TW200536517A - Compositions of a phenyl acetic acid cyclooxygenase-2 selective inhibitor for the treatment of cyclooxygenase-2 mediated ocular disorders - 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

200536517 IX. Description of the invention: [Technical field to which the invention belongs] The present invention provides a treatment for epoxidized orbital ocular diseases and its composition within 25 weeks. More specifically, the method of developing disease on Shidai 1 之 = In other words, the present invention is directed to the treatment of ocular diseases for edema of plaques, or the enzyme-2 selective inhibitor is administered to the subject. Tick [Prior technology] Persistent !: Eye = _) Regulated incidence of ophthalmic diseases (including glaucoma) "for striking signs: the continuing need for better One of the main reasons. The two types of H-precursors (open-angled and closed-angle glaucoma) can be distinguished according to the function of the inner chamber around the eye. Other forms of glaucoma include normal intraocular pressure. Sexual, acute, pigmented, exfoliative, and trauma related = eye. Of all types of glaucoma, the openness of the horns is the most common.-In general, risk factors related to glaucomatous nerve damage include high service, glaucoma Positive family history, African-American heredity, myopia, and depression. However, among all the risk factors, high IoP is believed to be the single most risk factor for glaucoma. In normal individuals, 101 ^ in In the range of 12 to 20 cm, the average is about 16 mm Hg. However, in individuals with glaucoma, the Ips usually rises to 25 mmHg or higher, and sometimes it can exceed 40 mmHg, resulting in fast and long-lasting vision Loss. Vision Impairment can be caused in eyes that are unusually sensitive to repeated forces for several years because I0ps is only slightly above the normal range. Extreme stress (eg 70 mm Hg) can be caused within a few days without treatment. Blindness. However 'some individuals have optic nerves that can withstand 100462.doc 200536517 IOPs of 24 to 29 mm Hg without suffering from optic nerve damage or failing to form glaucoma. These individuals are known as intraocular pressure. Other patients despite IOP in There is progressive glaucomatous optic nerve damage in the stigma of stigma. Although 10 months is an important factor in the formation of glaucoma, it is not the only pathogenic mechanism. The two keys to the treatment of glaucoma are to reduce the amount of water sample. Produce or promote its outflow from the eyes. The water sample is the liquid in the eye chamber that is filled after the horns and pancreas and in front of the lens.

body. It is formed by the ciliary body and is continuously secreted into the posterior chamber, causing continuous flow between the iris disc lenses and entering the eye chamber through the pupil. In individuals with a normal range of I0P, the concentration of the 'water sample solution' is adjusted by its generation and its balance.

The delicate balance of the festival was confounded. A, hold. When everything is working correctly, the intraocular pressure is normal and the water inflow and outflow are approximately equal. But when the equilibrium is destroyed by factors such as aging, inflammation, bleeding, or early inland whitening, it can become dangerously high if left untreated10]. / All previous therapies for the treatment of ophthalmic diseases regulated by high IOP are limited to reducing the production or outflow of water sample by 10% depending on the type and severity of the disease. Surgery or medical treatment and medical treatment are available For reducing I0P. By way of example " laser and surgical incision procedures can be used for the treatment of severe conditions such as open angle glaucoma. The atresia glaucoma caused by atresia or obstruction of the anterior chamber atreus angle therefore restricts the outflow of water sample fluid. Pharmacological agents are usually effective in the control of mild cases of open angle glaucoma, and in severe cases laser trabeculoplasty or filtering surgery is used to improve water drainage. Although surgical intervention for many types of glaucoma is usually Necessary and very '' but even if local anesthesia is available, it is an intrusive form of treatment. Pharmacological agents for dried breeds of dog shellfish can also be used to reduce IOP. One such pharmacological agent is 100462.doc 200536517 pupil. Although its clear effect _ has not been fully obtained _, the mitigating drug system reduces Ϊ 0 P by promoting the outflow of water sample fluid. Pupil dilators are also suitable for reducing IOP. For example, sympathomimetic amines (such as epinephrine and dipivefnn) reduce radon at least in part by stimulating h-adrenaline receptors in the trabecular meshwork. In addition, a2f epinephrine agonists (eg, apradonidine) have been shown to be effective in reducing UDP by inhibiting the formation of water samples. In addition, 'non-selective adrenaline blockers (such as morpholol (tim〇1〇1) and levobunolol (1__〇1〇1)) and βι selective ⑼ such as betaxolol ( betaxolol)) epinephrine blockers are also used to reduce IOP. Prostaglandin compounds have also been shown to have low intraocular pressure activity. Although the lack of these pharmacological agents is less invasive than surgical intervention, it is often accompanied by adverse confusion such as conjunctival function, blurred vision, eye pain and headache at the required effective therapeutic dose). In addition to IOP, glaucoma damage can also be caused by pathological mechanisms such as decreased blood flow or by eye inflammation. Usually, the inflamed cells physically block the rod-like network, reducing water outflow and keeping the horns open. Sometimes, the inflammatory cell 2 fibrin will form a connecting bridge between the peripheral iris and the horns, pulling the structure to the apposition and causing the horns to lock up. Because the anterior chamber makes inflammatory cells and proteins form adhesions between the posterior iris and the anterior crystalline lens, posterior rainbow is often formed. This will result in the protrusion of the iris, the blocking of the first angle, and the adhesion of the anterior iris. There may also be a group d system that increases IOP. If not treated, the patient will eventually experience glaucomatous optic nerve atrophy or may be retinal _ McQueen M gold, arterial occlusion. For example, 'traumatic injury, systemic disease' 3, and recurrent disease 'first formed in Portuguese patients with grapevine inflammatory glaucoma Yin 100462.doc 200536517. Secondary inflammation causes ιορ to rise through a variety of mechanisms. 『Recently developed drug’ cyclooxygenase · 2 selective inhibitor provides attractive treatment options for the treatment of several types of 3L χ syndrome, including ocular inflammation. These compounds selectively inhibit cyclooxygenase-2 activity to a greater extent than they inhibit cyclooxygenase-1 activity. Cyclooxygenase has been shown to be constitutive = and involves several non-inflammatory regulatory functions related to prostaglandins. In contrast, mounting oxygenase · 2 is an inducible enzyme that is primarily involved in regulating the inflammatory response. Because of their different manifestations and physiological effects, cyclooxygenase_2 selective inhibitors offer the advantage of including avoiding the harmful side effects associated with the inhibition of cyclooxygenase]. Several patents discuss compounds of different chemical classes that selectively inhibit cyclooxygenase_2, such as, for example, US Patent No. 5,434,178 (1,3,5-trisubstituted pyrazole compounds); US Patent No. 5,476,944 No. (derivative of cyclic phenol sulfide); U.S. Patent No. 5,643,933 (substituted sulfophenylene heterocyclic ring); U.S. Patent No. 5,859,257 (isoxazole compound); U.S. Patent No. 5,932'598 (containing ring Oxygenase-selective inhibitors of benzophenamine prodrugs); U.S. Patent No. 6,156,781 (substituted pyrazolyl benzsulfonamide); and U.S. Patent No. 6,11,960, the full text of which All incorporated herein by reference. SUMMARY OF THE INVENTION In some aspects of the invention, methods and compositions are provided for treating ocular cyclooxygenase-2 regulated diseases in a subject. The method includes administering a selective inhibitor of phenylacetate cyclooxygenase-2 to a subject. In one embodiment, the cyclooxygenase_2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof used in connection with the present invention may be selected from the group consisting of phenylacetic acid and 100462.doc 200536517. Enzyme-2 Selective Inhibition Sword Shows: Class Members' Its General Structure Table by Formula (m)

among them

318 R20 (III) R19 R16 is methyl or ethyl; R17 is gas or It; R18 is hydrogen or fluoro; methyl, ethyl, methoxy, ethoxy or R19 is hydrogen, alkyl, Gas group, hydroxyl group; r2 () is hydrogen or fluorine group; and

