CA2542277A1

CA2542277A1 - Method for the treatment or prevention of respiratory inflammation with a cyclooxygenase-2 inhibitor in combination with a phosphodiesterase 4 inhibitor and compositions therewith

Info

Publication number: CA2542277A1
Application number: CA002542277A
Authority: CA
Inventors: Walter G. Smith
Original assignee: Individual
Current assignee: Pharmacia LLC
Priority date: 2003-10-21
Filing date: 2004-10-21
Publication date: 2005-05-12
Also published as: WO2005041864A3; BRPI0415753A; JP2007509154A; MXPA06004499A; WO2005041864A2; EP1691797A2

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

INHIBITOR AND COMPOSITIONS THEREWITH
BACKGROUND OF THE INVENTION
(1) Field of the Invention [OOOi ] 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~h 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°I°, from 13.4 to 18.8 per million. See The Merck Manual of Diagnosis &
Therapy, Beers & Brakow, 17~" edition, Published by Merck Research Labs, Sec. 6, Chapter 68, Chronic Obstructive Ainway 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. /d Many factors contribute to tha 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 tong-term cigarette smoking andlor 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 r nflammatory 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 the 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.
[000?] 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., et al., Pharm. Exper, Therap., 297:280-290 (2001 ). 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.

[0008j 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., 157351-370 (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 59:193-212 (2000); Bundschuh, D. , et al., (2001 ), sc~pra.
(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, X9:14-22 (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. Barrette, M., Progress in Drug Research (tucker, E., ed.), voL 53, Birkhauser Verlag, Vasel, Switzerland (1999); Giembycz, M., Biochem_ 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., et al., (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., 365:284-289 (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, 46:512-523 (1991 ). Improved "second-generation"
PDE 4 inhibitors, such as cilomilast, firimiiast, and roflumilast, have been developed, and seem to maintain high anti-inflammatory activity while partially overcoming these side effects. See Barnette, M.S., et al., J.
Pharmacol. Exp. Ther., 284:420-426 (1998); Giembycz, M.A., Expert 4pin.
Invesfig. Drugs, 10:1361-1379 (2001); Sturton, G. and Fitzgerald, M., Chest, 121:192S-196S (2002); Bundschuh et aL, 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, cyclovxygenase-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).
j00014] 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 exarnpie, prostaglandin E2, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity, inflammation, and edema. See e.g. Samad, T.A. et al., Nafure 410:471-5 (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 fior use in therapies, especially in therapies that require maintenance administration.
(00016] Currently, the most prominent therapy for asthma, and far 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., 101:S427-33 (1998); Ducharme, F., BMJ, 324:1545-1552 (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, iit 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
(000181 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 inl-~ibitor 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-fiatal 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 administratiqn of such treatments encompasses both relatively short and relatively Tong 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.
[00037a 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.
[00033] Examples of NSAID compounds that are useful in the present invention include acemetacin, acety) salicylic acid, alclofenac, alminoprofen, azapropazone, benorylate, benoxaprofen, bucloxic acid, carprofen, choline magnesium trisaficyfate, 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, mefenam'ic, 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 ICSO value for inhibition of Cox-1, divided by the ICSO value for inhibition of Cox-2 (Cox-1 IC5~/Cox-2 IC5o). A Cox-2 selective inhibitor is any inhibitor for which the ratio of Cox-1 IC5o to Cox-2 ICSO 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.
[0004'1] As used herein, the term "ICSO" 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 IC5o of less than about 1 p.M, more preferred of less than about 0.5 p,M, and even more preferred of less than about 0.2 p.M.
[00042] Preferred Cox-2 selective inhibitors have a Cox-1 ICSO of greater than about 1 p.M, and more preferably of greater than 20 p.M.
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.
l H3 O

!~
CH3 Cl [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 "Ci-Cs", 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-1 y1, isobutenyl, penten-1 y1, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl, and the tike.
[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 (-CHz -) 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 polyhafoalkyl 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:
z \ z3 \z3 ,or I

z1 ~ , z~ ~~ z z where Z, Z', Z2, or Z3 is C, S, P, O, or N, with the proviso that one of Z, Z', 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, Z', 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 (-SO2-NH2).
[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=O) -. The term "afkylcarbonyl" 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=O) radical. Examples of such "alkoxycarbonyl" radicals include (CH3)3-C-O-C=O) - and - (O=)C- OCH3. The term "amino", whether used alone or with other terms, such as "aminocarbonyl", denotes -NH2.
[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 "alkylsulfinyf" 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 rertioval 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 chromenelchroman structural class, which encompasses substituted benzopyrans or substituted benzopyran analogs, as ~nrell as substituted benzothiopyrans, dihydroquinolines, or dihydronaphthalenes having the structure of any one of the general Formulas I, !l, fl t, 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 1:

;1 A
A2~
Ra wherein X' is selected from O, S, CRS Rb and NRa ;
wherein Ra is selected from hydrido, Ci -C3 -alkyl, (optionally substituted phenyl)-C1-C3 -alkyl, acyl and carboxy-C1 -C6 -alkyl;
i 0 wherein each of Rb and R° is independently selected from hydrido, Ci -C3 -alkyl, phenyl-Ci -Cs -alkyl, Ci -C3 -perfluoroalkyl, chloro, Ci -C6 -alkylthio, Ci -C6 -alkoxy, nitro, cyano and cyano-Ci -C3 -alkyl; or wherei n CRb R~ forms a 3-6 membered cycloalkyl ring;
wherein Ri is selected from carboxyl, aminocarbonyl, Ci -Cs -alkylsulfonylaminocarbonyl and Ci -C6 -alkoxycarbonyl;
wherein R2 is selected from hydrido, phenyl, thienyl, C1 -C6 -alkyl and C2 -C6 -alkenyl;
wherein R3 is selected from C1 -C3 -perfluoroalkyl, chloro, C1 -Cs -alkylthio, C1 -C6 -alkoxy, nitro, cyano and cyano-Ci -C3 -alkyl;
wherein R4 is one or more radicals independently selected from hydrido, halo, C1 -C6 -alkyl, C2 -Gs -alkenyl, C2 -C6 -alkynyl, halo-C2 -Cs -alkynyl, aryl-C1-Cs -alkyl, aryl-C2 -C6 -alkynyl, aryl-C2 -C6 -alkenyl, C1 -C6 -alkoxy, methylenedioxy, Ci -C6 -alkylthio, Ci -C6 -alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C1 -C6 -alkoxy-Ci -Cs -alkyl, aryl-C1 -G6 -alkyloxy, heteroaryl-C1 -Cs -alkyloxy, aryl-Ci -C6 -alkoxy-Ci -Cs -alkyl, Ci -C6 -haloalkyl, C1 -C6 -haloalkoxy, Ci -C6 -haloaikylthio, C1 -C6 -haloalkylsulfinyl, Ci -C6 -haloalkylsulfonyl, C1-Cs -(haloalkyl-1 -C3 -hydroxyalkyl, Ci -Cs -hydroxyalkyl, hydroxyimino-C1 -Cs -alkyl, C1 -C6 -alkylamino, arylamino, aryl-Ci -Cs -alkylamino, heteroaryfamino, heteroaryl-C1-Cs -alkylamino, nitro, cyano, amino, aminosulfonyl, C-, -C6 -alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-C1 -C6 -alkylaminosulfonyl, heteroaryl-Ci -Cs -alkylaminosulfonyl, heterocyclylsulfonyl, Ci -Cs -alkylsulfonyi, aryl-C1 -Cs -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-C1 -Cs -alkylcarbonyl, heteroaryl-Ci -Cs -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C1 -Ci -alkoxycarbonyl, formyl, C~ -Cs -haloalkylcarbonyl and Ci -Cs -alkylcarbonyl; and wherein the A ring atoms Ai, 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 11:
Rs Rg ~6 D 1l 7 ~ 2 D
~D4 x2 R7 wherein X2 is selected from O, S, CRS Rb and NRa ;
wherein Ra is selected from hydrido, C1 -C3 -alkyl, (optionally substituted phenyl)-Ci -C3 -alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-C1 -Cs -alkyl;

wherein each of Rb and R° is independently selected from hydrido, C1-C3 -alkyl, phenyl-C1 -C3 -alkyl, Ci -C3 -perfluoroalkyl, chloro, C1 -C6 -alkylthio, C1-Cs -alkoxy, nitro, cyano and cyano-Ci -C3 -alkyl;
or wherein CR° Rb form a cyclopropyf ring;
wherein R5 is selected from carboxyl, aminocarbonyl, Ci -C6 -alkylsulfonylaminocarbonyl and C~ -Cs -alkoxycarbonyl;
wherein R6 is selected from hydrido, phenyl, thienyl, C2 -C6 -alkynyl and C2 -C6 -alkenyl;
wherein R' is selected from Ci -C3 -perfluoroalkyl, chloro, C1 -C6 -alkylthio, Ci -Cs -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 -Cs -alkynyl, aryl-Ci -C3 -alkyl, aryl-C2 -C6 -alkynyl, aryl-C2 -C6 -alkenyl, C1-C6 -alkoxy, methylenedioxy, C~ -C6 -alkylthio, C1 -C6 -alkylsulfinyl, -O(CF2)2 O-, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, Ci -C6 -alkoxy-C~ -Cs -alkyl, aryl-C1 -C6 -alkyloxy, heteroaryl-Ci -C6 -alkyloxy, aryl-C1 -C6 -alkoxy-C1 -C6 -alkyl, C1 -C6 -haloalkyl, C~ -C6 -haloalkoxy, C~ -Cs -haloalkylthio, C1 -C6 -haloalkylsulfinyl, Ci -C6 -haloalkylsulfonyl, Ci -C3 -(haloalkyl-C1 -C3 -hydroxyalkyl), C1 -Cs -hydroxyalkyl, hydroxyimino-Ci -C6 -alkyl, C1 -C6 -alkylamino, arylamino, aryl-Ci -C6 -alkylamino, heteroarylamino, heteroaryl-Ci -C6 -alleylamino, nitro, cyano, amino, aminosulfonyl, C1 -Cs -alkylaminosulfonyl, arylaminosulfonyl, , heteroarylaminosuifonyl, aryl-C1 -C6 -afkylaminosulfonyl, heteroaryl-Ci -C6 -alkylaminosulfonyl, heterocyclylsulfonyl, Ci -C6 -alkylsulfonyl, aryl-Ci -C6 -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-C1 -C6 -alkylcarbonyl, heteroaryl-C1 -Cs -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C~ -C6 -alkoxycarbonyl, formyl, C1 -Cs -haloalkylcarbonyl and Ci -C6 -alkylcarbonyl; and wherein the D ring atoms D', D2, D3 and D~ are independently selected from carbon and nitrogen with the proviso that at least two of D', D2, D3 and D~ 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:
Rio wherein X3 is selected from the group consisting of O or S or NRa;
wherein Ra is alkyl;
wherein R9 is selected from the group consisting of H and aryl;
wherein Ri° is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminacarbonyl and alkoxycarbonyl;
wherein Rii 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, heteroaryfalkyfamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, 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 Gox-2 selective inhibitors in the present invention is described by Formulas 1V and V
below:

R15 G !V

wherein X4 is selected from Q or S or NRa ;
wherein Ra is alkyl;
wherein R13 is selected from carboxyl, aminocarbonyl, alkylsulfonyl,aminocarbonyl 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, arafkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, 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:

Ris Al , V
~5 R17 wherein:
X5 is selected from the group consisting of O or S or NRb;
Rb is alkyl;
R16 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyf;
R" is selected from the group consisting of haloalkyf, alkyl, aralkyl, cycloalkyf 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, vitro and alkyfsulfonyl; and Ri$ is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryfoxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, vitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein Ri$ 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;
R16 is 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 R'8 is one or more radicals selected fr~m the group of consisting of hydrido, halo, lawer alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyf, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, lower aikylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and Power alkylcarbonyl; or wherein R'8 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:
?C5 is selected from the group consisting of oxygen and sulfur;
R'6 is carboxyl;
R" is tower haloalkyl; and R'$ 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 heteroarylalkylaminosulfonyf, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R'$ 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:
7C5 is selected from the group consisting of oxygen and sulfur;
R'6 is selected from the group consisting of carboxyl, tower alkyl, lower aralkyl and lower alkoxycarbonyl;
R" is selected from the group consisting of fluoromethyl, chforomethyl, dichloromethyl, trichforomethyl, pentafluoroethyl, heptafluoropropyf, 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, tert-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-methylaminosulfonyl, 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;
R" is selected from the group consisting trifluoromethyl and pentafluoroethyl; and R1$ is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, t~ert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N-(2-furylmethyf)aminosulfonyl, N,N
dimethyfaminosulfonyl, N-methylaminosulfonyl, N-(2,2 dimethylethyl)aminosulfonyl, dimethylaminosulfonyl, 2-methylpropylaminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, and phenyl; or wherein Ri8 together with ring A forms a naphthyl radical;
or an isomer or prodrug thereof.

