WO2005084654A2

WO2005084654A2 - Methods and compositions for treating or preventing psychiatric disorders with cox-2 inhibitors alone and in combination with antidepressant agents

Info

Publication number: WO2005084654A2
Application number: PCT/US2005/006818
Authority: WO
Inventors: Diane Stephenson; Duncan P. Taylor
Original assignee: Pharmacia Corporation
Priority date: 2004-03-02
Filing date: 2005-03-02
Publication date: 2005-09-15
Also published as: BRPI0508254A; CA2556380A1; JP2007526328A; WO2005084654A3; EP1725222A2

Abstract

The present invention relates to a novel method of treating and/or preventing psychiatric disorders in a subject by administering to the subject at last one Cox-2 inhibitor alone or in combination with one or more antidepressant agents. Compositions, pharmaceutical compositions and kits are also described.

Description

METHODS AND COMPOSITIONS FOR TREATING OR PREVENTING PSYCHIATRIC DISORDERS WITH COX-2 INHIBITORS ALONE AND IN COMBINATION WITH ANTIDEPRESSANT AGENTS BACKGROUND OF THE INVENTION

(1 ) Field of the Invention:

[0001] The present invention relates generally to the use of an enzyme inhibitor alone and in combination with an antidepressant agent for the treatment or prevention of psychiatric disorders, and in particular to the use of a cyclooxygenase-2 inhibitor alone and in combination with an antidepressant agent.

(2) Description of the Related Art:

[0002] Many people in the United States and around the world suffer from some form or combination of psychiatric disorders. A broad spectrum of psychiatric disorders has now been recognized, many of which have overlapping and interacting etiologies. Two of the most widespread and prevalent of the psychiatric disorders are depression (unipolar disorder or major depressive disorder) and manic depression (bipolar disorder). [0003] The most common category of psychiatric disorders is mood disorders, accounting for 25% of patients in public mental institutions, 65% of psychiatric outpatients, and 10% of all patients seen in nonpsychiatric medical settings. Mood disorders are a group of typically recurrent illnesses characterized by pervasive disturbances, psychomotor dysfunction and vegetative symptoms, including depression, manic depression, dysthymic disorders, and cyclothymic disorder. Some type of mood disorder affects 20% of women and 12% of men during their lifetime, with a major part of these figures representing subjects suffering from depression. See The Merck Manual of Diagnosis & Therapy, Beers & Brakow, 17^th edition, Published by Merck Research Labs, Sec. 15, Chap.

189, Psychiatric Disorders, Mood Disorders (1999). [0004] A subject suffering from depression may display a variety of symptoms and moods. The mood of a subject suffering from depression can generally be depressed, irritable, anxious, miserable, morbid, preoccupied with guilt, self-degenerating, indecisive, helpless, hopeless, or any combination thereof. The subject may also have social withdrawal, recurrent thoughts of death or suicide, sleep disorders, decreased ability to concentrate, diminished interest in usual activities, or any combination of these symptoms. [0005] While the exact cause of depression and other mood disorders is unknown, it has been suggested that impaired limbic- diencephalic function is the final pathway causing mood disorders. Also, cholinergic, catecholaminergic (noradrenergic or dopaminergic) and serotonergic (5-HT) neurotransmission imbalances have been implicated as a cause of many mood disorders. Most antidepressant agents are directed toward these systems as a treatment or prevention of psychiatric disorders.

[0006] Other causes of mood disorders can be stressors that provoke affective episodes either psychologically or biologically. Traumatic life events, especially separations, commonly precede depressive and manic depressive episodes. This type of mood disorder may arise in a subject with any type of personality, although, such events may trigger depression symptoms from manifesting in a subject suffering from a subtle mood disorder rather than its cause. [0007] Some subjects suffering from one or more psychiatric disorders also have signs of physical pain, sickness, headaches, or other physical conditions. Subjects diagnosed with one or more psychiatric disorders are often treated as outpatients, although other patients require full-time supervision and treatment. Antidepressant agents play a large role in this treatment, usually in combination with supportive therapy. Many different types of antidepressant agents with varying functionalities have emerged over the years and are used as pharmaceutical therapies. See Abies, A., et al., Am. Fam. Physician 67(3):547-54 (2003). These antidepressant agents are helpful to the patient by helping to treat and prevent the emergence of symptoms associated with the psychiatric disorder. See Hegarty K. et al., Aust. Fam. Physician 32(4):229-34, 236-7, 239 (2003). In fact, symptom remission is usually the goal of treatment of a subject suffering from a psychiatric disorder.

[0008] An example of one of the most prevalently prescribed antidepressant agents is the compound sertraline (Zoloft®). Sertraline was initially introduced for the treatment of depression, but it is now used to treat a wide variety of psychiatric disorders. See Khouzam H., et al., Compr. Ther. 29(1) 47-53 (2003). Sertraline acts as a selective serotonin reuptake inhibitor (SSRI). However, it is structurally unrelated to other SSRIs, tricyclic, tetracyclic, or other available antidepressant agents. [0009] Even after treatment with an antidepressant agent, a subject suffering from depression often continues to have symptoms. See Menza M., et al., J. Clin. Psychiatry 64(5):516-23 (2003).

[0010] Some subjects also develop physical side effects during treatment with an antidepressant agent. These side effects may include sexual dysfunction, sickness, headaches, pain, sleep disorders, physical dependence and addiction to the antidepressant agent, and other adverse side effects. Also, many subjects suffering from depression do not respond as expected to conventional treatment with antidepressant drugs. [0011] Moreover, the treatment of psychiatric disorders with only antidepressant agents fails to address all the underlying causes of psychiatric disorders. This is problematic because some psychiatric disorders are thought to arise, in part, from the release of inflammatory mediators formed within the brain. For example, several clinical studies have suggested that depression may be accompanied by an activation of the inflammatory response system. See Tiemeier, H., et al., Epidemiology 14(1)Λ03-7 (2003). Another study reported that an association exists between depression and the presence of low-grade systemic inflammation. See Danner, M., et al., Psychosom. Med. 65(3) 347-56 (2003). Conventional antidepressants fail to address this inflammatory aspect of psychiatric disorders.

[0012] Inhibitors of the cyclooxygenase-2 (Cox-2) enzyme have been increasingly recognized as having beneficial effects on inflammation. For example, typical of the development of many inflammatory symptoms is upregulation of the Cox-2 enzyme. Cox-2 is an enzyme produced by an inducible gene, which is responsible for the biosynthesis of prostaglandins in inflammatory cells. Inflammation causes the induction of the Cox-2 enzyme, leading to the release of prostanoids (prostaglandin E2), which sensitize peripheral nociceptor terminals and produce localized inflammation and edema. See e.g., Samad, T., et al., Nature 4J0(6827):471-5 (2001).

[0013] Historically, physicians have treated inflammation-related disorders with a regimen of nonsteroidal anti-inflammatory drugs (NSAIDS), such as, for example, aspirin and ibuprofen. Undesirably, however, some NSAIDS are known to cause gastrointestinal (Gl) bleeding or ulcers in patients undergoing consistent long term regimens of NSAID therapy. See Henry, D., et al., Lancet 337:730 (1991 ). [0014] A reduction of unwanted side effects of common NSAIDS was made possible by the discovery that two cyclooxygenases are involved in the transformation of arachidonic acid as the first step in the prostaglandin synthesis pathway. These enzymes exist in two forms and have been termed cyclooxygenase-1 (Cox-1 ) and cyclooxygenase-2 (Cox- 2). See Needleman, P. et al., J. Rheumatol. 24, Suppl. 49:6-8 (1997). [0015] Cox-1 is a constitutive enzyme responsible for the biosynthesis of prostaglandins in the gastric mucosa and in the kidney. Cox-2 is an enzyme that is produced by an inducible gene that is responsible for the biosynthesis of prostaglandins in inflammatory cells. Inflammation causes the induction of Cox-2, leading to the release of prostanoids (prostaglandin E2), which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity, inflammation, and oedema. See Samad, T., et al., Nature 410(6827):47 -5 (2001 ). [0016] Many common NSAIDs are now known to be inhibitors of both Cox-1 and Cox-2. Accordingly, when administered in sufficiently high levels, these NSAIDs not only alleviate the inflammatory consequences of Cox-2 activity, but also inhibit the beneficial gastric maintenance activities of Cox-1.

[0017] Research into the area of arachidonic acid metabolism has resulted in the discovery of compounds that selectively inhibit the Cox-2 enzyme to a greater extent than the activity of Cox-1. The Cox-2 selective inhibitors are believed to offer advantages that include the capacity to prevent or reduce inflammation while avoiding harmful side effects associated with the inhibition of Cox-1. Thus, Cox-2 selective inhibitors have shown great promise for use in therapies -- especially in therapies that require maintenance administration, such as for pain and inflammation control. [0018] While Cox-2 inhibitors have been described heretofore for treating pain and inflammation, they have not been described for the treatment or prevention of psychiatric disorders. [0019] Despite the recent advances that have been made in understanding psychiatric disorders, they remain notoriously difficult to treat or prevent. Although significant progress has been made in the field of antidepressant agents, a continuing need still exists for better antidepressant agents that also have fewer side-effects and a more targeted functionality. From the foregoing, it can be seen that a need exists for improved methods and therapeutic compositions to treat psychiatric disorders. It would also be useful to provide an improved method and composition for reducing the symptoms associated with psychiatric disorders. Likewise, methods and compositions that improve patient outcomes following treatment with antidepressant agents would be desirable. Also, methods and compositions that reduce dosages or reduce unwanted side effects in conventional treatments for psychiatric disorders are desirable. Finally, methods and compositions that improve the efficacy of treating psychiatric disorders that are resistant in a particular subject to known methods of therapy alone would also be desirable.

SUMMARY OF THE INVENTION [0020] Briefly, therefore, the present invention is directed to a novel method of treating or preventing a psychiatric disorder in a subject comprising administering to the subject at least one Cox-2 inhibitor. [0021] The present invention is also directed to a novel method o-f treating or preventing a psychiatric disorder in a subject comprising administering to the subject at least one Cox-2 inhibitor in combination with an antidepressant agent.

[0022] The present invention is also directed to a novel therapeutic composition comprising a Cox-2 inhibitor and an antidepressant agent. [0023] The present invention is also directed to a novel pharmaceutical comprising a Cox-2 inhibitor, an antidepressant agent, and a pharmaceutically acceptable carrier.

[0024] The present invention is also directed to a novel kit for preventing or treating psychiatric disorders in a subject that is in need of such prevention or treatment, the kit comprising one dosage form comprising a Cox-2 inhibitor and a second dosage form comprising an antidepressant agent.

[0025] Among the several advantages found to be achieved by trie present invention, therefore, may be noted the provision of improved methods, therapeutic compositions, pharmaceutical compositions, and kits for the prevention or treatment of psychiatric disorders such as depression. Other advantages achieved by the present invention include improved methods, compositions, and kits for reducing both the inflammation and depression symptoms that may be associated with psychiatric disorders. Still other advantages achieved by the present invention include methods, compositions, and kits that improve patient recurrences of psychiatric symptoms. In addition, the present invention provides methods, compositions, and kits that reduce dosages or reduce unwanted side effects in conventional treatments for psychiatric disorders. Finally, the present invention provides methods and compositions that improve the efficacy of treating a psychiatric disorder that is considered resistant or intractable to known methods of therapy alone.

DETAILED DESCRIPTION [0026] In accordance with the present invention, it has been discovered that the treatment and/or prevention of psychiatric disorders, including such disorders as depression and manic depression, is provided by a therapy comprising a Cox-2 inhibitor alone or in combination with an antidepressant agent.

[0027] For purposes of the present invention, the novel therapy comprising at least one Cox-2 inhibitor alone or in combination with at least one antidepressant agent is useful for the purpose of preventing or treating psychiatric disorders. The present therapy is also useful for the purpose of preventing or treating psychiatric disorders in a subject that is in need of such prevention or treatment. '

[0028] The therapy of the present invention is useful, for example, to reduce such psychiatric disorder symptoms as a mood that is depressed, irritable, anxious, miserable, morbid, preoccupied with guilt, self-degenerating, indecisive, helpless, hopeless, or any combination of the foregoing. The subject may also have social withdrawal, recurrent thoughts of death or suicide, sleep disorders, decreased ability to concentrate, diminished interest in usual activities, or any combination of these symptoms. The therapy of the present invention would also be useful to prevent the occurrence of such symptoms. [0029] The methods and compositions of the present invention are also useful to reduce the number of hospitalizations of subjects suffering from a chronic psychiatric disorder. [0030] The administration of a Cox-2 inhibitor alone or in combination with at least one antidepressant agent for the prevention or treatment of a psychiatric disorder is an unexpectedly effective treatment and preventative therapy. Such administration is effective for improving the symptoms of a psychiatric disorder while avoiding or reducing certain disadvantages of current treatments. The therapy of a Cox-2 inhibitor alone or in combination with at least one antidepressant agent is also useful for decreasing the required number of separate dosages, thus, potentially improving patient compliance.

[0031] Therapies comprising at least one Cox-2 inhibitor alone or in combination with at least one antidepressant agent are useful not only for improving psychiatric disorder symptoms and shortening recovery times, but also for reducing or eliminating the dosages of antidepressant agents that are normally required. The elimination of or administration of lower dosages of antidepressant agents provides a reduction in side effects corresponding to such antidepressant agents. [0032] Another embodiment of the present invention is a combination therapy for treating or preventing psychiatric disorders and psychiatric disorder symptoms in a subject in need of such treatment and prevention comprising at least one Cox-2 inhibitor and at least one antidepressant agent. [0033] Such administration is effective for improving the symptoms of psychiatric disorders while avoiding or reducing certain disadvantages of current treatments. The combination therapy of a Cox-2 inhibitor and an antidepressant agent is also useful for decreasing the required number of separate dosages, thus, potentially improving patient compliance. For example, in one embodiment, the combination therapy of the present invention is useful for reducing the dosing frequency of conventional antidepressant treatment agents. One antidepressant agent, buproprion (Wellbutrin®), is typically dosed three to four times daily. Dosing three to four times daily may become problematic for a subject suffering from a neurodegenerative symptom, such as short term memory loss or from seriously ill subjects who have difficulty complying with multiple doses/day.

Thus, administering the combination therapy of the present invention to a subject undergoing dosing with buproprion may reduce the required number of separate doses normally prescribed with buproprion. [0034] Combination therapies comprising Cox-2 inhibitors and antidepressant agents are useful not only for improving psychiatric disorder symptoms and shortening recovery times, but also for reducing the dosages of conventional antidepressant agents that are normally required.

[0035] For example, the combination therapy is effective for lowering the dosages of antidepressant agents that are normally prescribed as a monotherapy. The administration of lower dosages of antidepressant agents provides a reduction in side effects corresponding to such agents. Reduced dosages of antidepressant agents are beneficial where normal dosages often exhibit harmful side effects, for example, with such conventional antidepressant agents as fluoxetine (Prozac®). In some patients, fluoxetine causes sexual dysfunction, which can lead to reduced patient compliance with the treatment regimen. [0036] The administration of a Cox-2 inhibitor in combination with an antidepressant agent is an effective treatment for psychiatric¹ disorders and psychiatric disorder-related symptoms, and in preferred embodiments, is superior to the use of either agent alone.

[0037] Moreover, in one embodiment, the combination therapy demonstrates a synergistic efficacy for treating and preventing psychiatric disorders and psychiatric disorder-related complications that is greater than what would be expected from simply combining the two therapies. [0038] The term "synergistic" refers to the combination of a Cox-2 inhibitor and an antidepressant agent as a combined therapy having an efficacy for the prevention and treatment of psychiatric disorders that is greater than what would be expected merely from the sum of their individual effects. [0039] The synergistic effects of the embodiments of the present invention's combination therapy encompass additional advantages for the treatment and prevention of psychiatric disorders. Such additional advantages include, but are not limited to, lowering the required dose of antidepressant agents, reducing the side effects of antidepressant agents, and rendering those agents more tolerable to subjects in need of psychiatric disorder therapy. [0040] As used herein, the phrases "combination therapy", "co- administration", "co-administering", "administration with", "administering", "combination", or "co-therapy", when referring to the embodiment of the present invention that comprises the use of a Cox-2 inhibitor in combination with an antidepressant agent, 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 as well to embrace co-administration of these agents in a substantially simultaneous manner. Thus, the Cox-2 inhibitor and antidepressant agent may be administered in one therapeutic dosage form, such as in a single capsule, tablet, or injection, or in two separate therapeutic dosage forms, such as in separate capsules, tablets, or injections. [0041] Sequential administration of such treatments encompasses both relatively short and relatively long periods between the administration of each of the drugs of the present method. However, for purposes of the present invention, the second drug is administered while the first drug is still having an efficacious effect on the subject.

[0042] Preferably, the second of the two drugs is to be given to the subject within the therapeutic response time of the first drug to be administered. For example, the combination therapy of the present invention encompasses administration of a Cox-2 inhibitor to the subject and the later administration of an antidepressant agent, as long as the antidepressant agent 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 antidepressant agent is therapeutically effective, and vice versa. [0043] As used herein, the term "therapeutic response time" means the duration of time that a compound is present or detectable within a subject's body at therapeutic concentrations. [0044] As used herein, the term "monotherapy" is intended to embrace administration of a Cox-2 inhibitor to a subject suffering from a psychiatric disorder as a single therapeutic treatment without any additional therapeutic treatment comprising an antidepressant agent. However, the Cox-2 inhibitor may still be administered in multiple dosage forms. Thus, the Cox-2 inhibitor may be administered in one therapeutic dosage form, such as in a single capsule, tablet, or injection, or in two separate therapeutic dosage forms, such as in separate capsules, tablets, or injections.

[0045] In one embodiment, the present invention provides a method for treating or preventing psychiatric disorders in a subject in need of such treatment or prevention.

[0046] In another embodiment, the present invention provides a method for preventing psychiatric disorders in a subject comprising administering to the subject a Cox-2 inhibitor alone or in combination with an antidepressant agent. [0047] As used herein, the terms "to prevent", "preventing", or

"prevention" refer to any reduction, no matter how slight, of a subject's predisposition or risk for developing a psychiatric disorder. This definition includes either preventing the onset of a psychiatric disorder altogether or preventing the onset of a preclinically evident stage of a psychiatric disorder in individuals at risk.

[0048] In yet another embodiment, the present invention provides a method for treating psychiatric disorders in a subject comprising administering to the subject a Cox-2 inhibitor alone or in combination with an antidepressant agent. [0049] As used herein, the terms "treating", "treatment", "treated", or

"to treat," mean to alleviate symptoms, eliminate the cause of symptoms either on a temporary or permanent basis, or to alter or slow the appearance of symptoms or symptom worsening. The term "treatment" includes alleviation or elimination of the cause of the symptoms associated with, but not limited to, any of the psychiatric disorders or psychiatric disorder-related symptoms described herein. [0050] Without being bound by this or any other theory, it is believed that a therapy comprising a Cox-2 inhibitor alone or in combination with an antidepressant agent is efficacious for preventing or treating psychiatric disorders and psychiatric disorder-related symptoms. [0051] The combination therapy embodiment of the present invention also provides for the treatment of psychiatric disorder-related symptoms, which may arise indirectly from having a psychiatric disorder, by treating the underlying psychiatric disorder itself. For example, if a subject is suffering from a psychiatric disorder-related symptom, such as a depressed mood, the treatment of the underlying psychiatric disorder, such as depression, by the methods and compositions of the present invention will likewise improve the symptoms of the associated complication.

[0052] The present invention encompasses a novel method of preventing or treating psychiatric disorders and psychiatric disorder-related symptoms in a subject that is in need of such prevention or treatment comprising administering to the subject at least one Cox-2 inhibitor. In a second embodiment, the present invention encompasses a novel method of preventing or treating psychiatric disorders and psychiatric disorder- related symptoms in a subject that is in need of such prevention or treatment comprising administering to the subject at least one Cox-2 inhibitor and one or more antidepressant agents. [0053] A component of the present invention is a Cox-2 inhibitor.

[0054] Inhibitors of the cyclooxygenase pathway in the metabolism of arachidonic acid used in the prevention and treatment of psychiatric disorders may inhibit enzyme activity through a variety of mechanisms. By the way of example, the inhibitors used in the methods described herein may block the enzyme activity directly by acting as a substrate for the enzyme.

[0055] 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.

