WO2005105099A1

WO2005105099A1 - Monotherapy for the treatment of psoriasis with cyclooxygenase-2 selective inhibitors

Info

Publication number: WO2005105099A1
Application number: PCT/US2005/013256
Authority: WO
Inventors: Diane T. Stephenson
Original assignee: Pharmacia and Upjohn Co; Upjohn Co; Pharmacia and Upjohn Co LLC
Current assignee: Pharmacia and Upjohn Co; Pharmacia and Upjohn Co LLC
Priority date: 2004-04-23
Filing date: 2005-04-18
Publication date: 2005-11-10
Anticipated expiration: 2006-10-23
Also published as: TW200603792A

Abstract

The present invention provides compositions and methods for treating psoriasis in a subject. More particularly, the invention provides a therapy for the treatment of psoriasis comprising administering to a subject a cyclooxygenase-2 selective inhibitor.

Description

MONOTHERAPY FOR THE TREATMENT OF PSORIASIS WITH CYCLO- OXYGENASE-2 SELECTIVE INHIBITORS 1

FIELD OF THE INVENTION [oooi] The present invention provides compositions and methods for treating skin disorders. More particularly, the invention is directed toward a method for treating psoriasis comprising administering to a subject a composition having a cyclooxygenase-2 (COX-2) selective inhibitor.

BACKGROUND OF THE INVENTION [0002] Psoriasis is a chronic skin disease characterized by red scaly patches that usually affect the scalp, elbows and knees, although any part of the skin may be involved. At the cellular level, psoriasis is a benign proliferative disease of keratinocytes of unknown etiology. It has been estimated that psoriasis affects about 2 percent of the population in Western countries, 0.1 to 0.3 percent in the Far East and is rather rare in Africa (Krueger et al., 1984, J. Am. Acad. Dermatol. 11 :937-947; Yui-Yip, 1984, J. Am. Acad. Dermatol. 10:965-968). Although the disease appears to be inherited, its mode of transmission is not known and more than one genetic locus may be involved (Henseler, 1997, J. Am. Acad. Dermatol. 37:S1-11). Furthermore, the disease can be triggered or exacerbated by external factors such as trauma, infection and drugs. [0003] Although psoriasis comes in different forms and varies in intensity from a few random spots to a massive outbreak covering the entire body and requiring hospitalization, the underlying problem in all types of psoriasis is overproduction of epidermal cells. Instead of adhering to the 21 to 28 day cycle of cell turnover, those afflicted with psoriasis race through the cycle in 3 or 4 days. The epidermis may grow to 5 to 10 times its normal thickness. The thickened epidermis, overgrowth of blood vessels, and infiltrate of neutrophils and lymphocytes account for the psoriatic lesions being raised and easily palpable. [0004] The etiology of psoriasis is still poorly understood, however, evidence has accumulated clearly indicating a role for T cells. Large numbers of activated T cells are found in psoriatic skin and almost none in healthy skin. It has also been discovered that these activated T cells secrete interleukin-6, which has as one of its effects the ability to stimulate skin cell growth. The infiltration of activated white blood cells suggests that an immune response has been mustered against something. There are various theories about what that "something" is. One suggests a genetic abnormality. Other theories suggest that psoriasis is an immune system overreaction against invading organisms, or toxins produced by those organisms ("superantigens"), as it is known that latent psoriasis can be activated by various infections as well as certain drugs and injury to the skin. Bone marrow transplantation has resulted in clearance of the disease. In any event, psoriasis is currently considered to be an immunologic skin disorder. In psoriasis, the immune system is somehow triggered, which in turn speeds up the growth cycle of skin cells, which pile up on the surface and form the elevated red lesions when the body can't shed them fast enough. [0005] Psoriasis, as detailed briefly above, is considered to be a pluricausal hereditary disease whose onset occurs due to the genetic makeup in the body. Since it is known that psoriasis has a close relationship with histocompatibility antigen (HLA), which exhibits polymorphism due to the variation of the HLA gene, it is clear that psoriasis is a hereditary disease. Psoriasis has a genetic component that makes certain people more likely to develop it. A family association exists in one out of three cases. It is not possible, however, to predict who will get psoriasis. Environmental factors may trigger the onset of psoriasis, even in people without an apparent family history of psoriasis. These triggers, which can cause the body to go from a very mild case to a severe case within days, may include emotional stress, injury to the skin, some types of infections and reaction to certain drugs, climates, or foods. [0006] Irrespective of what triggers it, once psoriasis begins, there are only remissions and relapses of varying degrees of intensity. There is no known cure, only possible control over the severity, but there are many different treatments, both topical and systemic, that can help ameliorate the symptoms (itching, flaking, and red patches) for periods of time. Experimentation is often required to find a treatment that works for a particular person. Some people who have psoriasis experience spontaneous remissions, but no one knows why this happens and they are unpredictable. Once a psoriasis outbreak occurs, the body will continue to utilize the nails, scalp, and skin to achieve balance. The psoriasis sufferer can achieve control and may even be spot free for years, but that is not considered "cured." [0007] Although psoriasis is rarely life-threatening, several hundred people in the United States alone die from complications caused by psoriasis each year. Primarily, such complications occur in relation to a severe, extensive form of psoriasis, such as generalized pustular psoriasis or erythrodermic psoriasis, where large areas of skin are shed. The skin plays an important role in regulating body temperature and serving as a barrier to infection. When a person's skin is compromised to such a great extent, secondary infections are possible. Fluid loss is a complicating factor in these serious forms of psoriasis, and a great strain is also placed on the circulatory system. [0008] Psoriasis has a physical impact on the skin, but it also affects people's feelings, behaviors, and experiences. Due to the characteristic formation of skin lesions and eruptions, psoriasis gives its victims an unfavorable psychological outlook on life. Recognizing and acknowledging the social implications of psoriasis is an important step toward learning to cope with the disease. Psoriasis can be a mildly annoying problem or can destroy the self-esteem and life of the victim. [0009] There is no known cure for psoriasis. Moreover, not all patients respond to or tolerate currently available therapies. New treatment options for psoriasis, with improved efficacy, safety, and side effect profiles, are needed.

SUMMARY OF THE INVENTION [0010] Among the several aspects of the invention is provided a method and a composition that may be employed to treat psoriasis. The method comprises administering to a subject a cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof. [ooil] In one embodiment, the cyclooxygenase-2 selective inhibitor is a member of the chromene class of compounds. For example, the chromene compound may be a compound of the formula:

[0012] wherein: [0013] n is an integer which is 0, 1 , 2, 3 or 4; [0014] G is O, S or NR^a; [0015] R^a is alkyl; [0016] R¹ is selected from the group consisting of H and aryl; [0017] R² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; [0018] R³ 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 [0019] each R⁴ is independently selected from the group consisting of 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 R⁴ together with the carbon atoms to which it is attached and the remainder of ring E forms a naphthyl radical. [0020] In another embodiment, the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or a prodrug thereof comprises a compound of the formula:

[0021] wherein: [0022] A is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings; [0023] Rι is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein Ri 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; [0024] R2 is methyl or amino; and [0025] R3 is selected from the group consisting of 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-alkyi-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl. [0026] Other aspects of the invention are described in more detail below.

