⁸⁰ is Ci -C₆ or Ci -C₆ branched alkyl. [000118] Materials that can serve as a Cox-2 selective inhibitor of the present invention include pyridazinone compounds that are described in

U.S. Patent No. 6,307,047. Such pyridazinone compounds have the formula shown below in formula XXXVI:

XXXVI

or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:

X²⁶ is selected from the group consisting of O, S, — NR¹⁸⁵, — NOR^a, and - NNR^b R^c ;

R¹⁸⁵ is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclic alkyl;

R^a, R^b, and R^c are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl; R¹⁸¹ is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocyclic, heterocyclic alkoxy, heterocyclic alkyl, heterocyclic oxy, hydroxyalkyl, hydroxyiminoalkoxy, — (CH₂)_n C(0)R¹⁸⁶, — (CH₂)_n CH(OH)R^18β, — (CH₂)_n C(NOR^d)R¹⁸⁶, — (CH₂)_n CH(NOR^d)R¹⁸⁶, — (CH₂)_n CH(NR^d R^e)R¹⁸⁶, — R¹⁸⁷

R¹⁸⁸, -(CH₂)_π C≡CR¹⁸⁸, ~(CH₂)_π [CH(CX²⁶ ₃)]m (CH₂)_P R¹⁸⁸, -(CH₂)_n (CX^2δ'₂)_m (CH₂)_P R¹⁸⁸, and -(CH₂)_n (CHX²⁶')_m (CH₂)_m R¹⁸⁸ ; R¹⁸⁶ is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, haloalkynyl, heterocyclic, and heterocyclic alkyl;

R¹⁸⁷ is selected from the group consisting of alkenylene, alkylene, halosubstituted alkenylene, and halo-substituted alkylene; R¹⁸⁸ is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclic, and heterocyclic alkyl;

R^d and R^β are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl; X^26' is halogen; m is an integer from 0-5; n is an integer from 0-10; p is an integer from 0-10;

R¹⁸², R ⁸³, and R¹⁸⁴ are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyiminoalkoxy, alkoxyiminoalkyl, alkyl, alkynyl, alkylcarbonylalkoxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, aminoalkoxy, aminoalkylcarbonyloxyalkoxy aminocarbonylalkyl, aryl, arylalkenyl, arylalkyl, arylalkynyl, carboxyalkylcarbonyloxyalkoxy, cyano, cycloalkenyl, cycloalkyl, cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy, haloalkyl, halogen, heterocyclic, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl, mercaptoalkoxy, nitro, phosphonatoalkoxy, Y⁸, and Z¹⁴; provided that one of R¹⁸², R¹⁸³, or R¹⁸⁴ must be Z¹⁴, and further provided that only one of R¹⁸², R¹⁸³, or R¹⁸⁴ is Z¹⁴; Z¹⁴ is selected from the group consisting of:

X²⁷ is selected from the group consisting of S(0)₂, S(0)(NR¹⁹¹), S(O),

Se(0)₂, P(0)(OR¹⁹²), and P(0)(NR¹⁹³ R¹⁹⁴);

X²³ is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen; R ⁹⁰ is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, — NHNH₂, and — NCHN(R¹⁹¹)R¹⁹² ;

R ⁹¹, R¹⁹², R¹⁹³, and R¹⁹⁴ are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R¹⁹³ and R ⁹⁴ can be taken together, with the nitrogen to which they are attached, to form a 3-6 membered ring containing 1 or 2 heteroatoms selected from the group consisting of O, S, and NR¹⁸⁸ ;

Y⁸ is selected from the group consisting of -OR¹⁹⁵, — SR¹⁹⁵, —

C(R¹⁹⁷)(R¹⁹⁸)R¹⁹⁵, — C(0)R¹⁹⁵, — C(0)OR¹⁹⁵, — N(R¹⁹⁷)C(0)R¹⁹⁵, — NC(R¹⁹⁷)R¹⁹⁵, and — N(R¹⁹⁷)R¹⁹⁵ ;

R¹⁹⁵ is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, hydroxyalkyl, and NR¹⁹⁹ R²⁰⁰ ; and R ⁹⁷, R¹⁹⁸, R¹⁹⁹, and R²⁰⁰ are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl. [000119] Benzosulphonamide derivatives that are described in U.S. Patent No. 6,004,948 are useful as Cox-2 selective inhibitors of the present invention. Such benzosulphonamide derivatives have the formula shown below in formula XXXVII:

XXXVII

wherein:

A¹² denotes oxygen, sulphur or NH;

R²⁰¹ denotes a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted by halogen, alkyl, CF₃ or alkoxy;

D⁵ denotes a group of formula XXXVIII or XXXIX:

XXXVIII

or

XXXIX

R²⁰² and R²⁰³ independently of each other denote hydrogen, an optionally polyfluorinated alkyl radical, an aralkyl, aryl or heteroaryl radical or a radical (CH₂)_π -X²⁹; or

R²⁰² and R²⁰³ together with the N-atom denote a three- to seven- membered, saturated, partially or totally unsaturated heterocycle with one or more heteroatoms N, O, or S, which may optionally be substituted by oxo, an alkyl, alkylaryl or aryl group or a group (CH₂)_n -X²⁹, R²⁰²' denotes hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH₂)_n -X²⁹, wherein:

X²⁹ denotes halogen, N0₂, —OR²⁰⁴, —COR²⁰⁴, — C0₂ R²⁰⁴, — OC0₂ R²⁰⁴, — CN, —CONR²⁰⁴ OR²⁰⁵, —CONR²⁰⁴ R²⁰⁵, — SR²⁰⁴, — S(0)R²⁰⁴, — S(0)₂ R²⁰⁴, -NR²⁰⁴ R²⁰⁵, — NHC(0)R²⁰⁴, — NHS(0)₂ R²⁰⁴; Z¹⁵ denotes -CH₂ — — CH₂ -CH₂ — , — CH₂ -CH₂ -CH₂ — , — CH₂ - CH=CH— , — CH=CH— CH₂ — , — CH₂ —CO—, — CO— CH₂ — , —

NHCO— , — CONH— , — NHCH₂ — , — CH₂ NH— , — N=CH— , — NHCH— , -CH₂-CH₂— NH— , — CH=CH— , >N— R**, >C=0, >S(0) rtii

R²⁰⁴ and R²⁰⁵ independently of each other denote hydrogen, alkyl, aralkyl or aryl; n is an integer from 0 to 6;

R²⁰⁶ is a straight-chained or branched Ci -C₄ alkyl group which may optionally be mono- or polysubstituted by halogen or alkoxy, or R²⁰⁶ denotes CF₃; and m denotes an integer from 0 to 2; with the proviso that A¹² does not represent O if R²⁰⁶ denotes CF₃; and the pharmaceutically acceptable salts thereof.

[000120] Materials that can serve as Cox-2 selective inhibitors of the present invention include methanesulfonyl-biphenyl derivatives that are described in U.S. Patent No. 6,583,321. Such methanesulfonyl-biphenyl derivatives have the formula shown below in formula XXXX:

wherein:

R²⁰⁷ and R²⁰⁸ are respectively a hydrogen;

Ci -C₄-alkyl substituted or not substituted by halogens;

C₃ -Cycycloalkyl;

Ci -Cs-alkyl containing 1-3 ether bonds and/or an aryl substitute; substituted or not substituted phenyl; or substituted or not substituted five or six ring-cycled heteroaryl containing more than one hetero atoms selected from a group consisting of nitrogen, sulfur, and oxygen (wherein phenyl or heteroaryl can be one- or multi-substituted by a substituent selected from a group consisting of hydrogen, methyl, ethyl, and isopropyl).

[000121] Cox-2 selective inhibitors such as 1 H-indole derivatives described in U.S. Patent No. 6,599,929 are useful in the present invention.

Such 1 H-indole derivatives have the formula shown below in formula

XXXXI: XXXXI

wherein:

X³⁰ is -NHS0₂R²⁰⁹ wherein R²⁰⁹ represents hydrogen or C -C₃-alkyl;

Y⁹ is hydrogen, halogen, Ci -C₃-alkyl substituted or not substituted by halogen, N0₂, NH₂, OH, OMe, C0₂H, or CN; and

Q⁷ is C=0, C=S, or CH₂.

[000122] Compounds that are useful as Cox-2 selective inhibitors of the present invention include prodrugs of Cox-2 inhibitors that are described in

U.S. Patent Nos. 6,436,967 and 6,613,790. Such prodrugs of Cox-2 inhibitors have the formula shown below in formula XXXXII:

XXXXII

wherein:

A¹³ is a ring substituent selected from partially unsaturated heterocyclic, heteroaryl, cycloalkenyl and aryl, wherein A¹³ is unsubstituted or substituted with one or more radicals selected from alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocycloxy, alkylthio, cycloalkyl, aryl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, araalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N- arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, -arylamino, N- aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N- arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl;

R²¹⁰ is selected from heterocyclyl, cycloalkyl, cycloalkenyl, and aryl, wherein R²¹⁰ is unsubstituted or substituted with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio;

R²¹¹ is selected from hydrido and alkoxycarbonylalkyl; R²¹² is selected from alkyl, carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, amino acid residue, and alkylcarbonylaminoalkylcarbonyl; provided A¹³ is not tetrazolium, or pyridinium; and further provided A¹³ is not indanone when R²¹² is alkyl or carboxyalkyl; further provided A¹³ is not thienyl, when R²¹⁰ is 4-fluorophenyl, when R²¹¹ is hydrido, and when R²¹² is methyl or acyl; and R^{2 3} is hydrido; or a pharmaceutically-acceptable salt thereof.

[000123] Specific non-limiting examples of substituted sulfonamide prodrugs of Cox-2 inhibitors disclosed in U.S. Patent No. 6,436,967 that are useful in the present invention include: N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1- yljphen yl]sulfonyl]propanamide;

N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1 - yljphen yl]sulfonyl]butanamide; N-[[4-[1 ,5-dimethyl)-3-phenyl-1 H-pyrazol-4-yl]phenyl]sulfonyl]acetamide;

N-[[4-(2-(3-pyridinyl)-4-(trifluoromethyl)-1 H-imidazol-1 - yl) phenyljsu If onyl]acetamide;

N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yl]phenyl]sulfonyl]acetamide;

N-[[4-[2-(2-methylpyridin-3-yl)-4-(trif luoromethyl)-1 H- imidazol-1 - yl]phenyl]sulfonyl]acetamide;

N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-ϊmidazol-1- yl]phenyl]sulfonyl]butanamide; N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yl]phenyl]sulfonyl]butanamide;

N-[[4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)- 1 H-imidazol-1 - yl]phenyl]sulfonyl]acetamide;

N-[[4-[3-(3-fluorophenyl)-5-methylisoxazol-4-yl]phenyl]sulfonyl]acetamide; 2-methyl-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]sulfonyl]propanamide;

N-[[4-(5-methyl-3-phenylisoxazol-4-yI]phenyl]sulfonyl]propanamide;

N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]benzamide;

2,2-dimethyl-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]su!fonyl]propanamide;

N-[[4-5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyI]butanamide;

N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]pentanamide;

N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]hexanamide;

3-methoxy-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]sulfonyl]propanamide ;

2-ethoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide;

N-[[4-[5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide;