[0056] 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. >

[0057] Examples of NSAID compounds that are useful in the present invention include acemetacin, acetyl salicylic acid, alclofenac, alminoprofen, azapropazone, benorylate, benoxaprofen, bucloxic acid, carprofen, choline magnesium trisalicylate, clidanac, clopinac, dapsone, diclofenac, diflunisal, droxicam, etodolac, fenoprofen, fenbufen, fenclofenec, fentiazac, floctafenine, flufenisal, flurbiprofen, (r)-flurbiprofen, (s)-flurbiprofen, furofenac, feprazone, flufenamic acid, fluprofen, ibufenac, ibuprofen, indometacin, indomethacin, indoprofen, isoxepac, isoxicam, ketoprofen, ketorolac, miroprofen, piroxicam, meloxicam, mefenamic, mefenamic acid, meclofenamic acid, meclofen, nabumetone, naproxen, niflumic acid, oxaprozin, oxipinac, oxyphenbutazone, phenylbutazone, podophyllotoxin derivatives, proglumetacin, piprofen, pirprofen, prapoprofen, salicylic acid, salicylate, sudoxicam, suprofen, sulindac, tenoxicam, tiaprofenic acid, tiopinac, tioxaprofen, tolfenamic acid, tolmetin, zidometacin, zomepirac, and 2-fluoro-a-methyl[1 ,1'-biphenyl]-4-acetic acid, 4-(nitrooxy)butyl ester. [0058] 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.

[0059] In practice, the selectivity of a Cox-2 inhibitor varies depending upon the condition under which the test is performed and on the inhibitors being tested. However, for the purposes of this specification, the selectivity of a Cox-2 inhibitor can be measured as a ratio of the in vitro or in vivo IC50 value for inhibition of Cox-1 , divided by the IC50 value for inhibition of Cox-2 (Cox-1 IC50/Cox-2 IC50). A Cox-2 selective inhibitor is any inhibitor for which the ratio of Cox-1 IC50 to Cox-2 IC50 is greater than 1. In preferred embodiments, this ratio is greater than 2, more preferably greater than 5, yet more preferably greater than 10, still more preferably greater than 50, and more preferably still greater than 100.

[0060] As used herein, the term "IC50" refers to the concentration of a compound that is required to produce 50% inhibition of cyclooxygenase activity. Preferred Cox-2 selective inhibitors of the present invention have a Cox-2 IC50 of less than about 1 μM, more preferred of less than about 0.5 μM, and even more preferred of less than about 0.2 μM.

[0061] Preferred Cox-2 selective inhibitors have a Cox-1 IC50 of greater than about 1 μM, and more preferably of greater than 20 μM. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects. [0062] 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. [0063] 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.

[0064] 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.

[0065] As used herein, the term "alkyl", either alone or within other terms such as "haloalkyl" and "alkylsulfonyl"; embraces linear or branched radicals having one to about twenty carbon atoms. Lower alkyl radicals have one to about ten carbon atoms. The number of carbon atoms can also be expressed as "C₁-C₅", for example. Examples of lower alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the like. [0066] The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains at least one double bond. The alkenyl radicals may be optionally substituted with groups such as those defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropylenyl, buten-1yl, isobutenyl, penten-1yl, 2-methylbuten-1-yl, 3-methylbuten-1~yl, hexen-1-yl, 3- hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl, and the like.

[0067] 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, propynyl, 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. [0068] The term "oxo" means a single double-bonded oxygen.

[0069] The terms "hydrido", "-H", or "hydrogen", denote a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical, or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH₂ -) radical. [0070] The term "halo" means halogens such as fluorine, chlorine, and bromine or iodine atoms. The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have a bromo, chloro, or a fluoro atom within the radical. Dihalo alkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. [0071] 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. [0072] 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 dialkoxyalkyl 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. [0073] The term "aryl", whether used alone or with other terms, means a carbocyclic aromatic system containing one, two, or three rings wherein such rings may be attached together in a pendent manner, or may be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronapthyl, indane, and biphenyl. The term "heterocyclyl" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms are replaced by N, S, P, or O. This includes, for example, structures such as:

where Z, Z¹, Z², or Z³ is C, S, P, O, or N, with the proviso that one of Z, Z¹, Z², or Z³ is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom. Furthermore, the optional substituents are understood to be attached to Z, Z¹, Z², or Z³ only when each is C. The term "heterocycle" also includes fully saturated ring structures, such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others.

[0074] The term "heteroaryl" embraces unsaturated heterocyclic radicals. Examples of unsaturated heterocyclic radicals include thienyl, pyrryl, furyl, pyridyl, pyrimidinyl, 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.

[0075] The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -S0₂-

"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

[0076] 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 carboxy radical as defined above, attached to an alkyl radical. The term "carbonyl", whether used alone or with other terms, such as "alkylcarbonyl", denotes - (C=0) -. The term "alkylcarbonyl" embraces radicals having a carbonyl radical substituted with an alkyl radical. An example of an "alkylcarbonyl" radical is CH₃ - (CO) -. The term "alkoxycarbonyl" means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl (C=0) radical. Examples of such "alkoxycarbonyl" radicals include (CH₃)₃-C-0-C=0) - and - (0=)C- OCH₃. The term "amino", whether used alone or with other terms, such as "aminocarbonyl", denotes -NH₂. [0O77] 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 cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0078] The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of "alkylthio" is methylthio, (CH₃ -S-). The term

"alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent -S(-O) - atom. The term "acyl", whether used alone, or within a term such as "acylamino", denotes a radical provided by the residue after removal of hydroxyl from an organic acid.

[0079] The term "cyano", used either alone or with other terms, such as "cyanoalkyl", refers to C≡N. The term "nitro" denotes -N0₂. [0080] In one embodiment of the invention the Cox-2 selective inhibitor is of the chromene/chroman structural class, which encompasses substituted benzopyrans or substituted benzopyran analogs, as well as substituted benzothiopyrans, dihydroquinolines, or dihydronaphthalenes having the structure of any one of the general Formulas I, II, III, IV, V, and VI, shown below, and including, by way of non-limiting example, the structures disclosed in Table 1 , and the diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof.

[0081] Benzopyrans that can serve as a Cox-2 selective inhibitor of the present invention include substituted benzopyran derivatives that are described in U.S. Patent Nos. 6,271 ,253 and 6,492,390. One such class of compounds is defined by the general formula shown below in formula I:

wherein X¹ is selected from O, S, CR^C R^b and NR^a ; wherein R^a is selected from hydrido, Ci -C₃ -alkyl, (optionally substituted phenyl)-Cι -C₃ -alkyl, acyl and carboxy-Ci -C₆ -alkyl; wherein each of R^b and R° is independently selected from hydrido, Ci -C₃ -alkyl, phenyl-Ci -C₃ -alkyl, Ci -C₃ -perfluoroalkyl, chloro, Ci -C₆ -alkylthio, Ci -Cβ -alkoxy, nitro, cyano and cyano-C-i -C₃ -alkyl; or wherein CR^ϋ R^c forms a 3-6 membered cycloalkyl ring; wherein R¹ is selected from carboxyl, aminocarbonyl, Ci -Cβ - alkylsulfonylaminocarbonyl and Ci -C₆ -alkoxycarbonyl; wherein R² is selected from hydrido, phenyl, thienyl, Ci -Cβ -alkyl and C₂ -C₆ -alkenyl; wherein R³ is selected from Ci -C₃ -perfluoroalkyl, chloro, Ci -Cβ - alkylthio, Ci -C₆ -alkoxy, nitro, cyano and cyano-Ci -C₃ -alkyl; wherein R⁴ is one or more radicals independently selected from hydrido, halo, Ci -C₆ -alkyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl, halo-C₂ -C₆ -alkynyl, aryl-Ci -C₃ -alkyl, aryl-C₂ -C₆ -alkynyl, aryl-C₂ -C₆ -alkenyl, Ci

-Cβ -alkoxy, methylenedioxy, Ci -CQ -alkylthio, Ci -Cβ -alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, Ci -C₆ -alkoxy-Ci -C₆ -alkyl, aryl-Ci -C₆ -alkyloxy, heteroaryl-Ci -C₆ -alkyloxy, aryl-Ci -C₆ -alkoxy-Ci -C₆ -alkyl, Ci -C₆ -haloalkyl, Ci -C₆ -haloaikoxy, Ci -C₆ -haloalkylthio, Ci -C₆ -haloalkylsulfinyl, Ci -C₆ -haloalkylsulfonyl, d -C₃ -(haloalkyl-i -

C₃ -hydroxyalk l, Ci -Cβ -hydroxyalkyl, hydroxyimino-Ci -Cβ -alkyl, Ci - C₆ -alkylamino, arylamino, aryl-Ci -C₆ -alkylamino, heteroarylamino, heteroaryl-Ci -Cβ -alkylamino, nitro, cyano, amino, aminosulfonyl, Ci -Cβ -alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-Ci - C₆ -alkylaminosulfonyl, heteroaryl-Ci -C₆ -alkylaminosulfonyl, heterocyclylsulfonyl, Ci -Cβ -alkylsulfonyl, aryl-Ci -Cβ -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-Ci -C₆ - alkylcarbonyl, heteroaryl-Ci -C₆ -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, Ci -Ci -alkoxycarbonyl, formyl, Ci -C₆ - haloalkylcarbonyl and Ci -Cβ -alkylcarbonyl; and wherein the A ring atoms A¹, A², A³ and A⁴ are independently selected from carbon and nitrogen with the proviso that at least two of A¹, A², A³ and A⁴ are carbon; or wherein R⁴ together with ring A forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl, or an isomer or pharmaceutically acceptable salt thereof. [0082] Another class of benzopyran derivatives that can serve as the Cox-2 selective inhibitor of the present invention includes compounds having the structure of formula II:

wherein X² is selected from O, S, CR^C R^b and NR^a ; wherein R^a is selected from hydrido, Ci -C₃ -alkyl, (optionally substituted phenyl)-Cι -C -alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-Ci -Cβ -alkyl; wherein each of R^b and R^c is independently selected from hydrido, Ci -C₃ -alkyl, phenyl-Ci -C₃ -alkyl, Ci -C₃ -perfluoroalkyl, chloro, Ci -C₆ -alkylthio, Ci -C₆ -alkoxy, nitro, cyano and cyano-Ci -C₃ -alkyl; or wherein CR^C R^b form a cyclopropyl ring; wherein R⁵ is selected from carboxyl, aminocarbonyl, Ci -C₆ - alkylsulfonylaminocarbonyl and Ci -C₆ -alkoxycarbonyl; wherein R⁶ is selected from hydrido, phenyl, thienyl, C₂ -C₆ -alkynyl and C₂ -C₆ -alkenyl; wherein R⁷ is selected from Ci -C₃ -perfluoroalkyl, chloro, Ci -C₆ - alkylthio, Ci -C₆ -alkoxy, nitro, cyano and cyano-Ci -C₃ -alkyl; wherein R⁸ is one or more radicals independently selected from hydrido, halo, Ci -C₆ -alkyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl, halo-C₂ -C₆ - alkynyl, aryl-C₁ -C₃ -alkyl, aryl-C₂ -C₆ -alkynyl, aryl-C₂ -C₆ -alkenyl, Ci - Cβ -alkoxy, methylenedioxy, Ci -Cβ -alkylthio, Ci -Cβ -alkylsulfinyl, — 0(CF₂)₂ O—, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, Ci -C₆ -alkoxy- Ci -C₆ -alkyl, aryl-Ci -C₆ -alkyloxy, heteroaryl-d -C₆ -alkyloxy, aryl-Ci - C₆ -alkoxy-Ci -C₆ -alkyl, d -C₆ -haloalkyl, Ci -C₆ -haloalkoxy, Ci -C₆ - haloalkylthio, Ci -C₆ -haloalkylsulfinyl, Ci -C₆ -haloalkylsulfonyl, Ci -C₃ - (haloalkyl-Ci -C₃ -hydroxyalkyl), Ci -C₆ -hydroxyalkyl, hydroxyimino-Ci - Cβ -alkyl, Ci -Cβ -alkylamino, arylamino, aryl-Ci -Cβ -alkylamino, heteroarylamino, heteroaryl-Ci -C₆ -alkylamino, nitro, cyano, amino, aminosulfonyl, Ci -Cβ -alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-Ci -Cβ -alkylaminosulfonyl, heteroaryl-Ci - Cβ -alkylaminosulfonyl, heterocyclylsulfonyl, Ci -Cβ -alkylsulfonyl, aryl-Ci -C₆ -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-Ci -Cβ -alkylcarbonyl, heteroaryl-Ci -C₆ -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, Ci -Cβ -alkoxycarbonyl, formyl, Ci -Cβ -haloalkylcarbonyl and Ci -Cβ -alkylcarbonyl; and wherein the D ring atoms D¹, D², D³ and D⁴ are independently selected from carbon and nitrogen with the proviso that at least two of D¹, D², D³ and D⁴ are carbon; or wherein R⁸ together with ring D forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof. [0083] Other benzopyran Cox-2 selective inhibitors useful in the practice of the present invention are described in U.S. Patent Nos. 6,034,256 and 6,077,850. The general formula for these compounds is shown in formula III:

wherein X³ is selected from the group consisting of O or S or NR^a; wherein R^a is alkyl; wherein R⁹ is selected from the group consisting of H and aryl; wherein R¹⁰ is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; wherein R¹¹ 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, heteroarylalkylamino, 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 diastereonners, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof.

[0084] A related class of compounds useful as Cox-2 selective inhibitors in the present invention is described by Formulas IV and V below:

wherein X⁴ is selected from O or S or NR^a ; wherein R^a is alkyl; wherein R¹³ is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; wherein R¹⁴ is selected from haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and wherein R¹⁵ is one or more radicals selected from hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, 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. [0085] Formula V is:

wherein: X⁵ is selected from the group consisting of O or S or NR^b; R^b is alkyl; R¹⁶ is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; R¹⁷ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl each is independently optionally substituted with one or more radicals selected from the group consisting of alkylthio, nitro and alkylsulfonyl; and R¹⁸ is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein R¹⁸ together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof. [0086] 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; R^1δ 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 R¹⁸ is one or more radicals selected from the group of consisting of hydrido, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5- membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R¹⁸ together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof. [0087] The Cox-2 selective inhibitor may also be a compound of Formula V, wherein: X⁵ is selected from the group consisting of oxygen and sulfur; R¹⁶ is carboxyl; R¹⁷ is lower haloalkyl; and R¹⁸ is one or more radicals selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen- containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R¹⁸ together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.

[0088] The Cox-2 selective inhibitor may also be a compound of

Formula V, wherein: X⁵ is selected from the group consisting of oxygen and sulfur; R¹⁶ is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; R¹⁷ is selected from the group consisting of fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyl; and R¹⁸ is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, terf-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. [0089] The Cox-2 selective inhibitor may also be a compound of

Formula V, wherein: X⁵ is selected from the group consisting of oxygen and sulfur; R¹⁶ is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; R¹⁷ is selected from the group consisting trifluoromethyl and pentafluoroethyl; and R¹⁸ is one or more radicals selected from the grou consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, fe/if-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, N,N- dimethylaminosulfonyl, N-methylaminosulfonyl, N-(2,2- dimethylethyl)aminosulfonyl, dimethylaminosulfonyl, 2- methylpropylaminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, and phenyl; or wherein R¹⁸ together with ring A forms a naphthyl radical; or an isomer or prodrug thereof.

[0090] The Cox-2 selective inhibitor of the present invention can also be a compound having the structure of Formula VI:

wherein: X⁶ is selected from the group consisting of O and S; R¹⁹ is lower haloalkyl; R²⁰ is selected from the group consisting of hydrido, and halo; R²¹ is selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5-membered nitrogen-containing 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 alkoxy, and aryl; or an isomer or prodrug thereof. [0091] The Cox-2 selective inhibitor can also be a compound of having the structure of Formula VI, wherein: X⁶ is selected from the group consisting of O and S; R¹⁹ is selected from the group consisting of trifluoromethyl and pentafluoroethyl; R²⁰ is selected from the group consisting of hydrido, chloro, and fluoro; R²¹ is selected from the group consisting of hydrido, chloro,, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl, and morpholinosulfonyl; R²² is selected from the group consisting of hydrido, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, and phenyl; and R²³ is selected from the group consisting of hydrido, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, and phenyl; or an isomer or prodrug thereof. Table 1. Examples of Chromene Cox-2 Selective Inhibitors

[0092] In preferred embodiments the chromene Cox-2 inhibitor is selected from (S)-6-chloro-7-(1 ,1-dimethylethyl)-2-(trifluoromethyl)-2H-1- benzopyran-3-carboxylic acid, (2S)-6,8-dimethyl-2-(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. [0093] In a preferred embodiment of the invention the Cox-2 inhibitor can be selected from the class of tricyclic Cox-2 selective inhibitors represented by the general structure of formula VII:

wherein: Z¹ is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings; 24 R is selected from the group consisting of heterocyclyl, cycloalkyl, 24 cycloalkenyl and aryl, wherein R is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; 25 R is selected from the group consisting of methyl or amino; and 26 R is selected from the group consisting of a radical selected from H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N- arylaminocarbonyl, N-alkyl-N- arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N- arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl- N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N- arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl; or a prodrug thereof. [0094] In a preferred embodiment of the invention the tricyclic 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. [0095] Additional information about selected examples of the tricyclic Cox-2 selective inhibitors discussed above can be found as follows: celecoxib (CAS RN 169590-42-5, C-2779, SC-58653, and in U.S. Patent No. 5,466,823); deracoxib (CAS RN 169590-41-4); rofecoxib (CAS RN 162011-90-7); compound B-24 (U.S. Patent No. 5,840,924); compound B-26 (WO 00/25779); and etoricoxib (CAS RN 202409-33-4, MK-663, SC-86218, and in WO 98/03484).

[0096] Table 2. Examples of Tricyclic Cox-2 Selective Inhibitors

[0097] In a more preferred embodiment of the invention, the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib. [0098] 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.

[0100] A preferred form of parecoxib is sodium parecoxib. [0101] 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.

[0102] In a further embodiment of the invention, the Cox-2 inhibitor can be selected from the class of phenylacetic acid derivative Cox-2 selective inhibitors represented by the general structure of formula VIII:

wherein:

R²⁷ is methyl, ethyl, or propyl;

R²⁸ is chloro or fluoro;

R²⁹ is hydrogen, fluoro, or methyl;

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

R³¹ is hydrogen, fluoro, or methyl; and

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

R³⁰ is H.

[0103] An exemplary phenylacetic acid derivative Cox-2 selective inhibitor that is described in WO 99/11605 is a compound that has the structure shown in formula VIII, wherein:

R²⁷ is ethyl;

R²⁸ and R³⁰ are chloro;

R²⁹ and R³¹ are hydrogen; and

R³² is methyl.

[0104] Another phenylacetic acid derivative Cox-2 selective inhibitor is a compound that has the structure shown in formula VIII, wherein:

R²⁷ is propyl;

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

R³² is ethyl.

[0105] Another phenylacetic acid derivative Cox-2 selective inhibitor that is disclosed in WO 02/20090 is a compound that is referred to as

COX-189 (also termed lumiracoxib; CAS Reg. No. 220991-20-8), having the structure shown in formula VIII, wherein:

R²⁷ is methyl;

R²⁸ is fluoro;

R³² is chloro; and

R²⁹, R³⁰, and R³¹ are hydrogen.

[0106] Compounds having a structure similar to that shown in formula VIII, that can serve as the Cox-2 selective inhibitor of the present invention, are described in U.S. Patent Nos. 6,451 ,858, 6,310,099,

6,291 ,523, and 5,958,978.

[0107] Other Cox-2 selective inhibitors that can be used in the present invention have the general structure shown in formula IX, where the J group is a carbocycle or a heterocycle. Preferred embodiments have the structure:

wherein:

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

R³⁵ group, (nimesulide), or

X⁷ is O; J is 1-oxo-inden-5-yl; R³³ is 2-F; R³⁴ is 4-F; and R³⁵ is 6- NHS0₂CH₃, (flosulide); or

X⁷ is O; J is cyclohexyl; R³³ is 2-NHS0₂CH₃; R³⁴ is 5-N0₂; and there is no R³⁵ group, (NS-398); or X⁷ is S; J is 1-oxo-inden-5-yl; R³³ is 2-F; R³⁴ is 4-F; and R³⁵ is 6-N^"S0₂CH₃

• Na⁺, (L-745337); or

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

NHSO₂CH₃, (RWJ-63556); or

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

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

[0108] The Cox-2 selective inhibitor NS-398, also known as N-(2- cyclohexyloxynitrophenyl) methane sulfonamide (CAS RN 123653-11-2), having a structure as shown below in formula B-29, has been described in, for example, Yoshimi, N. et al., in Japanese J. Cancer Res., 90(4):406 -

412 (1999).

[0109] 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 Ther282, 1094-1101

(1997).