ABBREVIATIONS AND DEFINITIONS [0027] The term "acyl" is a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such lower alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and trifluoroacetyl. [0028] The term "alkenyl" is a linear or branched radical having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. [0029] The terms "alkenyl" and "lower alkenyl" also are radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. The term "cycloalkyl" is a saturated carbocyclic radical having three to twelve carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. [0030] The terms "alkoxy" and "alkyloxy" are linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. [0031] The term "alkoxyalkyl" is an alkyl radical having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals. More preferred haloalkoxy radicals are "lower haloalkoxy" radicals having one to six carbon atoms and one or more halo radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. [0032] The term "alkoxycarbonyl" is a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are "lower alkoxycarbonyl" radicals with alkyl porions having 1 to 6 carbons. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. [0033] Where used, either alone or within other terms such as "haloalkyl", "alkylsulfonyl", "alkoxyalkyl" and "hydroxyalkyl", the term "alkyl" is a linear, cyclic or branched radical having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. [0034] The term "alkylamino" is an amino group that has been substituted with one or two alkyl radicals. Preferred are "lower N-alkylamino" radicals having alkyl portions having 1 to 6 carbon atoms. Suitable lower alkylamino may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. [0035] The term "alkylaminoalkyl" is a radical having one or more alkyl radicals attached to an aminoalkyl radical. [0036] The term "alkylaminocarbonyl" is an aminocarbonyl group that has been substituted with one or two alkyl radicals on the amino nitrogen atom. Preferred are "N- alkylaminocarbonyl" or "N,N-dialkylaminocarbonyl" radicals. More preferred are "lower N- alkylaminocarbonyl" "lower N,N-dialkylaminocarbonyl" radicals with lower alkyl portions as defined above. [0037] The terms "alkylcarbonyl", "arylcarbonyl" and "aralkylcarbonyl" include radicals having alkyl, aryl and aralkyl radicals, as defined above, attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and benzylcarbonyl. [0038] The term "alkylthio" is a radical containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. [0039] The term "alkylthioalkyl" is a radical containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkyl radicals are "lower alkylthioalkyl" radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkyl radicals include methylthiomethyl. [0040] The term "alkylsulfinyl" is a radical containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent -S(=O)- radical. More preferred alkylsulfinyl radicals are "lower alkylsulfinyl" radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. [0041] The term "alkynyl" is a linear or branched radical having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like. [0042] The term "aminoalkyl" is an alkyl radical substituted with one or more amino radicals. More preferred are "lower aminoalkyl" radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like. [0043] The term "aminocarbonyl" is an amide group of the formula -C(=O)NH₂. [0044] The term "aralkoxy" is an aralkyl radical attached through an oxygen atom to other radicals. [0045] The term "aralkoxyalkyl" is an aralkoxy radical attached through an oxygen atom to an alkyl radical. [0046] The term "aralkyl" is an aryl-substituted alkyl radical such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable. [0047] The term "aralkylamino" is an aralkyl radical attached through an amino nitrogen atom to other radicals. The terms "N-arylaminoalkyl" and "N-aryl-N-alkyl- aminoalkyl" are amino groups which have been substituted with one aryl radical or one aryl and one alkyl radical, respectively, and having the amino group attached to an alkyl radical. Examples of such radicals include N-phenylaminomethyl and N-phenyl-N- methylaminomethyl. [0048] The term "aralkylthio" is an aralkyl radical attached to a sulfur atom. [0049] The term "aralkylthioalkyl" is an aralkylthio radical attached through a sulfur atom to an alkyl radical. [0050] The term "aroyl" is an aryl radical with a carbonyl radical as defined above. Examples of aroyl include benzoyl, naphthoyl, and the like and the aryl in said aroyl may be additionally substituted. [0051] The term "aryl", alone or in combination, is 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" includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl. [0052] The term "arylamino" is an amino group, which has been substituted with one or two aryl radicals, such as N-phenylamino. The "arylamino" radicals may be further substituted on the aryl ring portion of the radical. [0053] The term "aryloxyalkyl" is a radical having an aryl radical attached to an alkyl radical through a divalent oxygen atom. [0054] The term "arylthioalkyl" is a radical having an aryl radical attached to an alkyl radical through a divalent sulfur atom. [0055] The term "carbonyl", whether used alone or with other terms, such as "alkoxycarbonyl", is -(C=O)-. [0056] The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", is -CO₂H. [0057] The term "carboxyalkyl" is an alkyl radical substituted with a carboxy radical. More preferred are "lower carboxyalkyl" which are lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. [0058] The term "cycloalkenyl" is a partially unsaturated carbocyclic radical having three to twelve carbon atoms. More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl. [0059] The term "cyclooxygenase-2 selective inhibitor" is a compound able to selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Typically, it includes compounds that have a cyclooxygenase-2 IC₅₀ of less than about 0.2 micro molar, and also have a selectivity ratio of cyclooxygenase-1 (COX-1) IC₅₀ to cyclooxygenase-2 (COX- 2) IC₅₀ of at least about 5, more typically of at least about 50, and even more typically, of at least about 100. Moreover, the cyclooxygenase-2 selective inhibitors as described herein have a cyclooxygenase-1 IC₅₀ of greater than about 1 micro molar, and more preferably of greater than 10 micro molar. The term "cyclooxygenase-2 selective inhibitor" also encompasses any isomer, pharmaceutically acceptable salt, ester, or prodrug thereof. Inhibitors of the cyclooxygenase pathway in the metabolism of arachidonic acid used in the present method may inhibit enzyme activity through a variety of mechanisms. By the way of example, and without limitation, the inhibitors used in the methods described herein may block the enzyme activity directly by acting as a substrate for the enzyme. [0060] The term "halo" is a halogen such as fluorine, chlorine, bromine or iodine. [0061] The term "haloalkyl" is a radical wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically included are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. "Lower haloalkyl" is a radical having 1-6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafiuoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. [0062] The term "heteroaryl" is an unsaturated heterocyclyl radical. Examples of unsaturated heterocyclyl radicals, also termed "heteroaryl" radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1 ,2,4-triazolyl, 1 H-1 ,2,3-triazolyl, 2H-1 ,2,3-triazolyl, etc.) tetrazolyl (e.g. 1 H- tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[1 ,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,5- oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1 ,2,4- thiadiazolyl, 1 ,3,4-thiadiazolyl, 1 ,2,5- thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term also includes radicals where heterocyclyl radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heterocyclyl group" may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino. [0063] The term "heterocyclyl" is a saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radical, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. [0064] The term "heterocyclylalkyl" is a saturated and partially unsaturated heterocyclyl-substituted alkyl radical, such as pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals, such as pyridyl methyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. [0065] The term "hydrido" is 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. [0066] The term "hydroxyalkyl" is a linear or branched alkyl radical having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. [0067] The term "pharmaceutically acceptable" is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product; that is the "pharmaceutically acceptable" material is relatively safe and/or non-toxic, though not necessarily providing a separable therapeutic benefit by itself. 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 physiologically acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like. [0068] The term "prodrug" refers to a chemical compound that can be converted into a therapeutic compound by metabolic or simple chemical processes within the body of the subject. For example, a class of prodrugs of cyclooxygenase-2 inhibitors is described in US Patent No. 5,932,598, herein incorporated by reference. [0069] The term "subject" for purposes of treatment includes any human or animal subject who is in need of such treatment. The subject can be a domestic livestock species, a laboratory animal species, a zoo animal or a companion animal. In one embodiment, the subject is a mammal. In another embodiment, the mammal is a human being. [0070] The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, is a divalent radical -SO₂-. "Alkylsulfonyl" is an alkyl radical attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The "alkylsulfonyl" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals. The terms "sulfamyl", "aminosulfonyl" and "sulfonamidyl" are NH₂O₂S-. [0071] The phrase "therapeutically-effective" is intended to qualify the amount of cyclooxygenase-2 selective inhibitor that will achieve the goal of improvement in disorder severity and the frequency of incidence over no treatment.