[00071 ] The Cox-2 selective inhibitar of the present invention can also be a compound having the structure of Formula VI:
R2t Vf R2' wherein:
X6 is selected from the group consisting of O and S;
R'9 is lower haloalkyl;
R2° is selected from the group consisting of hydrido, and halo;
R2' is selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkyfcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, and 6- membered nitrogen-containing heterocyclosulfonyl;
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 aikoxy, 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;
Ri9 is selected from the group consisting of trifluoromethyl and pentafluoroethyl;
R2° is selected from the group consisting of hydrido, chloro, and fluoro;

RZ' is selected from the group consisting of hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzyfcarbonyl, 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 Compound Structural Formula Number B_3 0 -OH

6-Nitro-2-trifluoromethyl-2N-1-benzopyran 3-carboxylic acid c1 OH

6-Chloro-8-methyl-2-trifluoromethyl-2H-1 benzopyran-3-carboxylic acid Comaound Structural Formula Number C1 ~ \ _ OH

((S)-6-Chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl-2H-1-benzopyran-3-carboxylic acid B_6 0 \ \ \ ~oH

2-Trifluoromethyi-2H-naphtho[2,3-b]pyran-3 carboxylic acid i OZN ~ ~ C1 ~ \ \
-OH
/ 0 / O~CF

6-Chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3 carboxylic acid Com op and ~ Structural Formula Number g_g o ~OH

( (S)-6,8-Dichloro-2-(trifluoromethyl)-2H-1-benzopyran 3-carboxylic acid B_9 l C~
~ox O- 'CF3 6-Chloro-2-(trifluoromethyl)-4-phenyl-2H-1-benzopyran 3-carboxylic acid ~ ~ ~ ~ off 6-(4-Hydroxybenzoyl)-2-(trifluoromethyl)-2H-1 benzopyran-3-carboxylic acid s F3C~ ~ ~ ~ OOH

2-(Trifluoromethyl)-6-[(trifluoromethyl)thin]-2H-1-benzothiopyran-3-carboxylic acid Compound Structural Formula Number B-12 °
c1 ~OH

6,8-Dichloro-2-trifluoromethyl-2H-1-benzothiopyran 3-carboxylic acid B-13 °
\ \ ~oH

6-(1,1-Dimethylethyl)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid B-14 °
F
~OH
F ~ H CF3 6,7-Difluoro-1,2-dihydro-2-(trifluoromethyl)-3 quinolinecarboxylic acid Compound Structural Formula Number B-15 °
c1 ~ ~ off N -CF

6-Chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3 quinoiinecarboxyfic acid B-16 °
c1 .\ \
~OH

6-Chloro-2-(trifluoromethyl)-1,2-dihydro[i ,8]naphthyridine 3-carboxylic acid B-17 °
c1 .\
~OH

((S)-6-Chloro-1,2-dihydro-2-(trifluoromethyl)-3 quinoiinecarboxylic acid Compound Structural Formula Mumber ~oH
O F
F
(2S)-6,8-dimethyl-2-(trifluoromethyl}-2H-chromene-3 carboxylic acid B-19 ~ o F3C,0 L ~ .~ OH
/ O~CF3 (2S)-8-ethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H
chromene-3-carboxylic acid O
B-20 a ( ~ ~ o / O~F
F
F
(2S)-6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3 carboxylic acid [00073] In preferred embodiments the chromene Cox-2 inhibitor is selected from (S)-6-chloro-7-(1,1-dimethylethyi)-2-(trifluoromethyl)-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-(triffuorornethyl)-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 VIl:

VII
I
25 ~ ~ 26 R R
wherein:
Z' is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings;
R24 is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R24 is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyf, haloalkoxy, amino, alkylamino, arylamino, vitro, alkoxyalkyl, alkyisulfinyl, halo, alkoxy and alkylthio;
R25 is selected from the group consisting of methyl or amino; and R26 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, alkoxyaralkoxyalkyf, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N- arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonyfaikyl, 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-arylaminosuifonyl;
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.
j00076] 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 98103484).

Table 2. Examples of Tricyclic COX-2 Selective Inhibitors Compound Structural Formula Number B-21 ° si° cH
H2N ~ ~ / ~ 3 / N
N~

Seo HaNi ~ ~ /
\N
HgC O
B-23 ° 0 F
H N~sj ~ / OCHg N
N ~\

Compound Structural Formula Number o s~o p/ "0 B-25 o Sjo cH
H3C/ ~ ~~ 3 N
cL' o s~o p~N
'~~C~/Hg [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.
F
F

[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;

R2~ O
OH
NH
VIII
wherein:
R2' is methyl, ethyl, or propyl;
R28 is chloro or fluoro;
R29 is hydrogen, fluoro, or methyl;
R3° 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, R3° and R3~ are not all fluoro when R2' is ethyl and R3° 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:
R2' is ethyl;
R2$ and R3° are chloro;
R29 and R3' 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:
R2' is propyl;
R28 and R3° are chloro;

R2s and R3' are methyl; and R32 is ethyl.
[00084] Another phenylacetic acid derivative Cox-2 selective inhibitor that is disclosed in WO 02120090 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:
R2' is methyl;
R28 is fluoro;
R32 is chloro; and Ras~ Rsot and R3' are hydrogen.
[00085] Compounds having a structure similar to that shown in formula VI11, 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:
R33 x7 IX
Rs~
wherein:
X' is 0; J is 1-phenyl; R33 is 2-NHS02CH3; R34 is 4-N02; and there is no R35 group, (nimesulide), or X' is O; J is 1-oxo-inden-5-yl; R33 is 2-F; R34 is 4-F; and R~5 is 6-NHS02CH3, (flosulide); or X' is O; J is cyclohexyl; R33 ~S 2-NHS02CH3; R34 is 5-N02; and there is no R35 group, (NS-398); or X' is S; J is 1-oxo-inden-5-yi; R33 is 2-F; R34 is 4-F; and R35 is 6-N-SOZCH3 Na+, (L-745337); or X' is S; J is thiophen-2-yl; R33 is 4-F; there is no R~~ group; and R35 is 5-NHS02CH3, (RWJ-63556); or X' is O; J is 2-oxo-5(R)-methyl-5-(2,2,2-trifluoroethyl)furan-(5H)-3-y1; 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 123653-1 i -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 I~es,, 90(4):400 -412 (1999).

[00088a 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 et al., in J Pharmacol Exp Ther 282, 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:
H~ /SO2CH3 N

X
L
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 Q', Q2, L' or L2 is an -S(O)" -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 Q' and Q2 or L' and L2 are a methylenedioxy group; and R36, R3', 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, futyl and pyridyl; or, R36, R3' or R3a, R39 are an oxygen atom; or R36, R3' or R3a, 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) methyl)benzenesulfonamide.
[00091 ) Other Cox-2 selective inhibitors that are useful in the present invention include darbufelone (Pfizer), CS-502 (Sankyo), LAS 34475 (Alrnirall 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:

R4o N
XI

R41 z2 wherein: -Z2 is an oxygen atom;
one of R4° and R41 is a group of the formula wherein:
R43 is lower alkyl, amino or lower alkylamino; and Rte, R45, Ras and R4' 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, RCS, R4s and R4' is not hydrogen atom, and the other is an optionally substituted cycloaikyl, an optionally substituted heterocyclic group or an optionally substituted aryl; and R3° is a lower alkyl or a halogenated Power 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:

Xff R5°

wherein:
Z3 is selected from the group consisting of linear or branched C1-C6 alkyl, linear or branched C~ -Cs alkoxy, unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl wherein the substituents are selected from the group consisting of hydrogen, halo, C~ -Cs alkoxy, CN, C, -C3 fluoroalkyl Ci -Cs alkyl, and -C02 H;
R48 is, selected from the group consisting of NH2 and CH3, R49 is selected from the group consisting of C1-C6 alkyl unsubstituted or substituted with C3 -C6 cycloafkyl, and C3 -C6 cycloalkyl;
R5° is selected from the group consisting of:
Cy -C° alkyl unsubstituted or substituted with one, two or three fluoro atoms, and C3 -C6 cycloalkyl;
with the proviso that R49 and R5° are not the same.
[000961 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 Gox-2 selective inhibitors of the present invention, have the general formula described by formula VIII:

R52 Xllil wherein:
R5' is selected from the group consisting of CH3, NH2, NHC(O)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, C1-Cs alkoxy, C1 -Cs alkylthio, CN, Ci -C6 alkyl, C1 -Cs fluoroalkyl, N3, -CO2R53, hydroxyl, -C(R54)(R5s)-OH, - C1 -Cs alkyl-1 O CO2-RSS, Ci -Cs fluoroalkoxy;
R52 is chosen from the group consisting of: halo, C~ -Cs alkoxy, C1 -Cs alkylthio, CN, Cy -Cs alkyl, Cy -Cs fluoroalkyl, N3, -C02R5', hydroxyl, -C(R5$)(R59)-OH, - C, -Cs alkyl-C02-Rs°, C~ -Cs fluoroalkoxy, NO2, NRslRs2, and NHCORs3;
R53, R54, R55, R5s, R5', RSS, R59, Rs°, R6', Rs2, and Rs3, are each independently chosen from the group consisting of hydrogen andCy -Cs alkyl;
or R54 and R55, R58 and R59, or Rs1 and Rs2 together with the atom to which they are attached fiorm 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 X1V:

Rss 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 C~ -C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a nitra group, a nitrite group, or a carboxyl group;
R66 is a group of a formula: S(O)~R6$ wherein n is an integer of 0~2, R68 is a hydrogen atom, a C1 -Cs lower alkyl group, or a group of a formula: NR6s R'° wherein R6s and R'°, identical to or different from each other, are independently a hydrogen atom, or a C1-C6 lower alkyl group; and R6' is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a C1 -C6 lower alkyl group, indanyl, pyrazinyl, or a substituted group represented by the following structures:
~.6 -., .72 7s R7s N N
R7s R7s wherein:
R" through R'S, identical to or different from one another, are independently a hydrogen atom, a halogen atom, a C1 -C6 lower alkyl group, a trifluoromethyf group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a group of a formula: S(Q)"R68, a group of a formula: NR69 R'°, a trifluoromethoxy group, a nitrite group a carboxyl group, an acetyl group, or a formyl group, wherein n, R68, R69 and R'° have the same meaning as defined by R6s above; and R'6 is a hydrogen atom, a halogen atom, a Cy -C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a trifluoromethoxy group, a carboxyl group, or an acetyi 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-pyrazofines have the formula shown below in formula XV:

wherein:
X9 is selected from the group consisting of C1 -Cs trihafomethyl, preferably trifluoromethyl; Ci -G6 alkyl; and an optionally substituted or di-substituted phenyl group of formula XVI:
_ ~ XV1 (I _ wherein:
R" and R'8 are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl;
nitro; C~ -C6 alkyl, preferably Cj -C3 alkyl; C, -C6 alkoxy, preferably Cy -Cs alkoxy; carboxy; C1 -C6 trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyf; and cyano;
~.8 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:
R'9 O
R$°S(O)2 XVII
wherein:
R'9 is a mono-, di-, or tri-substituted Ci -C12 alkyl, or a mono-, or an unsubstituted or mono-, di- or tri-substituted linear or branched C2 -Cio alkenyl, or an unsubstituted or mono-, di- or tri-substituted linear or branched C2 -C1o alkynyl, or an unsubstituted or mono-, di- or tri-substituted C3 -Cy2 cycloalkenyl, or an unsubstituted or mono-, di- or tri-substituted C5 -C12 cycloalkynyl, wherein the substituents are chosen from the group consisting of halo selected from F, Cf, Br, and I, OH, CF3, Ca -Co cycloalkyl, =O,dioxolane, CN;
R8° is selected from the group consisting of CH3, NH2, NHC(O)CF3, and NHCH3;
R$' and R82 are independently chosen from the group consisting of hydrogen and C1 -Cyo alkyl;
or R$' 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:

Xufll (O)2SH3C

wherein Xi° 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:
Rs4. ~. ~. i Ras Rs~
Rss X11! ~ ~( ~ )n OR91 Rso as ~ es ~10 or a pharmaceutically acceptable salt thereof, XIX
wherein:
X" is selected from the group consisting of O, S, and a bond;
nis0orl;

R83 is selected from the group consisting of CHa, NH2, and NHC(O)CF3;
R~4 is chosen from the group consisting of halo, C1-C6 alkoxy, C1-Cs alkylthio, CN, C1-Cs alkyl, C1-C6 fluoroalkyl, N3, -C02 R92, hydroxyl, -C(R93)(R9~)-OH, -Ci -C6 alkyl-C02 -R95, C1-Cs fluoroalkoxy, N02, NR96 R9', and NHCOR9a;
R85 to Rs9 are independently chosen from the group consisting of hydrogen and C1-C6 alkyl;
or R85 and Rs9, or R89 and R9° together with the atoms to which they are attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R85 and R$' 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:
8101 A6' XX
a A' ~~~ s Rlo2~ q and pharmaceutically acceptable salts thereof wherein:
-A5=As-A'=A8- is selected from the group consisting of:
(a) -CH=CFi-CH=CH-, (b) -CH2 -CH2 -CH2 -C(O)-, -CH2 -CH2 -C(O)-CH2 -, -CH2 -C(O)-CH2 -CH2, -C(O)-CH2 -CH2 -CHz, (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)-O-CH2 -CH2 -, (f) -C(R'o5)2 -O-C(O)-, -C(O)-O-C(RloS)2 _~ -O-C(O)-C(R105)2 -~ -C(R105)2 -C(O)-O-(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) -N=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-;
R99 is selected from the group consisting of S(O)2CH3, S(O)2NH2, S(O)2NHCOCF3, S(O)(NH)CH3, S(O)(NH)NH2, S(O)(NH)NHCOCF3, P(O)(CH3)OH, and P(O)(CH3)NH2;
Rioo is selected from the group consisting of:
(a) C~ -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) C, -Cs afkoxy, (4) C1 -C6 alkylthio, (5) CN, (6) CF3, (7) C1 -Cs alkyl, (8) Ns~

(9) -C02 H, (10) -C02 -C~ -C4 alkyl, (11 ) -C(R103)(R104)-OH' (12) -C(R'°3)(Rlo4.)-O-Ci -C4 alkyl, and (13) -Ci -Cs alkyl-C02 -R~os;
(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 1 O atom which is N, and optionally l, 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 -Cs alkyl, (4) C1 -Cs alkoxy, (5) C1-Cs alkylthio, (6) CN, (7) C F3, (8) Na (9) -C(Rlo3)(R~o4)-OH, and (10) -C(R103)(Ri04)-O-Ci -C4 alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
Ri°~ and R'°2 are the substituents residing on any position of -A5=As-A'=A8- and are selected independently from the group consisting of:
(a) hydrogen, (b) CFs, (c) CN, (d) C1 -C6 alkyl, (e) -Q3 wherein Q3 is Q4, C02 H, C(Rlos)(Rlo4)OH, (f) -O-Q4, (g) -S-Q4, and (h) optionally substituted:

(1) -Ci -Cs alkyl-Q3, (2) -O-C1 -C5 alkyl-Q3, (3) -S-Ci -C5 alkyl-Q3, (4) -C1-C3 alkyl-O-C1_3 alkyl-Q3, (5) -C1-C3 alkyl-S-C1_3 alkyl-Q3, (6) -Ci -C5 alkyl-O-Q4, (7) -C1-C5 alkyl-S-Q4, wherein the substituent resides on the alkyl chain and the substituent is Ci -C3 alkyl, and Q3 is Q4, CO2 H, C(R'°3)(Rio4)OH Q4 IS CO2 -C1-C4 alkyl, tetrazolyl-5-yl, or Cr(R103)(R104)O-C1 -C4 alkyl;
8103' 8104 and Rlos are each independently selected from the group consisting of hydrogen and C1 -C6 alkyl; or R'o3 and R'o4 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 8105 groups on the same carbon form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
Rlos is hydrogen or Ci -Cs alkyl;
R1°' is hydrogen, C1 -C6 alkyl or aryl;
X' its O, S, NRloy CO, C(R107)2~ C(Rlo~)(OH)~ -C(Rlo~)=C(Rlo~)-; -.
C(R'°')=N-; or-N=C{R'°')-.
[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:
R~lo N
XXI
Rlos N

wherein:
Ri oa is:
~R112) --(CH2)p {Riii) m 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=NR'13 where 8113 Is hydrogen, loweralkyl, hydroxyl, loweralkoxy, amino, loweralkylamino, diloweralkylamino or cyano;
8111 and 8112 are independently halogen, cyano, trifiluoromethyl, loweralkanoyl, vitro, loweralkyl, loweralkoxy, carboxy, lowercarbalkoxy, trifuloromethoxy, acetamido, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfinyl, or trifluoromethylsulfonyl;
R1°9 is amino, mono or diloweralkyl amino, acetamido, acetimido, ureido, formamido, or guanidino; and R"° 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 5,136,831 can serve as a Cox-2 selective inhibitor of the present invention.
Such pyrazole derivatives have the formula shown below in formula XXII:

N
8115 ~ R117 x14 ,N
XXII

N
wherein:
8114 is hydrogen or halogen;
8115 and 8116 are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl or lower alkanoyloxy;
R"' 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:

X15 S~~~m R119 0 0 ~ ~N~ XXIII

Rl2a~S~NH

wherein:
AC'S denotes oxygen, sulphur or NH;

R11$ 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;
8119 and R12°, independently from one another, denote hydrogen, an optionally polyfluorised alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH2)n -X16; or 8119 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)~ X16;
X16 denotes halogen, NO2, -OR121, -COR121, -~O2 R121 ~ -OCO2 8121 ~
-C(V, -CONR121 OR122, -CONR121 R122~ -SR121~ -S(O)R121, -S(O)2 R121~ -NRl2i R122~ -NHC(O)R121, -NHS(O)2 8121!
n denotes a whole number from 0 to 6;
8123 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;
8124 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~ -eO2 R121~ -OCO2 8121' -eN~ ,~ONR121 OR122~ -CONR121 8122, -SR121, -S(O)R121' -S(O)2 8121, -NR121 R122~ -NHC(O)R121~ -NHS(O)2 8121, or a polyfluoroalkyl group;
8121 clad 8122, independently from one another, denote hydrogen, alkyl, aralky! 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:
XXiV
Ri26 or pharmaceutically acceptable salts thereof wherein:
X"-Y1-Z'-is selected from the group consisting of:
(a) -CH2 CH2 CH2 -, (b) -C(O)CH2 CH2 -, (c) -CH2 CH2 C(O)-, (d) -G,R129 (R129')-O-C O)-(e) -C(O)-O-CRl2s (Rl2s')-, (f) - CH2 -NR127 -CH2 -, (g) -CRizs (R129')-NR12~ -C(O)-(h) -CRl2s=CRl2a' -S-' (i) - S-CR128-CRlza' -(j) S-N=CH-, -(k) -CH=N-S-, (I) N=CRl2a ~~_,~
-(m) -O-CR12$ =N-, (n) -N=CR12$ -NH-, (o) -N=CR12$ -S-, and (P) -"SwCRl2a=N-C(O -NR127 -CR129 (R129')-r (r) -R'2' N-CH=CH- provided R'22 is not -S(O)2CH3, (s) -CH=CH-NR'27 - provided R'25 is not -S(O)2CH3;
when side b is a double bond, and sides a and c are single bonds; and X"-Y'-Z'-is selected from the group consisting of:
(a) =CH-O-CH=, and (b) =CH-NR'2' -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;
8125 is selected from the group consisting of:
(a) S(O)2 CH3, (b) S(O)2 NN2, (c) S(O)2 NHC(O)CF3, (d) S(O)(NH)CH3, (e) S(O)(NH)NH2, (f) S(O)(NH)NHC(O)CF3, (g) P(O)(CH3)OH, and (h) P(O)(CH3)NH2; , R'26 is selected from the group consisting of (a) C1 -C6 alkyl, (b) C3, C4, C5, C6, and C~, cycloalkyl, (c) mono-, dl- 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) C1 -Cs alkyl, ($) nls~
(9) -C02 H, (10) -C02 -Ci -C4 alkyl, (11 ) -C(R129)(R130)-OH, (12) --C(R129)(R130)-O-C1 -C4 alkyl, and (13) -Ci -C6 alkyl-C02 -8129 ;
(d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 additionally N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of:
(1 ) hydrogen, (2) halo, including fluoro, chloro, bromo and iodo, (3) C1 -Cs alkyl, (4) C1 -C6 alkoxy, (5) C1 -C6 alkylthio, (6) CN, (7) CF3, ($) nls~
(9) -C(R'29)(Rl3o)-OH, and (1 O) -e(R129)(R130)-O-Ci -C4 alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
i~'~' is selected from the group consisting of:
(a) hydrogen, (b) CF3, (c) CN, (d) C1 -C6 alkyl, (e) hydroxyl C1 -C6 alkyl, (f) -C(O)- C1 -C6 alkyl, (g) optionally substituted:
(1 ) -C1 -C5 alkyl-Q5, (2) -Ci -C5 alkyl-O-C1-C3 alkyl-Q5, (3) -C1 -C3 alkyl-S-C1-C3 alkyl-Q5, (4) -C1 -C5 alkyl-O-Q5, or (5) -Ci -Cs alkyl-S-Q5, wherein the substituent resides on the alkyl and the substituent is Cy -C3 alkyl;
(h) -Q5;
R12$ and R'28~ are each independently selected from the group consisting of:
(a) hydrogen, (b) C F3, (c) CN, (d) C1 -C6 alkyl, (e) -Q5, (f) -O- Qs;

(g) -S- Q5, and (h) optio nally substituted:

(1) - C1 -C5 alkyl-Q5, 2 - O-C1 -C5 alkyl-Q5, (3) - S-C1 -C5 alkyl-Q5, (4) - C1 -C3 alkyl-O-C1 -C3 alkyl-Q5, (5) - C1 -C3 alkyl-S-C1 -C3 alkyl-Q5, (6) - C1 -C5 alkyl-O-Q5, (7) -C1 -C5 alkyl-S-Q5, wherein the substitueni~ resides on the alkyl and the substituent is C1 -C3 alkyl, and R,129~ Rl2s~' ~ 130' 8131 and 8132 are each independently selected from the group consisting of:
(a) hydrogen, (b) C1 -C6 alkyl;

or 8129 and R'3° or R'3' and 8132 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 CO2 H, C02 -C1 -C4 alkyl, tetrazolyl-5-yl, C(R131)(R132)(OH), Or ( J(R131)(R132)(O-Ci -C4 alkyl);
provided that when X-Y-Z is -S-CRl2a=CR'28~, then R'2a and R128~ 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:

(X19)n XXV
CH2)q \zio ~CH2)r Y2~(CH2)m or the pharmaceutically acceptable salts thereof wherein:
A9 is C1 -Cs alkylene or-NR133 -;
ZS IS C(=L3)R' 34, Or SO2 R~35 ;
Z9 is CH or N;
Z1° and Y2 are independently selected from -CH2 -, O, S and -N-R'33;
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-(Ci -C4 alkyl)amino and cyano;
nis0,1,2, 3or4;
L3 is oxygen or sulfur;
8133 is hydrogen or Ci -C4 alkyl;
8134 is hydroxyl, Ci -Cs alkyl, halo-substituted Ci -Cs alkyl, Ci -Cs alkoxy, halo-substituted Cy -Cs alkoxy, Cs -C~ cycloalkoxy, C1 -C4 alkyl(C3 -C~
cycloalkoxy), -NRl3s 8137' C1-C4 alkylphenyl-O- or phenyl-O-, said phenyl being optionally substituted with one to five substituents independently selected from halogen, C1-C4 alkyl, hydroxyl, C1 -C4 alkoxy and nitro;
8135 Is Ci -Cs alkyl or halo-substituted Ci -Cs alkyl; and Rl3s and R~3' are independently selected from hydrogen, C1_s alkyl and halo-substituted C1 -Cs 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:
N
(X21>n ~ \ CR140 CR139 X138 xxv~
/ N
m or a pharmaceutically acceptable salt thereof, wherein:
Ai° 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 atoms) in addition to said hetero atom, or a 6-membered rnonocyclic aromatic ring having one N atom and optionally containing one to four N atoms) 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;
X2° is independently selected from halo, Ci -C4 alkyl,°hydroxyl, Cy -C4 alkoxy, halo-substituted Ci -C4 alkyl, hydroxyl-substituted C1-C4 alkyl, (C1 -C4 alkoxy)Ci -C4 alkyl, halo-substituted C1 -C4 alkoxy, amino, N-(C1 -C4 alkyl)amino, N, N-di(Ci -C4 alkyl)amino, [N-(Ci -C4 alkyl)amino]Ci -Ca alkyl, [N, N-di(C-, -C4 alkyl)amino]Ci -C4 alkyl, N-(Ci -C4 alkanoyl)amonio, N-(C1-C4 alleyl) (C1 -C4 alkanoyl)amino, N-[(Ci -C4 alkyl)sulfonyl]amino, N-[(halo-substituted Ci -C4 alkyl)sulfonyl]amino, C~ -C4 alkanoyl, carboxy, (C1 -C4 alkoxy)carbonyl, carbamoyl, [N-(Ci -C4 alkyl)amino]carbonyl, [N, N-di(C1 -C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (C~ -C4 alkyl)thio, (C1 -C4 alkyl)sulfinyl, (C1 -C4 alkyl)sulfonyl, aminosulfonyl, [N-(C~ -C4 alkyl)amino]sulfonyl and [N, N-di(C1 -C4 alkyl)amino]sulfonyl;
X2' is independently selected from halo, C1 -C4 alkyl, hydroxyl, Cy -C4 alkoxy, halo-substituted Ci -C4 alkyl, hydroxyl-substituted Cy -C4 alkyl, (C1 -C4 alkoxy)C1 -C4 alkyl, halo-substituted C1 -C4 alkoxy, amino, N-(C1 -C4 alkyl)amino, N, N-di(C1 -C~ alkyl)amino, [N-(C1 -C4 alkyl)amino]Ci -C4 alkyl, [N, N-di(C-, -C4 alkyl)amino]C1 -C4 alkyl, N-(Cy -C4 alkanoyl)amino, N-(C1 -C4 alkyl)-N-(C1 -C4 alkanoyl) amino, N-[(C1 -C4 alkyl)sulfonyl]amino, N-[(halo-substituted Ci -C4 alkyl)sulfonyl]amino, Ci -C4 alkanoyl, carboxy, (C1 -C4 alkoxy)hydroxyl, cabamoyl, [N-(Ci -C4 alkyl) amino]carbonyl, [N, N-di(Cy -C4 alkyl)amino]carbonyl, N-carbomoylamino, cyano, nitro, mercapto, (C1 -C4 alkyl)thio, (C1 -C4 alkyl)sulfinyl, (Cy -C4 alkyl)sulfonyl, aminosulfonyl, [N-(C1 -C4 alkyl)amino]sulfonyl and [N, N-di(C1-C4 alkyl)amino]sulfonyl;
8138 is selected from:
hydrogen;
straight or branched C1 -C4 alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxyl, Ci -C4. alkoxy, amino, N-(C1 -C4 alkyl)amino and N, N-di(C1-C4 alkyl)amino;
C3 -Cs cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are indepently selected from halo, C1 -C4 alkyl, hydroxyl, Ci -C4 alkoxy, amino, N-(C1 -C4 alkyl)amino and N, N-di(C1 -C4 alkyl)amino;
C4 -Cs cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, Cy -C4 alkyl, hydroxyl, C1 -C4 alkoxy, amino, N-(Cy -C4 alkyl)amino and N, N-di(C1-C~. alkyl)amino;
phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1 -C4 alkyl, hydroxyl, Cy -C~ alkoxy, halo-substituted C1 -C4 alkyl, hydroxyl-substituted C1 -C4 alkyl, (C1 -C4 alkoxy)Cy -C4 alkyl, halo-substituted Ci -C4 alkoxy, amino, N-(Ci -C4 alkyl)amino, N, N-di(C1 -C4 alkyl)amino, [N-(C1 -C4 , alkyl)amino]Cy -C4 alkyl, [N, N-di(C1 -C4 alkyl)amino]C1 -C4 alkyl, N-(C1 -C4 alkanoyl)amino, N-[C1 -C4 alkyl)(C1 -C4 alkanoyl)]amino, N-[(C1 -C4 alkyl)sulfony]amino, N-[(halo-substituted C~ -C4 alkyl)sulfonyl]amino, C1 -C4 alkanoyl, carboxy, (C1 -C4 alkoxy)carbonyl, carbomoyl, [N-(C1 -C4 alky)amino]carbonyl, [N, N-di(Ci -C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (C1 -C~. alkyl)thio, (Cy -C4 alkyl)sulfinyl, (C1 -C4 alkyl)sulfonyl, aminosulfonyl, [N-(C1 -C4 alkyl)amino]sulfonyl and [N, N-di(C1 -C~
alkyl)amino]sulfonyl; and heteroaryl selected from:
a 5-membered monocyclic aromatic ring having one hetero atom selected from 0, S and N and optionally containing one to three N atoms) in addition to said hetero atom; or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atoms) in addition to said N atom; and said heteroaryl being optionally substituted with one to three substituent(s) selected from X2o ;
R'39 and F3lao are independently selected from:

hydrogen;
halo;
C1-C4 alkyl;
phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, Ci -C4 alkyl, hydroxyl, C1 -C4 alkoxy, amino, N-(Ci -C4 alkyl)amino and N, N-di(Ci -C4 alkyl)amino;
or 8138 and 8139 can form, together with the carbon atom to which they are attached, a C3 -C~ cycloalkyl ring;
m is 0, 1, 2, 3, 4 or 5; and nis0, 1,2,3or4.
[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
(X22>n-_Q6 H
and the pharmaceutically acceptable salts thereof, wherein:
L4 is oxygen or sulfur;
'f3 is a direct bond or C1 -C4 alkylidene;
Q6 is:
(a) Ci -C6 alkyl or halosubstituted C1 -C6 alkyl, said alkyl being optionally substituted with up to three substituents independently selected from hydroxyl, C1 -C4 alkoxy, amino and mono- or di-( C1 -C4 alkyl)amino, (b) C3 -C7 cycloalkyl optionally substituted with up to three substituents independently selected from hydroxyl, C1 -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, C1 -Ca. alkyl, halosubstituted Ci -C4 alkyl, hydroxyl, C1 -C4 alkoxy, halosubstituted Ci -C4 alkoxy, S(O)m Ri'~, S02 NH2, S02 N(Ci -C4 alkyl)2, amino, mono- or di-( Cy -C4 alkyl)amino, NHS02 8143, NHC(O)R'43, CN, C02 H, C02 (C1-C4 alkyl), Ci -C4 alkyl-OH, C1-C4 alkyl-OR'''s, CONH2, CONH(Ci -C4 alkyl), CON(C1 -C4 alleyl)2 and -O-Y-phenyl, said phenyl being optionally substituted with one or two substituents independently selected from halo, Ci -C4 alkyl, CF3, hydroxyl, OR~43, S(O)mR1'~, amino, mono- or di-( C1-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, C1-C4 alkyl, halosubstituted C1 -C4 alkyl, hydroxyl, C1 -C4 alkoxy, halosubstituted C1 -C4 alkoxy, C1 -C4 alkyl-OH, S(O)m R'43 S02 NH2, S02 N(C1 -C4 alkyl)2, amino, mono- or di-( Ci -C4 alkyl)amino, NHS02 8143, NHC(O)R'~, CN, C02 H, C02 (C1 -C4 alkyl), Ci -C4 alkyl-OR143, CONH2, CONH(Cy -C4 alkyl), CON(C1 -C4 alkyl)2, phenyl, and mono-, di= or tri-substituted phenyl wherein the substituent is independently selected from halo, CF3, C1 -C4 alkyl, hydroxyl, C1 -C4 alkoxy, OCF3, SR'43, S02 CH3, S02 NH2, amino, Cy_4 alkylamino and NHS02 8143;
(e) a rnonocyclic 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 );
8141 jS hydrogen or C1 -C6 alkyl optionally substituted with a substituent selected independently from hydroxyl, OR'43, nitro, amino, mono- or di-( C1 -C4 alkyl)amino, C02 H, C02 (C1-C4 alkyl), CONH2, CONH(C1 -C4 alkyl) and CON(C1 -C4 alkyl)2 ;
8142 is:
(a) hydrogen, (b) C1-C4 alkyl, (c) C(O)R145, wherein 8145 is selected from:
(c-1 ) C1-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, OR''~, S(O)m R1'~, nitro, amino, mono- or di-C1 -C4 alkyl)amino, NHS02 R''~, C02 H, CO2 (C1-C4 alkyl), CONH2, CONH(C1 -C4 alkyl), CON(C1-C4 alkyl)2, OC(O)R143, thienyl, naphthyl and groups of the following formulas:

(x22) ~x22)n (x )n ~ (X22)n /~ ~ / >

/(CH2)p /(CH2)p N~ ~ N
O
(C\)q N~ (C\~q 1 s and (c-2) C1-C22 alkyl or C2 -C22 alkenyl, said alkyl or alkenyl being optionally substituted with five to forty-five halogen atoms, (c-3) -Y5-C3 -C~ cycloalkyl or -Y5-C3 -C~ cycloalkenyl, said cycloalkyl or cycloalkenyl being optionally substituted with up to three substituent independently selected from:
(c-3-1 ) Ci -C4 alkyl, t-~ydroxyl, OR143, S(O)m R143~ amino, mono- or di-( Ci -C4 alkyl)amino, CONH2, CONH(C1 -C4 alkyl) and CON(C1 -C4 alkyl)2, (c-4) phenyl or naphthyt, said phenyl or naphthyl being optionally substituted with up to seven (preferably up to seven) substituents independently selected from:

(c-4-1 ) halo, C1 -Cg alkyl, C1-C4 alkyl-OH, hydroxyl, C1 -Ca alkoxy, halosubstituted Ci -C8 alkyl, halosubstituted Ci -C$ alkoxy, CN, nitro, S(O)m R143~ ~O2 NH2, S02 NH(Ci -C4 alkyl), S02 N(Ci -C4 alkyl)2, amino, Ci -C4 alkylamino, di-(Ci -C4 alkyl)amino, CONH2, CONH(C1 -C4 alkyl), CON(Ci -C4 alkyl)2, OC(O)R''~, 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-(C1 -C4 alkyl)amino, C02 H, C02 (C1 -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, C1 -C8 alkyl, Ci -C4 alkyl-OH, hydroxyl, Ci -C$ alkoxy, CF3, OCF3, CN, nitro, S(O)m R'''~, amino, mono- or di-( C1-C4 alkyl)amino, CONH2, CONH(Ci -C4 alkyl), CON(Ci -C4 alkyl)2, C02 H and C02 (C1 -C4 alkyl), and -Y-phenyl, said phenyl being optionally substituted with up to three substituents independently selected halogen, Ci -C4 alkyl, hydroxyl, C1 -C4 alkoxy, CF3, OCF3, CN, nitro, S(O)m 8143, amino, mono- or di-( Ci -C4 alkyl)amino, C02 ~ H, C02 (C1 -C4 alkyl), CONH2, CONH(C1 -C4 alkyl) and CON(C1 -C4 alkyl)2, (c-6) a group of the following formula:
(CH2~9 \Z11 (CH2)n X22 is halo, C1 -C4 alkyl, hydroxyl, C1 -C4 alkoxy, halosubstitutued C1 -C4 alkoxy, S(O)m 8143, amino, mono- or di-(C1 -C4 alkyl)amino, NHS02 8143, nitro, halosubstitutued Ci -C4 alkyl, CN, C02 H, C02 (C1 -C4 alkyl), C1 -C4 alkyl-OH, C1-C4 alkylOR143, CONH2, CONH(C1 -C4 alkyl) or CON(C1 -C4 alkyl)2 ;

8143 is C1 -C4 alkyl or halosubstituted C1-C4 alkyl;
mis0,1or2;nis0,1,2or3;pis1,2,3,4or5;qis2or3;
Z'1 is oxygen, sulfur or NR''~ ; and R''~ is hydrogen, C1 -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, C, -C4 alkoxy, S(O)m R'~, amino, mono- or di-(Ci -C~ 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;
8141 is hydrogen; and R'42 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:
H
N
N/
H ~ XXVIII
i X« Ys 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-aryloxy, 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:

R
XXIX
or a pharmaceutical salt thereof, wherein:
8146 is selected from the group consisting of SCH3, -S(O)2 CH3 and -S(O)2 NH2 ;
R14' is selected from the group consisting of OR15°, mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;
RlSO is unsubstituted or mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;
8148 IS H, Ci -C4 alkyl optionally substituted with 1 to 3 groups of F, CI or Br; and 8149 IS H, Ci -C4 alkyl optionally substituted with 1 to 3 groups of F, CI or Br, with the proviso that R14$ and 8149 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:

(R 151 )0_i /Z R

A
U

or a pharmaceutically acceptable salt, ester or tautomer thereof, wherein:
Z13 (S C Or N;
when Z13 is N, 8151 represents H or is absent, or is taken in conjunction with 8152 as described below:
when Z13 is C, 8151 represents H and 8152 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 1~0 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 8151 and 8152 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 Ra group selected from the group consisting of: C1-C2 alkyl, -OCi -C2 alkyl, -NHCi -C2 alkyl, -N(C1-C2 alkyl)2, -C(O) Ci -C2 alkyl, -S-Ci -C2 alkyl and -C(S) Ci -C2 alkyl;
Y7 represents N, CH or C-OC1 -C3 alkyl, and when Z13 is N, Y' can also represent a carbonyl group;
8153 represents H, Br, CI or F; and 8154 represents H or CH3.
j000114] 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:

Ri60 8157 \
N N O Risi XXXI
N
w C~ C
R156~_ ~9 wherein:
8155' 8156' R157~ and R15$ are independently selected from the groups consisting of hydrogen, C1 -C5 alkyl, C~ -C5 alkoxy, phenyl, halo, hydroxyl, ' 20 C1 -C5 alkylsulfonyl, C1-C5 alkylthio, trihaloCl -C5 alkyl, amino, nitro and 2-quinolinylmethoxy;

8159 IS hydrogen, C1 -C5 alkyl, trihaloC~ -C5 alkyl, phenyl, substituted phenyl where the phenyl substitutents are halogen, C1-Cs alkoxy, trihaloCi -C5 alkyl or vitro or R'59 Is heteroaryl of 5-7 ring members where at least one of the ring members is nitrogen, sulfur or oxygen;
R~6o is hydrogen, Ci -C5 alkyl, phenyl Cy -C5 alkyl, substituted phenyl C1 -C5 alkyl where the phenyl substitutents are halogen, Ci -C5 alkoxy, trihaloCi -C5 alkyl or vitro, or 8160 is Ci -C5 alkoxycarbonyl, phenoxycarbonyl, substituted phenoxycarbonyl where the phenyl substitutents are halogen, Ci -C5 alkoxy, trihaloC~ -C5 alkyl or vitro;
R'6~ is Ci -Cio alkyl, substituted C1 -Cio alkyl where the substituents are halogen, trihaloCi -C5 alkyl, Ci -Cs alkoxy, carboxy, C, -C5 alkoxycarbonyl, amino, C1 -C5 alkylamino, diCi -C5 alkylamino, diCy -C5 aikylaminoCi -C5 alkylamino, Cy -C5 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 Cy -C5 alkyl; or Rise Is phenyl, substituted phenyl (where the phenyl substitutents are one or more of C1 -Cs alkyl, halogen, C~ -C5 alkoxy, trihaloCl -C5 alkyl or vitro), or R'6' 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 8161 is 11R163 8164 where R'63 and Rls4 are independently selected from hydrogen and Ci_5 alkyl or R'63 and Rls4 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 C1 -Cs alkyl; 8162 IS
hydrogen, C1 -C5 alkyl, vitro, 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:

8165 , N

wherein:
8164 jS 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 Ci_5 alkyl, halogen, nitro, trifluoromethyl and nitrite;
8165 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 C1-C5 alkyl and halogen, or substituted phenyl, wherein the substituents are independently selected from one or members of the group consisting of Ci -Cs alkyl, halogen, nitro, trifluoromethyl and nitrite;
8166 is hydrogen, 2-(trimethylsilyl)ethoxymethyl), Ci -G5 alkoxycarbonyl, aryloxycarbonyl, arylCi -C5 alkyloxycarbonyl, arylCi -C5 alkyl, phthalimidoCi -C5 alkyl, aminoCi -Cs alkyl, diaminoCi -C5 alkyl, succinimidoCi -C5 alkyl, Ci -C5 alkylcarbonyl, arylcarbonyl, C1 -C5 alkylcarbonylCi -C5 alkyl, aryloxycarbonylC-, -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 C1-C5 alkyl, C1-C5 alkoxy, halogen, amino, Ci -C5 alkylamino, and diCy -C5 alkylamino;
8167 is ~A11~~ -~CH165~q -X24 wherein:
A'1 is sulfur or carbonlyl;
nis0orl;
q is 0-9;
X24 is selected from the group consisting of hydrogen, hydroxyl, halogen, vinyl, ethynyl, C1 -C5 alkyl, C3 -C~ cycloalkyl, Ci -C5 alkoxy, phenoxy, phenyl, arylCl -C5 alkyl, amino, Ci -C5 alkylamino, nitrite, phthalimido, amido, phenylcarbonyl, Ci -C5 alkylaminocarbonyl, phenylaminocarbonyl, arylC~ -C5 alkylaminocarbonyl, Ci -C5 alkylthio, C, -C5 alkylsulfonyl, phenylsulfonyl, substituted sulfonamido, wherein the sulfonyl substituent is selected from the group consisting of C1 -C5 alkyl, phenyl, araC1 -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 C1 -C5 alkoxy, trihaloalkyl, phthalirnido and amino, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C1 -C5 alkyl, halogen and C1 -C5 alkoxy, substituted phenoxy, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C1-C5 alkyl, halogen and C1-C5 alkoxy, substituted C1-C5 alkoxy, wherein the alkyl substituent is selected from the group consisting of phthalimido and amino, substituted arylCl -C5 alkyl, wherein the alkyl substituent is hydroxyl, substituted arylCy -C5 alkyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of Cy -C5 alkyl, halogen and Cy -C5 alkoxy, substituted amido, wherein the carbonyl substituent is selected from the group consisting of C1 -C5 alkyl, phenyl, arylCl -C5 alkyl, thienyl, furanyl, and naphthyl, substituted phenylcarbonyl, wherein the phenyl substituents are independently selected from one or members of the group consisting of C~ -C5 alkyl, halogen and Ci -C5 alkoxy, substituted C1 -C5 alkylthio, wherein the alkyl substituent is selected from the group consisting of hydroxyl and phthalimido, substituted C1 -C5 alkylsulfonyl, wherein the alkyl substituent is selected from the group consisting of hydroxyl and phthalimido, substituted phenylsulfQnyl, wherein the phenyl substituents are independently selected from one or members of the group consisting of bromine, fluorine, chlorine, Cy -Cs alkoxy and trifluoromethyl, with the proviso:

if Aii is sulfur and X24 is other than hydrogen, Ci -C5 alkylaminocarbonyl, phenylaminocarbonyl, arylCi -C5 alkylam inocarbonyl, Ci -C5 alkylsulfonyl or phenylsulfonyl, then q must be equal to or greater than 1;
if Aii is sulfur and q is 1, then X24 cannot be Ci -C2 alkyl;
if Aii is carbonyl and q is 0, then X24 cannot be vinyl, ethynyl, C1 -C5 alkylaminocarbonyl, phenylaminocarbonyl, arylCi -C5 alkylaminocarbonyl, Ci -C5 alkylsulfonyl or phenylsulfonyl;
if Ai 1 is carbonyl, q is 0 and X24 is H, then 8166 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
N N

Rlsa wherein:
R16$ and 8169 are independently selected from the group consisting of hydrogen, halogen, (C1 -C6)alkyl, (C1 -C6)alkoxy, nitro, amino, hydroxyl, trifluoro, -S(C1 -C6)alkyl, -SO(C~ -C6)alkyl and -S02 (C1-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:
;173 ,or wherein:

R17° is selected from the group consisting of hydrogen, halogen, hydroxyl and carbonyl;

or Ri7° and R1'1 taken together form a moiety selected from the group consisting of -OCOCH2 -, -ONH(CH3)COCH2 -, -OCOCH= and -O-;
R"1 and R"2 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (Cj -Cs)alkyl, (C1 -Cs)alkoxy, =NOH, -NR"4 R"5, -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(Ci -Cs)alkyl and di(Cy -Cs)alkoxy;
R"3 is selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (C1 --Cs)alkyl, (C1 -Cs)alkoxy and optionally substituted carboxyphenyl, wherein substituents on the carboxyphenyi group are selected from the group consisting of halogen, hydroxyl, amino, (C1 -Cs)alkyl and (Ci -Cs)alkoxy;
or Ri'2 and Ri'3 taken together form a moiety selected from the group consisting of -O-and R"4 is selected from the group consisting of hydrogen, OH, -OCOCH3, -COCH3 and (C1 -Cs)alkyl; and R1'S is selected from the group consisting of hydrogen, OH, -OCOCH3, -COCH3, (C1 -Cs)alkyl, -CONH2 and -SO~ CH3 ;
with the proviso that if M is a cyclohexyl group, then Ri'~ through R~'3 may not all be hydrogen;
and pharmaceutically acceptable salts, esters and pro-drug forms thereof.
[0001 y 7j . 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:

!X25 R17~ XXXV

Rl7s wherein:
8176 is Ci -C6 alkyl, Ci -C6 branched alkyl, C4 -C8 cycloalkyl, Ci -Cs hydroxyalkyl, branched C1 -Cs hydroxyalkyl, hydroxyl substituted C4 -C8 aryl, primary, secondary or tertiary C1 -C6 alkylamino, primary, secondary or tertiary branched C1-C6 alkylamino, primary, secondary or tertiary C~ -C$ arylamino, Ci -C6 alkylcarboxylic acid, branched C1 -C6 aikylcarboxylic acid, C1 -Cs alkylester, branched C1 -C6 alkylester, C4 -C$ aryl, C4 -Ca arylcarboxylic acid, C4 -CS arylester, C4 -C$ aryl substituted C1 -C6 alkyl, C4 -Ca 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;
8177 is Gi -Cs alkyl, C1 -C6 branched alkyl, C4 -Cs cycloalkyl, C4 -Cg aryl, C4 -Cs aryl-substituted G1 -C6 alkyl, C1 -C6 alkoxy, Ci -C6 branched alkoxy, C4 -Cs aryloxy, or halo-substituted versions thereof or Ri'7 is halo where halo is chloro, fluoro, bromo, or iodo;
Rl7a is hydrogen, C1 -Cs alkyl or Ci -C6 branched alkyl;

R'79 is C f -C& alkyl, C4 -C8 aroyl, C4 -C$ aryl, C~. -C$ heterocyclic alkyl or aryl with O, N or S in the ring, C4 -C8 aryl-substituted Ci -Cs alkyl, alkyi-substituted or aryl-substituted C4 -C8 heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-substituted C4 -C$ aroyl, or alkyl-substituted C4 -C$
aryl, or halo-substituted versions thereof where halo is chloro, bromo, or iodo;
n is 1, 2, 3, or 4; and X2~ is O, NH, or N-R18°, where R'8° is C1-C6 or Ci -C6 branched alkyl.
[OOOiiB] 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
Ri.
R~°' or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:
X26 is selected from the group consisting of O, S, -NR'8~, -NORa, and -NNRb R~ ;
Ri85 is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclic alkyl;
Ra, Rb, and R~ are independently selected from the group consisting of alkyl, aryl, aryla(kyl, cycloalkyl, and cycloalkylalkyl;
R'$' is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonyialkyl, alkylsuifonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxya(kyl, aryloxy, aryloxyhaloaikyl, aryloxyhydroxyalkyl, arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocyclic, heterocyclic alkoxy, heterocyclic alkyl, heterocyclic oxy, hydroxyalkyl, hydroxyiminoalkoxy, -(CHz)n C(O)R'ss, -(GHz)n CH(QH)Rlss, -(CHz)n C(NORd)R'ss, -(CHz)n CH(NORd)R'ss, -(CHz)n CH(NRd RB)Rlss, -R's~
Riss~ -(CHz)n C=CRiss~ -(CHz)n [C1"I(CXz6~3)Jm (CHz)p Rias~ -(CHz)n (CX26~2)m (CHz)p Riss~ and -(CH2)n (CH?t2s~)m (CHz)m Risa ;
R',ss is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, haloalkynyl, heterocyclic, and heterocyclic alkyl;
R's' is selected from the group consisting of alkenylene, alkylene, halo-substituted alkenylene, and halo-substituted alkylene;
R's8 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
Rd and Re are independently selected from the group consisting of hydrogen, alkenyl, alkyl, afkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl; , Xzs~ is halogen;
m is an integer from 0-5;
n is an integer from 0-10;
p is an integer from 0-10;
R'sz, R's3, and R's4 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, haloalkenyioxy, haloalkoxy, haloalkyl, halogen, heterocyclic, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl, mercaptoalkoxy, nitro, phosphonatoalkoxy, Ys, and Z'4;

provided that one of Ri82, 8183, or 8184 must be Z14, and further provided that only one of Ri82, Ri83, or Ri84 is Z14;
Z14 is selected from the group consisting of:

X27 8190 and 27 190 X -R
S' X2' is selected from the group consisting of S(O)2, S(O)(NRigi), S(O), Se(O)2, P(O)(ORisz)~ and P(O)(NRi9s Ry94) X28 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen;
Rig° is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylarnino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, -NHNH2, and -NCHN(Rigi)Rig2 ;
8191' Risz~ R193~ and 8194 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or Riga and Rig4 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 NRi88 ;
Y8 is selected from the group consisting of --ORisS, _SR195~ -C(R19'T)(R198)R195' rC(o)R195~ _,C(0)QR195~ -N(Ris~)C(O)R195~ ,-2O NC(R197)R195~ and -N(Rig7)Riss ;
Rigs is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthiaafkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aryfalkyl, heterocyclic, heterocyclic alkyl, hydroxyalkyl, and NRigg R2°° ; and Rig7, Rigs, Rigg, and R2oo are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl. , j000119] 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 benzosulphonarnide derivatives have the formula shown below in formula XXXVII:

~ 5 xxxvll \S/ D
R2os ~
H
wherein:
A12 denotes oxygen, sulphur or NH;
R2°' 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:
S(O)m R2o2 XXXVIII

or S(o)m R2°2~ XXX1X

8202 and R2°3 independently of each other denote hydrogen, an optionally polyfluorinated alkyl radical, an aralkyl, aryl or heteroaryl radical or a radical (CH2)" -X2g; or R2°2 and R2°3 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)r, -X29, R2o2~ denotes hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH2)" -X29, wherein:
X29 denotes halogen, N02, -OR2°4, -COR2°4, -C02 R204~ -OC02 -CN, -CONR2o4 OR2os~ -CONR2°4 (~2os~ -SR2o4~ -S(O)R2o4~ -S(O)2 R204~ -NR204 R205~ -NHC(O)R2o4, --NHS(O)2 R2o4;
Z'S 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-R2°3, >C=0, >S(O)m;
R2°4 and R2os independently of each other denote hydrogen, alkyl, aralkyl or aryl;
n is an integer from 0 to 6;
R2°s is a straight-chained or branched C1 -C4 alkyl group which may optionally be mono- or polysubstituted by halogen or alkoxy, or R2os denotes CF3; and m denotes an integer from 0 to 2;
with the proviso that A12 does not represent O if R2os 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:

XXXX
wherein:
R2o' and R2°$ are respectively a hydrogen;
C1 -C4-alkyl substituted or not substituted by halogens;
C3 -C~-cycloafkyl;
C1 -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:

Xgn xxxxl wherein:
X3° is -NHS02R2°9 wherein R2°9 represents hydrogen or Ci -C3-alkyl;
Y9 is hydrogen, halogen, C1-C3-alkyl substituted or not substituted by halogen, N02, NH2, OH, OMe, C02H, or CN; and Q' is C=O, 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:

~ X210 XXXXII

n 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, vitro, 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, arninocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyf, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, -arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoafkyf, 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; .
R2'° is selected from heterocyclyl, cycloalkyl, cycloalkenyl, and aryl, wherein R2'o is unsubstituted or substituted with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, vitro, alkoxyalkyl, alkyfsulfinyl, halo, alkoxy, and alkylthio;
R2" is selected from hydrido and alkoxycarbonylalkyl;
R2'2 is selected from alkyl, carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, amino acid residue, and alkyicarbonylaminoalkylcarbonyl;
provided A13 is not tetrazolium, or pyridinium; and further provided A~3 is not indanone when R2'2 is alkyl or carboxyalkyl; further provided A13 is not thienyl, when R2'° is 4-fluorophenyl, when R2'~ is hydrido, and when is methyl or acyl; and R2i3 is hydrido;
or a pharmaceutically-acceptable salt thereof.
X000123] Specific non-limiting examples of substituted sulfonamide prodrugs of Gox-2 inhibitors disclosed in U.S. Patent No. 6,436,967 that are useful in the present invention include:
N-[[4-[3-(difluaromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazof-1-yl)phen yl)sulfonyl)propanamide;
N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1-yi)phen yl)sulfonyl)butanamide;

N-[[4-[1,5-dimethyl)-3-phenyl-1 H-pyrazol-4-yl]phenyl]sulfonyl]acetamide;
N-[[4-(2-(3-pyridiny!)-4-(trifluoromethyl)-1 H-imidazol-1-yl)phenyl]sulfonyl]acetamide;
N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yf]phenyl]sulfonyl]acetamide;
N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-smidazol-1-yl]phenyl]sulfonyl]acetamide;
N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-iimidazol-1-yl]phenyl]sulfonyl]butanamide;
N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-iH-irnidazol-1-yl]phenyl]sulfonyl]butanamide;
N-[[4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)-'I 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-yl]phenyl]sulfonyl]propanamide;
N-[[4-(5-methyl-3-phenylisoxazol-4-yf)phenyl]sulfonyl]benzamide;
2,2-dimethyl-N-[[4-(5-methyl=3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide;
N-[[4-5-methyl-3-phenylisoxazol-4-yl}phenyl]sulfonyl]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)phenyf]s ulfonyf]acetamide;
N-[[4-[5-methyl-3-phenyfisoxazol-4-yl]phenyl]sulfonyl]acetamide;
N-[[4-[5-(4-chlorophenyl)-3-(trifluorvmethyl)-1 H pyrazol-y -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-rnethoxy-[2Jbenzothiopyrano [4,3-c]pyrazol-1-yl)phenyl]sulfonyl]acetamide;
N-[[4-[6-fluoro-1,5-dihydro-7-methoxy-3-(trifluoromethyl)-[2]benzothiopyran 0[4,3-c]pyrazol-1-yl]phenylJsulfonyl]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]sulfonyl]acetamide;
N-[[4-[5-(difluoromethyl)-3-phenylisoxazol-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-[[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-phenylisoxazof-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]sulfonylJglycine, ethyl ester;
N-[[4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-y()phenyl]sulfonyl]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-y1]phenyl]sulfonyl]acetamide;
N-[[4-[2-(3-chloro-4-fluorophenyl)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]sulfonyllpropanamide.
[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, afkynyl, alkylthio, alkylthioalkyl, alkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkylsutfinyi, alkylsulfonyl, aminosulfonyl, and alkylaminosulfonyl;
R2'° is a phenyl group optionally substituted at a substitutable position with one or mare radicals independently selected at each occurrence from the group consisting of alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, nitro, alkoxyalkyf, alkylsulfinyl, halo, alkoxy, and alkylthio; .
8211 and R2'2 are independently selected from the group consisting of hydroxyalkyl and hydrido but at least one of R2li and 8212 is other than hydrido; and 8213 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-(trifluoromethyl)-1 H-pyraz ot-1-yl]benzenesulfonamide, or phamnaceuticaly-acceptable salts thereof.
[000126] Cox-2 selective inhibitors such as sulfamoylheleroaryl pyrazole compounds that are described in U.S. Patent No. 6,583,32 y may serve as Cox-2 inhibitors of the present invention. Such sulfamoylheleroaryl pyrazole compounds have the formula shown below in formula XXXXIII:

n wherein:
8214 IS furyl, thiazolyf or oxazolyl;
R2'S is hydrogen, fluoro or ethyl; and X31 and X32 are independently hydrogen or chloro.

(000127] Heteroaryl substituted amidinyf and imidazolyl compounds such as those described in U.S. Patent No. 6,555,563 are useful as Gox-2 selective inhibitors of the present invention. Such heteroaryl substituted amidinyl and imidazolyl compounds have the formula shown below in formula XXXXIV:
R21 s N'~
N ~ _8218 N/ \ N XXXXIV
~Z16 ~ 217 wherein:
216 is O or S, 8216 is optionally substituted aryl, R21' is aryl optionally substituted with aminosulfonyl, and 8218 and 8219 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:

14,~~r10 N ~H XXXXV
/l O R22$ OH O H
R22~ ~~ ~ ~ 15._Y1 1 N N XXXXVI
0 ~ 225 R
(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 aikoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
Yi° is selected from lower alkenylene and lower alkynylene;
R22° is a substituent selected from 5- and 6-membered heterocyclo, lov~ser cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R22° is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloaikyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lov~rer haloalkoxy, amino, lower aikylamino, phenylmino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower aikoxy and lower alkylthio;
8221 is selected from lower alkyl and amino; and R22~ is selected from hydrido, lower aikyl, 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 Shawn above in formula XXXXVI, wherein:
A15 4S pyrazolyl optionally substituted with a substituent selected from acyl, halo, hydroxyl, Power afkyi, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminoearbonyl, lower alkoxycarbonyl, Power carboxyalkyl, lower cyanoalkyl, and tower hydroxyalkyl;
Y" is selected from lower alkylene, lower alkenylene and lower alkynylene;

8223 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein 8223 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 aikylsulfinyl, halos lower alkoxy and lower alkylthio;
8224 is selected from lower alkyl and amino; and 8225 is selected from hydrido, lower alkyl;
or a pharmaceutically-acceptable salt thereof.
[00013'1] Heterocyclo substituted hydroxamic acid derivatives described in U.S. Patent No. 6,512,121 have the formula shown above in formula XXXXV, wherein:
Aj4 is a ring substiuent selected from oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isochiazolyl, isoxazolyl, cyclopentenyl, phenyl, and pyridyl;
wherein A'4 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;
Y1° is lower alkylene, lower alkenylene, and lower alkynylene;
R22° is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R22o 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, tower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
R22' is selected from lower alkyl and amino; and 8222 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:
A'5 is a ring substituent selected from oxazolyl, fury!, 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 hydroxyalkyf;
, Y" is selected from lower alkyl, lower alkenyl and lower alkynyl;
8223 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein 8223 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;
8224 is selected from lower alkyl and amino; and 8225 is selected from hydrido and alkyl; or a pharmaceutically-acceptable salt thereof.
(OOOi33~ Thiophene substituted hydroxamic acid derivatives described in U.S. Patent No. 6,515,014 have the formula shown above in formula XXXXV, wherein:
A'4 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 cyanoalkyi, and lower hydroxyalkyl;
Y'° is ethylene, isopropylene, propylene, butylene, lower alkenylene, and lower alkynylene;
R22° is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R22° 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 haloafkoxy, amino, lower alkylamino, phenylamino, vitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
8221 is selected from lower alkyl and amino; and 8222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically-acceptable salt thereof.
[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:
A'S is thienyl optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, vitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
Y" is selected from lower alkyl, tower alkeny! and lower alkynyl;
8223 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein 8223 is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, tower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, vitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
8224 is selected from lower alkyl and amino; and 8225 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 XXXXV11:

XXXXVII
wherein:
8226 and R22' are independently selected from the group consisting of H, halogen, Ci -C6 alkyl, Ci -C6 alkoxy, and C1-C6 alkoxy substituted by one or more fluorine atoms;
8228 is halogen, CN, CON R23° 8231, C02 H~ C02 C1 -Cs alkyl, or NHS02R23o;
8229 is C~ -Cs alkyl or NH2 ; and 8225 and 8225 are independently selected from the group consisting of H, Ci -C6 alkyl, phenyl, phenyl substituted by one or more atoms or groups selected from the group consisting of halogen, Ci -C6 alkyl, Ci -C6 alkoxy, and C~ -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-diaryi-3(2H)-furanone derivatives have the formula shown below in formula XXXXVI11:

8229 n wherein:
X33 represents halo, hydrido, or alkyl;
XXXXVN~
Y12 represents alkylsulfonyl, aminosulfonyl, alkylsulfinyl, (N-acylamino)-sulfonyl, (N-alkylamino}sulfonyl, or alkylthio;
Z" represents oxygen or sulfur atom;
8233 and 8234 are selected independently from lower alkyl radicals;
and 8232 represents a substituted or non-substituted aromatic group of 5 to atoms;
10 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. 8,492,416. 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':