N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H pyrazol-1 - yl]phenyl]sulfonyl]propanamide; N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yl]phenyl]sulfonyl]butanamide; N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yl]phenyl]sulfonyl]acetamide;

N-[[4-[3-(difluoromethyl)-6-fluoro-1,5-dihydro-7-methoxy-

[2]benzothiopyrano [4,3-c]pyrazol-1-yl)phenyl]sulfonyl]acetamide; N-[[4-[6-fluoro-1 ,5-dihydro-7-methoxy-3-(trifluoromethyl)-[2]benzothiopyran o[4,3-c]pyrazol-1-yl]phenyl]sulfonyl]acetamide;

N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1 - yl]phenyl]sulfonyl]acetamide;

N-[[4-(2-methyl-4-phenyloxazol-5-yl)phenyl]sulfonyl]acetamide; methyl[[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]sulfonyl]amino]oxoacetate;

2-methoxy-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]su If ony l]acetamide;

N-[[4-[5-(difluoromethyl)-3-phenyIisoxazol-4- yl]phenyl]sulfonyl]propanamide;

N-[[4-[5-(difluoromethyl)-3-phenyiisoxazol-4-yl]phenyl]sulfonyl]butanamide;

N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]formamide;

1 ,1 -dimethylethyl-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]sulfonyl]carbamate; N-[[.sup.4 -(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine;

2-amino-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide;

2-(acetylamino)-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]sulfonyl]acetamide; methyl 4-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]-4- oxobutanoate; methyl N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]carbamate;

N-acetyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine, ethyl ester;

N-[[4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yl)phenyl]su!fonyl]acetamide; methyl 3-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]-3- oxopropanoate; 4-[5-(3-bromo-5-fluoro-4-methoxyphenyl)-2-(trifluoromethyl)oxazol-4-yl]-N- methylbenezenesulfonamide; N-(1 ,1 -dimethylethyl)-4-(5-methyl-3-phenylisoxazol-4- yl)benzenesulfonamide; 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-N- methylbenzenesulfonamide;

N-methyl-4-(5-methyl-3-phenylisoxazol-4-yl)benezenesulfonamide; N-[[4-[5-(hydroxymethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide: N-[[4-[5-(acetoxymethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide; N-[[4-[2-(3-chloro-4-f luorophenyl)cyclopenten-1 - yl)phenyl]sulfonyl]acetamide;

4-[2-(4-fluorophenyl)-1 H-pyrrol-1-yl]-N-methylbenzenesulfonamide; N-[[4-(3,4-dimethyl-1-phenyl-1 H-pyrazol-5-yl]phenyl]sulfonyl]propanamide; N-[[4-[2-(2-methylpyridin-3-yl)-4-trifluoromethylimidazol-1- yl]phenyl]sulfonyl]propanamide;

4-[2-(4-fluorophenyl)cyclopenten-1-yl]-N-methylbenezenesulfonamide; and N-[[4-(3-phenyl-2,3-dihydro-2-oxofuran-4-yl)phenyl]sulfonyI]propanamide. [000124] Those prodrugs disclosed in U.S. Patent No. 6,613,790 have the general formula shown above in formula XXXXII wherein: A¹³ is a pyrazole group optionally substituted at a substitutable position with one or more radicals independently selected at each occurrence from the group consisting of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, intro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, alkenyl, alkynyl, alkylthio, alkylthioalkyl, alkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkylsutfinyl, alkylsulfonyl, aminosulfonyl, and alkylaminosulfonyl; R²¹⁰ is a phenyl group optionally substituted at a substitutable position with one or more radicals independently selected at each occurrence from the group consisting of alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio;

R²¹ and R²¹² are independently selected from the group consisting of hydroxyalkyl and hydrido but at least one of R²¹¹ and R²¹² is other than hydrido; and

R²¹³ is selected from the group consisting of hydrido and fluoro. [000125] Examples of prodrug compounds disclosed in U.S. 6,613,790 that are useful as Cox-2 inhibitors of the present invention include, but are not limited to, N-(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)- 1 H-pyrazol-1- yl]benzenesulfonamide, N,N-bis(2-hydroxyethyl)-4-[5-(4- methylphenyl)-3-(trif luoromethyl)-1 H-pyraz ol-1 -yl]benzenesulfonamide, or pharmaceuticaly-acceptable salts thereof.

[000126] Cox-2 selective inhibitors such as sulfamoylheleroaryl pyrazole compounds that are described in U.S. Patent No. 6,583,321 may serve as Cox-2 inhibitors of the present invention. Such sulfamoylheleroaryl pyrazole compounds have the formula shown below in formula XXXXIII:

XXXXIII

wherein: R²¹⁴ is furyl, thiazolyl or oxazolyl;

R²¹⁵ is hydrogen, fluoro or ethyl; and

X³¹ and X³² are independently hydrogen or chloro. [000127] Heteroaryl substituted amidinyl and imidazolyl compounds such as those described in U.S. Patent No. 6,555,563 are useful as Cox-2 selective inhibitors of the present invention. Such heteroaryl substituted amidinyl and imidazolyl compounds have the formula shown below in formula XXXXIV:

XXXXIV

wherein:

Z¹⁶ is O or S,

R²¹⁶ is optionally substituted aryl,

R²¹⁷ is aryl optionally substituted with aminosulfonyl, and

R²¹⁸ and R²¹⁹ cooperate to form an optionally substituted 5-membered ring.

[000128] Materials that can serve as Cox-2 selective inhibitors of the present invention include substituted hydroxamic acid derivatives that are described in U.S. Patent Nos. 6,432,999, 6,512,121 , and 6,515,014.

These compounds also act as inhibitors of the lipoxygenase-5 enzyme.

Such substituted hydroxamic acid derivatives have the general formulas shown below in formulas XXXXV and XXXXVI:

XXXXV

XXXXVI

[000129] Pyrazole substituted hydroxamic acid derivatives described in

U.S. Patent No. 6,432,999 have the formula shown above in formula

XXXXV, wherein: A¹⁴ is pyrazolyl optionally substituted with a substituent selected from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;

Y¹⁰ is selected from lower alkenylene and lower alkynylene; R²²⁰ is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R²²⁰ is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylmino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;

R²²¹ is selected from lower alkyl and amino; and

R²²² is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically-acceptable salt thereof.

[000130] Pyrazole substituted hydroxamic acid derivatives described in

U.S. Patent No. 6,432,999 may also have the formula shown above in formula XXXXVI, wherein:

A¹⁵ is pyrazolyl optionally substituted with a substituent selected from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;

Y¹¹ is selected from lower alkylene, lower alkenylene and lower alkynylene; R²²³ is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R²²³ is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylmino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R²²⁴ is selected from lower alkyl and amino; and R²²⁵ is selected from hydrido, lower alkyl; or a pharmaceutically-acceptable salt thereof.

[000131] Heterocyclo substituted hydroxamic acid derivatives described in U.S. Patent No. 6,512,121 have the formula shown above in formula XXXXV, wherein: A¹⁴ is a ring substiuent selected from oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isochiazolyl, isoxazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A¹⁴ is optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y¹⁰ is lower alkylene, lower alkenylene, and lower alkynylene;

R²²⁰ is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R²²⁰ is otionallv substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R²²¹ is selected from lower alkyl and amino; and R²²² is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically-acceptable salt thereof. [000132] Heterocyclo substituted hydroxamic acid derivatives described in U.S. Patent No. 6,512,121 may also have the formula shown above in formula XXXXVI, wherein: A¹⁵ is a ring substituent selected from oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A is optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarboryl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; , Y¹¹ is selected from lower alkyl, lower alkenyl and lower alkynyl; R²²³ is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R²²³ is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitto, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R²²⁴ is selected from lower alkyl and amino; and R²²⁵ is selected from hydrido and alkyl; or a pharmaceutically-acceptable salt thereof. [000133] Thiophene substituted hydroxamic acid derivatives described in U.S. Patent No. 6,515,014 have the formula shown above in formula XXXXV, wherein: A¹⁴ is thienyl optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y¹⁰ is ethylene, isopropylene, propylene, butylene, lower alkenylene, and lower alkynylene; R²²⁰ is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R²²⁰ is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl , lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R²²¹ is selected from lower alkyl and amino; and

[000134] Thiophene substituted hydroxamic acid derivatives described in U.S. Patent No. 6,515,014 may also have the formula shown above in formula XXXXV, wherein:

A¹⁵ is thienyl optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;

Y¹¹ is selected from lower alkyl, lower alkenyl and lower alkynyl; R²²³ is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R²²³ is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R²²⁴ is selected from lower alkyl and amino; and R²²⁵ is selected from hydrido and alkyl; or a pharmaceutically-acceptable salt thereof.

[000135] Compounds that are useful as Cox-2 selective inhibitors of the present invention include pyrazolopyridine compounds that are described in U.S. Patent No. 6,498,166. Such pyrazolopyridine compounds have the formula shown below in formula XXXXVII: XXXXVII

wherein:

R²²⁶ and R²²⁷ are independently selected from the group consisting of H, halogen, Ci -Cβ alkyl, Ci -Cβ alkoxy, and Ci -Cβ alkoxy substituted by one or more fluorine atoms;

R^^B is halogen, CN, CON R^^ϋ R^ C0₂ H, C0₂ Ci -C₆ alkyl, or

NHSO≥R²³⁰;

R²²⁹ is Ci -C₆ alkyl or NH₂ ; and

R²²⁵ and R²²⁵ are independently selected from the group consisting of H, C -C₆ alkyl, phenyl, phenyl substituted by one or more atoms or groups selected from the group consisting of halogen, Ci -Cβ alkyl, Ci -Cβ alkoxy, and Ci -C₆ alkoxy substituted by one or more fluorine atoms, or a pharmaceutically acceptable salt, solvate, ester, or salt or solvate of such ester thereof. [000136] Materials that are useful as Cox-2 selective inhibitors of the present invention include 4,5-diaryl-3(2H)-furanone derivatives that are described in U.S. Patent No. 6,492,416. Such 4,5-diaryl-3(2H)-furanone derivatives have the formula shown below in formula XXXXVIII: XXXXVIII

wherein:

X³³ represents halo, hydrido, or alkyl;

Y¹² represents alkylsulfonyl, aminosulfonyl, alkylsulfinyl, (N-acylamino)- sulfonyl, (N-alkylamino)sulfonyl, or alkylthio;

Z¹⁷ represents oxygen or sulfur atom;

R²³³ and R²³⁴ are selected independently from lower alkyl radicals; and R²³² represents a substituted or non-substituted aromatic group of 5 to

10 atoms; or a pharmaceutically-acceptable salt thereof.

[000137] Cox-2 selective inhibitors that can be used in the present invention include 2-phenyl-1 ,2-benzisoselenazol-3(2H)-one derivatives and 2-phenylcarbomyl-phenylselenyl derivatives that are described in U.S.

