CN1771034A - Combinations of peroxisome proliferators-activated receptor-alpha agonists and cyclooxygenase-2 selective inhibitors and therapeutic uses therefor - Google Patents

Abstract

Methods for the treatment, prevention, or inhibition of pain, inflammation, or inflammation-related disorder, and for the treatment or inhibition of cardiovascular disease or disorder, and for the treatment or inhibition of cancer, and for the treatment of Alzheimer's disease in a subject in need of such treatment, prevention, or inhibition, include treating the subject with a peroxisome proliferator activated receptor-alpha agonist and a cyclooxygenase-2 selective inhibitor or prodrug thereof. Compositions, pharmaceutical compositions and kits for effecting the particular methods are also described.

Description

The combination of peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant and therapeutic use thereof

The cross reference of related application

The preferential patent application series number 60/348297 of the U.S. that the application relates on January 14th, 2002 and submits also requires its priority, and it is attached to herein in full by reference.

Background of invention

(1) invention field

The present invention relates to comprise the compositions of peroxisome proliferation-activated receptors agonist and cyclo-oxygenase-2 selective depressant, more particularly, relate to the compositions that comprises the peroxisome proliferation-activated receptors-alfa agonists and the combination of cyclo-oxygenase-2 selective depressant and their treatments, prevention or suppress cancer, cardiovascular/metabolic disease or disorder, Alzheimer, pain, inflammation or the purposes of the disease relevant with inflammation.

(2) description of association area

Peroxisome proliferation-activated receptors (PPARs) belongs to the superfamily of the nuclear receptor of the activated transcription factor of part.Once by the part combination, PPARs that with 9-cis-retinoic acid receptor (RXRs) heterodimerization of nuclear.These hydridization dimers are incorporated into the interior specific peroxisome Proliferators of promotion of target gene and reply element (PPRE), thereby regulate these gene transcription and expression.Identified three isomer α, δ and the γ of PPARs, there is difference in they in tissue distribution, to the affinity of specific aglucon and physiological significance.Referring to for example Corton, J.C. etc., Annu.Rev.Pharmacol.Toxicol., 40:491-518 (2000) and Chawla, A. etc., Science, 294:1866-1870 (2001).

One of PPARs that at first identifies is PPAR α (PPAR α), and the latter is by for example the special class (fiber acid esters (fibrates)) of shellfish, Carboxymethylcellulose (fibric acid) derivant and long-chain fatty acid combine activation with such chemical compound.Referring to for example Staels, B. etc., Circulation, 98 (19): 2088-93 (1998).Cause important function of gene change of Expression in the lipid biological oxidation by part in conjunction with activating PPAR α.Fruchart, J.C. etc. are at Curr.Opin.Lipidol., and 10 (3): report PPAR α activates the mediation pleiotropic effects among the 245-57 (1999), for example stimulates lipid oxidation, changes lipoprotein metabolism and suppresses vascular inflammation.The PPAR alpha activators increases liver picked-up (helatic uptake) and makes the free fatty esterification by stimulating fatty acid transport protein and acyl group-CoA synzyme to express.At skeletal muscle and heart, PPAR α increases the picked-up of mitochondrion free fatty and causes the free-fat acid oxidase by stimulated muscle type Carnitine palmitoyltransferase.

To other relevant PPARs activity, the particularly general information of PPAR alpha active, referring to for example Schoonjans, K. etc., Biochim.Biophys.Acta, 1302 (2): 93-109 (1996); Kersten, S. etc., EXS, 89:141-51 (2000); And Hertz, R. etc., Toxicol.Lett., 102-103:85-90 (1998).

Because the result of these variations in gene expression, the chemical compound for example special class of shellfish works with the adjusting lipid metabolism as the PPAR alpha ligands, and fenofibrate (as an example) has been approved for treatment hypercholesterolemia and hypertriglyceridemia.Referring to for example, TRICOR , Prescribing information #011-030-0565-1, August calendar year 2001, Abbott Laboratories, North Chicago, IL 60064.

By causing that with receptors bind some physiology result's part is known as agonist.Existing evidence shows that the PPAR alfa agonists has the potential clinical application except that treatment hypercholesterolemia and hypertriglyceridemia.For example, Seedorf, U. etc., Nutr.Metab.Cardiovasc.Dis., 11 (3): 189-94 (2001) has described the function of PPAR α in potential X syndrome therapy; Robins, S.J., J.of Cardiovascular Risk, 8 (4): 195-201 (2001) and Marx, N. etc., J.of Cardiovascular Risk, 8 (4): 203-210 (2001) has reported that the PPAR alpha ligands can reduce cardiovascular risk; Barger, P.M. etc., J.Biol.Chem., Sep.27 (2001) have discussed the effect of PPAR α in the reaction of control heart metabolic stress; Plutzky, J., Curr.Opin.Lipidol., 12 (5): 511-8 (2001) and Duez, H. etc., J.Cardiovascular Risk, 8:187-194 (2001) have discussed the effect of the special class of shellfish in changing Atherosclerosis; Michalik, L. etc., J.Cell.Biol., 154 (4): 799-814 (2001) has described the effect of PPAR α in the quick epithelium of skin wound forms; Vanden Heuvel, J.P., Toxicol.Sci., 47 (1): 1-8 (1999) and James, N.H. etc., Toxicol.Lett., 102-103:91-96 (1998) has discussed the relation of PPAR α and carcinogenesis regulating liver-QI carcinogenesis.

Nearest work has shown result likely, be that PPAR α can avoid suffering from Alzheimer (referring in ' t Veld, B.A., Deng, The New England J.of Med., 345 (21): 1515-1521 (2001)) and play the effect of regulating the pro-inflammatory that amyloid beta stimulates (referring to Combs, C.K. etc., Neuorchem Int., 39 (5-6): 449-457 (2001)).

Owing to illustrate the bioactive work of PPAR α in lipid metabolism and make progress, the research in arachidonic acid metabolic field has caused selectivity to suppress the discovery of the chemical compound of cyclo-oxygenase-2 enzyme.The activity that these compound selectives suppress Cox-2 is surpassing inhibition Cox-1 activity to a greater extent.Believe that new Cox-2 selective depressant can provide some advantages, these advantages comprise prevention or reduce inflammation, avoid the ability of the deleterious side effect relevant with inhibition Cox-1 simultaneously.Therefore, the cyclo-oxygenase-2 selective depressant has shown and the big prospect that is used for the treatment of-particularly prolong administration at needs for example has been used for the treatment of arthritic pain and inflammation control.Find in the document below about the out of Memory of identifying the cyclo-oxygenase-2 selective depressant: (1) Buttgereit, F. etc., Am.J.Med., 110 (3Suppl.1): 13-9 (2001); (2) Osiri, M. etc., Arthritis Care Res., 12 (5): 351-62 (1999); (3) Buttar, N.S. etc., Mayo Clin.Proc., 75 (10): 1027-38 (2000); (4) Wollheim, F.A., Current Opin.Rheumatol., 13:193-201 (2001); (5) No. the 5434178th, United States Patent (USP) (1,3,5-three substituted pyrazole compounds); (6) 5476944 (ring-type phenol thioether analog derivatives); (7) 5643933 (substituted sulphonyl phenyl heterocycles classes); 5859257 (isoxazole compounds); (8) 5932598 (prodrugs that contain the Cox-2 inhibitor of benzsulfamide); (9) 6156781 (substituted pyrazolecarboxylic base benzene sulfonamides) and (10) 6,110,960 (about dihydrobenzopyrans and related compounds).

Effectiveness and side effect that the cyclo-oxygenase-2 selective depressant is used for the treatment of inflammation are in the news.List of references comprises: Hillson, J.L. etc., Expert Opin.Pharmacother., 1 (5): 1053-66 (2000), (rofecoxib, Vioxx , Merck ﹠amp; Co., Inc.); Everts, B. etc., Clin.Rheumatol., 19 (5): 331-43 (2000), (celecoxib, Celebrex , Pharmacia Corporation and rofecoxib); Jamali, F., J.Pharm.Pharm.Sci., 4 (1): 1-6 (2001), (celecoxib); United States Patent (USP) the 5521207th and No. 5760068 (substituted pyrazolecarboxylic benzene sulfonamide); Davies, N.M. etc., Clinical Genetics, Abstr.At http://www.mmhc.com/cg/articles/CG0006/davies.html (meloxicam, celecoxib, valdecoxib, parecoxib, deracoxib and rofecoxib); Http:// www.celebrex.com (celecoxib); Http:// www.docguide.com/dg.nsf/PrintPrint/F1F8DDD2D8B0094085256,98F00742187,5/9/2001 (support is examined former times, MK-663, Merck ﹠amp; Co., Inc.); Saag, K. etc., Arch.Fam.Med., 9 (10): 1124-34 (2000), (rofecoxib); International patent application no WO 00/24719 (ABT 963, Abbott Laboratories).

The Cox-2 inhibitor also is described and is used for the treatment of cancer (WO 98/16227) and treats tumor (referring to EP 927555 and Rozic etc., Int.J.Cancer, 93 (4): 497-506 (2001)).Celecoxib , a Cox-2 selective depressant, to fibroblast growth factor in the rat body inductive cornea vascularization present effective inhibitory action (Masferrer etc., Proc.Am.Assoc.Cancer Research 1999,40:396).WO 98/41511 has described 5-(4-salphunyl-the phenyl)-pyridazinone derivative that is used for the treatment of cancer.WO 98/41516 has described (methyl sulphonyl) phenyl-2-(the 5H)-furanone derivatives that can be used for treating cancer.Kalgutkar, A.S. etc., Curr.Drug Targets, 2 (1): 79-106 (2001) prompting Cox-2 selective depressant can be used in prevention or treatment cancer by influencing tumor viability, growth and transfer.Masferrer etc. have described the Cox-2 selective depressant and have had potential therapeutic use as anti-angiogenic medicaments in the cancer of several types at Ann.NY Acad.Sci. among the 889:84-86 (1999).Lynch, P.M. at Oncology, 15 (3): described the purposes of Cox-2 inhibitory action in the clinical cancer prevention among the 21-26 (2001), Watanabe etc. have described the potentiality of Cox-2 selective depressant conduct to the chemoprophylactic drug of colon cancer in Biofactors 2000,12 (1-4): 129-133 (2000).

In addition, the various combination treatments that adopt the assembled scheme of Cox-2 inhibitor and other selection to be used for the treatment of cancer also are in the news.Referring to for example FR 27 71 005 (compositions that comprises cyclooxygenase-2 inhibitor and N-methyl-d-aspartic acid (NMDA) antagonist that is used for the treatment of cancer and other disease); WO 99/18960 (can be used for treating the combination that comprises cyclooxygenase-2 inhibitor and inducible nitric oxide synthase inhibitor (iNOS) of colon and breast carcinoma); WO99/13799 (combination of cyclooxygenase-2 inhibitor and opium kind analgesics); WO 97/36497 (being used for the treatment of the combination that comprises cyclooxygenase-2 inhibitor and 5-lipoxidase inhibitor of cancer); WO 97/29776 (compositions that comprises cyclooxygenase-2 inhibitor and leukotriene B42 receptor antagonist and immunosuppressant); WO 97/29775 (combination of using cyclooxygenase-2-inhibitor 2 and leukotriene A hydrolase inhibitor and immunosuppressant); WO 97/29774 (being used for the treatment of the combination of cyclooxygenase-2 inhibitor and the prostaglandin or the antiulcerative of cancer); WO97/11701 (being used for the treatment of the combination that comprises cyclooxygenase-2 inhibitor and leukotriene B receptor antagonist of straight colon cancer); WO 96/41645 (comprising the combination of cyclooxygenase-2 inhibitor and leukotriene A hydrolase inhibitor); WO 96/03385 (adopt separately or be used for 3 of treatment of cancer, 4-disubstituted pyrazole chemical compound with NSAIDs, steroidal, 5-LO inhibitor, LTB4 antagonist or LTA4 hydrolase inhibitor use in conjunction); WO 98/47890 (can use separately or unite the substituted benzene benzopyran derivatives of use) with other active component; WO00/38730 (adopting cyclooxygenase-2 inhibitor and a kind of or more kinds of antitumor drug method) as the therapeutic alliance of treatment tumor; Mann, M. etc., Gastroenterology, 120 (7): 1713-1719 (2001) (reducing straight colon cancer growth) with Cox-2 and HER-2/neu inhibitor conjoint therapy.