N
XXXXIX

~23s 'V 'Se 823'7 xxxxix°

wherein:
8235 is a hydrogen atom or an alkyl group having 1-3 carbon atoms;
R23s is a hydrogen atom, a hydroxyl group, an ;organothiol group that is bound to the selenium atom by its sulfur atom, or 8235 and R23s are joined to each other by a single bond;
R23' 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;
8238 and 8239 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 R23$ and 8239 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:
S02R2~y ' R2e XXXXX
O
wherein:

X34 is selected from the group consisting of:
(a) a bond, (b) --(CH2)m --, wherein m 1 or 2, (c) --C(O)--, (d) --O--, (e) --S--, and (f) --N(R244)__;
R24° is selected from the group consisting of:
(a) C1 -C1o alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of: hydroxy, halo, C1 -Cio alkoxy, C1 -Cyo 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, C1-Cio alkoxy, Ci -C,o alkylthio, CN, C1 -Cyo alkyl, optionally substituted to its maximum with halo, and N3 ;
R24' is selected from the group consisting of (a) Ci -C6 alkyl, optionally substituted to its maximum with halo, (b) NH2, and (c) NHC(O)Cy -Cio alkyl, optionally substituted to its maximum with halo;
8242 and 8243 are each independently selected from the group consisting of: hydrogen, halo, and C1 -C6 alkyl, optionally substituted to its maximum with halo; and 8244 is selected from the group consisting of: hydrogen and C~ -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-methylsulfonyl)phenyl-3-phenoxy-pyran-2-one, 6-Methyl-4-(4-methylsulfonyl)phenyl-3-pyridin-3-yl-pyran-2-one, 3-Isopropylthio-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one, 4-(4-Methylsulfonyl)phenyl)-3-phenylthio-6-trifluoromethyl-pyran-2-one, 3-Isopropylthio-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-rnethylbutyl)-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.
200310165588, are useful as Cox-2 selective inhibitors of the present invention. Such free-B-ring flavanoids have the general structure shown in formula XXXXXf:

xxxxxi wherein:
R246~ Ra~.7~ R24a~ R249~ and R2so are independently selected from the group consisting of: --H, --OH, --SH, --OR, --SR, --NH2, --NHR245, --N(R245)21 --N~R245~3'r'X35- ~ a carbon, oxygen, nitrogen or sulfiur, glycoside of a single or a combination of multiple sugars including, aldopentoses, methyl-aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; wherein 8245 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.
[000'141) 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

N, \'s or a pharmaceutically acceptable salt thereof, wherein:
the ring of the formula (R255)-A-(SOmR254) is selected from the group consisting of:
SOm 8254 SOm 8254 SOm 8254 R255~ \X'1~3~5 N 8255 .J'W11~ , JWLh , .MM .

R2.

m is 0, 1 or 2;
X35 IS >CR255 or >N;
and 8251 is a radical selected from the group consisting of H, N02, CN, (C1-Cs}alkyl, (C1-Cs)alkyl-S02-, (Cs -C10)a~'YI-S02-s H-(G=O)-~ (C1-Cs)alkyl-(C=O)-, (C1-Cs)alkyl-)-(C=O)-, (C1 -Cs)heteroaryl-(C=O}-, (C1 -Cs)heterocyclYl-(C=O)-, H2N-(C=O)-, {C1-Cs)alkyl-NH-(C=O)-, [(C1 -Cs)alkYl]2-N-(C=O}-~ [(Cs -C1o)aryl]2-NH-(C=O)-~ [{G1-Gs)alkyl]-[((Cs -C1o)aryl-N]-(C=O)-, HO-NH-(C=O)-, and (C1 -Cs)alkyl-O-NH-(C=O)-;
8252 is a radical selected from the group consisting of H, -N02, -CN, (G2-Cs)alkenyl, (C2-Cs)alkynyl, {C3-C~)cycloalkyl, {Cs-C1o)aryl, (C1-Cs)heteroaryl, (C1-Cs)heterocyclyl, (C1-Cs)alkyl-O-, (C3-C7)cycloalkyl-O-, (Cs-C1o)aryl-O-, (C1-Cs)heteroaryl-O-, (Cs -Cs)heterocyclyl-O-, H-(C=O)-, (C1-Cs)alkyl-(C=O)-~ {C3-C7)cycloalkyl-(C=O}-s {Cs-C1o}aryl-(G=O)-, (C1-Cs)heteroaryl-(C=O)-, {C1-Cs)heterocyclyl-(C=O)-, (C1-Cs)aikyl-O-(C=O)-, (C3-C~)cycloalkyl-O-(C=O)-, (Gs-C1o}aryl-O-(C=O)-, (C1-Cs)heteroaryl-O-{C=O)-, (C1-Cs}heterocyclyi-O-(C=O)-, (C1-Cs)alkyl-(C=O)-O-, (C3-C~)cycloalkyl-(C=O)-O-, (Cs-C1o)aryl-{C=O)-O-, (C1-Cs)heteroaryl-(C=O)-O-, (C1-Cs)heterocyclyl-(C=O)-O-, (C1-Cs)alkyl-{C=O)-NH-, (C3-C7)cycloalkyl-(C=0)-NH-, (Cs-Cloaryl-{C=O)-NH-. (C1-Gs)heteroaryl-(C=O)-NH-, (C1-Cs)heterocyclyl-(C=O)-NH-, (C1-Cs)alkyl-O-{C=O)-NH-, (C1-Cs)alkyl-NH, [(C1-C6)alkyl]2-N-, (C3-C7)cycfoalkyl-NH-. [(C3-C7)cycloalkyl]2-N-~ [(Cs-C1o)aryl]-NH-~ [(Cs-C1 o)arYl]2-N-s [{C1-Cs}alkyl]-[{{Cs-C1o)arYl)-N]-~
[(C1-Cs)heteroaryl]-NH-, [(C1-Cs)heteroaryl]2-N-, [(C1-Cs}heterocycly]-NH-, [{C1-Cs)heterocyclyl]2-N-, H2N-(C=O)-, HO-NH-(C=O)-, (C1-Cs)alkyl-O-NH
(C=O)-, [{C1-Cs)alkyl]-NH-(C=O)-, [(C1-Cs)alkYl]2-N-(C=O}-, [{C3 C7)cycloalkyl]-NH-(C=O)-, [(C3-CycYcloalkyl]2-N-(C=O)-, [{Cs-C1o)aryl]-NHv (C=O)-~ [(Cs-C~oarYlJ2-N-(C=O)-~ [(C1-C s)alkylJ-[((Cs-Cio)atYl)-NJ-(C=O)-, [(C1-C9)heteroaryfJ-NH-(C=O)-, [(Ci-C9)heferoarylJ2-N-(O=O)-, [(Ci-C9)heterocycIyIJ-NH-(C=O)-, (C1-Cs)alkyl-S- and (Ci-C6)alkyl optionally substituted by one -OH substituent or by one to four fluoro substituents;
8253 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-, -O-, 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-Cs)alkenyl, (C2-Cs)afkynyl, (C3-C7)cycloalkyl, (Cs-C1o)aryl, (C2-C9)hetorocyclyl, (C~ -Cs)alkyl-O-, H-(C=0)-, (Cy-Cs)alkyl-(C=O)-, HO-(C=O)-, (Ci-Cs)alkyl-O-(C=O}-, -NH2, (C~-Cs)alkyl-NH-, [(Ci-Cs) alkylJ2-N-, (C3-C~)cycloalkyl-NH-, (Cs-Cio)aryl-NH-, [(Ci-Cs)alkylJ-[((Cs-Cio)aryl)-N]-, (C~-C9)heteroaryl-NH-, H2N-(C=O)-[(Cy-Cs)aIkyIJ-NH-(C=O)-, [(Ci-Cs)alkylJ2-N-(C=O)-~ [(Cs-C~o)a~'YlJ-NH-(C=O)-~ [(C1-Cs)aIkyIJ-[((Cs-Cio)atyl)-NJ-(C=O)-, (Ci-Cs)alkyl-O-NH-(C=O)-, (Cy-Cs)alkyl-(C=O)-HN-, (C1-Cs)alkyl-(C=O)-[(Gy-Cs)alkyl-NJ-, -SH, (C1-Cs}alkyl-S-, (Cy-Cs}alkyl-(S=0)-, (C1-Cs)alkyl-S02- and (C~-Cs}alkyl optionally substituted with one to fourfluoro moieties;
wherein said saturated (3- to 4-membered)-heteracyclyl ring radical; or said saturated, partially saturated or aromatic (7- to 9-membered)-heterocyclyf 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)cyoloalkyf, (Cs-C1o)aryl, (C2-C9)heterocyclyl, H-(C=O)-, (Ci-Cs)alkyl-(C=O)-, (C~-Cs)alkyl-O-(C=O)-, H2N-(C=O)-, ((Ci-Cs)alkyl]-NH-(C=O)-, L(C1-Cs)alkyl]2-N-(C=O)-, E(Cs-'Cio)a~'Yll-NH-(C=O)-, [(C~-Cs)alkyl]-(((Cs-Cio)aryl)-N]-(C=O)-, (C1 -Cs)alkyl-O-NH-(C=O)-, and (C1-Cs)alkyi optionally substituted with one to four fluoro moieties;
8254 is an (C~-Cs)alkyl radical optionally substituted by one to four fluoro substituents; and 8255 is a radical selected from the group consisting of H, halo, -OH, (C1-Cs)alkyl-O-, (C2-Cs)alkenyl, (C2-Cs) alkynyl, (C3-C7)cycloalkyl, -CN, H-i 0 (C=O)-, (C1-Cs)alkyl-(C=O)-, (Cy-Cs)alkyi-(C=O)-O-, HO-(C=O)-, (Cy-Cs)alkyl-O-(C=O)-, (C1-Cs)alkyl-NH-. ((C1-Cs)alkyl]2-N-, (C3-C7)cycloalkyl-NH-, (Cs-Cyo)aryl-NH-, L(C~-Cs)alkyl]-[((Cs-C,o)aryl)-N]-, (C1-C9)heteroaryl-NH-, H2N-(C=O)-, (Ci-Cs)alkyl-NH-(C=O)-. ((C1-Cs)alkyl]2-N-(C=O)-, (Cs-Cyo)atyl-(C=O)-, L(Ci-Cs)alkyl]-[((Cs-Cio)ar'Yl)-N]-(C=O)-, (Ci-Cs)alkyl-O-NH-(C=O)-, (C~-Cs)alkyl-S-, and (Ci-Cs)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 XXXXXItt:

XXXXXI I f wherein:
8256 represents an alkyl or -NR25s 8260 group, wherein 8259 and R2s°
each independently represents a hydrogen atom or an alkyl group;
R25~ 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, hydroxyaikyl or hydroxycarbonyl groups;
R25$ represents a methyl, hydroxymethyl, alkoxymethyl, C3 -C~
cycloalkoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrite, trifluoromethyl or difluoromethyl group or a CH2 -- R2s' group wherein R26' 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.
[OOO~f 43] Examples of 2-phenylpyran-4-one derivatives useful in the present invention include, but are not limited to:
3-(4-fluorophenyl)-2-(4-methanesulfont'!phenyl)-6-methylpyran-4-one, 3-(2-fluorophenyl)-2-(4-methanesulfont'!phenyl)-6-methylpyran-4-one, 3-(4-chlorophenyl)-2-(4-methanesulfont'!phenyl)-6-methylpyran-4-one, 3-(4-bromophenyl)-2-(4-methylsulfont'!phenyl)-6-methylpyran-4-one, 3-(2,4-difluorophenyl)-2-(4-methanesulfont'!phenyl}-6-methylpyran-4-one, 3-(3,4-dichlorophenyl)-2-(4-methanesulfont'!phenyl)-6-methylpyran-4-one, 3-(3-chloro-4-methylphenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one , 2-{4-methanesulfont'!phenyl)-6-methyl-3-phenoxypyran-4-one, 3-(4-fluorophenoxy)-2-(4-methanesulfont'!phenyl)-6-methylpyran-4-one, 3-(2-fluorophenoxy)-2-(methanesulfont'!phenyl)-6-methylpyran-4-one, 3-(4-chlorophenoxy}-2-(methanesulfont'!phenyl)-6-methylpyran-4-one, 3-(2-chlorophenoxy)-2-(methanesulfont'!phenyl)-6-methylpyran-4-one, 3-(4-bromophenoxy)-2-(4-methanesulfont'!phenyl)-6-methylpyran-4-one, 2-(4-methanesulfont'!phenyl)-6-methyl-3-(4-methylphenoxy)pyran-4-one, 3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4.
one, 3-(2,5-difluorophenoxy)-2-{methanesulfont'!phenyl)-6-methylpyran-4-one, 3-(4-chlorophenyl)-2-(4-methanesulfont'!phenyl)-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-acetyl-3-(4-fluorophenyl)-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)-1H-pyrazo!-1-yl)benzenesulfonamide;
a7) 4-(5-(4-chlorophenyl)-3-phenyl-1 H-pyrazol-1-yl)benzenesulfonamide;
a8) 4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;
a9) 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1 H-pyrazol-1-yl)benzenesulfonamide;