Patent No. 6,492,416. Such 2-phenyl-1 ,2-benzisoselenazol-3(2H)-one derivatives and 2-phenylcarbomyl-phenylselenyl derivatives have the formulas shown below in formulas XXXXIX or XXXXIX':

XXXXIX

XXXXIX'

wherein:

R²³⁵ is a hydrogen atom or an alkyl group having 1 -3 carbon atoms;

R²³⁶ is a hydrogen atom, a hydroxyl group, an organothiol group that is bound to the selenium atom by its sulfur atom, or R²³⁵ and R²³⁶ are joined to each other by a single bond;

R²³⁷ is a hydrogen atom, a halogen atom, an alkyl group having 1 -3 carbon atoms, an alkoxyl group having 1 -3 carbon atoms, a trifluoromethyl group, or a nitro group;

R²³⁸ and R²³⁹ are identical to or different from each other, and each is a hydrogen atom, a halogen atom, an alkoxyl group having 1 -4 carbon atoms, a trifluoromethyl group, or R²³⁸ and R²³⁹ are joined to each other to form a methylenedioxy group, a salt thereof, or a hydrate thereof.

[000138] Pyrones such as those disclosed in U.S. Patent No. 6,465,509 are also useful as Cox-2 inhibitors of the present invention. These pyrone compounds have the general formula shown below in formula XXXXX:

XXXXX

wherein: X³⁴ is selected from the group consisting of:

(a) a bond,

(b) -(CH₂)_m --, wherein m 1 or 2,

(c) --C(O)--, (d) -0-,

(e) -S-, and

(f) -N(R²⁴⁴)-;

R²⁴⁰ is selected from the group consisting of:

(a) Ci -Cio alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of: hydroxy, halo, Ci -Cio alkoxy, Ci -

Cio alkylthio, and CN,

(b) phenyl or naphthyl, and

(c) heteroaryl, which is comprised of a monocyclic aromatic ring of 5 atoms having one hetero atom which is S, O or N, and optionally 1 , 2, or 3 additional N atoms; or a monocyclic ring of 6 atoms having one hetero atom which is N, and optionally 1 , 2, or 3 additional N atoms, wherein groups (b) and (c) above are each optionally substituted with 1 -3 substituents independently selected from the group consisting of: halo, Ci -Cio alkoxy, Ci -Cio alkylthio, CN, Ci -Cio alkyl, optionally substituted to its maximum with halo, and N₃ ; R²⁴¹ is selected from the group consisting of

(a) Ci -C₆ alkyl, optionally substituted to its maximum with halo,

(b) NH₂, and (c) NHC(0)Cι -Cio alkyl, optionally substituted to its maximum with halo;

R²⁴² and R²⁴³ are each independently selected from the group consisting of: hydrogen, halo, and Ci -C₆ alkyl, optionally substituted to its maximum with halo; and R²⁴⁴ is selected from the group consisting of: hydrogen and Ci -C₆ alkyl, optionally substituted to its maximum with halo.

[000139] Examples of pyrone compounds that are useful as Cox-2 selective inhibitors of the present invention include, but are not limited to: 4-(4-Methylsulfonyl)phenyl-3-phenyl-pyran-2-one, 3-(4-Fluorophenyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one, 3-(3-Fluorophenyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one, 6-Methyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one, 6-Difluoromethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one,

6-Fluoromethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one, 6-Methyl-4-(4-methylsulfonyl)phenyl-3-phenylthio-pyran-2-one, 6-Methyl-4-(4-methylsuIfonyl)phenyl-3-phenoxy-pyran-2-one, 6-Methyl-4-(4-methylsulfonyl)phenyl-3-pyridin-3-yl-pyran-2-one, 3-lsopropylthio-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one,

4-(4-Methylsulfonyl)phenyl)-3-phenylthio-6-trifluoromethyl-pyran-2-one, 3-lsopropylthio-4-(4-methylsulfonyl)phenyl-6-trifluoromethyl-pyran-2-one, 4-(4-Methylsulfonyl)phenyl-3-phenyl-6-(2,2,2-trifluoroethyl)-pyran-2-one, and 3-(3-Hydroxy-3-methylbutyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2- one.

[000140] Organically synthesized or purified from plant sources, free-B- ring flavanoids such as those described in U.S. Published Application No. 2003/0165588, are useful as Cox-2 selective inhibitors of the present invention. Such free-B-ring flavanoids have the general structure shown in formula XXXXXI:

XXXXXI

wherein:

R²⁴⁶, R²⁴⁷, R²⁴⁸, R²⁴⁹, and R²⁵⁰ are independently selected from the group consisting of: -H, -OH, -SH, -OR, -SR, -NH₂, --NHR²⁴⁵, -N(R²⁴⁵)₂, ~N(R²⁴⁵)₃ ⁺X³⁵~ , a carbon, oxygen, nitrogen or sulfur, glycoside of a single or a combination of multiple sugars including, aldopentoses, methyl- aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; wherein R²⁴⁵ is an alkyl group having between 1-10 carbon atoms; and X³⁵ is selected from the group of pharmaceutically acceptable counter anions including, hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride and carbonate.

[000141] Heterocyclo-alkylsulfonyl pyrazoles such as those described in European Patent Application No. EP 1312367 are useful as Cox-2 selective inhibitors of the present invention. Such heterocyclo-alkylsulfonyl pyrazoles have the general formula shown below in formula XXXXXII:

XXXXXII

or a pharmaceutically acceptable salt thereof, wherein: the ring of the formula (R²⁵⁵)-A-(SO_mR²⁵⁴) is selected from the group consisting of:

m is 0, 1 or 2; X³⁵ is >CR²⁵⁵ or >N;

R²⁵¹ is a radical selected from the group consisting of H, N0₂, CN, (Ci - C₆)alkyl, (Ci -C₆)alkyl-S0₂-, (C₆ -Cι₀)aryl-SO₂-, H-(C=0)-, (d -C₆)alkyl- (C=0)-, (d -C₆)alkyl-)-(C=0)-, (Ci -C₉)heteroaryl-(C=0)-, (d - C₉)heterocyclyl-(C=0)-, H₂N-(C=0)-, (Ci -C_β)alkyl-NH-(C=0)-, [(d - C₆)alkyl]₂-N-(C=0)-, [(C_β

[(d -C₆)alkyl]-[((C₆ - Cιo)aryl-N]-(C=0)-, HO-NH-(C=0)-, and (Ci -C₆)alkyl-0-NH-(C=0)-; R²⁵² is a radical selected from the group consisting of H, -N0₂, -CN, (C₂- C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, (C₆-Cι₀)aryl, (d- C₉)heteroaryl, (C C₉)heterocyclyl, (d-C₆)alkyl-0-, (C₃-C )cycloalkyl-0-, (C₆-Cιo)aryl-0-, (Ci -C₉)heteroaryl-0-, (C₆ -C₉)heterocyclyl-0-, H-(C=0)-, (Ci-C₆)alkyl-(C=0)-, (C₃-C₇)cycloalkyl-(C=0)-, (C₆-Cι₀)aryl-(C=O)-, (C C₉)heteroaryl-(C=0)-, (Ci-C₉)heterocyclyl-(C=0)-, (Ci-C₆)alkyl-0-(C=0)-, (C₃-C₇)cycloalkyl-0-(C=0)-, (C₆-C ₀)aryl-O-(C=O)-, (Ci -C₉)heteroaryl-0-

C₇)cycloalkyl-(C=0)-0-, (C₆-C₁₀)aryl-(C=O)-O-, (Ci-C₉)heteroaryl-(C=0)- 0-, (C C₉)heterocyclyl-(C=0)-0-, (d-C₆)alkyl-(C=0)-NH-, (C₃- C₇)cycloalkyl-(C=0)-NH-, (C₆-Cι₀aryl-(C=O)-NH-. (d-C₉)heteroaryl-(C=0)- NH-, (d-C₉)heterocyclyl-(C=0)-NH-, (d-C₆)alkyl-0-(C=0)-NH-, (d- C₆)alkyl-NH, [(C C₆)alkyl]₂-N-, (C₃-C₇)cycloalkyl-NH-. [(C₃-C₇)cycloalkyl]₂- N-, [(C₆-do)aryl]-NH-, [(C₆-Cι ₀)aryl]₂-N-, [(Cι -C₆)alkyl]-[((C₆-C₁₀)aryl)-N]-, [(Ci -C₉)heteroaryl]-NH-, [(CrC₉)heteroaryl]₂-N-, [(C -C₉)heterocycly]-NH-, [(Ci-C₉)heterocyclyl]₂-N-, H₂N-(C=0)-, HO-NH-(C=0)-, (C C₆)alkyl-0-NH- (C=0)-, [(d-C₆)alkyl]-NH-(C=0)-, [(C C₆)alkyl]₂-N-(C=0)-, [(C₃- C₇)cycloalkyl]-NH-(C=0)-, [(C₃-C₇)cycloalkyl]₂-N-(C=0)-, [(C₆-Cιo)aryl]-NH- (C=0)-, [(C₆-Cι₀aryl]₂-N-(C=O)-, [(C C ₆)alkyl]-[((C₆-Cι₀)aryl)-N]-(C=O)-, [(CrC₉)heteroaryl]-NH-(C=0)-, [(Ci-C₉)heferoaryl]₂-N-(0=0)-, [(C C₉)heterocyclyl]-NH-(C=0)-, (Cι-C₆)alkyl-S- and (C C₆)alkyl optionally substituted by one -OH substituent or by one to four fluoro substituents; R²⁵³ is a saturated (3- to 4-membered)-heterocyclyl ring radical; or a saturated, partially saturated or aromatic (7- to 9-membered)-heterocyclyl ring radical; wherein said saturated (3- to 4-membered)-heterocyclyl ring radical orsaid saturated, partially saturated or aromatic (7- to 9-membered)- heterocyclyl ring radical; may optionally contain one to four ring heteroatoms independently selected Irom the groups consisting of -N=, -NH-, -0-. and -S-; wherein said saturated (3- to 4-membered)-heterooyclyl ring radical; or said saturated, partially saturated or aromatic (7- to 9- nembered)-heterocyclyl ring radical; may optionally be substituted on any ring carbon atom by one to three substituents per ring independently selected from the group consisting of halo, -OH, -CN, -N0₂, (C₂- C₆)alkenyl, (C -C₆)alkynyl, (C₃-C₇)cycloalkyl, (C₆-d₀)aryl, (C₂- C₉)hetorocyclyl, (Ci -C₆)alkyl-0-, H-(C=0)-, (C C₆)alkyl-(C=0)-, HO- (C=0)-, (Ci-C₆)alkyl-0-(C=0)-, -NH₂, (C C₆)alkyl-NH-, [(C C₆) alkyl]₂-N-,

(C₃-C₇)cycloalkyl-NH-, (C₆-Cιo)aryl-NH-, [(Cι-C₆)alkyl]-[((C₆-Cιo)aryl)-N]-, (Cι-C₉)heteroaryl-NH-, H₂N-(C=0)-[(d-C₆)alkyl]-NH-(C=0)-, [(C C₆)alkyl]₂-N-(C=0)-, [(C6-Cιo)aryl]-NH-(C=0)-, [(CrC₆)alkyl]-[((C₆-do)aryl)- N]-(C=0)-, (Cι-C₆)alkyl-0-NH-(C=0)-, (d-C₆)alkyl-(C=0)-HN-, (d- C₆)alkyl-(C=0)-[(d-C₆)alkyl-N3-, -SH, (C C₆)alkyl-S-,