[0110] Materials that can serve as the Cox-2 selective inhibitor of the present invention include diarylmethylidenefuran derivatives that are described in U.S. Patent No. 6,180,651. Such diarylmethylidenefuran derivatives have the general formula shown below in formula X:

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

1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an -S0₂NH₂ group; and is located in the para position, the others independently being a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a trifluoromethyl radical, or a lower O-alkyl radical having 1 to 6 carbon atoms, or Q¹ and Q² or L¹ and L² are a methylenedioxy group; and R >36 , R )37 , R )38 and R j39 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, furyl and pyridyl; or, R³⁶, R³⁷ or R³⁸, R³⁹ are an oxygen atom; or R³⁶, R³⁷ or R³⁸, R³⁹, together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms; or an isomer or prodrug thereof. [0111] Particular diarylmethylidenefuran derivatives that can serve as the Cox-2 selective inhibitor of the present invention include, for example, N-(2-cyclohexyloxynitrophenyI)methane sulfonamide, and (E)-4- [(4-methylphenyl)(tetrahydro-2-oxo-3-furanylidene) methyfjbenzenesulfonamide.

[0112] Other Cox-2 selective inhibitors that are useful in the present invention include darbufelone (Pfizer), CS-502 (Sankyo), LAS 34475 (Almirall Profesfarma), LAS 34555 (Almirall Profesfarma), S-33516 (Servier), SD 8381 (Pharmacia, described in U.S. Patent No. 6,034,256), BMS-347070 (Bristol Myers Squibb, described in U.S. Patent No.

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

[0113] 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. [0114] Conjugated linoleic, as described in U.S. Patent No.

6,077,868, is useful as a Cox-2 selective inhibitor in the present invention. [0115] Compounds that can serve as a Cox-2 selective inhibitor of the present invention include heterocyclic aromatic oxazole compounds that are described in U.S. Patents 5,994,381 and 6,362,209. Such heterocyclic aromatic oxazole compounds have the formula shown below in formula XI:

wherein: Z is an oxygen atom; one of R⁴⁰ and R⁴¹ is a group of the formula

wherein; R⁴³ is lower alkyl, amino or lower alkylamino; and R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷ are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxyl or amino, provided that at least one of R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷ is not hydrogen atom, and the other is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group or an optionally substituted aryl; and R³⁰ is a lower alkyl or a halogenated lower alkyl, and a pharmaceutically acceptable salt thereof. [0116] Cox-2 selective inhibitors that are useful in the method and compositions of the present invention include compounds that are described in U.S. Patent Nos. 6,080,876 and 6,133,292, and described by formula XII:

wherein: Z³ is selected from the group consisting of linear or branched Ci - Cβ alkyl, linear or branched Ci -Cβ alkoxy, unsubstituted, mono-, di- or tri- substituted phenyl or naphthyl wherein the substituents are selected from the group consisting of hydrogen, halo, Ci -C₃ alkoxy, CN, Ci -C₃ fluoroalkyl Ci -C₃ alkyl, and -C0₂ H; R⁴⁸ is selected from the group consisting of NH₂ and CH₃, R⁴⁹ is selected from the group consisting of Ci -Cβ alkyl unsubstituted or substituted with C₃ -C₆ cycloalkyl, and C₃ -C₆ cycloalkyl; R⁵⁰ is selected from the group consisting of Ci -C₆ alkyl unsubstituted or substituted with one, two or three fluoro atoms, and C₃ - C cycloalkyl; with the proviso that R⁴⁹ and R⁵⁰ are not the same. [0117] Pyridines that are described in U.S. Patent Nos. 6,596,736,

6,369,275, 6,127,545, 6,130,334, 6,204,387, 6,071 ,936, 6,001 ,843 and 6,040,450, and can seve as Cox-2 selective inhibitors of the present invention, have the general formula described by formula XIII:

wherein: R⁵¹ is selected from the group consisting of CH₃, NH₂, NHC(0)CF₃, and NHCH₃; Z⁴ is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N- oxide thereof), wherein the substituents are selected from the group consisting of hydrogen, halo, Ci -C₆ alkoxy, Ci -C₆ alkylthio, CN, Ci -C₆ alkyl, d -C₆ fluoroalkyl, N₃₎ -C0₂R⁵³, hydroxyl, -C(R⁵⁴)(R⁵⁵)— OH, - C-, - C₆ alkyl-C0₂— R⁵⁶, Ci -C₆ fluoroalkoxy; R⁵² is selected from the group consisting of halo, Ci -Cβ alkoxy, Ci -C₆ alkylthio, CN, Ci -C₆ alkyl, Ci -C₆ fluoroalkyl, N₃, — C0₂R⁵⁷, hydroxyl, — C(R⁵⁸)(R⁵⁹)— OH, — Ci -C₆ alkyl-C0₂— R⁶⁰, Ci -C₆ fluoroalkoxy, N0₂, NR⁶¹R⁶², and NHCOR⁶³; R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², and R⁶³, are each independently selected from the group consisting of hydrogen andCi -Cβ alkyl; or R⁵⁴ and R⁵⁵, R⁵⁸ and R⁵⁹, or R⁶¹ and R⁶² together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6, or 7 atoms.

[0118] Materials that can serve as the Cox-2 selective inhibitor of the present invention include diarylbenzopyran derivatives that are described in U.S. Patent No. 6,340,694. Such diarylbenzopyran derivatives have the general formula shown below in formula XIV:

wherein:

X⁸ is an oxygen atom or a sulfur atom;

R⁶⁴ and R⁶⁵, identical to or different from each other, are independently a hydrogen atom, a halogen atom, a Ci -Cβ lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a nitro group, a nitrile group, or a carboxyl group; R⁶⁶ is a group of a formula: S(0)_nR⁶⁸ wherein n is an integer of 0-2, R⁶⁸ is a hydrogen atom, a Ci -C₆ lower alkyl group, or a group of a formula: NR⁶⁹ R⁷⁰ wherein R⁶⁹ and R⁷⁰, identical to or different from each other, are independently a hydrogen atom, or a Ci -Cβ lower alkyl group; and R⁶⁷ is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a Ci -Cβ lower alkyl group, indanyl, pyrazinyl, or a substituted group represented by the following structures:

wherein: R⁷¹ through R⁷⁵, identical to or different from one another, are independently a hydrogen atom, a halogen atom, a Ci -C₆ lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a group of a formula: S(0)_nR⁶⁸, a group of a formula: NR⁶⁹ R⁷⁰, a trifluoromethoxy group, a nitrile group a carboxyl group, an acetyl group, or a formyl group, wherein n, R⁶⁸, R⁶⁹ and R⁷⁰ have the same meaning as defined by R⁶⁶ above; and R⁷⁶ is a hydrogen atom, a halogen atom, a Ci -Cβ lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a trifluoromethoxy group, a carboxyl group, or an acetyl group. [0119] Materials that can serve as the Cox-2 selective inhibitor of the present invention include 1-(4-sulfamylaryl)-3-substituted-5-aryl-2- pyrazolines that are described in U.S. Patent No. 6,376,519. Such 1-(4- sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines have the formula shown below in formula XV:

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

wherein:

' R⁷⁷ and R⁷⁸ are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl; nitro; C -Cβ alkyl, preferably Ci -C₃ alkyl; Ci -Cβ alkoxy, preferably Ci - C₃ alkoxy; carboxy; Ci -Cβ trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano; Z⁵ is selected from the group consisting of substituted and unsubstituted aryl. [0120] Compounds useful as Cox-2 selective inhibitors of the present invention include heterocycles that are described in U.S. Patent No. 6,153,787. Such heterocycles have the general formulas shown below in formulas XVII and XVIII:

wherein: R⁷⁹ is a mono-, di-, or tri-substituted Ci -C₁₂ alkyl, or a mono-, or an unsubstituted or mono-, di- or tri-substituted linear or branched C₂ -Cιo alkenyl, or an unsubstituted or mono-, di- or tri-substituted linear or branched C₂ -C-io alkynyl, or an unsubstituted or mono-, di- or tri- substituted C₃ -Ci₂ cycloalkenyl, or an unsubstituted or mono-, di- or tri- substituted C₅ -Cι₂ cycloalkynyl, wherein the substituents are selected from the group consisting of halo selected from F, Cl, Br, and I, OH, CF₃, C-₃ -C₆ cycloalkyl, =0,dioxolane, CN; R⁸⁰ is selected from the group consisting of CH₃, NH₂, NHC(0)CF₃, and NHCH₃; R⁸¹ and R⁸² are independently selected from the group consisting of hydrogen and Ci -C₁₀ alkyl; or R⁸¹ and R⁸² together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms. [0121] Formula XVIII is: XVIII

wherein X¹⁰ is fluoro or chloro.

[0122] Materials that can serve as the Cox-2 selective inhibitor of the present invention include 2,3,5-trisubstituted pyridines that are described in U.S. Patent No. 6,046,217. Such pyridines have the general formula shown below in formula XIX:

or a pharmaceutically acceptable salt thereof, wherein: X¹¹ is selected from the group consisting of O, S, and a bond; n is 0 or 1 ; R⁸³ is selected from the group consisting of CH₃, NH₂, and NHC(0)CF₃; R⁸⁴ is selected from the group consisting of halo, Ci -CQ alkoxy, Ci -C₆ alkylthio, CN, Ci -C₆ alkyl, Ci -C₆ fluoroalkyl, N₃₎ — C0₂ R⁹², hydroxyl,

— d -C₆ alkyl-C0₂ — R^9b, Ci -C₆ fluoroalkoxy, N0₂, NR 9^a6^D _D R9^a7', and NHCOR J9^a8^o.; R⁸⁵ to R⁸⁹ are independently selected from the group consisting of hydrogen and Ci -C₆ alkyl; or R⁸⁵ and R⁸⁹, or R⁸⁹ and R⁹⁰ together with the atoms to which they are attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R⁸⁵ and R⁸⁷ are joined to form a bond.

[0123] Compounds that are useful as the Cox-2 selective inhibitor of the present invention include diaryl bicyclic heterocycles that are described in U.S. Patent No. 6,329,421. Such diaryl bicyclic heterocycles have the general formula shown below in formula XX:

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

(a) — CH=CH— CH=CH— ,

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

(c) — CH₂ — CH₂ — C(O)— , — CH₂ — C(O)— CH₂ — , — C(O)— CH₂ — CH₂ — (d) — CH₂ — CH₂ — O— C(O)— , CH₂ — O— C(O)— CH₂ — , — O— C(O)— CH₂ — CH₂ — , (e) — CH₂ — CH₂ — C(O)— O— , — CH₂ — C(O)— OCH₂ — , — C(O)— O— CH₂ — CH₂ — , (f) — C(R¹⁰⁵)₂ — O— C(O)— , — C(O)— O— C(R¹⁰⁵)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— H— , (q) — CH=N — S— , and

(r) — N=CH— S— ;

R⁹⁹ is selected from the group consisting of S(0)₂CH₃, S(0)₂NH₂,

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

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

(a) Cι -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, Cl, Br, I, (3) Ci -C₆ alkoxy, (4) Ci -C₆ alkylthio, (5) CN, (6) CF₃, (7) Ci -C₆ alkyl, (8) N₃, (9) — C0₂ H, (10) — C0₂ — Ci -C₄ alkyl, (11) — C(R¹⁰³)(R¹⁰⁴)— OH, (12) — C(R¹⁰³)(R¹⁰⁴)— O— Ci -C₄ alkyl, and (13) — d -C₆ alkyl-C0₂ — R¹⁰⁶; (d) mono- or di-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1 , 2, or 3 additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1 , 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of (1 ) hydrogen, (2) halo, including fluoro, chloro, bromo and iodo, (3) Ci -C₆ alkyl, (4) Ci -C₆ alkoxy, (5) Ci -C₆ alkylthio, (6) CN, (7) CF₃, (8) N₃, (9) — C(R¹⁰³)(R¹⁰⁴)— OH, and (10) — C(R¹⁰³)(R¹⁰⁴)— O— Ci -C₄ alkyl;

(e) benzoheteroaryl which includes the benzo fused analogs of (d); R¹⁰¹ and R¹⁰² are the substituents residing on any position of -A⁵=A⁶— A⁷=A⁸ — and are selected independently from the group consisting of (a) hydrogen,

(b) CF₃,

(c) CN,

(d) Ci -C₆ alkyl,

(e) — Q³ wherein Q³ is Q⁴, C0₂ H, C(R¹⁰³)(R¹⁰⁴)OH, (f) — O— Q⁴,

(g) — S— Q⁴, and

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

-C₃ alkyl, and Q³ is Q⁴, C0₂ H, C(R¹⁰³)(R¹⁰⁴)OH Q⁴ is C0₂ — Ci -C₄ alkyl, tetrazolyl-5-yl, or C(R^{1 03})(R¹⁰⁴)O— Ci -C₄ alkyl;

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

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

4, 5, 6 or 7 atoms;

R¹⁰⁶ is hydrogen or d -C₆ alkyl;

R¹⁰⁷ is hydrogen, Ci — C₆ alkyl or aryl;

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

[0124] Compounds that may act as Cox-2 selective inhibitors include salts of 5-amino or a substituted amino 1 ,2,3-triazole compound that are described in U.S. Patent No. 6,239,137. The salts are of a class of compounds of formula XXI:

wherein: R¹⁰⁸ is:

wherein: p is 0 to 2; m is 0 to 4; and n is 0 to 5; X¹³ is 0, S, SO, S0₂, CO, CHCN, CH₂ or C=NR¹¹³ where R¹¹³ is hydrogen, loweral yl, hydroxyl, loweralkoxy, amino, loweralkylamino, diloweralkylamino or cyano; R¹¹¹ and R^{1 2} are independently halogen, cyano, trifluoromethyl, loweralkanoyl, nitro, loweralkyl, loweralkoxy, carboxy, lowercarbalkoxy, trifuloromethoxy, acetamido, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfinyl, or trifluoromethylsulfonyl; R¹⁰⁹ is amino, mono or diloweralkyl amino, acetamido, acetimido, ureido, formamido, or guanidino; and R¹¹⁰ is carbamoyl, cyano, carbazoyl, amidino or N- hydroxycarbamoyl; wherein the loweralkyl, loweralkyl containing, loweralkoxy and loweralkanoyl groups contain from 1 to 3 carbon atoms.

[0125] Pyrazole derivatives such as those described in U.S. Patent

6,136,831 can serve as a Cox-2 selective inhibitor of the present invention. Such pyrazole derivatives have the formula shown below in formula XXII:

wherein: R >114 is hydrogen or halogen; R¹¹⁵ and R ¹⁶ are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl or lower alkanoyloxy; R¹¹⁷ is lower haloalkyl or lower alkyl;

X¹⁴ is sulfur, oxygen or NH; and

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

[0126] Materials that can serve as a Cox-2 selective inhibitor of the present invention include substituted derivatives of benzosulphonamides that are described in U.S. Patent 6,297,282. Such benzosulphonamide derivatives have the formula shown below in formula XXIII:

XXIII

wherein:

X¹⁵ denotes oxygen, sulphur or NH;

R¹¹⁸ is an optionally unsaturated alkyl or alkyloxyalkyl group, optionally mono- or polysubstituted or mixed substituted by halogen, alkoxy, oxo or cyano, a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted or mixed substituted by halogen, alkyl, CF₃, cyano or alkoxy;

R¹¹⁹ and R¹²⁰, independently from one another, denote hydrogen, an optionally polyfluorised alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH₂)_n -X¹⁶; or R¹¹⁹ and R¹²⁰, together with the N- atom, denote a 3 to 7-membered, saturated, partially or completely unsaturated heterocycle with one or more heteroatoms N, O or S, which can optionally be substituted by oxo, an alkyl, alkylaryl or aryl group, or a group (CH₂)_n — X¹⁶;

X¹⁶ denotes halogen, NO₂, —OR¹²¹, —COR¹²¹, — C0₂ R¹²¹, — OC0₂ R¹²¹, — CN, — CONR¹²¹ OR¹²², —CONR¹²¹ R¹²², — SR¹²¹, — S(0)R¹²¹, — S(0)₂

_R ⁱ²ⁱ _f __NR ¹²¹ _R ¹²² ₎ __NHC(0)R¹²¹, -NHS(0)₂ R¹²¹; n denotes a whole number from 0 to 6; R¹²³ denotes a straight-chained or branched alkyl group with 1-10 C- atoms, a cycloalkyl group, an alkylcarboxyl group, an aryl group, aralkyl group, a heteroaryl or heteroaralkyl group which can optionally be mono- or polysubstituted or mixed substituted by halogen or alkoxy; R¹²⁴ denotes halogen, hydroxyl, a straight-chained or branched alkyl, alkoxy, acyloxy or alkyloxycarbonyl group with 1 to 6 carbon atoms, which can optionally be mono- or polysubstituted by halogen, N0₂, — OR¹²¹, — COR¹²¹, — C0₂ R¹²¹, — OC0₂ R¹²¹, — CN, —CONR¹²¹ OR¹²², —CONR¹²¹

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

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

[0127] Compounds that are useful as Cox-2 selective inhibitors of the present invention include phenyl heterocycles that are described in

U.S. Patent Nos. 5,474,995 and 6,239,173. Such phenyl heterocyclic compounds have the formula shown below in formula XXIV:

or pharmaceutically acceptable salts thereof wherein: X¹⁷ — Y¹ — Z⁷-is selected from the group consisting of (a) — CH₂ CH₂ CH₂ — , (b) — C(0)CH₂ CH₂ — , (c) — CH₂ CH₂ C(O)— , (d) — CR¹²⁹ (R^129')— O— C(O)— ,

(e) — C(O)— O— CR¹²⁹ (R^129')— ,

(f) — CH₂ — NR¹²⁷ — CH₂ — ,

(g) _CR¹²⁹ (R^129')-NR¹²⁷ -0(0)—, (h) _CR¹²⁸=CR^128' -S— ,

(j) _S-CR¹²⁸=CR^128' -,

(j) _S-N=CH-,

(k) — CH=N— S— ,

(I) — N=CR¹²⁸ — O— , (m) — O— CR¹²⁸ =N— ,

(n) — N=CR¹²⁸ — NH— ,

(o) — N=CR¹²⁸ — S— , and

(p) — S— CR¹²⁸=N— ,

(q) _c(0)-NR¹²⁷ -CR¹²⁹ (R^129')— , (r) — R¹²⁷ N— CH=CH— provided R¹²² is not — S(0)₂CH₃,

(s) — CH=CH— NR¹²⁷ — provided R¹²⁵ is not — S(0)₂CH₃; when side b is a double bond, and sides a and c are single bonds; and

X¹⁷ — Y¹ — Z⁷-is selected from the group consisting of

(a) =CH— O— CH=, and (b) =CH— NR¹²⁷ — CH=,

(c) =N— S— CH=,

(d) =CH— S— N=,

(e) =N— O— CH=,

(f) =CH— O— N= (g) =N— S— N=,

(h) =N— O— N=, when sides a and c are double bonds and side b is a single bond; R¹²⁵ is selected from the group consisting of (a) S(0)₂ CH₃, (b) S(0)₂ NH₂,

(c) S(0)₂ NHC(0)CF₃,

(d) S(0)(NH)CH₃, (e) S(0)(NH)NH₂,

(f) S(0)(NH)NHC(0)CF_3>

(g) P(0)(CH₃)OH, and (h) P(0)(CH₃)NH₂; R¹²⁶ is selected from the group consisting of

(a) Ci -C₆ alkyl,

(b) C₃, C₄, C₅, C₆, and C₇, cycloalkyl,

(c) mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituent is selected from the group consisting of (1 ) hydrogen, (2) halo, (3) Ci -C₆ alkoxy, (4) Ci -C₆ alkylthio, (5) CN, (6) CF₃, (7) Ci -C₆ alkyl, (8) N_3> (9) -C0₂ H, (10) — C0₂ — Ci -C₄ alkyl, (11) — C(R¹²⁹)(R¹³⁰)— OH, (12) — C(R ²⁹)(R¹³⁰)— O— Ci -C₄ alkyl, and (13) — Ci -C₆ alkyl-C0₂ — R¹²⁹ ;

(d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1 , 2, or 3 additionally N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1 , 2, 3, or 4 ad itional N atoms; said substituents are selected from the group consisting of (1 ) hydrogen, (2) halo, including fluoro, chloro, bromo and iodo, (3) Ci -C₆ alkyl, (4) Ci -C₆ alkoxy, (5) Ci -C₆ alkylthio, (6) CN, (7) CF₃, (8) N₃, (9) — C(R¹²⁹)(R¹³⁰)— OH, and (10) — C(R¹²⁹)(R¹³⁰)— O— Ci -C₄ alkyl; (e) benzoheteroaryl which includes the benzo fused analogs of (d); R¹²⁷ is selected from the group consisting of (a) hydrogen, (b) CF₃,

(c) CN,

(d) Ci -C₆ alkyl,

(e) hydroxyl Ci -C₆ alkyl, (f) —C(0)— Cι -C₆ alkyl, (g) optionally substituted: (1) —Ci -C₅ alkyl-Q⁵, (2) — Ci -C₅ alkyl-O— Ci -C₃ alkyl-Q⁵, (3) — Ci -C₃ alkyl-S— Ci -C₃ alkyl-Q⁵, (4) — Ci -C₅ alkyl-O— Q⁵, or (5) — Ci -C₅ alkyl-S— Q⁵, wherein the substituent resides on the alkyl and the substituent is Ci - C₃ alkyl; (h) -Q⁵;

R¹²⁸ and R^128' are each independently selected from the group consisting of

(a) hydrogen,

(b) CF₃,

(c) CN,

(d) Ci -C₆ alkyl, (e) -Q⁵,

(f) _0— Q⁵;

(g) — S— Q⁵, and (h) optionally substituted: (1) — C1 -C5 alkyl-Q⁵, (2) — O— Ci -C₅ alkyl-Q⁵, (3) — S— Ci -C₅ alkyl-Q⁵, (4) — Ci -C-3 alkyl-O— Ci -C₃ alkyl-Q⁵, (5) — Ci -C-3 alkyl-S— Ci -C₃ alkyl-Q⁵, (6) — Ci -C₅ alkyl-O— Q⁵, (7) — Ci -C-5 alkyl-S— Q⁵, wherein the substituent resides on the alkyl and the su stituent is Ci - ' C-3 alkyl, and

R¹²⁹, R^129', R¹³⁰, R¹³¹ and R¹³² are each independently selected from the group consisting of

(a) hydrogen,

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

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

C(R¹³¹)(R¹³²)(0— Ci -C-₄ alkyl); provided that when X— Y— Z is — S— CR¹²⁸=CR^128', then R¹²⁸ and R^128' are other than CF₃.