a1 0) 4-(5-(4-chloropheny!)-3-(4-nitrophenyi)-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-yi)benzenesulfonamide b3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazoi-1-y1]benzenesulfonamide;
b4) 4-[5-phenyl-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzenesulfonamide;
b5) 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
b6) 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazof-1-yl]benzenesulfonamide;
b7} 4-[5-{4-chlorophenyl)-3-(difluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
b8) 4-[5-(4-methylphenyl}-3-{trifluoromethyl)-iH-pyrazol-1-yl]benzenesulfonamide;
b9) 4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
b10) 4-[3-(difluoromethyi)-5-{4-methylphenyl)-1 H-pyrazol-1-yl]benzenesulfanamide;
c1 ) 4-[3-(difluoromethyl)-5-phenyl-1 H-pyrazol-1-yl]benzenesulfonamide;
c2) 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
c3) 4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
c4) 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
c5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
c6) 4-[4-chloro-5-phenyl-1 H-pyrazol-1-yl]benzenesulfonamide;
c7) 4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;

c8) 4-[5-(4-(N,N-dimethylamino)phenyl}-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
c9) 5-(4-fluorophenyl)-6-[4-(methylsulfony!)phenyl]spiro[2.4]hept-5-ene;
c10) 4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;
d1} 6-(4-fluorophenyl)-7-[4-(methylsulfonyl}phenyl]spiro[3.4]oct-6-ene;
d2) 5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfont'!)phenyl]spiro[2.4]hept-5-ene;
d3) 4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;
d4) 5-(3,5-dichioro-4-methoxyphenyl)-6-[4-(methylsulfont'!)phenyl]spiro[2.4]hept-5-ene;
d5) 5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfont'!)phenyl]spiro[2.4]hept-5-ene;
d6) 4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;
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-methylsulfont'!phenyl)-2-(2-thienyl)thiazole;
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)phenyl]thiazole;
e5) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;

e6) 1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene;
e7) 4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide;
e8) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6-diene;
e9) 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl]benzenesulfonamide;
e10) 6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsuffonyl)phenyl]-pyridine-3-carbonitrile;
f1 ) 2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyridine-3-carbonitrile;
f2) 6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyl-pyridine-3-carbonitrile;
f3) 4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
f4) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
f5) 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
f6) 3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
f7) 2-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyf)-1 H-imidazol-2-yl]pyridine;
f8) 2-methyl-4-[1-[4-(methylsulfonyl)phenyl~4-(trifluoromethyl)-iH-imidazol-2-yl]pyridine;
f9) 2~methyl-6-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H-imidazol-2-yl]pyridine;
f10) 4-[2-(6~methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
g1) 2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1 H-imidazole;

g2) 4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
g3) 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1 H-imidazole;
g4) 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1 H-imidazole;
g5) 2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1 H-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-methyiphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazole;
g9) 4-[2-(3-chloro-4-methylphenyl)-4-(trifluorornethyl)-iH-imidazol-1-yl]benzenesulfonamide;
g10) 2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1 H-imidazole;
h 1 ) 4-[2-(3-fluoro-5-methyiphenyl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
h2) 2-(3-methylphenyl)-i-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazole;
h3) 4-[2-(3-methylphenyl)-4-trifluoromethyf-1 H-imidazol-1-yl]benzenesulfonamide;
h4) 1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-1 H-imidazole;
h5) 4-[2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;
h6) 4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;
h7) 4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1 H-imidazol-1-yl]benzenesulfonamide;

h8) 1-allyl-4-(4-fluorophenyl}-3-[4-(methylsulfonyl}phenyl]-5-(trifluoromethyl)-1 H-pyrazole;
h9) 4-[1-ethyl-4-(4-fluorophenyl)-5-{trifluoromethyl)-1 H-pyrazol-3-yl]benzenesulfonamide;
ii) N-phenyl-[4-(4-luorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1 H-pyrazol-1-yl]acetamide;
i2) ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl}phenyl]-5-(trifluoromethyl)-1 H-pyrazol-1-yl]acetate;
i3) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-1 H-pyrazole;
i4) 4-{4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl}-5-(trifluoromethyl)pyrazole;
i5) 't-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1 H-pyrazole;
i6) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1 H-imidazole;
i7) 4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1 H-imidazole;
i8) 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phehyl]-6-(trifluoromethyl)pyridine;
i9) 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;
ii0) 5-(4-fluorophenyl)-4~[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine;
j1 ) 2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;
j2) 4-[2-(3-chloro-4~methoxyphenyl)-4,5-difluorophenyf]benzenesulfonamide;
j3) 1-{4-fluorophenyl)-2-[4-(methylsulfonyf)phenyl]benzene;

j4) 5-difluoromethyl-4-{4~methylsulfonylphenyl)-3-phenylisoxazole;

j5) 4-[3-ethyl-5-phenylisaxazol-4-yl]benzenesulfonamide;

j6) 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

j7) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
j8) 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide;
j9) 1-[2-(4-fluorophenyl)cyciopenten-1-yl]-4-(methylsulfonyl)benzene;
j 10) 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
k1 ) 1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
k2) 1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
k3) 1-(2-(4-trifluoromethylphenyi)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
k4) 1-[2-(4-methylthiophenyl)cyclopenten-i -yl]-4-(methylsulfonyl)benzene;
k5) 1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl)-4-{methylsulfonyl)benzene;
k6) 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonamide;
k7) 1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene;
k8) 4-[2-{4-chlorophenyl)-4,4-dimethylcyclopenten-1-ylJbenzenesulfonamide;
k9) 4-(2-(4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;
k10) 4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide;

11 ) 1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

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

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

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

15) 4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl)benzenesulfonamide;
15) 4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]benzenesulfonamide;

17) ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyl]oxazol-2-yl]-2-benzyl-acetate;
18) 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]acetic acid;
19) 2-(tent butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazole;

110) 4-(4-fluarophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole;

m1) 4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole;

and m2) 4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyf-4-oxazolyl]benzenesulfonamide.
m3) 6-chloro-2-trifluoromethy!-2H-1-benzopyran-3-carboxylic acid;
m4) 6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
m5) 8-(1-methylethyf)-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;
m10) 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-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
n4) 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
n5) 7,8-dimethyl-2-trifluoromethyf-2H-1-benzopyran-3-carboxylic acid;
n6) 6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benxopyran-3-carboxylic acid;

n7) 7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
n8) 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
n9) 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
n10) 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
01) 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

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

05) 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
06) 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
07) 8-chloro-6-methoxy-2-triouoromethyl-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-trifluoromethyl-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)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

p5) 6-((dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p6) 6-((methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p7) 6-((4-morpholino)sulfonyi]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p8) 6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p9) 6-[{2-methylpropyl)aminosulfonyi]-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]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q2) 6-phenyiacetyl-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-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q5) 6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q6) 6-benzylsulfonyl-2-trifluoromethyi-2H-1-benzopyran-3-carboxylic acid;
q7) 6-[(N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; .
q8) 6-[(N-(2-phenylethyl)amino]sulfonyl)-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-yl]benzenesulfonamide;
r4) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
r5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
r6) 3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-iH-imidazol-2-yl]pyridine;
r7) 2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;
r8) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
r9) 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
r10) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
s1 ) [2-trifluoromethyf-5-(3,4-difluorophenyl)-4-oxazolyl]benzenesulfonamide;
s2) 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; or s3) 4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzenesulfonamide;
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, et al. 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.

[OOOi 47~ 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 Spuibb, 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.

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[000151 j, The phosphodiesterase 4 inhibitor of the present invention is preferably selected from the group consisting of roflumilast, cilomilast, etazolate hydrochloride, Ro 20-1724, rofipram, (Fi7=(-)-rolipram, (S)-(+)-rolipram, zardaverine, V11294A, CDP840, denbufylline, mesopram, cipamfylline, SCH 351591, SCH 365351, L-791,943, 7-benzylamino-6 chloro-2-piperazino-pteridine, piclamifast, 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, CI 1018, D-22888, and combinations thereof. In preferred embodiments, the phosphodiesterase 4 inhibitor is roflumifast.
[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 COPl7, 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.
[000'156] 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 mgtkg per day; more preferably about 0.5 mglkg 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 welt 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 C~PD 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"(1998).
<www.cpsa.ab.ca/qoc/Guidefines%20for%20Spirometry%20&%20FIow%2 OVolume%20Measurements.doc>.
[000165] Common parameters that spirometry measures include Forced Vital Capacity (FVC) and Forced Expiratory Volume (FEV). FVC is the i 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. Neaithatozcom, 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 difuents. 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, parenteralfy, 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 injectabie aqueous or oleaginous suspensions.
[000i72] 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.
i 0 [00017fi] 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, fior 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 (END) 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 cone-like 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.
[000i80] 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.
[00018'1 J 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-s lingual" administration, which includes lozenges or a chewable gum comprising 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.
[OOOi 86] 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, polyoxyethylenelpofyoxypropylene 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.
[000189] 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 dimethylsulfoxide (DMSO), dimethylformamide, methyl dodecyl sulfoxide, dimethylacetamide; esters, such as isopropyl myristatelpalmitate, 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 capryfic acid; lactam compounds, such as ozone; alkanols, such as oleyl alcohol; dialkylamino acetates, and admixtures thereof.
[000191] The above considerations concerning efifective formulations and administration procedures are well known in the art and are described in standard textbooks. See e.g. Gennaro, A. R., Reminaton: The Science and Practice of Pharmacy, 20'" Edition, (Lippincott, Williams and Wilkins), 2000; Hoover, John E., Reminaton'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 Exciaients (3'd 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.

' [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°l°) 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-pyrazo!-1-yl]benzenesulfonamide.
(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 C1~ H14 N3 02 SF~ ;
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.

[000199] This example demonstrates the preparation of 3-cyclo-propyimethoxy-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 thionyf 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.

(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 mil! or mixing device suitable far 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 p,g of roflumilast and 100 p.g 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

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, zidornetacin, zomepirac, 2-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-trifluoromethyl-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-trifluoromethyl-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-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-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-benzapyran-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-[(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)amino]sulfonyl]-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-trifluoromethyf-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-i -benzopyran-3-carboxylic acid, 6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, 6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzapyran-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-trifluoromethyl-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, 2,8-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, 6,8-dichloro-2-trifluoromethyl-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-(trifluoromethyl)-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)-2 H-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, imides, substituted 1,3,4-oxadiazoles, cyano derivatives of substituted styrenes, carboxy derivatives of substituted styrenes, substituted phenethylsulfones, nitrites, succinimide cytokine inhibitors, maleimide cytokine inhibitors, nicotinamide benzofused-heterocyclyl derivatives, ether derivatives, roflumilast, cilomilast, etazolate hydrochloride, Ro 20-1724, rolipram, (R)-(-)-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, piclamifast, D-4418, Cl 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, nitrites, 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, (R)(-)-rolipram, (S)-{+)-rolipram, zardaverine, V11294A, GDP840, denbufylline, mesopram, cipamfylline, SGH 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, Cl 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, 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, 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-783003, 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-triouoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-7-methyl-2-trilluoromethyl-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-trifluoromethyl-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-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-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-[(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-8-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)amino]sulfonyl]-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-(trifiluoromethyl)-3-quinolinecarboxylic acid, 7-(1,1-dimethylethyl)-2-trifluoromethyl-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-(trifiluoromethyl)-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-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid, and mixtures thereof.

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 (S)-6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-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.

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, (R)-(-)-rolipram, (S)-(+)-rolipram, zardaverine, V11294A, CDP840, denbufylline, mesopram, cipamfylline, SCH 351591, SCH 365351, L-791,943, 7-benzylamino-6-chloro-2-piperazino-pteridine, picfamilast, 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.