CA2556380A1 - Methods and compositions for treating or preventing psychiatric disorders with cox-2 inhibitors alone and in combination with antidepressant agents - Google Patents

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

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 (un,i-polar disorder or major depressive disorder) and manic depression (bi-polar 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, 17t~' edition, Published by Merck Research Labs, Sec. 15, Chap.
1 ~9, 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 Ables, 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):103-7 (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 410(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 (GI) 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):471-5 (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 ofi 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 the present invention, therefore, may be noted the provision of improved methods, therapeutic compositions, pharmaceutical compositions, and hits for the prevention or treatment of psychiatric disorders such as depression. Other advantages achieved by the present invention includ a 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 ore 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 psychiatric°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 a 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 p,M, more preferred of less than about 0.5 ~,M, and even more preferred of less than about 0.2 ~M.

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

[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.

'I .~", [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 "C~-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-1y1, isobutenyl, penten-1y1, 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:
Z ~Z3 \Z3 ,or I
Z~ ~:Z2 Z Z Z
where Z, Z~, Z2, or Z3 is C, S, P, O, or N, with the proviso that one of Z, Z~, Z2, or Z3 is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S
atom. Furthermore, the optional substituents are understood to be attached to Z, Z~, Z2, or Z3 only when each is C. The term "heterocycle"
also includes fully saturated ring structures, such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others.

[0074] The term "heteroaryl" embraces unsaturated heterocyclic rad icals. Examples of unsaturated heterocyclic radicals include thienyl, pyrryl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, and tetrazolyl. The term also embraces rad icals 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 ternns such as alkylsulfonyl, denotes respectively divalent radicals -SO2-.
"Alkylsulfonyl", embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. The term "arylsulfonyl" embraces sulfonyl radicals substituted with an aryl radical. The term "aminosulfonyl" denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-S02-NH2).

(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 carboxyradical as defined above, attached to an alkyl radical. The term "carbonyl", whether used alone or with other terms, such as "alkylcarbonyl", denotes - (C=O) -. The term "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=O) radical. Examples of such "alkoxycarbonyl" radicals include (CH3)3-C-O-C=O) - and - (O=)C- OCH3. The term "amino", whether used alone or with other terms, such as "aminocarbonyl", denotes -N H2.

(0077] 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:
R~

A2,A1 \ R

3 ~
A~ 4 1I \ 3 A X R
wherein X' is selected from O, S, CR° R'~ and NRa ;

wherein Ra is selected from hydrido, C~ -C3 -alkyl, (optionally substituted phenyl)-C~ -C3 -alkyl, acyl and carboxy-C~ -C6 -alkyl;
wherein each of Rb and R~ is independently selected from hydrido, C~ -C3 -alkyl, phenyl-C~ -C3 -alkyl, C~ -C3 -perfluoroalkyl, chloro, C~ -C6 -alkylthio, C~ -C6 -alkoxy, vitro, cyano and cyano-C~ -C3 -alkyl; or wherein CR'~ R° forms a 3-6 membered cycloalkyl ring;
wherein R~ is selected from carboxyl, aminocarbonyl, C~ -C6 -alkylsulfonylaminocarbonyl and C~ -C6 -alkoxycarbonyl;
wherein R2 is selected from hydrido, phenyl, thienyl, C~ -C6 -alkyl and C2 -C6 -alkenyl;
wherein R3 is selected from C~ -C3 -perfluoroalkyl, chloro, C~ -C6 -alkylthio, C~ -C6 -alkoxy, vitro, cyano and cyano-C~ -C3 -alkyl;
wherein R4 is one or more radicals independently selected from hydrido, halo, C~ -C6 -alkyl, C2 -C6 -alkenyl, C2 -C6 -alkynyl, halo-C2 -C6 -alkynyl, aryl-C~ -C3 -alkyl, aryl-C2 -C6 -alkynyl, aryl-C2 -C6 -alkenyl, C~
-C6 -alkoxy, methylenedioxy, C~ -C6 -alkylthio, C~ -C6 -alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C~ -C6 -alkoxy-C~ -C6 -alkyl, aryl-C~ -C6 -alkyloxy, heteroaryl-C~ -C6 -alkyloxy, aryl-C~ -C6 -alkoxy-C~
-C6 -alkyl, C~ -C6 -haloalkyl, C~ -C6 -haloalkoxy, C~ -C6 -haloalkylthio, C~ -C6 -haloalkylsulfinyl, C~ -C6 -haloalkylsulfonyl, C~ -C3 -(haloalkyl-~ -C3 -hydroxyalkyl, C~ -C6 -hydroxyalkyl, hydroxyimino-C~ -C6 -alkyl, C~ -C6 -alkylamino, arylamino, aryl-C~ -C6 -alkylamino, heteroarylamino, heteroaryl-C~ -C6 -alkylamino, vitro, cyano, amino, aminosulfonyl, C~ -C6 -alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-C~ -C6 -alkylaminosulfonyl, heteroaryl-C~ -C6 -alkylaminosulfonyl, heterocyclylsulfonyl, C~ -C6 -alkylsulfonyl, aryl-C~ -C6 -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-C~ -C6 -alkylcarbonyl, heteroaryl-C~ -C6 -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C~ -C~ -alkoxycarbonyl, formyl, C~ -C6 -haloalkylcarbonyl and C~ -C6 -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:

6 :~ 4~
R8 ~ D n D~ $4 ~ j2' \ 7 D X R
wherein X~ is selected from O, S, CR° R'~ and NRa ;
wherein Ra is selected from hydrido, C1 -C3 -alkyl, (optionally substituted phenyl)-C1 -C3 -alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-C1 -C6 -alkyl;
wherein each of Rb and R° is independently selected from hydrido, C1 -C3 -alkyl, phenyl-C1 -C3 -alkyl, C1 -C3 -perfluoroalkyl, chloro, C1 -C6 -alkylthio, C1-C6 -alkoxy, nitro, cyano and cyano-C1 -C3 -alkyl;
or wherein CRS Rb form a cyclopropyl ring;
wherein R5 is selected from carboxyl, aminocarbonyl, C1 -C6 -alkylsulfonylaminocarbonyl and C1 -C6 -alkoxycarbonyl;
wherein R6 is selected from hydrido, phenyl, thienyl, C2 -C6 -alkynyl and C2 -C6 -alkenyl;
wherein R' is selected from C1 -C3 -perfluoroalkyl, chloro, C1 -C6 -alkylthio, C1 -C6 -alkoxy, nitro, cyano and cyano-C1 -C3 -alkyl;
wherein R$ is one or more radicals independently selected from hydrido, halo, C1 -C6 -alkyl, C2 -C6 -alkenyl, C2 -C6 -alkynyl, halo-C2 -C6 -alkynyl, aryl-C1 -C3 -alkyl, aryl-C2 -C6 -alkynyl, aryl-C2 -C6 -alkenyl, C1 -C6 -alkoxy, methylenedioxy, C1 -C6 -alkylthio, C1 -C6 -alkylsulfinyl, -O(CF2)2 O-, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C1 -C6 -alkoxy-C1 -C6 -alkyl, aryl-C1 -C6 -alkyloxy, heteroaryl-C1 -C6 -alkyloxy, aryl-C1-C6 -alkoxy-C1 -C6 -alkyl, C1 -C6 -haloalkyl, C1 -C6 -haloalkoxy, C1 -C6 -haloalkylthio, C1-C~ -haloalkylsulfinyl, C1-C6 -haloalkylsulfonyl, C1 -C3 -(haloalkyl-C1 -C3 -hydroxyalkyl), C1 -C6 -hydroxyalkyl, hydroxyimino-C1 -C6 -alkyl, C1 -C6 -alkylamino, arylamino, aryl-C1 -C6 -alkylamino, heteroarylamino, heteroaryl-C1 -C6 -alkylamino, nitro, cyano, amino, aminosulfonyl, C1-C6 -alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-C1 -C6 -alkylaminosulfonyl, heteroaryl-C1 -C6 -alkylaminosulfonyl, heterocyclylsulfonyl, C1 -C6 -alkylsulfonyl, aryl-C1 -C6 -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-C1 -C6 -alkyl carbonyl, heteroaryl-C1 -C6 -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C1 -C6 -alkoxycarbonyl, formyl, C1-C6 -haloalkylcarbonyl and C1 -C6 -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 R$ 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:
~5 R1~ ~ E ~~ ~ III
X3' ~R11 wherein X3 is selected from the group consisting of O or S or NRa;
wherein Ra is alkyl;
wherein R9 is selected from the group consisting of H and aryl;
wherein R1° 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 diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prod rugs 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:

IV

~4 R14 wherein X4 is selected from O or S or NRa ;

wherein Ra 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, vitro 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, vitro, 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:

R1$ AI V
~5 R17 wherein:
X5 is selected from the group consisting of O or S or NRb;
Rb is alkyl;
R16 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
R1' 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, vitro and alkylsulfonyl; and R~$ 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 R~$ together with ring A
forms a naphthyl radical;
or an isomer or pharmaceutically acceptable salt thereof.
[0086] The Cox-2 selective inhibitor rnay also be a compound of Formula V, wherein:
X5 is selected from the group consisting of oxygen and sulfur;
R~6 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;
R~' is selected from the group consisting of lower haloalkyl, tower cycloalkyl and phenyl; and R'$ is one or more radicals selected from the group of consisting of hydrido, halo, lower alkyl, lower alkoxy, louver 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 alkylcarb~nyl; or wherein R~$ 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;
R~6 is carboxyl;

R~' is lower haloalkyl; and R'$ is one or more radicals selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R~$ together with ring A forms a naphthyl radical;
or an isomer or pharmaceutically acceptable salt thereof.
[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;
R~6 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;
R" is selected from the group consisting of fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyl; and R~$ is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tart-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;
R~6 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;
R~' is selected from the group consisting trifluoromethyl and pentafluoroethyl; and R~$ is one or more radicals selected from the grou p consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-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 R~$ 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:
R2o VI
wherein:
X6 is selected from the group consisting of O and S;
R~9 is lower haloalkyl;
R2° is selected from the group consisting of hydrido, and halo;
R2~ is selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, and 6- membered nitrogen-containing heterocyclosulfonyl;
Rz2 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;
R~9 is selected from the group consisting of trifluoromethyl and pentafluoroethyl;
R2° is selected from the group consisting of hydrido, chloro, and fluoro;
R2~ 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 Compound Structural Formula Number B-3 °
OZN \ \ OH
s ~
O' -CF

6-Nitro-2-trifluoromethyl-2H-1-benzopyran 3-carboxylic acid B-4 °
C1 \ \
-OH

6-Chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid Cl \ \
~OH

((S)-6-Chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl-2H-1 benzopyran-3-carboxylic acid B_6 0 \ \ \ ~oH
/ / ° CF3 2-Trifluoromethyl-2H-naphtho[2,3-b]pyran-3 carboxylic acid Compound Structural Formula Number B_7 0 \ \
~OH
O / O~CF

6-Chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3 carboxylic acid o C1 \
~OH

Cl ((S)-6,8-Dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid B_g I \
i ~O H
O~CF3 6-Chloro-2-(trifluoromethyl)-4-phenyl-2H-1-benzopyran-3-carboxylic acid \ ~ \ \ ~oH

6-(4-Hydroxybenzoyl)-2-(trifluoromethyl)-2H-1 benzopyran-3-carboxylic acid Compound Structural Formula Number B-11 °
s F3C~ ~ ~ ~ \OH

