WO2005097110A1 - Monotherapy for the modulation of intraocular pressure with cyclooxygenase-2 selective inhibitors - Google Patents

Abstract

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

Description

MONOTHERAPY FOR THE MODULATION OF INTRAOCULAR PRESSURPWITH CYCLOOXYGENASE-2 SELECTIVE INHIBITORS

FIELD OF THE INVENTION [0001] The present invention provides compositions and methods for modulating intraocular pressure. More particularly, the invention is directed toward a method for treating ophthalmic disorders mediated by low intraocular pressure, such as hypotony, comprising administering to a subject a composition having a cyclooxygenase-2 selective inhibitor.

BACKGROUND OF THE INVENTION [0002] A number of ocular disorders are marked by variations in intraocular ^; pressure (IOP). Elevated IOP, for example is a leading risk factor for the development of glaucoma. In normal individuals, lOPs range from 12 to 20 mm Hg, averaging approximately 16 mm Hg. But in individuals suffering from glaucoma, lOPs typically rise to 25 mm Hg or greater, and can sometimes exceed 40 mm Hg resulting in rapid and permanent visual loss. Loss of vision can result from lOPs only slightly above the normal range in eyes that are unusually pressure-sensitive over a period of years. Extremely high pressures, e.g., 70 mm Hg, may cause blindness within only a few days if left untreated. Some individuals, however, have optic nerves able to tolerate lOPs in the mid to high twenties without suffering optic nerve damage or without developing glaucoma. These individuals are referred to as ocular hypertensive. Other patients have progressive glaucomatous optic nerve damage despite having lOPs in the normal range. So while IOP may be an important factor in the development of glaucoma, it is not the sole causative mechanism. [0003] All therapies currently employed to treat ophthalmic disorders mediated by elevated IOP are restricted to reducing IOP by either affecting the production or outflow of aqueous humor. Depending upon the type and severity of the condition, either surgical or pharmacological treatments may be employed to lower IOP. By way of example, both laser and incisional surgical procedures may be used for the treatment of severe conditions such as open-angle glaucoma. Angle-closure glaucoma entails closure or blockage of the anterior chamber angle, thereby restricting outflow of aqueous humor. While pharmacological agents generally effectively control mild cases of open-angle glaucoma, laser trabeculoplasty or filtering surgery to improve aqueous drainage is employed in severe cases. Though often necessary and quite effective for many types of glaucoma, surgical intervention is an invasive form of treatment, even if local anesthesia can be used. [0004] Several classes of pharmacological agents may also be employed to lower IOP. One such class of pharmacological agent is miotic agents. Though their precise mechanism of action has not yet been fully elucidated, miotic drugs lower IOP by facilitating aqueous humor outflow. Mydriatic agents are also useful for lowering IOP. For example, the sympathomimetic amines, such as epinephrine and dipivefrin, lower IOP, at least in part through stimulation of beta₂ -adrenergic receptors in the trabecular meshwork. Additionally, alpha₂-adrenergic agonists (e.g. apraclonidine) have been shown to be effective in lowering IOP by inhibition of aqueous humor formation. Moreover, both non-selective betar and beta₂ -adrenergic blocking agents (e.g., timolpl and levobunolol) and betarselective (e.g., betaxolol) adrenergic blocking agents are also used to lower IOP. Prostaglandin compounds have also been shown to have an ocular hypotensive activity. Although these pharmacological agents are all less invasive than surgical intervention, they nevertheless are still often accompanied by adverse effects (e.g. conjunctival irritation, burred vision, ocular pain, and headaches) at the dosages required for effective treatment. [0005] Glaucomatous damage, in addition to IOP, also may result from pathologic mechanisms such as reduced blood flow or from ocular inflammation. Often, the inflammatory cells physically block the trabecular meshwork, decreasing aqueous outflow, with the angle remaining open. Occasionally, the inflammatory cells and fibrous protein will form a connective bridge between the peripheral iris and cornea, pulling these structures into apposition, and resulting in an angle closure. Because the inflammatory cells and protein in the anterior chamber form adhesions between the posterior iris and anterior lens, posterior synechiae commonly form. This will lead to iris bombe, secondary angle closure and peripheral anterior synechiae formation. There may also be a combination of mechanisms that increases IOP. Untreated, the patient will eventually experience glaucomatous optic atrophy, or possibly central retinal artery occlusion. For example, in uveitic glaucoma the patient first develops uveitis, either due to trauma, systemic disease or idiopathically. The ensuing inflammation results in a rise in IOP through several mechanisms. [0006] A number of ocular disorders are also mediated by low IOP. In hypotony, where the intraocular pressure is lower than the episcleral venous pressure, aqueous humour outflow must be via unconventional channels, such as uveoscleral outflow pathways. Typically, a hypotonic condition exists when IOP falls below about 6 mm Hg. The facility of unconventional outflow has been shown to be increased in eyes with experimentally induced hypotony from cyclodialysis, ciliochoroidal detachment, iridocyclitis, or retinal detachment. [0007] Hypotony can be a serious complication in glaucoma treatment. Postoperative hypotony is a common complication of glaucoma filtering surgery, particularly with adjunctive use of antifibrotic agents. Associated structural sequelae and reduced visual function may occur in some eyes, resulting in the low-pressure syndrome. Precautions may be taken intraoperatively and postoperatively to decrease the likelihood of hypotony. Sometimes, despite these measures, the low-pressure syndrome still can occur, the management of which can be difficult. In addition, in some glaucoma patients, the drugs used to control the patient's intraocular pressure can lower the pressure to the point that the eye globe partially collapses. [0008] The treatment options for ocular hypotony are limited. Generally, the condition remains untreated or intraocular injections of a viscous substance, such as, sodium hyaluronate are used. Apart from treatment of the specific cause of hypotony, reduction of the accompanying inflammatory response is essential for normalization of aqueous dynamics and intraocular pressure. [0009] A recently developed class of drugs, cyclooxygenase-2 selective inhibitors, provides an attractive therapeutic option to treat several types of inflammation, including ocular inflammation. Moreover, when administered at certain therapeutic doses, NSAIDS have been shown to effectively raise IOP (see, e.g., Kunapuli et al., (1997) J. Biol. Chem. 272(43): 27147-27154; and Kaplan-Messas et al., (2003) Eur. J. Ophthalmol. 13(1): 18-23.). These compounds selectively inhibit the activity of cyclooxygenase-2 to a greater extent than they inhibit cyclooxygenase-1 activity. Cyclooxygenase-1 has been shown to be constitutively expressed and is involved in several non-inflammatory regulatory functions associated with prostaglandins. Cyclooxygenase-2, in contrast, is an inducible enzyme having significant involvement in mediating the inflammatory response. Because of their different expression patterns and physiological roles, cyclooxygenase-2 selective inhibitors offer advantages that include avoiding harmful side effects associated with the inhibition of cyclooxygenase-1. Several patents discuss different chemical classes of compounds that selectively inhibit cyclooxygenase-2, such as, for example, U.S. Patent No. 5,434,178 (1 ,3,5-trisubstituted pyrazole compounds); U.S. Patent No. 5,476,944 (derivatives of cyclic phenolic thioethers); U.S. Patent No. 5,643,933 (substituted sulfonylphenylheterocycles); U.S. Patent No. 5,859,257 (isoxazole compounds); U.S. Patent No. 5,932,598 (prodrugs of benzenesulfonamide containing cyclooxygenase-2 selective inhibitors); U.S. Patent No. 6,156,781 (substituted pyrazolyl benzenesulfonamides); and U.S. Patent No. 6,110,960, all of which are hereby incorporated by reference in their entirety.