Other report has indicated the Cox-2 selective depressant and has had the cardiovascular purposes.For example, Saito, T. etc. are at Biochem.Biophys.Res.Comm., and report inhibition Cox-2 can improve the cardiac function in the myocardial infarction among the 273:772-775 (2000).Ridker, P.M. etc. be at The NewEngland J.of Med., and 336 (14): promoted anti-inflammatory agent among the 973-979 (1997) and can have the probability of the clinical benefit of angiocardiopathy preventing.In addition, when with the regulating action of inductivity nitric oxide synthetase (referring to Baker, C.S.R. etc., Arterioscler.Thromb.Vasc.Biol., when 19:646-655 (1999)) uniting and uniting with HMG-CoA reductase inhibitor (U.S. Patent number 6245797), the recommended cardiovascular disease that is used for the treatment of of Cox-2 selective depressant.

Therefore, can provide the effective ways of treatment, prevention or inhibition of pain, inflammation or inflammation related disease and also be that treatment and prophylaxis of cancer and cardiovascular disease or disorderly effective ways will have purposes.If it not is the useful character that is provided by the known and conventional method for the treatment of these symptoms that these methods provide, they also are useful so.

The present invention's general introduction

Therefore, in brief, the present invention relates to prevention in the patient of the treatment of this kind of needs, prevention or inhibition, treatment or inhibition of pain, inflammation or inflammation related disease or cancer or Alzheimer or cardiovascular disease or disorderly new method, this method comprises with peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug treats described patient.

The present invention also relates to have the new method that treatment among the patient of disease of inflammatory component or prevention have the disease of inflammatory component in needs treatments or prevention, this method comprises peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its pharmaceutically acceptable salt or the prodrug that gives the patient treatment effective dose.

The present invention also relates to be used for the treatment of, the new compositions of prevention or inhibition of pain, inflammation or inflammation related disease, said composition contains peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug.

The present invention also relates to contain the new Pharmaceutical composition of peroxisome proliferation-activated receptors-alfa agonists, cyclo-oxygenase-2 selective depressant or its prodrug and pharmaceutically acceptable excipient.

The present invention also relates to be applicable to the new kit of treatment, prevention or inhibition of pain, inflammation or inflammation related disease, described kit comprises first dosage form that contains peroxisome proliferation-activated receptors-alfa agonists and second dosage form that contains cyclo-oxygenase-2 selective depressant or its prodrug, and the treatment effective dose is used for the treatment of to contain for they, the amount of each chemical compound of prevention or inhibition of pain, inflammation or inflammation related disease exists.

The present invention also relates in the patient of the treatment of this kind of needs, prevention or inhibition treatment, prevention or suppress cardiovascular disease or disorderly new method, this method comprises with peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its pharmaceutically acceptable salt or prodrug treats described patient.

The present invention also relates to be used for the treatment of, prevent or suppress cardiovascular disease or disorderly new compositions, said composition contains peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug.

The present invention also relates to be applicable to treatment, prevention or suppress cardiovascular disease or disorderly new kit, wherein said kit comprises first dosage form that contains peroxisome proliferation-activated receptors-alfa agonists and second dosage form that contains cyclo-oxygenase-2 selective depressant or its prodrug, and they exist with the amount that contains each chemical compound that is used for the treatment of, prevents or suppress cardiovascular disease or disorder for the treatment of effective dose.

The present invention also relates in the patient of the prevention of this kind of needs, treatment or inhibition prevention, treatment or suppress the new method of cancer, this method comprises with peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its pharmaceutically acceptable salt or prodrug treats described patient.

The present invention also relates to treat, prevent or suppress the new compositions of cancer, said composition comprises peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug.

The new kit that the present invention also relates to be applicable to treatment, prevention or suppress cancer, wherein said kit comprises first dosage form that contains peroxisome proliferation-activated receptors-alfa agonists and second dosage form that contains cyclo-oxygenase-2 selective depressant or its prodrug, and they exist with the amount that is used for the treatment of, prevents or suppress each chemical compound of cancer that contains the treatment effective dose.

The patient who the present invention also relates to prevent like this, treat or suppress at needs is used to prevent, treat or suppresses disease or disorderly new method by the activity mediation of PPAR α, this method comprises the combination that gives patient's peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug, and wherein the amount that lumps together of two kinds of materials constitutes the effective dose of described combination.

The present invention also relates in the patient of the treatment of this kind of needs, prevention or inhibition treatment, prevention or suppress the new method of Alzheimer, this method comprises with peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its pharmaceutically acceptable salt or prodrug treats described patient.

The present invention also relates to be used for the treatment of, prevent or suppress the new compositions of Alzheimer, said composition contains peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug.

The new kit that the present invention also relates to be applicable to treatment, prevention or suppress Alzheimer, wherein said kit comprises first dosage form that contains peroxisome proliferation-activated receptors-alfa agonists and second dosage form that contains cyclo-oxygenase-2 selective depressant or its prodrug, and they exist with the amount that is used for the treatment of, prevents or suppress each chemical compound of Alzheimer that contains the treatment effective dose.

Therefore, in the several advantages that obtain by discovery of the present invention, it is worth mentioning the clause of the effective ways of treatment, prevention or inhibition of pain, inflammation or inflammation related disease, it simultaneously also is the clause of the effective ways of treatment and prophylaxis of cancer, Alzheimer and cardiovascular disease or disorder, the clause of these class methods provides and can quite or above those treat the advantageous feature of the known and conventional method of these symptoms, and the clause of implementing compositions, Pharmaceutical composition and the kit of these methods.

Detailed description of the preferred embodiments

According to the present invention, found can effectively prevent, suppress and/or treat pain, inflammation and disease and Alzheimer, cardiovascular disease and disorder and the cancer relevant among the patient who prevents like this, suppresses or treat at needs with inflammation by with the described patient of combined therapy who comprises peroxisome proliferation-activated receptors-alfa agonists (PPAR α) and a kind of or more kinds of cyclo-oxygenase-2 selective depressant.

The amount of the amount of used PPAR alfa agonists and cyclo-oxygenase-2 selective depressant in can selecting to treat, so that they constitute the effective dose of pain or inflammation suppression therapy or prevention together, the perhaps effective dose of cardiovascular disease or disorder treatment or prevention, the perhaps effective dose of treatment of cancer or prevention, the perhaps effective dose of treatment of alzheimer's disease or prevention.

New method with the described patient of combined therapy of PPAR alfa agonists and cyclo-oxygenase-2 selective depressant provides prevention and alleviating pain and inflammation and the prevention disease relevant with inflammation with treatment, and the safe and effective procedure of treatment and angiocardiopathy preventing and disorderly, Alzheimer and cancer.Except that for prevention and/or alleviate this type of disease treated the patient and the disorderly effective ways and compositions, these class methods and compositions also can provide desirable character, for example dissolubility, easy operating, be easy to chemical combination, reduce side effect, be easy to preparation or administration etc.

Described new method and compositions comprise the purposes of PPAR alfa agonists and the combination of cyclo-oxygenase-2 selective depressant.

As used herein, term " peroxisome proliferation-activated receptors-alfa agonists " or " PPAR alfa agonists " and " PPAR-alfa agonists " refer to chemical compound or compositions, when itself and PPAR α combination, can be directly or indirect stimulation or increase in the body of general receptor or vitro reactions, for example transcripting regulating activity.Preferred PPAR alfa agonists of the present invention is can be as activated part and the bonded chemical compound of PPAR α.

With respect to the PPARs, especially the PPAR γ that activate other, the preferred used PPAR alfa agonists of the present invention is the selective agonist of PPAR α.By setting forth, effectively activate the compound concentrations of PPAR and can use IC ₅₀(external or body in) or ED ₅₀(in the body) value representation.ED ₅₀Perhaps IC ₅₀Be worth lowly more, the activity of chemical compound is high more.Be purpose of the present invention, if IC ₅₀PPAR γ/IC ₅₀PPAR α ratio (perhaps comparable ED ₅₀Ratio) be at least 1, can understand chemical compound so is the selective PPAR alfa agonists, wherein the IC of two types PPARs ₅₀Perhaps ED ₅₀Determined and the so under the same conditions condition of value is conventional to the test of this type.Preferred described ratio is at least 10, even more preferably is at least 50.

By various tests well known by persons skilled in the art, the Gal-4 hPPAR transactivation test that includes, but is not limited to the transfection test described and describe in No. the 6200998th, United States Patent (USP) in No. the 6306854th, United States Patent (USP) can be determined the IC of PPAR alfa agonists and such chemical compound ₅₀Perhaps ED ₅₀Value.

The example of preferred PPAR alfa agonists is listed in the table 1, such agonist is accredited as the effective indication of treatment is presented in the table 2.

Table 1:PPAR alfa agonists

The PPAR alfa agonists a	The CAS registration number b	Chemical name	Citing document
				WY-14,643	50892-23-4	[4-chloro-6-(2, the 3-xylidino)-2-pyrimidine radicals sulfo-] acetic acid	Yoshikawa, etc., Eur.J.Pharmacol., 426 (3): 201-6 (2001)
Fenofibrate	54419-31-7		No. the 5830148th, 6074670,5827536,5545628,6277405, United States Patent (USP); Casas, F. etc., FEBS Lett., 482 (1-2): 71-4 (2000)
				Medium chain and long-chain fatty acid; Fiber acid derivative; Clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate (beclobrate), the etofibrate gemfibrozil	--- --- --- 637-07-0 49562-28-9 52214-84-3 --- 55937-99-0 31637-97-5 25812-30-0		No. the 6008237th, 6200998, United States Patent (USP)
Arylthiazolidinedionderivatives derivatives (formula)			No. the 6200998th, 6008237, United States Patent (USP)
				Propanoic derivatives (formula)			No. the 6306854th, United States Patent (USP)

Pioglitazone	111025-46-8		Smith，U.，Int.J.Clin.Pract.Suppl.，121：13-18 (2001)
				Bezafibrate (bezafibrate)	41859-67-0		Yoshikawa etc., Eur.J.Pharmacol., 426 (3): 2001-6 (2001); Bonilla, S. etc., J.Physiol.Biochem., 57 (1): 1-8 (2001); Pedraza, N., etc., Diabetes, 49 (7): 1224-30 (2000)
(-)DRF2725		(-) 3-[4-[2-(benzoxazinyl-10-yl) ethyoxyl] phenyl]-the 2-ethoxy-propionic acid	Lohray, B.B. etc., J.Med.Chem., 44 (15): 2675-8 (2001)
				BM-17.0744			Carroll, R. etc., Physiol.Heart Circ.Physiol., 281 (2): H888-94 (2001)
Ciprofibrate	52214-84-3		Latruffe, N. etc., Cell Biochem.Ciophys., 32 Spring:213-20 (2000)
				Omega-3-fatty acid (common); 22 carbon caproic acids			Diep, Q.H. etc., Hypertension, 36 (5): 851-5 (2000)
Clofibrate	637-07-0		Mehendale，H.M.，Toxicol.Sci.，57(2)：187-90 (2000)
				JTT-501		4-[4-[2-(5-methyl-2-phenyl)-4-Evil azoles base] ethyoxyl] benzyl]-3,5-Yi Evil oxazolidinedione	Shibata, T. etc., Br.J.Pharmacol., 30 (3): 495-504 (2000)
Trichloroacetic esters;		---	Zhou, Y.C. etc., Environ.Health Perspect.,

The dichloroacetic acid ester; DHEA-S		---dehydroepiandros-sterone-3-β-sulfate	106(Suppl.4)：983-988(1998)
				Undersaturated C:18 fatty acid (common); Arachidonic acid; Leukotriene B4	--- --- ---		Lin, Q., etc., Biochemistry, 38 (1): 185-90 (1999)
The special class (common) of shellfish			Staels, B. etc., Biochimie, 79 (2-3): 95-9 (1997)
				Fat aryl (common)		Butanoic acid 4-iodine substituted phenyl ester; Butanoic acid 4-chlorophenyl ester; Clofibrate; The butanoic acid phenylester; The naphthyl acetic acid ester; 2,4-D; Acetic acid 4-chlorophenyl ester; The acetic acid phenylester; The iodo acetas;	Pineau, T. etc., Biochem.Pharmacol., 53 (4): 659-67 (1996)
The special class (common) of shellfish; Beclobrate; Bezafibrate; Ciprofibrate;	The dichloroacetic acid ester;		＿＿＿＿，Anatomical Classification Guidlines， http：//www.ephmra.rog/atc/6_002C10.html， 11/19/2001. ---

Clofibrate; Clofibride; The etofibrate fenofibrate; Gemfibrozil; Simfibrate

Annotate:

A. the marker code of the common name of chemical compound or exploitation is presented.

The b.CAS registration number means the Chemical Abstracts Service registration number.