DESCRIPTION OF THE PREFERRED EMBODIMENTS [0072] The present invention provides compositions and methods for treating skin disorders comprising the administration to a subject of a therapeutically effective amount of a cyclooxygenase-2 selective inhibitor. The cyclooxygenase-2 selective inhibitor may be administered to a subject to treat psoriasis and other inflammation mediated skin disorders.

CYCLOOXYGENASE-2 SELECTIVE INHIBITORS [0073] A number of suitable cyclooxygenase-2 selective inhibitors or an isomer, a pharmaceutically acceptable salt, ester, or prodrug thereof may be employed in the composition of the current invention. In one embodiment, the cyclooxygenase-2 selective inhibitor can be, for example, the cyclooxygenase-2 selective inhibitor meloxicam.

[0074] In yet another embodiment, the cyclooxygenase-2 selective inhibitor is the cyclooxygenase-2 selective inhibitor, 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).

[0075] In still another embodiment the cyclooxygenase-2 selective inhibitor is a chromene compound that is a substituted benzopyran or a substituted benzopyran analog, and even more typically, selected from the group consisting of substituted benzothiopyrans, dihydroquinolines, dihydronaphthalenes or a compound having Formula / shown below and possessing, by way of example and not limitation, the structures disclosed in Table 1. Furthermore, benzopyran cyclooxygenase-2 selective inhibitors useful in the practice of the present methods are described in U.S. Patent No. 6,034,256 and 6,077,850 herein incorporated by reference in their entirety. [0076] In another embodiment, the cyclooxygenase-2 selective inhibitor is a chromene compound represented by Formula /:

[0077] wherein: [0078] n is an integer which is 0, 1 , 2, 3 or 4; [0079] G is O, S or NR^a; [0080] R^a is alkyl; [0081] R¹ is selected from the group consisting of H and aryl; [0082] R² is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; [0083] R³ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from the group consisting of alkylthio, nitro and alkylsulfonyl; and [0084] each R⁴ is independently selected from the group consisting of 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 R⁴ together with the carbon atoms to which it is attached and the remainder of ring E forms a naphthyl radical. [0085] The cyclooxygenase-2 selective inhibitor may also be a compound of Formula (I), [0086] wherein: [0087] n is an integer which is 0, 1 , 2, 3 or 4; [0088] G is O, S or NR^a; [0089] R^a is alkyl; [0090] R¹ is H; [0091] R² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; [0092] R³ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from the group consisting of alkylthio, nitro and alkylsulfonyl; and [0093] each R⁴ is independently 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 R⁴ together with the carbon atoms to which it is attached and the remainder of ring E forms a naphthyl radical. [0094] In a further embodiment, the cyclooxygenase-2 selective inhibitor may also be a compound of Formula (I), [0095] wherein: [0096] n is an integer which is 0, 1 , 2, 3 or 4; [0097] G is oxygen or sulfur; [0098] R¹ is H; [0099] R² is carboxyl, lower alkyl, lower aralkyl or lower alkoxycarbonyl; [0100] R³ is lower haloalkyl, lower cycloalkyl or phenyl; and [0101] each R⁴ is independently H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, 6-membered-nitrogen containing heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, or lower alkylcarbonyl; or R⁴ together with the carbon atoms to which it is attached and the remainder of ring E forms a naphthyl radical. [0102] The cyclooxygenase-2 selective inhibitor may also be a compound of Formula (I), [0103] wherein: [0104] n is an integer which is 0, 1 , 2, 3 or 4; [0105] G is oxygen or sulfur; [0106] R¹ is H; [0107] R² is carboxyl; [0108] R³ is lower haloalkyl; and [0109] each R⁴ is independently H, 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, or lower alkylcarbonyl; or wherein R⁴ together with the carbon atoms to which it is attached and the remainder of ring E forms a naphthyl radical. [Olio] The cyclooxygenase-2 selective inhibitor may also be a compound of Formula (I), [0111] wherein: [0112] n is an integer which is 0, 1 , 2, 3 or 4; [0113] G is oxygen or sulfur; [0114] R¹ is H; [0115] R² is carboxyl; [0116] R³ is fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, or trifluoromethyl; and [0117] each R⁴ is independently H, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, ferf-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-dimethylaminosulfonyI, aminosulfonyl, N- methylaminosulfonyl, N-ethylsulfonyl, 2,2-dimethylethyIaminosulfonyl, N,N- dimethylaminosulfonyl, N-(2-methylpropyl)aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl or phenyl; or wherein R⁴ together with the carbon atoms to which it is attached and the remainder of ring E forms a naphthyl radical. [0118] The cyclooxygenase-2 selective inhibitor may also be a compound of Formula (I), [0119] wherein: [0120] n is an integer which is 0, 1 , 2, 3 or 4; [0121] G is oxygen or sulfur; [0122] R¹ is H; [0123] R² is carboxyl; [0124] R³ is trifluoromethyl or pentafluoroethyl; and [0125] each R⁴ is independently H, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, terf-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, or phenyl; or wherein R⁴ together with the carbon atoms to which it is attached and the remainder of ring E forms a naphthyl radical. [0126] In yet another embodiment, the cyclooxygenase-2 selective inhibitor used in connection with the method(s) of the present invention can also be a compound having the structure of Formula (I), [0127] wherein: [0128] n is 4; [0129] G is O or S; [0130] R¹ is H; [0131] R² is CO₂H; [0132] R³ is lower haloalkyl; [0133] a first R⁴ corresponding to R⁹ is hydrido or halo; [0134] a second R⁴ corresponding to R¹⁰ is H, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5- membered nitrogen-containing heterocyclosulfonyl, or 6- membered nitrogen-containing heterocyclosulfonyl; [0135] a third R⁴ corresponding to R¹¹ is H, lower alkyl, halo, lower alkoxy, or aryl; and [0136] a fourth R⁴ corresponding to R¹² is H, halo, lower alkyl, lower alkoxy, or aryl; [0137] wherein Formula (I) is represented by Formula (la):