R is a gas group, a fluoro group, a trimethyl group, or a methyl group, and the limitation is that when R16 is an ethyl group and R19 is a fluorene, not all of R17, Ri, r20, and R21 are a fluoro group. In other embodiments, 'the cyclooxygenase_2 regulated eye disease is macular edema. In another embodiment, 'the cyclooxygenase-2 regulated eye disease is glaucoma. In another embodiment, 'the cyclooxygenase-2 regulated ocular disease is high intraocular pressure. 100462.doc 200536517 In other embodiments, the ocular disease regulated by cyclooxygenase-2 is ocular pain or ocular inflammation. Other aspects of the invention are described in more detail below. Abbreviations and definitions The term alkynyl group is a group provided by a residue after removal of the group from the organic acid. Examples of such fluorenyl groups include alkylfluorenyl and arylfluorenyl. Examples of such low-carbon alkyl fluorenyl groups include methyl fluorenyl, ethyl fluorenyl, propyl fluorenyl, butyl fluorenyl, isobutyl alcohol

Base, pentamyl, isoamyl, tamyl, hexamethylene and trifluoroacetamyl. The term "alkenyl" is a straight or branched chain group having at least one carbon-carbon double bond, which has two to about twenty carbon atoms, or preferably two to about twelve carbon atoms. A more preferred alkenyl group is a low-carbon alkenyl group having two to about six carbon atoms. Examples of alkenyl include vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. "Surgelenyl" and "low-carbon alkenyl" are also groups having a " cis, and " reverse " orientation or a " Έ " and " Z "orientation. The term " cycloalkyl " is a saturated carbocyclic group having three to twelve carbon atoms. A more preferred cycloalkyl group is "lower cycloalkyl" having three to about eight carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl,% pentyl, and cyclohexyl. Terminology "Alkoxy" and "alkyloxy" are straight or branched radicals containing oxygen radicals each having an alkyl moiety of-to about ten carbon atoms. More preferred alkoxy radicals are-to six &Quot; lower oxygen of one carbon atom ". Examples of such groups include methoxy, ethoxy, propoxy, butoxy and tertiary butoxy. 2. The term "oxyalkyl group" refers to an alkyl group having-or multiple alkyl groups. The-or multiple alkyl groups are connected to the alkyl group to form a single oxygen group and 100462.doc • 10 -200536517 oxyalkyl. These "alkoxy" may be further substituted with one or more halogen atoms (e.g., fluoro, fluoro, or bromo) to provide a haloalkoxy. A more preferred alkoxy group is a low-carbon alkoxy group having one to six carbon atoms and one or more halo groups. "Examples of such groups include fluoromethoxy, gasmethoxy, Trifluoromethoxy-methyleneethoxy, ethoxy, and propylpropoxy. The term π-oxyalkoxy "is a group containing an alkoxy group as defined above, which alkoxy group is connected to via an oxygen atom Carbonyl. More preferred is a low-carbon alkoxycarbonyl group having an alkyl moiety of 6 to 6 carbons. "Examples of such low-carbon alkoxycarbonyl (ester) groups include substituted or unsubstituted methoxycarbonyl, Ethoxycarbonyl, propoxy Ik, butyloxy and hexanoyl. Alone or in other groups such as "halohalo", "halogeno", "halooxy", and " through alkyl The term "alkyl" used in the term "radical" is a straight-chain, cyclic or branched-chain group having one to about twenty carbon atoms, or preferably one to about twelve carbon atoms. More preferred alkane A radical is a low-carbon alkyl group having one to about ten carbon atoms. The most preferred is a lower-carbon alkyl group having one to about six carbon atoms. Examples of such groups include methyl, ethyl, n-propyl Group, isopropyl, n-butyl, isobutyl, second butyl, third butyl, pentyl, isopentyl, hexyl, and the like. The term "pi alkylamino" is one or two Alkyl substituted amine groups. A "lower carbon N-alkylamino group" having an alkyl moiety of 1 to 6 carbon atoms is preferred. A suitable lower carbon alkylamine group may be a mono- or dialkylamino group, such as N-methylamine Group, N-ethylamino, N, N-dimethylamino, N, N-diethylamino or similar groups. The term `` alkylaminoalkylalkylπ has one or more attached to an amine An alkyl group of an alkyl group. 100462.doc -11- 200536517 The term "alkylaminocarbonyl" is an aminocarbonyl group substituted with one or two alkyl groups on the amino nitrogen atom. It is preferably ΠΝ-alkylaminocarbonyl "," N, N-dialkylaminocarbonylπ. More preferred is a π-lower N-alkylaminocarbonyl carbonyl lower-carbon N, N-dialkylaminocarbonyl having a lower-carbon alkyl moiety as defined above. The term "carbocarbonyl", πaryl "Carbonyl" and "aralkylcarbonyl" include groups having alkyl, aryl and aralkyl groups as defined above attached to a carbonyl group. Examples of such groups include substituted or unsubstituted methylcarbonyl groups , Ethylidene, phenylidene, and benzylidene. The term `` alkylthio, '' is a straight or branched chain alkyl group containing one to about ten carbon atoms, the alkyl group being attached to a divalent Sulfur atom. A more preferred alkylthio group is a `` lower alkylthio group '' having an alkyl group of one to six carbon atoms. Examples of such low-carbon alkylthio groups are sulfanyl, ethylthio, propylthio, butyl Sulfur and hexylthio. The term "alkylthioalkyl" is a group containing an alkylthio group which is attached to an alkyl group having from one to about ten carbon atoms by a divalent sulfur atom. More preferably, the alkylthioalkyl group has A "lower alkylthioalkyl" group of an alkyl group of one to six carbon atoms. Examples of the lower alkylthioalkyl groups include methylthiomethyl. The term '' alkanesulfinyl group π is a group of a straight or branched chain alkyl group containing one to ten carbon atoms, the alkyl group being attached to a divalent -S (= 0)-group. A more preferred alkylsulfinyl group is a "lower alkylsulfinyl group" having an alkyl group of one to six carbon atoms. Examples of such low carbon alkylidene groups include dihalite, yellow phosphinoyl, diethylene Rhenyl, butylenesulfinyl and hexylenesulfinyl. The term "alkynyl" is a straight or branched chain group having two to about twenty carbon atoms, or more preferably two to about twelve. Carbon atoms. More preferred alkynyl groups are π low-carbon alkynyl groups having two to about ten carbon atoms. Most preferred are low-carbon alkynyl groups having two to about six 100462.doc -12-200536517 carbon atoms. The Examples of such groups include propargyl, propargyl and the like. The term `` aminoalkyl '' is an alkyl substituted with one or more amino groups. More preferably, it is a `` low-carbon amino group Alkyl π. Examples of such groups include aminemethyl, amineethyl, and the like. The term πaminocarbonyl is `` amidoamine group of formula -c (= o) nh2. The term `` aromatic An alkoxy'f is an aralkyl group attached to another group via an oxygen atom. • The term πaralkoxyalkyl "is an aralkoxy group attached to an alkyl group via an oxygen atom. The term "aralkyl" is an aryl-substituted alkyl group such as benzyl, benzyl, trityl, phenethyl, and diphenethyl. The aryl group in the aralkyl group may be additionally I-, alkyl-, alkoxy-, i-alkyl, and halo-alkoxy substitutions. The terms benzyl and phenylfluorenyl are interchangeable. The term pi aralkylamino pi is connected by an amine nitrogen atom Arylalkyl to other groups. The terms Π-arylaminoalkyl "and" 仏 aryl-N-alkyl-aminoalkyl "are those that have undergone an aryl or an aryl and an alkyl group, respectively. Substituted amine group and has an amine group attached to an alkyl group. Examples of such groups include N-anilinomethyl and N-phenyl-N-methylaminomethyl. The term πaralkylthio is an aralkyl group attached to a sulfur atom. '' The term `` aralkylthioalkyl '' is an aralkylthio "group attached to an alkyl group through a sulfur atom. The term" arylfluorenyl "is an aryl group having a carbonyl group as defined above. Examples include phenylfluorenyl, naphthylmethyl, and the like and the aryl group in the arylfluorene 100462.doc -13-200536517 group may be additionally substituted. The term " aryl group, alone or in combination, Is a carbocyclic aromatic system containing one, two or three rings, where the rings can be linked together or can be fused. The term "aryl" includes aromatic groups such as phenyl, naphthyl , Tetrahydronaphthyl, immandyl, and biphenyl. The aryl moiety may also be substituted at the substitutable position by one or more substituents, which are independently selected from alkyl, alkoxyalkane Alkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkyloxy, hydroxyl, amino, dentyl, nitro, alkylamino, Fluorenyl, cyano, carboxyl, aminocarbonyl, alkoxycarbonyl, and aralkyloxycarbonyl. The term "arylamino" is an amine, which has been Substituted with one or two aryl groups, e.g., N- anilino. The " arylamino group " may be further substituted in the aryl ring portion of the group. The term "aryloxyalkyl" is a group having an aryl group attached to an alkyl group through a divalent oxygen atom. The term "arylthioalkyl" is a group having an aryl group attached to an alkyl group through a divalent sulfur atom. The group of a square group. The term "M group alone or in other terms such as, alkoxycarbonyl," is-(C = 0)-〇 term "carboxy" or, carb 〇xyl) "(alone or in other terms such as πcarbonylalkylπ) is -CO2H. The term f'carboxyalkyl is an alkyl substituted with a retarder. More preferred is a "low-carbon alkyl," which is a low-carbon alkyl as defined above, and may additionally be substituted on the alkyl group by a radical. . Examples of these lower carbon carboxyalkyl groups include carboxymethyl, carboxyethyl, and tert-propyl. 100462.doc -14- 200536517 "Salene", alkenyl "is a partially unsaturated carbon% group having three to twelve carbon atoms. A more preferred cycloalkenyl is" low carbon hafnium "having four to about eight carbon atoms. Alkenyl ''. Examples of such groups include cyclobutenyl, cyclopentenyl, cyclopentenyl and cyclohexenyl. The "selective inhibitor of cyclooxygenase-2" is a compound that can selectively inhibit cyclooxygenase-2 instead of cyclooxygenase]. Generally, it includes compounds having less than: 0.2 micromolar Cyclooxygenase_2 heart compound, and also has a selectivity ratio of cyclooxygenase-1 (C0X-1) IC5Q to cyclooxygenase_2 (c0x_2) IC5q of at least about 5, more usually Is at least about 50, and even more usually at least about. In addition, the cyclooxygenase_2 selective inhibitors described herein have a cyclooxygenase q iCw greater than about i micromolar, and more preferably greater than 1 〇Mole. The term "selective inhibitor of cyclooxygenase-2" also covers any of its isomers, pharmaceutically acceptable salts, esters or prodrugs. The metabolism of arachidonic acid used in this method Inhibitors of the cyclooxygenase pathway can inhibit enzyme activity by various mechanisms. By way of example and not limitation, the inhibitors used in the methods described herein can directly block enzyme activity by acting as substrates for the enzyme. The term ' 'Dental-based' is halogen, such as I, Qi, Mo, or Iodine. The term "dental alkyl" refers to any group in which one or more alkyl carbon atoms are substituted with a halo group as defined above. Specifically, it includes mono-alkyl, di-alkyl, and poly- Alkyl. For example, monodentate alkyl has one iodine, bromine, gas, or fluorine atom in the group. Di-A and poly-alkyl may have two or more of the same halogen atoms or different The combination of radicals. "Low-carbon halogenated radicals" are radicals having 6 carbon atoms. Examples of haloalkyl include fluoromethyl, difluorofluorenyl, trifluorofluorenyl, fluorenyl, dichloromethyl, trifluorofluorenyl 'I00462.doc -15-200536517 difluoromethyl, pentafluoroethyl, Heptafluoropropyl, difluorofluoromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, difluoroethyl and dichloropropyl. The term "heteroaryl" is an unsaturated heterocyclic group. Examples of unsaturated heterocyclic groups (also known as heteroarylπ) include unsaturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms , Such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazinyl, triazolyl (such as 411-1, 2, 'diazolyl, 1Η-1, 2,3_triazolyl, 2Η1,2,3-triazolyl, etc.), tetrazolyl (eg 1Η-tetrazolyl, 2Η-tetrazolyl, etc.), etc .; containing 1 to 5 nitrogen atoms Unsaturated fused heterocyclic groups, such as indolyl, isoindolyl, indazinyl, benzimidazolyl, quinolinyl, isoquinolinyl, indazolyl, benzotriazole, tetrazole