The indication of table 2:PPAR alfa agonists therapeutic use

Indication	Citing document
		Hyperglycemia, hyperlipemia	Shibata, T. etc., Br.J.Pharmacol., 30 (3): 495-504 (2000)
Atherosclerosis	Fruchart, J.C. etc., J.Soc.Biol., 193 (1): 67-75 (1999); Plutzky, J., Curr.Opin.Lipidol., 12 (5): 511-518 (2001)
		Ischemic heart disease	Kinoshita, M., Nippon Rinsho, 57 (12): 2826-30 (1999)
With old and feeble diseases associated: fat metabolic disturbance, insulin resistance, chronic inflammatory disease, atherosclerotic easy susceptibility	Pineda Torra, I., etc., Curr.Opin.Lipidol., 10 (2): 151-9 (1999)
		Tumor takes place	Vanden Heuvel, J.P., Toxicol.Sci., 47 (1): 1-8 (1999)
Hepatocarcinoma takes place	Peters, J.M., etc., Carcinogenesis, 18 (2): 2029-33 (1997)
		Atheromatous disease	No. the 5880148th, United States Patent (USP)
Diabetes, hyperglycemia, obesity, hyperlipemia, hypertriglyceridemia, hypercholesterolemia, the HDL level that raises, atherosclerosis, vascular restenosis, the irritable bowel trace integration is levied, pancreatitis, abdominal obesity, the adipose cell tumor, the adipose cell cancer, liposarcoma, insulin resistance is the disease of the cause of disease, X syndrome, the too much disease of ovary excessive androgen.	No. the 6200998th, United States Patent (USP)
		Obesity, X syndrome, hyperlipemia, tangier's disease, type ii diabetes, atherosclerosis	Seedorf etc., Nutr.Metab.Cardiovasc.Dis., 11 (3): 189-194 (2001)
Angiopathy	Marx, N. etc., Z.Kardiol., 90 (7): 470-7 (2001)
		Skin wound healing	Michalik, L., etc., J.Cell.Biol., 154 (4): 799-814 (2001)
Fat metabolic disturbance	Lohray, B.B. etc., J.Med.Chem, 44 (15): 2675-8 (2001)

Can be used as chemical compound that PPAR alfa agonists of the present invention works and obtain describing in No. the 6200998th, United States Patent (USP), the latter has described Arylthiazolidinedionderivatives derivatives.Described chemical compound or its pharmaceutically acceptable salt are described to have the structure of formula X:

Wherein

Ar ¹For (1) arlydene or

(2) inferior heteroaryl,

Wherein arlydene and inferior heteroaryl are selected from R by 1-4 ^aOptional replacement of group; Ar ²For the aryl of (1) neighbour-replacement or

(2) heteroaryl of neighbour-replacement,

Wherein said ortho-substituent is selected from R;

And aryl and heteroaryl independently are selected from R by 1-4 ^aGroup optional further replace; X and Y independently are O, S, N-R ^bOr CH ₂Z is O or S; N is 0-3; R is selected from halogen and C for (1) by 1-4 _3-6The optional C that replaces of the group of cycloalkyl _3-10Alkyl,

(2) C _3-10Alkenyl, perhaps

(3) C _3-8Cycloalkyl; R ^aBe (1) C _1-5Alkanoyl,

(2) C _1-5Alkyl,

(3) C _2-15Alkenyl,

(4) C _2-15Alkynyl,

(5) halogen,

(6)OR ^b，

(7) aryl, perhaps

(8) heteroaryl,

Wherein said alkyl, alkenyl, alkynyl and alkanoyl are selected from R by 1-5 ^cOptional replacement of group, and described aryl and heteroaryl are selected from R by 1-5 ^dOptional replacement of group; R ^bBe (1) hydrogen,

(2) C _1-10Alkyl,

(3) C _2-10Alkenyl,

(4) C _2-10Alkynyl,

(5) aryl,

(6) heteroaryl,

(7) aryl C _1-15Alkyl,

(8) heteroaryl C _1-5Alkyl,

(9) C _1-5Cycloalkyl,

(10) C _3-8Cycloalkyl,

Wherein alkyl, alkenyl, alkynyl independently are selected from R by 1-4 ^cOptional replacement of substituent group, and cycloalkyl, aryl and heteroaryl independently are selected from R by 1-4 ^dOptional replacement of substituent group; Perhaps R ^cBe (1) halogen,

(2) aryl,

(3) heteroaryl,

(4)CN，

(5)NO ₂，

(6)OR ^f，

(7) S (O) _mR ^f, m=0,1 or 2, condition is when m is 1 or 2, R ^fBe not H;

(8)NR ^fR ^f，

(9)NR ^fCOR ^f，

(10)NR ^fCO ₂R ^f，

(11)NR ^fCON(R ^f) ₂，

(12) NR ^fSO ₂R ^f, condition is R ^fBe not H,

(13)COR ^f，

(14)CO ₂R ^f，

(15)CON(R ^f) ₂，

(16)SO ₂N(R ^f) ₂，

(17) OCON (R ^f) ₂, perhaps

(18) C _3-8Cycloalkyl,

Wherein said cycloalkyl, aryl and heteroaryl are by 1-3 halogen or C _1-6The group of alkyl is optional to be replaced; R ^dFor (1) is selected from R ^cGroup,

(2) C _1-10Alkyl,

(3) C _2-10Alkenyl,

(4) C _2-10Alkynyl,

(5) aryl C _1-10Alkyl, perhaps

(6) heteroaryl C _1-10Alkyl,

Wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl independently are selected from R by one ^eOptional replacement of group; R ^eBe (1) halogen,

(2) amino,

(3) carboxyl,

(4) C _1-4Alkyl,

(5) C _1-4Alkoxyl,

(6) hydroxyl

(7) aryl,

(8) aryl C _1-4Alkyl, perhaps

(9) aryloxy group; R ^fBe (1) hydrogen,

(2) C _1-10Alkyl,

(3) C _2-10Alkenyl,

(4) C _2-10Alkynyl,

(5) aryl,

(6) heteroaryl,

(7) aryl C _1-15Alkyl,

(8) heteroaryl C _1-15Alkyl,

(9) C _1-15Alkanoyl;

(10) C _3-8Cycloalkyl;

Wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkanoyl and cycloalkyl are selected from R by 1-4 ^eOptional replacement of group.

United States Patent (USP) has been described the chemical compound that can be used as PPAR alfa agonists of the present invention No. 6306854.Described compound or its salt has the formula of formula XI, and wherein formula is:

Wherein m is 0-20, R ⁶Be selected from hydrogen and

And R ⁸Be selected from

Wherein y is 0,1 or 2, and each alk is independently for hydrogen or comprise the alkyl of 1-6 carbon atom, each R group independently be hydrogen, halogen, cyano group ,-NO ₂, phenyl, comprise the straight or branched alkyl or the fluoro-alkyl of 1-6 carbon atom, and it can comprise hetero atom, and for example nitrogen, oxygen or sulfur and Qi Ke comprise functional group for example ketone or ester, the cycloalkyl that comprises 3-7 carbon atom, two R groups that perhaps are connected in adjacent carbon atom can form aliphatic series or aromatic ring or multiple loop systems with the carbon atom that they connected, and wherein each ring that is described has no more than 3 alk groups.

Example with preferred compound of formula II structure comprises:

2-(4-(2-(1-(4-xenyl ethyl)-3-cyclohexyl urea groups) ethyl) thiophenyl)-2 Methylpropionic acid,

2-(4-(2-(1-(2-(4-morpholino phenyl) ethyl-3-cyclohexyl urea groups) ethyl) thiophenyl)-2 Methylpropionic acid;

2-(4-(2-(1-(cyclohexane extraction butyl)-3-cyclohexyl urea groups) ethyl) thiophenyl)-2 Methylpropionic acid;

2-(4-(2-(1-heptyl-3-(2,4 difluorobenzene base) urea groups) ethyl) thiophenyl)-2 Methylpropionic acid;

2-(4-(2-(1-(2-chloro-4-(2-trifluoromethyl) phenyl methyl)-3-(cyclohexyl) urea groups) ethyl) thiophenyl)-2 Methylpropionic acid, or its salt.

The antagonist of PPAR alpha inhibitor also can be used as PPAR alfa agonists of the present invention and works.Kehrer, J.P. etc., Biochem.J., 356 (Pt.3): 899-906 (2001) have discussed a kind of such PPAR alpha inhibitor, and it is described to MK886.Therefore, to disturb or to reduce that its PPAR α suppresses active mode and MK886 or any other interactional any chemical compound of PPAR alpha inhibitor can be the PPAR alfa agonists on the meaning of the present invention.

Can be provided for PPAR alfa agonists of the present invention by any source, as long as the PPAR alfa agonists is acceptable pharmaceutically.The PPAR alfa agonists can or can synthesize from natural origin separation and purification.The PPAR alfa agonists preferably has the quality and the purity of the routine that is used for the medicinal product trade.

The another kind of composition of combination of the present invention is the cyclo-oxygenase-2 selective depressant.Term " cyclo-oxygenase-2 selective depressant " or " Cox-2 selective depressant " comprise that selectivity suppresses the chemical compound that cyclo-oxygenase-2 surpasses cyclo-oxygenase-1, and also comprise the pharmaceutically acceptable salt of those chemical compounds in this commutative use.

In fact, the Cox-2 selection of inhibitors changes with the inhibitor that is experimentized according to the condition that experimentizes.Yet, in this description, the Cox-2 selection of inhibitors can be determined as the inhibiting IC of Cox-1 in external or the body ₅₀Value is divided by the inhibiting IC of Cox-2 ₅₀Value (Cox-1 IC ₅₀/ Cox-2 IC ₅₀).The Cox-2 selective depressant is Cox-1IC ₅₀With Cox-2 IC ₅₀Ratio greater than any inhibitor of 1.In preferred embodiments, this ratio is greater than 2, more preferably greater than 5, and still more preferably greater than 10, also more preferably greater than 50, and more preferably greater than 100.

Term " IC as used herein ₅₀" refer to produce 50% inhibiting compound concentrations to the activity of cyclo-oxygenase.Preferred cyclo-oxygenase-2 selective depressant of the present invention has the cyclo-oxygenase-2 IC less than about 1 μ M ₅₀, be more preferably less than about 0.5 μ M, and even more preferably less than about 0.2 μ M.

Preferred cyclo-oxygenase-2 selective depressant has the cyclo-oxygenase-1IC greater than about 1 μ M ₅₀, and more preferably greater than 20 μ M.This preferred selectivity can show the ability of the incidence rate that reduces the inductive side effect of common NSAID.

Be also contained in the scope of the invention is the chemical compound that the prodrug as the cyclo-oxygenase-2 selective depressant works.When relating to the Cox-2 selective depressant, term " prodrug " refers to can be converted into by metabolism or simple chemical process the chemical compound of active Cox-2 selective depressant in patient's body as used herein.An example of the prodrug of Cox-2 selective depressant is a parecoxib, and it is the effective prodrug of treatment of three ring cyclo-oxygenase-2 selective depressant valdecoxibs.An example of preferred Cox-2 selective depressant prodrug is a parecoxib sodium.The prodrug of one class Cox-2 inhibitor is described in No. the 5932598th, United States Patent (USP).