2-(Trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzothiopyran-3-carboxylic acid B-12 °

-OH

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

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

6-Chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3 quinolinecarboxylic acid B-16 °
cl ~OH

6-Chloro-2-(trifluoromethyl)-1,2-dihydro[1, 8]naphthyridine-3-carboxylic acid B-17 °
cl -OH

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

i I ~ ~oH
O F
F
(2S)-6,8-dimethyl-2-(trifluoromethyl)-2H-chromene 3-carboxylic acid Compound Structural Formula Number F3Ci0 I ~ ~ OH
O~CF3 (2S)-8-ethyl-6-(trifluoromethoxy)-2-(trifluoromethyl) 2H-chromene-3-carboxylic acid ci I w w o_H
/ O~F
'\F
F
(2S)-6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H
chromene-3-carbox lic acid [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:

p R24 VII
25 ~ ~ 26 R R
wherein:
Z~ is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings;
R24 is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R24 is optionally substituted at a substitutable position with one or more radicals selected from alkyl, . haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
R25 is selected from the group consisting of methyl or amino; and R26 is selected from the group consisting of a radical selected from H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, 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 Compound Structural Formula Number o~ so HzNiS ~ / CH3 ~ N ~
N~

o~s~o H2Ni I ~ / I
\N
H C~o'~

Compound Structural Formula Number ~s° ocH
N, ~ ~ / ~ a / N
N~
CHFz o~s~o /
O o B-25 °vs~° CH
H C/ ~ /~ 3 ~N
\N
cl' o~s~o HaN ~
/
p' ' N
~CH3 [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.
o S/o HN~ ~ \
\ B-27 0 1 / ~ _ N

[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.
F
N \ F
N

[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:

Rz~ O
OH
VIII
Rze Rsz Rzs Rs~
wherein:
R2' is methyl, ethyl, or propyl;
R2$ is chloro or fluoro;
R~9 is hydrogen, fluoro, or methyl;
R3° is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxyl;
R3' is hydrogen, fluoro, or methyl; and R32 is chloro, fluoro, trifluoromethyl, methyl, or ethyl, provided that R28, R29, R3° and R3~ are not all fluoro when R2' is ethyl and s R3° 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:
R2' is ethyl;
R2$ and R3° are chloro;
R29 and R3~ 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:
R2' is propyl;
R~$ and R3° are chloro;

R29 and R3' 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:
R2' is methyl;
R2$ is fluoro;
R32 is chloro; and R29, R3°, and R3~ 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:
R33 x7 Ix /~ I
R°'" I
2o R35 r wherein:
X' 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-NHSO2CH3, (flosulide); or X' 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 X~ is S; J is thiophen-2-yl; R33 is 4-F; there is no R34 group; and R35 is 5-NHS02CH3, (RWJ-63556); or X~ is O; J is 2-oxo-5(R)-methyl-5-(2,2,2-trifluoroethyl)furan-(5H)-3-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).
H ~ /S02CH3 N
\ O\

NO~
[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 Ther 282, 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:

X
L.~ , wherein:
the rings T and M independently are a phenyl radical, a naphthyl radical, a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms;
at least one of the substituents Q1, Q2, L1 or L2 is an -S(O)n -R group, in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an -S02NH2 group;
and is located in the para position, the others independently being a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a trifluoromethyl radical, or a lower O-alkyl radical having 1 to 6 carbon atoms, or Q1 and Q2 or L1 and L2 are a methylenedioxy group; and R36, R3', R3$ and R39 independently are a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or, R36, R3' or R38, R39 are an oxygen atom; or R36, R3' 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-cyclohexyloxynitrophenyl)methane sulfonamide, and (E)-4-[(4-methylphenyl)(tetrahydro-2-oxo-3-furanylidene) methyl]benzenesulfonamide.
[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:
R4o N
XI

R4~ z2 wherein:

ZZ is an oxygen atom;
one of R4° and R4' is a group of the formula R43 02S t47 R4n wherein;
R43 is lower alkyl, amino or lower alkylamino; and R44, R45~ R4s 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, R4s 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 R3° 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:

XII
Rso R48o2S
wherein:

Z3 is selected from the group consisting of linear or branched C1 -C6 alkyl, linear or branched C1 -C6 alkoxy, unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl wherein the substituents are selected from the group consisting of hydrogen, halo, C1 -C3 alkoxy, CN, C1 -C3 fluoroalkyl C1 -C3 alkyl, and -C02 H;
R4$ is selected from the group consisting of NH2 and CH3, R49 is selected from the group consisting of C1 -C6 alkyl unsubstituted or substituted with C3 -C6 cycloalkyl, and C3 -C6 cycloalkyl;
R5° is selected from the group consisting of C1 -C6 alkyl unsubstituted or substituted with one, two or three fluoro atoms, and C3 C6 cycloalkyl; with the proviso that R49 and R5° are not the same.
[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:

XIII
wherein:
R51 is selected from the group consisting of CH3, NH2, NHC(O)CF3, and NHCH3;
Z4 is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-oxide thereof), wherein the substituents are selected from the group consisting of hydrogen, halo, C1 -C6 alkoxy, C1 -C6 alkylthio, CN, C1-C6 alkyl, C1 -C6 fluoroalkyl, N3, -CO2R53, hydroxyl, -C(R54)(R55)-OH, - C1 -C6 alkyl-C02-R56, C1 -C6 fluoroalkoxy;
R52 is selected from the group consisting of halo, C1 -C6 alkoxy, C1 -C6 alkylthio, CN, C1 -C6 alkyl, C1 -C6 fluoroalkyl, N3, -CO2R5', hydroxyl, N L' -C(R5$)(R59)-OH, - C~ -C6 alkyl-C02-R6°, C~ -C6 fluoroalkoxy, N02, NR6~R62, and NHCOR6s;
R53, R54, R55, R56, R5', R58, R59, R6°, R6~, R62, and R63, are each independently selected from the group consisting of hydrogen andC~ -C6 alkyl;
or R54 and R55, R5$ and R59, or R6~ 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:
x$
XIV

wherein:
X$ is an oxygen atom or a sulfur atom;
R64 and R65, identical to or different from each other, are independently a hydrogen atom, a halogen atom, a C~ -C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a nitro group, a nitrite group, or a carboxyl group;
R66 is a group of a formula: S(O)nR6$ wherein n is an integer of 0~2, R6$ is a hydrogen atom, a C~ -C6 lower alkyl group, or a group of a formula: NR69 R'° wherein R69 and R'°, identical to or different from each other, are independently a hydrogen atom, or a C~ -C6 lower alkyl group; and R6' is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a C~ -C6 lower alkyl group, indanyl, pyrazinyl, or a substituted group represented by the following structures:

,75 ~ R73 N N

wherein:
R'~ through R75, identical to or different from one another, are independently a hydrogen atom, a halogen atom, a C~ -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(O)nR68, a group of a formula: NR69 R'°, a trifluoromethoxy group, a nitrite group a carboxyl group, an acetyl group, or a formyl group, wherein n, R68, R69 and R'° have the same meaning as defined by R66 above; and R'6 is a hydrogen atom, a halogen atom, a C~ -C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a trifluoromethoxy group, a carboxyl group, or an acetyl group.
[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:

N
Z5 N~ XV

wherein:
X9 is selected from the group consisting of C~ -C6 trihalomethyl, preferably trifluoromethyl; C~ -C6 alkyl; and an optionally substituted or di-substituted phenyl group of formula XVI:
R~~
XVI
~/
7a R
wherein:
R" and R'8 are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl;
nitro; C~ -C6 alkyl, preferably C~ -C3 alkyl; C~ -C6 alkoxy, preferably C~ -C3 alkoxy; carboxy; C~ -C6 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:
R~9 O
R$°S(O)2 XVI I
wherein:
R'9 is a mono-, di-, or tri-substituted C~ -C~~ alkyl, or a mono-, or an unsubstituted or mono-, di- or tri-substituted linear or branched C2 -C~°
alkenyl, or an unsubstituted or mono-, di- or tri-substituted linear or branched C2 -C~° alkynyl, or an unsubstituted or mono-, di- or tri-substituted C3 -C~2 cycloalkenyl, or an unsubstituted or mono-, di- or tri-substituted C5 -C~2 cycloalkynyl, wherein the substituents are selected from the group consisting of halo selected from F, CI, Br, and I, OH, CF3, C3 -C6 cycloalkyl, =O,dioxolane, CN;
R$° is selected from the group consisting of CH3, NH2, NHC(O)CF3, and NHCH3;
R8~ and R82 are independently selected from the group consisting of hydrogen and C~ -C~° alkyl; or R8~ 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:

(O)2SH3C
XVIII
wherein X~° 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:

\ XIX
Rs5 Rs~
Rs9 ~1~- ~ - ~ OR9~
( I )n R90 Rss Rss or a pharmaceutically acceptable salt thereof, wherein:
X'~ is selected from the group consisting of O, S, and a bond;
nis0or1;
R83 is selected from the group consisting of CH3, NH2, and NHC(O)CF3;
R84 is selected from the group consisting of halo, C~ -C6 alkoxy, C~
-C6 alkylthio, CN, C~ -C6 alkyl, C~ -C6 fluoroalkyl, N3, -C02 R92, hydroxyl, -C(R93)(R94)-OH, -C1 -C6 alkyl-CO2 -R95, C1-C6 fluoroalkoxy, N02, NR96 R9', and NHCOR98;
R85 to R89 are independently selected from the group consisting of hydrogen and C1 -C6 alkyl; or R85 and R89, or R89 and R9° together with the atoms to which they are attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R85 and R$' are joined to form a bond.
[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:

8101 A6=~A5 A\~ ~ ~\ Rloo 8102 ~A$

and pharmaceutically acceptable salts thereof wherein:
-A5=A6-A'=A$- 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(RloS)2 -, -O-C(O)-C(R105)2 -~ -C(R105)2 -~(O)-O-(g) -N=CH-CH=CH-, (h) -CH=N-CH=CH-, (i) -CH=CH-N=CH-, Q) -CH=CH-CH=N-, (k) -N=CH-CH=N-, (I) -N=CH-N=CH-, (m) -CH=N-CH=N-, (n) -S-CH=N-, (o) -S-N=CH-, (p) -N=N-NH-, (q) -CH=N-S-, and (r) -N=CH-S-;
R99 is selected from the group consisting of S(O)2CH3, S(O)2NH2, S(O)2NHCOCF3, S(O)(NH)CH3, S(O)(NH)NH2, S(O)(NH)NHCOCF3, P(O)(CH3)OH, and P(O)(CH3)NH2;
R~oo is selected from the group consisting of (a) C~ -C6 alkyl, , (b) C3 -C7 cycloalkyl, (c) mono- or di-substituted phenyl or naphthyl wherein the substituent is selected from the group consisting of (1 ) hydrogen, (2) halo, including F, CI, Br, I, (3) C~ -C6 alkoxy, (4) C~ -C6 alkylthio, (5) CN, (6) CF3, (7) C~ -C6 alkyl, (8) Ns, (9) -CO~ H, (10) -C02 -C~ -C4 alkyl, (11 ) -C(R~°3)(R~o4)-OH, (12) -C(R~03)(R104)-~-C1 -C4 alkyl, and (13) -C~ -C6 alkyl-CO2 -R~o6;

