Use of Compositions Comprising Cyclooxygenase-2 Selective Inhibitors in Combination With Radiation F

专利摘要:
Provided are methods of preventing or inhibiting cardiovascular disease, comprising administering a dose of radiation and a cyclooxygenase-2 selective inhibitor.
公开号:KR20040032100A
申请号:KR10-2003-7015571
申请日:2002-05-29
公开日:2004-04-14
发明作者:패트리시아 지. 켈러
申请人:파마시아 코포레이션；
IPC主号:

专利说明:

Use of Compositions Comprising Cyclooxygenase-2 Selective Inhibitors in Combination With Radiation For Inhibition or Prevention of Cardiovascular Disease}
[1] Cross Reference to Related Application
[2] This application claims priority from Provisional Application No. 60 / 294,077, filed May 29, 2001, which is incorporated by reference in its entirety.
[4] Cardiovascular disease is the first cause of death in the world. Many heart disorders (eg, coronary artery disease [CAD], systemic hypertension, adjuvant aortic valve, hypertrophic cardiomyopathy, mitral valve prolapse) have a hereditary principle. The exact pathogenesis of CAD is unclear, but risk factors are well known: high blood levels of low density lipoprotein cholesterol (LDL-C) and lipoprotein a, low blood levels of high density lipoprotein cholesterol (HDL-C) and serum vitamin E, and Bad physical health is also. High blood levels of triglycerides and insulin that reflect insulin resistance may be a risk factor, but the data are less clear. CAD risks include smoking, high fat, high calorie, and phytochemicals (found in fruits and vegetables), fibrin and Diets low in vitamins E and C, or meals with relatively low levels of omega-3 polyunsaturated fatty acids (PUFAs), increased stress control, and lack of activity. Various systemic diseases (eg hypertension, diabetes, hypothyroidism) are also associated with increased CAD risk.
[5] Ischemic heart disease due to coronary artery stenosis is a cause of serious morbidity and mortality in the United States. Reversal and control of coronary artery disease was achieved using coronary artery bypass graft (CABG), originally developed in the 1960s. In the 1970s and 1980s, the development of percutaneous percutaneous coronary angioplasty (PTCA) enabled additional treatment methods. Now more than 400,000 dilatations are performed each year in the United States alone.
[6] Despite the success of treating coronary artery disease, a recurrent problem with dilatation is that restenosis occurs. Restenosis is called PTCA's Achilles' heel. Studies show that, if untreated, 30% -60% of dilatation causes restenosis. The mechanism by which restenosis occurs after PTCA includes: 1) elastic peninsula; 2) thrombus organization and wall thrombosis; 3) smooth muscle cell migration, proliferation, and synthesis of extracellular matrix; And 4) late vascular tomographic contraction (negative remodeling).
[7] The first element, peninsula and remodeling include mechanical collapse and contraction of the treated blood vessels, and do not seem to progress beyond the first day of treatment. The second factor, thrombi, involves a complex interaction between a number of hemostatic factors that are promoted by vascular damage. This factor is related as the major early mechanism that is the source of restenosis. The third element is a proliferative response to injury and involves endometrial proliferation, which usually consists of smooth muscle cells and matrix formation. The process begins within a few days after vascular injury and lasts for weeks to months until equilibrium is established between the vessel wall and the lumen. In excessive cases, endometrial proliferation can cause severe internal reconstruction. A fourth factor, negative remodeling, appears to be similar to wound contraction, and may be associated with contraction of vascular envelope membrane elastic scars.
[8] As endovascular stent technology was developed in the 1990s that solved the problems of mechanical collapse and contraction, the rate of stenosis decreased dramatically. The use of stents reduced the incidence of restenosis by about 30%. However, stents do not solve the problem of endometrial proliferation and may even cause local inflammation and damage to the endometrial wall or endometrial junction, making the problem more serious. Restenosis is a problem, particularly in situations involving small blood vessels, uterine canal lesions, complex persistent and branched lesions, venous grafts and restenosis in diffuse stents.
[9] Recently, topical radiation or short-range therapy has been used to prevent restenosis. The use of radiation to prevent restenosis stems from the notion that restenosis is a proliferative wound healing process and that proliferating cells are sensitive to low doses of radiation. It is known in the art that ionizing radiation is an effective antiproliferative agent for both malignant and benign diseases and uses radiation to modulate the wound healing response.
[10] Radiation may be delivered over a sustained period of time using an implantable instrument, such as a stent containing a radioisotope, or temporarily inserted and delivered to the site where the dilatation has been performed for a time sufficient to provide antiproliferative dose of radiation. Can be. Various implantable devices for preventing restenosis are known in the art. US Pat. Nos. 5,871,437 and 6,159,142, which disclose, for example, stents coated with a biodegradable coating comprising a radiation source; US Patent No. 5,919,126, which discloses a stent coated with a radiopaque material comprising beta-emitting radioisotopes; US Patent No. 6,179,789, which discloses a stent coated with a biocompatible material with dispersed radioactive material; US Patent No. 6,187,037, which discloses a metal stent comprising a stable radioisotope having a half life of less than two months; US Patent No. 6,196,963, which discloses temporarily implantable short-range therapy instruments; And US Pat. No. 6,210,313, which discloses an implantable device coated with a chelating agent selected according to binding affinity for a particular radioisotope.
[11] Transient application of antiproliferative radiation is typically accomplished by inserting a catheter, ribbon or other such instrument into the coronary artery for a time sufficient to deliver a dose of radiation sufficient to prevent endothelium proliferation. Apparatus for transient delivery of radiation is described, for example, in US Pat. No. 5,662,580; 6,196,996; 6,196,996; And 6,200,256.
[12] The examples discussed previously include the use of beta or gamma radiation, but ultraviolet (“UV”) radiation may also be used. Examples of UV irradiation include US Pat. No. 5,053,033; US Patent No. 5,116,864; US Patent No. 5,620,438; And US Pat. No. 6,200,307.
[13] Restenosis is also thought to include inflammatory elements. Damage to the artery wall during arterial procedures such as dilation and artery transplantation results in the release of proinflammatory compounds such as cytokines from macrophages. It is hypothesized that the effect of radiation to prevent restenosis is partly due to the effect of radiation on inflammatory cells. For example, Rubin et al . ( Intl. J. Radiat Oncol. Biol. Phys. , 40: 929-941, 1998) reported that after irradiation of balloon-damaged rat carotid arteries, monocytes and outer membrane macrophages are reduced to intima Proliferation decreased.
[14] Because of the inflammatory component of restenosis, various anti-inflammatory agents are used. For example, Rab et al. ( J. Am Coll. Cardiol. , 18: 1524-1528, 1991) administered glucocorticoids with or without colchicine to patients receiving stents to prevent coronary aneurysm development. Reported an increase. Valero et al . ( J. Cardiovasc. Pharmacol. , 31: 513-519, 1998) introduced hydrocortisone-loaded microspheres into the arterial walls of rabbits during dilation. They reported that hydrocortisone-loaded microspheres were associated with a marked decrease in endothelial proliferation. Strecker et al . ( Cardiovasc. Intervent. Radiol. , 21: 487-496 , 1998) reported that dexamethasone-coated stents decreased neovascular endothelial proliferation compared to uncoated stents. In contrast, Lee et al . ( Am. Heart J. , 138: 304, 1999) found that intravenous pretreatment of single-dose methylpyridinisolone prior to coronary stent surgery affected the change in minimum lumen diameter at 6 months. Reported not giving.
[15] Nonsteroidal anti-inflammatory agents are also used to reduce restenosis. Chaldakov ( Med. Hypotheses, 37: 74-75, 1992) proposed the use of anti-inflammatory sulfasalazine, griseofulbin, and colchicine to reduce coronary restenosis after dilation. Huang et al . ( Eur. J. Pharmacol. , 221: 381-384, 1992) reported that curcumin, an anti-inflammatory from Curcuma longa , reduced the proliferation of vascular smooth muscle cells in vitro. Ishiwata et al . ( J. Am. Coll. Cardio. 35: 1331-1337, 2000) showed that porcine arteries of orally administered N- (3,4-dimethoxycinnamoyl) anthranilic acid (trianilast) Reported a reduction in restenosis in the stent implanted in. Conversely, Grinstead et al . ( Coron. Artery Dis. 4: 277-281, 1993) reported that oral administration of synthetic carbohydrates, aniprilose hydrochloride with anti-inflammatory and anti-proliferative properties, resulted in a restenosis pig model. It has been found that it does not prevent coronary endothelial proliferation. None of these references disclose or suggest the use of anti-inflammatory agents and radiation to prevent restenosis.
[16] Prostaglandins play a major role in the inflammatory process, and inhibition of prostaglandin production, in particular PGG2, PGH2 and PGE2 production, has been a major goal of anti-inflammatory development. However, conventional nonsteroidal anti-inflammatory drugs (NSAID's) that are active in reducing prostaglandin-induced pain and edema associated with the inflammatory process also affect other prostaglandin-modulating responses not associated with the inflammatory process. Therefore, high doses of the most common NSAIDs can cause serious side effects, including life-threatening ulcers, limiting their therapeutic efficacy. Corticosteroids are used in place of NSAIDs, especially when prolonged treatment involves serious side effects and questions about their usefulness in preventing restenosis ( Kong, Am. Heart J. , 138: 3-4 , 1999).
[17] NSAIDs have been shown to prevent prostaglandin production by inhibiting enzymes in the human arachidonic acid / prostaglandin pathway, including cyclooxygenase (COX) enzymes. The recent discovery of inducible enzymes associated with inflammation (called "cyclooxygenase-2" or "prostaglandin G / H synthase II") has provided practical inhibition targets that reduce inflammation more effectively and cause fewer serious side effects.
[18] Compounds that selectively inhibit cyclooxygenase-2 are described in US Pat. No. 5,380,738; 5,344,991; 5,344,991; 5,393,790; 5,393,790; 5,434,178; 5,474,995; 5,474,995; 5,510,368 and WO documents WO 96/06840, WO 96/03388, WO 96/03387, WO 96/19469, WO 96/25405, WO 95/15316, WO 94/15932, WO 94/27980, WO 95/00501 , WO 94/13635, WO 94/20480, and WO 94/26731.
[19] [Pyrazol-1-yl] benzenesulfonamide has been described as an inhibitor of cyclooxygenase-2 and has proven hopeful in treating inflammation, arthritis and pain with minimal side effects in preclinical and clinical trials. Its use in the treatment of inflammation of vascular diseases is described in US Pat. No. 5,466,823. Its use for the prevention of cardiovascular-related diseases is described in co-pending US application Ser. No. 09 / 402,634.
[20] The present invention relates to the use of a selective inhibitor of cyclooxygenase-2 in combination with radiation to prevent restenosis (endothelial proliferation) after vascular surgery. More particularly, the present invention relates to the use of cyclooxygenase-2 selective inhibitors or derivatives or pharmaceutically acceptable salts or prodrugs thereof in combination with radiation to prevent restenosis after coronary surgery.
[21] Summary of the Invention
[22] In various aspects of the invention, a method of inhibiting or preventing a cardiovascular disease in a subject comprising administering to the subject a cyclooxygenase-2 inhibitor or a pharmaceutically acceptable salt or prodrug thereof, and a single dose of radiation Is provided.
[23] In one embodiment, the cyclooxygenase-2 selective inhibitor comprises a compound of the formula or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof:
[24]
[25] Where n is an integer of 0, 1, 2, 3 or 4;
[26] G is O, S or NR ^a ;
[27] R ^a is alkyl;
[28] R ¹ is selected from the group consisting of H and aryl;
[29] R ² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
[30] R ³ 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;
[31] Each R ⁴ is H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino , Heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylalkylsulfonyl, heterocyclosulfonyl, alkylsul Independently selected from the group consisting of: polyyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl and alkylcarbonyl Or; or
[32] R ⁴ together with the carbon atom to which it is attached and the rest of the ring E form a naphthyl radical.
[33] In another embodiment, the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof includes a compound of the formula:
[34]
[35] Wherein A is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings;
[36] R ¹ is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R ¹ is alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxy at a substitutable position Optionally substituted with one or more radicals selected from alkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
[37] R ² is selected from the group consisting of methyl and amino;
[38] R ³ is 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, arkenyl, alkoxyalkyl, arylthioalkyl, aryl Oxyalkyl, aralkylthioalkyl, araloxyoxy, alkoxy aralkyloxy, 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, aralkyloxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N -Arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl.
[39] In another embodiment, the radiation that prevents or inhibits cell proliferation includes alpha particles, beta particles, gamma rays, X-rays, ultraviolet rays, or any combination thereof.
[40] In other embodiments, the radiation dose that prevents or inhibits cell proliferation is from about 3 Gray to about 60 Gray.
[41] In a further embodiment, the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof is administered for a continuous period of time beginning before radiation and ending after radiation.
[42] In still further embodiments, the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof is administered for a continuous period that begins on the same day as the start of radiation and extends until after the end of radiation.
[43] Acronyms and Definitions
[44] The term "prevention" includes preventing the development of a clinically apparent restenosis stage in an individual or preventing the development of a preclinical manifestation of a restenosis stage. This definition includes prophylactic treatment.
[45] As used herein, the term "inhibition" refers to preventing or reducing the depth of restenosis compared to what may occur if the method of the present invention is not applied.
[46] The phrase “therapeutically effective” refers to the amount of each agent that can achieve the goal of improving the severity and incidence of disease, typically without treatment or avoiding the side effects associated with alternative treatments, or beyond the treatment by each agent itself. It is to indicate.
[47] The phrase "inhibiting cell proliferation" refers to an amount that results in a lower cell proliferation rate than would occur if the present method is not applied.
[48] The term "subject" for therapeutic purposes includes any human or animal subject in which endometrial proliferation or restenosis may occur. The subject may be a livestock species, experimental animal species, zoo animal or companion animal. In one embodiment, the subject is a human.
[49] The term "cyclooxygenase-2 selective inhibitor" denotes a compound capable of inhibiting cyclooxygenase-2 without significantly inhibiting cyclooxygenase-1. Preferably, they have a cyclooxygenase-2 IC ₅₀ of less than about 0.2 micromolar, and the selectivity ratio of cyclooxygenase-2 inhibition to cyclooxygenase-1 inhibition is at least 50, more preferably 100 It includes the above compound. Even more preferably, the compound has a cyclooxygenase-1 IC ₅₀ of greater than about 1 micromolar, more preferably greater than 10 micromolar. Inhibitors of the cyclooxygenase pathway in the metabolism of arachidonic acid used in the method of the present invention can inhibit enzyme activity through various mechanisms. For example (but not limited to), inhibitors used in the methods described herein can directly block enzyme activity by functioning as a substrate of the enzyme.
[50] The term "hydrido" denotes a single hydrogen atom (H). These hydrido radicals may, for example, bind to oxygen atoms to form hydroxyl radicals, or two hydrido radicals may bind to carbon atoms to form methylene (—CH ₂ —) radicals.
[51] When the terms "haloalkyl", "alkylsulfonyl", "alkoxyalkyl" and "hydroxyalkyl" are used alone or in other terms, the term "alkyl" is preferably from 1 to about 20 carbon atoms, preferably Preferably a straight or branched radical having 1 to about 12 carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having 1 to about 10 carbon atoms. Most preferred are lower alkyl radicals having 1 to about 6 carbon atoms. Such radicals include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.
[52] The term "alkenyl" includes straight or branched radicals having one or more carbon-carbon double bonds of 2 to about 20 carbon atoms, or preferably 2 to about 12 carbon atoms. More preferred alkyl radicals are "lower alkenyl" radicals having 2 to about 6 carbon atoms. Alkenyl radicals include, for example, ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
[53] The term "alkynyl" refers to a straight or branched radical having 2 to about 20 carbon atoms, or preferably 2 to about 12 carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having 2 to about 10 carbon atoms. Most preferred are lower alkynyl radicals having 2 to about 6 carbon atoms. Such radicals include, for example, propargyl, butynyl and the like.
[54] The terms "alkenyl", "lower alkenyl" include radicals having "cis" and "trans" orientations, or alternatively "E" and "Z" orientations. The term "cycloalkyl" includes saturated carbocyclic radicals having 3 to 12 carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having 3 to about 8 carbon atoms. Such radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[55] The term "cycloalkenyl" includes partially unsaturated carbocyclic radicals having 3 to 12 carbon atoms. More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having 4 to about 8 carbon atoms. Such radicals include, for example, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl.
[56] The term "halo" means a halogen such as fluorine, chlorine, bromine or iodine.
[57] The term "haloalkyl" includes radicals in which any one or more alkyl carbon atoms are substituted with halo as defined above. Particularly included are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. As an example, monohaloalkyl radicals may have iodo, bromo, chloro or fluoro atoms in the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals, respectively. "Lower haloalkyl" includes radicals having 1-6 carbon atoms. Haloalkyl radicals are for example fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoro Methyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
[58] The term "hydroxyalkyl" includes straight or branched alkyl radicals having 1 to about 10 carbon atoms and any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having 1 to 6 carbon atoms and at least one hydroxyl radical. Such radicals include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.
[59] The terms "alkoxy" and "alkyloxy" include straight or branched oxy-comprising radicals each having an alkyl portion of 1 to about 10 carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having 1 to 6 carbon atoms. Such radicals include, for example, methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
[60] The term "alkoxyalkyl" includes alkyl radicals having one or more alkoxy radicals which bind to the alkyl radicals, ie form monoalkoxyalkyl and dialkoxyalkyl radicals. "Alkoxy" radicals may also be substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide a haloalkoxy radical. More preferred haloalkoxy radicals are "lower haloalkoxy" radicals having 1 to 6 carbon atoms and at least one halo radical. Such radicals include, for example, fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
[61] The term "aryl", alone or in combination, refers to a carbocyclic aromatic system comprising one, two or three rings that can be bonded or fused together in a pendant manner. The term "aryl" includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkyloxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, It may be substituted with one or more substituents independently selected from cyano, carboxy, aminocarbonyl, alkoxycarbonyl and araloxycarbonyl.
[62] The term “heterocyclyl” includes saturated, partially saturated and unsaturated heteroatoms including cyclic radicals, where the heteroatoms can be selected from nitrogen, sulfur and oxygen. Saturated heterocyclyl radicals are, for example, saturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl Etc); Saturated 3-6 membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg, morpholinyl, etc.); Saturated 3 to 6-membered heteromonocyclic groups (eg, thiazolidinyl, etc.) containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms. Partially unsaturated heterocyclyl radicals include, for example, dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
[63] The term "heteroaryl" includes unsaturated heterocyclyl radicals. Unsaturated heterocyclyl radicals, also referred to as “heteroaryl” radicals, include, for example, unsaturated 3-6 membered heteromonocyclic groups containing 1-4 nitrogen atoms, for example pyrrolyl, pyrrolinyl, Imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H- 1,2,3-triazolyl and the like), tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl and the like) and the like; Unsaturated condensed heterocyclyl groups containing 1 to 5 nitrogen atoms, for example indolyl, isoindoleyl, indolinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolo Pyridazinyl (eg, tetrazolo [1,5-b] pyridazinyl and the like) and the like; Unsaturated 3 to 6 membered heteromonocyclic groups containing one oxygen atom such as pyranyl, furyl and the like; Unsaturated 3-6 membered heteromonocyclic groups containing one sulfur atom such as thienyl and the like; Unsaturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as oxazolyl, isoxazolyl, oxdiazolyl (eg 1,2, 4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl and the like); Unsaturated condensed heterocyclyl groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg, benzoxazolyl, benzoxadiazolyl, etc.); Unsaturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example thiazolyl, thiadiazolyl (eg 1,2,4-thiadiazolyl , 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and the like); Unsaturated condensed heterocyclyl groups (eg benzothiazolyl, benzothiadiazolyl, etc.) containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms. The term also includes radicals in which heterocyclyl radicals are fused with aryl radicals. Such fused bicyclic radicals include, for example, benzofuran, benzothiophene and the like. The "heterocyclyl group" may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino.
[64] The term "alkylthio" includes radicals comprising straight or branched alkyl radicals of 1 to about 10 carbon atoms bonded to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having alkyl radicals of 1 to 6 carbon atoms. The lower alkylthio radicals are for example methylthio, ethylthio, propylthio, butylthio and hexylthio.
[65] The term "alkylthioalkyl" includes radicals comprising alkylthio radicals bonded to alkyl radicals of 1 to about 10 carbon atoms with divalent sulfur atoms. More preferred alkylthioalkyl radicals are "lower alkylthioalkyl" radicals having alkyl radicals of 1 to 6 carbon atoms. The lower alkylthioalkyl radical includes, for example, methylthiomethyl.
[66] The term "alkylsulfinyl" includes radicals comprising straight or branched alkyl radicals of 1 to 10 carbon atoms bonded to a divalent -S (= 0)-radical. More preferred alkylsulfinyl radicals are "lower alkylsulfinyl" radicals having alkyl radicals of 1 to 6 carbon atoms. The lower alkylsulfinyl radicals include, for example, methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.
[67] The term "sulfonyl", used alone or in connection with other terms such as alkylsulfonyl, each represents a divalent radical -S02-. "Alkylsulfonyl" includes an alkyl radical bonded to a sulfonyl radical, where alkyl is as defined above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having 1 to 6 carbon atoms. The lower alkylsulfonyl radicals include, for example, methylsulfonyl, ethylsulfonyl and propylsulfonyl. "Alkylsulfonyl" radicals may also be substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide a haloalkylsulfonyl radical. "Sulfamoyl", "aminosulfonyl" and "sulfonamidyl" refer to NH202S-.
[68] The term "acyl" refers to a radical provided by a residue after removal of hydroxyl from an organic acid. Such acyl radicals include, for example, alkanoyl and aroyl radicals. The lower alkanoyl radicals include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl.
[69] The term "carbonyl", alone or in combination with other terms such as "alkoxycarbonyl", refers to-(C = O)-.
[70] The term "aroyl" includes aryl radicals having carbonyl radicals as defined above. Aroyl includes, for example, benzoyl, naphthoyl, and the like, in which the aryl may be further substituted.
[71] The term "carboxy" or "carboxyl", alone or in combination with other terms such as "carboxyalkyl", refers to -C02H.
[72] The term "carboxyalkyl" includes alkyl radicals substituted with carboxy radicals. More preferred are "lower carboxyalkyls" comprising lower alkyl radicals as defined above and may be further substituted with halo on the alkyl radicals. The lower carboxyalkyl radicals include, for example, carboxymethyl, carboxyethyl and carboxypropyl.