Cyclo-oxygenase-2 selective depressant of the present invention can be for example Cox-2 selective depressant meloxicam, formula B-1 (CAS registration number 71125-38-7) or its pharmaceutically acceptable salt or prodrug.

In another embodiment of the invention; the cyclo-oxygenase-2 selective depressant can be Cox-2 selective depressant RS 57067; 6-[[5-(4-chlorobenzene formoxyl)-1; 4-dimethyl-1H-pyrroles-2-yl] methyl]-3 (2H)-2H-Pyridazin-3-ones, formula B-2 (CAS registration number 179382-91-3) or its pharmaceutically acceptable salt or prodrug.

In another embodiment of the invention, the cyclo-oxygenase-2 selective depressant belongs to .alpha.-5:6-benzopyran/benzodihydropyran structure type, it is the .alpha.-5:6-benzopyran of replacement or the benzopyran analogs of replacement, and even more preferably be selected from the benzo thiapyran class of replacement, category of dihydro quinolines or dihydronaphthalene class, the diastereomer that comprises them, enantiomer, racemic modification, tautomer, salt, ester, amide and prodrug, they have the general formula I by following demonstration, II, III, IV, the structure that V and VI show and have structure by example (but being not limited to) any chemical compound of disclosed structure in table 3.

The benzopyrans compounds that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the 1-benzopyran derivatives of the replacement of describing in No. the 6271253rd, the United States Patent (USP).Define a kind of chemical compound of the type by the following general formula that in formula I, shows:

X wherein ¹Be selected from O, S, CR ^cR ^bAnd NR ^a

R wherein ^aBe selected from hydrogen, C ₁-C ₃-alkyl, (the optional phenyl that replaces)-C ₁-C ₃-alkyl, acyl group and carboxyl-C ₁-C ₆-alkyl;

R wherein ^bAnd R ^cIndependently be selected from hydrogen, C separately ₁-C ₃-alkyl, phenyl-C ₁-C ₃-alkyl, C ₁-C ₃-perfluoroalkyl, chloro, C ₁-C ₆-alkylthio group, C ₁-C ₆-alkoxyl, nitro, cyano group and cyano group-C ₁-C ₃-alkyl; Perhaps CR wherein ^bR ^cForm 3-6 unit cycloalkyl ring;

R wherein ¹Be selected from carboxyl, amino carbonyl, C ₁-C ₆-alkyl sulfonyl-amino carbonyl and C ₁-C ₆-alkoxy carbonyl;

R wherein ²Be selected from hydrogen, phenyl, thienyl, C ₁-C ₆-alkyl and C ₂-C ₆-alkenyl;

R wherein ³Be selected from C ₁-C ₃-perfluoroalkyl, chloro, C ₁-C ₆-alkylthio group, C ₁-C ₆-alkoxyl, nitro, cyano group and cyano group-C ₁-C ₃-alkyl;

R wherein ⁴For one or more independently is selected from following group, comprising: hydrogen, halo, C ₁-C ₆-alkyl, C ₂-C ₆-alkenyl, C ₂-C ₆-alkynyl, halo-C ₂-C ₆-alkynyl, aryl-C ₁-C ₃-alkyl, aryl-C ₂-C ₆-alkynyl, aryl-C ₂-C ₆-alkenyl, C ₁-C ₆-alkoxyl, methylene-dioxy, C ₁-C ₆-alkylthio group, C ₁-C ₆-alkyl sulphinyl, aryloxy group, arylthio, aryl sulfonyl kia, heteroaryloxy, C ₁-C ₆-alkoxy-C ₁-C ₆-alkyl, aryl-C ₁-C ₆-alkoxyl, heteroaryl-C ₁-C ₆-alkoxyl, aryl-C ₁-C ₆-alkoxy-C ₁-C ₆-alkyl, C ₁-C ₆-haloalkyl, C ₁-C ₆-halogenated alkoxy, C ₁-C ₆-halogenated alkylthio, C ₁-C ₆-haloalkyl sulfinyl, C ₁-C ₆-halogenated alkyl sulfonyl, C ₁-C ₃-(haloalkyl)-C ₁-C ₃-hydroxy alkyl, C ₁-C ₆-hydroxy alkyl, oxyimino-C ₁-C ₆-alkyl, C ₁-C ₆-alkyl amino, arylamino, aryl-C ₁-C ₆-alkyl amino, heteroaryl amino, heteroaryl-C ₁-C ₆-alkyl amino, nitro, cyano group, amino, amino-sulfonyl, C ₁-C ₆-alkyl amino sulfonyl, n-aryl sulfonyl, heteroaryl amino sulfonyl, aryl-C ₁-C ₆-alkyl amino sulfonyl, heteroaryl-C ₁-C ₆-alkyl amino sulfonyl, heterocyclic radical sulfonyl, C ₁-C ₆-alkyl sulphonyl, aryl-C ₁-C ₆-alkyl sulphonyl, the optional aryl that replaces, optional heteroaryl, the aryl-C that replaces ₁-C ₆-alkyl-carbonyl, heteroaryl-C ₁-C ₆-alkyl-carbonyl, heteroaryl carbonyl, aryl carbonyl, amino carbonyl, C ₁-C ₁-alkoxy carbonyl, formoxyl, C ₁-C ₆-halogenated alkyl carbonyl and C ₁-C ₆-alkyl-carbonyl; With

A annular atoms A wherein ¹, A ², A ³And A ⁴Independently be selected from carbon and nitrogen, condition is A ¹, A ², A ³And A ⁴In at least two be carbon;

Perhaps R wherein ⁴A forms and is selected from following group with ring, comprising: naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuran group; Perhaps their isomer or pharmaceutically acceptable salt.

The another kind of 1-benzopyran derivatives that can be used as Cox-2 selective depressant of the present invention comprises chemical compound or its isomer or the pharmaceutically acceptable salt with formula II structure:

X wherein ²Be selected from O, S, CR ^cR ^bAnd NR ^a

R wherein ^aBe selected from hydrogen, C ₁-C ₃-alkyl, (the optional phenyl that replaces)-C ₁-C ₃-alkyl, alkyl sulphonyl, phenyl sulfonyl, benzyl sulfonyl, acyl group and carboxyl-C ₁-C ₆-alkyl;

R wherein ^bAnd R ^cIndependently be selected from hydrogen, C separately ₁-C ₃-alkyl, phenyl-C ₁-C ₃-alkyl, C ₁-C ₃-perfluoroalkyl, chloro, C ₁-C ₆-alkylthio group, C ₁-C ₆-alkoxyl, nitro, cyano group and cyano group-C ₁-C ₃-alkyl; Perhaps CR wherein ^cR ^bForm cyclopropyl rings;

R wherein ⁵Be selected from carboxyl, amino carbonyl, C ₁-C ₆-alkyl sulfonyl-amino carbonyl and C ₁-C ₆-alkoxy carbonyl;

R wherein ⁶Be selected from hydrogen, phenyl, thienyl, C ₂-C ₆-alkynyl and C ₂-C ₆-alkenyl;

R wherein ⁷Be selected from C ₁-C ₃-perfluoroalkyl, chloro, C ₁-C ₆-alkylthio group, C ₁-C ₆-alkoxyl, nitro, cyano group and cyano group-C ₁-C ₃-alkyl;

R wherein ⁸Independently be selected from following group for one or more, comprise: hydrogen, halo, C ₁-C ₆-alkyl, C ₂-C ₆-alkenyl, C ₂-C ₆-alkynyl, halo-C ₂-C ₆-alkynyl, aryl-C ₁-C ₃-alkyl, aryl-C ₂-C ₆-alkynyl, aryl-C ₂-C ₆-alkenyl, C ₁-C ₆-alkoxyl, methylene-dioxy, C ₁-C ₆-alkylthio group, C ₁-C ₆-alkyl sulphinyl ,-O (CF ₂) ₂O-, aryloxy group, arylthio, aryl sulfonyl kia, heteroaryloxy, C ₁-C ₆-alkoxy-C ₁-C ₆-alkyl, aryl-C ₁-C ₆-alkoxyl, heteroaryl-C ₁-C ₆-alkoxyl, aryl-C ₁-C ₆-alkoxy-C ₁-C ₆-alkyl, C ₁-C ₆-haloalkyl, C ₁-C ₆-halogenated alkoxy, C ₁-C ₆-halogenated alkylthio, C ₁-C ₆-haloalkyl sulfinyl, C ₁-C ₆-halogenated alkyl sulfonyl, C ₁-C ₃-(haloalkyl-C ₁-C ₃-hydroxy alkyl), C ₁-C ₆-hydroxy alkyl, oxyimino-C ₁-C ₆-alkyl, C ₁-C ₆-alkyl amino, arylamino, aryl-C ₁-C ₆-alkyl amino, heteroaryl amino, heteroaryl-C ₁-C ₆-alkyl amino, nitro, cyano group, amino, amino-sulfonyl, C ₁-C ₆-alkyl amino sulfonyl, n-aryl sulfonyl, heteroaryl amino sulfonyl, aryl-C ₁-C ₆-alkyl amino sulfonyl, heteroaryl-C ₁-C ₆-alkyl amino sulfonyl, heterocyclic radical sulfonyl, C ₁-C ₆-alkyl sulphonyl, aryl-C ₁-C ₆-alkyl sulphonyl, the optional aryl that replaces, optional heteroaryl, the aryl-C that replaces ₁-C ₆-alkyl-carbonyl, heteroaryl-C ₁-C ₆-alkyl-carbonyl, heteroaryl carbonyl, aryl carbonyl, amino carbonyl, C ₁-C ₆-alkoxy carbonyl, formoxyl, C ₁-C ₆-halogenated alkyl carbonyl and C ₁-C ₆-alkyl-carbonyl; With

D annular atoms D wherein ¹, D ², D ³And D ⁴Independently be selected from carbon and nitrogen, condition is D ¹, D ², D ³And D ⁴In at least two be carbon; Perhaps

R wherein ⁸D forms and is selected from following group with ring, comprising: naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuran group.

Other the .alpha.-5:6-benzopyran Cox-2 selective depressant that is used for the present invention's practice has been described in United States Patent (USP) the 6034256th and No. 6077850.The general formula of these chemical compounds is presented in the formula III:

Formula III is following formula: compound or their isomer or pharmaceutically acceptable salt, and comprises their diastereomer, enantiomer, racemic modification, tautomer, salt, ester, amide and prodrug:

X wherein ³Be selected from O or S or NR ^a

R wherein ^aBe alkyl;

R wherein ⁹Be selected from H and aryl;

R wherein ¹⁰Be selected from carboxyl, amino carbonyl, alkyl sulfonyl-amino carbonyl and alkoxy carbonyl;

R wherein ¹¹Be selected from optional haloalkyl, alkyl, aralkyl, cycloalkyl and the aryl that replaces of group that is selected from alkylthio group, nitro and alkyl sulphonyl by one or more; With

R wherein ¹²Be selected from one or more and be selected from following group, comprising: H, halo, alkyl, aralkyl, alkoxyl, aryloxy group, heteroaryloxy, aralkoxy, assorted aralkoxy, haloalkyl, halogenated alkoxy, alkyl amino, arylamino, aryl alkyl amino, heteroaryl amino, heteroaryl alkyl amino, nitro, amino, amino-sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, the heteroaryl amino sulfonyl, the aryl alkyl amino sulfonyl, the heteroarylalkyl amino-sulfonyl, the heterocyclic radical sulfonyl, alkyl sulphonyl, the hydroxyaryl carbonyl, the nitro aryl, the optional aryl that replaces, the optional heteroaryl that replaces, aromatic alkyl carbonyl, the heteroaryl carbonyl, aryl carbonyl, amino carbonyl and alkyl-carbonyl; Perhaps

R wherein ¹²E forms naphthyl with ring.