SUMMARY OF THE INVENTION [0010] Among the several aspects of the invention is provided a method and a composition that may be employed to modulate IOP. The method comprises administering to the subject a cyclooxygenase-2 selective inhibitor or a i pharmaceutically acceptable salt of a cyclooxygenase-2 selective inhibitor or a prodrug of a cyclooxygenase-2 selective inhibitor. [0011] 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; [0020] or wherein R⁴ together with the carbon atoms to which it is attached and the remainder of ring E forms a naphthyl radical; [0021] or prodrug thereof. [0022] In another embodiment, the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or a prodrug thereof comprises a compound of the , formula:

[0023] wherein: [0024] A is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings; [0025] 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; [0026] R₂ is methyl or amino; and [0027] 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. [0028] Other aspects of the invention are described in more detail below.

ABBREVIATIONS AND DEFINITIONS [0029] 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. [0030] 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. [0031] 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. [0032] 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. [0033] 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. [0034] 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. [0035] 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 i 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. [0036] 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. [0037] The term "alkylaminoalkyl" is a radical having one or more alkyl radicals attached to an aminoalkyl radical. [0038] 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" "N,N-dialkylaminocarbonyl" radicals. More preferred are "lower N-alkylaminocarbonyl" "lower N,N-dialkylaminocarbonyl" radicals with lower alkyl portions as defined above. [0039] 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. [0040] 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. [0041] 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. [0042] 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. [0043] 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. [0044] 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. [0045] The term "aminocarbonyl" is an amide group of the formula -C(=O)NH₂. [0046] The term "aralkoxy" is an aralkyl radical attached through an oxygen atom to other radicals. [0047] The term "aralkoxyalkyl" is an aralkoxy radical attached through an oxygen atom to an alkyl radical. [0048] 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. [0049] 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. [0050] The term "aralkylthio" is an aralkyl radical attached to a sulfur atom. [0051] The term "aralkylthioalkyl" is an aralkylthio radical attached through a sulfur atom to an alkyl radical. [0052] 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. [0053] 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. [0054] 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. [0055] The term "aryloxyalkyl" is a radical having an aryl radical attached to an alkyl radical through a divalent oxygen atom. [0056] The term "arylthioalkyl" is a radical having an aryl radical attached to an alkyl radical through a divalent sulfur atom. [0057] The term "carbonyl", whether used alone or with other terms, such as "alkoxycarbonyl", is -(C=O)-. [0058] The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", is -CO₂H. [0059] 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. [0060] 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. [0061] 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. [0062] The term "halo" is a halogen such as fluorine, chlorine, bromine or iodine. [0063] 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, dihaloalkyi 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, dichloromethyi, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. [0064] 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. [0065] 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. [0066] 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, thienyl methyl, furylethyl, and quinolylethyl. The heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. [0067] 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. [0068] 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. [0069] 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. [0070] 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 COX-2 inhibitors is described in US Patent No. 5,932,598, herein incorporated by reference. [0071] 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. [0072] 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-. [0073] 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 [0074] The present invention provides compositions and methods for modulating intraocular pressure comprising the administration to a subject of a therapeutically effective amount of a COX-2 selective inhibitor. The COX-2 selective inhibitor may be administered to a subject to treat a number of ophthalmic disorders mediated by low IOP, such as hypotony.

CYCLOOXYGENASE-2 SELECTIVE INHIBITORS [0075] 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.

[0076] In yet another embodiment, the cyclooxygenase-2 selective inhibitor is the cyclooxygenase-2 selective inhibitor, 6-[[5-(4-chlorobenzoyl)-1 ,4-dimethyl-1H-pyrrol- 2-yl]methyl]-3(2H)-pyridazinone, Formula B-2 (CAS registry number 179382-91-3).

[0077] 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. [0078] In another embodiment, the cyclooxygenase-2 selective inhibitor is a chromene compound represented by Formula /:

[0079] wherein: [0080] n is an integer which is O, 1 , 2, 3 or 4; [0081] G is O, S or NR^a; [0082] R^a is alkyl; [0083] R¹ is selected from the group consisting of H and aryl; [0084] R² is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; [0085] 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 [0086] 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. [0087] The cyclooxygenase-2 selective inhibitor may also be a compound of Formula (I), [0088] wherein: [0089] n is an integer which is 0, 1 , 2, 3 or 4; [0090] G is O, S or NR^a; [0091] R^a is alkyl; [0092] R¹ is H; [0093] R² is selected from the group consisting of carboxyl, aminocarbonyl, aikylsulfonylaminocarbonyl and alkoxycarbonyl; [0094] 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 [0095] 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. [0096] In a further embodiment, the cyclooxygenase-2 selective inhibitor may also be a compound of Formula (I), [0097] wherein: [0098] n is an integer which is 0, 1, 2, 3 or 4; [0099] G is oxygen or sulfur; [0100] R¹ is H; [oioi] R² is carboxyl, lower alkyl, lower aralkyl or lower alkoxycarbonyl; [0102] R³ is lower haloalkyl, lower cycloalkyl or phenyl; and [0103] 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. [0104] The cyclooxygenase-2 selective inhibitor may also be a compound of Formula (I), [0105] wherein: [0106] n is an integer which is 0, 1 , 2, 3 or 4; [0107] G is oxygen or sulfur; [0108] R¹ is H; [0109] R² is carboxyl; [Olio] R³ is lower haloalkyl; and [0111] each R⁴is 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. [0112] The cyclooxygenase-2 selective inhibitor may also be a compound of Formula (I), [0113] wherein: [0114] n is an integer which is 0, 1 , 2, 3 or 4; [0115] G is oxygen or sulfur; [0116] R¹ is H; [0117] R² is carboxyl; [0118] R³ is fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, or trifluoromethyl; and [0119] 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- 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. [0120] The cyclooxygenase-2 selective inhibitor may also be a compound of Formula (I), [0121] wherein: [0122] n is an integer which is 0, 1 , 2, 3 or 4; [0123] G is oxygen or sulfur; [0124] R¹ is H; [0125] R² is carboxyl; [0126] R³ is trifluoromethyl or pentafluoroethyl; and [0127] each R⁴ is independently H, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, ferf-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N- phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N-(2- furylmethyl)aminosulfonyl, N.N-dimethylaminosulfonyl, N-methylaminosuifonyl, 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. [0128] 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), [0129] wherein: [0130] n is 4; [0131] G is O or S; [0132] R is H; [0133] R² is CO₂H; [0134] R³ is lower haloalkyl; [0135] a first R⁴ corresponding to R⁹ is hydrido or halo; [0136] 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; [0137] a third R⁴ corresponding to R¹¹ is H, lower alkyl, halo, lower alkoxy, or aryl; and [0138] a fourth R⁴ corresponding to R ² is H, halo, lower alkyl, lower alkoxy, or aryl; [0139] wherein Formula (I) is represented by Formula (la):