(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) C~ -C6 alkyl, (4) C~ -C6 alkoxy, (5) C~ -C6 alkylthio, (6) CN, (7) CF3, ($) Ns~
(9) -C~R~03)(R104)-OH, and (10) -C(R~°3)(R104)-O-C~ -C4 alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
R~o~ and R~°2 are the substituents residing on any position of -A5=A6-A'=A$- and are selected independently from the group consisting of (a) hydrogen, (b) CF3, (c) CN, (d) C~ -C6 alkyl, (e) -Q3 wherein Q3 is Q4, C02 H, C(R'o3)(R~o4)OH, (f) -O-Q4, (g) -S-Q4, and (h) optionally substituted:
(1 ) -C~ -C5 alkyl-Q3, (2) -O-C~ -C5 alkyl-Q3, (3) -S-C~ -C5 alkyl-Q3, (4) -C~ -C3 alkyl-O-C~_3 alkyl-Q3, (5) -C~ -C3 alkyl-S-C~_3 alkyl-Q3, (6) -C1 -C5 alkyl-O-Q4, (7) -C1-C5 alkyl-S-Q4, wherein the substituent resides on the alkyl chain and the substituent is C1 -C3 alkyl, and Q3 is Q4, C02 H, C(Rlo3)(Rloa.)OH Q4 is CO2 -C1-C4 alkyl, tetrazolyl-5-yl, or C(R~ °3)(Rloa.)O-C1 -C4 alkyl;
R103~ Rloa. and R1°5 are each independently selected from the group consisting of hydrogen and C1 -C6 alkyl; or R1°3 and Rloa. together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms, or two 8105 groups on the same carbon form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
R1°6 is hydrogen or C-, -C6 alkyl;
R1°' is hydrogen, C1-C6 alkyl or aryl;
X' is O, S, NRloy CO, C(R107)2, C(Rlo~)(OH)~ -C(Rlo~)_C(Rlo~)-; -C(R1°')=N-; or-N=C(R1o')-[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:

N
~~N xxl Rlos N
~ 1os wherein:
R1°s is:
_ (R112)n -(CH2)p ~(R111)m wherein:
pisOto2;misOto4;andnisOtoS;
X13 is O, S, SO, S02, CO, CHCN, CHI or C=NR113 where 8113 IS
hydrogen, loweralkyl, hydroxyl, loweralkoxy, amino, loweralkylamino, diloweralkylamino or cyano;
8111 and R1'2 are independently halogen, cyano, trifluoromethyl, loweralkanoyl, nitro, loweralkyl, loweralkoxy, carboxy, lowercarbalkoxy, trifuloromethoxy, acetamido, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfinyl, or trifluoromethylsulfonyl;
R1°9 is amino, mono or diloweralkyl amino, acetamido, acetimido, ureido, formamido, or guanidino; and R11° 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:
R1' 4.
~i N
8115 ~ 117 I ,R
~ 14 11'6\ X /N XXII
R N

wherein:
8114 IS hydrogen or halogen;
8115 and 8116 are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl or lower alkanoyloxy;

R11' 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:

X15 S(o)m 8119 0 0 ~ ~N/ XXIII
\\ll ~ I

/S\ \ \ R

wherein:
X15 denotes oxygen, sulphur or NH;

R11$ is an optionally unsaturated alkyl or alkyloxyalkyl group, optionally mono- or polysubstituted or mixed substituted by halogen, alkoxy, oxo or cyano, a cycloalkyl, aryl or fleteroaryl group optionally mono- or polysubstituted or mixed su bstituted by halogen, alkyl, CF3, cyano or alkoxy;
8119 and 8120, independently from one another, denote hydrogen, an optionally polyfluorised alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH2)~ -X16; or 8119 and R12°, together with the N- atom, denote a 3 to 7-membered, saturated, partially or completely unsaturated heterocycle with one or more heteroatoms N, O or S, which can optionally be substituted by oxo, an alkyl, alkylaryl or aryl group, or a group (CH2)n X16;
X16 denotes halogen, N02, -OR121, -COR121, -C02 8121, -OC02 8121, -CN, -CONR121 OR122, -CONR121 8122, -SR121, -S(O)R121, -S(O)2 R121~ -NR121 R122~ -NHC(O)R121, -NHS(O)2 8121;
n denotes a whole number from 0 to 6;

8123 denotes a straight-chained or branched alkyl group with 1-10 C-atoms, a cycloalkyl group, an alkylcarboxyl group, an aryl group, aralkyl group, a heteroaryl or heteroaralkyl group which can optionally be mono-or polysubstituted or mixed substituted by halogen or alkoxy;
8124 denotes halogen, hydroxyl, a straight-chained or branched alkyl, alkoxy, acyloxy or alkyloxycarbonyl group with 1 to 6 carbon atoms, which can optionally be mono- or polysubstituted by halogen, N02, -OR121, -C~1~121, -CO2 R121~ -oC~2 8121 ~ -CN, -CONR121 OR122, -CONR121 R122~ -SR121~ -S(~)R121~ -S(O)2 R121~ -NR121 R122~ -NHC(O)R121, -NHS(O)2 1121, or a polyfluoroalkyl group;
8121 and 8122, 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:
XXIV
8126 n~' '~Z7 e' a X17--Y1 or pharmaceutically acceptable salts thereof wherein:
X1'-Y1-Z'-is selected from the group consisting of (a) -CH2 CH2 CH2 -, (b) -C(O)CH2 CH2 -, (c) -CH2 CH2 C(O)-, (d) -CR~29 (R129')-O-C(O)-(e) -C(O)-O-CR129 (R129')-~
(f) -CHZ -NR~z~ -CHZ -, (g) -CR~29 (R~as')-NR~27 -C(O)-, (h) -CR~z$=CR~z8~ -S-, (i) -S-CR'2$=CR~28' -, (j) -S-N=CH-, (k) -CH=N-S-, (I) -N=CR~zs -O-s (m) -O-CR'2$ =N- , (n) -N=CR~2$ -NH-, (o) -N=CR'2$ -S-, and (p) -S-CR~za=N-(q) -C(O)-NR~27 -CR~29 (R129')-(r) -R~2' N-CH=CH- provided R~ ~2 is not -S(O)2CH3, (s) -CH=CH-NR~2' - provided R'25 is not -S(O)2CH3;
when side b is a double bond, and sides a and c are single bonds; and X~'-Y'-Z'-is selected from the group consisting of (a) =CH-O-CH=, and (b) =CH-NR~2' -CH=, (c) =N-S-CH=, (d) =CH-S-N=, (e) =N-O-CH=, (f) =CH-O-N=, (g) =N-S-N=, (h) =N-O-N=, when sides a and c are double bonds and side b is a single bond;
R'25 is selected from the group consisting of (a) S(O)2 CH3, (b) S(O)2 NH2, (c) S(O)2 NHC(O)CF3, (d) S(O)(NH)CH3, (e) S(O)(NH)NH2, (f) S(O)(NH)NHC(O)CF3, (g) P(O)(CH3)OH, and (h) P(O)(CH3)NH2;
R~26 is selected from the group consisting of (a) C~ -C6 alkyl, (b) C3, C4, C5, C6, and C~, 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) C~ -C6 alkoxy, (4) C~ -C6 alkylthio, (5) CN, (6) CF3, (7) C~ -C6 alkyl, (8) Ns~
(9) -C02 H, (10) -C02 -C~ -C4 alkyl, (11 ) -C(R~29)(R~so)-OH, (12) -C(R~29)(R~30)-O-C~ -C4 alkyl, and (13) -C~ -C6 alkyl-CO~ -R~29 (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 add itionally 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 add itional N atoms; said substituents are selected from the group consisting of (1 ) hydrogen, (2) halo, including fluoro, chloro, bromo and iodo, (3) C~ -C6 alkyl, (4) C~ -C6 alkoxy, (5) C~ -C6 alkylthlo, (6) CN, (7) CF3, ($) Ns~
(9) -C(R129)(R130)-~H, and (10) -C(R~29)(R130)-O-C~ -C4 alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
R'~' is selected from the group consisting of (a) hydrogen, (b) CF3, (c) CN, (d) C~ -C6 alkyl, (e) hydroxyl C~ -C6 alkyl, (f) -C(O)- C~ -C6 alkyl, (g) optionally substituted:
(1 ) -C~ -C5 alkyl-Q5, (2) -C~ -C5 alkyl-O-C~ -C3 alkyl-Q5, (3) -C~ -C3 alkyl-S-C~ -C3 alkyl-Q5, (4) -C~ -C5 alkyl-O-Q5, or (5) -C~ -C5 alkyl-S-Q5, wherein the substituent resides on the alkyl and the substituent is C~ -C3 alkyl;
(h) -Q5~
R~~$ and R'28~ are each independently selected from the group consisting of (a) hydrogen, (b) CF3, (c) CN, (d) C~ -C6 alkyl, (e) -Q5, (f) -O-Q5~
(g) -S-Q5, and (h) optionally substituted:
(1 ) -C1 -C5 alkyl-Q5, (2) -O-C1 -C5 alkyl-Q5, (3) -S-C1 -C5 alkyl-Q5, (4) -C1-C3 alkyl-O-C1-C3 alkyl-Q5, (5) -C1 -C3 alkyl-S-C1 -C3 alkyl-Q5, (6) -C1 -C5 alkyl-O-Q5, (7) -C1 -C5 alkyl-S-Q5, wherein the substituent resides on the alkyl and the su bstituent is C1 -C3 alkyl, and Rl2s, R129', R130~ 8131 and 8132 are each independently selected from the group consisting of (a) hydrogen, (b) C1 -C6 alkyl;
or 8129 and R13° or 8131 and 8132 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
Q5 is C02 H, C02-C1 -C4 alkyl, tetrazolyl-5-yl, C(Rla1)(Rla2)(OH), or C(R131)(R132)(O-C1 -C4 alkyl);
provided that when X-Y-Z is -S-CR12$=CR128~, then R12$ and R128~ 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:

Z$

A
O
(X19)n ~ ~ XXV
Z9 ~ (CH2)q \Z10 "." , , .(CH2)m or the pharmaceutically acceptable salts thereof wherein:
A9 is C1 -C6 alkylene or-NR133 -;
Z$ IS C(=L3)R134, Or SO2 8135 ;
Z9 is CH or N;
Z1° and Y~ are independently selected from -CH2 -, O, S and -N-8133;
m is 1, 2 or 3;
q and r are independently 0, 1 or 2;
X1$ is independently selected from halogen, C1 -C4 alkyl, halo-substituted , C1 -C4 alkyl, hydroxyl, C1 -C4 alkoxy, halo-substituted C1-C4 alkoxy, C1 -C4 alkylthio, vitro, amino, mono- or di-(C1 -C4 alkyl)amino and cyano;
n is 0, 1, 2, 3 or 4;
L3 is oxygen or sulfur;
8133 iS hydrogen or C1 -C4 alkyl;
8134 is hydroxyl, C1 -C6 alkyl, halo-substituted C1 -C6 alkyl, C1 -C6 alkoxy, halo-substituted C1 -C6 alkoxy, C3 -C7 cycloalkoxy, C1-C4 alkyl(C3 -C7 cycloalkoxy), -NRl3s R13', C1 -C4 alkylphenyl-O- or phenyl-O-, said phenyl being optionally substituted with one to five substituents independently selected from halogen, C1 -C4 alkyl, hydroxyl, C1 -C4 alkoxy and vitro;
8135 iS C1 -C6 alkyl or halo-substituted C1-C6 alkyl; and Rl3s and R13' are independently selected from hydrogen, C1_6 alkyl and halo-substituted C1 -C6 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:
N
~X21)n ~ ~ CR140~-CR139~R138 XXV~
N
10-(X20~m or a pharmaceutically acceptable salt thereof, wherein:
A1° is heteroaryl selected from:
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atoms) in addition to said hetero atom, or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atoms) in addition to said N atom; and said heteroaryl being connected to the nitrogen atom on the benzirnidazole through a carbon atom on the heteroaryl ring;
X2° is independently selected from halo, C1 -C4 alkyl, hydroxyl, C4 alkoxy, halo-substituted C1 -C4 alkyl, hydroxyl-substituted C1 -C4 alkyl, (C1 -C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, N-(C1 -C4 alkyl)amino, N, N-di(C1-C4 alkyl)amino, [N-(C1 -C4 alkyl)amino]C1-C4 alkyl, [N, N-di(C1-C4 alkyl)amino]C1-C4 alkyl, N-(C1 -C4 alkanoyl)amonio, N-(C1-C4 alkyl)(C1 -C4 alkanoyl)amino, N-((C1 -C4 alkyl)sulfonyl]amino, N-[(halo-substituted C1 -C4 alkyl)sulfonyl]amino, C1 -C4 alkanoyl, carboxy, (C1 -C4 alkoxy)carbonyl, carbamoyl, (N-(C1 -C4 alkyl)amino]carbonyl, [N, N-di(C1 -C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (C1 -C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1 -C4 alkyl)sulfonyl, aminosulfonyl, [N-(C1 -C4 alkyl)amino]sulfonyl and (N, N-di(C1 -C4 alkyl)amino]sulfonyl;
X21 is independently selected from halo, C1-C4 alkyl, hydroxyl, C1 -C4 alkoxy, halo-substituted C1 -C4 alkyl, hydroxyl-substituted C1 -G4 alkyl, (C~ -C4 alkoxy)C~ -C4 alkyl, halo-substituted C~ -C4 alkoxy, amino, N-(C~
-C4 alkyl)amino, N, N-di(C~ -C4 alkyl)amino, [N-(C~ -C4 alkyl)amino]C~ -C4 alkyl, [N, N-di(C~ -C4 alkyl)arni no]C~ -C4 alkyl, N-(C~ -C4 alkanoyl)amino, N-(C~ -C4 alkyl)-N-(C~ -C4 alkanoyl) amino, N-[(C~ -C4 alkyl)sulfonyl]amino, N-[(halo-substituted C~ -C4 alkyl)sulfonyl]amino, C~ -C4 alkanoyl, carboxy, (C~ -C4 alkoxy)hydroxyl, cabamoyl, [N-(C~ -C4 alkyl) amino]carbonyl, [N, N-di(C~ -C4 alkyl)amino]carbonyl, N-carbomoylamino, cyano, vitro, mercapto, (C~ -C4 al kyl)thio, (C~ -C4 alkyl)sulfinyl, (C~ -C4 alkyl)sulfonyl, aminosulfonyl, [N-(C~ -C4 alkyl)amino]sulfonyl and [N, N-di(C~ -C4 alkyl)amino]sulfonyl;
R~3$ is selected from hydrogen; straight or branched C~ -C4 alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxyl, C~ -C4 alkoxy, amino, N-(C~ -C4 alkyl)amino and N, N-di(C~ -C4 alkyl)amino; C3 -C$ cycloalkyl optionally substituted with one to three su.bstituent(s) wherein said substituents are indepently selected from halo, ~C~ -C4 alkyl, hydroxyl, C~ -C4 alkoxy, amino, N-(C~ -C4 alkyl)amino and N, N-di(C~ -C4 alkyl)amino; C4 -C$ cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C~ -C4 alkyl, hydroxyl, C~ -C~. alkoxy, amino, N-(C~ -C4 alkyl)amino and N, N-di(C~ -C4 alkyl)amino; phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C~ -C4 alkyl, hydroxyl, C~ -C4 alkoxy, halo-substituted C~ -C4 alkyl, hydroxyl-substituted C~ -C4 alkyl, (C~ -C~. alkoxy)C~ -C4 alkyl, halo-substifiuted C~ -C4 alkoxy, amino, N-(C~ -C4 alkyl)amino, N, N-di(C~ -C4 alkyl)amino, [N-(C~ -Ca alkyl)arni no]C~ -C4 alkyl, [N, N-di(C~ -C4 alkyl)amino]C~ -C4 alkyl, N-(C~ -C4 alkanoyl)amino, N-[C~ -C4 alkyl)(C~ -C4 alkanoyl)]amino, N-[(C~ -C4 alkyl)sulfony]amino, N-[(halo-substituted C-, -C4 alkyl)sulfonyl]amino, C~ -C4 alkanoyl, carboxy, (C~ -C4 alkoxy)carbonyl, carbomoyl, [N-(C~ -C4 alky)amino]carbonyl, [N, N-di(C~ -C4 alkyl)amino]carbonyl, cyano, vitro, mercapto, (C~ -C4 alkyl)thio, (C~ -C~.

alkyl)sulfinyl, (C~ -C4 alkyl)sulfonyl, aminosulfonyl, [N-(C~ -C4 alkyl)amino]sulfonyl and [N, N-di(C~ -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 atoms) in addition to said hetero atom; or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atoms) in addition to said N atom; and said heteroaryl being optionally substituted with one to three substituent(s) selected from X2° ;
R~39 and R~4o are independently selected from: hydrogen; halo; C~ -C4 alkyl; phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C~ -C4 alkyl, hydroxyl, C~ -C4 alkoxy, amino, N-(C~ -C4 alkyl)amino and N, N-di(C~ -C4 alkyl)amino; or R~3$ and R'39 can form, together with the carbon atom to which they are attached, a C3 -C7 cycloalkyl ring;
m is 0, 1, 2, 3, 4 or 5; and nis0,1,2,3or4.
[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:
_4 XXVII
~X22)n-~3-Q6 and the pharmaceutically acceptable salts thereof, wherein:
L4 is oxygen or sulfur;
Y3 is a direct bond or C~ -C4 alkylidene;
Q6 is:

\N (~~42 (a) C~ -C6 alkyl or halosubstituted C~ -C6 alkyl, said alkyl being optionally substituted with up to three substituents independently selected from hydroxyl, C~ -C4 alkoxy, amino and mono- or di-( C~ -C4 alkyl)amino, (b) C3 -C~ cycloalkyl optionally substituted with up to three substituents independently selected from hydroxyl, C~ -C4 alkyl and C~ -C4 alkoxy, (c) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to four substituents independently selected from:
(c-1 ) halo, C~ -C4 alkyl, halosubstituted C~ -C4 alkyl, hydroxyl, C~ -C4 alkoxy, halosubstituted C~ -C4 alkoxy, S(O)m R~43, SO2 NH2, S02 N(C~
-C4 alkyl)2, amino, mono- or di-( C~ -C4 alkyl)amino, NHS02 R~43, NHC(O)R'43, CN, C02 H, C02 (C~ -C4 alkyl), C~ -C4 alkyl-OH, C~ -C4 alkyl-OR~43, CONH2, CONH(C~ -C4 alkyl), CON(C~ -C4 alkyl)2 and -O-Y-phenyl, said phenyl being optionally substituted with one or two substituents independently selected from halo, C~ -C4 alkyl, CF3, hydroxyl, OR~43, S(O)mR143~ amino, mono- or di-( C~ -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, C~ -C4 alkyl, halosubstituted C~ -C4 alkyl, hydroxyl, C~ -C4 alkoxy, halosubstituted C~ -C4 alkoxy, C~ -C4 alkyl-OH, S(O)m R~43, S02 NH2, SO~ N(C~ -C4 alkyl)2, amino, mono- or di-( C~ -C4 alkyl)amino, NHS02 R~43, NHC(O)R~43, CN, C02 H, CO~ (C~ -C4 alkyl), C~ -C4 alkyl-OR''~3, CONH2, CONH(C~ -C4 alkyl), CON(C~ -C4 alkyl)2, phenyl, and mono-, di- or tri-substituted phenyl wherein the substituent is independently selected from halo, CF3, C~ -C4 alkyl, hydroxyl, C~ -C4 alkoxy, OCF3, SR~43, S02 CH3, S02 NH2, amino, C~_4 alkylamino and NHS02 R~43;
(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 );
8141 IS hydrogen or C1-C6 alkyl optionally substituted with a substituent selected independently from hydroxyl, ORl4s, vitro, amino, mono- or di-( C1 -C4 alkyl)amino, C02 H, C02 (C1 -C4 alkyl), CONH2, CONH(C1-C4 alkyl) and CON(C1 -C4 alkyl)2 ;
8142 jS:
(a) hydrogen, (b) C1 -C4 alkyl, (c) C(O)R145~
wherein 8145 is selected from:
(c-1 ) C1 -C22 alkyl or C2 -C22 alkenyl, said alkyl or alkenyl being optionally substituted with up to four substituents independently selected from:
(c-1-1 ) halo, hydroxyl, OR143, S(O)m 8143, vitro, amino, mono- or di-C1 -C4 alkyl)amino, NHS02 8143, C02 H, CO2 (C1 -C4 alkyl), CONH2, CONH(C1 -C4 alkyl), CON(C1 -C4 alkyl)2, OC(O)Rl4a, thienyl, naphthyl and groups of the following formulas:

(X22)n NHS02 ~ NHS02 (X22)n (X22)n ~ (X22)n S ' ~ ' O
O
N/(CH2)p N/(CH2)P
> >
O
(CH2)q (CH2)q N~ ~Z~~ and N~ ~Z11 (c-2) C~ -C22 alkyl or C2 -C22 alkenyl, said alkyl or alkenyl being optionally substituted with five to forty-five halogen atoms, (c-3) -Y5-C3 -C~ cycloalkyl or -Y5-C3 -C7 cycloalkenyl, said cycloalkyl or cycloalkenyl being optionally substituted with up to three substituent independently selected from:
(c-3-1 ) C~ -C4 alkyl, hydroxyl, OR~43, S(O)m R143~ amino, mono- or di-( C~ -C4 alkyl)amino, CONH2, CONH(C~ -C4 alkyl) and CON(C~ -C4 alkyl)2, (c-4) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to seven (preferably up to seven) substituents independently selected from:

(c-4-1 ) halo, C1-C$ alkyl, C1-C4 alkyl-OH, hydroxyl, C1 -C$ alkoxy, halosubstituted C1 -C$ alkyl, halosubstituted C1 -C$ alkoxy, CN, nitro, S(O)", R143~ S02 NH2, S02 NH(C1 -C4 alkyl), S02 N(C1-C4 alkyl)2, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, CONH2, CONH(C1 -C4 alkyl), CON(C1 -C4 alkyl), OC(O)R143' and phenyl optionally substituted with up to three substituents independently selected from halo, C1-C4 alkyl, hydroxyl, OCH3, CF3, OCF3, CN, nitro, amino, mono- or di-(C1 -C4 alkyl)amino, C02 H, C02 (C1 -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, C1-C$ alkyl, C1 -C4 alkyl-OH, hydroxyl, C1 -C$ alkoxy, CF3, OCF3, CN, nitro, S(O)m 8143, amino, mono- or di-( C1 -C4 alkyl)amino, CONH~, CONH(C1 -C4 alkyl), CON(C1-Cø alkyl)2, C02 H and C02 (C1 -C4 alkyl), and -Y-phenyl, said phenyl being optionally substituted with up to three substituents independently selected halogen, C1 -C4 alkyl, hydroxyl, C1 -C4 alkoxy', CF3, OCF3, CN, nitro, S(O)m 1143, amino, mono- or di-( C1 -C4 alkyd )amino, C02 H, C02 (C1-C4 alkyl), CONH2, CONH(C1-C4 alkyl) and CON(C1 -C4 alkyl)2, (c-6) a group of the following formula:
(CH\2)e \Z11 (CH2)n X22 is halo, C1-C4 alkyl, hydroxyl, C1 -C4 alkoxy, halosubstitutued C1 -C4 alkoxy, S(O)m 1143, amino, mono- or di-(C1 -C4 alkyl)amino, NHS02 8143' nitro, halosubstitutued C1 -C4 alkyl, CN, C02 H, C02 (C1 -Cue. alkyl), C1 -C4 alkyl-OH, C1 -C4 alkylOR143, CONH2, CONH(C1 -C4 alkyl) o r CON(C1 -C4 alkyl)2 ;
8143 is C1 -C4 alkyl or halosubstituted C1 -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;