Through type IV and V describe chemical compound or their isomer or the pharmaceutically acceptable salt that is used as a correlation type of cyclo-oxygenase-2 selective depressant in the present invention:

X wherein ⁴Be selected from O or S or NR ^a

R wherein ^aBe alkyl;

R wherein ¹³Be selected from carboxyl, amino carbonyl, alkyl sulfonyl-amino carbonyl and alkoxy carbonyl;

R wherein ¹⁴Be selected from by one or more optional haloalkyl, alkyl, aralkyl, cycloalkyl and the aryl that replace of group that are selected from alkylthio group, nitro and alkyl sulphonyl; With

R wherein ¹⁵Be selected from following group for one or more, comprise: hydrogen, halo, alkyl, aralkyl, alkoxyl, aryloxy group, heteroaryloxy, aralkoxy, assorted aralkoxy, haloalkyl, halogenated alkoxy, alkyl amino, arylamino, aryl alkyl amino, heteroaryl amino, heteroaryl alkyl amino, nitro, amino, amino-sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, the heteroaryl amino sulfonyl, the aryl alkyl amino sulfonyl, the heteroarylalkyl amino-sulfonyl, the heterocyclic radical sulfonyl, alkyl sulphonyl, the optional aryl that replaces, the optional heteroaryl that replaces, aromatic alkyl carbonyl, the heteroaryl carbonyl, aryl carbonyl, amino carbonyl and alkyl-carbonyl;

Perhaps R wherein ¹⁵G forms naphthyl with ring.

Formula V is following formula: compound or their isomer or pharmaceutically acceptable salt:

Wherein:

X ⁵Be selected from O or S or NR ^b

R ^bBe alkyl;

R ¹⁶Be selected from carboxyl, amino carbonyl, alkyl sulfonyl-amino carbonyl and alkoxy carbonyl;

R ¹⁷Be selected from haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl and aryl are separately by one or more optional independently replacements of group that are selected from alkylthio group, nitro and alkyl sulphonyl; With

R ¹⁸Be selected from following group for one or more, comprise: hydrogen, halo, alkyl, aralkyl, alkoxyl, aryloxy group, heteroaryloxy, aralkoxy, assorted aralkoxy, haloalkyl, halogenated alkoxy, alkyl amino, arylamino, aryl alkyl amino, heteroaryl amino, heteroaryl alkyl amino, nitro, amino, amino-sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, the heteroaryl amino sulfonyl, the aryl alkyl amino sulfonyl, the heteroarylalkyl amino-sulfonyl, the heterocyclic radical sulfonyl, alkyl sulphonyl, the optional aryl that replaces, the optional heteroaryl that replaces, aromatic alkyl carbonyl, the heteroaryl carbonyl, aryl carbonyl, amino carbonyl and alkyl-carbonyl; Perhaps R wherein ¹⁸A forms naphthyl with ring.

Described cyclo-oxygenase-2 selective depressant also can be chemical compound or their isomer or the pharmaceutically acceptable salt of formula V, wherein:

X ⁵Be selected from oxygen and sulfur;

R ¹⁶Be selected from carboxyl, low alkyl group, rudimentary aralkyl and elementary alkoxy carbonyl;

R ¹⁷Be selected from low-grade halogenated alkyl, low-grade cycloalkyl and phenyl; With

R ¹⁸Be selected from following group for one or more, comprise: hydrogen, halo, low alkyl group, rudimentary aryloxy group, low-grade halogenated alkyl, elementary halogenated alkoxy, low-grade alkyl amino, nitro, amino, amino-sulfonyl, low-grade alkyl amino sulfonyl, 5-unit heteroaryl alkyl amino-sulfonyl, 6-unit heteroaryl alkyl amino-sulfonyl, rudimentary aryl alkyl amino sulfonyl, 5-member heterocyclic ring containing nitrogen base sulfonyl, 6-member heterocyclic ring containing nitrogen base sulfonyl, low alkyl group sulfonyl, optional phenyl, lower aralkylcarbonyl and the lower alkylcarbonyl that replaces; Perhaps

R wherein ¹⁸A forms naphthyl with ring.

Described cyclo-oxygenase-2 selective depressant also can be chemical compound or their isomer or the pharmaceutically acceptable salt of formula V, wherein:

X ⁵Be selected from oxygen and sulfur;

R ¹⁶Be carboxyl;

R ¹⁷Be low-grade halogenated alkyl; With

R ¹⁸Be selected from following group for one or more, comprise: hydrogen, halo, low alkyl group, low-grade halogenated alkyl, elementary halogenated alkoxy, low-grade alkyl amino, amino, amino-sulfonyl, low-grade alkyl amino sulfonyl, 5-unit heteroaryl alkyl amino-sulfonyl, 6-unit heteroaryl alkyl amino-sulfonyl, rudimentary aryl alkyl amino sulfonyl, low alkyl group sulfonyl, 6-member heterocyclic ring containing nitrogen base sulfonyl, optional phenyl, lower aralkylcarbonyl and the lower alkylcarbonyl that replaces; Perhaps R wherein ¹⁸A forms naphthyl with ring.

Described cyclo-oxygenase-2 selective depressant also can be chemical compound or their isomer or the pharmaceutically acceptable salt of formula V, wherein:

X ⁵Be selected from oxygen and sulfur;

R ¹⁶Be selected from carboxyl, low alkyl group, rudimentary aralkyl and elementary alkoxy carbonyl;

R ¹⁷Be selected from fluoro methyl, chloro methyl, dichloromethyl, trichloromethyl, pentafluoroethyl group, seven fluoropropyls, two fluoro ethyls, two fluoropropyls, Dichloroethyl, two chloropropyls, difluoromethyl and trifluoromethyl; With

R ¹⁸Be selected from following group for one or more, comprise: hydrogen, chlorine, fluorine, bromine, iodine, methyl, ethyl, isopropyl, the tert-butyl group, butyl, isobutyl group, amyl group, hexyl, methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N, the N-dimethylamino, N, the N-diethylamino, N-phenyl methyl amino-sulfonyl, N-phenylethyl amino-sulfonyl, N-(2-furyl methyl) amino-sulfonyl, nitro, N, N-dimethylamino sulfonyl, amino-sulfonyl, N-methylamino sulfonyl, the N-ethylsulfonyl, 2,2-dimethyl ethyl amino-sulfonyl, N, N-dimethylamino sulfonyl, N-(2-methyl-propyl) amino-sulfonyl, N-morpholino sulfonyl, methyl sulphonyl, benzyloxycarbonyl group, 2,2-dimethyl propyl carbonyl, phenyl acetyl and phenyl; Perhaps

R wherein ²A forms naphthyl with ring.

Described cyclo-oxygenase-2 selective depressant also can be chemical compound or its isomer or the prodrug of formula V, wherein:

X ⁵Be selected from oxygen and sulfur;

R ¹⁶Be selected from carboxyl, low alkyl group, rudimentary aralkyl and elementary alkoxy carbonyl;

R ¹⁷Be selected from trifluoromethyl and pentafluoroethyl group; With

R ¹⁸Be selected from following group for one or more, comprise: hydrogen, chlorine, fluorine, bromine, iodine, methyl, ethyl, isopropyl, the tert-butyl group, methoxyl group, trifluoromethyl, trifluoromethoxy, N-phenyl methyl amino-sulfonyl, N-phenylethyl amino-sulfonyl, N-(2-furyl methyl) amino-sulfonyl, N, N-dimethylamino sulfonyl, N-methylamino sulfonyl, N-(2, the 2-dimethyl ethyl) amino-sulfonyl, dimethylamino sulfonyl, 2-methyl-propyl amino-sulfonyl, N-morpholino sulfonyl, methyl sulphonyl, benzyloxycarbonyl group and phenyl; Perhaps R wherein ¹⁸A forms naphthyl with ring.

Cyclo-oxygenase-2 selective depressant of the present invention also can be chemical compound or their isomer or the prodrug with formula VI structure:

Wherein

X ⁶Be selected from O and S;

R ¹⁹Be low-grade halogenated alkyl;

R ²⁰Be selected from hydrogen and halo;

R ²¹Be selected from hydrogen, halo, low alkyl group, elementary halogenated alkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, low-grade alkyl amino sulfonyl, rudimentary aryl alkyl amino sulfonyl, rudimentary heteroarylalkyl amino-sulfonyl, 5-member heterocyclic ring containing nitrogen base sulfonyl and 6-member heterocyclic ring containing nitrogen base sulfonyl;

R ²²Be selected from hydrogen, low alkyl group, halo, lower alkoxy and aryl; With

R ²³Be selected from hydrogen, halo, low alkyl group, lower alkoxy and aryl.

Described cyclo-oxygenase-2 selective depressant also can be chemical compound or their isomer or the prodrug with formula VI structure, wherein:

X ⁶Be selected from O and S;

R ¹⁹Be selected from trifluoromethyl and pentafluoroethyl group;

R ²⁰Be selected from hydrogen, chlorine and fluorine;

R ²¹Be selected from hydrogen, chlorine, bromine, fluorine, iodine, methyl, the tert-butyl group, trifluoromethoxy, methoxyl group, benzyloxycarbonyl group, dimethylamino sulfonyl, isopropyl amino-sulfonyl, methylamino sulfonyl, benzylamino sulfonyl, phenylethyl amino-sulfonyl, methyl-propyl amino-sulfonyl, methyl sulphonyl and morpholino sulfonyl;

R ²²Be selected from hydrogen, methyl, ethyl, isopropyl, the tert-butyl group, chlorine, methoxyl group, diethylamino and phenyl; With

R ²³Be selected from hydrogen, chlorine, bromine, fluorine, methyl, ethyl, the tert-butyl group, methoxyl group and phenyl.

Table 3: the example of .alpha.-5:6-benzopyran Cox-2 selective depressant

The example that is used for the particular compound of described cyclo-oxygenase-2 selective depressant includes, but is not limited to following compounds or its pharmaceutically acceptable salt or prodrug:

A1) 8-acetyl group-3-(4-fluorophenyl)-2-(4-methyl sulphonyl) phenyl-imidazo (1,2-a) pyridine;

A2) 5,5-dimethyl-4-(4-methyl sulphonyl) phenyl-3-phenyl-2-(5H)-furanone;

A3) 5-(4-fluorophenyl)-1-[4-(methyl sulphonyl) phenyl]-3-(trifluoromethyl) pyrazoles;

A4) 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-1-phenyl-3-(trifluoromethyl) pyrazoles;

A5) 4-(5-(4-chlorphenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-yl) benzsulfamide;

A6) 4-(3, two (4-the aminomethyl phenyl)-1H-pyrazol-1-yls of 5-) benzsulfamide;

A7) 4-(5-(4-chlorphenyl)-3-phenyl-1H-pyrazol-1-yl) benzsulfamide;

A8) 4-(3, two (4-the methoxyphenyl)-1H-pyrazol-1-yls of 5-) benzsulfamide;

A9) 4-(5-(4-chlorphenyl)-3-(4-aminomethyl phenyl)-1H-pyrazol-1-yl) benzsulfamide;

A10) 4-(5-(4-chlorphenyl)-3-(4-nitrobenzophenone)-1H-pyrazol-1-yl) benzsulfamide;

B1) 4-(5-(4-chlorphenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl) benzsulfamide;

B2) 4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl) benzsulfamide;

B3) 4-[5-(4-chlorphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide;

B4) 4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide;

B5) 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide;

B6) 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide;

B7) 4-[5-(4-chlorphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl] benzsulfamide;

B8) 4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide;

B9) 4-[4-chloro-5-(4-chlorphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide;

B10) 4-[3-(difluoromethyl)-5-(4-aminomethyl phenyl)-1H-pyrazol-1-yl] benzsulfamide;

C1) 4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl] benzsulfamide;

C2) 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl] benzsulfamide;

C3) 4-[3-cyano group-5-(4-fluorophenyl)-1H-pyrazol-1-yl] benzsulfamide;

C4) 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl] benzsulfamide;

C5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide;

C6) 4-[4-chloro-5-phenyl-1H-pyrazol-1-yl] benzsulfamide;

C7) 4-[5-(4-chlorphenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl] benzsulfamide;