[0128] 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. [0129] Bicycliccarbonyl indole compounds such as those described in U.S. Patent No. 6,303,628 are useful as Cox-2 selective inhibitors of the present invention. Such bicycliccarbonyl indole compounds have the formula shown below in formula XXV:

or the pharmaceutically acceptable salts thereof wherein:

A⁹ is Ci -C₆ alkylene or — NR¹³³ — ;

Z⁸ is C(=L³)R¹³⁴, or S0₂ R¹³⁵ ; Z⁹ is CH or N;

Z¹⁰ and Y² are independently selected from — CH₂ — , O, S and — N— R¹³³; m is 1 , 2 or 3; q and r are independently 0, 1 or 2;

X¹⁸ is independently selected from halogen, Ci -C₄ alkyl, halo-substituted Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy, halo-substituted Ci -C₄ alkoxy, Ci -

C alkylthio, nitro, amino, mono- or di-(Cι -C alkyl)amino and cyano; n is O, 1 , 2, 3 or 4;

L³ is oxygen or sulfur;

R¹³³ is hydrogen or Ci -C₄ alkyl; R¹³⁴ is hydroxyl, Ci -C₆ alkyl, halo-substituted Ci -C₆ alkyl, Ci -C₆ alkoxy, halo-substituted Ci -C₆ alkoxy, C₃ -C cycloalkoxy, Ci -C₄ alkyl(C₃ -C₇ cycloalkoxy), — NR¹³⁶ R¹³⁷, Ci -C₄ alkylphenyl-O— or phenyl-O— , said phenyl being optionally substituted with one to five substituents independently selected from halogen, Ci -C alkyl, hydroxyl, Ci -C₄ alkoxy and nitro; R¹³⁵ is Ci -C₆ alkyl or halo-substituted Ci -C₆ alkyl; and

R¹³⁶ and R¹³⁷ are independently selected from hydrogen, C₁-₆ alkyl and halo-substituted Ci -Cβ alkyl. [0130] Materials that can serve as a Cox-2 selective inhibitor of the present invention include benzimidazole compounds that are described in U.S. Patent No. 6,310,079. Such benzimidazole compounds have the formula shown below in formula XXVI:

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

C₄ alkoxy, halo-substituted Ci -C₄ alkyl, hydroxyl-substituted Ci -C₄ alkyl, (Ci -C₄ alkoxy)Cι -C₄ alkyl, halo-substituted Ci -C₄ alkoxy, amino, N-(Cι -C₄ alkyl)amino, N, N-di(Cι -C₄ alkyl)amino, [N-(Cι -C₄ alkyl)amino]Cι - C₄ alkyl, [N, N-di(Cι -C₄ alkyl)amino]Cι -C₄ alkyl, N-(Cι -C₄ alkanoyl)amonio, N-(Cι -C₄ alkyl)(Cι -C₄ alkanoyl)amino, N-[(Cι — C₄ alkyl)sulfonyl]amino, N-[(halo-substituted Ci -C₄ alkyl)sulfonyl]amino, Ci - C alkanoyl, carboxy, (Ci -C₄ alkoxy)carbonyl, carbamoyl, [N-(Cι — C₄ alkyl)amino]carbonyl, [N, N-di(Cι -C₄ alkyl)amino]carbonyl, cyano, nitro, mercapto, (Ci -C alkyl)thio, (Ci -C₄ alkyl)sulfinyl, (Ci -C₄ alkyl)sulfonyl, aminosulfonyl, [N-(Cι -C₄ alkyl)amino]sulfonyl and [N, N-di(Cι -C₄ alkyl)amino]sulfonyl; X²¹ is independently selected from halo, Ci -C₄ alkyl, hydroxyl, Ci - C₄ alkoxy, halo-substituted Ci -C₄ alkyl, hydroxyl-substituted Ci -C₄ alkyl, (Ci -C₄ alkoxy)Cι -C₄ alkyl, halo-substituted Ci -C₄ alkoxy, amino, N-(Cι -C₄ alkyl)amino, N, N-di(Cι -C₄ alkyl)amino, [N-(Cι -C₄ alkyl)amino]Cι - C₄ alkyl, [N, N-di(Cι -C₄ alkyl)amino]Cι -C₄ alkyl, N-(Cι -C₄ alkanoyl)amino, N-(Cι -C₄ alkyl)-ϊM-(Cι -C₄ alkanoyl) amino, N-[(Cι -C₄ alkyl)sulfonyl]amino, N-[(halo-substituted Ci -C₄ alkyl)sulfonyl]amino, Ci -

C₄ alkanoyl, carboxy, (Ci -C₄ alkoxy)hydroxyl, cabamoyl, [N-(Cι -C₄ alkyl) amino]carbonyl, [N, N-di(Cι -C₄ alkyl)amino]carbonyl, N-carbomoylamino, cyano, nitro, mercapto, (Ci -C alkyl)thio, (Ci -C₄ alkyl)sulfinyl, (Ci -C alkyl)sulfonyl, aminosulfonyl, [N-(Cι -C₄ alkyl)amino]sulfonyl and [N, N- di(Cι -C₄ alkyl)amino]sulfonyl; R¹³⁸ is selected from hydrogen; straight or branched Ci -C₄ alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxyl, Ci -C₄ alkoxy, amino, N-(Cι -C₄ alkyl)amino and N, N-di(Cι -C₄ alkyl)amino; C₃ -C₈ cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are indepently selected from halo, Ci -C alkyl, hydroxyl, Ci -C₄ alkoxy, amino, N-(Cι -C₄ alkyl)amino and N, N-di(Cι -C4 alkyl)amino; C₄ -Cs cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, Ci -C alkyl, hydroxyl, Ci -C₄ alkoxy, amino, N-(Cι -C₄ alkyl)amino and N, N-di(Cι -C₄ alkyl)amino; phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy, halo-substituted Ci -C₄ alkyl, Dydroxyl-substituted Ci -C alkyl, (Ci -C₄ alkoxy)Cι -C₄ alkyl, halo- substituted Ci -C₄ alkoxy, amino , N-(Cι -C₄ alkyl)amino, N, N-di(Cι -C₄ alkyl)amino, [N-(Cι -C₄ alkyl)ami no]Cι -C₄ alkyl, [N, N-di(Cι -C₄ alkyl)amino]Cι -C₄ alkyl, N-(Cι — C alkanoyl)amino, N-[Cι -C₄ alkyl)(Cι - C₄ alkanoyl)]amino, N-[(Cι -C₄ alkyl)sulfony]amino, N-[(halo-substituted C-i -C₄ alkyl)sulfonyl]amino, Ci -C alkanoyl, carboxy, (Ci -C₄ alkoxy)carbonyl, carbomoyl, [N-(Cι -C₄ alky)amino]carbonyl, [N, N-di(Cι -

C₄ alkyl)amino]carbonyl, cyano, nitro, mercapto, (Ci -C₄ alkyl)thio, (Ci -C₄ alkyl)sulfinyl, (Ci -C₄ alkyl)sulfonyl, aminosulfonyl, [N-(Cι -C₄ alkyl)amino]sulfonyl and [N, N-di(Cι -C₄ alkyl)amino]sulfonyl; and heteroaryl selected from: a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom; or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and said heteroaryl being optionally substituted with one to three substituent(s) selected from X²⁰ ; R¹³⁹ and R¹⁴⁰ are independently selected from: hydrogen; halo; Ci - C₄ alkyl; phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy, amino, N-(Cι -C₄ alkyl)amino and N, N- di(Cι -C₄ alkyl)amino; or R¹³⁸ and R¹³⁹ can form, together with the carbon atom to which they are attached, a C₃ -C cycloalkyl ring; m is 0, 1 , 2, 3, 4 or 5; and n is O, 1 , 2, 3 or 4. [0131] Compounds that may be employed as a Cox-2 selective inhibitor of the present invention include indole compounds that are described in U.S. Patent No. 6,300,363. Such indole compounds have the formula shown below in formula XXVII:

XXVII

and the pharmaceutically acceptable salts thereof, wherein: L⁴ is oxygen or sulfur; Y³ is a direct bond or Ci -C₄ alkylidene; Q⁶ is: (a) Ci -C₆ alkyl or halosubstituted Ci -C₆ alkyl, said alkyl being optionally substituted with up to three substituents independently selected from hydroxyl, C-i -C₄ alkoxy, amino and mono- or di-( Ci -C₄ alkyl)amino,

(b) C₃ -C₇ cycloalkyl optionally substituted with up to three substituents independently selected from hydroxyl, Ci -C₄ alkyl and Ci -C₄ alkoxy,

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

(d) a monocyclic aromatic group of 5 atoms, said aromatic group having one heteroatom selected from O, S and N and optionally containing up to three N atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substitutents independently selected from: (d-1) halo, Ci -C₄ alkyl, halosubstituted Ci -C₄ alkyl, hydroxyl, C-i -C₄ alkoxy, halosubstituted Ci -C₄ alkoxy, d -C₄ alkyl-OH, S(0)_m R¹⁴³, S0₂ NH₂, S0₂ N(d -C₄ alkyl)₂, amino, mono- or di-( Ci -C₄ alkyl)amino, NHS0₂ R¹⁴³, NHC(0)R¹⁴³, CN, C0₂ H, C0₂ (Ci -C₄ alkyl), Ci -C₄ alkyl-OR¹⁴³, CONH₂, CONH(Cι -C₄ alkyl), CON(Cι -C₄ alkyl)₂, phenyl, and mono-, di- or tri-substituted phenyl wherein the substituent is independently selected from halo, CF₃, Ci -C₄ alkyl, hydroxyl, Ci - C₄ alkoxy, OCF₃, SR¹⁴³, S0₂ CH₃, S0₂ NH₂, amino, C₁-₄ alkylamino and NHS0₂ R¹⁴³;

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

R¹⁴¹ is hydrogen or Ci -Cβ alkyl optionally substituted with a substituent selected independently from hydroxyl, OR¹⁴³, nitro, amino, mono- or di-( Ci

-C₄ alkyl)amino, C0₂ H, C0₂ (Ci -C₄ alkyl), CONH₂, CONH(d -C₄ alkyl) and CON(Cι -C₄ alkyl)₂ ; R¹⁴² is: (a) hydrogen, (b) Ci -C₄ alkyl,

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

(c-2) Ci -C₂₂ alkyl or C₂ -C₂₂ alkenyl, said alkyl or alkenyl being optionally substituted with five to forty-five halogen atoms, (c-3) -Y⁵— C₃ -C-₇ cycloalkyl or -Y⁵— C₃ -C₇ cycloalkenyl, said cycloalkyl or cycloalkenyl being optionally substituted with up to three substituent independently selected from: (c-3-1 ) d -C₄ alkyl, hydroxyl, OR¹⁴³, S(0)_m R¹⁴³, amino, mono- or di- ( Ci -C₄ alkyl)amino, CONH₂, CONH(C -C₄ alkyl) and CON(d -C₄ alkyl)_2l (c-4) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to seven (preferably up to seven) substituents independently selected from: (c-4-1) halo, Ci -C₈ alkyl, Ci -C₄ alkyl-OH, hydroxyl, -C₈ alkoxy, halosubstituted Ci -C₈ alkyl, halosubstituted Ci -C₈ alkoxy, CN, nitro, S(0)_m R¹⁴³, S0₂ NH₂, S0₂ NH(Cι -C₄ alkyl), S0₂ N(C, -C₄ alkyl)₂, amino, Ci -C₄ alkylamino, di-(Cι -C₄ alkyl)amino, CONH₂, CONH(Cι -C₄ alkyl), CON(Cι -C₄ alkyl)₂, OC(0)R¹⁴³, and phenyl optionally substituted with up to three substituents independently selected from halo, Ci -C₄ alkyl, hydroxyl, OCH₃, CF₃, OCF₃, CN, nitro, amino, mono- or di-(Cι -C₄ alkyl)amino, C0₂ H, C0₂ (Ci -C₄ al kyl) and CONH₂, (c-5) a monocyclic aromatic group as defined in (d) and (e) above, said aromatic group being optionally substituted with up to three substituents independently selected from: (c-5-1) halo, Ci -C₈ alkyl, Ci -C₄ alkyl-OH, hydroxyl, C_t -C₈ alkoxy, CF₃, OCF₃, CN, nitro, S(0)_m R¹⁴³, amino, mono- or di-( Ci -C₄ alkyl)amino, CONH₂, CONH(Cι -C₄ alkyl), CON(d -C4- alkyl)₂, C0₂ H and C0₂ (Ci -C₄ alkyl), and — Y-phenyl, said phenyl being optionally substituted with up to three substituents independently selected halogen, Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy, CF₃, OCF₃, CN, nitro, S(0)_m R¹⁴³, amino, mono- or di-( Ci -C alkyl )amino, C0₂ H, C0₂ (Ci -C₄ alkyl), CONH₂, CONH(Cι -C₄ alkyl) and CON(Cι -C₄ alkyl)₂, (c-6) a group of the following formula:

X²² is halo, Ci -C₄ alkyl, hydroxyl, Ci -C₄ alkoxy, halosubstitutued Ci -C4 alkoxy, S(0)_m R¹⁴³, amino, mono- or di-(d -C₄ alkyl)amino, NHS0₂ R¹⁴³, nitro, halosubstitutued Ci -C₄ alkyl, CN, C0₂ H, C0₂ (Ci -C^ alkyl), Ci -C₄ alkyl-OH, Ci -C₄ alkylOR¹⁴³, CONH₂, CONH(Cι -C₄ alkyl) or CON(Cι -C₄ alkyl)₂ ;

R¹⁴³ is Ci -C₄ alkyl or halosubstituted Ci -C₄ alkyl; m is 0, 1 or 2; n is 0, 1 , 2 or 3; p is 1 , 2, 3, 4 or 5; q is 2 or 3; Z¹¹ is oxygen, sulfur or NR¹⁴⁴ ; and

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

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

X²² is hydrogen;

L⁴ is oxygen;

R¹⁴¹ is hydrogen; and

R¹⁴² is acetyl.

[0132] Aryl phenylhydrazides that are described in U.S. Patent No.

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

Such aryl phenylhydrazides have the formula shown below in formula

XXVIII:

XXVIII

wherein:

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

[0133] 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:

or a pharmaceutical salt thereof, wherein:

R ⁴⁶ is selected from the group consisting of SCH₃, — S(0)₂ CH₃ and —

S(0)₂ NH₂ ; R¹⁴⁷ is selected from the group consisting of OR¹⁵⁰, mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;

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

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

Br; and

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

Br, with the proviso that R¹⁴⁸ and R¹⁴⁹ are not the same. [0134] Materials that can serve as a Cox-2 selective inhibitor of the present invention include bisaryl compounds that are described in U.S.

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

or a pharmaceutically acceptable salt, ester or tautomer thereof, wherein: Z¹³ is C or N; when Z¹³ is N, R¹⁵¹ represents H or is absent, or is taken in conjunction with R¹⁵² as described below: when Z¹³ is C, R¹⁵¹ represents H and R¹⁵² is a moiety which has the _; following characteristics:

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

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

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

N(d -C₂ alkyl)₂, — C(O) Ci -C₂ alkyl, — S— Ci -C₂ alkyl and — C(S) Ci -

C₂ alkyl;

Y⁷ represents N, CH or C— OCι -C₃ alkyl, and when Z¹³ is N, Y⁷ can also represent a carbonyl group;

R¹⁵³ represents H, Br, Cl or F; and

R¹⁵⁴ represents H or CH₃.

[0135] Compounds useful as Cox-2 selective inhibitors of the present invention include 1 ,5-diarylpyrazoles that are described in U.S.

Patent No. 6,028,202. Such 1 ,5-diarylpyrazoles have the formula shown below in formula XXXI:

wherein:

R¹⁵⁵, R¹⁵⁶, R¹⁵⁷, and R¹⁵⁸ are independently selected from the groups consisting of hydrogen, Ci -C₅ alkyl, Ci -C₅ alkoxy, phenyl, halo, hydroxyl,

Ci -C₅ alkylsulfonyl, Ci -C₅ alkylthio, trihaloCi -C₅ alkyl, amino, nitro and

2-quinolinylmethoxy;

R¹⁵⁹ is hydrogen, Ci -C₅ alkyl, trihaloCi -C₅ alkyl, phenyl, substituted phenyl where the phenyl substitutents are halogen, Ci -C₅ alkoxy, trihaloCi -C5 alkyl or nitro or R¹⁵⁹ is heteroaryl of 5-7 ring members where at least one of the ring members is nitrogen, sulfur or oxygen; R¹⁶⁰ is hydrogen, Ci -C₅ alkyl, phenyl Ci -C₅ alkyl, substituted phenyl Ci - C₅ alkyl where the phenyl substitutents are halogen, Ci -C₅ alkoxy, trihaloCi -C₅ alkyl or nitro, or R¹⁶⁰ is Ci -C₅ alkoxycarbonyl, phenoxycarbonyl, substituted phenoxycarbonyl where the phenyl substitutents are halogen, Ci -C₅ alkoxy, trihaloCi -C₅ alkyl or nitro; R¹⁶¹ is Ci -C10 alkyl, substituted Ci -C₁₀ alkyl where the substituents are halogen, trihaloCi -C₅ alkyl, Ci -C₅ alkoxy, carboxy, Ci -C₅ alkoxycarbonyl, amino, Ci -C₅ alkylamino, diCi -C₅ alkylamino, diCi -C alkylaminoCi -C₅ alkylamino, Ci -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 Ci -C₅ alkyl; or R¹⁶¹ is phenyl, substituted phenyl (where the phenyl substitutents are one or more of Ci -C₅ alkyl, halogen, Ci -C₅ alkoxy, trihaloCi -C₅ alkyl or nitro), or R¹⁶¹ is heteroaryl having 5-7 ring atoms where one or more atoms are nitrogen, oxygen or s'ulfur, fused heteroaryl where one or more 5-7 membered aromatic rings are fused to the heteroaryl; or R¹⁶¹ is NR¹⁶³ R¹⁶⁴ where R¹⁶³ and R¹⁶⁴ are independently selected from hydrogen and C₁-₅ alkyl or R¹⁶³ and R¹⁶⁴ may be taken together with the depicted nitrogen to form a heteroaryl ring of 5-7 ring members where one or more of the ring members is nitrogen, sulfur or oxygen where said heteroaryl ring may be optionally substituted with Ci -C₅ alkyl; R¹⁶² is hydrogen, Ci -C₅ alkyl, nitro, amino, and halogen; and pharmaceutically acceptable salts thereof.