[0140] 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), [0141] wherein: [0142] G is O or S; [0143 ] R³ is trifluoromethyl or pentafluoroethyl; [0144] R⁹ is H, chloro, or fluoro; [0145] R¹⁰ is H, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl, or morpholinosulfonyl; [0146] R¹¹ is H, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, or phenyl; and [0147] R¹² is H, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, or phenyl. [0148] 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

[0149] 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 //,

[0150] wherein: [0151] A is selected from the group consisting of a partially unsaturated or unsaturated heterocyclyl ring and a partially unsaturated or unsaturated carbocyclic ring; [0152] 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; [0153] R₂ is methyl or amino; and [0154] 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. [0155] 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

[0156] 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 cyciooxygenase inhibitor (US 5,932,598, herein incorporated by reference).

[0157] One form of parecoxib is sodium parecoxib. [0158] 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.

[0159] 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.

[0160] 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):

[0161] wherein: [0162] R¹⁶ is methyl or ethyl; [0163] R¹⁷ is chloro or fluoro; [0164] R¹⁸ is hydrogen or fluoro; [0165] R¹⁹ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; [0166] R²⁰ is hydrogen or fluoro; and [0167] 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. [0168] 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), [0169] wherein: [0170] R¹⁶ is ethyl; [0171] R¹⁷ and R¹⁹ are chloro; [0172] R¹⁸ and R²⁰ are hydrogen; and [0173] R²¹ is methyl. [0174] In yet another embodiment, the cyclooxygenase-2 selective inhibitor is represented by Formula (IV): 77

[0175] wherein: [0176] X is O or S; [0177] J is a carbocycle or a heterocycle; [0178] R²² is NHSO₂CH₃ or F; [0179] R²³ is H, NO₂, or F; and [0180] R²⁴ is H, NHSO₂CH₃, or (SO₂CH₃)C₆H₄. [0181] According to another embodiment, the cyclooxygenase-2 selective inhibitors used in the present method(s) have the structural Formula (V):

[0182] wherein: [0183] 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; [0184] 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 [0185] 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 [0186] 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; [0187] Q , 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. [0188] In another embodiment, the compounds N-(2-cyclohexyloxy 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. [0189] 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: [0190] 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-27); [0191] 6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-28); [0192] 8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-29); [0193] 6-chloro-8-(1 -methylethyl)-2-trif luoromethyl-2H-1 -benzopyran-3- carboxylic acid (B-30); [0194] 2-trifluoromethyl-3H-naphtho[2,1-b]pyran-3-carboxylic acid (B-31 ); [0195] 7-(1 , 1 -dimethylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-32); [0196] 6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-33); [0197] 8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-34); [01 8] 6-trifluoromethoxy-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-35); [01 9 5,7-dichloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-36); [0200] 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-37); [0201] 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-38); [0202] 6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-39); [0203] 7-(1 -methylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-40) [0204] 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-41); [0205] 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

(B-42 [0206] 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-43 [0207] 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-44 [0208] 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-45 [0209] 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-46 [0210] 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-47 [0211] 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-48 [0212] 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-49); [0213] 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-50 [0214] 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