C8) 4-[5-(4-(N, N-dimethylamino) phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide;

C9) 5-(4-fluorophenyl)-6-[4-(methyl sulphonyl) phenyl] spiral shell [2.4] heptan-5-alkene;

C10) 4-[6-(4-fluorophenyl) spiral shell [2.4] heptan-5-alkene-5-yl] benzsulfamide;

D1) 6-(4-fluorophenyl)-7-[4-(methyl sulphonyl) phenyl] spiral shell [3.4] oct-6-ene;

D2) 5-(3-chloro-4-methoxyphenyl)-6-[4-(methyl sulphonyl) phenyl] spiral shell [2.4] heptan-5-alkene;

D3) 4-[6-(3-chloro-4-methoxyphenyl) spiral shell [2.4] heptan-5-alkene-5-yl] benzsulfamide;

D4) 5-(3,5-two chloro-4-methoxyphenyls)-6-[4-(methyl sulphonyl) phenyl] spiral shell [2.4] heptan-5-alkene;

D5) 5-(3-chloro-4-fluorophenyl)-6-[4-(methyl sulphonyl) phenyl] spiral shell [2.4] heptan-5-alkene;

D6) 4-[6-(3, the 4-Dichlorobenzene base) spiral shell [2.4] heptan-5-alkene-5-yl] benzsulfamide;

D7) 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methyl sulphonyl phenyl) thiazole;

D8) 2-(2-chlorphenyl)-4-(4-fluorophenyl)-5-(4-methyl sulphonyl phenyl) thiazole;

D9) 5-(4-fluorophenyl)-4-(4-methyl sulphonyl phenyl)-2-methylthiazol;

D10) 4-(4-fluorophenyl)-5-(4-methyl sulphonyl phenyl)-2-trifluoromethyl thiazole;

E1) 4-(4-fluorophenyl)-5-(4-methyl sulphonyl phenyl)-2-(2-thienyl) thiazole;

E2) 4-(4-fluorophenyl)-5-(4-methyl sulphonyl phenyl)-2-benzylamino thiazole;

E3) 4-(4-fluorophenyl)-5-(4-methyl sulphonyl phenyl)-2-(1-propyl group amino) thiazole;

E4) 2-[(3, the 5-dichlorophenoxy) methyl)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl] thiazole;

E5) 5-(4-fluorophenyl)-4-(4-methyl sulphonyl phenyl)-2-trifluoromethyl thiazole;

E6) 1-methyl sulphonyl-4-[1,1-dimethyl-4-(4-fluorophenyl) ring penta-2,4-diene-3-yl] benzene;

E7) 4-[4-(4-fluorophenyl)-1,1-diformazan basic ring penta-2,4-diene-3-yl] benzsulfamide;

E8) 5-(4-fluorophenyl)-6-[4-(methyl sulphonyl) phenyl] spiral shell [2.4] heptan-4, the 6-diene;

E9) 4-[6-(4-fluorophenyl) spiral shell [2.4] heptan-4,6-diene-5-yl] benzsulfamide;

E10) 6-(4-fluorophenyl)-2-methoxyl group-5-[4-(methyl sulphonyl) phenyl]-pyridine-3-formonitrile HCN;

F1) 2-bromo-6-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-pyridine-3-formonitrile HCN;

F2) 6-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-2-phenyl-pyridine-3-formonitrile HCN;

F3) 4-[2-(4-picoline-2-yl)-4-(trifluoromethyl)-1H-imidazoles-1-yl] benzsulfamide;

F4) 4-[2-(5-picoline-3-yl)-4-(trifluoromethyl)-1H-imidazoles-1-yl] benzsulfamide;

F5) 4-[2-(2-picoline-3-yl)-4-(trifluoromethyl)-1H-imidazoles-1-yl] benzsulfamide;

F6) 3-[1-[4-(methyl sulphonyl) phenyl]-4-(trifluoromethyl)-1H-imidazoles-2-yl] pyridine;

F7) 2-[1-[4-(methyl sulphonyl) phenyl]-4-(trifluoromethyl)-1H-imidazoles-2-yl] pyridine;

F8) 2-methyl-4-[1-[4-(methyl sulphonyl) phenyl-4-(trifluoromethyl)-1H-imidazoles-2-yl] pyridine;

F9) 2-methyl-6-[1-[4-(methyl sulphonyl) phenyl-4-(trifluoromethyl)-1H-imidazoles-2-yl] pyridine;

F10) 4-[2-(6-picoline-3-yl)-4-(trifluoromethyl)-1H-imidazoles-1-yl] benzsulfamide;

G1) 2-(3, the 4-difluorophenyl)-1-[4-(methyl sulphonyl) phenyl]-4-(trifluoromethyl)-1H-imidazoles;

G2) 4-[2-(4-aminomethyl phenyl)-4-(trifluoromethyl)-1H-imidazoles-1-yl] benzsulfamide;

G3) 2-(4-chlorphenyl)-1-[4-(methyl sulphonyl) phenyl]-4-methyl isophthalic acid H-imidazoles;

G4) 2-(4-chlorphenyl)-1-[4-(methyl sulphonyl) phenyl]-4-phenyl-1H-imidazoles;

G5) 2-(4-chlorphenyl)-4-(4-fluorophenyl)-1-[4-(methyl sulphonyl) phenyl]-the 1H-imidazoles;

G6) 2-(3-fluoro-4-methoxyphenyl)-1-[4-(methyl sulphonyl) phenyl-4-(trifluoromethyl)-1H-imidazoles;

G7) 1-[4-(methyl sulphonyl) phenyl]-2-phenyl-4-Trifluoromethyl-1 H-imidazoles;

G8) 2-(4-aminomethyl phenyl)-1-[4-(methyl sulphonyl) phenyl]-4-Trifluoromethyl-1 H-imidazoles;

G9) 4-[2-(3-chloro-4-aminomethyl phenyl)-4-(trifluoromethyl)-1H-imidazoles-1-yl] benzsulfamide;

G10) 2-(3-fluoro-5-aminomethyl phenyl)-1-[4-(methyl sulphonyl) phenyl]-4-(trifluoromethyl)-1H-imidazoles;

H1) 4-[2-(3-fluoro-5-aminomethyl phenyl)-4-(trifluoromethyl)-1H-imidazoles-1-yl] benzsulfamide;

H2) 2-(3-aminomethyl phenyl)-1-[4-(methyl sulphonyl) phenyl]-4-Trifluoromethyl-1 H-imidazoles;

H3) 4-[2-(3-aminomethyl phenyl)-4-Trifluoromethyl-1 H-imidazoles-1-yl] benzsulfamide;

H4) 1-[4-(methyl sulphonyl) phenyl]-2-(3-chlorphenyl)-4-Trifluoromethyl-1 H-imidazoles;

H5) 4-[2-(3-chlorphenyl)-4-Trifluoromethyl-1 H-imidazoles-1-yl] benzsulfamide;

H6) 4-[2-phenyl-4-Trifluoromethyl-1 H-imidazoles-1-yl] benzsulfamide;

H7) 4-[2-(4-methoxyl group-3-chlorphenyl)-4-Trifluoromethyl-1 H-imidazoles-1-yl] benzsulfamide;

H8) 1-pi-allyl-4-(4-fluorophenyl)-3-[4-(methyl sulphonyl) phenyl]-5-(trifluoromethyl)-1H-pyrazoles;

H10) 4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl] benzsulfamide;

I1) N-phenyl-[4-(4-fluorophenyl)-3-[4-(methyl sulphonyl) phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl] acetamide;

I2) [4-(4-fluorophenyl)-3-[4-(methyl sulphonyl) phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl] ethyl acetate;

I3) 4-(4-fluorophenyl)-3-[4-(methyl sulphonyl) phenyl]-1-(2-phenylethyl)-1H-pyrazoles;

I4) 4-(4-fluorophenyl)-3-[4-(methyl sulphonyl) phenyl]-1-(2-phenylethyl)-5-(trifluoromethyl) pyrazoles;

I5) 1-ethyl-4-(4-fluorophenyl)-3-[4-(methyl sulphonyl) phenyl]-5-(trifluoromethyl)-1H-pyrazoles;

I6) 5-(4-fluorophenyl)-4-(4-methyl sulphonyl phenyl)-2-Trifluoromethyl-1 H-imidazoles;

I7) 4-[4-(methyl sulphonyl) phenyl]-5-(2-thienyl)-2-(trifluoromethyl)-1H-imidazoles;

I8) 5-(4-fluorophenyl)-2-methoxyl group-4-[4-(methyl sulphonyl) phenyl]-6-(trifluoromethyl) pyridine;

I9) 2-ethyoxyl-5-(4-fluorophenyl)-4-[4-(methyl sulphonyl) phenyl]-6-(trifluoromethyl) pyridine;

I10) 5-(4-fluorophenyl)-4-[4-(methyl sulphonyl) phenyl]-2-(2-third alkynyloxy group)-6-(trifluoromethyl) pyridine;

J1) 2-bromo-5-(4-fluorophenyl)-4-[4-(methyl sulphonyl) phenyl]-6-(trifluoromethyl) pyridine;

J2) 4-[2-(3-chloro-4-methoxyphenyl)-4, the 5-difluorophenyl] benzsulfamide;

J3) 1-(4-fluorophenyl)-2-[4-(methyl sulphonyl) phenyl] benzene;

J4) 5-difluoromethyl-4-(4-methyl sulphonyl phenyl)-3-phenyl-isoxazole azoles;

J5) 4-[3-ethyl-5-phenyl-isoxazole azoles-4-yl] benzsulfamide;

J6) 4-[5-difluoromethyl-3-phenyl-isoxazole azoles-4-yl] benzsulfamide;

J7) 4-[5-hydroxymethyl-3-phenyl-isoxazole azoles-4-yl] benzsulfamide;

J8) 4-[5-methyl-3-phenyl-isoxazole azoles-4-yl] benzsulfamide;

J9) 1-[2-(4-fluorophenyl) cyclopentenes-1-yl]-4-(methyl sulphonyl) benzene;

J10) 1-[2-(4-fluoro-2-aminomethyl phenyl) cyclopentenes-1-yl]-4-(methyl sulphonyl) benzene;

K1) 1-[2-(4-chlorphenyl) cyclopentenes-1-yl]-4-(methyl sulphonyl) benzene;

K2) 1-[2-(2, the 4-Dichlorobenzene base) cyclopentenes-1-yl]-4-(methyl sulphonyl) benzene;

K3) 1-[2-(4-trifluoromethyl) cyclopentenes-1-yl]-4-(methyl sulphonyl) benzene;

K4) 1-[2-(4-methyl mercapto phenyl) cyclopentenes-1-yl]-4-(methyl sulphonyl) benzene;

K5) 1-[2-(4-fluorophenyl)-4,4-dimethylcyclopentene-1-yl]-4-(methyl sulphonyl) benzene;

K6) 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopentene-1-yl] benzsulfamide;

K7) 1-[2-(4-chlorphenyl)-4,4-dimethylcyclopentene-1-yl]-4-(methyl sulphonyl) benzene;

K8) 4-[2-(4-chlorphenyl)-4,4-dimethylcyclopentene-1-yl] benzsulfamide;

K9) 4-[2-(4-fluorophenyl) cyclopentenes-1-yl] benzsulfamide;

K10) 4-[2-(4-chlorphenyl) cyclopentenes-1-yl] benzsulfamide;

L1) 1-[2-(4-methoxyphenyl) cyclopentenes-1-yl]-4-(methyl sulphonyl) benzene;

L2) 1-[2-(2, the 3-difluorophenyl) cyclopentenes-1-yl]-4-(methyl sulphonyl) benzene;

L3) 4-[2-(3-fluoro-4-methoxyphenyl) cyclopentenes-1-yl] benzsulfamide;

L4) 1-[2-(3-chloro-4-methoxyphenyl) cyclopentenes-1-yl]-4-(methyl sulphonyl) benzene;

L5) 4-[2-(3-chloro-4-fluorophenyl) cyclopentenes-1-yl] benzsulfamide;