幷 Hazinyl (such as tetrazolium [,, ..., etc.), etc .; unsaturated 3 to 6-membered heteromonocyclic groups containing oxygen atoms, such as piperanyl, furanyl, etc .; Unsaturated 3 to 6-membered heteromonocyclic groups containing sulfur atoms, such as thienyl, etc .; Unsaturated 3 to 6 containing 1 to 2 oxygen atoms and 3 to 6 nitrogen = heteromonocyclic groups, such as Hydrazyl, isofluorenyl, amodisialyl (such as U, Xinxin, monozolyl, disialyl, oxadialyl, etc.), etc .; those containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms Unsaturated slightly heterocyclic groups (such as phenoxalyl, phenylsulfonyl, etc.); unsaturated 3 to 6-membered heteromonocyclic groups containing 硫 sulfur atoms and ^ to 3 nitrogen atoms, such as Fluorenyl, oxadiazolyl (e.g., i, 2,4 · thiadiazolyl, 1,3,4-thiadiazolyl, 152,5-thia: salyl, etc.), etc .; containing 1 to 2 Residues of sulfur and 1 to 3 nitrogen atoms and slightly heterocyclic groups (such as fluorenyl, benzene fluorenyl) and similar groups. The term also includes groups in which heterocyclyl and aryl are fused. Examples of fused bicyclic groups include benzene, benzophenone, and the like. 100462.doc -16- 200536517. The "heterocyclic group" may have 1 to 3 substituents such as an alkyl group, a hydroxy group, an i group, an alkoxy group, an oxy group, an amine group, and an alkylamine group. The term "heterocyclyl" is a saturated, partially unsaturated, and unsaturated heteroatom-containing cyclic group, wherein the heteroatom may be selected from nitrogen, sulfur, and oxygen. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, N-hexahydropyridyl, hexahydropyrazine: etc. ); Saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 3 to 3 nitrogen atoms (such as morpholinyl, etc.); containing 1 to 2 sulfur atoms and 3 to 6 nitrogen atoms Saturated 3- to 6-membered heteromonocyclic groups (such as thiazolidinyl, etc.). Examples of partially unsaturated heterocyclic groups include dihydrophene, dihydropyran, dihydroran, and difluorene. The term " heterocyclylalkyl " is a saturated and partially unsaturated heterocyclyl-substituted alkyl group, such as _ ° denylmethyl, and a heteroaryl-substituted filament, such as a methyl group and a methyl group. , The base drink ethyl and sultyl ethyl. The heteroaryl group in the heteroaryl group may be additionally subjected to fluorene, alkyl group, and oxygen

Group, substituted alkyl, and substituted alkoxy. The term "hydrogen" is a single hydrogen atom. For example, the hydrogen group can be connected to an oxygen atom to form a radical or two hydrogen radicals surrounding the oxygen. The I ring can be connected to a carbon atom to form a methylene group. (-CH〗-). The term "carboalkyl" is a straight or branched alkyl group having one to about ten carbon atoms. Any of the straight or branched alkynyl groups may be substituted with-or polyfluorenyl groups. A more preferred hydroxyalkyl group is a "lower hydroxyalkyl group" having one to six rabbit atoms and one or more hydroxyl groups. Examples of such groups include methylol, hydroxyethyl, hydroxypropyl, hydroxybutyl, and hydroxyhexyl. 100462.doc -17- 200536517