[0138] The cyclooxygenase-2 selective inhibitor used in connection with the method(s) of the present invention can also be a compound having the structure of Formula (la), [0139] wherein: [0140] G is O or S; [0141] R³ is trifluoromethyl or pentafluoroethyl; [0142] R⁹ is H, chloro, or fluoro; [0143] R¹⁰ is H, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropyiaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl, or morpholinosulfonyl; [0144] R¹¹ is H, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, or phenyl; and [0145] R¹² is H, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, or phenyl. [0146] Examples of exemplary chromene cyclooxygenase-2 selective inhibitors are depicted in Table 1 below. TABLE 1 EXAMPLES OF CHROMENE CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS

[0147] In a further embodiment, the cyclooxygenase-2 selective inhibitor is selected from the class of tricyclic cyclooxygenase-2 selective inhibitors represented by the general structure of Formula //,

[0148] wherein: [0149] A is selected from the group consisting of a partially unsaturated or unsaturated heterocyclyl ring and a partially unsaturated or unsaturated carbocyclic ring; [0150] Ri is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein Ri 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; [0151] R₂ is methyl or amino; and [0152] R₃ is selected from the group consisting of 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, and N-alkyl-N-arylaminosulfonyl. [0153] In another embodiment, the cyclooxygenase-2 selective inhibitor represented by the above Formula // is selected from the group of compounds illustrated in Table 2, consisting of celecoxib (B-18; U.S. Patent No. 5,466,823; CAS No. 169590-42-5), valdecoxib (B-19; U.S. Patent No. 5,633,272; CAS No. 181695-72-7), deracoxib (B-20; U.S. Patent No. 5,521 ,207; CAS No. 169590-41-4), rofecoxib (B-21 ; CAS No. 162011-90- 7), etoricoxib (MK-663; B-22; PCT publication WO 98/03484), tilmacoxib (JTE-522; B-23; CAS No. 180200-68-4), and cimicoxib (UR-8880; B23a; CAS No. 265114-23-6).

TABLE 2 EXAMPLES OF TRICYCLIC CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS

[0154] In yet another embodiment, the cyclooxygenase-2 selective inhibitor parecoxib (B-24, U.S. Patent No. 5,932,598, CAS No. 198470-84-7), which is a therapeutically effective prodrug of the tricyclic cyclooxygenase-2 selective inhibitor valdecoxib, B-19, may be advantageously employed as a source of a cyclooxygenase inhibitor (US 5,932,598, herein incorporated by reference).

[0155] One form of parecoxib is sodium parecoxib. [0156] In another embodiment of the invention, the compound having the formula B-25 that has been previously described in International Publication number WO 00/24719 (which is herein incorporated by reference) is another tricyclic cyclooxygenase-2 selective inhibitor that may be advantageously employed.

[0157] Another cyclooxygenase-2 selective inhibitor that is useful in connection with the method(s) of the present invention is N-(2-cyclohexyloxy nitrophenyl)-methane sulfonamide (NS-398) having a structure shown below as B-26.

[0158] In yet a further embodiment, the cyclooxygenase-2 selective inhibitor used in connection with the method(s) of the present invention can be selected from the class of phenylacetic acid derivative cyclooxygenase-2 selective inhibitors represented by the general structure of Formula (III):

[0159] wherein: [0160] R¹⁶ is methyl or ethyl; [0161] R¹⁷ is chloro or fluoro; [0162] R¹⁸ is hydrogen or fluoro; [0163] R¹⁹ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; [0164] R²⁰ is hydrogen or fluoro; and [0165] R²¹ is chloro, fluoro, trifluoromethyl or methyl, provided, however, that each of R¹⁷, R¹⁸, R²⁰ and R²¹ is not fluoro when R¹⁶ is ethyl and R¹⁹ is H. [0166] Another phenylacetic acid derivative cyclooxygenase-2 selective inhibitor used in connection with the method(s) of the present invention is a compound that has the designation of COX 189 (lumiracoxib; B-211) and that has the structure shown in Formula

(III), [0167] wherein: [0168] R¹⁶ is ethyl; [0169] R¹⁷ and R¹⁹ are chloro; [0170] R¹⁸ and R²⁰ are hydrogen; and [0171] R²¹ is methyl. [0172] In yet another embodiment, the cyclooxygenase-2 selective inhibitor is represented by Formula (IV):

[0173] wherein: [0174] X is O or S; [0175] J is a carbocycle or a heterocycle; [0176] R²² is NHSO₂CH₃ or F; [0177] R²³ is H, NO₂, or F; and [0178] R²⁴ is H, NHSO₂CH₃, or (SO₂CH₃)C₆H₄. [0179] According to another embodiment, the cyclooxygenase-2 selective inhibitors used in the present method(s) have the structural Formula (V): Q¹

[0180] wherein: [0181] T and M are independently phenyl, naphthyl, 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; [0182] R²⁵, R²⁶, R²⁷, and R²⁸ are independently hydrogen, halogen, lower alkyl radical having from 1 to 6 carbon atoms, lower haloalkyl radical having from 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or [0183] R²⁵ and R²⁶, together with the carbon atom to which they are attached, form a carbonyl or a saturated hydrocarbon ring having from 3 to 7 carbon atoms; or [0184] R²⁷and R²⁸, together with the carbon atom to which they are attached, form a carbonyl or a saturated hydrocarbon ring having from 3 to 7 carbon atoms; [0185] Q¹, Q², L¹ or L² are independently hydrogen, halogen, lower alkyl having from 1 to 6 carbon atoms, trifluoromethyl, lower methoxy having from 1 to 6 carbon atoms, alkylsulfinyl or alkylsulfonyl; and at least one of Q¹, Q², L¹ or L² is in the para position and is -S(O)_n-R, wherein n is 0, 1 , or 2 and R is a lower alkyl radical having 1 to 6 carbon atoms or a lower haloalkyl radical having from 1 to 6 carbon atoms, or an -SO₂NH₂; or Q¹ and Q² together form methylenedioxy; or L¹ and L² together form methylenedioxy. [0186] In another embodiment, the compounds N-(2-cyclohexyIoxy nitrophenyl)methane sulfonamide, and (E)-4-[(4-methylphenyl)(tetrahydro-2-oxo-3- furanylidene)methyl]benzenesulfonamide having the structure of Formula (V) are employed as cyclooxygenase-2 selective inhibitors. [0187] In a further embodiment, compounds that are useful for the cyclooxygenase-2 selective inhibitor used in connection with the method(s) of the present invention, the structures for which are set forth in Table 3 below, include, but are not limited to: [0188] 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-27); [0189] 6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-28); [0190] 8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-29); [0191] 6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-30); [0192] 2-trifluoromethyl-3H-naphtho[2,1-b]pyran-3-carboxylic acid (B-31); [0193] 7-(1 ,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