(B-51 [0215] 8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-52 [0216] 8-bromo-5-fluoro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-53 [0217] 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-54 [0218] 6-bromo-8-methoxy-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-55); [0219] 6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid (B-56); [0220] 6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid (B-57); [0221] 6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid (B-58); [0222] 6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H- 1 -benzopyran-3- carboxylic acid (B-59); [0223] 6-[(1 ,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid (B-60); [0224] 6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran- 3-carboxylic acid (B-61); [0225] 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-62); [0226] 8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid (B-63); [0227] 6-phenylacetyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid (B-64); [0228] 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-65); [0229] 8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-66); [0230] 6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-67); [0231] 6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-68); [0232] 6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran- 3-carboxylic acid (B-69); [0233] 6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid (B-70); [0234] 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-71); [0235] 7-(1 , 1 -dimethylethyl)-2-pentafluoroethyl-2H-1 -benzopyran-3-carboxylic acid (B-72); [0236] 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid (B-73); [0237] 3-[(3-chloro-phenyl)-(4-methanesulfonyl-phenyl)-methylene]-dihydro- furan-2-one (B-74); [0238] 8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl)phenyl-imidazo (1 ,2-a) pyridine (B-75); [0239] 5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2-(5H)-furanone (B- 76); [0240] 5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3- (trifluoromethyl)pyrazole (B-77); [0241] 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1 -phenyl-3- (trifluoromethyl)pyrazole (B-78); [0242 ] 4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1 H-pyrazol-1 -yl) benzenesulfonamide (B-79); [0243] 4-(3,5-bis(4-methylphenyl)-1 H-pyrazol-1 -yl)benzenesulfonamide (B- 80); [0244] 4-(5-(4-chlorophenyl)-3-phenyl-1 H-pyrazol-1 -yl)benzene sulfonamide (B-81); [0245] 4-(3,5-bis(4-methoxyphenyl)-1 H-pyrazol-1 -yl)benzenesulfonamide (B- 82); [0246] 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1 H-pyrazol-1 -yl) benzenesulfonamide (B-83); [0247] 4-(5-(4-chlorophenyl)-3-(4-nιtrophenyl)-1 H-pyrazol-1 -yl) benzenesulfonamide (B-84); [0248] 4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1 H-pyrazol-1 -yl) benzenesulfonamide (B-85); [0249] 4-(4-chloro-3,5-diphenyl-1 H-pyrazol-1-yl)benzenesulfonamide (B-86); [0250] 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-87); [0251] 4-[5-pheny!-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-88); [0252] 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-89); [0253] 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-90); [0254] 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-91); [0255] 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-92); [0256] 4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-93); [0257] 4-[3-(difluoromethyl)-5-(4-methylphenyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-94); [0258] 4-[3~(difluoromethyl)-5-phenyl-1 H-pyrazol-1 -yl] benzenesulfonamide (B-95); [0259] 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-96); [0260] 4-[3-cyano-5-(4-fluorophenyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B- 97); [0261] 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-98); [0262] 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-99); [0263] 4-[4-chloro-5-phenyl-1 H-pyrazol-1-yl]benzenesulfonamide (B-100); [0264] 4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-101); [0265] 4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (B-102); [0266] 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene (B- 103); [0267] 4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl] benzenesulfonamide (B- 104); [0268] 6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[3.4]oct-6-ene (B- 105); [0269] 5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl) phenyl]spiro [2.4]hept-5-ene (B-106); [0270] 4-[6-(3-chIoro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl] benzenesulfonamide (B-107); [0271] 5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro [2.4]hept-5-ene (B-108); [0272] 5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl] spiro[2.4]hept- 5-ene (B-109); [0273] 4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl] benzenesulfonamide (B-110); [0274] 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonyl phenyl)thiazole (B-111); [0275] 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonyl phenyl)thiazole (B-112); [0276] 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole (B-113); [0277] 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole (B-114); [0278] 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole (B- 115); [0279] 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole (B-116); [0280] 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino) thiazole (B-117); [0281] 2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-(methyl sulfonyl)phenyl]thiazole (B-118); [0282] 5-(4-fluorophenyI)-4-(4-methylsulfonyIphenyl)-2-trifluoromethylthiazole (B-119); [0283] 1-methylsulfonyl-4-[1 ,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien- 3-yl]benzene (B-120); [0284] 4-[4-(4-fluorophenyl)-1 ,1-dimethylcyclopenta-2,4-dien-3-yl] benzenesulfonamide (B-121); [0285] 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6- diene (B-122); [0286] 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl] benzenesulfonamide (B-123); [0287] 6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)phenyl]-pyridine-3- carbonitrile (B-124); [0288] 2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyridine-3- carbonitrile (B-125); [0289] 6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyl-pyridine-3- carbonitrile (B-126); [0290] 4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl] benzenesulfonamide (B-127); [0291] 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl] benzenesulfonamide (B-128); [0292] 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl] benzenesulfonamide (B-129); [0293] 3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1 H-imidazol-2-yl] pyridine (B-130); [0294] 2-[1-[4-(methylsuifonyl)phenyl-4-(trifluoromethyl)-1 H-imidazol- 2-yl]pyridine (B-131); [0295] 2-methyl-4-[1-[4-(methyisulfonyl)phenyl-4-(trifiuoromethyl)-1 H-imidazol- 2-yl]pyridine (B-132); [0296] 2-methyl-6-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H-imidazol- 2-yl]pyridine (B-133); [0297] 4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl] benzenesulfonamide (B-134); [0298] 2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)- 1 H-imidazole (B-135); [0299] 4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl] benzenesulfonamide (B-136); [0300] 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyi]-4-methyl-1 H-imidazole (B-137); [0301] 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1 H-imidazole (B-138); [0302] 2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1 H- imidazole (B-139); [0303] 2-(3-fluoro-4-methoxyphenyl)-1 -[4-(methylsulfonyl)phenyl-4-(trifluoro methyl)-1 H-imidazole (B-140); [0304] 1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1 H-imidazole (B-141 ); [0305] 2-(4-methyiphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H- imidazole (B-142); [0306] 4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1- yl]benzenesulfonamide (B-143); [0307] 2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4- (trifluoromethyl)-l H-imidazole (B-144); [0308] 4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1- yl]benzenesulfonamide (B-145); [0309] 2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H- imidazole (B-146); [0310] 4-[2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl] benzene sulfonamide (B-147); [0311] 1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-1 H- imidazole (B-148); [0312] 4-[2-(3-chlorophenyI)-4-trifluoromethyl-1 H-imidazol-1-yl] benzenesulfonamide (B-149); [0313] 4-[2-phenyl-4-trifluoromethyl-1 H-imidazol-1-yl] benzenesulfonamide (B- 150); [0314] 4-[2-(4-methoxy-3-chlorophenyl)-4-trifIuoromethyl-1H-imidazol-1- yl]benzenesulfonamide (B-151); [0315] 1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5- (trifluoromethyl)-l H-pyrazole (B-152); [0316] 4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1 H-pyrazol-3-yl] benzenesulfonamide (B-153); [0317] N-phenyl-[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5- (trifluoromethyl)-l H-pyrazol-1 -yl]acetamide (B-154); [0318] ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5- (trifluoromethyl)-l H-pyrazol-1 -yl]acetate (B-155); [0319] 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1 -(2-phenylethyl)-1 H- pyrazole (B-156); [0320] 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1 -(2-phenylethyl)-5- (trifluoromethyl)pyrazole (B-157); [0321] 1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5- (trifluoromethyl)-l H-pyrazole (B-158); [0322] 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1 H- imidazole (B-159); [0323] 4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1 H- imidazole (B-160); [0324] 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine (B-161 ); [0325] 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine (B-162); [0326] 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6- (trifluoromethyl)pyridine (B-163); [0327] 2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine (B-164); [0328] 4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl] benzenesulfonamide (B-165); [0329] 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene (B-166); [0330] 5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole (B-167); [0331] 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide (B-168); [0332] 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide (B-169); [0333] 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide (B- 170); [0334] 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide(B-171 ); [0335] 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl) benzene (B- 172); [0336] 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl) benzene (B-173); [0337] 1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl) benzene (B- 174); [0338] 1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl) benzene (B-175); [0339] 1 -[2-(4-trif luoromethylphenyl)cyclopenten-1 -yl]-4-(methylsulfonyl) benzene (B-176); [03 0] 1 -[2-(4-methylthiophenyl)cyclopenten-1 -yl]-4-(methyl sulfonyl)benzene (B-177); [0341] 1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl) benzene (B-178); [0342] 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]benzene sulfonamide (B-179); [0343 ] 1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1 -yl]-4-(methylsulfonyl) benzene (B-180); [0344] 4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]benzene sulfonamide (B-181); [0345] 4-[2-(4-fluorophenyl)cyclopenten-1 -yl]benzenesulfonamide (B-182); [0346] 4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide (B-183); [0347] 1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl) benzene (B-184); [0348] 1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl) benzene (B-185); [0349] 4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1 -yl] benzenesulfonamide (B-186); [0350] 1 -[2-(3-chloro-4-methoxyphenyl)cyclopenten-1 -yl]-4-(methylsulfonyl) benzene (B-187); [0351] 4-[2-(3-chloro-4-fluoropheny!)cyc!openten-1 -yl] benzenesulfonamide (B-188); [0352] 4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]benzenesulfonamide (B- 189); [0353] ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyl]oxazol-2-yl]-2- benzyl-acetate (B-190); [0354] 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl] acetic acid (B-191 ); [0355] 2-(terf-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl] oxazole (B-192); [0356] 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole (B- 193); [0357] 4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole (B-194); [0358] 4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl] benzenesulfonamide (B-195); [0359] 6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid (B-196); [0360] 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-197); [0361] 5,5-dimethyl-3-(3-fluorophenyl)-4-methylsulfonyl-2(5H)-furanone (B-198); [0362] 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid (B- 199); [0363] 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzene sulfonamide (B-200); [0364] 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzene sulfonamide (B-201); [0365] 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1 H-pyrazol-1 - yl]benzenesulfonamide (B-202); [0366] 3-[1 -[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazol-2- yl]pyridine (B-203); [0367] 2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazol- 2-yl]pyridine (B-204); [0368] 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-yl] benzenesulfonamide (B-205); [0369] 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (B-206); [0370] 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide (B- 207); [0371] [2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzene sulfonamide (B-208); [0372] 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide (B-209); [0373] 4-[5-(2-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl] benzenesulfonamide (B-210); [0374] [2-(2-chloro-6-fluoro-phenylamino)-5-methyl-phenyl]-acetic acid or COX 189 (lumiracoxib; B-211); [0375] N-(4-Nitro-2-phenoxy-phenyl)-methanesulfonamide or nimesulide (B- 212); [0376] N-[6-(2,4-difluoro-phenoxy)-1-oxo-indan-5-yl]-methanesulfonamide or flosulide (B-213); [0377] N-[6-(2,4-Difluoro-phenylsulfanyl)-1-oxo-1 H-inden-5-yl]- methanesulfonamide, sodium salt (B-214); [0378] N-[5-(4-fluoro-phenylsulfanyl)-thiophen-2-yl]-methanesulfonamide (B- 215); [0379] 3-(3,4-Difluoro-phenoxy)-4-(4-methanesulfonyl-phenyl)-5-methyl-5- (2,2,2-trifluoro-ethyl)-5H-furan-2-one (B-216); [0380] (5Z)-2-amino-5-[[3,5-bis(1 ,1-dimethylethyl)-4-hydroxyphenyl] methylene]-4(5H)-thiazolone (B-217); [0381] CS-502 (B-218); [0382] LAS-34475 (B-219); [0383] LAS-34555 (B-220); [0384] S-33516 (B-221 ); [0385] SD-8381 (B-222); [0386] L-783003 (B-223); [0387] N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]- methanesulfonamide (B-224); [0388] D-1367 (B-225); [0389] L-748731 (B-226); [0390] (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); [0391] CGP-28238 (B-228); [0392] 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); [0393] GR-253035 (B-230); [0394] 6-dioxo-9H-purin-8-yl-cinnamic acid (B-231 ); [0395] S-2474 (B-232); [0396] 4-[4-(methyl)-sulfonyl)phenyl]-3-phenyl-2(5H)-furanone; [0397] 4-(5-methyl-3-phenyl-4-isoxazolyl); [0398] 2-(6-methylpyrid-3-yl)-3-(4-methylsulfonylphenyl)-5-chloropyridine; [0399] 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]; [0400] N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]; [0401] 4-[5-(3-fluoro-4-methoxyρhenyl)-3-difluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide; [0402] (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid; [0403] 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methyl sulfonyl)phenyl]-3(2H)-pyridzainone; [0404] 2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid; [0405] 6-chloro-7-(1 ,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid; and [0406] [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;