(d-C₆)alkyl-(S=0)-, (C C₆)alkyl-S0₂- and (C C₆)alkyl optionally substituted with one to fourfluoro moieties; wherein said saturated (3- to 4-membered)-heterocyclyl ring radical; or said saturated, partially saturated or aromatic (7- to 9- membered)-heterocyclyl ring radical; may also optionally be substituted on any ring nitrogen atom by one to three substituents per ring independently selected from the group consisting of (C₃-C₇)cyoloalkyl, (C₆-Cι₀)aryl, (C₂- C₉)heterocyclyl, H-(C=0)-, (d-C₆)alkyl-(C=0)-, (C C₆)alkyl-0-(C=0)-, H₂N-(C=0)-, [(C C₆)alkyl]-NH-(C=0)-, [(C C₆)alkyl]₂-N-(C=0)-, [(C₆- C₁₀)aryl]-NH-(C=O)-, [(Ci-C₆)alkyl]-[((C₆-d₀)aryl)-N]-(C=O)-, (d -C₆)alkyl- 0-NH-(C=0)-, and (CrC₆)alkyl optionally substituted with one to four fluoro moieties;

R²⁵⁴ is an (d-C₆)alkyl radical optionally substituted by one to four fluoro substituents; and

R²⁵⁵ is a radical selected from the group consisting of H, halo, -OH, (d- C₆)alkyl-0-, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₃-C₇)cycloalkyl, -CN, H- (C=0)-, (Cι-C₆)alkyl-(C=0)-,

HO-(C=0)-, (d-

C₆)alkyl-0-(C=0)-, (C C₆)alkyl-NH-. [(d-C₆)alkyl]₂-N-, (C₃-C₇)cycloalkyl- NH-, (C₆-Cιo)aryl-NH-, [(d-C₆)alkyl]-[((C₆-Cιo)aryl)-N]-, (d-Cg)heteroaryl- NH-, H₂N-(C=0)-, (Cι-C₆)alkyl-NH-(C=0)-. [(C C₆)alkyl]₂-N-(C=0)-, (C₆- Cιo)aryl-(C=0)-, [(Cι-C6)alkyl]-[((C₆-Cιo)aryl)-N]-(C=0)-, (Cι-Ce)alkyl-O- NH-(C=0)-, (Cι-C₆)alkyl-S-, and (C C₆)alkyl optionally substituted by one to four fluoro substituents.

[000142] 2-phenylpyran-4-one derivatives such as those described in U.S. Patent No. 6,518,303 are also useful as Cox-2 selective inhibitors of the present invention. Such 2-phenylpyran-4-one derivatives have the general formula shown below in formula XXXXXIII:

XXXXXIII

wherein:

R²⁵⁶ represents an alkyl or -NR²⁵⁹ R²⁶⁰ group, wherein R²⁵⁹ and R²⁶⁰ each independently represents a hydrogen atom or an alkyl group;

R²⁵⁷ represents an alkyl, C₃ -C₇ cycloalkyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups; R²⁵⁸ represents a methyl, hydroxymethyl, alkoxymethyl, C₃ -C₇ cycloalkoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrile, trifluoromethyl or difluoromethyl group or a CH₂ - R²⁶¹ group wherein R²⁶¹ represents an alkyl group; and X³⁶ represents a single bond, an oxygen atom, a sulfur atom or a methylene group; or a pharmaceutically acceptable salt thereof.

[000143] Examples of 2-phenylpyran-4-one derivatives useful in the present invention include, but are not limited to:

3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(2-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-bromophenyl)-2-(4-methylsulfonylphenyl)-6-methylpyran-4-one, 3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(3,4-dichlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(3-chloro-4-methylphenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-

4-one ,

2-(4-methanesulfonylphenyl)-6-methyl-3-phenoxypyran-4-one, 3-(4-fluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(2-fluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,

3-(2-chlorophenoxy)-2-(methanesuIfonylphenyl)-6-methylpyran-4-one, 3-(4-bromophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 2-(4-methanesulfonylphenyl)-6-methyl-3-(4-methylphenoxy)pyran-4-one, 3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4- one,

3-(2,5-difluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methoxymethylpyran-4- one,

3-(4-chlorophenyl)-6-difluoromethyl-2-(4-methanesulfonylphenyl)pyran-4- one, and pharmaceutically acceptable salts thereof. [000144] Cox-2 selective inhibitors that are useful in the subject method and compositions can include the compounds that are described in U.S.

Patent No. 6,472,416 (sulfonylphenylpyrazoles); U.S. Patent No.

6,451 ,794 (2,3-diaryl-pyrazolo[1 ,5-b]pyridazines); U.S. Patent Nos.

6,169,188, 6,020,343, and 5,981 ,576 ((methylsulfonyl)phenyl furanones); U.S. Patent No. 6,222,048 (diaryl-2-(5H)-furanones); U.S. Patent No.

6,057,319 (3,4-diaryl-2-hydroxy-2,5-dihydrofurans); U.S. Patent No.

6,046,236 (carbocyclic sulfonamides); U.S. Patent Nos. 6,002,014 and

5,945,539 (oxazole derivatives); and U.S. Patent Nos. 6,359,182 and

6,538,116 (C-nitroso compounds). [000145] Examples of specific compounds that are useful as Cox-2 selective inhibitors include, without limitation: a1 ) 8-acety!-3-(4-f luorophenyl)-2-(4-methylsulfonyl)phenyl-imidazo(1 ,2- a)pyridine; a2) 5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2-(5H)-furanone; a3) 5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-

(trifluoromethyl)pyrazole; a4) 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1 -phenyl-3-

(trifluoromethyl)pyrazole; a5) 4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1 H-pyrazol-1 - yl)benzenesulfonamide a6) 4-(3,5-bis(4-methylphenyl)-1 H-pyrazol-1 -yl)benzenesuIfonamide; a7) 4-(5-(4-chlorophenyl)-3-phenyl-1 H-pyrazol-1 - yl)benzenesulfonamide; a8) 4-(3,5-bis(4-methoxyphenyl)-1 H-pyrazol-1 -yl)benzenesulfonamide; a9) 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1 H-pyrazol-1 - yl)benzenesulfonamide; a10) 4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1 H-pyrazol-1 - yl)benzenesulfonamide; b1 ) 4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1 H-pyrazol-1 - yl)benzenesulfonamide; b2) 4-(4-chloro-3,5-diphenyl-1 H-pyrazol-1 -yl)benzenesulfonamide b3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b4) 4-[5-phenyl-3-(trif luoromethyl)-1 H-pyrazol-1 -yljbenzenesulfonamide; b5) 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b6) 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b7) 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b8) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b9) 4-[4-chloro-5-(4-chlorophenyl)-3-(trif luoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b10) 4-[3-(dif!uoromethyl)-5-(4-methylphenyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; d ) 4-[3-(difluoromethyl)-5-phenyl-1 H-pyrazol-1 -yljbenzenesulfonamide; c2) 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; c3) 4-[3-cyano-5-(4-fluorophenyl)-1 H-pyrazol-1 -yljbenzenesulfonamide; c4) 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; c5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; c6) 4-[4-chloro-5-phenyl-1 H-pyrazol-1 -yljbenzenesulfonamide; c7) 4-[5-(4-chIorophenyl)-3-(hydroxymethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; c8) 4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-

1 -yljbenzenesulfonamide; c9) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyljspiro[2.4jhept-5-ene; c10) 4-[6-(4-fluorophenyl)spiro[2.4jhept-5-en-5-yljbenzenesulfonamide; d1 ) 6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyljspiro[3.4joct-6-ene; d2) 5-(3-chloro-4-methoxyphenyl)-6-[4-

(methylsulfonyl)phenylJspiro[2.4]hept-5-ene; d3) 4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4jhept-5-en-5- yljbenzenesulfonamide; d4) 5-(3,5-dichloro-4-methoxyphenyl)-6-[4-

(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene; d5) 5-(3-chloro-4-fluorophenyl)-6-[4-

(methylsulfonyl)phenyl]spiro[2.4jhept-5-ene; d6) 4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5- yljbenzenesulfonamide; d7) 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4- methylsulfonylphenyl)thiazole; d8) 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4- methylsulfonylphenyl)thiazole; d9) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole; d10) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2- trifluoromethylthiazole; e1) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazoIe; e2) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2- benzylaminothiazole; e3) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1 - propylamino)thiazole; e4) 2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-

(methylsulfonyl)phenyljthiazole; e5) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2- trifiuoromethylthiazole; e6) 1 -methylsulfonyl-4-[1 ,1 -dimethyl-4-(4-fluorophenyl)cyclopenta-2,4- dien-3-yljbenzene; e7) 4-[4-(4-fluorophenyl)-1 , 1 -dimethylcyclopenta-2,4-dien-3- yljbenzenesulfonamide; e8) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyljspiro[2.4jhepta-4,6- diene; e9) 4-[6-(4-fluorophenyl)spiro[2.4jhepta-4,6-dien-5- yl jbenzenesu If onamide; e10) 6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)phenylj-pyridine- 3-carbonitrile; f1) 2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyridine-3- carbonitrile; f2) 6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenylj-2-phenyl-pyridine-3- carbonitrile; f3) 4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; f4) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; f5) 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; f6) 3-[1 -[4-(methylsulfonyl)phenylj-4-(trifluoromethyl)-1 H-imidazol-2- yljpyridine; f7) 2-[1 -[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H-imidazol-2- yljpyridine; f8) 2-methyl-4-[1 -[4-(methylsulfonyl)ρhenyl-4-(trifluoromethyl)-1 H- imidazol-2-yl]pyridine; f9) 2-methyl-6-[1 -[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H- imidazol-2-yl]pyridine; f 10) 4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; g1 ) 2-(3,4-dif luorophenyl)-1 -[4-(methylsulfonyl)phenylj-4-

(trifluoromethyl)-l H-imidazole; g2) 4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; g3) 2-(4-chlorophenyl)-1 -[4-(methylsulfonyl)phenylj-4-methyl-1 H- imidazole; g4) 2-(4-chlorophenyl)-1 -[4-(methylsulfonyl)phenylj-4-phenyl-1 H- imidazole; g5) 2-(4-chlorophenyl)-4-(4-fluorophenyI)-1-[4-(methylsulfonyl)phenylj-

1H-imidazole; g6) 2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-4- (trifluoromethyl)- 1 H-imidazole; g7) 1 -[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1 H- imidazole; g8) 2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenylj-4-trifluoromethyl-

1 H-imidazole; g9) 4-[2-(3-chloro-4-methyIphenyl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; g10) 2-(3-fluoro-5-methylphenyl)-1 -[4-(methylsulfonyl)phenylj-4-

(trifluoromethyl)-l H-imidazole; h 1 ) 4-[2-(3-fluoro-5-methylphenyl)-4-(trif luoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; h2) 2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenylj-4-trifluoromethyl-

1 H-imidazole; h3) 4-[2-(3-methylphenyl)-4-trif luoromethyl-1 H-imidazol-1 - yljbenzenesulfonamide; h4) 1 -[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trif luoromethyl-

1 H-imidazole; h5) 4-[2-(3-chlorophenyl)-4-trif luoromethyl-1 H-imidazol-1 - yljbenzenesulfonamide; h6) 4-[2-phenyl-4-trif luoromethyl-1 H-imidazol-1 -yljbenzenesulfonamide; h7) 4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1 H-imidazol-1 - yljbenzenesulfonamide; h8) 1 -allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-

(trifluoromethyl)-l H-pyrazole; h9) 4-[1 -ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1 H-pyrazol-3- yljbenzenesulfonamide; i1) N-phenyl-[4-(4-luorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-