[0136] Materials that can serve as a Cox-2 selective inhibitor of the present invention include 2-substituted imidazoles that are described in U.S. Patent No. 6,040,320. Such 2-substituted imidazoles have the formula shown below in formula XXXII:

wherein:

R¹⁶⁴ is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6 ring atoms, or substituted phenyl; wherein the substituents are independently selected from one or members of the group consisting of Cι_₅ alkyl, halogen, nitro, trifluoromethyl and nitrile;

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

R¹⁶⁶ is hydrogen, 2-(trimethylsilyl)ethoxymethyl), Ci -C₅ alkoxycarbonyl, aryloxycarbonyl, arylCi -C₅ alkyloxycarbonyl, arylCi -C₅ alkyl, phthalimidoCi -C₅ alkyl, aminoCi -C₅ alkyl, diaminoCi -C5 alkyl, succinimidoCi -C5 alkyl, Ci -C₅ alkylcarbonyl, arylcarbonyl, Ci -C5 alkylcarbonylCi -C₅ alkyl, aryloxycarbonylCi -C₅ alkyl, heteroarylCi -C₅ alkyl where the heteroaryl contains 5 to 6 ring atoms, or substituted arylCi -C₅ alkyl, wherein the aryl substituents are independently selected from one or more members of the group consisting of Ci -C₅ alkyl, Ci -C₅ alkoxy, halogen, amino, Ci -C₅ alkylamino, and diC-i -C₅ alkylamino; R¹⁶⁷ is (A¹¹)„ -(CH¹⁶⁵), -X²⁴ wherein: A¹¹ is sulfur or carbonyl; n is 0 or 1 ; q is 0-9;

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

-C5 alkyl, phenyl, araCi -C5 alkyl, thienyl, furanyl, and naphthyl; substituted vinyl, wherein the substituents are independently selected from one or members of the group consisting of fluorine, bromine, chlorine and iodine, substituted ethynyl, wherein the substituents are independently selected from one or more members of the group consisting of fluorine, bromine chlorine and iodine, substituted Ci -C₅ alkyl, wherein the substituents are selected from the group consisting of one or ' more Ci -C₅ alkoxy, trihaloalkyl, phthalimido and amino, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of Ci -C₅ alkyl, halogen and Ci -C5 alkoxy, substituted phenoxy, wherein the phenyl substituents are independently selected from one or more members of the group consisting of Ci -C₅ alkyl, halogen and Ci -C₅ alkoxy, substituted Ci -C₅ alkoxy, wherein the alkyl substituent is selected from the group consisting of phthalimido and amino, substituted arylCi -C₅ alkyl, wherein the alkyl substituent is hydroxyl, substituted arylCi -C₅ alkyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of Ci -C₅ alkyl, halogen and Ci -C₅ alkoxy, substituted amido, wherein the carbonyl substituent is selected from the group consisting of

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

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

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

[0137] 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:

XXXIV

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

wherein:

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

O— ;

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

C₆)alkoxy, =NOH, — NR¹⁷⁴ R¹⁷⁵, — OCH₃, — OCH₂ CH₃, — OS0₂ NHC0₂

CH₃, ⁼CHC0₂ CH₂ CH₃, — CH C0₂ H, — CH₂ C0₂ CH3, — CH2 CO2 CH2

CH₃, — CH₂ CON(CH₃)₂, — CH₂ C0₂ NHCH3, — CHCHCO2 CH₂ CH₃, —

OCON(CH₃)OH, — C(COCH₃)₂, di(Cι -C₆)alkyl and di(Cι -C₆)alkoxy;

R¹⁷³ is selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (Ci -C₆)alkyl, (Ci -Ce)alkoxy and optionally substituted carboxyphenyl, wherein substituents on the carboxyphenyl group are selected from the group consisting of halogen, hydroxyl, amino, (Ci -

C₆)alkyl and (Ci -Ce)alkoxy; or R¹⁷² and R¹⁷³ taken together form a moiety selected from the group consisting of — O — and

R¹⁷⁴ is selected from the group consisting of hydrogen, OH, — OCOCH₃,

— COCH₃ and (Ci -C₆)alkyl; and

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

— COCH3, (Ci -C₆)alkyl, — CONH₂ and — S0₂ CH₃ ; with the proviso that if M is a cyclohexyl group, then R¹⁷⁰ through R¹⁷³ may not all be hydrogen; and pharmaceutically acceptable salts, esters and pro-drug forms thereof.

[0138] Esters derived from indolealkanols and novel amides derived from indolealkylamides that are described in U.S. Patent No. 6,306,890 can serve as Cox-2 selective inhibitors of the present invention. Such compounds have the general formula shown below in formula XXXV:

wherein: R >1¹7'6⁰ is Ci -C₆ alkyl, Ci -C₆ branched alkyl, C₄ -C₈ cycloalkyl, Ci -C₆ hydroxyalkyl, branched Ci -Cβ hydroxyalkyl, hydroxyl substituted C₄ -C₈ aryl, primary, secondary or tertiary Ci -C₆ alkylamino, primary, secondary or tertiary branched Ci -C₆ alkylamino, primary, secondary or tertiary C₄ - C₈ arylamino, Ci -C₆ alkylcarboxylic acid, branched Ci -C₆ alkylcarboxylic acid, Ci -C₆ alkylester, branched Ci -C₆ alkylester, C₄ -C₈ aryl, C₄ -C₈ arylcarboxylic acid, C₄ -C₈ arylester, C₄ -C₈ aryl substituted Ci -C₆ alkyl, C -C₈ heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-substituted or aryl-substituted C₄ -C₈ heterocyclic alkyl or aryl with O, N or S in the ring, or halo-substituted versions thereof, where halo is chloro, bromo, fluoro or iodo;

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

X²⁵ is O, NH, or N— R¹⁸⁰, where R¹⁸⁰ is Ci -C₆ or d -C₆ branched alkyl. [0139] Materials that can serve as a Cox-2 selective inhibitor of the present invention include pyridazinone compounds that are described in U.S. Patent No. 6,307,047. Such pyridazinone compounds have the formula shown below in formula XXXVI:

XXXVI

or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein: X²⁶ is selected from the group consisting of O, S, — NR¹⁸⁵, — NOR^a, and - NNR^b R^c ;

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

R^a, R^b, and R^c are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl; R¹⁸¹ is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocyclic, heterocyclic alkoxy, heterocyclic alkyl, heterocyclic oxy, hydroxyalkyl, hydroxyiminoalkoxy, — (CH₂)_n C(0)R¹⁸⁶, — (CH₂)_n CH(OH)R¹⁸⁶, — (CH₂)_n C(NOR^d)R¹⁸⁶, — (CH₂)_n CH(NOR^d)R¹⁸⁶, — (CH₂)_n CH(NR^d R^e)R¹⁸⁶, — R¹⁸⁷ R¹⁸⁸, -(CH₂)_n C≡CR¹⁸⁸, -(CH₂)_n [CH(CX²⁶ ₃)]_m (CH₂)_P R ⁸⁸, -(CH₂)_n (CX²⁶'₂)_m (CH₂)_P R¹⁸⁸, and -(CH₂)_n (CHX²⁶')_m (CH₂)_m R¹⁸⁸ ; R¹⁸⁶ is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, haloalkynyl, heterocyclic, and heterocyclic alkyl; R¹⁸⁷ is selected from the group consisting of alkenylene, alkylene, halosubstituted alkenylene, and halo-substituted alkylene; R¹⁸⁸ is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclic, and heterocyclic alkyl; R^d and R^e are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl;

X^26' is halogen; m is an integer from 0-5; n is an integer from 0-10; p is an integer from 0-10;

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

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

Se(0)₂, P(0)(OR¹⁹²), and P(0)(NR¹⁹³ R ⁹⁴);

X²⁸ is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen;

R¹⁹⁰ is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, — NHNH₂, and — NCHN(R ⁹¹)R¹⁹² ;

R¹⁹¹, R¹⁹², R ⁹³, and R ⁹⁴ are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R¹⁹³ and R¹⁹⁴ can be taken together, with the nitrogen to which they are attached, to form a 3-6 membered ring containing 1 or 2 heteroatoms selected from the group consisting of O, S, and NR¹⁸⁸ ; Y⁸ is selected from the group consisting of -OR¹⁹⁵, — SR¹⁹⁵, — C(R¹⁹⁷)(R¹⁹⁸)R¹⁹⁵, — C(0)R¹⁹⁵, — C(0)OR¹⁹⁵, — N(R¹⁹⁷)C(0)R¹⁹⁵, - NC(R¹⁹⁷)R¹⁹⁵, and — N(R¹⁹⁷)R¹⁹⁵ ;

R¹⁹⁵ is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, hydroxyalkyl, and NR¹⁹⁹ R²⁰⁰ ; and

R¹⁹⁷, R¹⁹⁸, R¹⁹⁹, and R²⁰⁰ are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl.

[0140] Benzosulphonamide derivatives that are described in U.S.

Patent No. 6,004,948 are useful as Cox-2 selective inhibitors of the present invention. Such benzosulphonamide derivatives have the formula shown below in formula XXXVII: _R201 A¹² °w Xff /? \ _R xxxvu _R206 / \ ^κ_| / ^R W wherein:

A¹² denotes oxygen, sulphur or NH;

R²⁰¹ denotes a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted by halogen, alkyl, CF₃ or alkoxy; D⁵ denotes a group of formula XXXVIII or XXXIX:

XXXVIII

or

XXXIX

R²⁰² and R²⁰³ independently of each other denote hydrogen, an optionally polyfluorinated alkyl radical, an aralkyl, aryl or heteroaryl radical or a radical (CH₂)_n -X 29. , or R ₅202 and R203 together with the N-atom denote a three- to seven- membered, saturated, partially or totally unsaturated heterocycle with one or more heteroatoms N, O, or S, which may optionally be substituted by oxo, an alkyl, alkylaryl or aryl group or a group (CH2)_n -X²⁹, R²⁰²' denotes hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or , heteroaryl group or a group (CH₂)_n -X²⁹, wherein: X²⁹ denotes halogen, N0₂₎ —OR²⁰⁴, —COR²⁰⁴, — C0₂ R²⁰⁴, — OC0₂ R²⁰⁴, -CN, -CONR²⁰⁴ OR²⁰⁵, -CONR²⁰⁴ R²⁰⁵, -SR²⁰⁴, - S(0)R²⁰⁴, — S(0)₂ R²⁰⁴, — NR²⁰⁴ R²⁰⁵, — NHC(0)R²⁰⁴, — NHS(0)₂ R²⁰⁴; Z¹⁵ denotes -CH₂ — , — CH₂ -CH₂ — , — CH₂ -CH₂ -CH₂ — , — CH₂ -CH=CH— , — CH=CH— CH₂ — , — CH₂ —CO—, — CO— CH₂ — , — MHCO— , — CONH— , — NHCH₂ — , — CH₂ NH— , — N=CH— , — NHCH— , — CH₂-CH₂— NH— , — CH=CH— , >N— R²⁰³, >C=0, >S(0)_m; R²⁰⁴ and R²⁰⁵ independently of each other denote hydrogen, alkyl, aralkyl or aryl; n is an integer from .0 to 6; R²⁰⁶ is a straight-chained or branched Ci -C₄ alkyl group which may optionally be mono- or polysubstituted by halogen or alkoxy, or R²⁰⁶ denotes CF₃; and m denotes an integer from 0 to 2; with the proviso that A¹² does not represent O if R²⁰⁶ denotes CF₃; and the pharmaceutically acceptable salts thereof. [0141] Materials that can serve as Cox-2 selective inhibitors of the present invention include methanesulfonyl-biphenyl derivatives that are described in U.S. Patent No. 6,583,321. Such methanesulfonyl-biphenyl derivatives have the formula shown below in formula XXXX:

wherein: R²⁰⁷ and R²⁰⁸ are respectively a hydrogen; Ci -C₄-alkyl substituted or not substituted by halogens; C₃ -C₇-cycloalkyl; Ci -C_δ-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). [0142] Cox-2 selective inhibitors such as 1 H-indole derivatives described in U.S. Patent No. 6,599,929 are useful in the present invention. Such 1 H-indole derivatives have the formula shown below in formula XXXXI:

XXXXI

wherein: X³⁰ is -NHS0₂R²⁰⁹ wherein R²⁰⁹ represents hydrogen or Ci -C₃- alkyl; Y⁹ is hydrogen, halogen, Ci -C₃-alkyl substituted or not substituted by halogen, N0₂, NH₂, OH, OMe, C0₂H, or CN; and Q⁷ is C=0, C=S, or CH₂. ,

[0143] Compounds that are useful as Cox-2 selective inhibitors of the present invention include prodrugs of Cox-2 inhibitors that are described in U.S. Patent Nos. 6,436,967 and 6,613,790. Such prodrugs of Cox-2 inhibitors have the formula shown below in formula XXXXII:

XXXXII

wherein : A¹³ is a ring substituent selected from partially unsaturated heterocyclic, heteroaryl, cycloalkenyl and aryl, wherein A¹³ is unsubstituted or substituted with one or more radicals selected from alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocycloxy, alkylthio, cycloalkyl, aryl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, araalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N- arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, -arylamino, N- aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N- arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl; R²¹⁰ is selected from heterocyclyl, cycloalkyl, cycloalkenyl, and aryl, wherein R²¹⁰ is unsubstituted or substituted with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio; R²¹¹ is selected from hydrido and alkoxycarbonylalkyl; R²¹² is selected from alkyl, carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, amino acid residue, and alkylcarbonylaminoalkylcarbonyl; provided A¹³ is not tetrazolium, or pyridinium; and further provided A¹³ is not indanone when R²¹² is alkyl or carboxyalkyl; further provided A¹³ is not thienyl, when R²¹⁰ is 4-fluorophenyl, when R²¹¹ is hydrido, and when R²¹² is methyl or acyl; and R²¹³ is hydrido; or a pharmaceutically-acceptable salt thereof. [0144] Specific non-limiting examples of substituted sulfonamide prodrugs of Cox-2 inhibitors disclosed in U.S. Patent No. 6,436,967 that are useful in the present invention include: N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1- yl]phen yl]sulfonyl]propanamide;

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

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

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

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

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

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

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

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

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

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

2,2-dimethyl-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]sulfonyl]propanamide; N-[[4-5-methyl-3-phenylisoxazol-4-yl)phenyI]sulfonyl]butanamide;

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

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

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

N-[[4-[5-methyI-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide; N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H pyrazol-1- yl]phenyl]sulfonyl]pro panamide;

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

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

[2]benzothiopyrano [4,3-c]pyrazol-1-yl)phenyl]sulfonyl]acetamide;

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

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

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

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

1 ,1-dimethylethyl-N-[[4-(5-methyL3-phenylisoxazol-4- yl)phenyl]sulfonyl]ca rbamate;

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

N-acetyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine, ethyl ester; N-[[4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yl)phenyl]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-yl]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-fluorophenyI)cyclopenten-1 -yl]-N-methylbenezenesulfonamide; and

N-[[4-(3-phenyl-2,3-dihydro-2-oxofuran-4-yl)phenyl]sulfonyl]propanamide.

[0145] Those prodrugs disclosed in U.S. Patent No. 6,613,790 have the general formula shown above in formula XXXXII wherein: A¹³ is a pyrazole group optionally substituted at a substitutable position with one or more radicals independently selected at each occurrence from the group consisting of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, intro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, alkenyl, alkynyl, alkylthio, alkylthioalkyl, alkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkylsutfinyl, alkylsulfonyl, aminosulfonyl, and alkylaminosulfonyl; R²¹⁰ is a phenyl group optionally substituted at a substitutable position with one or more radicals independently selected at each occurrence from the group consisting of alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio; R²¹¹ and R²¹² are independently selected from the group consisting of hydroxyalkyl and hydrido but at least one of R²¹¹ and R²¹² is other than hydrido; and R²¹³ is selected from the group consisting of hydrido and fluoro.

[0146] 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)-l H-pyrazol-1 -yl]benzenesulfonamide, N,N-bis(2- hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyraz ol-1 - yl]benzenesulfonamide, or pharmaceuticaly-acceptable salts thereof.

[0147] Cox-2 selective inhibitors such as sulfamoylheleroaryl pyrazole compounds that are described in U.S. Patent No. 6,583,321 may serve as Cox-2 inhibitors of the present invention. Such sulfamoylheleroaryl pyrazole compounds have the formula shown below in formula XXXXIII:

XXXXIII

wherein: R²¹⁴ is furyl, thiazolyl or oxazolyl; R²¹⁵ is hydrogen, fluoro or ethyl; and X³¹ and X³² are independently hydrogen or chloro. [0148] Heteroaryl substituted amidinyl and imidazolyl compounds such as those described in U.S. Patent No. 6,555,563 are useful as Cox-2 selective inhibitors of the present invention. Such heteroaryl substituted amidinyl and imidazolyl compounds have the formula shown below in formula XXXXIV:

XXXXIV

wherein: Z¹⁶ is O or S, R²¹⁶ is optionally substituted aryl, R²¹⁷ is aryl optionally substituted with aminosulfonyl, and R²¹⁸ and R²¹⁹ cooperate to form an optionally substituted 5- membered ring.

[0149] Materials that can serve as Cox-2 selective inhibitors of the present invention include substituted hydroxamic acid derivatives that are described in U.S. Patent Nos. 6,432,999, 6,512,121 , and 6,515,014. These compounds also act as inhibitors of the lipoxygenase-5 enzyme. Such substituted hydroxamic acid derivatives have the general formulas shown below in formulas XXXXV and XXXXVI:

XXXXV

[0150] Pyrazole substituted hydroxamic acid derivatives described in U.S. Patent No. 6,432,999 have the formula shown above in formula XXXXV, wherein: A¹⁴ is pyrazolyl optionally substituted with a substituent selected from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y¹⁰ is selected from lower alkenylene and lower alkynylene; R²²⁰ is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R²²⁰ is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylmino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R²²¹ is selected from lower alkyl and amino; and R²²² is selected from hydrido, lower alkyl, phenyl, 5- and 6- membered heterocyclo and lower cycloalkyl; or a pharmaceutically- acceptable salt thereof.

[0151] Pyrazole substituted hydroxamic acid derivatives described in U.S. Patent No. 6,432,999 may also have the formula shown above in formula XXXXVI, wherein: A¹⁵ is pyrazolyl optionally substituted with a substituent selected from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y¹¹ is selected from lower alkylene, lower alkenylene and lower alkynylene; R²²³ is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R²²³ is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylmino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R²²⁴ is selected from lower alkyl and amino; and R²²⁵ is selected from hydrido, lower alkyl; or a pharmaceutically-acceptable salt thereof. [0152] Heterocyclo substituted hydroxamic acid derivatives described in U.S. Patent No. 6,512,121 have the formula shown above in formula XXXXV, wherein: A¹⁴ is a ring substiuent selected from oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isochiazolyl, isoxazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A¹⁴ is optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y¹⁰ is lower alkylene, lower alkenylene, and lower alkynylene; R²²⁰ is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R²²⁰ is otionallv substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R²²¹ is selected from lower alkyl and amino; and R²²² is selected from hydrido, lower alkyl, phenyl, 5- and 6- membered heterocyclo and lower cycloalkyl; or a pharmaceutically- acceptable salt thereof.

[0153] Heterocyclo substituted hydroxamic acid derivatives described in U.S. Patent No. 6,512,121 may also have the formula shown above in formula XXXXVI, wherein: A¹⁵ is a ring substituent selected from oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A is optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarboryl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y¹¹ is selected from lower alkyl, lower alkenyl and lower alkynyl; R²²³ is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R²²³ is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitto, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R²²⁴ is selected from lower alkyl and amino; and R²²⁵ is selected from hydrido and alkyl; or a pharmaceutically- acceptable salt thereof.

[0154] Thiophene substituted hydroxamic acid derivatives described in U.S. Patent No. 6,515,014 have the formula shown above in formula XXXXV, wherein: A¹⁴ is thienyl optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y¹⁰ is ethylene, isopropylene, propylene, butylene, lower alkenylene, and lower alkynylene; R²²⁰ is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R²²⁰ is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R²²¹ is selected from lower alkyl and amino; and R²²² is selected from hydrido, lower alkyl, phenyl, 5- and 6- membered heterocyclo and lower cycloalkyl; or a pharmaceutically- acceptable salt thereof.

[0155] Thiophene substituted hydroxamic acid derivatives described in U.S. Patent No. 6,515,014 may also have the formula shown above in formula XXXXV, wherein: A¹⁵ is thienyl optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y¹¹ is selected from lower alkyl, lower alkenyl and lower alkynyl; R²²³ is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R²²³ is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R²²⁴ is selected from lower alkyl and amino; and R²²⁵ is selected from hydrido and alkyl; or a pharmaceutically- acceptable salt thereof.