acid;

[0408] 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. [0409] 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, benzenesuifonic, 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. [0410] 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. [0411] 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. [0412] 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. [0413] 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. [0414] 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. [0415] 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. [0416] 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. ROUTES OF ADMINISTRATION [0417] Generally speaking, the composition comprising a therapeutically effective amount of a cyclooxygenase-2 selective inhibitor may be administered by a number of different means that will deliver a therapeutically effective dose, as detailed herein or as otherwise known in the art. For example, formulation of agents is discussed in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975), and Liberman, H.A. and Lachman, L, Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980). [0418] In one aspect, the composition is administered directly to the eye by any means known in the art such as in a solution, cream, ointment, emulsion, suspension and slow release formulations. Administration of a composition to the eye. generally results in direct contact of the agents with the cornea, through which at least a portion of the administered agents pass. In general, the composition has an effective residence time in the eye of about 2 to about 24 hours, more typically about 4 to about 24 hours and most typically about 6 to about 24 hours. [0419] A composition of the invention can illustratively take the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition may include a gel formulation. In other embodiments, the liquid composition is aqueous. Alternatively, the composition can take the form of an ointment. [0420] In one embodiment, the composition is an aqueous solution, suspension or solution/suspension, which can be presented in the form of eye drops. By means of a suitable dispenser, a desired dosage of each agent can be metered by administration of a known number of drops into the eye. For example, for a drop volume of 25 μl, administration of 1-6 drops will deliver 25-150 μl of the composition. Aqueous compositions of the invention typically contain from about 0.01% to about 50%, more typically about 0.1% to about 20%, still more typically about 0.2% to about 10%, and most typically about 0.5% to about 5%, weight/volume of the COX-2 selective inhibitor. [0421] Generally speaking, aqueous compositions of the invention have ophthalmically acceptable pH and osmolality. Ophthalmically acceptable" with respect to a formulation, composition or ingredient typically means having no persistent detrimental effect on the treated eye or the functioning thereof, or on the general health of the subject being treated. It will be recognized that transient effects such as minor irritation or a "stinging" sensation are common with topical ophthalmic administration of agents and the existence of such transient effects is not inconsistent with the formulation, composition or ingredient in question being "ophthalmically acceptable" as detailed herein. But formulations, compositions and ingredients employed in the present invention are those that generally cause no substantial detrimental effect, even of a transient nature. [0422] In an aqueous suspension or solution/suspension composition, the agent can be present predominantly in the form of nanoparticles, i.e., solid particles smaller than about 1000 nm in their longest dimension. A benefit of this composition is more rapid release of the agent, and therefore more complete release during the residence time of the composition in a treated eye than occurs with larger particle size. Another benefit is reduced potential for eye irritation by comparison with larger particle size. Reduced eye irritation in turn leads to a reduced tendency for loss of the composition from the treated eye by lacrimation, which is stimulated by such irritation. [0423] In a related composition, the agent typically has a DQQ particle size of about 10 to about 2000 nm, wherein about 25% to 100% by weight of the particles are nanoparticles. "DQQ" is a linear measure of diameter having a value such that 90% by volume of particles in the composition, in the longest dimension of the particles, are smaller than that diameter. For practical purposes a determination of DQQ based on