[73] The term "alkoxycarbonyl" means a radical comprising an alkoxy radical as defined above bonded to an carbon atom with an oxygen atom. More preferred are "lower alkoxycarbonyl" radicals having alkyl moieties having 1 to 6 carbons. The lower alkoxycarbonyl (ester) radicals include, for example, substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.
[74] The terms "alkylcarbonyl", "arylcarbonyl" and "aralkylcarbonyl" include radicals having alkyl, aryl and aralkyl radicals as defined above that are bonded to a carbonyl radical. Such radicals include, for example, substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and benzylcarbonyl.
[75] The term "aralkyl" includes aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The aryl of the aralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The terms benzyl and phenylmethyl may be exchanged.
[76] The term “heterocyclylalkyl” refers to saturated and partially unsaturated heterocyclyl-substituted alkyl radicals such as pyrrolidinylmethyl, and heteroaryl substituted alkyl radicals such as pyridylmethyl, quinolylmethyl, thi Nylmethyl, furylethyl and quinolylethyl. The heteroaryl of the heteroaralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.
[77] The term "aralkyloxy" includes aralkyl radicals bonded to oxygen radicals by other radicals.
[78] The term "aralkyloxy" includes aralkyloxy radicals bonded to an alkyl radical by an oxygen atom.
[79] The term "aralkylthio" includes aralkyl radicals bonded to sulfur atoms.
[80] The term "aralkylthioalkyl" includes aralkylthio radicals bonded with sulfur atoms to alkyl radicals.
[81] The term "aminoalkyl" includes alkyl radicals substituted with one or more amino radicals. More preferred are "lower aminoalkyl" radicals. Such radicals include, for example, aminomethyl, aminoethyl and the like.
[82] The term "alkylamino" denotes an amino group substituted with one or two alkyl radicals. Preferred are "lower N-alkylamino" radicals having alkyl moieties 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 and the like.
[83] The term "arylamino" denotes an amino group substituted with one or two aryl radicals, for example N-phenylamino. "Arylamino" radicals may also be substituted on the aryl ring portion of the radical.
[84] The term "aralkylamino" includes aralkyl radicals bonded to other radicals with amino nitrogen atoms. The terms " N-arylaminoalkyl " and " N-aryl-N-alkyl-aminoalkyl " are amino groups each having one amino group or an amino group substituted with one aryl and one alkyl radical and bonded to an alkyl radical Indicates. Such radicals include, for example, N-phenylaminomethyl and N-phenyl-N-methylaminomethyl.
[85] The term "aminocarbonyl" denotes an amino group of the formula -C (= 0) NH2.
[86] The term "alkylaminocarbonyl" denotes an aminocarbonyl group substituted with one or two alkyl radicals on an amino nitrogen atom. Preferred are the "N-alkylaminocarbonyl", "N, N-dialkylaminocarbonyl" radicals. More preferred are "lower N-alkylaminocarbonyl", "lower N, N-dialkylaminocarbonyl" radicals having lower alkyl moieties as defined above.
[87] The term "alkylaminoalkyl" includes radicals having one or more alkyl radicals bonded to an aminoalkyl radical.
[88] The term "aryloxyalkyl" includes radicals having an aryl radical bonded to a divalent oxygen atom to an alkyl radical.
[89] The term "arylthioalkyl" includes radicals having an aryl radical bonded to an alkyl radical with a divalent sulfur atom.
[90] Description of the Preferred Embodiments
[91] Combination therapy comprising administering to the subject a cyclooxygenase-2 selective inhibitor with a single dose of radiation has been shown to inhibit or prevent cardiovascular disease, particularly vascular restenosis. As described above, restenosis occurs due to the interaction of various biological phenomena, including traumatic and inflammatory reactions that are triggered as a result of procedures such as coronary artery dilation. Ionizing radiation is known in the art to improve the response to trauma. In addition, cyclooxygenase-2 selective inhibitors are known in the art to be potent anti-inflammatory agents. Since cyclooxygenase-2 selective inhibitors and radiation each attenuate independent biological phenomena known to cause restenosis, the combination therapies described herein are useful in the treatment of cardiovascular disease without being bound by any particular theory. Do. Thus, the combination of cyclooxygenase-2 selective inhibitors with radiation provides synergistic therapies for the treatment of cardiovascular disease. In addition, the use of cyclooxygenase-2 selective inhibitors is highly desirable in terms of minimizing gastric side effects that can be caused by non-selective NSAIDs, particularly when long-term treatment is required.
[92] Thus, the method may be useful for the prevention or inhibition of restenosis after vascular surgery, such as dilatation, transplantation, stent insertion, endarterectomy, atherosclerosis (including rotational, directional and excisional atherosclerosis) or excimer laser treatment of coronary stenosis. Can be used. In one embodiment, the method can be used to prevent or inhibit restenosis after dilation and in particular, coronary angioplasty (percutaneous percutaneous coronary angioplasty or PTCA). In other embodiments, the methods can be used to prevent or inhibit stenosis after vascular grafts and in particular after coronary artery bypass graft (CABG).
[93] Any cyclooxygenase-2 selective inhibitor, or prodrug or pharmaceutically acceptable salt thereof, can be used in the methods of the present invention. In one embodiment, the cyclooxygenase-2 selective inhibitor is for example cyclooxygenase-2 selective inhibitor meloxycamp, Formula B-1 (CAS Registry No. 71125-38-7), or a pharmaceutical thereof Acceptable salts or prodrugs.
[94] B-1
[95] In another embodiment, the cyclooxygenase-2 selective inhibitor is a cyclooxygenase-2 selective inhibitor, 6-[[5- (4-chlorobenzoyl) -1,4-dimethyl-1H-pyrrol-2-yl ] Methyl] -3 (2H) -pyridazinone, Formula B-2 (CAS Registry No. 179382-91-3), or a pharmaceutically acceptable salt or prodrug thereof.
[96] B-2
[97] In a preferred embodiment, the cyclooxygenase-2 selective inhibitor is a group of chromene structures, preferably substituted benzopyrans or substituted benzopyran analogs, more preferably having the formula (I) and for example, but not limited to: Substituted benzothiopyrans, dihydroquinolines, or dihydronaphthalene, including diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof having the structures set forth in Table 1 below. It is selected from the group consisting of. In addition, benzopyran cyclooxygenase-2 selective inhibitors useful in the practice of this method are described in US Pat. Nos. 6,034,256 and 6,077,850, which are incorporated herein by reference in their entirety.
[98] In one embodiment, the cyclooxygenase-2 selective inhibitor is a chromene structural group and is a compound of formula (I), or an isomer, pharmaceutically acceptable salt, ester, or prodrug thereof:
[99] <Formula I>
[100]
[101] here,
[102] n is an integer of 0, 1, 2, 3 or 4;
[103] G is O, S or NR ^a ;
[104] R ^a is alkyl;
[105] R ¹ is selected from the group consisting of H and aryl;
[106] R ² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
[107] R ³ 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;
[108] Each R ⁴ is H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino , Heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylalkylsulfonyl, heterocyclosulfonyl, alkylsul Independently selected from the group consisting of: polyyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl and alkylcarbonyl Or; or
[109] R ⁴ together with the carbon atom to which it is attached and the rest of the ring E form a naphthyl radical.
[110] Cyclooxygenase-2 selective inhibitors are also
[111] n is an integer of 0, 1, 2, 3 or 4;
[112] G is O, S or NR ^b ;
[113] R ¹ is H;
[114] R ^b is alkyl;
[115] R ² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
[116] R ³ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl and aryl are each selected from the group consisting of alkylthio, nitro and alkylsulfonyl Optionally substituted with one or more radicals;
[117] Each R ⁴ is hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, hetero Arylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, Independently selected from the group consisting of alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl and alkylcarbonyl; or
[118] R ⁴ may be a compound of formula (I) or an isomer, pharmaceutically acceptable salt, ester or prodrug thereof, together with ring E to form a naphthyl radical.
[119] In further embodiments the cyclooxygenase-2 selective inhibitor is also
[120] n is an integer of 0, 1, 2, 3 or 4;
[121] G is oxygen or sulfur;
[122] R ¹ is H;
[123] R ² is carboxyl, lower alkyl, lower aralkyl or lower alkoxycarbonyl;
[124] R ³ is lower haloalkyl, lower cycloalkyl or phenyl;
[125] Each R ⁴ is H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, 6-membered-nitrogen containing heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower Aralkylcarbonyl or lower alkylcarbonyl; or
[126] It may be a compound of formula (I) or an isomer thereof, a pharmaceutically acceptable salt, ester, or prodrug, wherein R ⁴ together with the carbon atom to which it is attached and the rest of ring E form a naphthyl radical.
[127] Cyclooxygenase-2 selective inhibitors are also
[128] R ² is carboxyl;
[129] R ³ is lower haloalkyl;
[130] Each R ⁴ is H, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroaryl Alkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, or lower alkylcarbonyl, or
[131] R ⁴ may be a compound of formula (I) or an isomer, pharmaceutically acceptable salt, ester, or prodrug thereof, together with ring E to form a naphthyl radical.
[132] Cyclooxygenase-2 selective inhibitors are also
[133] n is an integer of 0, 1, 2, 3 or 4;
[134] R ³ is fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl or trifluoro Romethyl;
[135] Each R ⁴ is H, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert -butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tert-butyl Oxy, 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
[136] It may be a compound of formula (I) or an isomer thereof, a pharmaceutically acceptable salt, ester, or prodrug, wherein R ⁴ together with the carbon atom to which it is attached and the rest of ring E form a naphthyl radical.
[137] Cyclooxygenase-2 selective inhibitors are also
[138] n is an integer of 0, 1, 2, 3 or 4;
[139] R ³ is trifluoromethyl or pentafluoroethyl;
[140] Each R ⁴ is independently H, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert -butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl , N-phenylethylaminosulfonyl, N- (2-furylmethyl) aminosulfonyl, N, N-dimethylaminosulfonyl, N-methylaminosulfonyl, N- (2,2-dimethylethyl) aminosulfonyl , Dimethylaminosulfonyl, 2-methylpropylaminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, or phenyl; or
[141] It may be a compound of formula (I) or an isomer thereof, a pharmaceutically acceptable salt, ester, or prodrug, wherein R ⁴ together with the carbon atom to which it is attached and the rest of ring E form a naphthyl radical.
[142] In another embodiment, the cyclooxygenase-2 selective inhibitor used in connection with the method of the present invention is also a compound having the structure of formula (I) or an isomer, pharmaceutically acceptable salt, ester, or prodrug thereof. Can be:
[143] here,
[144] n = 4;
[145] G is O or S;
[146] R ¹ is H;
[147] R ² is CO ₂ H;
[148] R ³ is lower haloalkyl;
[149] The first R ⁴ corresponding to R ⁹ is hydrido or halo;
[150] The second R ⁴ corresponding to R ¹⁰ 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;
[151] The third R ⁴ corresponding to R ¹¹ is H, lower alkyl, halo, lower alkoxy or aryl;
[152] The fourth R ⁴ corresponding to R ¹² is H, halo, lower alkyl, lower alkoxy or aryl;
[153] Formula (I) is represented by the following formula (Ia).
[154]
[155] The cyclooxygenase-2 selective inhibitor used in connection with the method of the present invention may also be a compound having the structure of formula (Ia) or an isomer thereof, a pharmaceutically acceptable salt, ester, or prodrug,
[156] here
[157] R ⁸ is trifluoromethyl or pentafluoroethyl;
[158] R ⁹ is H, chloro or fluoro;
[159] R ¹⁰ is H, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, Benzylaminosulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl or morpholinosulfonyl;
[160] R ¹¹ is H, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino or phenyl;
[161] R ¹² is H, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy or phenyl.
[162] Examples of chromen cyclooxygenase-2 selective inhibitors are shown in Table 1 below.
[163] Examples of Chromen Cyclooxygenase-2 Selective Inhibitors as Embodiments Compound number constitutional formula B-36-nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid B-46-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid B-5(S) -6-chloro-7- (1,1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid
[164] Compound number constitutional formula B-62-Trifluoromethyl-2H-naphtho [2,3-b] pyran-3-carboxylic acid B-76-chloro-7- (4-nitrophenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid B-8(S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid B-96-chloro-2- (trifluoromethyl) -4-phenyl-2H-1-benzopyran-3-carboxylic acid B-106- (4-hydroxybenzoyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid B-112- (trifluoromethyl) -6-[(trifluoromethyl) thio] -2H-1-benzothiopyran-3-carboxylic acid
[165] Compound number constitutional formula B-126,8-dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid B-136- (1,1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid B-146,7-difluoro-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid B-156-chloro-1,2-dihydro-1-methyl-2- (trifluoromethyl) -3-quinolinecarboxylic acid B-166-chloro-2- (trifluoromethyl) -1,2-dihydro [1,8] naphthyridine-3-carboxylic acid B-17(S) -6-chloro-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid
[166] In a further preferred embodiment, the cyclooxygenase inhibitor is selected from the group of tricyclic cyclooxygenase-2 selective inhibitors represented by the general structure of formula (II) or a pharmaceutically acceptable salt thereof:
[167]
[168] here,
[169] A is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings;
[170] R ¹ is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R ¹ is alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, Optionally substituted with one or more radicals selected from hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
[171] R ² is selected from the group consisting of methyl and amino;
[172] R ³ is 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, arkenyl, alkoxyalkyl, arylthioalkyl, aryl Oxyalkyl, aralkylthioalkyl, araloxyoxy, alkoxy aralkyloxy, 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, aralkyloxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N- It is selected from the group consisting of a radical selected from arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl.
[173] Also in a more preferred embodiment of the invention, the cyclooxygenase-2 selective inhibitor of Formula II is celecoxib (B-18; US Pat. No. 5,466,823; CAS No. 169590-42-5), Valdecoxib (B-19; US Pat. No. 5,633,272; CAS No. 181695-72-7), Deracoxib (B-20; US Pat. 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) and JTE-522 (B-23) Group or isomers, esters, pharmaceutically acceptable salts or prodrugs thereof.
[174] Examples of Tricyclic Cyclooxygenase-2 Selective Inhibitors as Embodiments Compound number constitutional formula B-18 B-19 B-20 B-21 B-22 B-23
[175] In even more preferred embodiments, the cyclooxygenase-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib.
[176] In another highly preferred embodiment of the invention, the tricyclic cyclooxygenase-2 selective inhibitor valdecoxib, parecoxib, a therapeutically effective prodrug of B-19 (B-24, US Pat. No. 5,932,598, CAS) No. 198470-84-7) can be preferably used as a source of cyclooxygenase inhibitors (US 5,932,598, incorporated herein by reference).
[177] B-24
[178] A preferred form of parecoxib is sodium parecoxib.
[179] In another preferred embodiment of the invention, compounds having the formula B-25 described in the past in International Publication No. WO 00/24719 (incorporated herein by reference) may be used with other tricyclic cyclooxygena which may be preferably used. It is a second selective inhibitor.
[180] B-25
[181] Another preferred cyclooxygenase-2 selective inhibitor useful in connection with the process of the invention is N- (2-cyclohexyloxynitrophenyl) -methane sulfonamide (NS-398) having the structure of B-26 below.
[182] B-26
[183] Furthermore, in a further preferred embodiment of the present invention, the cyclooxygenase inhibitors used in connection with the method of the present invention are a group of phenylacetic acid derivative cyclooxygenase-2 selective inhibitors or isomers thereof such as , Pharmaceutically acceptable salts, esters, or prodrugs:
[184]
[185] here,
[186] R ¹⁶ is methyl or ethyl;
[187] R ¹⁷ is chloro or fluoro;
[188] R ¹⁸ is hydrogen or fluoro;
[189] R ¹⁹ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy;
[190] R ²⁰ is hydrogen or fluoro;
[191] R ²¹ is chloro, fluoro, trifluoromethyl or methyl,
[192] Provided that when R ¹⁶ is ethyl and R ¹⁹ is H, R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are not all fluoro.
[193] Particularly preferred phenylacetic acid derivative cyclooxygenase-2 selective inhibitors used in connection with the process of the present invention are compounds which have the structure of formula (III) or isomers thereof, pharmaceutically acceptable, called COX 189 (B-211) Being salts, esters, or prodrugs:
[194] here,
[195] R ¹⁶ is ethyl;
[196] R ¹⁷ and R ¹⁹ are chloro;
[197] R ¹⁸ and R ²⁰ are hydrogen;
[198] R ²¹ is methyl.
[199] In yet another embodiment, the cyclooxygenase-2 selective inhibitor is a compound of formula (IV) or an isomer, pharmaceutically acceptable salt, ester, or prodrug thereof:
[200]
[201] here,
[202] X is O or S;
[203] J is carbocycle or heterocycle;
[204] R ²² is NHSO ₂ CH ₃ or F;
[205] R ²³ is H, NO ₂ or F;
[206] R ²⁴ is H, NHSO ₂ CH ₃ , or (SO ₂ CH ₃ ) C ₆ H ₄ .
[207] According to another embodiment, the cyclooxygenase-2 selective inhibitor used in the method is a compound of formula (V) or an isomer, pharmaceutically acceptable salt, ester, or prodrug thereof:
[208]
[209] here,
[210] T and M are independently phenyl, naphthyl, radicals derived from heterocycles containing 5 to 6 elements and containing 1 to 4 heteroatoms, or radicals derived from saturated hydrocarbon rings having 3 to 7 carbon atoms;
[211] Q ¹ , Q ² , L ¹ or L ² are independently hydrogen, halogen, lower alkyl having 1 to 6 carbon atoms, trifluoromethyl, or lower methoxy having 1 to 6 carbon atoms;
[212] At least one of Q ¹ , Q ² , L ¹ or L ² is in the para position, and -S (O) nR (where n is 0, 1 or 2, and R is lower alkyl having 1 to 6 carbon atoms) Radicals or lower haloalkyl radicals having 1 to 6 carbon atoms) or -SO ₂ NH ₂ ;
[213] Q ¹ and Q ² are methylenedioxy; or
[214] L ¹ and L ² are methylenedioxy;
[215] R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are independently hydrogen, halogen, lower alkyl radicals having 1 to 6 carbon atoms, lower haloalkyl radicals having 1 to 6 carbon atoms, or phenyl, naphthyl, thienyl, An aromatic radical selected from the group consisting of furyl and pyridyl; or,
[216] R ²⁵ and R ²⁶ are O;
[217] R ²⁷ and R ²⁸ are O; or,
[218] R ²⁵ , R ²⁶ together with the carbon atom to which they are attached form a saturated hydrocarbon ring having 3 to 7 carbon atoms; or,
[219] R ²⁷ , R ²⁸ together with the carbon atoms to which they are attached form a saturated hydrocarbon ring having 3 to 7 carbon atoms.
[220] In a particularly preferred embodiment, the compound N- (2-cyclohexyloxynitrophenyl) methane sulfonamide, and (E) -4-[(4-methylphenyl) (tetrahydro-2-oxo having the structure of formula (V) 3-furanylidene) methyl] benzenesulfonamide is used as the cyclooxygenase-2 selective inhibitor.
[221] Exemplary compounds of cyclooxygenase-2 selective inhibitors useful in connection with the methods of the present invention include the following compounds or their isomers, pharmaceutically acceptable salts, esters or prodrugs whose structures are shown in Table 3 below. But not limited to:
[222] 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-27);
[223] 6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-28);
[224] 8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-29);
[225] 6-chloro-8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-30);
[226] 2-trifluoromethyl-3H-naphtho [2,1-b] pyran-3-carboxylic acid (B-31);
[227] 7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-32);
[228] 6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-33);
[229] 8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-34);
[230] 6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-35);
[231] 5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-36);
[232] 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-37);
[233] 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-38);
[234] 6,8-bis (dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-39);
[235] 7- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-40);
[236] 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-41);
[237] 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-42);
[238] 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-43);
[239] 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-44);
[240] 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-45);
[241] 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-46);
[242] 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-47);
[243] 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-48);
[244] 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-49);
[245] 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-50);
[246] 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-51);
[247] 8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-52);
[248] 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-53);
[249] 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-54);
[250] 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-55);
[251] 6-[[(phenylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-56);
[252] 6-[(dimethylamino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-57);
[253] 6-[(methylamino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-58);
[254] 6-[(4-morpholino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-59);
[255] 6-[(1,1-dimethylethyl) aminosulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-60);
[256] 6-[(2-methylpropyl) aminosulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-61);
[257] 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-62);
[258] 8-chloro-6-[[(phenylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-63);
[259] 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-64);
[260] 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-65);
[261] 8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-66);
[262] 6,8-dichloro- (S) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-67);
[263] 6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-68);
[264] 6-[[N- (2-furylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-69);
[265] 6-[[N- (2-phenylethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-70);
[266] 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-71);
[267] 7- (1,1-dimethylethyl) -2-pentafluoroethyl-2H-1-benzopyran-3-carboxylic acid (B-72);
[268] 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid (B-73);
[269] 3-[(3-Chloro-phenyl)-(4-methanesulfonyl-phenyl) -methylene] -dihydro-furan-2-one or BMS-347070 (B-74);
[270] 8-acetyl-3- (4-fluorophenyl) -2- (4-methylsulfonyl) phenyl-imidazo (1,2-a) pyridine (B-75);
[271] 5,5-dimethyl-4- (4-methylsulfonyl) phenyl-3-phenyl-2- (5H) -furanone (B-76);
[272] 5- (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole (B-77);
[273] 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) pyrazole (B-78);
[274] 4- (5- (4-chlorophenyl) -3- (4-methoxyphenyl) -1H-pyrazol-1-yl) benzenesulfonamide (B-79);
[275] 4- (3,5-bis (4-methylphenyl) -1H-pyrazol-1-yl) benzenesulfonamide (B-80);
[276] 4- (5- (4-chlorophenyl) -3-phenyl-1H-pyrazol-1-yl) benzenesulfonamide (B-81);
[277] 4- (3,5-bis (4-methoxyphenyl) -1H-pyrazol-1-yl) benzenesulfonamide (B-82);
[278] 4- (5- (4-chlorophenyl) -3- (4-methylphenyl) -1H-pyrazol-1-yl) benzenesulfonamide (B-83);
[279] 4- (5- (4-chlorophenyl) -3- (4-nitrophenyl) -1H-pyrazol-1-yl) benzenesulfonamide (B-84);
[280] 4- (5- (4-chlorophenyl) -3- (5-chloro-2-thienyl) -1H-pyrazol-1-yl) benzenesulfonamide (B-85);
[281] 4- (4-chloro-3,5-diphenyl-1H-pyrazol-1-yl) benzenesulfonamide (B-86);
[282] 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-87);
[283] 4- [5-phenyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-88);
[284] 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-89);
[285] 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-90);
[286] 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-91);
[287] 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-92);
[288] 4- [4-chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-93);
[289] 4- [3- (difluoromethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-94);
[290] 4- [3- (difluoromethyl) -5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide (B-95);
[291] 4- [3- (difluoromethyl) -5- (4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-96);
[292] 4- [3-cyano-5- (4-fluorophenyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-97);
[293] 4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-98);
[294] 4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-99);
[295] 4- [4-chloro-5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide (B-100);
[296] 4- [5- (4-chlorophenyl) -3- (hydroxymethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-101);
[297] 4- [5- (4- (N, N-dimethylamino) phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-102);
[298] 5- (4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene (B-103);
[299] 4- [6- (4-fluorophenyl) spiro [2.4] hept-5-en-5-yl] benzenesulfonamide (B-104);
[300] 6- (4-fluorophenyl) -7- [4- (methylsulfonyl) phenyl] spiro [3.4] oct-6-ene (B-105);
[301] 5- (3-chloro-4-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene (B-106);
[302] 4- [6- (3-chloro-4-methoxyphenyl) spiro [2.4] hept-5-en-5-yl] benzenesulfonamide (B-107);