The term used in this article as an adjective, "pharmaceutically acceptable" means that the term "revision" applies to pharmaceutical products; that is, "pharmaceutically acceptable" substances are relatively safe and / or non-toxic, although they may not be themselves Provides separable therapeutic benefits. Pharmaceutically acceptable cations include metal ions and organic ions. Better metal ions include (but are not limited to) suitable metal test salts, soil test 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 some trimethylamine, diethyl Amine, N, N, -Dibenzylethylenediamine, Chloroproine, Choline, Diethanolamine, Ethylenediamine, Meglumine (N-methylglucamine ) And procaine. Exemplary pharmaceutically acceptable I include (but are not limited to) hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetamidine, formic acid, tartaric acid, and maleic acid. , Malic acid, citric acid, iso Citric acid, lactic acid, gluconic acid, glucuronic acid, pyruvate, acetoacetate, fumaric acid, propionic acid, aspartic acid, glutamic acid, #formic acid and the like A `` drug '' refers to a chemical compound that can be converted into a therapeutic compound by metabolism or a simple chemical process in the subject's body. For example, a prodrug is described in US Patent No. 5,932,598, which is incorporated by reference The method is incorporated in this article. The purpose of Wu Bi * for treatment includes anyone who needs the treatment. The examinee can be an animal-like animal in a livestock park, and can be tested to the willow cheek animal. In one embodiment, the subject is a mammal. In another embodiment, the mammal is a human. 100462.doc -18- 200536517 The term "sulfofluorenyl, whether alone or in combination with The term fluorenyl is used in combination as the divalent group _s〇2_. "Alkylsulfonyl" is an alkyl group attached to a sulfonyl group, wherein alkyl is as defined above. A more preferred alkylsulfonyl group is a "lower alkylsulfonyl group" having one to six carbon atoms. Examples of such low-carbon alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, and sulfonylsulfonyl. "Alkylsulfonyl" may be further substituted with one or more bleach atoms (e.g., fluoro, fluoro, or bromo) to provide a haloalkylsulfonyl. In the term, sulfamyin, "aminosulfonyl, and '' continylamino" are nh2o2s-.

The phrase "therapeutic effect" is used to limit the amount of a selective inhibitor of cyclooxygenase_2, which will achieve the purpose of improving the severity and frequency of disease compared to untreated. [Embodiments] Preferred embodiments DESCRIPTION OF THE INVENTION The present invention provides a group of people and methods for treating ocular cyclooxygenase-2 regulated diseases, which comprises administering to a subject a therapeutically effective amount of phenyl vinegar: a cox-2 selective inhibitor. Phenylacetic acid cox-2 selective inhibitor can be administered: the examiner to treat many cyclooxygenase-2 regulated eye diseases " disease, including inflammation and pain after eye surgery, eye tissue I Macular edema, pupil shrinkage during surgery, "; injury, = eyes, photophobia, retinitis, retinopathy, Portuguese ... symptoms, potential gifts from numbness ^ human eyes double nine, endophthalmitis, leather: outer layer 外Keratitis, keratoconjunctivitis, dry keratoconjunctiva ... Mooren's ulcer and high intraocular pressure. Insufficient cyclooxygenase-2 selective inhibitors Many suitable cyclooxygenase-2 selective inhibitors or their pharmaceutically acceptable 100462.doc -19- 200536517 acceptable salts or prodrugs can be used in the present invention ^ M In one embodiment, the ring gas blending used in connection with ♦ I β

Yiguang ... Selective inhibitor or its pharmacological J-salt or peony optional_ / k-mesh base acetic acid v. Epoxy octadecine inhibitors, m mT, Yilikou 鲥 2 choice ] Bei is represented by the general structure of formula (III):

R is methyl or ethyl; R is gas or I; R 8 is hydrogen or fluoro; ethyl, methoxy, ethoxy or

Rl9 is hydrogen, fluoro, chloro, methyl hydroxy; R0 is hydrogen or fluoro; and r21 is a gas, fluoro, trifluoromethyl or methyl group, with the limitation that tRl6 is ethyl and R19 is At this time, R 'r18, r2 (and R21 are not all fluoro groups. /, Another -phenylacetic acid-derived cyclooxygenase 2 used in the method of this month, and the selective inhibitors have the number ⑺X 189 (B_2) a compound having a structure shown in formula (II) or a pharmaceutically acceptable salt thereof or a former 100462.doc -20-200536517 drug, wherein: R16 is ethyl; R17 and R19 are chloro; R18 and R2G is hydrogen; and R21 is methyl. In other embodiments, a cyclooxygenase-2 selective inhibitor related to the method of acetaminophen,-, and bememin, or a medicinal product thereof, is acceptable. Salt or prodrug compound, the structure of which is shown in Table 1 below,

Τ includes (but is not limited to): 2- [4 · (4_fluorophenyl) _5- [4_ (methyl its z-stilbyl ~ acyl) benzyl] oxazole-2yl] acetic acid (B-191 );

-Benzyl] -acetic acid or COX 0 (2-gas-6-fluoro-benzylamino) _5-methyl189 (B-211); and, 5-dimethyl-benzylaminopropyl-phenyl] -[2- (2,4 -Digas-6-ethylacetic acid (B-233). Table 1

100462.doc -21-200536517

The cyclooxygenase_2 selective inhibitor used in the present invention may exist in tautomeric, geometric or stereoisomeric forms. In general, suitable cyclooxygenase_2 selective inhibitors that exist in tautomeric: geometric or stereoisomeric forms are those that specifically inhibit epoxy covalentity in the presence of ⑽μM or less, More commonly Jona, and even more usually about 75% or more of Γ. The present invention encompasses all such compounds, including cis and trans geometric isomers, geometric isomers, enantiomers, diastereomers, 1-isomers, racemic compounds thereof, and Other mixtures such as tautomeric, geometric or stereoisomeric forms are pharmaceutically acceptable == invented. As used herein, the terms " cis ,, and, anti " represent a few (" cis ") of the formula: where two carbon atoms connected by a double bond are on the same side of the double bond (a) or on The opposite side of the double bond ("trans") will each have-one hydrogen atom. The compound contains :: group: and means to include cis-trans, or "Ε " Multiple stereo: and: two: including R, S and mixtures or 100462.doc -22- 200536517 for each stereo center present The selective cyclooxygenase_2 inhibitor used in the present invention can be free Alkali or medicated acid addition salt exists. The term " pharmaceutically acceptable salt " is a salt commonly used to form alkali metal salts and to form free acids or addition salts of free bases. If the salt is pharmaceutically acceptable, a suitable pharmaceutically acceptable acid addition salt of its compound can be prepared from an inorganic or organic acid. Examples of such inorganic acids are hydrochloric acid, hydrofluoric acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphonic acid. Suitable organic acids may be selected from the group consisting of aliphatic acids, cycloaliphatic acids, aromatic acids, araliphatic acids, heterocyclic acids, carboxylic acids, and sulfonic organic acids. Examples are formic acid, acetic acid, Z acid, succinic acid. , Glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, _sonson & uronic acid, maleic acid, fumaric acid, pyruvate, aspartic acid 、 船 蚣 々 # Branamine I, Benzoic acid, o-aminobenzoic acid, mesitate, 4-hydroxybenzoic acid, Xiao △ Benzoic acid, mandelic acid, embenic acid (dihydroxy acid), methanesulfonate Acid, ethanesulfonic acid, Ishidanban ^ Ben ^ acid, pantothenic acid, 2-acetylacetic acid, toluic acid, p-aminobenzenesulfonic acid, cyclohexyl-A-diyl ^ luteol, stearic acid Acid, algenic acid, hydroxybutyric acid, glutamic acid, lactobionic acid and galacturonic acid. Appropriate compounds for use in this method > ^ _ Accepted acceptable addition salts include metal salts made from aluminum, calcium, lithium, magnesium, Kouyi ##, potassium sodium, and N, or N, _ Dimethyl ethylene diamine, cloproca r M Choline, diethanolamine, hex-neck, meglumine (N-methylglucamine) and organic salts such as Purcaine can be borrowed It is prepared by the conventional method "" and all 4 are prepared from the corresponding compounds, for example, osmic acid or a base is reacted with any compound of the formula stated herein. Can be combined with a carrier substance to produce a single dose, tongue-like &# θ μ 玍 early clam middle-grade lice synthase-2 selectively inhibits the activity of d 丨 generation as 1 will depend on the patient and only + special The style changes. Generally, these pharmaceutical compositions may contain a cyclooxygenase-2 selective inhibitor in the range of about 0.1 to 2000 mg, more usually in the range of about 0.5 to 500 mg and also More usually between about 1 and 200 mg. A dosage of about 0.01 to 100 mg / kg body weight, or more usually between about 0.1 and about 50 mg / kg body weight, and even more usually about 2 to 20 mg / kg body weight may be appropriate. The daily dose can be administered in one to about four doses per day. Those who are eager to learn this technology should understand that agents can also be prepared by Goodman & Goldman ’s The Pharmacological Basis of Therapentipq, Ninth Edition (1996) ‘Appendix II’ on pages 1707-1711 and Goodman & Goldman ’s

Guidelines for The Pharmacological Basis of Therapeutics, Tenth Edition (2001), Appendix II, pp. 475-493. Routes of Administration In general, as detailed herein or otherwise known in the art, a composition comprising a therapeutically effective dose of a phenylacetate cyclooxygenase-2 selective inhibitor can be effective by many delivery therapies Different doses are administered. For example, the formulation of medicaments is discussed in Hoover, John E., Remington ’s Pharmaceutical Sciences, Mack Publishing Co. 5 Easton, Pennsylvania (1975) and Liberman, H.A. and Lachman, L., ed.