(trifluoromethyi)-l H-pyrazol-1 -yljacetamide; i2) ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenylj-5-

(trifluoromethyl)-l H-pyrazol-1 -yljacetate; i3) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)- 1 H-pyrazole; i4) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenylj-1-(2-phenylethyl)-5-

(trifluoromethyl)pyrazole; i5) 1 -ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenylj-5-

(trifluoromethyl)-l H-pyrazole; i6) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1 H- imidazole; i7) 4-[4-(methylsulfonyl)phenylj-5-(2-thiophenyl)-2-(trifluoromethyl)-1H- imidazole; i8) 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenylj-6- (trifluoromethyl)pyridine; i9) 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-

(trifluoromethyl)pyridine; i10) 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-

(trifluoromethyl)pyridine; j1 ) 2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenylj-6-

(trifluoromethyl)pyridine; j2) 4-[2-(3-chloro-4-methoxyphenyl)-4,5- difluorophenyljbenzenesulfonamide; j3) 1 -(4-f luorophenyl)-2-[4-(methylsulfonyl)phenyljbenzene; j4) 5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole; j5) 4-[3-ethyl-5-phenylisoxazol-4-yljbenzenesulfonamide; j6) 4-[5-difluoromethyl-3-phenylisoxazol-4-yljbenzenesulfonamide; j7) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yljbenzenesulfonamide; j8) 4-[5-methyl-3-phenyl-isoxazol-4-yljbenzenesulfonamide; j9) 1 -[2-(4-fluorophenyl)cyclopenten-1 -yl]-4-(methylsulfonyl)benzene; j10) 1 -[2-(4-fluoro-2-methylphenyl)cyclopenten-1 -yl]-4- (methylsulfonyl)benzene; k1 ) 1 -[2-(4-chlorophenyl)cyclopenten-1 -ylj-4-(methylsulfonyl)benzene; k2) 1 -[2-(2,4-dichlorophenyl)cyclopenten-1 -ylj-4-

(methylsulfonyl)benzene; k3) 1 -[2-(4-trifluoromethylphenyl)cyclopenten-1 -ylj-4- (methylsulfonyl)benzene; k4) 1 -[2-(4-methylthiophenyl)cyclopenten-1 -ylj-4-

(methylsulfonyl)benzene; k5) 1 -[2-(4-f luorophenyl)-4,4-dimethylcyclopenten- 1 -ylj-4-

(methylsulfonyl)benzene; k6) 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1- yljbenzenesulfonamide; k7) 1 -[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1 -ylj-4-

(methylsulfonyl)benzene; k8) 4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1 - yljbenzenesulfonamide; k9) 4-[2-(4-f luorophenyl)cyclopenten-1 -yljbenzenesulfonamide; k10) 4-[2-(4-chlorophenyl)cyclopenten-1 -yljbenzenesulfonamide;

11 ) 1 -[2-(4-methoxyphenyl)cyclopenten-1 -ylj-4-

(methylsulfonyl)benzene; 12) 1-[2-(2,3-difluorophenyl)cyclopenten-1-ylj-4-

(methylsulfonyl)benzene;

13) 4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1 - yljbenzenesulfonamide;

14) 1 -[2-(3-chloro-4-methoxyphenyl)cyclopenten-1 -ylj-4- (methylsulfonyl)benzene;

15) 4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1 -yljbenzenesulfonamide;

16) 4-[2-(2-methylpyridin-5-yl)cyclopenten-1 -yljbenzenesulfonamide; 17) ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyljoxazol-2-ylj- 2-benzyl-acetate;

18) 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yljacetic acid; 19) 2-(fet -butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyljoxazole;

110) 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole; ml) 4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyljoxazole; and m2) 4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyI-4- oxazolyljbenzenesulfonamide. m3) 6-chloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; m4) 6-chloro-7-methyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; m5) 8-(1 -methylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; m6) 6-chloro-7-(1 ,1 -dimethylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid; m7) 6-chloro-8-(1 -methylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid; m8) 2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid ; m9) 7-(1 ,1 -dimethylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid; ml 0) 6-bromo-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; n1 ) 8-chloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; n2) 6-trifluoromethoxy-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; n3) 5,7-dichloro-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid; n4) 8-phenyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; n5) 7,8-dimethyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; n6) 6,8-bis(dimethylethyl)-2-trif luoromethyl-2H-1 -benzopyran-3- carboxylic acid; n7) 7-(1 -methylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; n8) 7-phenyl-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid; n9) 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n 10) 6-chloro-8-ethyl-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid; o1 ) 6-chloro-7-phenyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; , o2) 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

03) 6,8-dichloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid;

04) 2-trif luoromethyl-3H-naptho[2, 1 -b]pyran-3-carboxylic acid;

05) 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; o6) 8-chloro-6-methyl-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid;

07) 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

08) 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

09) 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

010) 8-bromo-6-methyl-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid; p1 ) 8-bromo-5-fluoro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; p2) 6-chloro-8-fluoro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; p3) 6-bromo-8-methoxy-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; p4) 6-[[(phenylmethyl)aminojsulfonylJ-2-trifluoromethyl-2H-1 - benzopyran-3-carboxylic acid; p5) 6-[(dimethylamino)sulfonylj-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid; p6) 6-[(methylamino)sulfonylj-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid; p7) 6-[(4-morpholino)sulfonylj-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid; p8) 6-[(1 , 1 -dimethylethyl)aminosulfonylj-2-trif luoromethyl-2H-1 - benzopyran-3-carboxylic acid; p9) 6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1 - benzopyran-3-carboxylic acid; p10) 6-methylsulfonyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; q1 ) 8-chloro-6-[[(phenylmethyl)amino]sulfonylj-2-trifluoromethyl-2H-1 - benzopyran-3-carboxylic acid; q2) 6-phenylacetyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; q3) 6,8-dibromo-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; q4) 8-chloro-5,6-dimethyl-2-trif luoromethyl-2H-1 -benzopyran-3- carboxylic acid; q5) 6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q6) 6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q7) 6-[[N-(2-furylmethyl)aminoJsulfonyl]-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid; q8) 6-[[N-(2-phenylethyl)aminojsulfonylJ-2-trifluoromethyl-2H-1 - benzopyran-3-carboxylic acid; q9) 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q10) 7-(1 ,1 -dimethylethyl)-2-pentafluoroethyl-2H-1 -benzopyran-3- carboxylic acid; r1 ) 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methyl-sulphonyl-2(5H)- fluranone; r2) 6-chloro-2-trifluoromethyl-2H-1 -benzothiopyran-3-carboxylic acid; r3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesu If onam ide; r4) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; r5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; r6) 3-[1 -[4-(methylsulfonyl)phenylj-4-trifluoromethyl-1 H-imidazol-2- yljpyridine; r7) 2-methyl-5-[1 -[4-(methylsulfonyl)phenyl]-4-trif luoromethyl-1 H- imidazol-2-yljpyridine; r8) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; r9) 4-[5-methyl-3-phenylisoxazol-4-yljbenzenesulfonamide; r10) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yljbenzenesulfonamide; s1) [2-trifluoromethyl-5-(3,4-difluorophenyl)-4- oxazolyljbenzenesulfonamide; s2) 4-[2-methyl-4-phenyl-5-oxazoly!Jbenzenesulfonamide; or s3) 4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4- oxazolyljbenzenesulfonamide; or a pharmaceutically acceptable salt or prodrug thereof.

[000146] Cox-2 inhibitors that are useful in the methods and compositions of present invention can be supplied by any source as long as the Cox-2 inhibitor is pharmaceutically acceptable. Likewise, Cox-2 inhibitors that are useful in the compositions and methods of present invention can by synthesized, for example, according to the description in

Example 1. Several Cox-2 inhibitors that are suitable for use with the compositions and methods of the present invention may be synthesized by the methods described in, for example, U.S. Patent No. 5,466,823 to

Talley, etal. Cox-2 inhibitors can also be isolated and purified from natural sources. Cox-2 inhibitors should be of a quality and purity that is conventional in the trade for use in pharmaceutical products. [000147] Preferred Cox-2 selective inhibitor compounds are those compounds selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, RS 57067, T-614, BMS-347070 (Bristol Meyers Squibb, described in U.S. Patent No. 6,180,651), JTE-522 (Japan Tabacco), S-2474 (Shionogi),

SVT-2016, CT-3 (Atlantic Pharmaceutical), ABT-963 (Abbott), SC-58125 (GD Searle), nimesulide, flosulide, NS-398 (Taisho Pharmaceutical), L- 745337 (Merck), RWJ-63556, L-784512 (Merck), darbufelone (Pfizer), CS- 502 (Sankyo), LAS-34475 (Almirall Prodesfarma), LAS-34555 (Almirall Prodesfarma), S-33516 (Servier), SD-8381 (Pharmacia, described in U.S.

Patent No. 6,0340256), MK-966 (Merck), L-783003 (Merck), T-614 (Toyama), D-1376 (Chiroscience), L-748731 (Merck), CGP-28238 (Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome), prodrugs of any of them, and mixtures thereof. [000148] More preferred is that the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, lumiracoxib, etoricoxib, rofecoxib, prodrugs of any of them, and mixtures thereof. [000149] Even more preferred still is that the Cox-2 selective inhibitor is celecoxib.

[000150] The second component of the present invention is a phosphodiesterase 4 inhibitor. Examples of phosphodiesterase 4 inhibitors that are useful in the present invention are presented in Table 3.

122

ω o

[000151] The phosphodiesterase 4 inhibitor of the present invention is preferably selected from the group consisting of roflumilast, cilomilast, etazolate hydrochloride, Ro 20-1724, rolipram, (fl)-(-)-rolipram, (S)-(+)- rolipram, zardaverine, V11294A, CDP840, denbufylline, mesopram, cipamfylline, SCH 351591 , SCH 365351 , L-791 ,943, 7-benzylamino-6- chloro-2-piperazino-pteridine, piclamilast, NVP-ABE171 , 4-(8- benzo[1 ,2,5]oxadiazol-5-yl-[1 ,7]napthyridine-6-yl)-benzoic acid, YM976, KF19514, arofylline, XT-44, T-440, atizoram, tibenelast, D-4418, C1 1018, D-22888, and combinations thereof. In preferred embodiments, the phosphodiesterase 4 inhibitor is roflumilast.

[000152] In determining the effective amount or dose, a number of factors are considered by the attending diagnostician, including, but not limited to, the potency and duration of action of the compounds used, the nature and severity of the illness to be treated, as well as the sex, age, weight, general health and individual responsiveness of the patient to be treated, and other relevant circumstances. [000153] As used herein, the phrases "therapeutic amount", "therapeutically-effective", and "effective for the prevention or treatment " are intended to qualify the amount of each agent for use in the combination therapy which will achieve the goal of improvement in the severity of the respiratory inflammation and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. A respiratory disorder symptom or a respiratory disorder-related complication symptom is considered ameliorated or improved if any benefit is achieved, no matter how slight.