90% by weight rather than by volume is generally suitable. [0424] In one composition, substantially ail of the agent particles in the composition are smaller than 100 nm, i.e., the percentage by weight of nanoparticles is 100% or close to 100%. Generally speaking, the average particle size of the agent in this embodiment is typically about 100 to about 800 nm, more typically about 150 to about 600 nm, and even more typically, about 200 to about 400 nm. The agent can be in crystalline or amorphous form in the nanoparticles. Processes for preparing nanoparticles that involve milling or grinding typically provide the agent in crystalline form, whereas processes that involve precipitation from solution typically provide the agent in amorphous form. [0425] The ophthalmic composition in some embodiments can be an aqueous suspension of an agent of low water solubility, wherein typically the agent is present predominantly or substantially entirely in nanoparticulate form. Without being bound by theory, it is believed that release of the agent from nanoparticles is significantly faster than from a typical "micronized" composition having a D_g0 particle size of, for example, about 10,000 nm or greater. [0426] In another embodiment, an aqueous suspension composition of the invention can comprise a first portion of the agent in nanoparticulate form, to promote relatively rapid release, and a second portion of the agent having a Dg₀ particle size of about 10,000 nm or greater, that can provide a depot or reservoir of the agent in the treated eye for release over a period of time, for example about 2 to about 24 hours, more typically about 2 to about 12 hours, to promote sustained therapeutic effect and permit a reduced frequency of administration. [0427] In still another embodiment, an aqueous suspension can contain one, or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water- insoluble polymers such as cross-linked carboxyl-containing polymers. [0428] The composition can be an in situ gellable aqueous solution, suspension or solution/suspension having excipients substantially as disclosed in U.S. Patent No. 5,192,535, comprising about 0.1% to about 6.5%, typically about 0.5% to about 4.5%, by weight, based on the total weight of the composition, of one or more cross-linked carboxyl-containing polymers. Such an aqueous suspension is typically sterile and has an osmolality of about 10 to about 400 mOsM, typically about 100 to about 250 mOsM, a pH of about 3 to about 6.5, typically about 4 to about 6, and an initial viscosity, when administered to the eye, of about 1000 to about 30,000 cPs, as measured at 25°C using a Brookfield Digital LVT viscometer with #25 spindle and 13R small sample adapter at 12 rpm. More typically the initial viscosity is about 5000 to about 20,000 cPs. The polymer component has an average particle size not greater than about 50 μm, typically not greater than about 30 μm, more typically not greater than about 20 μm, and most typically about 1 μm to about 5 μm, in equivalent spherical diameter, and is lightly cross-linked to a degree such that, upon contact with tear fluid in the eye, which has a typical pH of about 7.2 to about 7.4, the viscosity of the suspension rapidly increases, to form a gel. This formation of a gel enables the composition to remain in the eye for a prolonged period without loss by lacrimal drainage. [0429] Suitable carboxyl-containing polymers for use in this composition are prepared from one or more carboxyl-containing monoethylenically unsaturated monomers such as acrylic, methacrylic, ethacrylic, crotonic, angelic, tiglic, α-butylcrotonic, α-phenylacrylic, α-benzylacrylic, α-cyclohexylacrylic, cinnamic, coumaric and umbellic acids, most typically acrylic acid. The polymers are cross-linked by using less than about 5%, typically about 0.1% to about 5%, more typically about 0.2% to about 1 %, by weight of one or more polyfunctional cross-linking agents such as non-polyalkenyl polyether difunctional cross-linking monomers, e.g., divinyl glycol. Other suitable cross-linking agents illustratively include 2,3-dihydroxyhexa-1 ,5-diene, 2,5-dimethylhexa-1 ,5-diene, divinylbenzene, N,N-diallylacrylamide and N,N- diallylmethacrylamide. Divinyl glycol is typically employed. Polyacrylic acid cross-linked with divinyl glycol is called polycarbophil. A polymer system containing polycarbophil is commercially available under the trademark DuraSite® of InSite Vision Inc., Alameda, CA, as a sustained-release topical ophthalmic delivery system. [0430] In another formulation, the composition can be an in situ gellable aqueous solution, suspension or solution/suspension having excipients substantially as disclosed in U.S. Patent No. 4,861 ,760, comprising about 0.1 % to about 2% by weight of a polysaccharide that gels when it contacts an aqueous medium having the ionic strength of tear fluid. One such polysaccharide is gellan gum. This composition can be prepared by a procedure substantially as disclosed in U.S. Patent No. 4,861 ,760. [0431] In yet another formulation, the composition can be an in situ gellable aqueous solution, suspension or solution/suspension having excipients substantially as disclosed in U.S. Patent No. 5,587,175, comprising about 0.2% to about 3%, typically about 0.5% to about 1%, by weight of a gelling polysaccharide, typically selected from gellan gum, alginate gum and chitosan, and about 1 % to about 50% of a water-soluble film-forming polymer, typically selected from alkylcelluloses (e.g., methylcellulose, ethylcellulose), hydroxyalkylcelluloses (e.g., hydroxyethylcellulose, hydroxypropyl methylcellulose), hyaluronic acid and salts thereof, chondroitin sulfate and salts thereof, polymers of acrylamide, acrylic acid and polycyanoacrylates, polymers of methyl methacrylate and 2-hydroxyethyl methacrylate, polydextrose, cyclodextrins, polydextrin, maltodextrin, dextran, polydextrose, gelatin, collagen, natural gums (e.g., xanthan, locust bean, acacia, tragacanth and carrageenan gums and agar), polygalacturonic acid derivatives (e.g., pectin), polyvinyl alcohol, polyvinylpyrrolidone and polyethylene glycol. The composition can optionally contain a gel-promoting counterion such as calcium in latent form, for example encapsulated in gelatin. This composition can be prepared by a procedure substantially as disclosed in U.S. Patent No. 5,587,175. [0432] In a further formulation, the composition can be an in situ gellable aqueous solution, suspension or solution/suspension having excipients substantially as disclosed in European Patent No. 0 /424.043, comprising about 0.1% to about 5% of a carrageenan gum. In this embodiment, a carrageenan having no more than 2 sulfate groups per repeating disaccharide unit is typical, including kappa-carrageenan, having 18-25% ester sulfate by weight, iota-carrageenan, having 25-34% ester sulfate by weight, and mixtures thereof. [0433] In still another particular formulation, the composition comprises an ophthalmically acceptable mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran. [0434] In another composition, the agent is solubilized at least in part by an ophthalmically acceptable solubilizing agent. The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain ophthalmically acceptable nonionic surfactants, for example polysorbate 80, can be useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers. [0435] A class of solubilizing agents suitable for use in solution and solution/suspension compositions of the invention is the cyclodextrins. Suitable cyclodextrins can be selected from α-cyclodextrin, α-cyclodextrin, -cyclodextrin, alkylcyclodextrins (e.g., methyl-α-cyclodextrin, dimethyl-α-cyclodextrin, diethyl-α- cyclodextrin), hydroxyalkylcyclodextrins (e.g., hydroxyethyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin), carboxyalkylcyclodextrins (e.g., carboxymethyl-α- cyclodextrin), sulfoalkylether cyclodextrins (e.g., sulfobutylether-α-cyclodextrin), and the like. Ophthalmic applications of cyclodextrins have been reviewed by Rajewski & Stella (1996), Journal of Pharmaceutical Sciences, 85, 1154, at pages 1155-1159. If desired, complexation of an agent by a cyclodextrin can be increased by addition of a water- soluble polymer such as carboxymethylcellulose, hydroxypropyl methylcellulose or polyvinylpyrrolidone, as described by Loftsson (1998), Pharmazie. 53, 733-740. [0436] In some embodiments, one or more ophthalmically acceptable pH adjusting agents or buffering agents can be included in a composition of the invention, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an ophthalmically acceptable range. [0437] In another embodiment, one or more ophthalmically acceptable salts can be included in the composition in an amount required to bring osmolality of the composition into an ophthalmically acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anioπs; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. Optionally one or more ophthalmically acceptable acids having at i least two dissociable hydrogen groups can be included in a polymer-containing composition as interactive agents to retard release of the agent through inhibition of erosion of the polymer, as disclosed in International Patent Publication No. WO 95/03784. Acids useful as interactive agents include boric, lactic, orthophosphoric, citric, oxalic, succinic, tartaric and formic glycerophosphoric acids. [0438] In still another embodiment, an ophthalmically acceptable xanthine derivative such as caffeine, theobromine or theophylline can be included in the composition, substantially as disclosed in U.S. Patent No. 4,559,343, to reduce ocular discomfort associated with administration of the composition. [0439] In yet another embodiment, one or more ophthalmically acceptable preservatives can be included in the composition to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride. [0440] In a further embodiment, one or more ophthalmically acceptable surfactants, typically nonionic surfactants, can be included in the composition to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. [0441] In another embodiment, one or more antioxidants can be included in the composition to enhance chemical stability where required. Suitable antioxidants include ascorbic acid and sodium metabisulfite. [0442] In still another embodiment, one or more ophthalmic lubricating agents can optionally be included in the composition to promote lacrimation or as a "dry eye" medication. Such agents include polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, etc. [0443] Aqueous suspension compositions of the invention can be packaged in single-dose non-reclosable containers. Such containers can maintain the composition in a sterile condition and thereby eliminate the need for preservatives such as mercury- containing preservatives, which can sometimes cause irritation and sensitization of the eye. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. [0444] As a further alternative, the composition can take the form of a solid article that can be inserted between the eye and eyelid or in the conjunctival sac, where it releases the agent as described, for example, in U.S. Patent No. 3,863,633 and U.S. Patent No. 3,868,445, both to Ryde & Ekstedt, incorporated herein by reference. Release is to the lacrimal fluid that bathes the surface of the cornea, or directly to the cornea itself, with which the solid article is generally in intimate contact. Solid articles suitable for implantation in the eye in such fashion are generally composed primarily of polymers and can be biodegradable or non-biodegradable. Biodegradable polymers that can be used in preparation of ocular implants carrying a COX-2 selective inhibitor in accordance with the present invention include without restriction aliphatic polyesters such as polymers and copolymers of poly(glycolide), poly(lactide), poly(α-caprolactone), poly(hydroxybutyrate) and poly(hydroxyvalerate), polyamino acids, polyorthoesters, polyan hydrides, aliphatic polycarbonates and polyether lactones. Suitable non- biodegradable polymers include silicone elastomers. [0445] In another aspect of the invention, the composition is not administered directly to the eye. By way of example, such a composition can be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. [0446] Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the agents of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered peros, an agent can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings. [0447] Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. [0448] The term parenteral includes subcutaneous injections, intravenous, intramuscular, intrastemal injection, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and nonionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful. [0449] For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. A contemplated therapeutic compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride solution, or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