Marcel Decker, New York, NM (1980) 0 In one aspect, the composition is directly administered to the eye by any method known in the art, such as a solution, cream, ointment, emulsion, suspension And slow release formulations. Administration of the composition to the eye usually results in direct contact of the agent with the cornea through at least a portion of the agent to which it is administered. Generally, the composition has an effective residence time in the eye of about 2 to about 24 hours, 100462.doc -24- 200536517 more usually about 4 to about 24 hours and most often ㈣ to about 24 hours. The composition of the present invention can be exemplified as a liquid

Exist in solution, county quenching ten workers 丄 丄 T 糸 月 J ^ ^ 3 _. Generally, when the composition is administered as a solution or a suspension, a part of the seven M, M, M is present as a solution and the medicament knife is present as particles in a suspension in a liquid matrix. . In some embodiments, the liquid body may include a gel formulation. In other embodiments, the liquid composition is aqueous. Alternatively, the composition may be in the form of a salve.

In the actual example, the composition is an aqueous solution, a suspension or a solution / suspension, and may be in the form of a 4-eye agent. With a suitable dispenser, the required dose of each drug f can be calculated 'for example' for a volume of 25 for a drop volume of 25 ... by giving a known number of drops into the eye. μΐ "Composition. The aqueous composition of the present invention generally comprises about 0.001% to about 5%, more usually about () · 1% to about 2 ()%, still more usually about ^ to about 5%, and most usually about 5% to About 5% weight / volume of phenyl acetate-2 selective inhibitor. In general, the aqueous composition of the present invention has an ophthalmically acceptable osmotic pressure. With respect to formulations, compositions or ingredients, "eye acceptable" generally means that the treated eye or its function does not have a continuing deleterious effect on the health of the subject being treated. It should be recognized that transient effects such as minor irritation or " acupuncture " sensations are common for topical eye administration, and the presence of such transient effects is related to the formulation, composition or ingredient in question as detailed herein, "Acceptable" is not the same. However, the § weekly formulations, compositions, and ingredients used in the present invention are those that do not generally cause a substantial adverse effect 100462.doc -25- 200536517 (even if they are transient in nature). In aqueous suspensions or solution / suspension short conjugates, the agent may be in the form of primary μnanoparticles, meaning solid particles with a longest dimension of less than about 1,000 μm. One benefit of the composition is the faster release of the agent, and therefore more complete release than the larger particle size during the residence time of the composition in the eye being treated. Another benefit is that the likelihood of eye irritation is reduced compared to larger particle sizes. The reduction in eye irritation in turn leads to a reduction in the tendency of the composition to lose eyes from the treated eye by tearing, which is triggered by this stimulus. In a related composition, the medicament typically has a d90 particle size of about 10 to about 2,000 coffee, of which about 25% to about 80% of the particles by weight are nano particles. " 〇9. " is a unit of length of diameter, which has a value of 90% of the particles in the composition in the longest dimension of the particle, which is smaller than its diameter. In order to achieve the purpose of Ling Shi, it is usually appropriate to determine Dm based on 90% by weight and lees instead of volume. In the: composition, substantially all the pharmaceutical particles in the composition are smaller than ⑽ :::, and the weight percentage of the nano particles is noodles or nearly 100%. In general ' the average particle size of the agent in this embodiment is usually about 100 scoops nm, more usually about 150 to about 600 nm, and even more usually about .nm to about 400 nm. Miscellaneous addition— * f μ table can be crystalline or amorphous in nano particles. Methods involving preparation of nano-particles by grinding or pulverization usually provide elixirs in a crystalline form, while methods involving self-solutions usually provide medicaments in an amorphous form. In some embodiments, the ophthalmic composition may be an aqueous suspension of a hua agent with low water solubility.

The book is mainly or essentially completely in the form of rice grains. D, ☆ M is not bound by the theory of X. It is believed that the release of this agent from nano particles 100462.doc -26- 200536517 is significantly faster than the typical "micron" size that has (for example) about 10, _ nm or larger ~ inches. "The composition is released. In another embodiment, the aqueous suspension composition of the present invention may comprise the first part of a pharmaceutical agent in the form of a nanogranule that promotes relatively rapid release: The second part of a medicament with a particle size of nm or larger, which can provide a stored or stored medicament for release in a treated eye for a period of time, such as M to about 24 hours, more usually about 2 to about 12 hour.

In another embodiment, the aqueous suspension may contain one or more polymers as a suspending agent. Useful polymers include water-soluble polymers such as cellulose polymers (e.g., hydroxypropylmethyl cellulose) and water-insoluble polymers such as carboxyl-containing crosslinked polymers. The composition may be an in-situ gelable aqueous solution, suspension, or solution / suspension, as disclosed in U.S. Patent No. 5,192,535, which has an excipient substantially comprising one or more of the total weight of the composition Based on a weight ratio of about 聚合物 to about 6.5% (usually about 0.5% to about 4.5%) of a carboxyl-containing crosslinked polymer. Water-resistant suspensions are usually sterile and have an osmotic pressure of about 10 to about 400 mSM (usually about 100 to about 250,000 mSM), and about 3 to about 6.5 (usually about 4 to about 6). pH 'and initial viscosity of about 10,000 to about 30,000 cPs when administered to the eye' which is a Brookfield at 25 ° C using a # 25 rotor with 12 rpm and a 13R small sample holder Measured by Digital LVT Viscometer. More typically, the initial viscosity is from about 5000 to about 20,000 cPs. The polymer component has an average particle size of no more than about 50 μm in terms of equivalent sphere diameter, typically no more than 30 μm, more typically no more than about 20 pm, and most typically about 1 to 100 462 .doc -27- 200536517 is about 5 μιη, and is slightly crosslinked to such an extent that the viscosity of the suspension rapidly increases to form a gel upon contact with tear fluid having a typical pH of about 7.2 to about 74 in the eye. This gel formation allows the composition to remain in the eyes for a long time without being lost by tearing.

Suitable carboxyl-containing polymers for use in the composition are prepared from one or more carboxyl-containing monoethylene-based unsaturated monomers, such as acrylic acid, methacrylic acid, ethacrylic acid, butenoic acid, European Acetic acid, maleic acid, butyl butyric acid, α-phenylpropanoic acid, α-benzylpropanoic acid, acetic acid, cinnamic acid, coumaric acid and umbellic acid, the most typical For acrylic. The specialty polymer is cross-linked using one or more polyfunctional cross-linking agents, such as non-polyalkenyl, with a weight ratio of less than about 5%, typically from about 0.00% to about 5%, and more typically from about 0.2% to about 1% by weight. Polyether difunctional cross-linking monomers, such as diethylene glycol. Other suitable cross-linking agents illustratively include 2,3-dihydroxyhexan, 5-diene, 2,5-monomethylhexa-1,5 · diene, divinylbenzene, N, N • Diallyl allylamine and N, N-diallyl methacrylamide. Diethylene glycol is typically used. The cross-linking of polyacrylic acid and diethylene glycol is called polycarbophil. Polycarbophil-containing polymer systems are marketed under the trademark Durasite®w, a continuous release topical ophthalmic delivery system, by On Inc., Alameda, CA. In another formulation, the composition may be an in-situ gelable aqueous solution, suspension, or solution / suspension, as disclosed in U.S. Patent No. 4,861,76 (), which has an excipient substantially comprising about A polysaccharide having a weight ratio of 0.1% to about 2% becomes a gel when it comes into contact with an aqueous medium having an ion concentration of tears. -The polysaccharide is gellan gum. The composition can be prepared by a procedure substantially as disclosed in U.S. Patent Nos. 100462.doc -28-200536517 4,861,760. In another formulation, the composition may be in situ, or a solution, suspension, such as US Patent No. 5,587, ~