[303] 5- (3,5-dichloro-4-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene (B-108);
[304] 5- (3-chloro-4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene (B-109);
[305] 4- [6- (3,4-dichlorophenyl) spiro [2.4] hept-5-en-5-yl] benzenesulfonamide (B-110);
[306] 2- (3-chloro-4-fluorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) thiazole (B-111);
[307] 2- (2-chlorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) thiazole (B-112);
[308] 5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-methylthiazole (B-113);
[309] 4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-trifluoromethylthiazole (B-114);
[310] 4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2- (2-thienyl) thiazole (B-115);
[311] 4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-benzylaminothiazole (B-116);
[312] 4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2- (1-propylamino) thiazole (B-117);
[313] 2-[(3,5-dichlorophenoxy) methyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] thiazole (B-118);
[314] 5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-trifluoromethylthiazole (B-119);
[315] 1-methylsulfonyl-4- [1,1-dimethyl-4- (4-fluorophenyl) cyclopenta-2,4-dien-3-yl] benzene (B-120);
[316] 4- [4- (4-fluorophenyl) -1,1-dimethylcyclopenta-2,4-dien-3-yl] benzenesulfonamide (B-121);
[317] 5- (4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hepta-4,6-diene (B-122);
[318] 4- [6- (4-fluorophenyl) spiro [2.4] hepta-4,6-dien-5-yl] benzenesulfonamide (B-123);
[319] 6- (4-fluorophenyl) -2-methoxy-5- [4- (methylsulfonyl) phenyl] -pyridine-3-carbonitrile (B-124);
[320] 2-bromo-6- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -pyridine-3-carbonitrile (B-125);
[321] 6- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-phenyl-pyridine-3-carbonitrile (B-126);
[322] 4- [2- (4-methylpyridin-2-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-127);
[323] 4- [2- (5-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-128);
[324] 4- [2- (2-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-129);
[325] 3- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine (B-130);
[326] 2- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine (B-131);
[327] 2-methyl-4- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine (B-132);
[328] 2-methyl-6- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine (B-133);
[329] 4- [2- (6-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-134);
[330] 2- (3,4-difluorophenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazole (B-135);
[331] 4- [2- (4-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-136);
[332] 2- (4-chlorophenyl) -1- [4- (methylsulfonyl) phenyl] -4-methyl-1H-imidazole (B-137);
[333] 2- (4-chlorophenyl) -1- [4- (methylsulfonyl) phenyl] -4-phenyl-1H-imidazole (B-138);
[334] 2- (4-chlorophenyl) -4- (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -1H-imidazole (B-139);
[335] 2- (3-fluoro-4-methoxyphenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazole (B-140);
[336] 1- [4- (methylsulfonyl) phenyl] -2-phenyl-4-trifluoromethyl-1H-imidazole (B-141);
[337] 2- (4-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazole (B-142);
[338] 4- [2- (3-chloro-4-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-143);
[339] 2- (3-fluoro-5-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazole (B-144);
[340] 4- [2- (3-fluoro-5-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-145);
[341] 2- (3-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazole (B-146);
[342] 4- [2- (3-methylphenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide (B-147);
[343] 1- [4- (methylsulfonyl) phenyl] -2- (3-chlorophenyl) -4-trifluoromethyl-1H-imidazole (B-148);
[344] 4- [2- (3-chlorophenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide (B-149);
[345] 4- [2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide (B-150);
[346] 4- [2- (4-methoxy-3-chlorophenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide (B-151);
[347] 1-allyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazole (B-152);
[348] 4- [1-ethyl-4- (4-fluorophenyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl] benzenesulfonamide (B-153);
[349] N-phenyl- [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazol-1-yl] acetamide (B -154);
[350] Ethyl [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazol-1-yl] acetate (B-155);
[351] 4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -1- (2-phenylethyl) -1H-pyrazole (B-156);
[352] 4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -1- (2-phenylethyl) -5- (trifluoromethyl) pyrazole (B-157);
[353] 1-ethyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazole (B-158);
[354] 5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-trifluoromethyl-1H-imidazole (B-159);
[355] 4- [4- (methylsulfonyl) phenyl] -5- (2-thiophenyl) -2- (trifluoromethyl) -1H-imidazole (B-160);
[356] 5- (4-fluorophenyl) -2-methoxy-4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyridine (B-161);
[357] 2-ethoxy-5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyridine (B-162);
[358] 5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2- (2-propynyloxy) -6- (trifluoromethyl) pyridine (B-163);
[359] 2-bromo-5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyridine (B-164);
[360] 4- [2- (3-chloro-4-methoxyphenyl) -4,5-difluorophenyl] benzenesulfonamide (B-165);
[361] 1- (4-fluorophenyl) -2- [4- (methylsulfonyl) phenyl] benzene (B-166);
[362] 5-difluoromethyl-4- (4-methylsulfonylphenyl) -3-phenylisoxazole (B-167);
[363] 4- [3-ethyl-5-phenylisoxazol-4-yl] benzenesulfonamide (B-168);
[364] 4- [5-difluoromethyl-3-phenylisoxazol-4-yl] benzenesulfonamide (B-169);
[365] 4- [5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide (B-170);
[366] 4- [5-methyl-3-phenyl-isoxazol-4-yl] benzenesulfonamide (B-171);
[367] 1- [2- (4-fluorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-172);
[368] 1- [2- (4-fluoro-2-methylphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-173);
[369] 1- [2- (4-chlorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-174);
[370] 1- [2- (2,4-dichlorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-175);
[371] 1- [2- (4-trifluoromethylphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-176);
[372] 1- [2- (4-methylthiophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-177);
[373] 1- [2- (4-fluorophenyl) -4,4-dimethylcyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-178);
[374] 4- [2- (4-fluorophenyl) -4,4-dimethylcyclopenten-1-yl] benzenesulfonamide (B-179);
[375] 1- [2- (4-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-180);
[376] 4- [2- (4-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] benzenesulfonamide (B-181);
[377] 4- [2- (4-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide (B-182);
[378] 4- [2- (4-chlorophenyl) cyclopenten-1-yl] benzenesulfonamide (B-183);
[379] 1- [2- (4-methoxyphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-184);
[380] 1- [2- (2,3-difluorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-185);
[381] 4- [2- (3-fluoro-4-methoxyphenyl) cyclopenten-1-yl] benzenesulfonamide (B-186);
[382] 1- [2- (3-chloro-4-methoxyphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene (B-187);
[383] 4- [2- (3-chloro-4-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide (B-188);
[384] 4- [2- (2-methylpyridin-5-yl) cyclopenten-1-yl] benzenesulfonamide (B-189);
[385] Ethyl 2- [4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazol-2-yl] -2-benzyl-acetate (B-190);
[386] 2- [4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazol-2-yl] acetic acid (B-191);
[387] 2- ( tert -butyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazole (B-192);
[388] 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-phenyloxazole (B-193);
[389] 4- (4-fluorophenyl) -2-methyl-5- [4- (methylsulfonyl) phenyl] oxazole (B-194);
[390] 4- [5- (3-fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide (B-195);
[391] 6-chloro-7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-196);
[392] 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-197);
[393] 5,5-dimethyl-3- (3-fluorophenyl) -4-methylsulfonyl-2 (5H) -furanone (B-198);
[394] 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid (B-199);
[395] 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-200);
[396] 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-201);
[397] 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (B-202);
[398] 3- [1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazol-2-yl] pyridine (B-203);
[399] 2-methyl-5- [1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazol-2-yl] pyridine (B-204);
[400] 4- [2- (5-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide (B-205);
[401] 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide (B-206);
[402] 4- [5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide (B-207);
[403] [2-trifluoromethyl-5- (3,4-difluorophenyl) -4-oxazolyl] benzenesulfonamide (B-208);
[404] 4- [2-methyl-4-phenyl-5-oxazolyl] benzenesulfonamide (B-209);
[405] 4- [5- (2-fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide (B-210);
[406] [2- (2-Chloro-6-fluoro-phenylamino) -5-methyl-phenyl] -acetic acid or COX 189 (B-211);
[407] N- (4-nitro-2-phenoxy-phenyl) -methanesulfonamide or nimesulide (B-212);
[408] N- [6- (2,4-Difluoro-phenoxy) -1-oxo-indan-5-yl] -methanesulfonamide or flosulfide (B-213);
[409] N- [6- (2,4-Difluoro-phenylsulfanyl) -1-oxo-1H-inden-5-yl] -methanesulfonamide, sodium salt or L-745337 (B-214);
[410] N- [5- (4-Fluoro-phenylsulfanyl) -thiophen-2-yl] -methanesulfonamide or RWJ-63556 (B-215);
[411] 3- (3,4-Difluoro-phenoxy) -4- (4-methanesulfonyl-phenyl) -5-methyl-5- (2,2,2-trifluoroethyl) -5H-furan- 2-on or L-784512 or L-784512 (B-216);
[412] (5Z) -2-amino-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4 (5H) -thiazolone or darbufelone (B-217 );
[413] CS-502 (B-218);
[414] LAS-34475 (B-219);
[415] LAS-34555 (B-220);
[416] S-33516 (B-221);
[417] SD-8381 (B-222);
[418] L-783003 (B-223);
[419] N- [3- (formylamino) -4-oxo-6-phenoxy-4H-1-benzopyran-7-yl] -methanesulfonamide or T-614 (B-224);
[420] D-1367 (B-225);
[421] L-748731 (B-226);
[422] (6aR, 1OaR) -3- (1,1-dimethylheptyl) -6a, 7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo [b, d] pyran- 9-carboxylic acid or CT3 (B-227);
[423] CGP-28238 (B-228);
[424] 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);
[425] GR-253035 (B-230);
[426] 6-dioxo-9H-purin-8-yl-cinnamic acid (B-231);
[427] S-2474 (B-232);
[428] 4- [4- (methyl) -sulfonyl) phenyl] -3-phenyl-2 (5H) -furanone;
[429] 4- (5-methyl-3-phenyl-4-isoxazolyl);
[430] 2- (6-methylpyrid-3-yl) -3- (4-methylsulfonylphenyl) -5-chloropyridine;
[431] 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl];
[432] N-[[4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonyl];
[433] 4- [5- (3-fluoro-4-methoxyphenyl) -3-difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
[434] (S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid;
[435] 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone;
[436] 2-trifluoromethyl-3H-naphtho [2,1-b] pyran-3-carboxylic acid;
[437] 6-chloro-7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[438] [2- (2,4-Dichloro-6-ethyl-3,5-dimethyl-phenylamino) -5-propyl-phenyl] -acetic acid.
[439] Examples of Cyclooxygenase-2 Selective Inhibitors as Embodiments Compound number constitutional formula B-26N- (2-cyclohexyloxynitrophenyl) methane sulfonamide or NS-398; B-276-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-286-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-298- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[440] Compound number constitutional formula B-306-chloro-8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-312-trifluoromethyl-3H-naphtho [2,1-b] pyran-3-carboxylic acid; B-327- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-336-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[441] Compound number constitutional formula B-348-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-356-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-365,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-378-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[442] Compound number constitutional formula B-387,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-396,8-bis (dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-407- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-417-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[443] Compound number constitutional formula B-426-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-436-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-446-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-456,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[444] Compound number constitutional formula B-466,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-476-chloro-8-methyl-2-trifluoromethyl-2H-I-benzopyran-3-carboxylic acid; B-488-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-498-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[445] Compound number constitutional formula B-506-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-518-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-528-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-538-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[446] Compound number constitutional formula B-546-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-556-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-566-[[(phenylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-576-[(dimethylamino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid
[447] Compound number constitutional formula B-586-[(methylamino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-596-[(4-morpholino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-606-[(1,1-dimethylethyl) aminosulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-616-[(2-methylpropyl) aminosulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[448] Compound number constitutional formula B-626-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-638-chloro-6-[[(phenylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-646-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-656,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[449] Compound number constitutional formula B-668-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-676,8-dichloro- (S) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-686-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-696-[[N- (2-furylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[450] Compound number constitutional formula B-706-[[N- (2-phenylethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-716-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-727- (1,1-dimethylethyl) -2-pentafluoroethyl-2H-1-benzopyran-3-carboxylic acid; B-736-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid;
[451] Compound number constitutional formula B-743-[(3-Chloro-phenyl)-(4-methanesulfonyl-phenyl) -methylene] -dihydro-furan-2-one or BMS-347070; B-758-acetyl-3- (4-fluorophenyl) -2- (4-methylsulfonyl) phenyl-imidazo (1,2-a) pyridine; B-765,5-dimethyl-4- (4-methylsulfonyl) phenyl-3-phenyl-2- (5H) -furanone; B-775- (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole;
[452] Compound number constitutional formula B-784- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) pyrazole; B-794- (5- (4-chlorophenyl) -3- (4-methoxyphenyl) -1H-pyrazol-1-yl) benzenesulfonamide; B-804- (3,5-bis (4-methylphenyl) -1H-pyrazol-1-yl) benzenesulfonamide;
[453] Compound number constitutional formula B-814- (5- (4-chlorophenyl) -3-phenyl-1H-pyrazol-I-yl) benzenesulfonamide; B-824- (3,5-bis (4-methoxyphenyl) -1H-pyrazol-1-yl) benzenesulfonamide; B-834- (5- (4-chlorophenyl) -3- (4-methylphenyl) -1H-pyrazol-1-yl) benzenesulfonamide;
[454] Compound number constitutional formula B-844- (5- (4-chlorophenyl) -3- (4-nitrophenyl) -1H-pyrazol-1-yl) benzenesulfonamide; B-854- (5- (4-chlorophenyl) -3- (5-chloro-2-thienyl) -1H-pyrazol-1-yl) benzenesulfonamide; B-864- (4-chloro-3,5-diphenyl-1H-pyrazol-1-yl) benzenesulfonamide;
[455] Compound number constitutional formula B-874- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; B-884- [5-phenyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; B-894- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
[456] Compound number constitutional formula B-904- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; B-914- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; B-924- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
[457] Compound number constitutional formula B-934- [4-chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; B-944- [3- (difluoromethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide; B-954- [3- (difluoromethyl) -5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide; B-964- [3- (difluoromethyl) -5- (4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide;
[458] Compound number constitutional formula B-974- [3-cyano-5- (4-fluorophenyl) -1H-pyrazol-1-yl] benzenesulfonamide; B-984- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide; B-994- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; B-1004- [4-chloro-5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide;
[459] Compound number constitutional formula B-1014- [5- (4-chlorophenyl) -3- (hydroxymethyl) -1H-pyrazol-1-yl) benzenesulfonamide; B-1024- [5- (4- (N, N-dimethylamino) phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; B-1035- (4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene;
[460] Compound number constitutional formula B-1044- [6- (4-fluorophenyl) spiro [2.4] hept-5-en-5-yl] benzenesulfonamide; B-1056- (4-fluorophenyl) -7- [4- (methylsulfonyl) phenyl] spiro [3.4] oct-6-ene; B-1065- (3-chloro-4-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene; B-1074- [6- (3-chloro-4-methoxyphenyl) spiro [2.4] hept-5-en-5-yl] benzenesulfonamide;
[461] Compound number constitutional formula B-1085- (3,5-dichloro-4-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene; B-1095- (3-chloro-4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene; B-1104- [6- (3,4-dichlorophenyl) spiro [2.4] hept-5-en-5-yl] benzenesulfonamide; B-1112- (3-chloro-4-fluorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) thiazole;
[462] Compound number constitutional formula B-1122- (2-chlorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) thiazole; B-1135- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-methylthiazole; B-1144- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-trifluoromethylthiazole;
[463] Compound number constitutional formula B-1154- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2- (2-thienyl) thiazole; B-1164- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-benzylaminothiazole; B-1174- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2- (1-propylamino) thiazole;
[464] Compound number constitutional formula B-1182-((3,5-dichlorophenoxy) methyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] thiazole; B-1195- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-trifluoromethylthiazole; B-1201-methylsulfonyl-4- [1,1-dimethyl-4- (4-fluorophenyl) cyclopenta-2,4-dien-3-yl] benzene;
[465] Compound number Compound number B-1214- [4- (4-fluorophenyl) -1,1-dimethylcyclopenta-2,4-dien-3-yl] benzenesulfonamide; B-1225- (4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hepta-4,6-diene; B-1234- [6- (4-fluorophenyl) spiro [2.4] hepta-4,6-dien-5-yl] benzenesulfonamide;
[466] Compound number Compound number B-1246- (4-fluorophenyl) -2-methoxy-5- [4- (methylsulfonyl) phenyl] -pyridine-3-carbonitrile; B-1252-bromo-6- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -pyridine-3-carbonitrile; B-1266- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-phenyl-pyridine-3-carbonitrile;
[467] Compound number constitutional formula B-1274- [2- (4-methylpyridin-2-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide; B-1284- [2- (5-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide; B-1294- [2- (2-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide; B-1303- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine;
[468] Compound number constitutional formula B-1312- [1- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl)]-1H-imidazol-2-yl] pyridine; B-1322-methyl-4- [1- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl)]-1H-imidazol-2-yl] pyridine; B-1332-methyl-6- [1- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl)]-1H-imidazol-2-yl] pyridine; B-1344- [2- (6-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide;
[469] Compound number constitutional formula B-1352- (3,4-difluorophenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazole; B-1364- [2- (4-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide; B-1372- (4-chlorophenyl) -1- [4- (methylsulfonyl) phenyl] -4-methyl-1H-imidazole;
[470] Compound number constitutional formula B-1382- (4-chlorophenyl) -1- [4- (methylsulfonyl) phenyl] -4-phenyl-1H-imidazole; B-1392- (4-chlorophenyl) -4- (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -1H-imidazole; B-1402- (3-fluoro-4-methoxyphenyl) -1- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl)]-1H-imidazole;
[471] Compound number constitutional formula B-1411- [4- (methylsulfonyl) phenyl] -2-phenyl-4-trifluoromethyl-1H-imidazole; B-1422- (4-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazole; B-1434- [2- (3-chloro-4-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide; B-1442- (3-fluoro-5-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazole;
[472] Compound number constitutional formula B-1454- [2- (3-fluoro-5-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide; B-1462- (3-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazole; B-1474- [2- (3-methylphenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide; B-1481- [4- (methylsulfonyl) phenyl] -2- (3-chlorophenyl) -4-trifluoromethyl-1H-imidazole;
[473] Compound number constitutional formula B-1494- [2- (3-chlorophenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide; B-1504- [2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide; B-1514- [2- (4-methoxy-3-chlorophenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide; B-1521-allyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazole;
[474] Compound number constitutional formula B-1534- [1-ethyl-4- (4-fluorophenyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl] benzenesulfonamide; B-154N-phenyl- [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazol-1-yl] acetamide; B-155Ethyl [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazol-1-yl] acetate;
[475] Compound number constitutional formula B-1564- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -1- (2-phenylethyl) -1H-pyrazole; B-1574- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -1- (2-phenylethyl) -5- (trifluoromethyl) pyrazole; B-1581-ethyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazole;
[476] Compound number constitutional formula B-1595- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-trifluoromethyl-1H-imidazole; B-1604- [4- (methylsulfonyl) phenyl] -5- (2-thiophenyl) -2- (trifluoromethyl) -1H-imidazole; B-1615- (4-fluorophenyl) -2-methoxy-4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyridine;
[477] Compound number constitutional formula B-1622-ethoxy-5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyridine; B-1635- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2- (2-propynyloxy) -6- (trifluoromethyl) pyridine; B-1642-bromo-5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyridine;
[478] Compound number constitutional formula B-1654- [2- (3-chloro-4-methoxyphenyl) -4,5-difluorophenyl] benzenesulfonamide; B-1661- (4-fluorophenyl) -2- [4- (methylsulfonyl) phenyl] benzene; B-1675-difluoromethyl-4- (4-methylsulfonylphenyl) -3-phenylisoxazole; B-1684- [3-ethyl-5-phenylisoxazol-4-yl] benzenesulfonamide;
[479] Compound number constitutional formula B-1694- [5-difluoromethyl-3-phenylisoxazol-4-yl] benzenesulfonamide; B-1704- [5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide; B-1714- [5-methyl-3-phenyl-isoxazol-4-yl] benzenesulfonamide; B-1721- [2- (4-fluorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene;
[480] Compound number constitutional formula B-1731- [2- (4-fluoro-2-methylphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; B-1741- [2- (4-chlorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; B-1751- [2- (2,4-dichlorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; B-1761- [2- (4-trifluoromethylphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene;
[481] Compound number constitutional formula B-1771- [2- (4-methylthiophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; B-1781- [2- (4-fluorophenyl) -4,4-dimethylcyclopenten-1-yl] -4- (methylsulfonyl) benzene; B-1794- [2- (4-fluorophenyl) -4,4-dimethylcyclopenten-1-yl] benzenesulfonamide;
[482] Compound number constitutional formula B-1801- [2- (3-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] -4- (methylsulfonyl) benzene; B-1814- [2- (4-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] benzenesulfonamide; B-1824- [2- (4-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide;
[483] Compound number constitutional formula B-1834- [2- (4-chlorophenyl) cyclopenten-1-yl] benzenesulfonamide; B-1841- [2- (4-methoxyphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; B-1851- [2- (2,3-difluorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; B-1864- [2- (3-fluoro-4-methoxyphenyl) cyclopenten-1-yl] benzenesulfonamide;
[484] Compound number constitutional formula B-1871- [2- (3-chloro-4-methoxyphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; B-1884- [2- (3-chloro-4-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide; B-1894- [2- (2-methylpyridin-5-yl) cyclopenten-1-yl] benzenesulfonamide; B-190Ethyl 2- [4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazol-2-yl] -2-benzyl-acetate;
[485] Compound number constitutional formula B-1912- [4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazol-2-yl] acetic acid; B-1922- (tert-butyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazole; B-1934- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-phenyloxazole;
[486] Compound number constitutional formula B-1944- (4-fluorophenyl) -2-methyl-5- [4- (methylsulfonyl) phenyl) oxazole; B-1954- [5- (3-fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide; B-1966-chloro-7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-1976-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