[000154] For example, any reduction in inflammation, bronchospasm, bronchoconstriction, shortness of breath, wheezing, lower extremity edema, ascites, productive cough, hemoptysis, or cyanosis in a subject suffering from a respiratory disorder such as COPD, no matter how slight, would be considered an ameliorated symptom. [000155] It will be appreciated that the amount of the Cox-2 inhibitor and the phosphodiesterase 4 inhibitor required for use in the treatment or prevention of respiratory disorders and respiratory disorder-related complications will vary within wide limits and will be adjusted to the individual requirements in each particular case. In general, for administration to adults, an appropriate daily dosage is described herein, although the limits that are identified as being preferred may be exceeded if expedient. The daily dosage can be administered as a single dosage or in divided dosages. [000156] The appropriate dosage level of a Cox-2 inhibitor will generally be from about 0.01 mg per kg to about 140 mg per kg subject body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 mg/kg to about 25 mg/kg per day; more preferably about 0.5 mg/kg to about 10 mg kg per day. [000157] In larger mammals, for example humans, a typical indicated dose is about 0.5 mg to 7 grams orally per day. A compound may be administered on a regimen of several times per day, for example 1 to 4 times per day, preferably once or twice per day. [000158] The amount of the Cox-2 inhibitor that may be combined with carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain from 0.5 mg to 7 g of active agent compounded optionally with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms for the Cox-2 inhibitor will generally contain between from about 1 mg to about 500 mg of an active ingredient.

[000159] The dosage level of a phosphodiesterase 4 inhibitor will necessarily depend on the particular phosphodiesterase 4 inhibitor that is used. However, in general, the appropriate dosage level of a phosphodiesterase 4 inhibitor will generally be from about 0.0001 mg per kg to about 200 mg per kg subject body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.001 mg per kg to about 100 mg per kg per day; more preferably about 0.01 mg per kg to about 50 mg per kg per day; even more preferably about 0.1 mg per kg to about 10 mg per kg subject body weight. [000160] A combination therapy comprising a phosphodiesterase 4 inhibitor that is intended for oral administration to humans may contain from about 10 micrograms to about 10 grams of active agent optionally compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95 percent of the total composition. More preferably, the phosphodiesterase 4 inhibitor is dosed at between about 0.1 mg and about 1 gram. Even more preferably, the phosphodiesterase 4 inhibitor is dosed at between about 1 mg and about 750 mg. More preferably still, the phosphodiesterase 4 inhibitor is dosed at between about 100 mg and about 500 mg. [000161] The exact dosage and regimen for administering a Cox-2 inhibitor in combination with a phosphodiesterase 4 inhibitor will necessarily depend upon the potency and duration of action of the compounds used, the nature and severity of the illness to be treated, as well as the sex, age, weight, general health, and individual responsiveness of the patient to be treated, and other relevant circumstances. Those skilled in the art will appreciate that dosages may also be determined with guidance from Goodman & Goldman's The Pharmacological Basis of Therapeutics. Ninth Edition (1996), Appendix II, pp. 1707-1711. [000162] The effectiveness of a particular dosage of a Cox-2 inhibitor in combination with a phosphodiesterase 4 inhibitor is determined by monitoring the effect of a given dosage on the progress or prevention of a particular symptom of the respiratory disorder. [000163] Because early COPD may produce no visible symptoms or signs, laboratory tests can be used to diagnose and/or follow the presence or degree of airflow obstruction. For example, the degree and severity of asthma and COPD can be determined by measuring lung expiratory flow volume and expiratory flow rates. Such a measurement can be accomplished with, for example, a spirometer, flow volume loop, or pneumotach, before and after each of the treatments. The use of spirometry can be a standard test for determining the efficacy of a combination of Cox-2 inhibitors and phosphodiesterase 4 inhibitors after administration to a subject suffering from a pulmonary inflammatory disorder.

[000164] Spirometry is a medical test that measures the physical volume of air an individual forcibly inhales or exhales into a device. The objective of spirometry is to assess ventilatory function. A device called a spirometer is used to measure how much air the lungs can hold and how well the respiratory system is able to move air into and out of the lungs. An estimate of flow rate, or the rate at which the volume is changing as a function of time can also be calculated with spirometery. See College of Physicians and Surgeons of Alberta, "Guidelines For Spirometry & Flow Volume Measurements"^ 998) .

<www.cpsa.ab.ca/qoc/Guidelines%20for%20Spirometry%20&%20Flow%2

0Volume%20Measurements.doc>.

[000165] Common parameters that spirometry measures include Forced

Vital Capacity (FVC) and Forced Expiratory Volume (FEV). FVC is the maximum volume of air, measured in liters, that can be forcibly and rapidly exhaled. FEV 1 is the volume of air expelled in the first second of a forced expiration. Normal parameters for a subject not suffering from an inflammatory disorder such as asthma or COPD are: Tidal volume - 5 to 7 milliliters per kilogram of body weight; Expiratory reserve volume - 25% of vital capacity; Inspiratory capacity - 75% of vital capacity forced expiratory volume - 75% of vital capacity after 1 second, 94% after 2 seconds, and 97% after 3 seconds. Healthatoz.com, wellness, test & procedures, spirometry <http://www.healthatoz.com /atoz/TestProcedures/TPspirometry.html>. [000166] Spirometry results are expressed as a percentage, and are considered abnormal if less than 80% of the normal predicted value. An abnormal result usually indicates the presence of some degree of obstructive lung disease such as COPD and chronic bronchitis, or restrictive lung disease such as pulmonary fibrosis or asthma. For example, an abnormally low FEV 1/FVC means that a subject's airflow is obstructed. If someone has COPD, a low FEV 1 not only reveals that the person has obstructive lung disease, but measures how severe the obstruction is.

[000167] Thus, with the methods and compositions of the present invention, spirometric comparisons of pulmonary airflow in a subject suffering from a respiratory disorder before and after treatment will elucidate similarities and differences that enable one of skill to determine the effectiveness of the treatment methods.

[000168] The combination of a Cox-2 inhibitor and a phosphodiesterase 4 inhibitor can be supplied in the form of a novel therapeutic composition that is believed to be within the scope of the present invention. [000169] The combination of a Cox-2 inhibitor and a phosphodiesterase

4 inhibitor can be provided in a pharmaceutically acceptable carrier or excipient to form a pharmaceutical composition. Examples of pharmaceutically acceptable carriers or excipients include, but are not limited to, physiological saline, Ringer's solution, phosphate solution or buffer, buffered saline and other carriers known in the art. Pharmaceutical compositions may also include stabilizers, anti-oxidants, colorants, and diluents. Pharmaceutically acceptable carriers and additives are chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not negated or inhibited to such an extent that treatment is ineffective. In one embodiment, the Cox-2 inhibitor and the phosphodiesterase 4 inhibitor are administered to a subject together in one pharmaceutical carrier. In another embodiment, they are administered separately. [000170] The pharmaceutical compositions may be administered enterally, parenterally, or topically, such as by inhalation. Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous, and other administrative methods known in the art. Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules, and syrups. When administered, the pharmaceutical composition may be at or near body temperature. [000171] The combination of a Cox-2 inhibitor and a phosphodiesterase 4 inhibitor, and compositions comprising the same, can also be administered parenterally, either subcutaneously, or intravenously, or intramuscularly, or intrasternally, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions. [000172] Aqueous suspensions can be produced that contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting agents may be naturally- occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. [000173] The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin. [000174] Oily suspensions may be formulated by suspending the active ingredients in an omega-3 fatty acid, a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. [000175] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, n-3 polyunsaturated fatty acids may find use in the preparation of injectables. [000176] The therapeutic composition containing the Cox-2 inhibitor and the phosphodiesterase 4 inhibitor can be administered by direct inhalation into the respiratory system for delivery as a mist or other aerosol or dry powder. Delivery of drugs or other active ingredients directly to the subject's lungs provides numerous advantages including, providing an extensive surface area for drug absorption, direct delivery of therapeutic agents to the disease site in the case of regional drug therapy, eliminating the possibility of drug degradation in the patient's intestinal tract (a risk associated with oral administration), and eliminating the need for repeated subcutaneous injections. Furthermore, delivery of drugs to the pulmonary system by means of aerosol inhalation may be used for targeted local administration for the treatment of respiratory ailments. Aerosols of liquid particles comprising the active materials may be produced by any suitable means, such as inhalatory delivery systems. Nebulizers are commercially available devices which transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of compressed gas, typically air or oxygen, through a narrow venturi orifice or by means of ultrasonic agitation. Suitable formulations for use in nebulizers consist of the active ingredient in a liquid carrier. The carrier is typically water, and most preferably sterile, pyrogen-free water, or a dilute aqueous alcoholic solution, preferably made isotonic, but may be hypertonic with body fluids by the addition of, for example, sodium chloride. Optional additives include preservatives if the formulation is not made sterile, for example, methyl hydroxybenzoate, as well as antioxidants, flavoring agents, volatile oils, buffering agents and surfactants, which are normally used in the preparation of pharmaceutical compositions. [000177] Aerosols of solid particles comprising the active materials may likewise be produced with any solid particulate medicament aerosol generator. Aerosol generators for administering solid particulate medicaments to a subject produce particles which are respirable, as explained above, and generate a volume of aerosol containing a predetermined metered dose of a medicament at a rate suitable for human administration. One type of solid particulate aerosol generator is an insufflator. Suitable formulations for administration by insufflation include finely comminuted powders which may be delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff. In the insufflator, the powder is contained in capsules or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by means of air drawn through the device upon inhalation or by means of a manually-operated pump. The powder employed in the insufflator consists either solely of the active ingredient or of a powder blend comprising the active materials, a suitable powder diluent, such as lactose, arid an optional surfactant. [000178] A second type of aerosol generator is a metered dose inhaler. Metered dose inhalers are pressurized aerosol dispensers, typically containing a suspension or solution formulation of the Cox-2 inhibitor and the phosphodiesterase 4 inhibitor in a liquified propellant. During use, the metered dose inhaler discharges the formulation through a valve, adapted to deliver a metered volume, to produce a fine particle spray containing the active materials. Any propellant may be used for aerosol delivery, including both chlorofluorocarbon-containing propellants and non- chlorofluorocarbon-containing propellants.

[000179] Another type of aerosol generator is an electrohydrodynamic (EHD) aerosol generating device, which has the advantage of being adjustable to create substantially monomodal aerosols having particles more uniform in size than aerosols generated by other devices or methods. Typical EHD devices include a spray nozzle in fluid communication with a source of liquid to be aerosolized, at least one discharge electrode, a first voltage source for maintaining the spray nozzle at a negative (or positive) potential relative to the potential of the discharge electrode, and a second voltage source for maintaining the discharge electrode at a positive (or negative) potential relative to the potential of the spray nozzle. Most EHD devices create aerosols by causing a liquid to form droplets that enter a region of high electric field strength. The electric field then imparts a net electric charge to these droplets, and this net electric charge tends to remain on the surface of the droplet. The repelling force of the charge on the surface of the droplet balances against the surface tension of the liquid in the droplet, thereby causing the droplet to form a cone-like structure known as a Taylor Cone. In the tip of this conelike structure, the electric force exerted on the surface of the droplet overcomes the surface tension of the liquid, thereby generating a stream of liquid that disperses into a many smaller droplets of roughly the same size. These smaller droplets form a mist which constitutes the aerosol cloud that the user ultimately inhales.