"Fu" generally contains about 0.2% to about 3% (usually about 0.5% to about 0.5% by weight gelatinized polysaccharide, which is usually selected from gellan gum, seaweed gum, and polyurethane. And about 1% to about 50% of a water-soluble polymer that forms a film, which is usually selected from the group consisting of calcined cellulose (e.g., methyl cellulose, ethyl cellulose), cellulose (e.g., ethyl cellulose, Via propyl methyl cellulose), hyaluronic acid and its salts, chondroitin sulfate and its salts, polymers of acrylamide, acrylic acid and polycyanoacrylate, methyl methacrylate and methacrylic acid 2 · Hydroxyl-based polymers, polydextrose, cyclodextrin, polydextrin, maltodextrin, dextran, polydextrose, gelatin, collagen, natural gums (such as xanthan gum, haricot bean Gum arabic knee, tragacanth gum and carrageenan, and fat fat), polygalactoide S-type biomimetics (such as gum), polyethylene glycol, polyethylene. Slight bite and polyethylene glycol. The combination It may optionally contain counterions that promote the gel, such as calcium in a latent form, such as those encapsulated in gelatin. The composition may be substantially as beautiful as Prepared by the procedure disclosed in Patent No. 5,587,175. In other formulations, the composition can be an in-situ gelable aqueous solution, suspension or solution / suspension, as disclosed in European Patent No. 0 / 424,043, which has The excipient generally contains about 0.1% to about 5% carrageenan. In this practical example, 'carrageenan having no more than 2 sulfate groups per repeating disaccharide unit is typical, Including 1 carrageenan with 18-25% by weight sulfate, I-carrageenan with 25-34% by weight sulfate, and mixtures thereof. In another specific formulation, the composition comprises ophthalmic Acceptable mucus 100462.doc -29- 200536517 1 Adhesive, which is selected from, for example, carboxymethylcellulose, poly (vinyl carbamate), σ in clothing, poly (methacrylic acid) Methyl ester), polypropylene, polycarboacrylic acid / butyl acrylate copolymer, sodium alginate, and dextran. In addition,, and the composition, the agent is at least partially through ophthalmically acceptable— The term `` solubilizing agent '' usually includes causing the agent to form microcells :: Solution agents. Certain ophthalmically acceptable nonionic surfactants such as polysorbate 80 can be used as solubilizers, such as ophthalmically acceptable alcohols, polyethylene glycols (such as polyethylene glycol 400), and Glycol ethers. Cyclodextrins are suitable for use in the solutions and solution / suspension compositions of the present invention. Suitable cyclodextrins can be selected from cardiac cyclodextrin, cardiac cyclodextrin, and alpha-cyclodextrin. , Alkylcyclodextrin (such as methylcyclodextrin, dimethylcyclodextrin-ethyl-α-cyclodextrin), hydroxyalkylcyclodextrin (such as hydroxyethyl_cyclodextrin, hydroxyl Propyl-α-cyclodextrin), carboxyalkylcyclodextrin (such as carboxymethyl-dextrin), alkyl acetate cyclodextrin (such as sulfobutyl ether cyclodextrin), and the like. The ophthalmic application of cyclodextrin has been described by Rajewski & Stella () '~ -urna ^ ^ 3 Xmaceutical Sciences. 85, 11 54, pages 1 155-1 159. 'If necessary, cyclodextrin-mixed agents, as described by Loftssoon (1998), Hwang Hwang and 53, 733-740, can be added by adding hydrocolloid polymers (such as carboxymethyl cellulose, Via propylmethyl cellulose or polyvinylpyrrolidone). In some embodiments, the compositions of the present invention may include one or more ophthalmically acceptable pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, and hydrochloric acid; such as hydroxide Sodium, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trimethylolamine; 100462.doc -30- 200536517 and buffers such as citrate / dextrose, sodium bicarbonate, and chlorination Ammonium. The acids, bases and buffers are included in amounts necessary to maintain the pH of the composition within an ophthalmologically acceptable range. In another embodiment, one or more ophthalmically acceptable salts may be included in the composition to bring the osmotic pressure of the composition into an ophthalmically acceptable range. Such salts include those having sodium, potassium, or ammonium cations and chlorides, #citrate, ascorbate, shed, linate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable Salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate. As disclosed in International Patent Publication No. WO 95/03784, the polymer-containing composition may optionally include one or more ophthalmically acceptable acids having at least two separable hydrogen groups as parenting agents by Suppressing the polymer's spoilage delays the release of the agent. Acids used as interacting agents include boric acid, lactic acid, orthophosphoric acid, citric acid, oxalic acid, succinic acid, tartaric acid, and glyceryl formate phosphate. In another example, substantially as disclosed in U.S. Patent No. 4,559,343, the composition may include ophthalmically acceptable xanthosine derivatives (such as caffeine, cocoline, or theophylline) to reduce Eye discomfort related to the composition. In alternative embodiments, the composition may include one or more ophthalmologically acceptable preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as mophene (read fen) and thimerosal; stable and stabilized dioxide gas; and tetra-compounds such as chlorinated compounds, evolved trimethylmerethane and gas Cetylpyridine. In other embodiments, the composition may include a surfactant (usually a non-ionic surfactant) that can be accessed at 100462.doc 200536517 in ophthalmology to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerol vinegar and vegetable oils (such as polyoxyethylene (60) hydrogenated sesame oil); and polyoxyethylene alkyl ethers and alkylphenyl ethers (such as octylbenzyl alcohol) 1O, octylbenzyl alcohol 40) 0 In another embodiment, the composition may include-or more antioxidants to enhance the desired chemical stability. Suitable antioxidants include ascorbic acid and sodium metabisulfite. In another example, the composition may optionally include one or more ophthalmic lubricants to promote tearing or as a " dry eye disease " administration method. These agents include polyvinyl alcohol, methyl cellulose, propyl methyl cellulose, polyethylene acetone, and other ketones. The aqueous suspension composition of the present invention can be enclosed in a single-dose non-reclosable container. These containers allow the composition to be kept in a sterile condition and therefore do not require such precautions as preservatives that can sometimes cause eye irritation and sensitization. Alternatively, multiple-dose reclosable containers can be used, in which case the composition usually contains a preservative. Alternatively, the composition can take the form of a solid article, a basin can be inserted between the eye and the eye test or in the conjunctival sac, where it releases the agent as described, for example, in US Patent No. 3,863,633 and US Patent No. 3 '868,445' are all Ryde & Coffee, incorporated herein by reference. Release to tears that moisturize the surface of the cornea, or directly to the cornea itself, usually in close contact with the solid object. Solid articles suitable for implantation into the eye in this manner usually consist mainly of polymers and can be biodegradable or non-biodegradable 100462.doc -32- 200536517. Biodegradable polymers useful in the preparation of ocular implantable drugs carrying a selective inhibitor of phenylacetic acid Cox_2 according to the present invention include, but are not limited to, aliphatic polyesters such as poly (glycolide), poly (glycolide), Polylactide, poly (hydroxycaprolactone), poly (hydroxybutyrate) and poly (hydroxyvalerate) polymers and copolymers, polyamino acids, polyortho acids, polyacid needles, fats Polycarbonate and polyether intrinsic properties. Suitable non-biodegradable polymers include poly elastomers. In another aspect of the invention, the composition is not directly administered to the eye. By way of example, the combination The substances can be administered orally, parenterally, by inhalation spray, rectal or topically in dosage unit formulations containing the required conventionally non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The solid dosage forms not used for oral administration may include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the medicament of the present invention is usually combined with one or more adjuvants suitable for the indicated administration route. Combination. If administered orally, the drug can be combined with lactose and sucrose 、 Powder-killing powder, burning acid cellulose_, cellulose burning ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, gum arabic, sodium alginate Polyvinylpyrrolidine and polyvinyl alcohol are mixed, and then, for the convenience of administration, tablets or sealed capsules can be prepared. These capsules or tablets can contain controlled release formulations, such as active compounds in hydroxypropylmethyl Dispersions in cellulose are provided. In the case of capsules, incinerators, and pills, the dosage form may also include buffering agents, such as sodium clavulanate, carbonic acid or bicarbonate, or! $. Tablets and pills may additionally be provided by the intestine Liquid-coating preparation. Liquid dosage forms for oral administration may contain pharmaceutically acceptable emulsions / solubilizers containing inert dilute # agents (such as water) commonly used in this technology. 100462.doc -33-200536517 Liquid, suspension Liquid, sugar polymer and alcohol. These compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents and sweeteners, flavors and fragrances. The term parenteral includes subcutaneous injection, intravenous Intramuscularly, intrasternally Injection or drip technology. Injectable preparations such as sterile injectable aqueous or oily suspensions can be formulated according to known techniques using suitable humectants and suspensions. Sterile injectable preparations can also be non-toxic parenteral An acceptable injectable diluent or solvent is a sterile injectable solution or suspension (eg, a solution in 3-butanediol). Among the acceptable vehicles and solvents that can be used are water and Ringer's (Ringer , S) solution and isotonic sodium vaporized solution. In addition, usually sterile, non-volatile oil is used as a solvent or suspension medium. To achieve this, any mild non-volatile oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid have been found to be used in the preparation of injectable solutions. Dimethylacetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. For example, they can also be used above A mixture of solvents and humectants discussed. For therapeutic purposes, the formulations for parenteral administration may be in the form of isotonic sterile injection solutions or suspensions, with or without water. These solutions and suspensions can be prepared from sterile powders or granules with one or more of the carriers or diluents mentioned in the formulations for oral administration. Covered metallurgical compounds are soluble in water, polyethylene glycol, propylene glycol, ethanol, corn oil cottonseed oil, turmeric oil, sesame oil, benzyl alcohol, sodium carbonate solution, or various buffers / nights. Other adjuvants and modes of administration are widely known in this medical technology. Indications for treatment Generally speaking, the composition of the present invention contains phenylacetic acid cyclooxygenase-2. 100462.doc • 34- 200536517 Selective inhibitor, which can be administered to the subject to be treated with ancient CDX-2. The purpose of the " ": effective postoperative treatment of a variety of different operations, it is widely stated that eye diseases can be sleeping disorders and pain, acute damage to the eye tissue, glaucoma, edema of the main spot, hand-to-hand, and ward-Shii ^ Pupil shrinkage during autopsy surgery m: light, retina [retinopathy, uveitis, inflammation, eye:;, :: external: inflammation, keratitis, keratoconjunctivitis, dry keratoconjunctivitis, Moy's ulcer and High intraocular pressure.