[0156] Compounds that are useful as Cox-2 selective inhibitors of the present invention include pyrazolopyridine compounds that are described in U.S. Patent No. 6,498,166. Such pyrazolopyridine compounds have the formula shown below in formula XXXXVII:

XXXXVII

w erein: R²²⁶ and R²²⁷ are independently selected from the group consisting of H, halogen, Ci -C₆ alkyl, Ci -C₆ alkoxy, and Ci — C₆ alkoxy substituted by one or more fluorine atoms; R²²⁸ is halogen, CN, CON R²³⁰ R²³¹, C0₂ H, C0₂ Ci -C₆ alkyl, or NHS0₂R²³⁰; R²²⁹ is Ci -C₆ alkyl or NH₂ ; and R²²⁵ and R²²⁵ 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 Ci -C₆ alkoxy substituted by one or more fluorine atoms, or a pharmaceutically acceptable salt, solvate, ester, or salt or solvate of such ester thereof. [0157] Materials that are useful as Cox-2 selective inhibitors of the present invention include 4,5-diaryl-3(2H)-furanone derivatives that are described in U.S. Patent No. 6,492,416. Such 4,5-diaryl-3(2H)-furanone derivatives have the formula shown below in formula XXXXVIII:

XXXXVIII

wherein: X³³ represents halo, hydrido, or alkyl; Y¹² represents alkylsulfonyl, aminosulfonyl, alkylsulfinyl, (N- acylamino)-sulfonyl, (N-alkylamino)sulfonyl, or alkylthio; Z¹⁷ represents oxygen or sulfur atom; R²³³ and R²³⁴ are selected independently from lower alkyl radicals; and R²³² represents a substituted or non-substituted aromatic group of 5 to 10 atoms; or a pharmaceutically-acceptable salt thereof. [0158] Cox-2 selective inhibitors that can be used in the present invention include 2-phenyl-1 ,2-benzisoselenazol-3(2H)-one derivatives and 2-phenylcarbomyl-phenylselenyl derivatives that are described in U.S. Patent No. 6,492,416. Such 2-phenyl-1 ,2-benzisoselenazol-3(2H)-one derivatives and 2-phenylcarbomyl-phenylselenyl derivatives have the formulas shown below in formulas XXXXIX or XXXXIX':

XXXXIX

XXXXIX'

wherein: R is a hydrogen atom or an alkyl group having 1-3 carbon atoms; R >2^36 is a hydrogen atom, a hydroxyl group, an organothiol group that is bound to the selenium atom by its sulfur atom, or R 235 and R >23 ^ύ6 are joined to each other by a single bond; R²³⁷ is a hydrogen atom, a halogen atom, an alkyl group having 1-3 carbon atoms, an alkoxyl group having 1-3 carbon atoms, a trifluoromethyl group, or a nitro group; R²³⁸ and R²³⁹ are identical to or different from each other, and each is a hydrogen atom, a halogen atom, an alkoxyl group having 1-4 carbon atoms, a trifluoromethyl group, or R ^■,238 and R 239 are joined to each other to form a methylenedioxy group, a salt thereof, or a hydrate thereof. [0159] Pyrones such as those disclosed in U.S. Patent No.

6,465,509 are also useful as Cox-2 inhibitors of the present invention. These pyrone compounds have the general formula shown below in formula XXXXX:

XXXXX

in: X³⁴ is selected from the group consisting of (a) ; a bond, (b) - ™(CH₂)_m — , wherein m 1 or 2, (c) - -C(O)-, (d) -0-, (e) -S-, and ( ) - -N(R²⁴⁴)~; R²⁴⁰ is selected from the group consisting of (a) Ci -Cio alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halo, Ci -Cio alkoxy, Ci -Cio alkylthio, and CN, (b) phenyl or naphthyl, and (c) heteroaryl, which is comprised of a monocyclic aromatic ring of 5 atoms having one hetero atom which is S, O or N, and optionally 1, 2, or 3 additional N atoms; or a monocyclic ring of 6 atoms having one hetero atom which is N, and optionally 1 , 2, or 3 additional N atoms, wherein groups (b) and (c) above are each optionally substituted with 1-3 substituents independently selected from the group consisting of halo, Ci -Cι₀ alkoxy, Ci -C₁₀ alkylthio, CN, Ci -C₁₀ alkyl, optionally substituted to its maximum with halo, and N₃ ; R²⁴¹ is selected from the group consisting of (a) Ci -Cβ alkyl, optionally substituted to its maximum with halo, (b) NH₂, and (c) NHC(0)Cι -Cio alkyl, optionally substituted to its maximum with halo; R²⁴² and R²⁴³ are each independently selected from the group consisting of hydrogen, halo, and Ci -C₆ alkyl, optionally substituted to its maximum with halo; and R²⁴⁴ is selected from the group consisting of hydrogen and Ci -Cβ alkyl, optionally substituted to its maximum with halo. [0160] Examples of pyrone compou nds 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-methyls lfonyl)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)phemyl-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-lsopropylthio-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one, 4-(4-Methylsulfonyl)phenyl)-3-phenylthio-Θ-trifluoromethyl-pyran-2-one, 3-lsopropylthio-4-(4-methylsulfonyl)phenyl-6-trifluoromethyl-pyran-2-one, 4-(4-Methylsulfonyl)phenyl-3-phenyl-6-(2,2,2-trifluoroethyl)-pyran-2-one, and

3-(3-Hydroxy-3-methylbutyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2- one. [0161] Organically synthesized or purified from plant sources, free-

B-ring flavanoids such as those described in U.S. Published Application No. 2003/0165588, are useful as Cox-2 selective inhibitors of the present invention. Such free-B-ring flavanoids have the general structure shown in formula XXXXXI:

XXXXXI

wherein: R²⁴⁶, R²⁴⁷, R²⁴⁸, R²⁴⁹, and R²⁵⁰ are independently selected from the group consisting of -H, -OH, -SH, -OR, -SR, -NH₂, -NHR²⁴⁵, - N(R²⁴⁵)₂, -N(R²⁴⁵)₃ ⁺X^35-, a carbon, oxygen, nitrogen or sulfur, glycoside of a single or a combination of multiple sugars including, aldopentoses, methyl- aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; wherein R²⁴⁵ is an alkyl group having between 1-10 carbon atoms; and X³⁵ is selected from the group of pharmaceutically acceptable counter anions including, hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride and carbonate.

[0162] Heterocyclo-alkylsulfonyl pyrazoles such as those described in European Patent Application No. EP 1312367 are useful as Cox-2 selective inhibitors of the present invention. Such heterocyclo-alkylsulfonyl pyrazoles have the general formula shown below in formula XXXXXII: XXXXXII

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

m is 0, 1 or 2; X³⁵ is >CR²⁵⁵ or >N; R ι2²5⁵1¹ is a radical selected from the group consisting of H, N0₂, CN, (d -C₆)alkyl, (Ci -C₆)alkyl-S0₂-, (C₆ -Cι₀)aryl-SO₂-, H-(C=0)-, (Ci -C₆)alkyl-(C=0)-, (Ci -C₆)alkyl-)-(C=0)-, (Ci -C₉)heteroaryl-(C=0)-, (Ci -C₉)heterocyclyl-(C=0)-, H₂N-(C=0)-, (Ci -C₆)alkyl-NH-(C=0)-, [(Ci - C₆)alkyl]₂-N-(C=0)-, [(C₆ -Cιo)aryl]₂-NH-(C=0)-, [(Ci -C₆)alkyl]-[((C₆ - Cio)aryl-N]-(C=0)-, HO-NH-(C=0)-, and (Ci -C₆)alkyl-0-NH-(C=0)-; R²⁵² is a radical selected from the group consisting of H, -N0₂, -CN, (C₂- C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, (C₆-Cι₀)aryl, (d- C₉)heteroaryl, (Ci-Cg)heterocyclyl, (CrC₆)alkyl-0-, (C₃-C₇)cycloalkyl-0-,

(Ce-Cιo)aryl-O-, (Ci -C₉)heteroaryl-0-, (C₆ -C₉)heterocyclyl-0-, H-(C=0)-, (d-C₆)alkyl-(C=0)-, (C₃-C₇)cycloalkyl-(C=0)-, (C₆-Cι₀)aryl-(C=O)-, (d- C₉)heteroaryl-(C=0)-, (Ci-C₉)heterocyclyl-(C=0)-, (Ci-C₆)alkyl-0-(C=0)-, (C₃-C₇)cycloalkyl-0-(C=0)-, (C₆-C₁₀)aryl-O-(C=O)-, (Ci-C₉)heteroaryl-0- (C=0)-, (Ci-C₉)heterocyclyl-0-(C=0)-, (C C₆)alkyl-(C=0)-0-, (C₃-

C₇)cycloalkyl-(C=0)-0-, (C₆-Cio)aryl-(C=0)-0-, (Ci-C₉)heteroaryl-(C=0)- 0-, (C C₉)heterocyclyl-(C=0)-0-, (d-C₆)alkyl-(C=0)-NH-, (C₃- C₇)cycloalkyl-(C=0)-NH-, (C₆-Ci₀aryl-(C=O)-NH-. (Ci-C₉)heteroaryl-(C=0)- NH-, (Cι-C₉)heterocyclyl-(C=0)-NH-, (d-C₆)alkyl-0-(C=0)-NH-, (d- C₆)alkyl-NH, [(Cι-C₆)alkyl]₂-N-, (C₃-C₇)cycloalkyl-NH-. [(C₃-C₇)cycloalkyl]₂-

N-, [(C₆-Cιo)aryl]-NH-, [(Ce-Ci ₀)aryl]₂-N-, [(C₁ -C₆)alkyl]-[((Ce-Cιo)aryl)-N]-, [(Ci -C₉)heteroaryl]-NH-, [(C C₉)heteroaryl]₂-N-, [(CrC₉)heterocycly]-NH-, [(Cι-C₉)heterocyclyl]₂-N-, H₂N-(C=0)-, HO-NH-(C=0)-, (d-Ce)alkyl-O-NH- (C=0)-, [(Cι-C₆)alkyl]-NH-(C=0)-, [(Ci-C₆)alkyl]₂-N-(C=0)-, [(C₃- C₇)cycloalkyl]-NH-(C=0)-, [(C₃-C₇)cycloalkyl]₂-N-(C=0)-, [(C₆-C₁₀)aryl]-NH-

(C=0)-,

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

C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, (C₆-Cι₀)aryl, (C₂- C₉)hetorocyclyl, (Ci -C₆)alkyl-0-, H-(C=0)-, (d-C₆)alkyl-(C=0)-, HO- (C=0)-, (Cι-C₆)alkyl-0-(C=0)-, -NH₂, (Cι-Ce)alkyl-NH-, [(Cι-C₆) alkyl]₂-N-, (C₃-C₇)cycloalkyl-NH-, (Ce-Cιo)aryl-NH-, [(Cι-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]-, (Cι-Cg)heteroaryl-NH-, H₂N-(C=0)-[(d-C₆)alkyl]-NH-(C=0)-, [(C

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

C₉)heterocyclyl, H-(C=0)-, (d-C₆)alkyl-(C=0)-, (d-C₆)alkyl-0-(C=0)-, H₂N-(C=0)-, [(CrC₆)alkyl]-NH-(C=0)-, [(C C₆)alkyl]₂-N-(C=0)-, [(C₆- Cio)aryl]-NH-(C=0)-, [(Cι-C₆)alkyl]-[((C₆-C₁₀)aryl)-N]-(C=O)-, (Ci -C₆)alkyl- 0-NH-(C=0)-, and (Cι-C₆)alkyl optionally substituted with one to four fluoro moieties; R²⁵⁴ is an (Cι-C₆)alkyl radical optionally substituted by one to fourfluoro substituents; and R²⁵⁵ is a radical selected from the group consisting of H, halo, -OH, (d-Cβ)alkyl-O-, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₃- C₇)cycloalkyl, -CN, H-(C=0)-, (d-C₆)alkyl-(C=0)-, (d-C₆)alkyl-(C=0)-0-,

HO-(C=0)-, (Cι-C₆)alkyl-0-(C=0)-, (d-Ce)alkyl-NH-. [(Cι-C₆)alkyl]₂-N-, (C₃-C₇)cycloalkyl-NH-, (C₆-Cιo)aryl-NH-, [(Cι-Ce)alkyl]-[((C₆-Cιo)aryl)-N]-, (Cι-C₉)heteroaryl-NH-, H₂N-(C=0)-, (d-C₆)alkyl-NH-(C=0)-. C(Cι- C₆)alkyl]₂-N-(C=0)-, (C₆-Cio)aryl-(C=0)-, [(Cι-C₆)alkyl]-[((C₆-Cιo)aryl)-N]- (C=0)-, (Cι-C₆)alkyl-0-NH-(C=0)-, (d-Ce)alkyl-S-, and (Cι-C₆)alkyl optionally substituted by one to four fluoro substituents. [0163] 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 XXXXXIIP.

XXXXXIII

wherein:

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

R²⁵⁷ represents an alkyl, C₃ -C₇ cycloalkyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups;

R²⁵⁸ represents a methyl, hydroxymethyl, alkoxymethyl, C₃ -C₇ cycloalkoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrile^, trifluoromethyl or difluoromethyl group or a CH₂ - R²⁶¹ group* wherein R²⁶¹ represents an alkyl group; and

X³⁶ represents a single bond, an oxygen atom, a sulfur atom or a methylene group; or a pharmaceutically acceptable salt thereof. [0164] Examples of 2-phenylpyran-4-one derivatives useful in the present invention include, but are not limited to: 3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(2-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

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

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

3-(4-bromophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 2-(4-methanesulfonylphenyl)-6-methyI-3-(4-methylphenoxy)pyran-4-one, 3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4- one, 3-(2,5-difluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,

3-(4-chlorophenyI)-2-(4-methanesulfonylphenyl)-6-methoxymethylpyran-4- one,

3-(4-chlorophenyl)-6-difluoromethyI-2-(4-methanesulfonylphenyl)pyran-4- one, and pharmaceutically acceptable salts thereof.

[0165] 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).

[0166] 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)-1 H-pyrazol-1 -yl)benzenesulfonamide; a7) 4-(5-(4-chlorophenyl)-3-phenyl-1 H-pyrazol-1 - yl)benzenesulfonamide; a8) 4-(3,5-bis(4-methoxyphenyl)-1 H-pyrazol-1 -yl)benzenesulfonamide; a9) 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1 H-pyrazol-1 - yl)benzenesulfonamide; a10) 4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1 H-pyrazol-1 - yl)benzenesulfonamide; b1 ) 4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1 H-pyrazol-1 - yl)benzenesulfonamide; b2) 4-(4-chloro-3,5-diphenyl-1 H-pyrazol-1 -yl)benzenesulfonamide b3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b4) 4-[5-phenyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yljbenzenesulfonamide; b5) 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b6) 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b7) 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b8) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b9) 4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b10) 4-[3-(difluoromethyl)-5-(4-methylphenyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; d ) 4-[3-(difluoromethyl)-5-phenyl-1 H-pyrazol-1 -yljbenzenesulfonamide; c2) 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; c3) 4-[3-cyano-5-(4-fluorophenyl)-1 H-pyrazol-1 -yljbenzenesulfonamide; c4) 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; c5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; c6) 4-[4-chloro-5-phenyl-1 H-pyrazol-1 -yljbenzenesulfonamide; c7) 4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; c8) 4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1 H-pyrazol-

1 -yljbenzenesulfonamide; c9) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4jhept-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[3.4joct-6-ene; d2) 5-(3-chloro-4-methoxyphenyl)-6-[4-

(methylsulfonyl)phenyl]spiro[2.4jhept-5-ene; d3) 4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5- yljbenzenesulfonamide; d4) 5-(3,5-dichloro-4-methoxyphenyl)-6-[4- (methylsulfonyl)phenyljspiro[2.4]hept-5-ene; d5) 5-(3-chloro-4-fluorophenyl)-6-[4- (methylsulfonyl)phenyl]spiro[2.4jhept-5-ene; d6) 4-[6-(3,4-dichlorophenyl)spiro[2.4jhept-5-en-5- yljbenzenesulfonamide; d7) 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4- methylsulfonylphenyl)thiazole; d8) 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4- methylsulfonylphenyl)thiazole; d9) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methyIthiazole; d 10) 4-(4-f luorophenyl)-5-(4-methylsulfonylphenyl)-2- trifluoromethylthiazole; e1 ) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-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)phenyljthiazole; 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- yljbenzenesulfonamide; e8) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6- diene; e9) 4-[6-(4-fluorophenyl)spiro[2.4jhepta-4,6-dien-5- yljbenzenesulfonamide; e10) 6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)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 - yljbenzenesulfonamide; f4) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; f5) 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; f6) 3-[1 -[4-(methylsulfonyl)phenylj-4-(trifluoromethyl)-1 H-imidazol-2- yljpyridine; f7) 2-[1 -[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H-imidazol-2- yljpyridine; f8) 2-methyl-4-[1 -[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H- im id azol-2-yl] py rid i ne ; 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)-1 H-imidazol-1 - yljbenzenesulfonamide; g1 ) 2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4- i (trifluoromethyl)-l H-imidazole; g2) 4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; 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)phenylj- 1 H-imidazole; g6) 2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-4-

(trifluoromethyl)-l H-imidazole; g7) 1 -[4-(methylsulfonyl)phenylj-2-phenyl-4-trifluoromethyl-1 H- imidazole; gδ) 2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenylj-4-trifluoromethyl- 1 H-imidazole; g9) 4-[2-(3-chloro-4-methylphenyl)-4-(trif luoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; g10) 2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-

(trifluoromethyl)-l H-imidazole; hi ) 4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyI)-1 H-imidazol-1 - yljbenzenesulfonamide; h2) 2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-

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

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

(trifluoromethyl)-l H-pyrazole; h9) 4-[1-ethyl-4-(4-fIuorophenyl)-5-(trifluoromethyl)-1 H-pyrazol-3- yljbenzenesulfonamide; i1 ) N-phenyl-[4-(4-luorophenyI)-3-[4-(methylsulfonyl)phenylj-5-

(trifluoromethyl)-l H-pyrazol-1 -yljacetamide; i2) ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5- (trifluoromethyl)-l H-pyrazol-1 -yljacetate; i3) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenylj-1-(2-phenylethyl)- 1 H-pyrazole; i4) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-5-

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

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

(trifluoromethyl)pyridine; i9) 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-

(trifluoromethyl)pyridine; i10) 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenylj-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- difluorophenyljbenzenesulfonamide; j3) 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene; j4) 5-difluoromethyl-4-(4-methyIsulfonylphenyl)-3-phenylisoxazole; j5) 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide; j6) 4-[5-difluoromethyl-3-phenylisoxazol-4-yljbenzenesulfonamide; j7) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; jδ) 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide; j9) 1 -[2-(4-fluorophenyl)cyclopenten-1 -yl]-4-(methylsulfonyl)benzene; j10) 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-

(methylsulfonyl)benzene; k1 ) 1 -[2-(4-chlorophenyI)cyclopenten-1 -yl]-4-(methyIsulfonyl)benzene; k2) 1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-

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

(methylsulfonyl)benzene; k4) 1 -[2-(4-methylthiophenyl)cyclopenten-1 -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 - yljbenzenesulfonamide; k7) 1 -[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1 -yl]-4- (methylsulfonyl)benzene; kδ) 4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1- yljbenzenesulfonamide; k9) 4-[2-(4-fluorophenyl)cyclopenten-1 -yljbenzenesulfonamide; k10) 4-[2-(4-chlorophenyl)cyclopenten-1 -yljbenzenesulfonamide;

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

12) 1 -[2-(2,3-difluorophenyl)cyclopenten-1 -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 -yljbenzenesulfonamide;

16) 4-[2-(2-methylpyridin-5-yl)cyclopenten-1 -yljbenzenesulfonamide;

17) ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyljoxazol-2-ylj- 2-benzyl-acetate;

Iδ) 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]acetic acid;

19) 2-(terf-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazole;

110) 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole; ml ) 4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole; and m2) 4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4- oxazolyljbenzenesulfonamide; m3) 6-chIoro-2-trifIuoromethyl-2H-1-benzopyran-3-carboxylic acid; m4) 6-chloro-7-methyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; m5) δ-(1 -methylethyl)-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid; m6) 6-chloro-7-(1 ,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid; m7) 6-chloro-δ-(1 -methylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid; mδ) 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 ) δ-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-trifluoromethyI-2H-1-benzopyran-3-carboxylic acid; n4) δ-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n5) 7,δ-dimethyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; n6) 6,δ-bis(dimethylethyl)-2-trifluoromethyl-2H-1 -beήzopyran-3- carboxyl ic acid; n7) 7-(1 -methylethyl)-2-trif luoromethyl-2H-1 -benzopyran-3-carboxylic acid; nδ) 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-3-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,δ-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; o4) 2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid; o5) 6-chloro-δ-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 06) δ-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

07) δ-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; oδ) 6-bromo-δ-chloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid;

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

010) δ-bromo-6-methyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; p1 ) δ-bromo-5-fluoro-2-trifluoromethyI-2H-1-benzopyran-3-carboxylic acid; p2) 6-chloro-δ-fluoro-2-trifluoromethyI-2H-1-benzopyran-3-carboxylic acid; p3) 6-bromo-δ-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p4) 6-[[(phenylmethyl)aminojsulfonyl]-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)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid; pδ) 6-[(1 ,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid; p9) 6-[(2-methylpropyl)aminosulfonyl]-2-trifIuoromethyl-2H-1 - benzopyran-3-carboxylic acid; p10) 6-methylsulfonyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; q1 ) δ-chIoro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1 - benzopyran-3-carboxylic acid; q2) 6-phenylacetyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; q3) 6,δ-dibromo-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; q4) δ-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid; q5) 6,δ-dichloro-(S)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; q6) 6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q7) 6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid; qδ) 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- carboxyl ic 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 - yljbenzenesulfonamide; r4) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; r5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; r6) 3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazol-2- yljpyridine; r7) 2-methyl-5-[1 -[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H- imidazol-2-yl]pyridine; rδ) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; r9) 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide; r10) 4-[5-hydroxymethyI-3-phenylisoxazoI-4-yl]benzenesulfonamide; s1 ) [2-trifluoromethyl-5-(3,4-difluorophenyl)-4- oxazolyljbenzenesulfonamide; s2) 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; or s3) 4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4- oxazolyljbenzenesulfonamide; or a pharmaceutically acceptable salt or prodrug thereof. [0167] 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. [0168] Preferred Cox-2 selective inhibitor compounds are those compounds selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, RS

57067, T-614, BMS-347070 (Bristol Meyers Squibb, described in U.S. Patent No. 6,180,651 ), JTE-522 (Japan Tabacco), S-2474 (Shionogi), SVT-2016, CT-3 (Atlantic Pharmaceutical), ABT-963 (Abbott), SC-58125 (GD Searle), nimesulide, flosulide, NS-396 (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-8331 (Pharmacia, described in U.S. Patent No. 6,0340256), MK-966 (Merck), L-7δ3003 (Merck), T-614 (Toyama), D-1376 (Chiroscience), L-748731 (Merck), CGP-23238 (Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome), prodrugs of any of them, and mixtures thereof. [0169] 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. [0170] Even more preferred still is that the Cox-2 selective inhibitor is celecoxib.