[487] Compound number constitutional formula B-1985,5-dimethyl-3- (3-fluorophenyl) -4-methylsulfonyl-2 (5H) -furanone; B-1996-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid; B-2004- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; B-2014- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
[488] Compound number constitutional formula B-2024- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; B-2033- [1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazol-2-yl] pyridine; B-2042-methyl-5- [1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazol-2-yl] pyridine;
[489] Compound number constitutional formula B-2054- [2- (5-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide; B-2064- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide; B-2074- [5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide; B-208[2-trifluoromethyl-5- (3,4-difluorophenyl) -4-oxazolyl] benzenesulfonamide;
[490] Compound number constitutional formula B-2094- [2-methyl-4-phenyl-5-oxazolyl] benzenesulfonamide; B-2104- [5- (2-fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide; B-211[2- (2-Chloro-6-fluoro-phenylamino) -5-methyl-phenyl] -acetic acid or COX 189 or lumiracoxib B-212N- (4-nitro-2-phenoxy-phenyl) -methanesulfonamide or nimesulide
[491] Compound number constitutional formula B-213N- [6- (2,4-Difluoro-phenoxy) -1-oxo-inden-5-yl] -methanesulfonamide or flosulfide B-214N- [6- (2,4-Difluoro-phenylsulfanyl) -1-oxo-1H-inden-5-yl] -methanesulfonamide, sodium salt, or L-745337 B-215N- [5- (4-Fluoro-phenylsulfanyl) -thiophen-2-yl] -methanesulfonamide or RWJ-63556
[492] Compound number constitutional formula B-2163- (3,4-Difluoro-phenoxy) -4- (4-methanesulfonyl-phenyl) -5-methyl-5- (2,2,2-trifluoro-ethyl) -5H-furan 2-one or L-784512 B-217(5Z) -2-amino-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4 (5H) -thiazolone or dabufelone B-218 CS-502 B-219 LAS-34475 B-220 LAS-34555 B-221 S-33516 B-222 SD-8381 B-223 L-783003 B-224N- [3- (formylamino) -4-oxo-6-phenoxy-4H-1-benzopyran-7-yl] -methanesulfonamide or T614
[493] Compound number constitutional formula B-225 D-1367 B-226 L-748731 B-227(6aR, 1OaR) -3- (1,1-dimethylheptyl) -6a, 7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo [b, d] pyran- 9-carboxylic acid or CT3 B-228 CGP-28238 B-2294-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] dihydro-2-methyl-2H-1,2-oxazin-3 (4H) -one or BF -389 B-230 GR-253035 B-2312- (6-Dioxo-9H-purin-8-yl) cinnamic acid B-232 S-2474
[494] The compounds used in the process of the invention may be in the form of their free base or pharmaceutically acceptable acid addition salts. The term "pharmaceutically acceptable salts" includes salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt can vary if it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds for use in the present methods may be prepared from inorganic or organic acids. The inorganic acid is for example hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonate, sulfuric acid and phosphoric acid. Suitable organic acids include aliphatic, alicyclic, aromatic, aliphatic, heterocyclic, carboxylic and sulfonyl groups of organic acids, for example formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, Citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (palmic acid), methanesulfonic acid, Selected from ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, algenic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid and galacturonic acid Can be. Suitable pharmaceutically acceptable base addition salts of the compounds used in the process are metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or N, N'-dibenzylethylenediamine, chloroprocaine, Organic salts prepared from choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All such salts can be prepared in a conventional manner from the corresponding compounds, for example by reacting the appropriate acid or base with a compound of any of the formulas presented herein.
[495] Cyclooxygenase-2 selective inhibitors useful in the practice of the present methods can be formulated into pharmaceutical compositions and administered by any method capable of delivering a therapeutically effective amount. The composition can be administered orally, parenterally, inhalationally, rectally, intradermally, transdermally, or as a unit dosage formulation comprising conventional, non-toxic pharmaceutically acceptable carriers, adjuvant and vehicle as desired. Can be. Topical administration also includes the use of transdermal administrations, such as transdermal patches or iontophoretic devices. As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular or internal sternum injection, or infusion techniques. Formulation of the drug is described, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975) and Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY (1980).
[496] 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. Sterile injectable formulations may also be sterile injectable solutions or suspensions in parenterally acceptable non-toxic diluents or solvents. Acceptable vehicles and solvents that can be used 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 may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are useful for the preparation of injectables. Dimethyl acetamide, surfactants including ionic and nonionic detergents, and polyethylene glycols can be used. Mixtures of solvents and humectants as discussed above are also useful.
[497] Suppositories for rectal administration of the compounds described herein may be prepared by mixing the active ingredient with a suitable non-irritating excipient such as cocoa butter, synthetic mono-, di- or triglycerides, fatty acids, or polyethylene glycols, The suppository is solid at normal temperatures but liquid at rectal temperatures and therefore melts in the rectum to release the drug.
[498] Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound is typically mixed with one or more adjuvant appropriate for the given route of administration. If administered orally, the compound may contain lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, acacia gum It may be mixed with sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol and then tableted or encapsulated for convenient administration. The capsule or tablet may comprise a controlled release formulation, such as may be provided as a dispersion of the active compound in hydroxypropylmethyl cellulose. For capsules, tablets and pills, the formulation may also include sodium citrate or buffers such as carbonic acid or magnesium bicarbonate or calcium. Tablets and pills can also be prepared with enteric coatings.
[499] For therapeutic purposes, preparations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the preparation for oral administration. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. Other adjuvant and methods of administration are well known in the pharmaceutical art.
[500] Liquid formulations for oral administration may include emulsions, solutions, suspensions, syrups and elixirs comprising inert diluents commonly used in the art, such as pharmaceutically acceptable water. The composition may also include reinforcing agents such as wetting agents, emulsifying and suspending agents, sweetening agents and flavoring agents.
[501] The amount of active ingredient that can be combined with a carrier material to produce a unit dosage form can vary depending upon the patient and the particular method of administration. Typically, the pharmaceutical composition may comprise a cyclooxygenase-2 selective inhibitor in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg, most preferably in the range of about 1 to 200 mg. A daily dose of about 0.01 to 100 mg / kg body weight, preferably about 0.1 to about 50 mg / kg body weight, most preferably about 1 to 20 mg / kg body weight, may be appropriate. The daily dose may be administered 1 to 4 times a day.
[502] In one embodiment when the cyclooxygenase-2 selective inhibitor comprises rofecoxib, the amount used is from about 0.15 to about 1.0 mg / day · kg, more preferably from about 0.18 to about 0.4 mg / day · kg It is preferable to exist in the range of.
[503] In another embodiment, where the cyclooxygenase-2 selective inhibitor comprises etoricoxib, the amount used is from about 0.5 to about 5 mg / day · kg, more preferably from about 0.8 to about 4 mg / day. It is preferable to exist in the range of kg.
[504] In addition, where the cyclooxygenase-2 selective inhibitor comprises celecoxib, the amount used is from about 1 to about 20 mg / day · kg, more preferably from about 1.4 to about 8.6 mg / day · kg, and even more Preferably it is within the range of about 2 to about 3 mg / day kg.
[505] If the cyclooxygenase-2 selective inhibitor comprises valdecoxib, the amount used is in the range of about 0.1 to about 5 mg / day · kg, more preferably about 0.8 to about 4 mg / day · kg. desirable.
[506] In further embodiments, where the cyclooxygenase-2 selective inhibitor comprises parecoxib, the amount used is from about 0.1 to about 5 mg / day · kg, more preferably from about 1 to about 3 mg / day. It is preferable to exist in the range of kg.
[507] Doses are also described in Goodman & Goldman, The Pharmacological Basis of Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711 and The Pharmacological Basis of Therapeutics, Tenth Edition (2001), Appendix II, pp. 475-493, which will be apparent to those skilled in the art.
[508] In other embodiments, pharmaceutical compositions comprising a suitable cyclooxygenase-2 selective inhibitor may also be administered topically to the site of vascular injury. For example, cyclooxygenase-2 selective inhibitors may be incorporated into, but are not limited to, stents to be implanted in the vasculature. The stent may be coated with a degradable polymer incorporating a cyclooxygenase-2 selective inhibitor. When the polymer degrades slowly, the cyclooxygenase-2 selective inhibitor is released to the area around the stent. Stents coated with degradable polymers are described, for example, in Strecker et al., Cardiovasc. Intervent. Radiol., 21: 487-496 , 1998). Alternatively, microspheres may be implanted locally in the vessel wall during vascular surgery. The use of microspheres to administer the compounds to the vessel wall is described, for example, in Valero et al., J. Cardiovasc. Pharmacol. 31: 513-519, 1998). Also included are catheterized topical delivery systems. Non-limiting examples of catheter-based topical delivery systems include a hydrophilic-coated catheter balloon that absorbs a cyclooxygenase-2 selective inhibitor and then releases it when pressed against the vessel wall, and a cyclooxygenase-2 selective inhibitor to the vessel wall Perforated balloon catheter embedded in the vessel wall using a high velocity jet to spray.
[509] The timing of administration of the cyclooxygenase-2 selective inhibitors may also vary. For example, the cyclooxygenase-2 selective inhibitor may be administered starting before vascular surgery, at vascular surgery, or at a time after vascular surgery. The administration may be administered in a single dose, or more preferably the cyclooxygenase-2 selective inhibitor over a long period of time. In one embodiment, administration of the cyclooxygenase-2 selective inhibitor begins one day prior to vascular surgery. In another embodiment, the cyclooxygenase-2 selective inhibitor is started at least 7 days, at least 14 days, at least 21 days, or at most 30 days before vascular surgery. After vascular surgery, cyclooxygenase-2 selective inhibitors are preferably administered for a period of time. In one embodiment, administration continues for 6 months after surgery. In another embodiment, administration of the cyclooxygenase-2 selective inhibitor lasts for one week, two weeks, one month, three months, nine months, or one year after vascular surgery. In one embodiment, the cyclooxygenase-2 selective inhibitor lasts for a lifetime of the subject following vascular surgery.
[510] In this method, the cyclooxygenase-2 selective inhibitor is administered in combination with radiation. The timing of administration of the cyclooxygenase-2 selective inhibitor and radiation may vary from subject to subject. In one embodiment of the invention, the cyclooxygenase-2 selective inhibitor and the radiation can be administered substantially simultaneously, meaning that both agents can be administered to the subject at about the same time. In one embodiment, for example, the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof is administered for a continuous period starting on the same day as the start of the radiation treatment and continuing until after the end of the radiation treatment. . Alternatively, cyclooxygenase-2 selective inhibitors and radiation can be administered continuously, meaning that they are administered at different times during separate treatment. In one embodiment, for example, the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof is administered for a continuous period of time beginning before radiation and ending after radiation. Of course, cyclooxygenase-2 selective inhibitors may be administered more or less frequently than radiotherapy. One skilled in the art can easily design a suitable treatment regimen for a particular subject.
[511] It will be apparent to those skilled in the art that various administration timings and methods may be combined and preferred in the practice of the present invention. For example, a subject may be systemically administered a cyclooxygenase-2 selective inhibitor during the period prior to vascular treatment, and then locally administered, for example, a cyclooxygenase-2 selective inhibitor release stent, Systemic administration may be followed by, but not limited to, radiotherapy followed by release or significantly reduced release of the cyclooxygenase-2 selective inhibitor.
[512] The exact radiation dose used may also vary depending on factors such as the location of the tissue, species, age, sex and physical condition of the subject, the size of the tissue and the type of vascular surgery involved. Radiation doses for coronary artery surgery range, for example, from about 3 Gray (Gy) to 60 Gray. In one embodiment, the dose is about 8 Gy to about 35 Gy, in another embodiment about 10 Gy to about 24 Gy, and in another embodiment about 12 Gy to about 20 Gy.
[513] Typically, radiation can be administered to any site in the subject's body to an extent that can result in some degree of cell proliferation inhibition upon delivery to that location. Typically, radiation is administered to coronary vessels. In one embodiment, the coronary vessels are coronary arteries.
[514] The radiation can be administered according to any method commonly known in the art. In one embodiment, a platform is used for radiation administration. The platform may be external, for example a linear accelerator, or may be an intravascular short range therapy using, for example, a catheter or a radioactive stent. One method of intravascular radiation treatment uses a commercially available high dose rate postload system. Another method uses a catheter and in particular a balloon catheter. The catheter may comprise a solid radiation source or a liquid source. In catheter-based systems, the catheter is advanced to the location to which radiation is to be inflated to bring the balloon into contact with the vessel wall. In other embodiments, implantable radiation sources are used. Implantable radiation sources include, but are not limited to, radioactive stents, particles, and microspheres. If ultraviolet (UV) is used, optical fibers or other waveguides may be used. Methods for endovascular short-range therapy are described, for example, in Masullo et al., Massullo et al., Intl. J. Radiation Oncol. Biol. Phys., 36: 973-975, 1996; Tyrstein et al., Teirstein et al., NEJ Med., 336: 1697-1703, 1997; Valero et al., Valero et al., J. Cardiovasc. Pharmacol., 31: 513-519; 1998; Ishiwata et al., Ishiwata et al., Jpn Heart J., 41: 541-570, 2000; And US Pat. No. 5,662,580; 5,871,437; 5,919,126; 5,919,126; 5,919,126; 5,919,126; No. 6,159,142; No. 6,179,789; No. 6,187,037; 6,196,963; 6,196,963; 6,196,996; 6,196,996; No. 6,200,256; And 6,210,313. Methods of administering UV radiation are described, for example, in US Pat. No. 5,116,864; 5,620,438; And 6,200,307.
[515] Any form of radiation that can inhibit or prevent endometrial proliferation can be used. In one embodiment, electromagnetic or particle radiation can be used. Suitable forms of radiation include, for example, alpha particles, beta particles, gamma rays, X-rays, and ultraviolet rays. One preferred form of X-rays is "soft X-rays" or border rays. Since the X-rays are long wavelengths, they transmit less than those commonly used for radiation therapy.
[516] In addition, antimony-120, antimony-127, astaxin-211, barium-128, barium-131, barium-140, bromine-80m, cadmium-115, cerium-134, cerium-141, cerium-143, cobalt-55, Copper-64, Copper-67, Dysprosium-166, Erbium-169, Erbium-172, Holmium-166, Gadolinium-159, Gallium-166, Gallium-68, Germanium-71, Gold-198, Gold-199, Iodine- 124, iodine-125, iodine-131, iridium-192, iridium-194, lanthanum-140, lutetium-172, lutetium-177, neodymium-140, nickel-66, niobium-95, osmium-191, palladium-100, Palladium-103, phosphor-32, phosphorus-33, platinum-188, platinum-191, platinum-193m, platinum-195m, platinum-197, praseodymium-143, rhenium-186, rhenium-188, rhodium-99, rhodium- 101m, rhodium-103m, rhodium-105, rubidium-82, ruthenium-103, samarium-153, scandium-47, scandium-48, silver-111, strontium-82, strontium-89, strontium-90, tantalum-177, Tantalum-183, Technetium-99m, Tellurium-132, Tellurium-118, Terbium-153, Terbium-156, Thallium-201, Thallium-204, Thulium-170, Thulium-172, Tin-11 7 m, tin-121, titanium-45, tungsten-178, vanadium-48, xenon-133, ytterbium-166, ytterbium-169, ytterbium-175, yttrium-87, yttrium-90, yttrium-91, zinc-72 and Various radiation sources can be used, including zirconium-89. Commonly used radiation sources are described in Table 4 below. It will be apparent to those skilled in the art that the radiation source can be used in combination of, for example, strontium-90 and yttrium-90 ( ⁹⁰ SR / ⁹⁰ Y).
[517] Radiation sources commonly used for vascular near-field therapy Isotope Release Max energy Half-life Indium-192 Gamma, beta 0.37 MeV 73.8 days Strontium-90 / Yttrium-90 beta 2.3 MeV 29.2 years Yttrium-90 beta 2.3 MeV 64.1 hours Inn-32 beta 1.71 MeV 14.3 days Rhenium-188 Beta, gamma 2.12 MeV 17 hours Rhenium-186 beta 1.08 MeV 90 hours Xenon-133 Beta, gamma, X-ray 360, 81, 32 keV 5.3 days Technetium-99m Beta, X-ray 0.14 MeV 6 hours
[518] In one embodiment, the method may also include an antithrombotic and / or platelet aggregation inhibitor. Administration of an antithrombotic agent or platelet aggregation inhibitor can typically begin before vascular surgery and continue for the postoperative period, often for the lifetime of the subject. Methods of administering antithrombotic and platelet aggregation inhibitors for use in vascular and coronary surgery may be particularly widely used.
[519] In another embodiment, the method may also include administration of a corticosteroid, preferably glucocorticoid. Suitable glucocorticoids include, for example, hydrocortisone, dexamethasone and methylpridnisolone.
[3] The present invention relates to a method of treating or preventing cardiovascular disease. More particularly, the present invention relates to a method of treating or preventing restenosis.
[520] The following examples are intended to illustrate the application of the present invention. The following examples are not intended to fully define or limit the scope of the invention.
[521] Example 1
[522] Restenosis animal model
[523] Several animal models have been developed to study common cardiovascular disease and in particular restenosis. An overview of this model is described in Herman et al., Drugs, 46: 18-52, 1993 and Landzberg et al., Landzberg et al., Prog. Cardiovasc. Dis. , 39: 361-398, 1997. One of the most widely used models is the balloon-damaged pig restenosis model of Karas et al., J. Am. Coll. Cardiol. , 20: 467-474, 1992. In this model, coronary angiography was performed on anesthetized livestock pigs using an induced catheter introduced into the femoral artery. Balloons commonly used to induce vascular damage have a diameter that is about 20% to 30% larger than the reference artery diameter. If the stent was implanted, the balloon was normally inflated twice for 30 seconds and then the catheter was removed. If no stent is implanted in the vessel, the balloon is typically inflated three times. Balloon inflation and / or stent locations may be irradiated prior to, during, or immediately after dilation. To determine the optimal dose, several doses of radiation could be used. Typically, the radiation dose can range from about 3 Gray to about 60 Gray, more typically from about 10 Gray to 24 Gray, even more typically from about 12 Gray to 20 Gray. The radiation dose is administered using any suitable method. Often radiation is administered using the same catheter used to dilate blood vessels. If UV radiation was used, an optical waveguide was inserted through the femoral artery into the extension site treated with UV light. After the procedure, the incisional wound for introducing the catheter was treated and the animal was recovered.
[524] To test the effect of the combined administration of the cyclooxygenase-2 selective inhibitor with radiation to prevent restenosis, the cyclooxygenase-2 selective inhibitor was administered at various doses and at various times before and after vascular surgery. The exact dosage range tested may vary depending upon the particular cyclooxygenase-2 selective inhibitor tested. Any suitable method of administration may be used, for example the compound may be administered to the animal orally 1 to 4 times a day. The duration of administration was also changed to determine the optimal duration of administration. Typically, administration of a cyclooxygenase-2 selective inhibitor may begin at or just prior to vascular surgery and then continue for various periods of time. Cyclooxygenase-2 selective inhibitors were to be administered throughout the course of the study. The exact duration of the experiment may vary depending on the particular situation, but is typically expected to last 1 to 6 months.
[525] Example 2
[526] Analysis of the effects of concurrent therapy on restenosis
[527] At various times during the course of the experiment, the effect of the combination therapy on restenosis could be evaluated. One of the evaluation methods was histological study. At several hours the animals of the treatment and control groups were killed and the treated blood vessels were quickly removed and fixed. The control group consisted of animals that underwent vascular surgery but did not receive a combination of cyclooxygenase-2 selective inhibitor and radiation. The immobilized vessels were embedded in suitable section material, cut, stained and examined by light or electron microscopy. Vascular sections could be examined for known variables related to restenosis, such as the size of the vascular lumen and the number of smooth muscle cells present in the sections.
[528] Alternatively, angiography or endovascular ultrasound can be used to measure the effect. This method has the advantage of tracking each animal and comparing data at different time points during the course of the study. Animals were anesthetized and angiography or intravascular ultrasound was performed in the same manner as dilation, and images were recorded. Catheter filled with contrast medium can be used as a measurement standard. The images obtained were then fitted to positions within the cardiac cycle and the lumen diameters were compared. Of course, the histological and angiographic or ultrasound analysis may be combined by measuring vessel diameter by angiography or ultrasound and then killing the animal at the end of the study to perform histological examination.
[529] Example 3
[530] Rat carrageenan plantar edema test
[531] The anti-inflammatory properties of cyclooxygenase-2 selective inhibitors for use in the method can be measured by the rat carrageenan plantar edema test. Carrageenan plantar edema testing is substantially described by Winter et al., Proc. Soc. Exp. Biol. Med., 111: 544, 1962, with materials, reagents and methods as described. Male Sprag-Dolei mice were selected from each group so that the average body weight was as close as possible. The rats were starved while giving water freely for 16 hours before the test. Mice were orally administered (1 mL) with only a compound suspended in vehicle, or vehicle, containing 0.5% methylcellulose and 0.025% surfactant. After 1 hour, 0.1 mL of a 1% solution of carrageenan / sterile 0.9% saline was injected by injection into the sole of the foot, and the volume of the injected foot was measured by a displacement flowmeter connected to a pressure transducer with a digital indicator. Three hours after carrageenan injection, the volume of the foot was measured again. Average foot swelling in the drug-treated animals was compared to swelling in the placebo-treated animals and the percentage inhibition of edema was determined (Otterness and Bliven, Laboratory Models for Testing NSAIDs , in Non-steroidal Anti-Inflammatory Drugs , (J. Lombardino, ed. 1985)).
[532] In view of the detailed description and examples of the present invention, various aspects achieved by the present invention can be understood.
[533] It will be appreciated that the present invention has been described in detail by way of example and example so that others skilled in the art may understand the invention, its principles and its practical application. The specific agents and methods of the present invention are not limited to the description of the specific embodiments described, and the description and examples should be judged in terms of the claims and their equivalents. While some embodiments and descriptions above include some conclusions as to how the invention can function, the present inventors are presented as merely possible explanations without being bound to such conclusions and functions.
[534] In addition, it is to be understood that the particular embodiments of the present invention are not intended to be exhaustive or to limit the invention, and that numerous alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing embodiments and detailed description. Accordingly, the present invention is intended to embrace all such alternatives, modifications and variations that fall within the spirit and scope of the following claims.