(B-32); [0194] 6-bromo-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-33); [0195] 8-chloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-34); [0196] 6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

(B-35); [0197] 5,7-dichloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-36); [0198] 8-phenyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-37); [0199] 7,8-dimethyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-38); [0200] 6,8-bis(dimethylethyI)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-39); [0201] 7-(1 -methylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid

(B-40); [0202] 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-41 ); [0203] 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

(B-42); [0204] 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

(B-43), [0205] 6-chloro-7-phenyI-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

(B-44) [0206] 6,7-dichloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-45); [0207] 6,8-dichloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-46); [0208] 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

(B-47) [0209] 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

(B-48) [0210] 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

(B-49) [0211] 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

(B-50) [0212] 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

(B-51 ) [0213] 8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-52); [0214] 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-53); [0215] 6-chloro-8-fluoro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-54); [0216] 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-55); [0217] 6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid (B-56); [0218] 6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid (B-57); [0219] 6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-58); [0220] 6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-59); [0221] 6-[(1 ,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid (B-60); [0222] 6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid (B-61); [0223] 6-methylsulfonyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-62); [0224] 8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid (B-63); [0225] 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-64); [0226] 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-65); [0227] 8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-66); [0228] 6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-67); [0229] 6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-68); [0230] 6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid (B-69); [0231] 6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid (B-70); [0232] 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-71 ); [0233] 7-(1 ,1-dimethylethyl)-2-pentafluoroethyl-2H-1-benzopyran-3-carboxylic acid (B-72); [0234] 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid (B-73); [0235] 3-[(3-chloro-phenyl)-(4-methanesulfonyl-phenyI)-methylene]-dihydro- furan-2-one (B-74); [0236] 8-acetyl-3-(4-fluorophenyI)-2-(4-methylsulfonyl)phenyl-imidazo (1 ,2-a) pyridine (B-75); [0237] 5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2-(5H)-furanone (B-76); [0238] 5-(4-fluorophenyl)-1-[4-(methylsuIfonyl)phenyl]-3-(trifluoromethyl)pyrazole (B-77); [0239] 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1 -phenyl-3- (trifluoromethyl)pyrazole (B-78); [0240] 4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1 H-pyrazol-1-yl) benzenesulfonamide (B-79); [0241] 4-(3,5-bis(4-methylphenyl)-1 H-pyrazol-1-yl)benzenesulfonamide (B-80); [0242] 4-(5-(4-chlorophenyl)-3-phenyl-1 H-pyrazol-1-yl)benzene sulfonamide (B- 81); [0243] 4-(3,5-bis(4-methoxyphenyl)-1 H-pyrazol-1-yl)benzenesulfonamide (B-82); [0244] 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1 H-pyrazol-1-yl) benzenesulfonamide (B-83); [0245] 4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1 H-pyrazol-1-yl) benzenesulfonamide (B-84); [0246] 4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1 H-pyrazol-1-yl) benzenesulfonamide (B-85); [0247] 4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)benzenesulfonamide (B-86); [0248] 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-87); [0249] 4-[5-phenyl-3-(trifluoromethyl)-1 H-pyrazol-1-yl] benzenesulfonamide (B- 88); [0250] 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-89); [0251] 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-90); [0252] 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-91 ); [0253] 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-92); [0254] 4-[4-chloro-5-(4-chIorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-93); [0255] 4-[3-(difluoromethyl)-5-(4-methylphenyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-94); [0256] 4-[3-(difluoromethyl)-5-phenyl-1 H-pyrazol-1 -yl] benzenesulfonamide (B- 95); [0257] 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-96); [0258] 4-[3-cyano-5-(4-fluorophenyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B- 97); [0259] 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-98); [0260] 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-99); [0261] 4-[4-chloro-5-phenyl-1 H-pyrazol-1 -yl]benzenesulfonamide (B-100); [0262] 4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-101); [0263] 4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl] benzenesulfonamide (B-102); [0264] 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene (B- 103); [0265] 4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl] benzenesulfonamide (B- 104); [0266] 6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[3.4]oct-6-ene (B- 105); [0267] 5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl) phenyl]spiro [2.4]hept- 5-ene (B-106); [0268] 4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl] benzenesulfonamide (B-107); [0269] 5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro [2.4]hept-5-ene (B-108); [0270] 5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl] spiro[2.4]hept-5- ene (B-109); [0271] 4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl] benzenesulfonamide (fil l 0); [0272] 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonyl phenyl)thiazole (B-111 ); [0273] 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonyl phenyl)thiazole (B-112); [0274] 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole (B-113); [0275] 4-(4-fluorophenyl)-5-(4-methylsulfonyIphenyl)-2-trifluoromethylthiazole (B- 114); [0276] 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole (B- 115); [0277] 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole (B- 116); [0278] 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino) thiazole (B-117); [0279] 2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-(methyl sulfonyl)phenyl]thiazole (B-118); [0280] 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole (B- 119); [0281] 1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3- yl]benzene (B-120); [0282] 4-[4-(4-fluorophenyl)-1 ,1-dimethylcyclopenta-2,4-dien-3-yl] benzenesulfonamide (B-121); [0283] 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6-diene (B-122); [0284] 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl] benzenesulfonamide (B-123); [0285] 6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)phenyl]-pyridine-3- carbonitrile (B-124); [0286] 2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyI)phenyl]-pyridine-3- carbonitrile (B-125); [0287] 6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyl-pyridine-3- carbonitrile (B-126); [0288] 4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyI)-1 H-imidazol-1-yI] benzenesulfonamide (B-127); [0289] 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl] benzenesulfonamide (B-128); [0290] 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl] benzenesulfonamide (B-129); [0291] 3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1 H-imidazol-2-yl] pyridine (B-130); [0292] 2-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H-imidazol-2-yl] pyridine (B-131 ); [0293] 2-methyl-4-[1-[4-(methylsulfonyl)phenyI-4-(trifluoromethyl)-1 H-imidazol-2- yl]pyridine (B-132); [0294] 2-methyl-6-[1-[4-(methyIsulfonyl)phenyl-4-(trifluoromethyl)-1 H-imidazol-2- yl]pyridine (B-133); [0295] 4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl] benzenesulfonamide (B-134); [0296] 2-(3,4-difluorophenyl)-1 -[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1 H- imidazole (B-135); [0297] 4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1-yl] benzenesulfonamide (B-136); [0298] 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1 