As detailed above, in some aspects the present invention provides a method for reducing IOP in a subject. The composition can also be used to treat various ophthalmic diseases that are regulated by high ⑴p in a subject. High IOP is usually harmful to the optic nerve of a particular subject = 100P level and can be easily dispersed by those skilled in the art. The service can be in the positive: 粑 Wai 'especially for patients with normal pressure glaucoma. Taking an example to illustrate, glaucoma is characterized by two progressive neuropathy due to the harmful effects of increased IOP on the optic nerve. In normal individuals, 101 > 3 is in the range of 12 to 20, with an average of about 6 mm Hg. At higher values, such as over 22 mm Hg, there is a risk that the eyes may be affected, and glaucoma formation will occur if left untreated. In one embodiment, if the high Iop in the subject is the cause of any type of glaucoma formation Factors, the composition can be administered to the subject. There are several different types of glaucoma, each with different pathophysiological abnormalities and risk factors, which can be treated by administering the composition of the invention. According to the taxonomy, glaucoma can first be considered to be "primary," or "secondary." Primary glaucoma is directly caused by the tissue structure and / or physiological disturbance of the flow of water-like fluid, which in turn causes an increase of 101 and> Occurred. Secondary glaucoma develops due to eye damage (such as trauma to the eye) 100462.doc -35- 200536517 or pre-existing diseases (such as intraocular swelling L, * 4 enlarged cataract). Although various secondary Primary glaucoma has different etiologies, but the similarities between the discriminative primary glaucoma and the primary glaucoma are that they all stand by…, x. 狎 A lesions caused by visual loss can be easily administered to the composition with any form of primary The subject of glaucoma. In one alternative embodiment of this embodiment ... the primary glaucoma is the horn

On = sexual glaucoma (also known as chronic or single glaucoma). Open-angle glaucoma is characterized by an abnormally high resistance to the discharge of liquid from the eye. In another alternative to this embodiment, the primary glaucoma is corneal angle-locked glaucoma (also known as closed-angle or narrow-angle glaucoma). In glaucoma, the anterior chamber angle is blocked or blocked by another eye structure (usually the iris), thus restricting the flow of water sample. In another alternative form of this embodiment, the primary glaucoma is congenital f-eye (also called infant pure glaucoma). In another embodiment, the composition may be advantageously administered to a subject having any form of bristles with 1 * moonlight eyes. By way of example, secondary glaucoma can be secondary open angle glaucoma or secondary closed angle glaucoma. In other embodiments, the composition is administered to a subject who has high eyesight but has not yet formed glaucoma. In this embodiment, typically the subject will have an IOP greater than about 20 mm Hg, more typically greater than about 21 and often greater than about 22 mm Hg. Further, in other embodiments, the composition may be administered to a subject having a high risk of developing glaucoma. In addition to subjects with high IOP, subjects in certain groups are at risk of developing glaucoma. These groups typically include subjects with a family history of glaucoma, people of African descent over the age of 40, every 100462.doc -36- 200536517 individuals over the age of 60, and people with diabetes. In an alternative form of this embodiment, the subject also has a high IOP. In another embodiment, the composition can be administered to a subject who is taking a particular drug that is known to increase the incidence of glaucoma. By way of example, it is known to administer corticosteroids (such as prednisol, dexarnethasone, and hydrocortisone) in ophthalmology and systemic administration.

Later, it induces glaucoma by increasing the resistance to the outflow of water-like fluid through the trabecular meshwork through a mechanism that is genetically related to primary open angle glaucoma to some extent. In detail, dexamethasone has been associated with the most significant increase in intraocular pressure, and usually ophthalmic administration leads to greater increases than systemic administration. In another aspect, the composition can be administered to a subject having an ophthalmic disease that is modulated by abnormal ocular water transport. By way of example, the ophthalmic disease may be idiopathic macular edema, corneal edema, diabetic macular edema, macular edema after cataract, m- fluid retinopathy, or any venous occlusive disease of the retina. Another aspect of the present invention encompasses administering the composition to a subject X who has received or will undergo eye surgery. The eye surgery may be prophylactic or corrective. = Illustration of Examples' The eye surgery can be a corneal transplant operation, a lens implantation operation, a retinal detachment operation, a cataract operation, and a refractive operation. A composition that selectively inhibits CD12 is more effective in slowing down or dying of a genital disease than a therapy involving NSAIDs that lack selective C-purchasing inhibition, and is treated with COX · 2 to regulate the eye. Suppress the dangers of related side effects. Therefore, when the composition of the present invention is particularly applicable, the NSAIDS shows that the treatment is not regular. By way of example, the known 100462.doc -37- 200536517 nsAIDs can show improper treatment in the following subjects: subjects with gastric ulcer, gastritis, localized enteritis, ulcerative colitis or diverticulitis, with gastrointestinal Subjects with a history of recurrence of the disease include those with gastrointestinal outbreaks, coagulopathy including anemia (such as hypothrombin, hemophilia, and other bleeding problems) or kidney disease. One advantage over the conventionally used nsaids for topical application to the eye is that it has no effect on baseline cox, segmental physiological functions (including wound healing after eye surgery and intraocular pressure control). Example 1-Endotoxin-Induced Uveitis in Rats