权利要求:
Claims (75)
[1" claim-type="Currently amended] A method of treating or preventing cardiovascular disease in a subject in need thereof, comprising administering to the subject a cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof and a single dose of radiation .
[2" claim-type="Currently amended] The method of claim 1, wherein the cardiovascular disease is one or more symptoms selected from the group consisting of thrombosis, endometrial proliferation, negative remodeling and local inflammation.
[3" claim-type="Currently amended] The method of claim 1, wherein the cardiovascular disease is due to coronary thrombosis.
[4" claim-type="Currently amended] The method of claim 1, wherein the cardiovascular disease is due to coronary endothelial proliferation.
[5" claim-type="Currently amended] The method of claim 1, wherein said radiation is administered to coronary vessels.
[6" claim-type="Currently amended] The method of claim 5, wherein the coronary vessel is a coronary artery.
[7" claim-type="Currently amended] The method of claim 1, wherein the radiation is administered by near field therapy, direct beam radiation, or a combination thereof.
[8" claim-type="Currently amended] The method of claim 1, wherein said radiation is administered in near field therapy.
[9" claim-type="Currently amended] The method of claim 1, wherein said radiation is administered by direct beam radiation.
[10" claim-type="Currently amended] The method of claim 8, wherein the near field therapy is performed by catheterization.
[11" claim-type="Currently amended] The method of claim 8, wherein the near field therapy is performed with a radioactive stent.
[12" claim-type="Currently amended] The method of claim 1, wherein the radiation is administered at a dose of about 3 Gray to about 60 Gray.
[13" claim-type="Currently amended] The method of claim 1, wherein the radiation is administered at a dose of about 8 Gray to about 35 Gray.
[14" claim-type="Currently amended] The method of claim 1, wherein the radiation is administered at a dose of about 10 Gray to about 25 Gray.
[15" claim-type="Currently amended] The method of claim 1, wherein the radiation is administered at a dose of about 12 Gray to about 20 Gray.
[16" claim-type="Currently amended] The method of claim 1 wherein said radiation comprises particle radiation.
[17" claim-type="Currently amended] The method of claim 1 wherein said radiation comprises electromagnetic radiation.
[18" claim-type="Currently amended] The method of claim 1, wherein the radiation is selected from the group consisting of alpha particles, beta particles, gamma rays, X-rays, ultraviolet rays, and any combination thereof.
[19" claim-type="Currently amended] The method of claim 1 wherein said radiation comprises a border line.
[20" claim-type="Currently amended] The method of claim 1, wherein the radiation is antimony-120, antimony-127, astaxin-211, barium-128, barium-131, barium-140, bromine-80m, cadmium-115, cerium-134, cerium-141, cerium -143, Cobalt-55, Copper-64, Copper-67, Dysprosium-166, Erbium-169, Erbium-172, Holmium-166, Gadolinium-159, Gallium-166, Gallium-68, Germanium-71, Gold-198 , Gold-199, iodine-124, iodine-125, iodine-131, iridium-192, iridium-194, lanthanum-140, lutetium-172, lutetium-177, neodymium-140, nickel-66, niobium-95, osmium -191, palladium-100, palladium-103, phosphorus-32, phosphorus-33, platinum-188, platinum-191, platinum-193m, platinum-195m, platinum-197, praseodymium-143, rhenium-186, rhenium-188 , Rhodium-99, rhodium-10m, rhodium 103m, rhodium-105, rubidium-82, ruthenium-103, samarium-153, scandium-47, scandium-48, silver-111, strontium-82, strontium-89, strontium-89 90, tantalum-177, tantalum-183, technetium-99m, tellurium-132, tellurium-118, terbium-153, terbium-156, thallium-201, thallium-204 , Thulium-170, Thulium-172, Tin-117m, Tin-121, Titanium-45, Tungsten-178, Vanadium-48, Xenon-133, Ytterbium-166, Ytterbium-169, Ytterbium-175, Yttrium-87, Yttrium -90, yttrium-91, zinc-72 and zirconium-89 and any combination thereof.
[21" claim-type="Currently amended] The radiation of claim 1 wherein the radiation is emitted from a radiation source selected from the group consisting of iridium-192, strontium-90, phosphorus-32, rhenium-186, rhenium-188, xenon-133, technetium-99m and any combination thereof. How to be.
[22" claim-type="Currently amended] The method of claim 1, wherein the radiation is emitted from iridium-192.
[23" claim-type="Currently amended] The method of claim 1, wherein the radiation is emitted from strontium-90.
[24" claim-type="Currently amended] The method of claim 1, wherein the radiation is emitted from phosphorus-32.
[25" claim-type="Currently amended] The method of claim 1, wherein the radiation is emitted from rhenium-186.
[26" claim-type="Currently amended] The method of claim 1, wherein the radiation is emitted from rhenium-188.
[27" claim-type="Currently amended] The method of claim 1, wherein the radiation is emitted from xenon-133.
[28" claim-type="Currently amended] The method of claim 1, wherein the radiation is emitted from technetium-99m.
[29" claim-type="Currently amended] The method of claim 1, wherein said cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof is administered for a sustained period of time beginning prior to radiation administration.
[30" claim-type="Currently amended] The method of claim 29, wherein the administration of the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof lasts about 6 months after vascular surgery.
[31" claim-type="Currently amended] The method of claim 29, wherein the administration of said cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof persists for the lifetime of the subject.
[32" claim-type="Currently amended] The method of claim 1, wherein said cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof is administered for a sustained period starting on the same day as the start of radiation administration.
[33" claim-type="Currently amended] 33. The method of claim 32, wherein the administration of said cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof lasts about 6 months after vascular surgery.
[34" claim-type="Currently amended] 33. The method of claim 32, wherein said administration of a cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof persists for the lifetime of the subject.
[35" claim-type="Currently amended] The method of claim 1, wherein said cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof is administered for a sustained period starting after radiation administration.
[36" claim-type="Currently amended] 36. The method of claim 35, wherein said administration of a cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof lasts for about 6 months.
[37" claim-type="Currently amended] 36. The method of claim 35, wherein said administration of a cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof persists for the lifetime of the subject.
[38" claim-type="Currently amended] The method of claim 1, further comprising administering a compound selected from the group consisting of antithrombotic agents, platelet aggregation inhibitors, and combinations thereof.
[39" claim-type="Currently amended] The method of claim 1, further comprising the administration of one or more corticosteroids.
[40" claim-type="Currently amended] The method of claim 1, further comprising administering one or more anti-inflammatory agents selected from the group consisting of sulfasalazine, griseofulvin, colchicine, curcumin, and tranilla.
[41" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is