H-imidazole (B- 137); [0299] 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1 H-imidazole (B- 138); [0300] 2-(4-chlorophenyl)-4-(4-fluorophenyl)-1 -[4-(methylsulfonyl)phenyl]-1 H- imidazole (B-139); [0301] 2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-4-(trifluoro methyl)-1 H-imidazole (B-140); [0302] 1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1 H-imidazole (B- 141); [0303] 2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyI]-4-trifluoromethyl-1 H- imidazole (B-142); [0304] 4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1-yl] benzenesulfonamide (B-143); [0305] 2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4- (trifluoromethyl)-l H-imidazole (B-144); [0306] 4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1 -yl] benzenesulfonamide (B-145); [0307] 2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H- imidazole (B-146); [0308] 4-[2-(3-methylphenyl)-4-trifluoromethyl-1 H-imidazol-1 -yl] benzene sulfonamide (B-147); [0309] 1 -[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-1 H- imidazole (B-148); [0310] 4-[2-(3-chlorophenyl)-4-trifluoromethyl-1 H-imidazol-1 -yl] benzenesulfonamide (B-149); [0311] 4-[2-phenyl-4-trifluoromethyl-1 H-imidazol-1 -yl] benzenesulfonamide (B- 150); [0312] 4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1 H-imidazol-1 - yljbenzenesulfonamide (B-151); [0313] 1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)- 1H-pyrazole (B-152); [0314] 4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl] benzenesulfonamide (B-153); [0315] N-phenyl-[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5- (trifluoromethyl)-l H-pyrazol-1 -yl]acetamide (B-154); [0316] ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)- 1 H-pyrazol-1 -yljacetate (B-155); [0317] 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1 -(2-phenylethyl)-1 H- pyrazole (B-156); [0318] 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-5- (trifluoromethyl)pyrazole (B-157); [0319] 1 -ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)- 1 H-pyrazole (B-158); [0320] 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyI-1 H- imidazole (B-159); [0321] 4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1H- imidazole (B-160); [0322] 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine (B-161 ); [0323] 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine (B-162); [0324] 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6- (trifluoromethyl)pyridine (B-163); [0325] 2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine (B-164); [0326] 4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl] benzenesulfonamide (B-165); [0327] 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene (B-166); [0328] 5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole (B-167); [0329] 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide (B-168); [0330] 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide (B-169); [0331] 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide (B-170); [0332] 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide(B-171); [0333] 1-[2-(4-fluorophenyl)cycIopenten-1-yl]-4-(methylsulfonyl) benzene (B- 172); [0334] 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl) benzene (B-173); [0335] 1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl) benzene (B- 174); [0336] 1-[2-(2,4-dichlorophenyl)cyclopenten-1-yI]-4-(methylsulfonyl) benzene (B- 175); [0337] 1 -[2-(4-trifluoromethylphenyl)cyclopenten-1 -yl]-4-(methylsulfonyl) benzene (B-176); [0338] 1-[2-(4-methylthiophenyl)cyclopenten-1-yI]-4-(methyl sulfonyl)benzene (B- 177); [0339] 1 -[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1 -yl]-4-(methylsulfonyl) benzene (B-178); [0340] 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1 -yl]benzene sulfonamide (B-179); [0341] 1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl) benzene (B-180); [0342] 4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]benzene sulfonamide (B-181 ); [0343] 4-[2-(4-fluorophenyl)cyclopenten-1-yI]benzenesulfonamide (B-182); [0344] 4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide (B-183); [0345] 1-[2-(4-methoxyphenyl)cycIopenten-1-yl]-4-(methyIsulfonyl) benzene (B- 184); [0346] 1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl) benzene (B- 185); [0347] 4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl] benzenesulfonamide (B-186); [0348] 1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl) benzene (B-187); [0349] 4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl] benzenesulfonamide (B- 188); [0350] 4-[2-(2-methylpyridin-5-yl)cyclopenten-1 -yl]benzenesulfonamide (B-189); [0351] ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyl]oxazol-2-yl]-2- benzyl-acetate (B-190); [0352] 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl] acetic acid (B-191); [0353] 2-(ferf-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl] oxazole (B-192); [0354] 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyIoxazole (B-193); [0355] 4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole (B-194); [0356] 4-[5-(3-fluoro-4-methoxyphenyl)-2-trifIuoromethyl-4-oxazoIyl] benzenesulfonamide (B-195); [0357] 6-chloro-7-(1 , 1 -dimethylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid (B-196); [0358] 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-197); [0359] 5,5-dimethyl-3-(3-fluorophenyl)-4-methylsulfonyl-2(5H)-furanone (B-198); [0360] 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxyIic acid (B-199); [0361] 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzene sulfonamide (B-200); [0362] 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzene sulfonamide (B-201 ); [0363] 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyI)-1 H-pyrazol-1 - yl]benzenesulfonamide (B-202); [0364] 3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazol-2-yl]pyridine (B-203); [0365] 2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazol-2- yl]pyridine (B-204); [0366] 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 -yl] benzenesulfonamide (B-205); [0367] 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (B-206); [0368] 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide (B-207); [0369] [2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzene sulfonamide (B-208); [0370] 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide (B-209); [0371] 4-[5-(2-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl] benzenesulfonamide (B-210); [0372] [2-(2-chloro-6-f luoro-phenylamino)-5-methyl-phenyl]-acetic acid or COX 189 (lumiracoxib; B-211); [0373] N-(4-Nitro-2-phenoxy-phenyl)-methanesulfonamide or nimesulide (B- 212); [0374] N-[6-(2,4-difluoro-phenoxy)-1-oxo-indan-5-yl]-methanesulfonamide or flosulide (B-213); [0375] N-[6-(2,4-Difluoro-phenyIsulfanyl)-1 -oxo-1 H-inden-5-yl]- methanesulfonamide, sodium salt (B-214); [0376] N-[5-(4-fluoro-phenylsulfanyl)-thiophen-2-yl]-methanesulfonamide (B- 215); [0377] 3-(3,4-Difluoro-phenoxy)-4-(4-methanesulfonyl-phenyl)-5-methyl-5-(2,2,2- trifluoro-ethyl)-5H-furan-2-one (B-216); [0378] (5Z)-2-amino-5-[[3,5-bis(1 ,1-dimethylethyl)-4-hydroxyphenyl] methylene]- 4(5H)-thiazolone (B-217); [0379] CS-502 (B-218); [0380] LAS-34475 (B-219); [0381] LAS-34555 (B-220); [0382] S-33516 (B-221 ); [0383] SD-8381 (B-222); [0384] L-783003 (B-223); [0385] N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]- methanesulfonamide (B-224); [0386] D-1367 (B-225); [0387] L-748731 (B-226); [0388] (6aR, 10aR)-3-(1 , 1 -dimethylheptyl)-6a,7, 10, 10a-tetrahydro-1 -hydroxy-6,6- dimethyl-6H-dibenzo[b,d]pyran-9-carboxylic acid (B-227); [0389] CGP-28238 (B-228); [0390] 4-[[3,5-bis(1 ,1-dimethylethyl)-4-hydroxyphenyl]methylene] dihydro-2- methyl-2H-1 ,2-oxazin-3(4H)-one or BF-389 (B-229); [0391] GR-253035 (B-230); [0392] 6-dioxo-9H-purin-8-yl-cinnamic acid (B-231); [0393] S-2474 (B-232); [0394] 4-[4-(methyl)-sulfonyl)phenyl]-3-phenyl-2(5H)-furanone; [0395] 4-(5-methyl-3-phenyl-4-isoxazolyl); [0396] 2-(6-methylpyrid-3-yl)-3-(4-methylsulfonylphenyl)-5-chloropyridine; [0397] 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]; [03 8] N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]; [03 9] 4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide; [0400] (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid; [0401] 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methyl sulfonyl)phenyl]-3(2H)-pyridzainone; [0402] 2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid; [0403] 6-chloro-7-(1 ,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid; and [0404] [2-(2,4-dichloro-6-ethyl-3,5-dimethyl-phenylamino)-5-propyl-phenyl]-acetic acid.