[0171] Cox-2 inhibitors that are useful in the methods and compositions and methods 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. 5,466,323 to Talley, et. al.

[0172] Various classes of Cox-2 inhibitors useful in the present invention can be prepared as follows. Pyrazoles can be prepared by methods described in WO 95/15316. Pyrazoles can further be prepared by methods described in WO 95/15315. Pyrazoles can also be prepared by methods described in WO 96/03335.

[0173] Thiophene analogs useful in the present invention can be prepared by methods described in WO 95/00501. Preparation of thiophene analogs is also described in WO 94/15932. [0174] Oxazoles useful in the present invention can be prepared by the methods described in WO 95/00501. Preparation of oxazoles is also described in WO 94/27930.

[0175] Isoxazoles useful in the present invention can be prepared by the methods described in WO 96/25405. [0176] Imidazoles useful in the present invention can be prepared by the methods described in WO 96/03338. Preparation of imidazoles is also described in WO 96/03387. [0177] Cyclopentene Cox-2 inhibitors useful in the present invention can be prepared by the methods described in U.S. Patent No. 5,344,991.

Preparation of cyclopentene Cox-2 inhibitors is also described in WO

95/00501. [0178] Terphenyl compounds useful in the present invention can be prepared by the methods described in WO 96/16934.

[0179] Thiazole compounds useful in the present invention can be prepared by the methods described in WO 96/03392.

[0180] Pyridine compounds useful in the present invention can be prepared by the methods described in WO 96/03392. Preparation of pyridine compounds is also described in WO 96/24585.

[0181] Benzopyranopyrazolyl compounds useful in the present invention can be prepared by the methods described in WO 96/09304.

[0182] Chromene compounds useful in the present invention can be prepared by the methods described in WO 93/47690. Preparation of chromene compounds is also described in WO 00/23433. Chromene compounds can further be prepared by the methods described in U.S. Patent No. 6,077,350. Preparation of chromene compounds is further described in U.S. Patent No. 6,034,256. [0183] Arylpyridazinones useful in the present invention can be prepared by the methods described in WO 00/24719. Preparation of arylpyridazinones is also described in WO 99/10332. Arylpyridazinones can further be prepared by the methods described in WO 99/10331. [0184] 5-Alkyl-2-arylaminophenylacetic acids and derivatives useful in the present invention can be prepared by the methods described in WO 99/11605. [0185] Diarylmethylidenefuran derivative Cox-2 selective inhibitors useful in the present invention can be prepared by the methods described in U.S. Patent No. 6,180,651. [0186] The celecoxib used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,466,823. [0187] The valdecoxib used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S. Patent

No. 5,633,272.

[0188] The parecoxib used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S. Patent

No. 5,932,598.

[0189] The rofecoxib used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S. Patent

No. 5,474,995. [0190] The deracoxib used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S. Patent

No. 5,521 ,207.

[0191] The etoricoxib used in the compositions and methods of the present invention can be prepared in the manner set forth in WO 98/03434.

[0192] The meloxicam used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S. Patent

No. 4,233,299.

[0193] The compound 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2- fluorobenzenesulfonamide used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S. Patent

No. 5,994,331.

[0194] The compound 2-(3,4-difluorophenyl)-4-(3-hydroxy-3- methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone used in the compositions and methods of the present invention can be prepared in the manner set forth in WO 00/24719.

[0195] The compound 2-(3,5-difluorophenyl)-3-[4-

(methylsulfonyl)phenyl]-2-cyclopenten-1-one used in the compositions and methods of the present invention can be prepared in the manner set forth in EP 363134. [0196] The compound 2-[(2-chloro-6-fluorophenyl)aminoj-5-methyl- benzeneacetic acid used in the compositions and methods of the present invention can be prepared in the manner set forth in WO 99/11605. [0197] The compound N-[2-(cyclohexyloxy)-4- nitrophenyljmethanesulfonamide used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S. Patent No. 4,δδ5,367.

[0198] The compound (3Z)-3-[(4-chlorophenyl)[4-

(methylsulfonyl)phenyljmethylene]dihydro-2(3H)-furanone used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S. Patent No. 6,130,651. [0199] 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. [020O] An optional component of the combination therapy embodiments of the present invention is an antidepressant agent. [0201 ] As used herein, the phrase "antidepressant agent" means an agent or compound, or a combination of two or more of such agents or compounds, which treat or prevent psychiatric disorders or symptoms of a psychiatric disorder in a subject in need of such treatment.

[0202] Antidepressant agents display a wide range of chemical structures. Some of the structural classes of antidepressant agents that are encompassed by the present invention include tricyclics, tetracylics, hydrazides/hydrazines, bicyclics, benzodiazepines, and pyrrolidones. [0203] Antidepressant agents also perform a wide range of functions within the subject's body. Some of the functional classes of antidepressant agents that are encompassed by the present invention include selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, noradrenaline reuptake inhibitors, selective serotonin and noradrenaline reuptake inhibitors, dual-action serotonin norepinephrine reuptake inhibitors, norepinephrine antagonist serotonin antagonists, selective serotonin and noradrenaline reuptake inhibitors, serotonin antagonist and reuptake inhibitors, norepinephrine dopamine reuptake inhibitor, and serotonin reuptake accelerators. [0204] In one embodiment, sertraline (Zoloft®), in particular, has been found to be a preferred antidepressant agent. Sertraline was initially introduced for the treatment of depression, but it is now used to treat a wide variety of psychiatric disorders. See Khouzam H., et al., Compr Ther 29(1 ):47-53 (2003). Sertraline acts as a selective serotonin reuptake inhibitor (SSRI) through oral administration. However, it is chemically unrelated to other SSRIs, tricyclic, tetracyclic, or other available antidepressant agents.

[0205] In another embodiment, the present invention encompasses one or more of the antidepressant agents described in Table 3 below.

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[0206] In a preferred embodiment, the class of antidepressant that is suitable for use with the methods and compositions of the present invention is selected from the group consisting of tricyclics, tetracylics, hydrazides/hydrazines, bicyclics, benzodiazepines, and pyrrolidones, and mixtures thereof.

[0207] In a preferred embodiment, the tricyclic antidepressant that is suitable for use with the methods and compositions of the present invention is selected from the group consisting of amitriptyline, desipramine, imipramine, nortriptyline, amineptine, clomipramine, doxepin, amoxapine, trimipramine, protriptyline, tianeptine, adinazolam, amitriptylinoxide, butriptyline, dibenzepin, dimetacrine, dothiepin, fluacizine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, noxiptilin, opipramol, pizotyline, propizepine, and quinupramine, and mixtures thereof.

[0208] In a preferred embodiment, the tetracyclic antidepressant that is suitable for use with the methods and compositions of the present invention is selected from the group consisting of maprotiline, mirtazapine, metralindole, and mianserin, and mixtures thereof. [0209] In a preferred embodiment, the bicyclic antidepressant that is suitable for use with the methods and compositions of the present invention is selected from the group consisting of sertraline, citalopram, paroxetine, trazodone, binodaline, caroxazone, dimethazan, fencamine, indalpine, indeloxazine hydrochloride, nefopam, nomifensine, oxitriptan, oxypertine, and thiazesim, and mixtures thereof. [0210] In a preferred embodiment, the benzodiazepine antidepressant that is suitable for use with the methods and compositions of the present invention is selected from the group consisting ofalprazolam and diazepam, and mixtures thereof.

[0211] In a preferred embodiment, the class of antidepressant that is suitable for use with the methods and compositions of the present invention is selected from the group consisting of selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, noradrenaline reuptake inhibitors, selective serotonin and noradrenaline reuptake inhibitors, dual- action serotonin norepinephrine reuptake inhibitors, norepinephrine antagonist serotonin antagonists, selective serotonin and noradrenaline reuptake inhibitors, serotonin antagonist and reuptake inhibitors, norepinephrine dopamine reuptake inhibitor, and serotonin reuptake accelerators, and mixtures thereof.

[0212] In a preferred embodiment, the selective serotonin reuptake inhibitor antidepressant that is suitable for use with the methods and compositions of the present invention is selected from the group consisting of sertraline, citalopram, escitalopram oxalate, fluvoxamine, paroxetine, and fluoxetine, and mixtures thereof.

[0213] In a preferred embodiment, the selective serotonin reuptake inhibitor antidepressant that is suitable for use with the methods and compositions of the present invention is selected from the group consisting of phenelzine, tranylcypromine, isocarboxazid, selegiline, caroxazone, and amiflamine, and mixtures thereof.

[0214] In a preferred embodiment, the serotonin antagonist and reuptake inhibitor antidepressant that is suitable for use with the methods and compositions of the present invention is selected from the group consisting of nefazodone and trazodone, and mixtures thereof. [0215] In a preferred embodiment, the serotonin and noradrenaline reuptake inhibitor antidepressant that is suitable for use with the methods and compositions of the present invention is selected from the group consisting of milnacipran and moclobemide, and mixtures thereof. [0216] In a preferred embodiment, the antidepressant that is suitable for use with the methods and compositions of the present invention is selected from the group consisting of sertraline, citalopram, escitalopram oxalate, fluvoxamine, paroxetine, fluoxetine, amitriptyline, desipramine, imipramine, maprotiline, reboxetine, nortriptyline, amineptine, zimelidine, venlafaxine, mirtazapine, milnacipran, phenelzine, tranylcypromine, nefazodone, trazodone, bupropion, clomipramine, tandospirone, isocarboxazid, lithium carbonate, lithium citrate, doxepin, amoxapine, moclobemide, trimipramine, selegiline, protriptyline, viloxazine, alprazolam, pargyline, dextroamphetamine, methylphenidate, diazepam, buspirone, tianeptine, binodaline, caroxazone, dimethazan, fencamine, indalpine, indeloxazine hydrochloride, nefopam, nomifensine, oxitriptan, oxypertine, thiazesim, benmoxine, iproclozide, iproniazid, L- tryptophan, nialamide, octamoxin, toloxatone, cotinine, rolicyprine, rolipram, metralindole, mianserin, adinazolam, amitriptylinoxide, butriptyline, dibenzepin, dimetacrine, dothiepin, fluacizine, imipramine N- oxide, iprindole, lofepramine, melitracen, metapramine, noxiptilin, opipramol, pizotyline, propizepine, quinupramine, tofenacin, adrafinil, benactyzine, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, hematoporphyrin, hypericin, levophacetoperane, medifoxamine, minaprine, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubdium chloride, sulpiride, thozalinone, amantadine, amiflamine, amisulpride, amphetamine, aprepitant, aripiprazole, atomoxetine, befloxatone, brofaromine, brornocriptine, buprenorphine, cericlamine, ciclazindol, cimoxatone, clorgyline, clovoxamine, dapoxetine, demexiptiline, dexmethylphenidate, etryptamine, fengabine, flerobuterol, flesinoxan, flibanserin, fluparoxan, gepirone, idazoxan, igmesine, incazane, ipsapirone, isradipine, levodopa, lamotrigine, levoprotiline, liothyronine, litoxetine, mazindol, mebanazine, mefexamide, memantine, mifepristone, modafinil, nemifitide, nisoxetine, nitroxazepine, olanzapine, oxaprotiline, oxycodone, ziprasidone, pemoline, pergolide, phenoxypropazine, phentermine, pindolol, piribedil, pirlindole or pyrazidol, pramipexole, pregabalin, pyrovalerone, risperidone, ropinirole, sibutramine, talipexole, tetrindole, thyroxine, tolcapone, vilazodone, viqualine, asenapine, 1-pyrimidinylpiperazine, 6-hydroxy-buspirone, and yohimbine, prodrugs of any of them, and mixtures thereof. [0217] Any combination that includes at least one of the Cox-2 inhibitors that are described alone and, optionally, at least one of the antidepressant agents that are described above can be used in the novel methods, compositions, pharmaceutical compositions and kits of the present invention. For example, a Cox-2 inhibitor such as celecoxib can be combined with any of the aforementioned antidepressant agents described in Table 3, including, for example, the antidepressant agent, sertraline.

[0218] One of skill in the art will understand how to make the antidepressant agents described above by following the teachings of the corresponding references.

[0219] Cox-2 inhibitors and antidepressant agents that are useful in the present invention can be of any purity or grade, as long as the preparation is of a quality suitable for pharmaceutical use. The Cox-2 inhibitor or antidepressant agent can be provided in pure form, or it can be accompanied with impurities or commonly associated compounds that do not affect its physiological activity or safety.

[022O] The Cox-2 inhibitors and antidepressant agents can be supplied in the form of a pharmaceutically active salt, a prodrug, an isomer, a tautomer, a racemic mixture, or in any other chemical form or combination that, under physiological conditions, still provides for inhibition of the Cox-2 enzyme and any physiological function that the antidepressant agent may perform. The present invention includes all possible diastereomers as well as their racemic and resolved, enantiomerically pure forms.

[0221] The present invention also encompasses a novel therapuetic composition comprising at least one Cox-2 inhibitor and one or more antidepressant agents.

[0222] In the present invention, a composition comprising a Cox-2 inhibitor in combination with a antidepressant agent is administered to a subject in need of such treatment according to standard routes of drug delivery that are well known to one of ordinary skill in the art.

[0223] The present invention also encompasses a pharmaceutical composition for preventing or treating a psychiatric disorder in a subject that is in need of such prevention and treatment, the pharmaceutical composition comprising at least one Cox-2 inhibitor, at least one antidepressant agent, and a pharmaceutically acceptable carrier. Thus, the combination of a Cox-2 inhibitor and an antidepressant agent can be provided in a pharmaceutically acceptable carrier or excipient to form a pharmaceutical composition.

[0224] The pharmaceutical compositions of the present invention comprise a Cox-2 inhibitor and an antidepressant agent as an active ingredient or a pharmaceutically acceptable salt, thereof, and also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. When the Cox-2 inhibitor and an antidepressant agent inhibitor are supplied along with a pharmaceutically acceptable carrier, a pharmaceutical composition is formed. A pharmaceutical composition of the present invention is directed to a composition suitable for the prevention, treatment, or amelioration of a psychiatric disorder. The pharmaceutical composition comprises a pharmaceutically acceptable carrier, a Cox-2 inhibitor, and an antidepressant agent. [0225] The term "pharmaceutically acceptable" is used herein to mean that the modified noun is appropriate for use in a pharmaceutical product.

[0226] Pharmaceutically acceptable carriers and excipients include, but are not limited to, physiological saline, Ringer's solution, phosphate solution or buffer, buffered saline and other carriers known in the art. Pharmaceutical compositions may also include stabilizers, anti-oxidants, colorants, and diluents. Pharmaceutically acceptable carriers and additives are chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not canceled or inhibited to such an extent that treatment is ineffective. In one embodiment the Cox-2 inhibitor alone or in combination with the antidepressant agent are administered to a subject together in one pharmaceutical carrier. In another embodiment, the Cox-2 inhibitor and the antidepressant agent are administered separately. [0227] The pharmaceutically acceptable carrier can also be selected on the basis of the desired route of administration of the compound. For example, in a preferred embodiment the carrier is suitable for oral administration. In a more preferred embodiment, the composition includes a carrier or additional agent that is suitable for promoting delivery of the compound to the brain. Carriers that can promote delivery of the compound to the brain can include any carrier that promotes translocation across the blood-brain barrier and any carrier that promotes uptake of the compound by neural cells. Examples of such carriers include those disclosed in U.S. Pat. Nos. 5,604,198 (issued to Poduslo, et al.), 5,827,619 (issued to Yatvin, et al.), 5,919,δ15 (issued to Bradley, et al.), 5,955,459 (issued to Bradley, et al.), and 5,977,174 (issued to Bradley, et al.).

[0228] The terms "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, trifluoroacetic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic acids.

[0229] Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic , non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0230] Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences.

[0231] Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include, without limitation, hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.

[0232] All of the above salts and ions can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention.

[0233] In the present invention, a Cox-2 inhibitor and/or antidepressant agent are administered to a patient in need of such treatment or prevention according to standard routes of drug delivery that are well known to one of ordinary skill in the art. The particular route and dosage of the Cox-2 inhibitor and the antidepressant agent depend upon the needs of the subject being treated, the type of treatment or prevention, the efficacy of the compound and the degree of disease severity in the subject.

[0234] The pharmaceutical compositions may be administered enterally and parenterally. Oral (intra-gastric) is a preferred route of administration. 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. [0235] 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.

[0236] 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.

[0237] 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.

[0238] 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, 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. 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.

[0239] 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. [0240] 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.

[0241] 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. [0100] Syrups and elixirs containing the Cox-2 inhibitor and/or antidepressant agent 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. [0242] The subject method of prescribing a Cox-2 inhibitor and/or antidepressant agent and compositions comprising the same can also be administered parenterally, either subcutaneously, or intravenously, or intramuscularly, or intrasternally, or by infusion techniques, in the form of sterile injectable aqueous or olagenous suspensions. Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous, and other administrative methods known in the art.

[0243] Administration of either one or both of the Cox-2 inhibitor and antidepressant agents can also be by inhalation, in the form of aerosols or solutions for nebulizers. Therefore, in one embodiment, the Cox-2 inhibitor and/or the antidepressant agent is administered by direct inhalation into the respiratory system of a subject 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 subject's intestinal tract (a risk associated with oral administration), and eliminating the need for repeated subcutaneous injections.

[0244] Aerosols of liquid particles comprising the active materials may be produced by any suitable means, such as inhalatory delivery systems. Nebulizers are commercially available devices which transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of compressed gas, typically air or oxygen, through a narrow venturi orifice or by means of ultrasonic agitation. Suitable formulations for use in nebulizers consist of the active ingredient in a liquid carrier. The carrier is typically water, and most preferably sterile, pyrogen-free water, or a dilute aqueous alcoholic solution, preferably made isotonic, but may be hypertonic with body fluids by the addition of, for example, sodium chloride. Optional additives include preservatives if the formulation is not made sterile, for example, methyl hydroxybenzoate, as well as antioxidants, flavoring agents, volatile oils, buffering agents and surfactants, which are normally used in the preparation of pharmaceutical compositions.

[0245] 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.

[0246] 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, and an optional surfactant. [0247] 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/or the antidepressant agent 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.

[0248] A third type of aerosol generator is a electrohydrodynamic

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

[0249] Administration of the compositions of the present invention can also be rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature, but liquid at the rectal temperature and will therefore, melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0250] Also encompassed by the present invention is buccal or

"sub-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.

[0251] The prevent invention further encompasses intranasal administration comprising the compounds set forth herein. Intranasal dosage forms include, but are not limited to, aerosols, drops, gels, powders, and mixtures thereof.

[0252] Other methods for administration of the Cox-2 inhibitor compound and/or the antidepressant agent include dermal patches that release the medicaments directly into a subject's skin.

[0253] Topical delivery systems are also encompassed by the present invention and include ointments, powders, sprays, creams, jellies, collyriums, solutions or suspensions.

[0254] The compositions of the present invention can optionally be supplemented with additional agents such as, for example, viscosity enhancers, preservatives, surfactants and penetration enhancers.

[0255] Viscosity is an important attribute of many medications.

Drops that have a high viscosity tend to stay in the body for longer periods and thus, increase absorption of the active compounds by the target tissues or increase the retention time. Such viscosity-building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents know to those skilled in the art. Such agents are typically employed at a level of from 0.01 % to 2% by weight.