Z'~ is oxygen, sulfur or NR~44 ; and R~44 Is hydrogen, C~ -C6 alkyl, halosubstitutued C~ -C4 alkyl or-Y5-phenyl, said phenyl being optionally substituted with up to two substituents independently selected from halo, C~ -C4 alkyl, hydroxyl, C~ -C4 alkoxy, S(O)m R~43, amino, mono- or di-(C~ -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;
1O 1~~41 IS hydrogen; and R'42 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: , H
~N ~ , XXVIII
~~i X23 ~r6 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:

lllllan O

O
or a pharmaceutical salt thereof, wherein:
8146 is selected from the group consisting of SCH3, -S(O)2 CH3 and -S(O)S NH2 ;
8147 is selected from the group consisting of OR15°, mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;
RlSO is unsubstituted or mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;
R14$ is H, C1 -C4 alkyl optionally substituted with 1 to 3 groups of F, CI or Br; and 8149 Is H, C1 -C4 alkyl optionally substituted with 1 to 3 groups of F, CI or Br, with the proviso that R14$ and 8149 are not the same.
[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:

(R151 )0_1 A
W

8154 ~CO2H
XXX
or a pharmaceutically acceptable salt, ester or tautomer thereof, wherein:
Z13 is C or N;
when Z13 IS N, 8151 represents H or is absent, or is taken in conjunction with 8152 as described below:
when Z13 IS C, 8151 represents H and 8152 is a moiety which has the , following characteristics:
(a) it is a linear chain of 3-4 atoms containing 0-2 double bonds, which can adopt an energetically stable transoid configuration and if a double bond is present, the bond is in the trans configuration, (b) it is lipophilic except for the atom bonded directly to ring A, which is either lipophilic or non-lipophilic, and (c) there exists an energetically stable configuration planar with ring A to within about 15 degrees;
or 8151 and 8152 are taken in combination and represent a 5- or 6-membered aromatic or non-aromatic ring D fused to ring A, said ring D
containing 0-3 heteroatoms selected from O, S and N;
said ring D being lipophilic except for the atoms attached directly to ring A, which are lipophilic or non-lipophilic, and said ring D having available an energetically stable configuration planar with ring A to within about 15 degrees;
said ring D further being substituted with 1 Ra group selected from the group consisting of C1-C2 alkyl, -OC1 -C2 alkyl, -NHC1-C2 alkyl, -N(C1 -C2 alkyl)2, -C(O) C1 -C2 alkyl, -S-C1 -C2 alkyl and -C(S) C1 -C2 alkyl;
Y7 represents N, CH or C-OC1 -C3 alkyl, and when Z13 is N, Y~ can also represent a carbonyl group;
8153 represents H, Br, CI or F; and 8154 represents H or CH3.
[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:

R15 ~~
N N ~ R161 N

O

R' ~~
wherein:
R155~ R156~ R157~ and R15$ are independently selected from the groups consisting of hydrogen, C1-C5 alkyl, C1 -C5 alkoxy, phenyl, halo, hydroxyl, C1 -C5 alkylsulfonyl, C1 -C5 alkylthio, trihaloCl -C5 alkyl, amino, vitro and 2-quinolinylmethoxy;
8159 Is hydrogen, C1 -C5 alkyl, trihaloCl -C5 alkyl, phenyl, substituted phenyl where the phenyl substitutents are halogen, C1 -C5 alkoxy, trihaloC~ -C5 alkyl or vitro or R~59 IS heteroaryl of 5-7 ring members where at least one of the ring members is nitrogen, sulfur or oxygen;
8160 jS hydrogen, C~ -C5 alkyl, phenyl C~ -C5 alkyl, substituted phenyl C~ -C5 alkyl where the phenyl substitutents are halogen, C~ -C5 alkoxy, trihaloC~ -C5 alkyl or vitro, or R~60 is C~ -C5 alkoxycarbonyl, phenoxycarbonyl, substituted phenoxycarbonyl where the phenyl substitutents are halogen, C~ -C5 alkoxy, trihaloC~ -C5 alkyl or vitro;
8161 jS C~ -C~o alkyl, substituted C~ -Coo alkyl where the substituents are halogen, trihaloC~ -C5 alkyl, C~ -C5 alkoxy, carboxy, C~ -C5 alkoxycarbonyl, amino, C~ -C5 alkylamino, diC~ -C5 alkylamino, diC~ -C5 alkylaminoC~ -C5 alkylamino, C~ -C5 alkylaminoC~ -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 C~ -C5 alkyl; or R~61 Is phenyl, substituted phenyl (where the phenyl substitutents are one or more of C~ -C5 alkyl, halogen, C~ -C5 alkoxy, trihaloC~ -C5 alkyl or vitro), or R'61 Is heteroaryl having 5-7 ring atoms where one or more atoms are nitrogen, oxygen or sulfur, fused heteroaryl where one or more 5-7 membered aromatic rings are fused to the heteroaryl; or 2O R~61 Is NR~63 8164 where R~63 and R'64 are independently selected from hydrogen and C~_5 alkyl or R~63 and R~64 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 C~ -C5 alkyl; R'62 is hydrogen, C~ -C5 alkyl, vitro, 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:

N

wherein:
8164 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 C1_5 alkyl, halogen, nitro, trifluoromethyl and nitrite;
8165 is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6 ring atoms, substituted heteroaryl;
wherein the substituents are independently selected from one or more members of the group consisting of C1-C5 alkyl and halogen, or substituted phenyl, wherein the substituents are independently selected from one or members of the group consisting of C1 -C5 alkyl, halogen, nitro, trifluoromethyl and nitrite;
8166 Is hydrogen, 2-(trimethylsilyl)ethoxymethyl), C1 -C5 alkoxycarbonyl, aryloxycarbonyl, arylCl -C5 alkyloxycarbonyl, arylCl -C5 alkyl, phthalimidoCl -C5 alkyl, aminoCl -C5 alkyl, diaminoCl -C5 alkyl, succinimidoCl -C5 alkyl, C1 -C5 alkylcarbonyl, arylcarbonyl, C1 -C5 alkylcarbonylCl -C5 alkyl, aryloxycarbonylCl -C5 alkyl, heteroarylCl -C5 alkyl where the heteroaryl contains 5 to 6 ring atoms, or substituted arylCl -C5 alkyl, wherein the aryl substituents are independently selected from one or more members of the group consisting of C1 -C5 alkyl, C1 -C5 alkoxy, halogen, amino, C1 -C5 alkylamino, and diC1 -C5 alkylamino;
8167 IS (A11 )" -(CH165)g -~2a. wherein:

A~~ is sulfur or carbonyl;
nis0or1;
q is 0-9;
Xa4 is selected from the group consisting of hydrogen, hydroxyl, halogen, vinyl, ethynyl, C~ -C5 alkyl, C3 -C~ cycloalkyl, C~ -C5 alkoxy, phenoxy, phenyl, arylC~ -C5 alkyl, amino, C~ -C5 alkylamino, nitrite, phthalimido, amido, phenylcarbonyl, C~ -C5 alkylaminocarbonyl, phenylaminocarbonyl, arylC~ -C5 alkylaminocarbonyl, C~ -C5 alkylthio, C~ -C5 alkylsulfonyl, phenylsulfonyl, substituted sulfonamido, wherein the sulfonyl substituent is selected from the group consisting of C~
-C5 alkyl, phenyl, araC~ -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 C~ -C5 alkyl, wherein the substituents are selected from the group consisting of one or more C~ -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 C~ -C5 alkyl, halogen and C~ -C5 alkoxy, substituted phenoxy, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C~ -C5 alkyl, halogen and C~ -C5 alkoxy, substituted C~ -C5 alkoxy, wherein the alkyl substituent is selected from the group consisting of phthalimido and amino, substituted arylC~ -C5 alkyl, wherein the alkyl substituent is hydroxyl, substituted arylC~ -C5 alkyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C~ -C5 alkyl, halogen and C~ -C5 al koxy, substituted amido, wherein the carbonyl substituent is selected from the group consisting of C~ -C5 alkyl, phenyl, arylC~ -C5 alkyl, thienyl, furanyl, and naphthyl, substituted phenylcarbonyl, wherein the phenyl substituents are independently selected from one or members of the group consisting of C~ -C5 alkyl, halogen and C~ -C5 alkoxy, substituted C~ -C5 alkylthio, wherein the alkyl substituent is selected from the group consisting of hydroxyl and phthalimido, substituted C~ -C5 alkylsulfonyl, wherein the alkyl substituent is selected from the group consisting of hydroxyl and phthalimido, substituted phenylsulfonyl, wherein the phenyl substituents are independently selected from one or members of the group consisting of bromine, fluorine, chlorine, C~ -C5 alkoxy and trifluoromethyl, with the proviso:
if A~~ is sulfur and X24 is other than hydrogen, C~ -C5 alkylaminocarbonyl, phenylaminocarbonyl, arylC~ -C5 alkylaminocarbonyl, C~ -C5 alkylsulfonyl or phenylsulfonyl, then q must be equal to or greater than 1;
if A~~ is sulfur and q is 1, then X24 cannot be C~ -C2 alkyl;
if A~~ is carbonyl and q is 0, then X24 cannot be vinyl, ethynyl, C~ -C5 alkylaminocarbonyl, phenylaminocarbonyl, arylC~ -C5 alkylaminocarbonyl, C~ -C5 alkylsulfonyl or phenylsulfonyl;

if A11 is carbonyl, q is 0 and X~4 is H, then Rls6 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:

XXXI I I

XXXIV

wherein:
R16$ and 8169 are independently selected from the group consisting of hydrogen, halogen, (C1 -C6)alkyl, (C1 -C6)alkoxy, nitro, amino Oydroxyl, trifluoro, -S(C1 -C6)alkyl, -SO(C1 -C6)alkyl and -S02 (C1-C6)alkyl;
and the fused moiety M is a group selected from the group consisting of an optionally substituted cyclohexyl and cycloheptyl group having the formulae:
.173 ,or Rl7o R17° is selected from the group consisting of hydrogen, halogen, hydroxyl and carbonyl;
or R17° and 8171 taken together form a moiety selected from the group consisting of -OCOCH2 -, -ONH(CH3)COCH2 -, -OCOCH= and -O-;
8171 and 8172 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (C1 -C6)alkyl, (C1 -C6)alkoxy, =NOH, -NR174 8175, -OCH3, -OCH2 CH3, -OS02 NHC02 CH3, =CHC02 CH2 CH3, -CH2 C02 H, -CH2 C02 CH3, -CH2 C02 CH2 CH3, -CH2 CON(CH3)2, -CH2 C02 NHCH3, -CHCHC02 CH2 CH3, -OCON(CH3)OH, -C(COCH3)2, di(C1 -C6)alkyl and di(C1 -C6)alkoxy;
8173 is selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (C1 -C6)alkyl, (C1 -C6)alkoxy and optionally substituted carboxyphenyl, wherein substituents on the carboxyphenyl group are selected from the group consisting of halogen, hydroxyl, amino, (C1 -C6)alkyl and (C1 -C6)alkoxy;
or 8172 and 8173 taken together form a moiety selected from the group consisting of -O-and wherein:

F
8174 is selected from the group consisting of hydrogen, OH, -OCOCH3, -COCH3 and (C1 -C6)alkyl; and 8175 is selected from the group consisting of hydrogen, OH, -OCOCH3, -COCH3, (C1 -C6)alkyl, -CONH2 and -S02 CH3 ;
with the proviso that if M is a cyclohexyl group, then 8170 through 8173 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:

~CH2)n-X25 8177 ~XV
~ R178 N/

wherein:
8176 is C1 -C6 alkyl, C1 -C6 branched alkyl, C4 -C$ cycloalkyl, C1-C6 hydroxyalkyl, branched C1 -C6 hydroxyalkyl, hydroxyl substituted C4 -C$

aryl, primary, secondary or tertiary C1-C6 alkylamino, primary, secondary or tertiary branched C1-C6 alkylamino, primary, secondary or tertiary C4 -C$ arylamino, C1 -C6 alkylcarboxylic acid, branched C1 -C6 alkylcarboxylic acid, C1 -C6 alkylester, branched C1 -C6 alkylester, C4 -C$ aryl, C4 -C$
arylcarboxylic acid, C4 -C$ arylester, C4 -C$ aryl substituted C1 -C6 alkyl, C4 -C$ heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-substituted or aryl-substituted C4 -C$ 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;
R1" is C1 -C6 alkyl, C1-C6 branched alkyl, C4 -C$ cycloalkyl, C4 -C$ aryl, C4 -C$ aryl-substituted C1 -C6 alkyl, C1 -C6 alkoxy, C1 -C6 branched alkoxy, C4 -C$ aryloxy, or halo-substituted versions thereof or R1" is halo where halo is chloro, fluoro, bromo, or iodo;
R1'8 is hydrogen, C1 -C6 alkyl or C1-C6 branched alkyl;
R1'9 is C1 -C6 alkyl, C4 -C$ aroyl, C4 -C$ aryl, C4 -C$ heterocyclic alkyl or aryl with O, N or S in the ring, C4 -C$ aryl-substituted C1 -C6 alkyl, .alkyl-substituted or aryl-substituted C4 -C$ hetero~yclic alkyl or aryl with~0, N or S in the ring, alkyl-substituted C4 -C$ aroyl, or alkyl-substituted C4 -C$
aryl, or halo-substituted versions thereof where halo is chloro, bromo, or iodo;
n is 1, 2, 3, or 4; and X25 is O, NH, or N-R1$°, where R1$° is C1 -C6 or C1 -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:

~N~
XXXVI
Rls3 or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:

X26 is selected from the group consisting of O, S, -NRls5, -NORa, and -N N Rb R~ ;
RIBS is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclic alkyl;
Ra, Rb, and R° are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl;
Rla1 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(O)RlBS, -(CH2)n CH(OH)R186, -(CH2)n C(NORd)Rls6, -(CH2)n CH(NORd)Rls6, -(CH~)~ CH(NRd Re)Rls6, -8187 188 188 26' 188 R , -(CH2)" C=CR , -(CH2)n (CH(CX s)]m (CH2)p R , -(CH2)n (CX26~2)m (CH2)p Rlsa~ and -(CH2)" (CHX26~)m (CH2)m Rlss ;
RIBS is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, haloalkynyl, heterocyclic, and heterocyclic alkyl;
R1s' is selected from the group consisting of alkenylene, alkylene, halo-substituted alkenylene, and halo-substituted alkylene;
RlsB is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
Rd and Re are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
X26 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 8184 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 8182, 8183, or 8184 must be Z14, and further provided that only one of 8182, 8183, or 8184 is X14;
Z14 is selected from the group consisting of x28 x28 --x27-8190 and x27-8190 S
X27 is selected from the group consisting of S(O)2, S(O)(NR191), S(Q), Se(O)2, P(O)(OR192), and P(O)(NR193 8194);
X28 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen;
R19° is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, -NHNH2, and -NCHN(R191)R192 ;
8191, 8192, 8193, and 8194 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or 8193 and 8194 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 ;

Y$ is selected from the group consisting of -OR~95, -SR~95, -C~R197~~R198~R195~ -C~O~R195~ _C~O~~R195~ -N~R197~C~~~R195~ -N'C(R~9/,')R~95, and -Nl(RI~9')R~95 ' l ' I;
R~95 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, hydroxyalkyl, and NR'99 R2oo ; and R~9', R'98, R~99, and R2°° 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:

~S~

wherein:
A~2 denotes oxygen, sulphur or NH;
8201 denotes a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted by halogen, alkyl, CF3 or alkoxy;
D5 denotes a group of formula XXXVIII or XXXIX:

S(o)m \ ~ R2o2 XXXVIII
\ R2oa or S(o)m /N R2o2~ XXXIX
\ X15 R2°2 and R2°3 independently of each other denote hydrogen, an optionally polyfluorinated alkyl radical, an aralkyl, aryl or heteroaryl radical or a radical (CH2)" -X29; or R2°2 and R2°3 together with the N-atom denote a three- to seven-membered, saturated, partially or totally unsaturated heterocycle with one or more heteroatoms N, O, or S, which may optionally be substituted by oxo, an alkyl, alkylaryl or aryl group or a group (CH2)~ -X29, R2°2' denotes x hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or a heteroaryl group or a group (CH2)n -X29, wherein:
X29 denotes halogen, N02, -OR2°4, -COR2°4, -C02 R2°4, -O~O2 R204~ -~N~ -CONR2°4 OR205~ -CONR2°4 R205~ -SR204~ -S~O)R204~ -S(~)2 R204~ -NR204 R205~ -NHC(O)R2°4, -NHS(O)2 8204;
X15 denotes -CH2 -, -CH2 -CH2 -, -CH2 -CH2 -CH2 -, -CH2 -CH=CH-, -CH=CH -CH2 -CH2 -CO-, -CO-CH2 -, --, NHCO-, CONH-, -NHCH2 -, -CH2 NH-, -N=CH-, -NHCH-, --CH2-CH2 -NH-, CH=CH- , >N-R23, >C=O, >S(O)m;
-R2o4 and R2°5 independently of each other denote hydrogen, alkyl, aralkyl or aryl;
n is an integer from .0 to 6;
R2°6 is a straight-chained or branched C1 -C4 alkyl group which may optionally be mono- or polysubstituted by halogen or alkoxy, or R2°s d enotes CF3; and m denotes an integer from 0 to 2;
with the proviso that A~2 does not represent O if R2os 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:
XXXX
OR2°$
wherein:
R2°' and R2°$ are respectively a hydrogen;
C~ -C4-alkyl substituted or not substituted by halogens;
C3 -C~-cycloalkyl;
C~ -C5-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).
OR~m [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:

N
XXXXI
wherein:
X3° is -NHS02R2°9 wherein R2°9 represents hydrogen or C1 -C3-alkyl;
Y9 is hydrogen, halogen, C1 -C3-alkyl substituted or not substituted by halogen, N02, NH2, OH, OMe, C02H, or CN; and Q' is C=O, C=S, or CH2.
[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 in hibitors have the formula shown below in formula XXXXII:

8211 ~ R210 XXXXII
N

wherein A13 is a ring substituent selected from partially unsaturated heterocyclic, heteroaryl, cycloalkenyl and aryl, wherein A13 is unsubstituted or substituted with one or more radicals selected from alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, 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;
R~~° is selected from heterocyclyl, cycloal.kyl, cycloalkenyl, and aryl, wherein R2~o is unsubstituted or substituted with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio;
R2'~ is selected from hydrido and alkoxycarbonylalkyl;
R2'~ is selected from alkyl, carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, amino acid residue, and alkylcarbonylaminoalkylcarbonyl;
provided A~3 is not tetrazolium, or pyridinium; and further provided A~3 is not indanone when R2~2 is alkyl or carboxyalkyl; further provided A~3 is not thienyl, when R2~° is 4-fluorophenyl, when 8211 IS hydrido, and when R2~2 is methyl or aryl; and R2~3 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)-1 H-pyrazol-1-yl]phen yl]sulfonyl]propanamide;
N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-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)phenyl]sulfonyl]butanamide;
N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]pentanamide;
N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]hexanamide;
3-methoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide ;
2-ethoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide;
N-[[4-[5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide;

N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H pyrazol-1-yl]phenyl]sulfonyl]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 0[4,3-c]pyrazol-1-yl]phenyl]sulfonyl]acetamide;
N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1-yl]phenyl]sulfonyl]acetamide;
N-[[4-(2-methyl-4-phenyloxazol-5-yl)phenyl]sulfonyl]acetamide;
methyl[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]oxoacetate;
2-methoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]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-ph enylisoxazol-4-yl)phenyl]sulfonyl]formamide;
1,1-dimethylethyl-N-[[4-(5-methyl-.3-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-fluorophenyl)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:
A~3 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;
R~~° 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;
R2'~ and R2'2 are independently selected from the group consisting of hydroxyalkyl and hydrido but at least one of R2~~ and R2~2 is other than hydrido; and R2~3 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)-1 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:

O
H2N~ ~ N
., ~N

wherein:
8214 Is furyl, thiazolyl or oxazolyl;
8215 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:

N
N ~ R2ls N/ ~ N~ XXXXIV
~Z16 ~ 217 wherein:
Z16 is O or S, 8216 is optionally substituted aryl, R21~ is aryl optionally substituted with aminosulfonyl, and R21$ and 8219 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 XXX:7CV and XXXXVI:

O

14-~r10 N OH

15-Y11 ~ ~ ~ Ne XXXXVI
A

[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;
Y1° is selected from lower alkenylene and lower alkynylene;
R22° is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R22° is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylmino, vitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
R22~ is selected from lower alkyl and amino; and 8222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically-acceptable salt thereof.
[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:
A~5 is pyrazolyl optionally substituted with a substituent selected from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, vitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
Y~' is selected from lower alkylene, lower alkenylene and lower alkynylene;
8223 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein 8223 is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylmino, vitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
8224 is selected from lower alkyl and amino; and 8225 is selected from hydrido, 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:
A~4 is a ring substiuent selected from oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isochiazolyl, isoxazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A~4 is optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, vitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
Y~° is lower alkylene, lower alkenylene, and lower alkynylene;
R22° is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R22° 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, vitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
R2a~ is selected from lower alkyl and amino; and 8222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically-acceptable salt thereof. ;
[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:
A~5 is a ring substituent selected from oxazolyl, furyl, pyrrolyl, thia~olyl, 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, vitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarboryl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
Y~~ is selected from lower alkyl, lower alkenyl and lower alkynyl;
8223 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein 8223 is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitto, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
R22a. is selected from lower alkyl and amino; and 8225 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:
A~4 is thienyl optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, vitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
Y~° is ethylene, isopropylene, propylene, butylene, lower alkenylene, and lower alkynylene;
R22° is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R22° is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, vitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
R22' is selected from lower alkyl and amino; and 8222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically-acceptable salt thereof.
[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:
A~5 is thienyl optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, vitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
Y~ ~ is selected from lower alkyl, lower alkenyl and lower alkynyl;
8223 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein 8223 is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
8224 is selected from lower alkyl and amino; and 8225 is selected from hydrido and alkyl; or a pharmaceutically-acceptable salt thereof.
[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:

R22s ,,, XXXXVI I

wherein:
8226 and R22~ are independently selected from the group consisting of H, halogen, C~ -C6 alkyl, C~ -C6 alkoxy, and C~ -C6 alkoxy substituted by one or more fluorine atoms;

R22$ is halogen, CN, CON R23° (~231~ C02 H, C02 C~ -C6 alkyl, or NHS02R23o;
8229 is C~ -C6 alkyl or NH2 ; and 8225 and 8225 are independently selected from the group consisting of H, C~ -C6 alkyl, phenyl, phenyl substituted by one or more atoms or groups selected from the group consisting of halogen, C~ -C6 alkyl, C~ -C6 alkoxy, and C~ -C6 alkoxy substituted by one or more fluorine atoms, or a pharmaceutically acceptable salt, solvate, ester, or salt or solvate of such ester thereof.
[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:
y12 XXXXV~~~
wherein:
X33 represents halo, hydrido, or alkyl;
Y~2 represents alkylsulfonyl, aminosulfonyl, alkylsulfinyl, (N-acylamino)-sulfonyl, (N-alkylamino)sulfonyl, or alkylthio;
Z~~ represents oxygen or sulfur atom;
8233 and 8234 are selected independently from louver alkyl radicals;
and 8232 represents a substituted or non-substituted aromatic group of 5 to 10 atoms; , or a pharmaceutically-acceptable salt thereof.
9~
RL3;i RL;54 (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':

N
XXXXIX

KGJJ

R

XXXXIX' ~GJJ VG

wherein:
8235 is a hydrogen atom or an alkyl group having 1-3 carbon atoms;
8236 is a hydrogen atom, a hydroxyl group, an organothiol group that is bound to the selenium atom by its sulfur atom, or 8235 and R23s are joined to each other by a single bond;
8237 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;
R23$ and 8239 are identical to or different from each other, and each is a hydrogen atom, a halogen atom, an alkoxyl group having 1-4 carbon atoms, a trifluoromethyl group, or R23$ and 8239 are joined to each other to form a methylenedioxy group, a salt thereof, or a hydrate thereof.
[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:

R2' XXXXX
O
wherein:
X34 is selected from the group consisting of (a) a bond, (b) --(CH2)m --, wherein m 1 or 2, (c) --C(O)--, (d) __~__, (e) --S--, and (f) --N(R244)--;
R24° is selected from the group consisting of (a) C1 -C1° alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halo, C1 -C1°
alkoxy, C1 -C1° 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 'I-3 substituents independently selected from the group consisting of halo, C~ -Coo alkoxy, C~ -Coo alkylthio, CN, C~ -Coo alkyl, optionally substituted to its maximum with halo, and N3 ;
R24' is selected from the group consisting of (a) C~ -C6 alkyl, optionally substituted to its maximum with halo, (b) NH2, and (c) NHC(O)C~ -Coo alkyl, optionally substituted to its maximum with halo;
8242 and 8243 are each independently selected from the group consisting of hydrogen, halo, and C~ -Cs alkyl, optionally substituted to its maximum with halo; and 8244 is selected from the group consisting of hydrogen and C~ -C6 alkyl, optionally substituted to its maximum with halo.
[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-methylsulfonyl)phenyl-pyran-2-one, 3-(3-Fluorophenyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one, 6-Methyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one, 6-Difluoromethyl-4-(4-methylsulfonyl)phen yl-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-pyr-idin-3-yl-pyran-2-one, 3-Isopropylthio-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one, 4-(4-Methylsulfonyl)phenyl)-3-phenylthio-6-trifluoromethyl-pyran-2-one, 3-Isopropylthio-4-(4-methylsulfonyl)phenyl-6-trifluoromethyl-pyran-2-one, 4-(4-Methylsulfonyl)phenyl-3-phenyl-6-(2,2,2-trifluoroethyl)-pyran-2-one, and 3-(3-Hydroxy-3-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:

R24~ R25o XXXXXI
8248 ~ 0 B

wherein:
R246~ R247~ R248~ R24s~ and R25° are independently selected from the group consisting of --H, --OH, --SH, --OR, --SR, --NH2, --NHR245, --N~R245~2~
--N(R245)3+X35-, a carbon, oxygen, nitrogen or sulfur, glycoside of a single or a combination of multiple sugars including, aldopentoses, methyl-aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; wherein 8245 is an alkyl group having between 1-10 carbon atoms;
and X35 is selected from the group of pharmaceutically acceptable counter anions including, hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride and carbonate.
[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:

N XXXXXII

N, \\a or a pharmaceutically acceptable salt thereof, wherein the ring of the formula (R255)-A-(SOmR254) is selected from the group consisting of SOmR~54 SOmR254 SOmR254 R25\ ~ i a \I
X~3s / N RzsS ~ N
SO,i,R254 gpmR2s4 SOmR254 R2ss N ~ N ~\ N a N
N ~ R255 R2ss ' , '~~.,.' , and 'M'v' m is 0, 1 or 2;
1 O X35 IS >CR255 Or >N;
8251 is a radical selected from the group consisting of H, N02, CN, (C1 -C6)alkyl, (C1 -C6)alkyl-S02-, (C6 -C1o)aryl-S02-, H-(C=O)-, (C1 -C6)alkyl-(C=O)-, (C1 -C6)alkyl-)-(C=O)-, (C1 -C9)heteroaryl-(C=O)-, (C1 -C9)heterocyclyl-(C=O)-, H2N-(C=O)-, (C1 -C6)alkyl-NH-(C=O)-, [(C1 -Cs)alkyl]2-N-(C=O)-~ [(Cs -C1o)aryl]2-NH-(C=O)-, [(C1-Cs)alkyl]-[((Cs -C1o)aryl-N]-(C=O)-, HO-NH-(C=O)-, and (C1 -Cs)alkyl-O-NH-(C=O)-;
8252 is a radical selected from the group consisting of H, -N02, -CN, (C2-Cs)alkenyl, (C2-Cs)alkynyl, (C3-C7)cycloalkyl, (Cs-C1o)aryl, (C1-C9)heteroaryl, (C1-C9)heterocyclyl, (C1-Cs)alkyl-O-, (C3-C7)cycloalkyl-O-, (Cs-C1o)aryl-O-, (C1-C9)heteroaryl-O-, (Cs -C9)heterocyclyl-O-, H-(C=O)-, (C1-Cs)alkyl-(C=O)-, (C3-C7)cycloalkyl-(C=O)-, (Cs-C1o)aryl-(C=O)-, (C1-C9)heteroaryl-(C=O)-, (C1-C9)heterocyclyl-(C=O)-, (C1-Cs)alkyl-O-(C=O)-, (C3-C~)cycloalkyl-O-(C=O)-, (Cs-C1o)aryl-O-(C=O)-, (C1-C9)heteroaryl-O-(C=O)-, (C1-C9)heterocyclyl-O-(C=O)-, (C1-C6)alkyl-(C=O)-O-, (C3-C~)cycloalkyl-(C=O)-O-, (Cs-C1o)aryl-(C=O)-O-, (C1-C9)heteroaryl-(C=O)-O-, (C1-C9)heterocyclyl-(C=O)-O-, (C1-Cs)alkyl-(C=O)-NH-, (C3-C~)cycloalkyl-(C=0)-NH-, (Cs-Cloaryl-(C=O)-NH-. (C1-C9)heteroaryl-(C=O)-NH-, (C1-C9)heterocyclyl-(C=O)-NH-, (C1-Cs)alkyl-O-(C=O)-NH-, (C1-Cs)alkyl-NH, [(C1-Cs)alkyl]2-N-, (C3-C7)cycloalkyl-NH-. [(C3-C7)cycloalkyl]2-N-~ [(Cs-C1o)aryl]-Nhi-~ [(Cs-C1 o)arYl]2-N-~ [(C1-Cs)alkyl]-[((Cs-C1o)aryl)-N]-~
[(C1-C9)heteroaryl]-NH-, [(C1-C9)heteroaryl]2-N-, [(C1-C9)heterocycly]-NH-, [(C1-C9)heterocyclyl]2-N-, H2N-(C=O)-, HO-NH-(C=O)-, (C1-Cs)alkyl-O-NH-(C=O)-a [(C1-Cs)alkyl]-NH-(C=O)-~ [(C1-Cs)alkyl]2-N-(C=O)-~ [(Cs-C7)cycloalkyl]-NH-(C=O)-, [(C3-C~)cycloalkyl]2-N-(C=O)-, [(Cs-C1o)aryl]-NH-(C=O)-~ [(Cs-CloarYl]2-N-(C-O)-~ [(C1-C s)alkyl]-[((Cs-C1o)arYl)-N]-(C=O)-~
[(C1-C9)heteroaryl]-NH-(C=O)-, [(C1-C9)heferoaryl]2-N-(O=O)-, [(C1-C9)heterocyclyl]-NH-(C=O)-, (C1-Cs)alkyl-S- and (C1-Cs)alkyl optionally substituted by one -OH substituent or by one to four fluoro substituents;
RzSS is a saturated (3- to 4-membered)-heterocyclyl ring radical; or a saturated, partially saturated or aromatic (7- to 9-membered)-heterocyclyl ring radical;
wherein said saturated (3- to 4-membered)-heterocyclyl ring radical orsaid saturated, partially saturated or aromatic (7- to 9-membered)-heterocyclyl ring radical; may optionally contain one to four ring heteroatoms independently selected Irom the groups consisting of -N=, -NH-, -O-, and -S-;