[000180] Oral (intra-gastric) is another preferred route of administration for the combination therapy. Pharmaceutically acceptable carriers can be in solid dosage forms for the methods of the present invention, which include tablets, capsules, pills, and granules, which can be prepared with coatings and shells, such as enteric coatings and others well known in the art. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example, maize starch, or alginic acid, binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. [000181] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. [000182] Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. [000183] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[000184] Syrups and elixirs containing the Cox-2 inhibitor alone or in combination with the phosphodiesterase 4 inhibitor may be formulated with sweetening agents, for example glycerol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

[000185] Also encompassed by the present invention is buccal or "sub- lingual" administration, which includes lozenges or a chewable gum ςomprising the compounds, set forth herein. The compounds can be deposited in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compounds in an inert base such as gelatin and glycerin or sucrose and acacia. [000186] Other methods for administration of the Cox-2 inhibitor compound and the phosphodiesterase 4 inhibitor include dermal patches that release the medicaments directly into a subject's skin. [000187] Topical delivery systems are also encompassed by the present invention and include ointments, powders, sprays, creams, jellies, collyriums, solutions or suspensions.

[000188] The solubility of the components of the present compositions may be enhanced by a surfactant or other appropriate co-solvent in the composition. Such co-solvents include polysorbate 20, 60, and 80, polyoxyethylene/polyoxypropylene surfactants (e.g. Pluronic F-68, F-84 and P-103), cyclodextrin, or other agents known to those skilled in the art.

Typically, such co-solvents are employed at a level of from 0.01% to 2% by weight.

[000 89] A penetration enhancer is an agent used to increase the permeability of the skin to an active agent to increase the rate at which the drug diffuses through the skin and enters the tissues and bloodstream.

Thus, in one embodiment of the present invention, a penetration enhancer may be added to a Cox-2 inhibitor and phosphodiesterase 4 inhibitor topical composition. [000190] Examples of penetration enhancers suitable for use with the compositions of the present invention include: alcohols, such as ethanol and isopropanol; polyols, such as n-alkanols, limonene, terpenes, dioxolane, propylene glycol, ethylene glycol, other glycols, and glycerol; sulfoxides, such as dimethylsu If oxide (DMSO), dimethylformamide, methyl dodecyl sulfoxide, dimethylacetamide; esters, such as isopropyl myristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate, and capric/caprylic triglycerides; ketones; amides, such as acetamides; oleates, such as triolein; various surfactants, such as sodium lauryl sulfate; various alkanoic acids, such as caprylic acid; lactam compounds, such as azone; alkanols, such as oleyl alcohol; dialkylamino acetates, and admixtures thereof. [000191] The above considerations concerning effective formulations and administration procedures are well known in the art and are described in standard textbooks. See e.g. Gennaro, A. R., Remington: The Science and Practice of Pharmacy, 20^th Edition, (Lippincott, Williams and Wilkins), 2000; Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3^rd Ed.), American Pharmaceutical Association, Washington, 1999. [000192] The present invention further comprises kits that are suitable for use in performing the methods of treatment described above. In one embodiment, the kit contains a first dosage form comprising a Cox-2 inhibitor in one or more of the forms identified above and a second dosage form comprising a phosphodiesterase 4 inhibitor, in amounts which comprise a therapeutically effective combination for the prevention or treatment of respiratory inflammation. Preferably, the first dosage form and the second dosage form together comprise a therapeutically effective amount of the compounds for the prevention or treatment of respiratory disorders.

[000193] The following examples describe embodiments of the invention. Other embodiments within the scope of the claims herein will be apparent to one skilled in the art from consideration of the specification or practice of the invention as disclosed herein. It is intended that the specification, together with the examples, be considered to be exemplary only, with the scope and spirit of the invention being indicated by the claims which follow the examples. EXAMPLE 1 [000194] This example demonstrates the preparation of celecoxib. [000195] Step 1 : Preparation of 1-(4-methylphenyl)-4,4,4-trifluorobutane-

1 ,3-dione.

[000196] Following the disclosure provided in U.S. Patent No. 5,760,068,

4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25%) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated.

100 mL 10% HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS0₄, filtered and concentrated to afford 8.47 g (94%) of a brown oil which was carried on without further purification.

[000197] Step 2: Preparation of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-

1 H-pyrazol-1 -yljbenzenesulfonamide.

[000198] To the dione from Step 1 (4.14 g, 18.0 mmol) in 75 mL absolute ethanol, 4.26 g (19.0 mmol) 4-sulphonamidophenylhydrazine hydrochloride was added. The reaction was refluxed under argon for 24 hours. After cooling to room temperature and filtering, the reaction mixture was concentrated to afford 6.13 g of an orange solid. The solid was recrystallized from methylene chloride/hexane to give 3.11 g (8.2 mmol, 46%) of the product as a pale yellow solid, having a melting point (mp) of

157°-159°C; and a calculated composition of Cι₇ H_H N₃ 0₂ SF₃ ; C, 53.54;

H, 3.70; N, 11.02. The composition that was found by analysis was: C,

53.17; H, 3.81 ; N, 10.90. EXAMPLE 2 [000199] This example demonstrates the preparation of 3-cyclo- propylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide

(roflumilast). [000200] Following the disclosure provided in U.S. Patent No. 5,712,298, 6.0 g of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid are heated at reflux in 40 ml of toluene with 19.6 g of thionyl chloride until the evolution of gas is complete. The solution is evaporated to dryness under vacuum and the residue is dissolved in about 60 ml of dry tetrahydrofuran.

This solution is added dropwise at 15°-20° C. to a suspension prepared from 4.9 g of 4-amino-3,5-dichloropyridine and 2.0 g of sodium hydride (80% strength in mineral oil) in 60 ml of dry tetrahydrofuran, with stirring and cooling. After stirring for one hour, the reaction mixture is acidified to a pH of 2.0 with 1 N hydrochloric acid. The toluene/tetrahydrofuran phase is separated off and the aqueous phase is extracted two additional times with ethyl acetate. The combined organic phases are washed with saturated sodium hydrogen carbonate solution and water, dried over sodium sulphate, and evaporated under vacuum. The residue is crystallized from isopropanol. The yield is 5.8 g (58.6% of theory) of the 3- cyclo-propylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]- benzamide compound having a melting point of 158°C. EXAMPLE 3 [000201] This example illustrates the production of a composition containing celecoxib and the PDE 4 inhibitor roflumilast, and of a pharmaceutical composition containing the combination. [000202] Celecoxib can be prepared as described in Example 1 or, alternatively, can be obtained under the trade name CELEBREX® from Pharmacia Corporation, Peapack, NJ. [000203] Roflumilast (3-cyclo-propylmethoxy-4-difluoromethoxy-N-[3,5- di-chloropyrid-4-yl]-benzamide) can be prepared as described in Example 2.

[000204] A therapeutic composition of the present invention can be produced by intermixing finely powdered roflumilast (5 mg, as prepared in Example 2) and celecoxib (25 mg, as produced in Example 1 , or as available from Pharmacia Corporation, Peapack, NJ, under the tradename CELEBREX®), in a laboratory mill or mixing device suitable for mixing of powders without generating shear force or temperature sufficient to degrade either of the two compounds.

[000205] After mixing, the combination of roflumilast and celecoxib can be dispersed in a suitable carrier such as water or ethanol, and combined with a pharmaceutically acceptable chlorofluorocarbon propellant. This composition is sufficient for the production of 250 inhaled aerolsolized human single dose units, each dose containing 20 μg of roflumilast and 100 μg of celecoxib. The doses can be administered, for example, using a metered dose inhaler. [000206] All references cited in this specification, including without limitation all papers, publications, patents, patent applications, presentations^ texts, reports, manuscripts, brochures, books, internet postings, journal articles, periodicals, and the like, are hereby incorporated by reference into this specification in their entireties. The discussion of the references herein is intended merely to summarize the assertions made by their authors and no admission is made that any reference constitutes prior art. Applicants reserve the right to challenge the accuracy and pertinency of the cited references. [000207] In view of the above, it will be seen that the several advantages of the invention are achieved and other advantageous results obtained.

[000208] As various changes could be made in the above methods and compositions without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

Claims

WHAT IS CLAIMED IS: 1. A method for the treatment and prevention of respiratory inflammation in a subject in need of such prevention or treatment, the method comprising administering to the subject a Cox-2 inhibitor and a phosphodiesterase 4 inhibitor.

2. The method according to claim 1 , wherein the Cox-2 inhibitor comprises a non-steroidal anti-inflammatory drug.

3. The method according to claim 2, wherein the Cox-2 inhibitor comprises at least one compound that is selected from the group consisting of acemetacin, acetyl salicylic acid, alclofenac, alminoprofen, azapropazone, benorylate, benoxaprofen, bucloxic acid, carprofen, choline magnesium trisalicylate, clidanac, clopinac, dapsone, diclofenac, diflunisal, droxicam, etodolac, fenoprofen, fenbufen, fenclofenec, fentiazac, floctafenine, flufenisal, flurbiprofen, (r)-flurbiprofen, (s)-flurbiprofen, furofenac, feprazone, flufenamic acid, fluprofen, ibufenac, ibuprofen, indometacin, indomethacin, indoprofen, isoxepac, isoxicam, ketoprofen, ketorolac, miroprofen, piroxicam, meloxicam, mefenamic, mefenamic acid, meclofenamic acid, meclofen, nabumetone, naproxen, niflumic acid, oxaprozin, oxipinac, oxyphenbutazone, phenylbutazone, podophyliotoxin derivatives, proglumetacin, piprofen, pirprofen, prapoprofen, salicylic acid, salicylate, sudoxicam, suprofen, sulindac, tenoxicam, tiaprofenic acid, tiopinac, tioxaprofen, tolfenamic acid, tolmetin, zidometacin, zomepirac, 2- ι fluoro-a-methyl[1 ,1'-biphenyl]-4-acetic acid, 4-(nitrooxy)butyl ester, and mixtures thereof.

4. The method according to claim 1 , wherein the Cox-2 inhibitor comprises a Cox-2 selective inhibitor.

5. The method according to claim 4, wherein the Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, RS 57067, T-614, BMS- 347070, JTE-522, S-2474, SVT-2016, CT-3, ABT-963, SC-58125, nimesulide, flosulide, NS-398, L-745337, RWJ-63556, L-784512, darbufelone, CS-502, LAS-34475, LAS-34555, S-33516, SD-8381 , MK- 966, L-783003, T-614, D-1376, L-748731 , CGP-28238, BF-389, GR- 253035, prodrugs of any of them, and mixtures thereof.

6. The method according to claim 4, wherein the Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, prodrugs of any of them, and mixtures thereof.

7. The method according to claim 4, wherein the Cox-2 selective inhibitor comprises celecoxib.

8. The method according to claim 4, wherein the Cox-2 selective inhibitor comprises a chromene Cox-2 selective inhibitor.

9. The method according to claim 8, wherein the chromene Cox-2 selective inhibitor comprises at least one compound selected from the group consisting of

6-chloro-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid,

6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-(1 -methylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,

6-chloro-7-(1 ,1 -dimethylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid,

6-chloro-8-(1-methylethyl)-2-trifluoromethyI-2H-1-benzopyran-3-carboxylic acid,

2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid,

7-(1 , 1 -dimethylethyl)-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid,

6-bromo-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid,

8-chloro-2-trifIuoromethyl-2H-1 -benzopyran-3-carboxylic acid,

6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-phenyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,

7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 7-(1 -methylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,

7-phenyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,

6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxyiic acid,

6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxyfic acid,

6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

2-trifluoromethyl-3H-naptho[2,1 -b]pyran-3-carboxylic acid,

6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-bromo-8-chloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxyl ic acid,

8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-bromo-5-fIuoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzop/ran-3- carboxylic acid,

6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,

6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-[(1 ,1 -dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid,

6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,

6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid, 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-[[N-(2-furylmethyl)aminojsulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,

6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,

6-iodo-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,

7-(1 ,1 -dimethylethyl)-2-pentafluoroethyl-2H-1 -benzopyran-3-carboxylic acid,

6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid.