Endotoxin-induced uveitis in rats was performed using materials, reagents, and procedures substantially as described by Tsuji et al. (Exp. Eye Res., 64, 31 (1997)). Female six-to-seven-week-old 1 ^ 8 rats weighing about 160 § were reared under 12 hr light and dark circles, humidity was maintained at 55%, and room temperature was at 23 degrees Celsius. Food and water were fed at will. Subcutaneous injection of Salmonella typhimurium (~ / mow // a) lipopolysaccharide (LPS) endotoxin (500 per kg, dissolved in saline at a concentration of 1 mg / mL) into the skin by foot subcutaneous injection to induce uveitis In topical application, the specific phenylacetic acid COX-2 inhibitor (0.01-1.0%) tested was slowly infused (5 μΐ / eye) three times 1 hr before LPS injection and 3 and 7 hours after. For systemic For application, the tested phenylacetic acid Cox_2 inhibitor was injected subcutaneously 3 hours after LPS injection. Twelve hours after LPS injection, animals were sacrificed and both eyes of each animal were used. By using a 27 gauge needle Collect the water sample in the anterior chamber of the broken eye. Place the water sample (5 μΐ) in phosphate buffered saline (495 μΐ) containing 1% trimeraldehyde. Calculate the water sample using a flow cytometer system The number of cells. The average number of cells in each eye of each animal was used for statistical analysis of the results. 100462.doc -38-2 00536517 Example 2-Endotoxin-induced guinea pig uveitis test Endotoxin-induced guinea pig uveitis is performed using materials, reagents, and procedures substantially as described by Tsuji et al. (Inflamm. Res., 46, 486 (1997)). Test. Male five to six week old Hartley guinea pigs weighing about 300-450 g were reared in a 12 hr light and dark circle, humidity was maintained at 55% and room temperature was at 23 degrees Celsius. Food and water were freely fed. In penbar Under pentobarbital anesthesia, lipopolysaccharide (LPS) of E. coli (10 μ1) was intracamerally injected into each eye of guinea pigs using a 30 gauge needle. This procedure was accompanied by puncture beta surgery. In topical application, the tested phenylacetic acid COX-2 inhibitor (0.01_1.0%) was slowly infused (10 μΐ / eye) twice 1 hr before and 3 hr after LPS injection. 12 hours after LPS injection The animals were sacrificed by bloodletting and both eyes of each animal were used. Water samples were collected by puncturing the anterior chamber of the eyes with a 27 gauge needle. Water samples (5 μΐ) were placed in a 1% trimer Formaldehyde structurate buffered saline (495 μΐ). Using a flow cytometer system Calculate the number of cells in the water sample solution. The average number of cells in each eye of each animal is used for statistical analysis of the results. Similar to the LPS-induced uveitis model in rabbits can be roughly used as described by Howes (J 〇urnai 0f 〇cuiar pharmacology, 10, 289 (1994)). Example 3-Trauma-induced rabbit eye inflammation test Trauma-induced rabbit eye inflammation test was performed using materials, reagents, and procedures substantially as described by Gamache et al. (Inflammation, 24, 357 (2000)). New Zealand white rabbits (2-2.5 kg) were tested with a single topical ocular dose of phenylacetic acid COX-2 inhibitor (0.01-1 · 0%) or vehicle (50μ " eye) at 100462.doc- 39- 200536517 Bilateral administration. At each time interval after administration (15 min to 8 hrs), each eye was treated with one drop (5 μ1) of 0.5% promecaine, and trauma was induced by puncture within 5 min. The water sample (150 μl / eye) was removed by puncturing the cornea with a 27 gauge needle. One hundred microliters of the water sample was diluted with 100 μl of EDTA (2%, pH 7.4) in saline and stored at -70 ° C for subsequent analysis of protein and PGE2 content. Thirty minutes after the initial puncture, animals were sacrificed with a marginal ear vein with pentobarbital sodium (100 mg / kg). Obtain and store a water sample after trauma as described above. The protein concentration of the water sample was analyzed according to a calorimetry method substantially as described by Bradford et al. (Anal. Biochem., 72, 248 (1976)). In order to monitor the formation of PGE2 by radioactive HPLC, the water sample extract was incubated with 10 gg / M14C-labeled arachidonic acid (1Q ton Ci / mol) at 37 ° C for 10 min. Quantification of PGe2 in organic extracts was generally performed by HPLC as described by Powell (Anal. Biochem., 148, 59 (1985)).

100462.doc 40-

Claims (1)

200536517 X. Scope of patent application: A method, which uses v, person >, & to treat patients with cyclooxygenase g & ap Α disease, in which the disease is a kind of disease, vertical ^ W means the eye Inflammation of the skin after surgery, dermatitis and ophthalmology and pain, acute damage to the eye tissue, pupil shrinkage during cyanectomy surgery, eye pain, eye inflammation, photophobia, retina Inflammation, retinopathy, grapevine inflammation, eyelid : Inflammation: episcleritis, keratitis, keratoconjunctivitis, dry cornea ^ Mooren's ulcer and high intraocular pressure. The method includes treating an effective dose of phenylacetic acid epoxy with a test Synthase selective inhibitor or pharmaceutically acceptable salt of phenylacetate cyclooxygenase-2 selective inhibitor or peony drug of phenylacetate cyclooxygenase_2 selective inhibitor 'The phenylacetate The cyclooxygenase-2 selective inhibitor has the formula: R18 Where: Rl6 is methyl or ethyl; Rl7 is gas or fluoro; R is hydrogen or fluoro; Rl9 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy 100462.doc 200536517 r2 () is hydrogen or fluoro; and R is milk, fluoro, trifluoromethyl or methyl, and the restriction is that when R16 is ethyl and R19 is fluorene, R17 ,, R20 and R21 are not all fluoro groups. 2. The method of claim 1, wherein R16 is ethyl; Rl7 and Rl9 are gas groups; R18 and R2G are hydrogen; and r21 is methyl. The method of member 1, wherein the phenylacetic acid cyclooxygenase_2 selective inhibition tablet 1 is 2- [4- (4-xiangbenzyl) _5_ [4_ (methylcontinyl) phenylphenyloxine Base] method for applicant 1, wherein the phenylacetate cyclooxygenase_2 selective inhibition = is [2 ♦ air-6-airyl_anilinemethyl · phenyl] _acetic acid. The method of seeking a person 1, wherein the phenylacetic acid cyclooxygenase_2 is selectively inhibited to be [2- (2,4-dichloroasthyl-3,5-dimethyl.aniline) propyl _ Phenyl] • Acetic acid. 6. Method as requested in item 1, macular edema. 7. Method as requested in item 1 Glaucoma. 8. The method of claim 7, wherein the disease regulated by the ocular cyclooxygenase_2 is wherein the disease regulated by the ocular cyclooxygenase_2 is wherein the glaucoma is selected from the group consisting of the following glaucoma · Primary corneal open glaucoma, secondary corneal open glaucoma, primary corneal atresia glaucoma, secondary corneal atresia 100462.doc 200536517 glaucoma, congenital glaucoma, and normal-pressure glaucoma. 9. The disease is the method of claim 1, wherein the ocular cyclooxygenase_2 regulates intraocular pressure. For example, the method of seeking item 1 is as follows, wherein the eye, eye Qiuche I, and lice mouth _ 2 disease is sleep.炎症 Postoperative inflammation and pain. 11 ·: The method of claim 10, wherein the eye surgery is selected from the group consisting of the following surgery: corneal transplant surgery, crystalline lens implantation surgery, retina; detachment surgery, cataract surgery, and refractive surgery . The method of claim 1, wherein the ocular cyclooxygenase_2 is selective for ocular pain. Proma Horse wherein the ocular cyclooxygenase-2 selective disease is where the ocular cyclooxygenase_2 selective disease is where the subject is human. 13 · Method as requested in item 1 Eye inflammation. 14. Method of acute damage to eye tissues as described in item 1 &15; Method of 100462.doc 200536517 as requested in item 1 7. Designated representative map: (1) Designated representative map in this case: (none) (II) Designated representative map Brief description of the component symbols: 8. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: NH? 17 (III) R21 ►20 319 100462.doc