L6) 4-[2-(2-picoline-5-yl) cyclopentenes-1-yl] benzsulfamide;

L7) 2-[4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl] oxazole-2-yl]-2-benzyl-ethyl acetate;

L8) 2-[4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl] oxazole-2-yl] acetic acid;

L9) 2-(tert-butyl group)-4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl] oxazole;

L10) 4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-2-Ben Ji oxazole;

M1) 4-(4-fluorophenyl)-2-methyl-5-[4-(methyl sulphonyl) phenyl] oxazole; With

M2) 4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl] benzsulfamide;

M3) 6-chloro-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

M4) 6-chloro-7-Methyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

M5) 8-(1-Methylethyl)-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

M6) 6-chloro-7-(1, the 1-dimethyl ethyl)-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

M7) 6-chloro-8-(1-Methylethyl)-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

M8) 2-trifluoromethyl-3H-aphthopyrans-3-formic acid;

M9) 7-(1, the 1-dimethyl ethyl)-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

M10) 6-bromo-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

N1) 8-chloro-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

N2) 6-trifluoromethoxy-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

N3) 5,7-two chloro-2-trifluoromethyls-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

N4) 8-phenyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

N5) 7,8-dimethyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

N6) 6, two (the dimethyl ethyl)-2-trifluoromethyls of 8--2H-1-.alpha.-5:6-benzopyran-3-formic acid;

N7) 7-(1-Methylethyl)-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

N8) 7-phenyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

N9) 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

N10) 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

O1) 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

O2) 6,7-two chloro-2-trifluoromethyls-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

O3) 6,8-two chloro-2-trifluoromethyls-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

O4) 2-trifluoromethyl-3H-naphtho-[2,1-b] pyrans-3-formic acid;

O5) 6-chloro-8-Methyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

O6) 8-chloro-6-Methyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

O7) 8-chloro-6-methoxyl group-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

O8) 6-bromo-8-chloro-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

O9) 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

O10) 8-bromo-6-Methyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

P1) 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

P2) 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

P3) 6-bromo-8-methoxyl group-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

P4) amino 6-[[(phenyl methyl)] sulfonyl]-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

P5) sulfonyl 6-[(dimethylamino)]-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

P6) sulfonyl 6-[(methylamino)]-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

P7) sulfonyl 6-[(4-morpholino)]-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

P8) 6-[(1, the 1-dimethyl ethyl) amino-sulfonyl]-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

P9) amino-sulfonyl 6-[(2-methyl-propyl)]-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

P10) 6-methyl sulphonyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

Q1) amino 8-chloro-6-[[(phenyl methyl)] sulfonyl]-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

Q2) 6-phenyl acetyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

Q3) 6,8-two bromo-2-trifluoromethyls-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

Q4) the 8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

Q5) 6,8-two chloro-(S)-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

Q6) 6-benzyl sulfonyl-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

Q7) 6-[[N-(2-furyl methyl) amino] sulfonyl]-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

Q8) 6-[[N-(2-phenylethyl) amino] sulfonyl]-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

Q9) 6-iodo-2-trifluoromethyl-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

Q10) 7-(1, the 1-dimethyl ethyl)-2-pentafluoroethyl group-2H-1-.alpha.-5:6-benzopyran-3-formic acid;

R1) 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methyl-sulfonyl-2 (5H)-furanone;

R2) 6-chloro-2-trifluoromethyl-2H-1-benzo thiapyran-3-formic acid;

R3) 4-[5-(4-chlorphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide;

R4) 4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide;

R5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl] benzsulfamide;

R6) 3-[1-[4-(methyl sulphonyl) phenyl]-4-Trifluoromethyl-1 H-imidazoles-2-yl] pyridine;

R7) 2-methyl-5-[1-[4-(methyl sulphonyl) phenyl]-4-Trifluoromethyl-1 H-imidazoles-2-yl] pyridine;

R8) 4-[2-(5-picoline-3-yl)-4-(trifluoromethyl)-1H-imidazoles-1-yl] benzsulfamide;

R9) 4-[5-methyl-3-phenyl-isoxazole azoles-4-yl] benzsulfamide;

R10) 4-[5-hydroxymethyl-3-phenyl-isoxazole azoles-4-yl] benzsulfamide;

S1) [2-trifluoromethyl-5-(3, the 4-difluorophenyl)-4-oxazolyl] benzsulfamide;

S2) 4-[2-methyl-4-phenyl-5-oxazolyl] benzsulfamide; Perhaps

S3) 4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl] benzsulfamide.

In another embodiment preferred of the present invention, the tricyclic antidepressants cyclo-oxygenase-2 selective depressant that the formula of the optional free style VII of described cyclooxygenase-2 inhibitor is represented or its prodrug:

Wherein:

Z ¹Be selected from undersaturated or undersaturated heterocyclic radical of part and the undersaturated or undersaturated carbocyclic ring of part;

R ²⁴Be selected from heterocyclic radical, cycloalkyl, cycloalkenyl group and aryl, wherein R ²⁴Be selected from by one or more that following group is optional to be replaced in commutable position, comprise: alkyl, haloalkyl, cyano group, carboxyl, alkoxy carbonyl, hydroxyl, hydroxy alkyl, halogenated alkoxy, amino, alkyl amino, arylamino, nitro, alkoxyalkyl, alkyl sulphinyl, halo, alkoxyl and alkylthio group;

R ²⁵Be selected from methyl or amino; With

R ²⁶Be selected from H; halo; alkyl; alkenyl; alkynyl; oxo; cyano group; carboxyl; the cyano group alkyl; heterocyclic oxy group; alkoxyl; alkylthio group; alkyl-carbonyl; cycloalkyl; aryl; haloalkyl; heterocyclic radical; cycloalkenyl group; aralkyl; the heterocyclic radical alkyl; acyl group; alkylthio alkyl; hydroxy alkyl; alkoxy carbonyl; aryl carbonyl; aromatic alkyl carbonyl; aralkenyl; alkoxyalkyl; arylthio alkyl; aryloxy alkyl; alkylthio-alkyl aryl; sweet-smelling alkoxy alkyl; the alkoxy aromatic alkoxyalkyl; alkoxy carbonyl alkyl; amino carbonyl; the amino carbonyl alkyl; alkyl amino-carbonyl; the N-aromatic yl aminocarbonyl; N-alkyl-N-aromatic yl aminocarbonyl; alkyl amino alkyl carbonyl; carboxyalkyl; alkyl amino; the N-arylamino; the N-aryl alkyl amino; N-alkyl-N-aryl alkyl amino; N-alkyl-N-arylamino; aminoalkyl; the alkyl amino alkyl; N-arylamino alkyl; the N-alkyl amino alkyl aryl; N-alkyl-N-alkyl amino alkyl aryl; N-alkyl-N-arylamino alkyl; aryloxy group; aralkoxy; arylthio; aromatic alkylthio; alkyl sulphinyl; alkyl sulphonyl; amino-sulfonyl; alkyl amino sulfonyl; the N-n-aryl sulfonyl; aryl sulfonyl; N-alkyl-N-n-aryl sulfonyl.

In an embodiment preferred of the present invention, the cyclo-oxygenase-2 selective depressant of being represented by following formula VII is selected from one group of chemical compound of setting forth in table 4, it comprises celecoxib (B-18), weary examines former times (B-19), deracoxib (B-20), rofecoxib (B-21), support is examined former times (MK-663; B-22), JTE-522 (B-23) or their prodrug.

The following other information of finding about the selected example of Cox-2 selective depressant discussed above: celecoxib (CAS RN 169590-42-5, C-2779, SC-58653 and in No. the 5466823rd, United States Patent (USP)); Deracoxib (CAS RN 169590-41-4); Rofecoxib (CAS RN 162011-90-7); Compd B-24 (No. the 5840924th, United States Patent (USP)); Compd B-26 (WO 00/25779) and support examine former times (CAS RN 202409-33-4, MK-663, SC-86218 and in WO 98/03484).

Table 4: the example of three ring COX-2 selective depressants

In a more preferred of the present invention, described Cox-2 selective depressant is selected from celecoxib, rofecoxib and support and examines former times.

In a preferred embodiment of the invention, parecoxib (referring to No. the 5932598th, United States Patent (USP) for example) has the structure that shows in B-24, it is that three ring cyclo-oxygenase-2 selective depressants are examined former times the effective prodrug of treatment (referring to No. the 5633272nd, United States Patent (USP) for example) of (B-19) wearyly, and it can be advantageously used for the source of cyclooxygenase-2 inhibitor.

A preferred form of parecoxib is a parecoxib sodium.

In another embodiment of the invention, the compd A BT-963 with formula B-25 that has before obtained describing in international publication number WO00/24719 is another three ring cyclo-oxygenase-2 selective depressants that can advantageously be used.

In another embodiment of the invention, the phenylacetic acid analog derivative cyclo-oxygenase-2 selective depressant that the formula of the optional free style VIII of described cyclooxygenase-2 inhibitor is represented:

Wherein:

R ²⁷Be methyl, ethyl or propyl group;

R ²⁸Be chlorine or fluorine;

R ²⁹Be hydrogen, fluorine or methyl;

R ³⁰Be hydrogen, fluorine, chlorine, methyl, ethyl, methoxyl group, ethyoxyl or hydroxyl;

R ³¹Be hydrogen, fluorine or methyl; With

R ³²Be chlorine, fluorine, trifluoromethyl, methyl or ethyl,

Prerequisite is to work as R ²⁷Be ethyl and R ³⁰During for H, R ²⁸, R ²⁹, R ³⁰And R ³¹Be not fluorine entirely.

A kind of phenylacetic acid derivatives cyclo-oxygenase-2 selective depressant of describing in WO 99/11605 is the chemical compound with the structure that shows in formula VIII,

Wherein:

R ²⁷Be ethyl;

R ²⁸And R ³⁰Be chlorine;

R ²⁹And R ³¹Be hydrogen; With

R ³²Be methyl.

Another kind of phenylacetic acid derivatives cyclo-oxygenase-2 selective depressant is the chemical compound with the structure that shows in formula VIII,

Wherein:

R ²⁷Be propyl group;

R ²⁸And R ³⁰Be chlorine;

R ²⁹And R ³¹Be methyl; With

R ³²Be ethyl.

The another kind of phenylacetic acid derivatives cyclo-oxygenase-2 selective depressant of describing in WO 02/20090 is for being referred to as the chemical compound of COX-189 (be also referred to as chlorine U.S.A and examine former times), and its CAS registration number is 220991-20-8, has the structure that shows in formula VIII,

Wherein:

R ²⁷Be methyl;

R ²⁸Be fluorine;

R ³²Be chlorine; With

R ²⁹, R ³⁰And R ³¹Be hydrogen.

In No. the 6310099th, 6291523 and 5958978, United States Patent (USP), describe and have the chemical compound that can be used as Cox-2 selective depressant of the present invention that is similar to the structure that in formula VIII, shows.

Can be used for other cyclo-oxygenase-2 selective depressant of the present invention and have the formula that shows in formula IX, wherein the J group is carbocyclic ring or heterocycle.Embodiment preferred has following structure:

Wherein:

X is O; J is the 1-phenyl; R ³³Be 2-NHSO ₂CH ₃R ³⁴Be 4-NO ₂And there is not R ³⁵Group, (nimesulide); With

X is O; J is 1-oxo-indenes-5-base; R ³³Be 2-F; R ³⁴Be 4-F; And R ³⁵Be 6-NHSO ₂CH ₃, (flosulide); With

X is O; J is a cyclohexyl; R ³³Be 2-NHSO ₂CH ₃R ³⁴Be 5-NO ₂And there is not R ³⁵Group, (NS-398); With

X is S; J is 1-oxo-indenes-5-base; R ³³Be 2-F; R ³⁴Be 4-F; And R ³⁵Be 6-N-SO ₂CH ₃Na ⁺, (L-745337); With

X is S; J is thiophene-2-base; R ³³Be 4-F; There is not R ³⁴Group; And R ³⁵Be 5-NHSO ₂CH ₃, (RWJ-63556); With

X is O; J is 2-oxo-5 (R)-methyl-5-(2,2, the 2-trifluoroethyl) furan-(5H)-3-base; R ³³Be 3-F; R ³⁴Be 4-F; And R ³⁵Be 4-(p-SO ₂CH ₃) C ₆H ₄, (L-784512).