6-chloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,

(S)-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-chloro-7-(1 ,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,

(S)-6-chloro-7-(1 ,1 -dimethylethyl)-2-(trifluoromethyl)-2H-1 -benzopyran-3- carboxylic acid,

6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

(S)-6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

6-chloro-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,

(S)-6-chloro-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,

6,8-dichloro-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,

7-(1 ,1 -dimethylethyl)-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid, 6,7-dichloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,

5,6-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

2,6-bis(trif luoromethyl)-2H-1 -benzopyran-3-carboxylic acid,

5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

6-iodo-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,

6-bromo-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,

6-chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid,

6,8-dichloro-2-trif luoromethyl-2H-1 -benzothiopyran-3-carboxylic acid, and mixtures thereof.

10. The method according to claim 8, wherein the chromene Cox-2 selective inhibitor comprises at least one compound selected from the group consisting of

(S)-6-chloro-7-(1 ,1 -dimethylethyl)-2-(trifIuorornethyl)-2H-1 -benzopyran-3- carboxylic acid,

(2S)-6,8-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (2S)-6-chloro-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (2S)-8-ethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3- carboxylic acid,

(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, (2S)-6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and mixtures thereof.

11. The method according to claim 1 , wherein the phosphodiesterase 4 inhibitor comprises at least one compound that is selected from the group consisting of amides, irnides, substituted 1 ,3,4- oxadiazoles, cyano derivatives of substituted styrenes, carboxy derivatives of substituted styrenes, substituted phenethylsulfones, nitriles, succinimide cytokine inhibitors, maleimide cytokine inhibitors, nicotinamide benzof used-heterocyclyl derivatives, ether derivatives, roflumilast, cilomilast, etazolate hydrochloride, Ro 20-1724, rolipram, ( ?)-(-)-rolipram, (S)-(+)-rolipram, zardaverine, V11294A, CDP84O, denbufylline, mesopram, cipamfylline, SCH 351591 , SCH 365351, L-791 , 943, 7-benzylamino-6- chloro-2-piperazino-pteridine, piclamilast, NVP-ABE171 , 4-(8- benzo[1 ,2,5]oxadiazol-5-yl-[1 ,7]napthyridine-6-yl)-benzoic acid, YM976, KF19514, arofylline, XT-44, T-440, atizoram, tibenelast, piclamilast, D- 4418, C1 1018, D-22888, and mixtures thereof.

12. The method according to claim 1 , wherein the phosphodiesterase 4 inhibitor comprises at least one compound that is selected from the group consisting of amides, imides, substituted 1 ,3,4- oxadiazoles, cyano derivatives of substituted styrenes, carboxy derivatives of substituted styrenes, substituted phenethylsulfones, nitriles, succinimide cytokine inhibitors, maleimide cytokine inhibitors, nicotinamide benzofused-heterocyclyl derivatives, ether derivatives, and mixtures thereof.

13. The method according to claim 1 , wherein the phosphodiesterase 4 inhibitor comprises at least one compound that is selected from the group consisting of roflumilast, cilomilast, etazolate hydrochloride, Ro 20-1724, rolipram, (/?)-(-)-rolipram, (S)-(+)-rolipram, zardaverine, V11294A, CDP840, denbufylline, mesopram, cipamfylline, SCH 351591 , SCH 365351 , L-791 ,943, 7-benzylamino-6-chloro-2- piperazino-pteridine, piclamilast, NVP-ABE171 , 4-(8- benzop ,2,5]oxadiazol-5-yl-[1 ,7]napthyridine-6-yl)-benzoic acid, YM976, KF19514, arofylline, XT-44, T-440, atizoram, tibenelast, piclamilast, D- 4418, C1 1018, D-22888, and mixtures thereof.

14. The method according to claim 1 , wherein the phosphodiesterase 4 inhibitor comprises roflumilast.

15. The method according to claim 1 , wherein the respiratory inflammation is associated with a disease or disorder selected from the group consisting of asthma, chronic obstructive airway disorder, pneumonia, respiratory syncytial viral infection, bronchitis, bronchiolitis, idiopathic pulmonary fibrosis, cystic fibrosis, acute respiratory distress syndrome, bronchopulmonary dysplasia, occupational respiratory disease, particulate exposure, pleurisy, amphysema, and pulmonary edema.

16. A therapeutic composition comprising at least one Cox-2 inhibitor and at least one phosphodiesterase 4 inhibitor.

17. The therapeutic composition according to claim 16, wherein a single dosage includes an amount of a Cox-2 inhibitor and an amount of a phosphodiesterase 4 inhibitor which together comprise a therapeutic amount.

18. The therapeutic composition according to claim 16, wherein the Cox-2 inhibitor comprises a non-steroidal anti-inflammatory drug.

19. The therapeutic composition according to claim 16, wherein the Cox-2 inhibitor comprises at least one compound that is selected from the group consisting of acemetacin, acetyl salicylic acid, alclofenac, alminoprofen, azapropazone, benorylate, benoxaprofen, bucloxic acid, carprofen, choline magnesium trisalicylate, clidanac, clopinac, dapsone, diclofenac, diflunisal, droxicam, etodolac, fenoprofen, fenbufen, fenclofenec, fentiazac, f loctafenine, flufenisal, flurbiprofen, (r)-flurbiprofen, (s)-flurbiprofen, furofenac, feprazone, flufenamic acid, fluprofen, ibufenac, ibuprofen, indometacin, indomethacin, indoprofen, isoxepac, isoxicam, ketoprofen, ketorolac, miroprofen, piroxicam, meloxicam, mefenamic, mefenamic acid, meclofeηamic acid, meclofen, nabumetone, naproxen, niflumic acid, oxaprozin, oxipinac, oxyphenbutazone, phenylbutazone, podophyllotoxin derivatives, proglumetacin, piprofen, pirprofen, prapoprofen, salicylic acid, salicylate, sudoxicam, suprofen, sulindac, tenoxicam, tiaprofenic acid, tiopinac, tioxaprofen, tolfenamic acid, tolmetin, zidometacin, zomepirac, 2-fluoro-a-methyl[1 ,1'-biphenyl]-4-acetic acid, 4- (nitrooxy)butyl ester, and mixtures thereof.

20. The therapeutic composition according to claim 16, wherein the Cox-2 inhibitor comprises a Cox-2 selective inhibitor.

21. The therapeutic composition according to claim 20, wherein the Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, RS 57067, T- 614, BMS-347070, JTE-522, S-2474, SVT-2016, CT-3, ABT-963, SC- 58125, nimesulide, flosulide, NS-398, L-745337, RWJ-63556, L-784512, darbufelone, CS-502, LAS-34475, LAS-34555, S-33516, SD-8381, MK- 966, L-783O03, T-614, D-1376, L-748731 , CGP-28238, BF-389, GR- 253035, prodrugs of any of them, and mixtures thereof.

22. The therapeutic composition according to claim 20, wherein the Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, prodrugs of any of them, and mixtures thereof.

23. The therapeutic composition according to claim 20, wherein the Cox-2 selective inhibitor comprises celecoxib.

24. The therapeutic composition according to claim 20, wherein the Cox-2 selective inhibitor comprises a chromene Cox-2 selective inhibitor.

25. The therapeutic composition according to claim 24, wherein the chromene Cox-2 selective inhibitor comprises at least one compound selected from the group consisting of

6-chloro-2-trif !uoromethyl-2H-1 -benzopyran-3-carboxylic acid,

6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-(1 -methylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,

6-chloro-7-(1 , 1 -dimethylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid,

6-chloro-8-(1 -methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid,

7-(1 ,1 -dimethylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,

6-bromo-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid,

8-chloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,

6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-phenyl-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid,

7,8-dimethyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid, 6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

7-(1 -methylethyl)-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid, 7-phenyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid, 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

2-trifluoromethyl-3H-naptho[2,1 -b]pyran-3-carboxylic acid, 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,

6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxyIic acid,

6-[(1 ,1-dimethylethyl)aminosulfony!]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,

6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid,

6-phenylacetyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,

6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,

6-iodo-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid,

7-(1 ,1 -dimethylethyl)-2-pentafluoroethyl-2H-1 -benzopyran-3-carboxylic acid,

6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid.

6-chloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,

(S)-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

(S)-6-chloro-7-(1 ,1 -dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3- carboxylic acid,

6-trifluoromethoxy-2-trifluoromethyI-2H-1-benzopyran-3-carboxylic acid,

(S)-6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-formyl-2-(trifluoromethyi)-2H-1-benzopyran-3-carboxylic acid,

6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,

(S)-6-chloro-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid, 6,8-dichloro-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,

7-(1 , 1 -dimethylethyl)-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid,

6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

5,6-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

2,6-bis(trifluoromethyl)-2H-1 -benzopyran-3-carboxylic acid,

5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

6-iodo-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,

6-bromo-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,

6-chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid,

26. The therapeutic composition according to claim 24, wherein the chromene Cox-2 selective inhibitor comprises at least one compound selected from the group consisting of

27. The therapeutic composition according to claim 16, wherein the phosphodiesterase 4 inhibitor comprises at least one compound that is selected from the group consisting of amides, imides, substituted 1 ,3,4- oxadiazoles, cyano derivatives of substituted styrenes, carboxy derivatives of substituted styrenes, substituted phenethylsulfones, nitriles, succinimide cytokine inhibitors, maleimide cytokine inhibitors, nicotinamide benzofused-heterocyclyl derivatives, ether derivatives, and mixtures thereof.

28. The therapeutic composition according to claim 16, wherein the phosphodiesterase 4 inhibitor comprises at least one compound that is selected from the group consisting of roflumilast, cilomilast, etazolate hydrochloride, Ro 20-1724, rolipram, (fl)-(-)-rolipram, (S)-(+)-rolipram, zardaverine, V11294A, CDP840, denbufylline, mesopram, cipamfylline,

^* SCH 351591 , SCH 365351 , L-791 ,943, 7-benzylamino-6-chloro-2- piperazino-pteridine, piclamilast, NVP-ABE171, 4-(8- benzo[1 ,2,5]oxadiazol-5-yl-[1 ,7]napthyridine-6-yl)-benzoic acid, YM976, KF19514, arofylline, XT-44, T-440, atizoram, tibenelast, piclamilast, D- 4418, CI 1018, D-22888, and combinations thereof.

29. The therapeutic composition according to claim 16, wherein the phosphodiesterase 4 inhibitor comprises roflumilast.

30. A pharmaceutical composition comprising a Cox-2 inhibitor, a phosphodiesterase 4 inhibitor, and a pharmaceutically-acceptable excipient.

31. A kit that is suitable for the prevention or treatment of respiratory inflammation, the kit comprising a first dosage form comprising a Cox-2 inhibitor and a second dosage comprising a phosphodiesterase 4 inhibitor, in amounts which comprise a therapeutically effective combination of the compounds for the prevention or treatment of the respiratory inflammation.