Preservatives are optionally employed to prevent microbial contamination during use. Suitable preservatives include polyquatemium-1 , benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art. The use of polyquaternium-1 as the antimicrobial preservative is preferred. Typically, such preservatives are employed at a level of from 0.001% to 1 .0% by weight. [0256] 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 60, polyoxyethylene/polyoxypropylene surfactants (e.g. Pluronic F-6δ, F-δ4 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.

[0257] 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 topical composition or a Cox-2 inhibitor and antidepressant agent or topical composition.

[0258] 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 myristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate, and capric/caprylic triglycerides; ketones; amides, such as acetamides; oleates, such as triolein; various surfactants, such as sodium lauryl sulfate; various alkanoic acids, such as caprylic acid; lactam compounds, such as azone; alkanols, such as oleyl alcohol; dialkylamino acetates, and admixtures thereof.

[0259] Pharmaceutically acceptable excipients and carriers encompass all the foregoing and the like. The above considerations concerning effective formulations and administration procedures are well known in the art and are described in standard textbooks. See e.g. Gennaro, A. R., Remington: The Science and Practice of Pharmacy, 20th Edition, (Lippincott, Williams and Wilkins), 2000; Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1930; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0260] For purposes of the present invention, it is preferred that the amount of a Cox-2 inhibitor and the amount of an antidepressant agent comprise an effective amount of each of the two treatment agents. In another embodiment of the present invention, the amount of the combination therapy with the Cox-2 inhibitor and antidepressant agent together comprises a therapeutically effective amount of the combined therapy.

[0261] As used herein, an "effective amount" means the dose or amount to be administered to a subject and the frequency of administration to the subject, which is readily determined by one having ordinary skill in the art, by the use of known techniques and by observing results obtained under analogous circumstances. [0262] 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.

[0263] As used herein, the terms "therapeutically effective" are intended to qualify the amount of an agent for use in therapy that will achieve the goal of preventing or improving the severity of the disorder being treated, while avoiding adverse side effects typically associated with alternative therapies. A psychiatric disorder symptom is considered ameliorated or improved if any benefit is achieved, no matter how slight. [0264] As used herein, the terms "prophylactically effective" refer to an amount of a Cox-2 inhibitor alone or in combination with at least one antidepressant agents that causes a decrease in the frequency of incidence of psychiatric disorders or psychiatric disorder-related symptoms. The term "prophylactic" refers to the prevention of psychiatric disorders or a psychiatric disorder-related symptom, whereas the term "therapeutic" refers to the effective treatment of an existing disorder such as psychiatric disorders or a psychiatric disorder-related symptom. [0265] It will be appreciated that the amount of the Cox-2 inhibitor alone or in combination with at least one antidepressant agent required for use in the treatment or prevention of psychiatric disorders and psychiatric disorder-related symptoms 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.

[0266] 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 rng/kg to about 25 mg/kg per day; more preferably about 0.5 mg/kg to about 10 mg/kg per day. [0267] In larger mammals, for example humans, a typical indicated dose is about 0.5 mg to 7 grams orally per day. A Cox-2 inhibitor 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. [0268] The amount of the Cox-2 inhibitor that may be combined with the 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 the oral administration of 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, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 rng. [0269] The dosage level of an antidepressant agent will necessarily depend on the particular antidepressant agent that is used. The appropriate dosage level of an antidepressant agent will generally be from about 0.001 mg per kg to about 50 mg per kg subject body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 mg/kg to about 25 mg/kg per day; more preferably about 1.0 mg/kg to about 10 mg/kg per day. [0270] In larger mammals, for example humans, a typical indicated dose of an antidepressant agent is about 0.1 mg to 2 grams orally per day. An antidepressant agent 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.

[0271] The exact dosage and regimen for administering a Cox-2 inhibitor alone or in combination with at least one antidepressant agent will necessarily depend upon the potency and duration of action of the compounds used, the nature and severity of the illness to be treated, as well as the sex, age, weight, general health, and individual responsiveness of the patient to be treated, and other relevant circumstances. Those skilled in the art will appreciate that dosages may also be determined with guidance from Goodman & Goldman's The Pharmacological Basis of Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711. [0272] The effectiveness of a particular dosage of a Cox-2 inhibitor alone or in combination with an antidepressant agent is determined by monitoring the effect of a given dosage on the progress or prevention of a particular psychiatric disorder. This monitoring may be done through outpatient therapy or in a hospitalized setting.

[0273] For example, monitoring the effectiveness of the methods and compositions of the present invention on a subject suffering from depression may involve evaluating the subject under out-patient therapy. In this setting, any changes in the subject's symptoms of depression are monitored and evaluated by a therapist.

[0274] Still other methods for monitoring the effectiveness of the methods and compositions of the present invention can include conducting an evaluation of a subject's limbic-diencephalic function/dysfunction. Such evaluation can be performed by utilizing such tests as the thyrotropin- releasing hormone (TRH) stimulation test, the dexamethasone suppression test (DST), and sleep EEG for rapid eye movement (REM) latency test. See The Merck Manual of Diagnosis & Therapy, Beers & Brakow, 17th edition, Published by Merck Research Labs, Sec. 15, Chap. 189, Psychiatric Disorders, Mood Disorders (1999). [0275] As used herein, the term "subject" for purposes of treatment includes any subject, and preferably is a subject who is in need of the treatment of psychiatric disorders, or who needs treatment of a psychiatric disorder-related symptom. For purposes of prevention, the subject is any subject, and preferably is a subject that is at risk for, or is predisposed to, developing a psychiatric disorder or a psychiatric disorder-related symptom. The subject is typically an animal, and yet more typically is a mammal. "Mammal", as that term is used herein, refers to any animal classified as a mammal, including humans, domestic and farm animals, zoo, sports, or pet animals, such as dogs, horses, cats, cattle, etc. Preferably, the mammal is a human. For purposes of the present invention, an adult human weighs approximately seventy kilograms. [0276] As used herein, the terms "a subject who is predisposed to a psychiatric disorder" and "a subject who is at risk for a psychiatric disorder," both of which are used interchangeably herein, mean any subject at risk for developing psychiatric disorders or any psychiatric disorder-related symptoms. The subject may be a human subject who is at risk for developing psychiatric disorders or any psychiatric disorder- related symptoms. The subject may be at risk due to genetic predisposition, diet, age, exposure to traumatic life events, exposure to a separation such as death, and the like. The subject may also be at risk due to physiological factors such as abnormalities in the brain. [0277] As used herein, the terms "subject is in need of the prevention or treatment of a psychiatric disorder or a psychiatric disorder- related symptom" refer to any subject who is suffering from or is predisposed to psychiatric disorders or any psychiatric disorder-related symptoms described herein. The terms "subject is in need of the prevention or treatment of a psychiatric disorder or a psychiatric disorder- related symptom" also refer to any subject that requires a lower dose of conventional antidepressant agents. In addition, the terms "subject is in need of the prevention or treatment of a psychiatric disorder or a psychiatric disorder-related symptom" mean any subject who requires a reduction in the side effects of a conventional antidepressant agent. Furthermore, the terms "subject is in need of the prevention or treatment of a psychiatric disorder or a psychiatric disorder-related symptom" mean any subject who requires improved tolerability to any conventional psychiatric disorder treatment agent for psychiatric disorders therapy. [0278] The present invention encompasses the prevention and/or treatment of any pychiatric disorder including, but not limited to, depression (uni-polar disorder or major depressive disorder), manic depression (bipolar disorders), anxiety disorder, anxious depression, panic disorder, attention deficit disorder, attention deficit/hyperactivity disorder, melancholia (endogenous depression), depressive pseudodementia, dysthymic disorder, cyclothymic disorder, somatization disorder, conversion disorder, hypochondriasis, pain disorder, posttraumatic stress disorder, acute stress disorder, obsessive compulsive disorder, premenstrual dysphonic disorder, body d^ysmorphic disorder, schizophrenia, autism, agoraphobia, specific phobias, social phobia, acute stress disorder, dissociative amnesia, dissociative fugue, dissociative identity disorder, depersonalization disorder, and any combination of the above.

[0279] In one embodiment, the present invention encompasses the treatment or prevention of depression.

[0280] In other embodiments, the present invention encompasses a kit for preventing or treating psychiatric disorders or any psychiatric disorder-related symptoms in a subject that is in need of such prevention or treatment, the kit comprising one dosa ge form comprising a Cox-2 inhibitor and a second dosage form comprising at least one antidepressant agent.

[0281] 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. In the examples, all percentages are given on a weight basis unless otherwise indicated.

EXAMPLE 1 [0282] This example shows the preparation of the Cox-2 inhibitor, celecoxib.

[0283] Step 1 : Preparation of 1-(4- methylphenyl)-4,4,4- trifluorobutane-1 ,3-dione. [0284] Following the disclosure provided in U.S. Patent No.

5,760,068, 4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25%) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10% HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS04, filtered and concentrated to afford 8.47 g (94%) of a brown oil which was carried on without further purification.

[0285] Step 2: Preparation of 4-[5-(4-methylphenyl)-3-

(trifluoromethyl)-l H-pyrazol-1 -yljbenzenesulfonamide. [0286] 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 C₁₇ H₁₄ N₃ 0₂ SF₃ ; C, 53.54; H, 3.70; N, 11.02. The composition that was found by analysis was: C, 53.17; H, 3.81 ; N, 10.90.

EXAMPLE 2 [0287] This example illustrates the production of a composition containing celecoxib and an antidepressant agent, and of a pharmaceutical composition containing the combination. [0288] An antidepressant such as sertraline may be supplied by any one of several commercially available preparations. One such preparation of sertraline is the trade name Zoloft® 100mg (NDC: 00049-4910-66) available from the Roerig Division of Pfizer Inc, NY, NY. Each tablet of

Zoloft® contains 100mg of sertraline.

[0289] Alternatively, one of skill in the art may synthesize sertraline from a reading of the general synthesis outline disclosed in U.S. Patent

Numbers 4,536,518 and 4,556,676.

[0290] A therapeutic composition of the present invention can be formed by intermixing sertraline, 100 g; and 4-[5-(4-methylphenyl)-3-

(trifluoromethyl)-l H-pyrazol-1 -yljbenzenesulfonamide (200 g, as produced in Example 1 , or as available from Pharmacia Corporation, Peapack, NJ, under the tradename Celebrex®), in a suspension or solution with a sterile pharmaceutically acceptable liquid.

[0291] After mixing, the combination of sertraline and celecoxib forms a therapeutic composition that is sufficient for the production of about 1000 human single dose units. Each single dose unit contains about 100 mg of sertraline and about 200 mg of celecoxib.

[0292] If desirable, a solid carrier and other materials may be intermixed with the therapeutic composition to form a pharmaceutical composition and the resulting pharmaceutical composition may be formed into capsules for human consumption, for example, by conventional capsule-forming equipment, where each capsule can contain about the same amount of the active ingredients as each of the single dose units of the liquid preparation described above.

[0293] Therapeutic and pharmaceutical compositions comprising a combination of any of the Cox-2 inhibitors alone and in combination with any of the sources of antidepressant agents that are described above can be formed by similar methods.

[0294] 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.

[0295] In view of the above, it will be seen that the several advantages of the invention are achieved and other advantageous results obtained.

[0296] 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. In addition, it should be understood that aspects of the various embodiments may be interchanged both in whole or in part.

Claims

WHAT IS CLAIMED IS:

1. A method of treating or preventing a psychiatric disorder in a subject, the method comprising administering a Cox-2 inhibitor to the subject.

2. The method as set forth in claim 1 , wherein the Cox-2 inhibitor is administered to the subject in combination with an antidepressant agent.

3. The method as set forth in claim 1 , wherein the subject is in need of the prevention or treatment of a psychiatric disorder or a psychiatric disorder-related symptom.

4. The method as set forth in claim 1 , 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.

137

5. The method as set forth in claim 1 , wherein the Cox-2 inhibitor comprises a Cox-2 selective inhibitor selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, meloxicam, rofecoxib, lumiracoxib, etoricoxib, RS 57067, T-614, BMS-347070, JTE- 522, S-2474, SVT-2016, CT-3, ABT-963, SC-53125, nimesulide, flosulide, NS-398, L-745337, RWJ-63556, L-784512, darbufelone, CS-502, LAS- 34475, LAS-34555, S-33516, SD-8331 , prodrugs of any such compounds, and mixtures thereof.

6. The method as set forth in claim 5, wherein the Cox-2 selective inhibitor comprises a tricyclic Cox-2 selective inhibitor selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, rofecoxib, lumiracoxib, prodrugs of any such compounds, and mixtures thereof.

7. The method as set forth in claim 5, wherein the Cox-2 selective inhibitor comprises a chromene Cox-2 selective inhibitor 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, 3-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-phenyI-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

6-chloro-7-ethyI-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,

3-chIoro-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,

3-bromo-6-methyI-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-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-benz:opyran-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-methyI-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,

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

(S)-6,δ-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,

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

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

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

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

6-bromo-1 ,2-dihydro-2-(trifluoromethyI)-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,

(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-δ-methyl-2-(trifluoromethyl)-2H-chrornene-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-(trifluoromethyI)-2H-chromene-3-carboxylic acid, and mixtures thereof. δ. The method as set forth in claim 2, wherein the antidepressant agent is selected from the group consisting of sertraline, citalopram, escitalopram oxalate, fluvoxamine, paroxetine, fluoxetine, amitriptyline, desipramine, imipramine, maprotiline, reboxetine, nortriptyline, amineptine, zimelidine, venlafaxine, mirtazapine, milnacipran, phenelzine, tranylcypromine, nefazodone, trazodone, bupropion, clomipramine, tandospirone, isocarboxazid, lithium carbonate, lithium citrate, doxepin, amoxapine, moclobemide, trimipramine, selegiline, protriptyline, viloxazine, alprazolam, pargyline, dextroamphetamine, methylphenidate, diazepam, buspirone, tianeptine, binodaline, caroxazone, dimethazan, fencamine, indalpine, indeloxazine hydrochloride, nefopam, nomifensine, oxitriptan, oxypertine, thiazesim, benmoxine, iproclozide, iproniazid, L-tryptophan, nialamide, octamoxin, toloxatone, cotinine, rolicyprine, rolipram, metralindole, mianserin, adinazolam, amitriptylinoxide, butriptyline, dibenzepin, dimetacrine, dothiepin, fluacizine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, noxiptilin, opipramol, pizotyline, propizepine, quinupramine, tofenacin, adrafinil, benactyzine, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, hematoporphyrin, hypericin, levophacetoperane, medifoxamine, minaprine, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubdium chloride, sulpiride, thozalinone, amantadine, amiflamine, amisulpride, amphetamine, aprepitant, aripiprazole, atomoxetine, befloxatone, brofaromine, bromocriptine, buprenorphine, cericlamine, ciclazindol, cimoxatone, clorgyline, clovoxamine, dapoxetine, demexiptiline, dexmethylphenidate, etryptamine, fengabine, flerobuterol, flesinoxan, flibanserin, fluparoxan, gepirone, idazoxan, igmesine, incazane, ipsapirone, isradipine, levodopa, lamotrigine, levoprotiline, liothyronine, litoxetine, mazindol, mebanazine, mefexamide, memantine, mifepristone, modafinil, nemifitide, nisoxetine, nitroxazepine, olanzapine, oxaprotiline, oxycodone, ziprasidone, pemoline, pergolide, phenoxypropazine, phentermine, pindolol, piribedil, pirlindole or pyrazidol, pramipexole, pregabalin, pyrovalerone, risperidone, ropinirole, sibutramine, talipexole, tetrindole, thyroxine, tolcapone, vilazodone, viqualine, yohimbine, asenapine, 1-pyrimidinylpiperazine, 6-hydroxy- buspirone, and mixtures thereof.

9. The method as set forth in claim 1 , wherein the subject suffers from or is predisposed to one or more psychiatric disorders selected from the group consisting of depression, manic depression, anxiety disorder, anxious depression, panic disorder, attention deficit disorder, attention deficit/hyperactivity disorder, dysthymic disorder, cyclothymic disorder, posttraumatic stress disorder, obsessive compulsive disorder, premenstrual dysphonic disorder, schizophrenia, autism, agoraphobia, specific phobias, social phobia, acute stress disorder, and dissociative disorders.

10. The method as set forth in claim 1 , wherein the subject suffers from or is predisposed to depression.

11. A pharmaceutical composition for preventing or treating psychiatric disorders in a subject, the composition comprising a Cox-2 inhibitor and an antidepressant agent.

12. The pharmaceutical composition as set forth in claim 11 , 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, phenyl butazone, 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.

13. The pharmaceutical composition as set forth in claim 11 , wherein the Cox-2 inhibitor comprises a Cox-2 selective inhibitor selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, meloxicam, rofecoxib, lumiracoxib, etoricoxib, RS 57067, T-614, BMS- 347070, JTE-522, S-2474, SVT-2016, CT-3, ABT-963, SC-58125, nimesulide, flosulide, NS-39δ, L-745337, RWJ-63556, L-734512, darbufelone, CS-502, LAS-34475, LAS-34555, S-33516, SD-8381 , prodrugs of any such compound, and mixtures thereof.

14. The pharmaceutical composition as set forth in claim 13, wherein the Cox-2 selective inhibitor comprises a tricyclic Cox-2 selective inhibitor selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, rofecoxib, lumiracoxib, prodrugs of any such compound, and mixtures thereof.

15. The pharmaceutical composition as set forth in claim 13, wherein the Cox-2 selective inhibitor comprises a chromene Cox-2 selective inhibitor 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, δ-phenyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid, 7,3-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,

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

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

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

6-bromo-δ-methoxy-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-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid, 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, δ-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-furyImethyl)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-chIoro-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,

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,δ-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,

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

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

6,7,δ-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,

(2S)-6,8-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid,

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

(S)-6,δ-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxyIic acid,

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

16. The pharmaceutical composition as set forth in claim 11 , wherein the antidepressant agent is selected from the group consisting of sertraline, citalopram, escitalopram oxalate, fluvoxamine, paroxetine, fluoxetine, amitriptyline, desipramine, imipramine, maprotiline, reboxetine, nortriptyline, amineptine, zimelidine, venlafaxine, mirtazapine, milnacipran, phenelzine, tranylcypromine, nefazodone, trazodone, bupropion, clomipramine, tandospirone, isocarboxazid, lithium carbonate, lithium citrate, doxepin, amoxapine, moclobemide, trimipramine, selegiline, protriptyline, viloxazine, alprazolam, pargyline, dextroamphetamine, methylphenidate, diazepam, buspirone, tianeptine, binodaline, caroxazone, dimethazan, fencamine, indalpine, indeloxazine hydrochloride, nefopam, nomifensine, oxitriptan, oxypertine, thiazesim, benmoxine, iproclozide, iproniazid, L-tryptophan, nialamide, octamoxin, toloxatone, cotinine, rolicyprine, rolipram, metralindole, mianserin, adinazolam, amitriptylinoxide, butriptyline, dibenzepin, dimetacrine, dothiepin, fluacizine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, noxiptilin, opipramol, pizotyline, propizepine, quinupramine, tofenacin, adrafinil, benactyzine, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, hematoporphyrin, hypericin, levophacetoperane, medifoxamine, minaprine, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubdium chloride, sulpiride, thozalinone, amantadine, amiflamine, amisulpride, amphetamine, aprepitant, aripiprazoie, atomoxetine, befloxatone, brofaromine, bromocriptine, buprenorphine, cericlamine, ciclazindol, cimoxatone, clorgyline, clovoxamine, dapoxetine, demexiptiline, dexmethylphenidate, etryptamine, fengabine, flerobuterol, flesinoxan, flibanserin, fluparoxan, gepirone, idazoxan, igmesine, incazane, ipsapirone, isradipine, levodopa, lamotrigine, levoprotiline, liothyronine, litoxetine, mazindol, mebanazine, mefexamide, memantine, mifepristone, modafinil, nemifitide, nisoxetine, nitroxazepine, olanzapine, oxaprotiline, oxycodone, ziprasidone, pemoline, pergolide, phenoxypropazine, phentermine, pindolol, piribedil, pirlindole or pyrazidol, pramipexole, pregabalin, pyrovalerone, risperidone, ropinirole, sibutramine, talipexole, tetrindole, thyroxine, tolcapone, vilazodone, viqualine, yohimbine, asenapine, 1-pyrimidinylpiperazine, 6-hydroxy- buspirone, and mixtures thereof.

17. The pharmaceutical composition as set forth in claim 11 , wherein the Cox-2 inhibitor comprises celecoxib and the antidepressant agent comprises sertraline.

18. A kit for preventing or treating psychiatric disorders in a subject, the kit comprising one dosage form comprising a Cox-2 inhibitor and a second dosage form comprising an antidepressant agent.

19. The kit as set forth in claim 1δ, wherein the Cox-2 inhibitor comprises celecoxib and the antidepressant agent comprises sertraline.