INDICATIONS TO BE TREATED [0450] In some aspects, the invention provides a method for modulating IOP in a subject. The composition may also be utilized to treat a number of ophthalmic disorders in a subject mediated by low IOP, such as hypotony. [0451] By way of example, in normal individuals, lOPs range from 12 to 20 mm Hg, averaging approximately 16 mm Hg. At higher values, for instance over 22 mm Hg, there is a risk that the eye may be affected, and if left untreated, result in the formation of glaucoma. When IOP is extremely low, such as below about 10 mm Hg, or even more typically, below about 6 mm Hg, a hypotonic condition may develop. In hypotony, the intraocular pressure is lower than the episcleral venous pressure. As a result, aqueous humour outflow must be via unconventional channels, such as uveoscleral outflow pathways. The facility of unconventional outflow may induce hypotony to develop from cyclodialysis, ciliochoroidal detachment, iridocyclitis, or retinal detachment. The present invention encompasses a method for the treatment of hypotony irrespective of its cause. [0452] In one embodiment, the composition may be administered to a subject where low IOP in a subject causes hypotony following a procedure to treat glaucoma. Hypotony can be a serious complication in glaucoma treatment. Postoperative hypotony is a common complication of glaucoma filtering surgery, particularly with adjunctive use of antifibrotic agents. Associated structural sequelae and reduced visual function may occur in some eyes, resulting in the low-pressure syndrome. In addition, in some glaucoma patients, the drugs used to control the patient's intraocular pressure can lower the pressure to the point that the eye globe partially collapses. [0453] In yet another aspect of the invention, the composition may be administered to a subject having a low IOP, where a hypotonic state has not been induced. In one embodiment, the subject may have an IOP between about 10 to about 12 mm Hg. In another embodiment, the IOP is between about 10 to about 11 mm Hg. [0454] One advantage of a composition that selectively inhibits COX-2 over therapies involving NSAIDs lacking selective COX-2 inhibition is that IOP may be lowered with greatly reduced risk of the side-effects commonly associated with COX-1 inhibition. The composition of the present invention, therefore, is particularly suitable where conventional NSAIDs are contraindicated. By way of example, convention NSAIDS may be contraindicated in subjects with peptic ulcers, gastritis, regional enteritis, ulcerative colitis or diverticulitis, in subjects with a recurrent history of gastrointestinal lesions, in subjects with gastrointestinal bleeding, coagulation disorders including anemia such as hypothrombinemia, hemophilia and other bleeding problems, or kidney disease.

EXAMPLES [0455] The efficacy of a cyclooxygenase-2 selective inhibitor for the modulation of intraocular pressure (IOP) can be evaluated in comparison to a control treatment such as a placebo treatment. By way of example, a cyclooxygenase-2 selective inhibitor can be celecoxib, rofecoxib, valdecoxib, etoricoxib, parecoxib or deracoxib. It should be noted that these are only several examples, and that any of the cyclooxygenase-2 selective inhibitors described herein may be tested. The dosages of a cyclooxygenase-2 selective inhibitor in a particular therapeutic preparation may be readily determined by a skilled artisan conducting the study. The length of the study treatment will vary on a particular study and can also be determined by one of ordinary skill in the art. By way of example, the combination therapy may be administered for 12 weeks. The cyclooxygenase-2 selective inhibitors can be administered by any route as described herein, but is preferably administered as an ocular formulation directly to the eye of the subject being tested. [0456] The laboratory animal study can generally be performed as described in Savinova et al., BMC Genetics 2:12, Aug. 9, 2001.

ANIMAL HUSBANDRY [0457] All experiments are performed in compliance with the ARVO statement for use of animals in ophthalmic and vision research. Briefly, mice are housed in cages containing white pine bedding and covered with polyester filters. For most experiments, the mice are fed NIH31 (6 % fat) chow ad libitum, and their water is acidified to pH 2.8 to 3.2. The mice are housed based on the experimental group and the cages are changed one time per week. If any cage appears soiled between scheduled changes, the mice are placed in a clean cage. The environment is kept at 21 °C with a 14 hour light: 10 hour dark cycle. The colony is monitored for specific pathogens routinely. [0458] Mice chosen for this study can be of C57BL/6J (BI/6) strain; however, other strains can also be used. Since glaucoma, which is associated with high intraocular pressure generally occurs in older individuals, mice used herein are older, between about 12 months and 24 months of age. It should be noted that the same experiment can be performed with younger animals, if desired. Control mice are selected from the same strain and same age group as the experimental mice (receiving cyclooxygenase-2 selective inhibitors therapy). By way of example, if the experimental group comprises 10 BI/6 mice, 3 BI/6 mice can be used as a control. [0459] Mice that have elevated intraocular pressure can also be used in this study. For example, mice that are heterozygous for bone morphogenetic protein 4 (Bmp4^"7. mice) have anterior segment abnormalities including malformed, absent or blocked trabecular meshwork and Schlemm's canal drainage structures. Mice with severe drainage structure abnormalities over 80% or more of their angle's extent have elevated IOP. The penetrance and severity of abnormalities is strongly influenced by genetic background, being most severe on the BI/6 background. On the BI/6 background, there is a persistence of hyaloid vasculature, diminished numbers of inner retinal cells, and absence of the optic nerve. See, e.g., Chang et al., BMC Genetics, 2:18, Nov. 6, 2001. Accordingly, an experimental group can consist of Bmp4⁺/_ mice receiving a COX-2 selective inhibitor therapy, whereas the control group consists of Bmp4⁺/. mice receiving a placebo treatment. The placebo treatment can be readily determined by a skilled artisan; for example, if the COX-2 selective inhibitor therapy is administered intravenously or intraperitoneally, the vehicle used for such administration can be used as a placebo.