TABLE 3 EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS

acid;

acid;

acid;

acid;

acid;

acid;

acid;

acid;

acid;

acid;

acid;

acid;

[0405] The cyclooxygenase-2 selective inhibitor employed in the present invention can exist in tautomeric, geometric or stereoisomeric forms. Generally speaking, suitable cyclooxygenase-2 selective inhibitors that are in tautomeric, geometric or stereoisomeric forms are those compounds that inhibit cyclooxygenase-2 activity by about 25%, more typically by about 50%, and even more typically, by about 75% or more when present at a concentration of 100 μM or less. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, l-isomers, the racemic mixtures thereof and other mixtures thereof. Pharmaceutically acceptable salts of such tautomeric, geometric or stereoisomeric forms are also included within the invention. The terms "cis" and "trans", as used herein, denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond ("cis") or on opposite sides of the double bond ("trans"). Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or "E" and "Z" geometric forms. Furthermore, some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures or R and S forms for each stereocenter present. [0406] The cyclooxygenase-2 selective inhibitors utilized in the present invention may be in the form of free bases or pharmaceutically acceptable acid addition salts thereof. The term "pharmaceutically-acceptable salts" are salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt may vary, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds for use in the present methods may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of use in the present methods include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound of any Formula set forth herein. [0407] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage of the cyclooxygenase-2 selective inhibitor will vary depending upon the patient and the particular mode of administration. In general, the pharmaceutical compositions may contain a cyclooxygenase-2 selective inhibitor in the range of about 0.1 to 2000 mg, more typically, in the range of about 0.5 to 500 mg and still more typically, between about 1 and 200 mg. A daily dose of about 0.01 to 100 mg/kg body weight, or more typically, between about 0.1 and about 50 mg/kg body weight and even more typically, from about 1 to 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to about four doses per day. [0408] In one embodiment, when the cyclooxygenase-2 selective inhibitor comprises rofecoxib, it is typical that the amount used is within a range of from about 0.15 to about 1.0 mg/day/kg, and even more typically, from about 0.18 to about 0.4 mg/day/kg. [0409] In still another embodiment, when the cyclooxygenase-2 selective inhibitor comprises etoricoxib, it is typical that the amount used is within a range of from about 0.5 to about 5 mg/day/kg, and even more typically, from about 0.8 to about 4 mg/day/kg. [0410] Further, when the cyclooxygenase-2 selective inhibitor comprises celecoxib, it is typical that the amount used is within a range of from about 1 to about 20 mg/day/kg, even more typically, from about 1.4 to about 8.6 mg/day/kg, and yet more typically, from about 2 to about 3 mg/day/kg. [0411] When the cyclooxygenase-2 selective inhibitor comprises valdecoxib, it is typical that the amount used is within a range of from about 0.1 to about 5 mg/day/kg, and even more typically, from about 0.8 to about 4 mg/day/kg. [0412] In a further embodiment, when the cyclooxygenase-2 selective inhibitor comprises parecoxib, it is typical that the amount used is within a range of from about 0.1 to about 5 mg/day/kg, and even more typically, from about 1 to about 3 mg/day/kg. [0413] 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 and from Goodman & Goldman's The Pharmacological Basis of Therapeutics, Tenth Edition (2001), Appendix II, pp. 475-493.

INDICATIONS TO BE TREATED [0414] The composition comprising a therapeutically effective amount of a cyclooxygenase-2 selective inhibitor may be employed to treat psoriasis in subjects having varying degrees of disease severity. Generally speaking, psoriasis is divided into three degrees of severity: mild, moderate, and severe. About 75 percent to 80 percent of subjects with psoriasis have what is considered mild disease, and about 20 percent to 25 percent have moderate to severe psoriasis. The physical measure of severity is based on how much skin on the body is affected by psoriasis. As a general rule, the psoriatic arthritisn of the hand represents 1 percent of the body's surface. Severity can also hinge on how psoriasis affects a subject's quality of life. By way of example, if psoriasis covers only a small area, yet is serious enough to be disabling--for example, bad psoriasis of the hands or feet--, it could be considered a severe case of the disease. [0415] In one aspect of the invention, the composition is administered to a subject having mild psoriasis. Mild psoriasis is typically defined as a subject having psoriasis on less than 2 percent of their body. Generally, isolated psoriatic arthritistches of psoriasis may be found on the knees, elbows, scalp, hands and feet of subjects having mild psoriasis. [0416] In another aspect of the invention, the composition is administered to a subject having moderate psoriasis. Moderate psoriasis is defined as affecting between 2 and 10 percent of the body's surface. Typically moderate psoriasis may appear on the arms, the legs, torso, scalp, and other areas. [0417] In still another aspect of the invention, the composition is administered to a subject having severe psoriasis. Severe psoriasis typically covers more than 10 percent of a subject's body. Extensive areas of skin may be covered with psoriasis plaques or pustules, or widespread erythrodermic psoriasis can cause severe peeling of the skin. Moreover, subjects with severe psoriasis are more likely to develop psoriatic arthritis. [0418] In addition, the composition of the invention may be employed to treat a number of different types of psoriasis. In one aspect of the invention, the composition is utilized to treat psoriasis vulgaris, commonly known as plaque psoriasis. Plaque psoriasis is the most typical form of the disease, affecting nearly four out of five people with psoriasis. It can and often does appear on a number of different skin surfaces, although the knees, elbows, scalp, trunk, and nails are the most common locations. As the name implies, plaque psoriasis is often characterized by the formation of several "plaques," or "legions," which are well-defined psoriatic arthritistches of red, raised skin. Often times, a flaky, silvery-white scale will develop on top of the plaques. The scale is composed of dead skin cells that eventually come loose and sheds constantly from the plaques. Skin affected with plaque psoriasis, therefore, is generally very dry, and other possible symptoms include skin psoriatic arthritisin, itching, and cracking. [0419] Another aspect of the invention comprises administering the composition to a subject having guttate psoriasis. Guttate psoriasis is characterized by small dot-like lesions that resembles small, red, individual drops on the. These lesions generally appear on the trunk and limbs, and sometimes on the scalp, and they are usually not as thick or as scale-covered as plaque psoriasis. Guttate psoriasis often starts in childhood or young adulthood, and it may be triggered by an infection of some sort. [0420] A further aspect of the invention comprises administering the composition to a subject having inverse psoriasis, also commonly known as flexural psoriasis. This type of the disease appears as smooth, dry areas of skin that are red and inflamed but do not have the scaling associated with plaque psoriasis. It typically appears in the armpits, groin, under the breasts and in other skin folds around the genitals and buttocks. [0421] In yet another aspect of the invention, the composition is used to treat a subject having erythrodermic psoriasis. Erythrodermic psoriasis is a psoriatic arthritisrticularly inflammatory form of psoriasis characterized by intense sloughing and inflammation of the skin. It typically involves erythma (reddening) and exfoliation (shedding) of the skin, which are often accompsoriatic arthritisnied by severe itching and psoriatic arthritisin. Swelling may also develop. Generally speaking, erythrodermic psoriasis most commonly is associated with subjects that have unstable plaque psoriasis, where lesions are not clearly defined. [0422] In still another aspect of the invention, the composition is employed to treat a subject having pustular psoriasis. Pustular psoriasis is characterized by weeping lesions, intense scaling, and typically spreads over wide areas of the body. In this relatively rare form of the disease, widespread areas of reddened skin (erythema) develop, and the skin becomes acutely psoriatic arthritisinful and tender and pustules, blisters of non-infectious pus, may appear on the skin, dry, and then reappear in repeated cycles lasting several days. [0423] Yet a further aspect of the invention comprises administering the composition to a subject having psoriatic arthritis. Generally speaking, psoriatic arthritis is a specific type of arthritis that develops in approximately 20 percent of subjects who have psoriasis. While psoriatic arthritis primarily involves the distal interphalangeal joints of fingers or toes, it may also affect the wrists, knees, ankles, lower back and neck. Asymmetric involvement of large and small joints, as well as of sacroiliac joints and spine, is also quite common. Psoriatic arthritis can at times be quite destructive, progressing to chronic arthritis and arthritis mutilans, with extensive destruction of large and small joints. The exact cause of the disease is unknown, although interplay of immune, genetic, and environmental factors are suspected. Psoriatic arthritis can start slowly with mild symptoms, or it can develop quickly. Left untreated, psoriatic arthritis can be a progressively disabling disease. A number of different types of psoriatic arthritis can be treated by the composition of the invention. In one embodiment, the psoriatic arthritis is symmetric arthritis. In another embodiment, the psoriatic arthritis is asymmetric arthritis. In still another embodiment, the psoriatic arthritis is spondylitis. In yet another embodiment, the psoriatic arthritis is arthritis mutilans.