Or a pharmaceutically acceptable salt or prodrug thereof.
[42" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is

Or a pharmaceutically acceptable salt or prodrug thereof.
[43" claim-type="Currently amended] The method of claim 1, wherein said cyclooxygenase-2 selective inhibitor comprises a compound of formula (I) or a pharmaceutically acceptable salt or isomer or prodrug thereof:
<Formula I>

Where n is an integer of 0, 1, 2, 3 or 4;
G is O, S or NR ^a ;
R ^a is alkyl;
R ¹ is selected from the group consisting of H and aryl;
R ² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
R ³ 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;
Each R ⁴ is H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino , Heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylalkylsulfonyl, heterocyclosulfonyl, alkylsul Independently selected from the group consisting of: polyyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl and alkylcarbonyl Or; or
R ⁴ together with the carbon atom to which it is attached and the rest of the ring E form a naphthyl radical.
[44" claim-type="Currently amended] The method of claim 43,
n is an integer of 0, 1, 2, 3 or 4;
G is O, S or NR ^b ;
R ¹ is H;
R ^b is alkyl;
R ² is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
R ³ is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl and aryl are each selected from the group consisting of alkylthio, nitro and alkylsulfonyl Optionally substituted with one or more radicals;
Each R ⁴ is hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, hetero Arylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, Independently selected from the group consisting of alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl and alkylcarbonyl; or
R ⁴ together with ring E forms a naphthyl radical.
[45" claim-type="Currently amended] The method of claim 43,
n is an integer of 0, 1, 2, 3 or 4;
G is oxygen or sulfur;
R ¹ is H;
R ² is carboxyl, lower alkyl, lower aralkyl or lower alkoxycarbonyl;
R ³ is lower haloalkyl, lower cycloalkyl or phenyl;
Each R ⁴ is H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen containing heterocyclosulfonyl, 6-membered-nitrogen containing heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower aral Kilccarbonyl or lower alkylcarbonyl; or
R ⁴ together with the carbon atom to which it is bonded and the rest of ring E form a naphthyl radical.
[46" claim-type="Currently amended] The method of claim 43,
R ² is carboxyl;
R ³ is lower haloalkyl;
Each R ⁴ is H, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroaryl Alkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, or lower alkylcarbonyl, or
R ⁴ together with ring E forms a naphthyl radical.
[47" claim-type="Currently amended] The method of claim 43,
n is an integer of 0, 1, 2, 3 or 4;
R ³ is fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl or trifluoro Romethyl;
Each R ⁴ is H, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert -butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tert-butyl Oxy, 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
R ⁴ together with the carbon atom to which it is bonded and the rest of ring E form a naphthyl radical.
[48" claim-type="Currently amended] The method of claim 43, wherein said cyclooxygenase-2 selective inhibitor comprises a compound of formula (la):
<Formula Ia>