COX-2 SELECTIVE INHIBITOR TREATMENT [0460] Mice in the experimental group are administered a COX-2 selective inhibitor or two or more COX-2 selective inhibitors as described above by any of the acceptable routes, e.g., intraperitoneal or intravenous. The duration and frequency of the treatment can readily be determined by a skilled artisan. By way of example, the COX-2 selective inhibitor therapy can be administered once a day for a period of 2 weeks. The amount of the therapy to be administered can also be readily determined by one skilled in the art. Control mice are treated according to the same protocol, except that they are administered a placebo rather than a COX-2 selective inhibitor. Following the treatment, eyes of the both experimental and control mice are examined to determine the effect of the treatment. The result can be evaluated by determining intraocular pressure, and e.g., by performing immunohistochemistry on the eyes. For example, histochemistry (performed as described below) can be used to determine if the iridocomeal angle and aqueous humor drainage structures are open to the anterior chamber and have normal morphology.

INTRAOCULAR PRESSURE (IOP) [0461] Intraocular pressure is measured as described, for example, in John SWM, Hagaman JR, MacTaggart TE, Peng L, Smithes O: Intraocular pressure in inbred mouse strains, Invest. Ophthalmol. Vis. Sci. 1997, 38:249-253. The mice are typically acclimatized to the procedure room for at least 2 weeks prior to measurement, but sometimes between 1 and 2 weeks. [0462] All dark period measurements are made between 1 and 3 hours after the lights are turned off. The room is equipped with dim red lights and mice are protected from all light exposure during set up. Each mouse is briefly exposed to the red light when the anesthetic agents are administered. When adequate anesthesia is achieved (after 3 to 4 minutes), the mouse is placed on the measurement platform and the white light of the microscope is turned on (for approximately 1 and a half minutes) to allow ocular cannulation. The white light is used at very low intensity and is dim to minimize, if not eliminate possibility that this brief exposure alters the IOP. All other mice are protected from light exposure throughout the time an individual mouse is analyzed.

CLINICAL EXAMINATIONS [0463] Anterior chambers are examined with a slit lamp and photographs are taken using a 40X objective lens. An indirect ophthalmoscope and a 60 or 90 diopter lens is used to visualize the retinas and optic nerves. For this analysis, pupils are dilated with a drop of 1% cyclopentolate.

HISTOLOGICAL ANALYSIS [0464] Eyes from at least several mice from the experimental and control group are fixed (4% paraformaldehyde or Fekete's acid-alcohol-formalin fixative) processed, paraffin embedded and sectioned as previously reported, except that the paraformaldehyde is buffered with 0.1 M phosphate buffer. Chang et al., Nat. Genet. 1999, 21 :405-409 and Smith RS, Nishina PM, Ikeda S, Jewett P, Zabaleta A, John SWM: Interpretation of Ocular Pathology in Genetically-Engineered and Spontaneous Mutant Mice. In: Pathology of Genetically Engineered Mice Edited by Ward J, Sundberg J. pp. 217-231. Iowa: University of Iowa Press; 2000, 217-231.

[0465] A number of the eyes are processed for plastic embedding (Historesin, Leica, Heidelberg, Germany), and sectioned as previously reported. J°^{nn et a}'-> Invest. Ophthalmol. Vis. Sci. 1998, 39:951-962 and Smith RS, Nishina PM, Ikeda S, Jewett P, Zabaleta A, John SWM: Interpretation of Ocular Pathology in Genetically-Engineered and Spontaneous Mutant Mice. In: Pathology of Genetically Engineered Mice Edited by Ward J, Sundberg J. pp. 217-231. Iowa: University of Iowa Press; 2000, 217-231 Saggital sections including the pupil and optic nerve are collected and analyzed as they contain most ocular structures.

RESULTS [0466] Older BI/6 mice can be used to determine if a COX-2 selective inhibitor treatment provides a prophylactic or therapeutic (if the mice have a high IOP) benefit. The benefit(s) can be evaluated by determining IOP levels prior and post treatment. Furthermore, the histology can be used to evaluate the presence or absence of pathological ocular features before and after the treatment. [0467] When Bmp4⁺/_ mice are used, it is expected that the COX-2 selective inhibitor therapy will result in a decrease in IOP in these mice following the treatment regimen. Eye histochemistry as described above can also be used to evaluate whether the treatment results in any improvement of drainage structure abnormalities. [0468] It should be noted that all of the above-mentioned procedures can be modified for a particular study, depending on factors such as a drug combination used, length of the study, subjects that are selected, etc. Such modifications can be designed by a skilled artisan without undue experimentation.

Claims

WHAT IS CLAIMED IS:

1. A method for treating hypotony 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 of a cyclooxygenase-2 selective inhibitor or a prodrug of a cyclooxygenase-2 selective inhibitor.

2. The method of claim 1 wherein the cyclooxygenase-2 selective inhibitor is a chromene compound.

3. The method of claim 2 wherein the chromene compound is a benzopyran or substituted benzopyran analog.

4. The method of claim 2 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 H or 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.

5. The method of claim 1 wherein the cyclooxygenase-2 selective inhibitor is a benzenesulfonamide or methylsulfonylbenzene.

6. The method of claim 5 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.

7. The method of claim 1 wherein the cyclooxygenase-2 selective inhibitor is a phenyl acetic acid.

8. The method of claim 7 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 R¹⁷, R¹⁸, R²⁰ and R²¹ are not all fluoro when R¹⁶ is ethyl and R¹⁹ is

H.

9. The method of claim 1 wherein the cyclooxygenase-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib, valdecoxib, etoricoxib, parecoxib, deracoxib, tilmacoxib, cimicoxib and lumiracoxib.

10. The method of claim 1 wherein the cyclooxygenase-2 selective inhibitor is celecoxib.

11. The method of claim 1 wherein the cyclooxygenase-2 selective inhibitor is rofecoxib.

12. The method of claim 1 wherein the cyclooxygenase-2 selective inhibitor is valdecoxib.

13. The method of claim 1 wherein the subject is a human.

14. The method of claim 13 wherein the human has an intraocular pressure of less than approximately 10 mm Hg.

15. The method of claim 13 wherein the human has been treated for glaucoma.