Claims

WHAT IS CLAIMED IS:

1. A method for treating psoriasis in a subject, the method comprising administering to the subject a therapeutically effective amount of a cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof, wherein the psoriasis is selected from the group consisting of psoriasis vulgaris, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, pustular psoriasis, and psoriatic arthritis and wherein the cyclooxygenase-2 selective inhibitor is a compound of the formula:

wherein: n is an integer which is 0, 1 , 2, 3 or 4; G is O, S or NR^a; R^a is alkyl; R¹ is selected from the group consisting of H and aryl; R² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; R³ 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 each R⁴ is independently selected from the group consisting of 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 R⁴ together with the carbon atoms to which it is attached and the remainder of ring E forms a naphthyl radical.

2. The method of claim 1 wherein: R¹ is H; R² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; R³ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl each is independently optionally substituted with one or more radicals selected from the group consisting of alkylthio, nitro and alkylsulfonyl; and each R⁴ is independently 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 R⁴ together with ring E forms a naphthyl radical.

3. The method of claim 1 wherein: G is oxygen or sulfur; R¹ is H; R² is carboxyl, lower alkyl, lower aralkyl or lower alkoxycarbonyl; R³ is lower haloalkyl, lower cycloalkyl or phenyl; and each R⁴ is H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, 6- membered-nitrogen containing heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, or lower alkylcarbonyl; or wherein R⁴ together with the carbon atoms to which it is attached and the remainder of ring E forms a naphthyl radical.

4. The method of claim 1 wherein: R² is carboxyl; R³ is lower haloalkyl; and each R⁴ is H, 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, or lower alkylcarbonyl; or wherein R⁴ together with ring E forms a naphthyl radical.

5. The method of claim 1 wherein: R³ is fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, or trifluoromethyl; and each R⁴ is H, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N,N-dimethylamino, N,N- diethylamino, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N-(2- furylmethyl)aminosulfonyl, nitro, N,N-dimethylaminosulfonyl, aminosulfonyl, N- methylaminosulfonyl, N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl, N,N- dimethylaminosulfonyl, N-(2-methylpropyl)aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl or phenyl; or wherein R⁴ together with the carbon atoms to which it is attached and the remainder of ring E forms a naphthyl radical.

6. The method of claim 1 wherein the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof comprises a compound of the formula

wherein: G is oxygen or sulfur; R⁸ is trifluoromethyl or pentafluoroethyl; R⁹ is H, chloro, or fluoro; R¹⁰ is H, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl, or morpholinosulfonyl; R¹¹ is H, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, or phenyl; and R¹² is H, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, or phenyl.

7. A method for treating psoriasis in a subject, the method comprising administering to the subject a therapeutically effective amount of a cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof, wherein the psoriasis is selected from the group consisting of psoriasis vulgaris, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, pustular psoriasis, and psoriatic arthritis and wherein the cyclooxygenase-2 selective inhibitor is a compound of the formula:

wherein: A is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings; Ri is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein Ri 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; R₂ is methyl or amino; and R₃ is selected from the group consisting of 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, and N-alkyl-N-arylaminosulfonyl.

8. The method of claim 7 wherein A is a ring substituent selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A is optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl.

9. A method for treating psoriasis in a subject, the method comprising administering to the subject a therapeutically effective amount of a cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof, wherein the psoriasis is selected from the group consisting of psoriasis vulgaris, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, pustular psoriasis, and psoriatic arthritis and wherein the cyclooxygenase-2 selective inhibitor is a compound of the formula:

wherein: R¹⁶ is methyl or ethyl; R¹⁷ is chloro or fluoro; R¹⁸ is hydrogen or fluoro; R¹⁹ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; R²⁰ is hydrogen or fluoro; and R²¹ is chloro, fluoro, trifluoromethyl or methyl, provided that each of R ,1"7, _D R18 ,

is not fluoro when R .1^I6^D is ethyl and

R¹⁹ is H.

10. The method of claim 9 wherein: R¹⁶ is ethyl; R¹⁷ and R¹⁹ are chloro; R >18 and R ϊ20 are hydrogen; and R²¹ is methyl.

11. The method of any of claims 1 , 7 or 9 wherein the psoriasis is psoriasis vulgaris.

12. The method of any of claims 1 , 7 or 9 wherein the psoriasis is guttate psoriasis.

13. The method of any of claims 1 , 7 or 9 wherein the psoriasis is inverse psoriasis.

14. The method of any of claims 1 , 7 or 9 wherein the psoriasis is erythrodermic psoriasis.

15. The method of any of claims 1 , 7 or 9 wherein the psoriasis is pustular psoriasis.