here,
G is oxygen or sulfur;
R ⁸ is trifluoromethyl or pentafluoroethyl;
R ⁹ is H, chloro or fluoro;
R ¹⁰ is H, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, Benzylaminosulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl or morpholinosulfonyl;
R ¹¹ is H, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino or phenyl;
R ¹² is H, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy or phenyl.
[49" claim-type="Currently amended] The method of claim 43, wherein the cyclooxygenase-2 selective inhibitor, a pharmaceutically acceptable salt, isomer, or prodrug thereof is
6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-chloro-7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-chloro-8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid;
7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6,8-bis (dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
7- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-chloro-7-ethyl-2-trifluoromethyl-2H-I-benzopyran-3-carboxylic acid;
6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
2-trifluoromethyl-3H-naphtho [2,1-b] pyran-3-carboxylic acid;
6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-[[(phenylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-[(dimethylamino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-[(methylamino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-[(4-morpholino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-[(1,1-dimethylethyl) aminosulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-[(2-methylpropyl) -aminosulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
8-chloro-6-[[(phenylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6,8-dichloro- (S) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-[[N- (2-furylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-[[N- (2-phenylethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
7- (1,1-dimethylethyl) -2-pentafluoroethyl-2H-1-benzopyran-3-carboxylic acid and
6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid.
[50" claim-type="Currently amended] The method of claim 43, wherein said cyclooxygenase-2 selective inhibitor, a pharmaceutically acceptable salt or prodrug thereof is
a)

6-nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid
b)

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

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

2-Trifluoromethyl-2H-naphtho [2,3-b] pyran-3-carboxylic acid
e)

6-chloro-7- (4-nitrophenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid
f)

(S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid
g)

6-chloro-2- (trifluoromethyl) -4-phenyl-2H-1-benzopyran-3-carboxylic acid
h)

6- (4-hydroxybenzoyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid
i)

2- (trifluoromethyl) -6-[(trifluoromethyl) thio] -2H-1-benzothiopyran-3-carboxylic acid
j)

6,8-dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid
k)

6- (1,1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid
l)

6,7-difluoro-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid
m)

6-chloro-1,2-dihydro-1-methyl-2- (trifluoromethyl) -3-quinolinecarboxylic acid
n)

6-chloro-2- (trifluoromethyl) -1,2-dihydro [1,8] naphthyridine-3-carboxylic acid
o)

(S) -6-chloro-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid and
Selected from the group consisting of any combination thereof.
[51" claim-type="Currently amended] The method of claim 1, wherein said cyclooxygenase inhibitor comprises a compound of the formula: or a pharmaceutically acceptable salt or prodrug thereof.

here,
A is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings;
R ¹ is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R ¹ is alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, Optionally substituted with one or more radicals selected from hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
R ² is selected from the group consisting of methyl and amino;
R ³ is 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, arkenyl, alkoxyalkyl, arylthioalkyl, aryl Oxyalkyl, aralkylthioalkyl, araloxyoxy, alkoxy aralkyloxy, 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, aralkyloxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N -Arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl.
[52" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof is
a)

b)

c)

d)

e)

f)

And any combination thereof.
[53" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof is
a)

6-nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid
b)

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

(S) -6-chloro-7- (1,1-dimethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid
d)

2-Trifluoromethyl-2H-naphtho [2,3-b] pyran-3-carboxylic acid
e)

6-chloro-7- (4-nitrophenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid
f)

(S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid
g)

6-chloro-2- (trifluoromethyl) -4-phenyl-2H-1-benzopyran-3-carboxylic acid
h)

6- (4-hydroxybenzoyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid
i)

2- (trifluoromethyl) -6-[(trifluoromethyl) thio] -2H-1-benzothiopyran-3-carboxylic acid
j)

6,8-dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid
k)

6- (1,1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid
l)

6,7-difluoro-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid
m)

6-chloro-1,2-dihydro-1-methyl-2- (trifluoromethyl) -3-quinolinecarboxylic acid
n)

6-chloro-2- (trifluoromethyl) -1,2-dihydro [1,8] naphthyridine-3-carboxylic acid
o)

(S) -6-chloro-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid
p)

q)

r)

s)

t)

u)

v)

w)

And any combination thereof.
[54" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is

Or a pharmaceutically acceptable salt or prodrug thereof.
[55" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is

Or a pharmaceutically acceptable salt or prodrug thereof.
[56" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is 4- [4- (methyl) -sulfonyl) phenyl] -3-phenyl-2 (5H) -furanone or a pharmaceutically acceptable salt thereof Methods comprising prodrugs.
[57" claim-type="Currently amended] The method of claim 1, wherein said cyclooxygenase-2 selective inhibitor comprises 4- (5-methyl-3-phenyl-4-isoxazolyl) or a pharmaceutically acceptable salt or prodrug thereof.
[58" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is 2- (6-methylpyrid-3-yl) -3- (4-methylsulfonylphenyl) -5-chloropyridine or a pharmaceutically acceptable thereof. Methods comprising salts or prodrugs thereof.
[59" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] or a pharmaceutically acceptable thereof Methods comprising salts or prodrugs thereof.
[60" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is N-[[4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonyl] or a pharmaceutically acceptable salt thereof Methods comprising prodrugs.
[61" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is 4- [5- (3-fluoro-4-methoxyphenyl) -3-difluoromethyl) -1H-pyrazol-1-yl ] Benzenesulfonamide or a pharmaceutically acceptable salt or prodrug thereof.
[62" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is (S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid or a pharmaceutical thereof. A method comprising a pharmaceutically acceptable salt or prodrug.
[63" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methylbutoxy) -5- [4- ( Methylsulfonyl) phenyl] -3 (2H) -pyridazinone or a pharmaceutically acceptable salt or prodrug thereof.
[64" claim-type="Currently amended] The method of claim 1, wherein said cyclooxygenase-2 selective inhibitor comprises a compound of formula (III) or an isomer thereof, a pharmaceutically acceptable salt, ester, or prodrug:
<Formula III>

here,
R ¹⁶ is methyl or ethyl;
R ¹⁷ is chloro or fluoro;
R ¹⁸ is hydrogen or fluoro;
R ¹⁹ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy;
R ²⁰ is hydrogen or fluoro;
R ²¹ is chloro, fluoro, trifluoromethyl or methyl,
Provided that when R ¹⁶ is ethyl and R ¹⁹ is H, R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are not all fluoro.
[65" claim-type="Currently amended] 65. The method of claim 64,
R ¹⁶ is ethyl;
R ¹⁷ and R ¹⁹ are chloro;
R ¹⁸ and R ²⁰ are hydrogen;
R ²¹ is methyl.
[66" claim-type="Currently amended] The method of claim 1, wherein said cyclooxygenase-2 selective inhibitor comprises a compound of formula (IV) or an isomer thereof, a pharmaceutically acceptable salt, ester, or prodrug:
<Formula IV>

here,
X is O or S;
J is carbocycle or heterocycle;
R ²² is NHSO ₂ CH ₃ or F;
R ²³ is H, NO ₂ or F;
R ²⁴ is H, NHSO ₂ CH ₃ or (SO ₂ CH ₃ ) C ₆ H ₄ .
[67" claim-type="Currently amended] The method of claim 1, wherein said cyclooxygenase-2 selective inhibitor comprises a compound of formula (V) or an isomer, pharmaceutically acceptable salt, ester, or prodrug thereof:
<Formula V>