wherein said saturated (3- to 4-membered)-heterooyclyl ring radical; or said saturated, partially saturated or aromatic (7- to 9-nembered)-heterocyclyl ring radical; may optionally be substituted on any ring carbon atom by one to three substituents per ring independently selected from the group consisting of halo, -OH, -CN, -N02, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C~)cycloalkyl, (C6-C~o)aryl, (C2-C9)hetorocyclyl, (C~ -C6)alkyl-O-, H-(C=0)-, (C~-C6)alkyl-(C=O)-, HO-(C=O)-, (C~-C6)alkyl-O-(C=O)-, -NH2, (C~-C6)alkyl-NH-, [(C~-C6) alkyl]2-N-, (C3-C~)cycloalkyl-NH-, (C6-C~o)aryl-NH-, [(C~-C6)alkyl]-[((C6-C~o)aryl)-N]-, (C~-C9)heteroaryl-NH-, H2N-(C=O)-[(C~-C6)alkyl]-NH-(C=O)-, [(C~-C6)alkyl]2-N-(C=O)-, [(Cs-C~o)ar'YI]-NH-(C=O)-~ [(C~-Cs)alkyl]-[((Cs-C~o)ai"YI)-N]-(C=O)-, (C~-C6)alkyl-O-NH-(C=O)-, (C~-C6)alkyl-(C=O)-HN-, (C~-C6)alkyl-(C=O)-[(C~-C6)alkyl-N]-, -SH, (C~-C6)alkyl-S-, (C~-C6)alkyl-(S=0)-, (C~-C6)alkyl-S02- and (C~-C6)alkyl optionally substituted with one to fourfluoro moieties;
wherein said saturated (3- to 4-membered)-heterocyclyl ring radical; or said saturated, partially saturated or aromatic (7- to 9-membered)-heterocyclyl ring radical; may also optionally be substituted on any ring nitrogen atom by one to three substituents per ring independently selected from the group consisting of (C3-C~)cyoloalkyl, (C6-C~o)aryl, (C2-C9)heterocyclyl, H-(C=O)-, (C~-C6)alkyl-(C=O)-, (C~-C6)alkyl-O-(C=O)-, HEN-(C=O)-, [(C~-C6)alkyl]-NH-(C=O)-, [(C~-C6)alkyl]2-N-(C=O)-, [(C6-C~o)arYl]-NH-(C=O)-, [(C~-C6)alkyl]-[((C6-C~o)arYl)-N]-(C=O)-, (C~ -C6)alkyl-O-NH-(C=O)-, and (C~-C6)alkyl optionally substituted with one to four fluoro moieties;
8254 is an (C~-C6)alkyl radical optionally substituted by one to four fluoro substituents; and 8255 is a radical selected from the group consisting of H, halo, -OH, (C~-C6)alkyl-O-, (C~-C6)alkenyl, (CZ-C6) alkynyl, (C3-C7)cycloalkyl, -CN, H-(C=O)-, (C~-C6)alkyl-(C=O)-, (C~-C6)alkyl-(C=O)-O-, HO-(C=O)-, (C~-C6)alkyl-O-(C=O)-, (C~-C6)alkyl-NH-. [(C~-C6)alkyl]2-N-, (C3-C7)cycloalkyl-NH-, (C6-C~o)aryl-NH-, [(C~-C6)alkyl]-[((C6-C~o)aryl)-N]-, (C~-C9)heteroaryl-NH-, H2N-(C=O)-, (C~-C6)alkyl-NH-(C=O)-. [(C~-C6)alkyl]2-N-(C=O)-, (Cs-C~o)a~"YI-(C=O)-~ L(C~-Cs)alkyl]-[((Cs-C~o)arYl)-N]_ (C=O)-, (C~-C6)alkyl-O-NH-(C=O)-, (C~-C6)alkyl-S-, and (C~-C 6)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 XX)CXXIII:

R25a XXXXXI I I

wherein:
8256 represents an alkyl or -NR259 R2so group, wherein 8259 and R26°
each independently represents a hydrogen atom or an alkyl group, R25~ represents an alkyl, C3 -C~ cycloalkyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluorom ethyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups;
R25$ represents a methyl, hydroxymethyl, alkoxymethyl, C3 -C7 cycloalkoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrile~, trifluoromethyl or difluoromethyl group or a CH2 -- R26~ group wherein 8261 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-methyl-3-(4-methylphenoxy)pyran-4-one, 3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(2,5-difluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methoxymethylpyran-4-one, 3-(4-chlorophenyl)-6-difluoromethyl-2-(4-methanesulfonylphenyl)pyran-4-one, and pharmaceutically acceptable salts thereof.
[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-yl]benzenesulfonamide;
b4) 4-[5-phenyl-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
b5) 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
b6) 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;

b7) 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
b8) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
b9) 4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
b10) 4-[3-(difluoromethyl)-5-(4-methylphenyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
c1 ) 4-[3-(difluoromethyl)-5-phenyl-1 H-pyrazol-1-yl]benzenesulfonamide;
c2) 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
c3) 4-[3-cyano-5-(4-fluorophenyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
c4) 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
c5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
c6) 4-[4-chloro-5-phenyl-1 H-pyrazol-1-yl]benzenesulfonamide;
c7) 4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
c8) 4-(5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
c9) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
c10) 4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;
d1) 6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[3.4]oct-6-ene;
d2) 5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
d3) 4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;
d4) 5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
d5) 5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;

d6) 4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;
d7) 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;
d8) 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;
d9) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole;
d10) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;
e1 ) 4-(4-fluorophenyl)-5-(4-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)phenyl]thiazole;
e5) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;
e6) 1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene;
e7) 4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide;
e8) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6-diene;
e9) 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl]benzenesulfonamide;
e10) 6-(4-fluorophenyl)-2-methoxy-5-[4-(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-yl]benzenesulfonamide;
f4) 4-(2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
f5) 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
f6) 3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1 H-imidazol-2-yl]pyridine;
f7) 2-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H-imidazol-2-yl]pyridine;
f8) 2-methyl-4-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H-imidazol-2-yl]pyridine;
f9) 2-methyl-6-[1-(4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
f10) 4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
g1 ) 2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1 H-imidazole;
g2) 4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
g3) 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1 H-imidazole;
g4) 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-~ H-imidazole;
g5) 2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1 H-imidazole;
g6) 2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H-imidazole;
g7) 1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1 H-imidazole;
g8) 2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazole;

g9) 4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
g10) 2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1 H-imidazole;
h1 ) 4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
h2) 2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazole;
h3) 4-[2-(3-methylphenyl)-4-trifluoromethyl-1 H-imidazol-1-yl]benzenesulfonamide;
h4) 1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-1 H-imidazole;
h5) 4-[2-(3-chlorophenyl)-4-trifluoromethyl-1 H-imidazol-1-yl]benzenesulfonamide;
h6) 4-[2-phenyl-4-trifluoromethyl-1 H-imidazol-1-yl]benzenesulfonamide;
h7) 4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1 H-imidazol-1-yl]benzenesulfonamide;
h3) 1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1 H-pyrazole;
h9) 4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1 H-pyrazol-3-yl]benzenesulfonamide;
i1 ) N-phenyl-[4-(4-luorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-( trifluoromethyl)-1 H-pyrazol-1-yl]acetamide;
i2) ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1 H-pyrazol-1-yl]acetate;
i3) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-1 H-pyrazole;
i4) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-5-(trifluoromethyl)pyrazole;
i5) 1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1 H-pyrazole;

i6) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1 H-imidazole;
i7) 4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1 H-imidazole;
i8) 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine; , i9) 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;
i10) 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine;
j1 ) 2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;
j2) 4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;
j3) 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
j4) 5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole;
j5) 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide;
j6) 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
j7) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
j8) 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide;
j9) 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
j10) 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
k1 ) 1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
k2) 1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
k3) 1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-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-yl]benzenesulfonamide;
k7) 1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene;
k8) 4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonamide;
k9) 4-[2-(4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;
k10) 4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide;
11 ) 1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
12) 1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
13) 4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl]benzenesulfonamide;
14) 1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene; °
15) 4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;
16) 4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]benzenesulfonamide;
17) ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyl]oxazol-2-yl]-2-benzyl-acetate;
18) 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]acetic acid;
19) 2-(tent-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazole;
110) 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole;
m1 ) 4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole;
and m2) 4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzenesulfonamide;
m3) 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
m4) 6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

m5) 8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

m6) 6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

m7) 6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

m8) 2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid;

m9) 7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

m10) 6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

n1 ) 8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
n2) 6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

n3) 5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

n4) 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

n5) 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
, a n6) 6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-berizopyran-3-carboxylic acid;

n7) 7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

n8) 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

n9) 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

n10) 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

01 ) 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

02) 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

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

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

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

06) 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
07) 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
08) 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
09) 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
010) 8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p1 ) 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p2) 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p3) 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p4) 6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p5) 6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p6) 6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p7) 6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p8) 6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p9) 6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
p10) 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q1 ) 8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

q2) 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q3) 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q4) 8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q5) 6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q6) 6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q7) 6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q8) 6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q9) 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q10) 7-(1,1-dimethylethyl)-2-pentafluoroethyl-2H-1-benzopyran-3-carboxylic acid;
r1 ) 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methyl-sulphonyl-2(5H)-fluranone;
r2) 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid;
r3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
r4) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
r5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
r6) 3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazol-2-yl]pyridine;
r7) 2-methyl-5-[1-(4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazol-2-yl]pyridine;
r8) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl]benzenesulfonamide;
r9) 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
r10) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

s1 ) [2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzenesulfonamide;
s2) 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; or s3) 4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzenesulfonamide;
or a pharmaceutically acceptable salt or prodrug thereof.
[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-398 (Taisho Pharmaceutical), L-745337 (Merck), RWJ-63556, L-784512 (Merck), darbufelone (Pfizer), CS-502 (Sankyo), LAS-34475 (Almirall Prodesfarma), LAS-34555 (Almirall Prodesfarma), S-33516 (Servier), SD-8381 (Pharmacia, described in U.S.
Patent No. 6,0340256), MK-966 (Merck), L-783003 (Merck), T-614 (Toyama), D-1376 (Chiroscience), L-748731 (Merck), CGP-28238 (Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome), prodrugs of any of them, and mixtures thereof.

[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.
5,466,823 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 96/03385.
[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 94/27980.
[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 96/03388. 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 98/47890. 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. 6,077,850. 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
98/03484.
[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. 5,994,381.
[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 WQ 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 863134.

[0196] The compound 2-[(2-chloro-6-fluorophenyl)amino]-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-nitrophenyl~methanesulfonamide used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S.
Patent No. 4,885,367.
[0198] The compound (3~)-3-[(4-chlorophenyl)[4-(methylsulfonyl)phenyl]methylene]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. 6,180,651.
[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.
(0200] 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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Q U r-[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.
[02'17) 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.
[0220] 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.), 5,827,819 (issued to Yatvin, et al.), 5,919,815 (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, malefic, 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, a-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-methylglueamine) and procaine. Exemplary pharmaceutically acceptable acids include, without limitation, hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, sulfuric acid, rnethanesulfonic acid, acetic acid, formic acid, tartaric acid, malefic 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 cone-like structure, the electric force exerted on the surface of the droplet overcomes the surface tension of the I iquid, 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 intran'asal 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 polyquaternium-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 80, polyoxyethylene/polyoxypropylene surfactants (e.g. Pluronic F-68, F-84 and P-103), cyclodextrin, or other agents known to those skilled in the art.
Typically, such co-solvents are employed at a level of from 0.01 % to 2%
by weight.
[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., 1980; and ICibbe, 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 amou nt 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 inhibifior will generally be from about 0.01 mg per kg to about 140 mg per kg subject body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 mg/kg to about 25 mg/kg per day; more preferably about 0.5 mg/kg to about 10 mg/kg per day.

[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 mg.
[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 ind icated 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 out-patient 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 a ny 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 dysmorphic 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 dose 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.

[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)-1 H-pyrazol-1-yl]benzenesulfonamide.
[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 C~7 H~4 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.

[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)-1 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 (19)

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.

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-58125, nimesulide, flosulide, NS-398, L-745337, RWJ-63556, L-784512, darbufelone, CS-502, LAS-34475, LAS-34555, S-33516, SD-8381, 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, 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid, 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 7-(1,1-dimethylethyl)-2-pentafluoroethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid.
6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, (S)-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, (S)-6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, 6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, (S)-6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, 6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, 6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid, (S)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid, 6,8-dichloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid, 7-(1,1-dimethylethyl)-2-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-(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, (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.
8. 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, roliprarn, 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, 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.

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-398, L-745337, RWJ-63556, L-784512, 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, 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 7-phenyl-2-trifluorornethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid, 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[(methylamino)su Ifonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[(1,1-dimethylethyl )aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 7-(1,1-dimethylethyl)-2-pentafluoroethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid.
6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, (S)-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, (S)-6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, 6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, (S)-6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, 6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, 6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid, (S)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid, 6,8-dichloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid, 7-(1,1-dimethylethyl)-2-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-(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, (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.

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, 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.

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 18, wherein the Cox-2 inhibitor comprises celecoxib and the antidepressant agent comprises sertraline.