here,
T and M are independently phenyl, naphthyl, radicals derived from heterocycles containing 5 to 6 elements and containing 1 to 4 heteroatoms, or radicals derived from saturated hydrocarbon rings having 3 to 7 carbon atoms;
Q ¹ , Q ² , L ¹ or L ² are independently hydrogen, halogen, lower alkyl having 1 to 6 carbon atoms, trifluoromethyl, or lower methoxy having 1 to 6 carbon atoms;
At least one of Q ¹ , Q ² , L ¹ or L ² is in the para position, and -S (O) nR (where n is 0, 1 or 2, and R is lower alkyl having 1 to 6 carbon atoms) Radicals or lower haloalkyl radicals having 1 to 6 carbon atoms) or -SO ₂ NH ₂ ;
Q ¹ and Q ² are methylenedioxy; or
L ¹ and L ² are methylenedioxy;
R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are independently hydrogen, halogen, lower alkyl radicals having 1 to 6 carbon atoms, lower haloalkyl radicals having 1 to 6 carbon atoms, or phenyl, naphthyl, thienyl, An aromatic radical selected from the group consisting of furyl and pyridyl; or,
R ²⁵ and R ²⁶ are O;
R ²⁷ and R ²⁸ are O; or,
R ²⁵ , R ²⁶ together with the carbon atom to which they are attached form a saturated hydrocarbon ring having 3 to 7 carbon atoms; or,
R ²⁷ , R ²⁸ together with the carbon atoms to which they are attached form a saturated hydrocarbon ring having 3 to 7 carbon atoms.
[68" claim-type="Currently amended] The method of claim 1, wherein said cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof comprises a chromen compound.
[69" claim-type="Currently amended] 69. The method of claim 68, wherein said chromen compound is a benzopyran or a substituted benzopyran analog.
[70" claim-type="Currently amended] 70. The method of claim 69, wherein said benzopyran or substituted benzopyran analog is selected from the group consisting of benzothiopyrans, dihydroquinoline and dihydronaphthalene.
[71" claim-type="Currently amended] The method of claim 1, wherein said cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof comprises a tricyclic compound.
[72" claim-type="Currently amended] The method of claim 71, wherein the tricyclic compound comprises benzenesulfonamide or methylsulfonylbenzene.
[73" claim-type="Currently amended] The method of claim 1, wherein said cyclooxygenase-2 selective inhibitor or a pharmaceutically acceptable salt or prodrug thereof comprises a phenyl acetic acid derivative.
[74" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor is
B-26
Or a pharmaceutically acceptable salt or prodrug thereof.
[75" claim-type="Currently amended] The method of claim 1, wherein the cyclooxygenase-2 selective inhibitor, a pharmaceutically acceptable salt, isomer, or prodrug thereof is
3-[(3-chloro-phenyl)-(4-methanesulfonyl-phenyl) -methylene] -dihydro-furan-2-one;
8-acetyl-3- (4-fluorophenyl) -2- (4-methylsulfonyl) phenyl-imidazo (1,2-a);
5,5-dimethyl-4- (4-methylsulfonyl) phenyl-3-phenyl-2- (5H) -furanone;
5- (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole;
4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) pyrazole;
4- (5- (4-chlorophenyl) -3- (4-methoxyphenyl) -1H-pyrazol-1-yl) benzenesulfonamide;
4- (3,5-bis (4-methylphenyl) -1H-pyrazol-1-yl) benzenesulfonamide;
4- (5- (4-chlorophenyl) -3-phenyl-1H-pyrazol-1-yl) benzenesulfonamide;
4- (3,5-bis (4-methoxyphenyl) -1H-pyrazol-1-yl) benzenesulfonamide;
4- (5- (4-chlorophenyl) -3- (4-methylphenyl) -1H-pyrazol-1-yl) benzenesulfonamide;
4- (5- (4-chlorophenyl) -3- (4-nitrophenyl) -1 H-pyrazol-1-yl) benzenesulfonamide;
4- (5- (4-chlorophenyl) -3- (5-chloro-2-thienyl) -1H-pyrazol-1-yl) benzenesulfonamide;
4- (4-chloro-3,5-diphenyl-1H-pyrazol-1-yl) benzenesulfonamide;
4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [5-phenyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [4-chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [3- (difluoromethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [3- (difluoromethyl) -5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide;
4- [3- (difluoromethyl) -5- (4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [3-cyano-5- (4-fluorophenyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [4-chloro-5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide;
4- [5- (4-chlorophenyl) -3- (hydroxymethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [5- (4- (N, N-dimethylamino) phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
5- (4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene;
4- [6- (4-fluorophenyl) spiro [2.4] hept-5-en-5-yl] benzenesulfonamide;
6- (4-fluorophenyl) -7- [4- (methylsulfonyl) phenyl] spiro [3.4] oct-6-ene;
5- (3-chloro-4-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene;
4- [6- (3-chloro-4-methoxyphenyl) spiro [2.4] hept-5-en-5-yl] benzenesulfonamide;
5- (3,5-dichloro-4-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene;
5- (3-chloro-4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hept-5-ene;
4- [6- (3,4-dichlorophenyl) spiro [2.4] hept-5-en-5-yl] benzenesulfonamide;
2- (3-chloro-4-fluorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) thiazole;
2- (2-chlorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) thiazole;
5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-methylthiazole;
4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-trifluoromethylthiazole;
4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2- (2-thienyl) thiazole;
4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-benzylaminothiazole;
4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2- (1-propylamino) thiazole;
2-[(3,5-dichlorophenoxy) methyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] thiazole;
5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-trifluoromethylthiazole;
1-methylsulfonyl-4- [1,1-dimethyl-4- (4-fluorophenyl) cyclopenta-2,4-dien-3-yl] benzene;
4- [4- (4-fluorophenyl) -1,1-dimethylcyclopenta-2,4-dien-3-yl] benzenesulfonamide;
5- (4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2.4] hepta-4,6-diene;
4- [6- (4-fluorophenyl) spiro [2.4] hepta-4,6-dien-5-yl] benzenesulfonamide;
6- (4-fluorophenyl) -2-methoxy-5- [4- (methylsulfonyl) phenyl] -pyridine-3-carbonitrile;
2-bromo-6- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -pyridine-3-carbonitrile;
6- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-phenyl-pyridine-3-carbonitrile;
4- [2- (4-methylpyridin-2-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide;
4- [2- (5-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide;
4- [2- (2-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide;
3- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine;
2- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine;
2-methyl-4- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine;
2-methyl-6- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine;
4- [2- (6-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide;
2- (3,4-difluorophenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazole;
4- [2- (4-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide;
2- (4-chlorophenyl) -1- [4- (methylsulfonyl) phenyl] -4-methyl-1H-imidazole;
2- (4-chlorophenyl) -1- [4- (methylsulfonyl) phenyl] -4-phenyl-1H-imidazole;
2- (4-chlorophenyl) -4- (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -1H-imidazole;
2- (3-fluoro-4-methoxyphenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazole;
1- [4- (methylsulfonyl) phenyl] -2-phenyl-4-trifluoromethyl-1H-imidazole;
2- (4-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazole;
4- [2- (3-chloro-4-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide;
2- (3-fluoro-5-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazole;
4- [2- (3-fluoro-5-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide;
2- (3-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazole;
4- [2- (3-methylphenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide;
1- [4- (methylsulfonyl) phenyl] -2- (3-chlorophenyl) -4-trifluoromethyl-1H-imidazole;
4- [2- (3-chlorophenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide;
4- [2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide;
4- [2- (4-methoxy-3-chlorophenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide;
1-allyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazole;
4- [1-ethyl-4- (4-fluorophenyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl] benzenesulfonamide;
N-phenyl- [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazol-1-yl] acetamide;
Ethyl [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazol-1-yl] acetate;
4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -1- (2-phenylethyl) -1H-pyrazole;
4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -1- (2-phenylethyl) -5- (trifluoromethyl) pyrazole;
1-ethyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazole;
5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-trifluoromethyl-1H-imidazole;
4- [4- (methylsulfonyl) phenyl] -5- (2-thiophenyl) -2- (trifluoromethyl) -1H-imidazole;
5- (4-fluorophenyl) -2-methoxy-4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyridine;
2-ethoxy-5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyridine;
5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2- (2-propynyloxy) -6- (trifluoromethyl) pyridine;
2-bromo-5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyridine;
4- [2- (3-chloro-4-methoxyphenyl) -4,5-difluorophenyl] benzenesulfonamide;
1- (4-fluorophenyl) -2- [4- (methylsulfonyl) phenyl] benzene;
5-difluoromethyl-4- (4-methylsulfonylphenyl) -3-phenylisoxazole;
4- [3-ethyl-5-phenylisoxazol-4-yl] benzenesulfonamide;
4- [5-difluoromethyl-3-phenylisoxazol-4-yl] benzenesulfonamide;
4- [5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide;
4- [5-methyl-3-phenyl-isoxazol-4-yl] benzenesulfonamide;
1- [2- (4-fluorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene;
1- [2- (4-fluoro-2-methylphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene;
1- [2- (4-chlorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene;
1- [2- (2,4-dichlorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene;
1- [2- (4-trifluoromethylphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene;
1- [2- (4-methylthiophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene;
1- [2- (4-fluorophenyl) -4,4-dimethylcyclopenten-1-yl] -4- (methylsulfonyl) benzene;
4- [2- (4-fluorophenyl) -4,4-dimethylcyclopenten-1-yl] benzenesulfonamide;
1- [2- (4-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] -4- (methylsulfonyl) benzene;
4- [2- (4-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] benzenesulfonamide;
4- [2- (4-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide;
4- [2- (4-chlorophenyl) cyclopenten-1-yl] benzenesulfonamide;
1- [2- (4-methoxyphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene;
1- [2- (2,3-difluorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene;
4- [2- (3-fluoro-4-methoxyphenyl) cyclopenten-1-yl] benzenesulfonamide;
1- [2- (3-chloro-4-methoxyphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene;
4- [2- (3-chloro-4-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide;
4- [2- (2-methylpyridin-5-yl) cyclopenten-1-yl] benzenesulfonamide;
Ethyl 2- [4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazol-2-yl] -2-benzyl-acetate;
2- [4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazol-2-yl] acetic acid;
2- ( tert -butyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazole;
4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-phenyloxazole;
4- (4-fluorophenyl) -2-methyl-5- [4- (methylsulfonyl) phenyl] oxazole;
4- [5- (3-fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide;
6-chloro-7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
5,5-dimethyl-3- (3-fluorophenyl) -4-methylsulfonyl-2 (5H) -furanone;
6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid;
4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
3- [1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazol-2-yl] pyridine;
2-methyl-5- [1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazol-2-yl] pyridine;
4- [2- (5-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide;
4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide;
4- [5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide;
[2-trifluoromethyl-5- (3,4-difluorophenyl) -4-oxazolyl] benzenesulfonamide;
4- [2-methyl-4-phenyl-5-oxazolyl] benzenesulfonamide;
4- [5- (2-fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide;
[2- (2-Chloro-6-fluoro-phenylamino) -5-methyl-phenyl] -acetic acid;
N- (4-nitro-2-phenoxy-phenyl) -methanesulfonamide or nimesulide;
N- [6- (2,4-Difluoro-phenoxy) -1-oxo-indan-5-yl] -methanesulfonamide;
N- [6- (2,4-Difluoro-phenylsulfanyl) -1-oxo-1H-inden-5-yl] -methanesulfonamide, sodium salt;
N- [5- (4-Fluoro-phenylsulfanyl) -thiophen-2-yl] -methanesulfonamide;
3- (3,4-Difluoro-phenoxy) -4- (4-methanesulfonyl-phenyl) -5-methyl-5- (2,2,2-trifluoroethyl) -5H-furan- 2-one;
(5Z) -2-amino-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4 (5H) thiazolone;
N- [3- (formylamino) -4-oxo-6-phenoxy-4H-1-benzopyran-7-yl] -methanesulfonamide;
(6aR, 10aR) -3- (1,1-dimethylheptyl) -6a, 7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6-dibenzo [b, d] pyran- 9-carboxylic acid;
4-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] dihydro-2-methyl-2H-1,2-oxazin-3 (4H) -one;
6-dioxo-9H-purin-8-yl-cinnamic acid;
4- [4- (methyl) -sulfonyl) phenyl] -3-phenyl-2 (5H) -furanone;
4- (5-methyl-3-phenyl-4-isoxazolyl);
2- (6-methylpyrid-3-yl) -3- (4-methylsulfonylphenyl) -5-chloropyridine;
4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl];
N-[[4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonyl];
4- [5- (3-fluoro-4-methoxyphenyl) -3-difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;
(S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid;
2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone;
2-trifluoromethyl-3H-naphtho [2,1-b] pyran-3-carboxylic acid;
6-chloro-7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid and
[2- (2,4-Dichloro-6-ethyl-3,5-dimethyl-phenylamino) -5-propyl-phenyl] -acetic acid.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US20180042975A1|2018-02-15|Phytocannabinoids in the treatment of cancer

---

US8557308B2|2013-10-15|Andrographis paniculata extract

---

Tapuria et al.2008|Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury—a review

---

ES2234324T3|2005-06-16|Combinations of a 5ht1b / 1d agonist and a cox-2 selective inhibitor for the treatment of migraine.

---

ES2564194T3|2016-03-18|Liquid formulations for the treatment of diseases or ailments

---

AU742787B2|2002-01-10|Improved methods and compositions for treating male erectile dysfunction

---

US7141599B2|2006-11-28|Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor, a leukotriene B4 receptor inhibitor and a cyclosporin

---

RU2239429C2|2004-11-10|Method for applying cyclooxygenase-2 inhibitor for treatment and prophylaxis of neoplasia

---

Setty et al.2005|Herbal medications commonly used in the practice of rheumatology: mechanisms of action, efficacy, and side effects

---

US20030232867A1|2003-12-18|Use

---

EP0888127B1|2001-12-12|Combinations having immunosuppressive effects, containing cyclooxygenase-2-inhibitors and 5-lipoxygenase inhibitors

---

US20070020254A1|2007-01-25|Methods and compositions for treatment of inflammatory disease

---

JP2004536809A|2004-12-09|Pharmaceutical compositions for coordinated delivery of NSAIDs

---

CA2415577C|2010-10-19|Use of cox-2 inhibitors for preventing immunodeficiency

---

US20080223379A1|2008-09-18|Methods and compositions for the treatment or prophylaxis of tendon and ligament injury

---

US20050227929A1|2005-10-13|Combination therapy comprising a Cox-2 inhibitor and an antineoplastic agent

---

Linet et al.1994|Intracavernous prostaglandin E 1 in erectile dysfunction

---

TW201410248A|2014-03-16|Method and composition for treating peripheral vascular diseases

---

UY27533A1|2003-05-30|Pharmaceutical compositions containing oxybutynin

---

Laev et al.2015|Anti-arthritic agents: progress and potential

---

US8148416B2|2012-04-03|Treatment of inflammatory, cancer, and thrombosis disorders

---

PT1608407E|2006-12-29|Dispersible formulation of an anti-inflammatory agent

---

CZ20033241A3|2004-08-18|Skin penetrating preparation containing selectively inhibiting cyclooxygenase-2 and monobasic alcohol

---

US20090192212A1|2009-07-30|Dithiol Compounds, Derivatives, and Uses Therefor

---

CA2704957A1|2009-05-22|Compositions for the treatment of gastrointestinal inflammation

同族专利:

---

公开号 | 公开日

---

WO2002096516A1|2002-12-05|

---

PL367028A1|2005-02-07|

---

US20030153801A1|2003-08-14|

---

CZ20033258A3|2004-12-15|

---

ZA200308822B|2005-02-14|

---

CO5540374A2|2005-07-29|

---

MXPA03011055A|2004-12-06|

---

AU2002312291B2|2006-03-16|

---

JP2004536073A|2004-12-02|

---

WO2002096516A8|2003-02-20|

---

CN1561246A|2005-01-05|

---

CA2447657A1|2002-12-05|

---

IL159111D0|2004-05-12|

---

EP1406696A1|2004-04-14|

---

NO20035299D0|2003-11-28|

---

BR0209776A|2004-07-13|

---

EA200301197A1|2004-08-26|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
2001-05-29|Priority to US29407701P

---

2001-05-29|Priority to US60/294,077

---

2002-05-29|Application filed by 파마시아 코포레이션

---

2002-05-29|Priority to PCT/US2002/017552

---

2004-04-14|Publication of KR20040032100A

优先权:

---

申请号 | 申请日 | 专利标题

---

US29407701P| true| 2001-05-29|2001-05-29|

---

US60/294,077|2001-05-29|

---

PCT/US2002/017552|WO2002096516A1|2001-05-29|2002-05-29|Use of compositions comprising cyclooxygenase-2 selective inhibitors in combination with radiation for inhibition or prevention of cardiovascular disease|