Cox-2 selective depressant N-(2-cyclohexyl oxygen base nitrobenzophenone) Methanesulfomide (NS-398, CAS RN 123653-11-2) has the structure that shows as in formula B-26, the other information of relevant its application is by for example Yoshimi, N. wait at Japanese J.CancerRes., 90 (4): 406-412 (1999); Falgueyret, J.-P. etc. are Science Spectra (can obtain in http://www.gbhap.com/Science_Spectra/20-1-article.htm (06/06/2001)); And Iwata, K. etc. are at Jpn.J.Pharmacol., and 75 (2): 191-194 (1997) is middle to be described.

The evaluation of the anti-inflammatory activity of cyclo-oxygenase-2 selective depressant RWJ63556 in the dog inflammatory model, is described among the 1094-1101 (1997) at J Pharmacol Exp Ther 282 by Kirchner etc.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the furan diarylmethylidene derivatives of describing in No. the 6180651st, the United States Patent (USP).This class furan diarylmethylidene derivatives or its isomer or prodrug have the following general formula that shows in formula X:

Wherein:

Ring T and M independently are:

Phenyl,

Naphthyl,

Be derived from and comprise 5-6 unit and have 1-4 heteroatomic heterocyclic group, perhaps

Be derived from the group of saturated hydrocarbons ring with 3-7 carbon atom;

Substituent group Q ¹, Q ², L ¹Or L ²In at least one is :-S (O) _n-R group, wherein n equals 0,1 or 2 integer, and R is:

Have 1-6 carbon atom low alkyl group or

Low-grade halogenated alkyl with 1-6 carbon atom, or

-SO ₂NH ₂Group;

And be positioned at para-position,

Other independently be:

Hydrogen atom,

Halogen atom,

Low alkyl group with 1-6 carbon atom,

Trifluoromethyl, or

Rudimentary O-alkyl with 1-6 carbon atom, or

Q ¹And Q ²Or L ¹And L ²Be methylene-dioxy; With

R ³⁶, R ³⁷, R ³⁸And R ³⁹Independently be:

Hydrogen atom,

Halogen atom,

Low alkyl group with 1-6 carbon atom,

Low-grade halogenated alkyl with 1-6 carbon atom, or

Be selected from the aromatic group of phenyl, naphthyl, thienyl, furyl and pyridine radicals; Or

R ³⁶, R ³⁷Or R ³⁸, R ³⁹Be oxygen atom, or

R ³⁶, R ³⁷Or R ³⁸, R ³⁹Form saturated hydrocarbons ring with the carbon atom that they connected with 3-7 carbon atom.

Be included in concrete material in the chemical compound family that can be used as cyclo-oxygenase-2 selective depressant of the present invention and comprise N-(2-cyclohexyl oxygen base nitrobenzophenone) Methanesulfomide and (E)-4-[(4-aminomethyl phenyl) (tetrahydrochysene-2-oxo-3-furylidene) methyl] benzsulfamide.

Be used for cyclo-oxygenase-2 selective depressant of the present invention and comprise Da Bufeilong (Pfizer), CS-502 (Sankyo), LAS 34475 (Almirall Profesfarma), LAS 34555 (Almirall Profesfarma), S-33516 (Servier), SD 8381 (Pharmacia, in No. the 6034256th, United States Patent (USP), describe), BMS-347070 (Bristol Myers Squibb describes in No. the 6180651st, United States Patent (USP)), MK-966 (Merck), L-783003 (Merck), T-614 (Toyama), D-1367 (Chiroscience), L-748731 (Merck), CT3 (Atlantic Pharmaceutical), CGP-28238 (Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome), 6-dioxo-9H-purine-8-base-cinnamic acid (Glaxo Wellcome) and S-2474 (Shionogi).

Information about above-mentioned S-33516 is found at http://www.current-drugs.com/NEWS/Inflaml.htm, Current Drugs HeadlineNews in 10/04/2001, report that wherein S-33516 is a tetrahydrochysene isoinde derivant, it has 0.1 and the IC of 0.001mM respectively to cyclo-oxygenase-1 and cyclo-oxygenase-2 ₅₀Value.In people's whole blood, it is reported that S-33516 has ED ₅₀=0.39mg/kg.

Can be used as chemical compound that the cyclo-oxygenase-2 selective depressant works and comprise and contain 2-10 the many binding compounds that are covalently attached to the aglucon of one or more connexons, see described in No. the 6395724th, the United States Patent (USP).

Can be used as chemical compound that cyclooxygenase-2 inhibitor works and be included in the conjugated linoleic acid of describing in No. the 6077868th, the United States Patent (USP).

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the heterocycle Fang Zu oxazole compounds of describing in United States Patent (USP) the 5994381st and No. 6362209.This class heterocycle Fang Zu oxazole chemical compound and their pharmaceutically acceptable salt have the following structural formula that shows in formula XI:

Wherein:

Z ²Be oxygen atom;

R ⁴⁰And R ⁴¹One of them is the group of following formula

Wherein:

R ⁴³Be low alkyl group, amino or low-grade alkyl amino; With

R ⁴⁴, R ⁴⁵, R ⁴⁶And R ⁴⁷Identical or different, and respectively do for oneself hydrogen atom, halogen atom, low alkyl group, lower alkoxy, trifluoromethyl, hydroxyl or amino, prerequisite is R ⁴⁴, R ⁴⁵, R ⁴⁶And R ⁴⁷In at least one is not a hydrogen atom, and other is optional cycloalkyl that replaces, the optional heterocyclic radical that replaces or the optional aryl that replaces; With

R ³⁰Be low alkyl group or junior alkyl halides.

The Cox-2 selective depressant that is used for the inventive method and compositions can be included in the chemical compound of United States Patent (USP) the 6080876th and No. 6133292 descriptions, and is described by formula XII:

Wherein:

Z ³Be selected from:

(a) linear or ramose C _1-6Alkyl,

(b) linear or ramose C _1-6Alkoxyl,

(c) unsubstituted, single-, two-or trisubstd phenyl or naphthyl, wherein said substituent group is selected from:

(1) hydrogen,

(2) halo,

(3) C _1-3Alkoxyl,

(4)CN，

(5) C _1-3Fluoroalkyl,

(6) C _1-3Alkyl,

(7)-CO ₂H；

R ⁴⁸Be selected from NH ₂And CH ₃,

R ⁴⁹Be selected from:

Unsubstituted or by C _3-6The C of cycloalkyl substituted _1-6Alkyl and C _3-6Cycloalkyl;

R ⁵⁰Be selected from:

C unsubstituted or that replaced by one, two or three fluorine atoms _1-6Alkyl; With

C _3-6Cycloalkyl;

Prerequisite is R ⁴⁹And R ⁵⁰Inequality.

The material that can be used as the cyclo-oxygenase-2 selective depressant is included in the pyridines of describing in No. the 6369275th, 6127545,6130334,6204387,6071936,6001843 and 6040450, the United States Patent (USP), and it has the general formula of being described by formula XIII:

Wherein:

R ⁵¹Be selected from:

(a)CH ₃，

(b)NH ₂，

(c)NHC(O)CF ₃，

(d)NHCH ₃；

Z ⁴For single-, two-or trisubstd phenyl or pyridine radicals (perhaps its N-oxide), wherein substituent group is selected from:

(a) hydrogen,

(b) halo,

(c) C _1-6Alkoxyl,

(d) C _1-6Alkylthio group,

(e)CN，

(f) C _1-6Alkyl,

(g) C _1-6Fluoroalkyl,

(h)N ₃，

(i)-CO ₂R ⁵³，

(j) hydroxyl,

(k)-C(R ⁵⁴)(R ⁵⁵)-OH，

(1)-C _1-6Alkyl-CO ₂-R ⁵⁶,

(m) C _1-6Fluoroalkyloxy;

R ⁵²Be selected from:

(a) halo,

(b) C _1-6Alkoxyl,

(c) C _1-6Alkylthio group,

(d)CN，

(e) C _1-6Alkyl,

(f) C _1-6Fluoroalkyl,

(g)N ₃，

(h)-CO ₂R ⁵⁷，

(i) hydroxyl,

(j)-C(R ⁵⁸)(R ⁵⁹)-OH，

(k)-C _1-6Alkyl-CO ₂-R ⁶⁰,

(l) C _1-6Fluoroalkyloxy;

(m)NO ₂，

(n) NR ⁶¹R ⁶²And

(o)NHCOR ⁶³；

R ⁵³, R ⁵⁴, R ⁵⁵, R ⁵⁶, R ⁵⁷, R ⁵⁸, R ⁵⁹, R ⁶⁰, R ⁶¹, R ⁶², R ⁶³Independently be selected from separately:

(a) hydrogen and

(b) C _1-6Alkyl; Perhaps R ⁵⁴And R ⁵⁵, R ⁵⁸And R ⁵⁹Perhaps R ⁶¹And R ⁶²Form the saturated monocycle of 3,4,5,6 or 7 atoms with the atom that they connected.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the diaryl 1-benzopyran derivatives of describing in No. the 6340694th, the United States Patent (USP).This class diaryl 1-benzopyran derivatives has the following general formula that shows in formula XIV:

Wherein:

X ⁸Be oxygen atom or sulphur atom;

R ⁶⁴And R ⁶⁵, be same to each other or different to each other, independent is hydrogen atom, halogen atom, C ₁-C ₆Low alkyl group, trifluoromethyl, alkoxyl, hydroxyl, nitro, itrile group or carboxyl;

R ⁶⁶Be formula S (O) _nR ⁶⁸Group, wherein n is the integer of 0-2, R ⁶⁸Be hydrogen atom, C ₁-C ₆Low alkyl group or formula NR ⁶⁹R ⁷⁰Group, R wherein ⁶⁹And R ⁷⁰, be same to each other or different to each other, independent is hydrogen atom or C ₁-C ₆Low alkyl group; With

R ⁶⁷Wei oxazolyl, benzo [b] thienyl, furyl, thienyl, naphthyl, thiazolyl, indyl, pyrrole radicals, benzofuranyl, pyrazolyl are by C ₁-C ₆The pyrazolyl, 2 that low alkyl group replaces, 3-indanyl, pyrazinyl, or the group of the replacement of representing by following structure:

Wherein:

R ⁷¹-R ⁷⁵, be same to each other or different to each other, independent is hydrogen atom, halogen atom, C ₁-C ₆Low alkyl group, trifluoromethyl, alkoxyl, hydroxyl, hydroxy alkyl, nitro, formula S (O) _nR ⁶⁸Group, formula NR ⁶⁹R ⁷⁰Group, trifluoromethoxy, itrile group, carboxyl, acetyl group or formoxyl,

Wherein n, R ⁶⁸, R ⁶⁹And R ⁷⁰Have and above R ⁶⁶The identical implication of definition; With

R ⁷⁶Be hydrogen atom, halogen atom, C ₁-C ₆Low alkyl group, trifluoromethyl, alkoxyl, hydroxyl, trifluoromethoxy, carboxyl or acetyl group.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in that 1-(4-sulfamoyl aryl)-3-of describing in No. the 6376519th, the United States Patent (USP) replaces-5-aryl-2-pyrazolines.This class 1-(4-sulfamoyl aryl)-3-replaces-and 5-aryl-2-pyrazolines has the following structural formula that shows in formula XV:

Wherein:

X ⁹Be selected from C ₁-C ₆Trihalomethyl group is preferably trifluoromethyl; C ₁-C ₆The phenyl of the formula XVI of alkyl and optional replacement or two-replacement:

Wherein:

R ⁷⁷And R ⁷⁸Independently be selected from hydrogen, halogen, be preferably chlorine, fluorine and bromine, hydroxyl, nitro, C ₁-C ₆Alkyl is preferably C ₁-C ₃Alkyl, C ₁-C ₆Alkoxyl is preferably C ₁-C ₃Alkoxyl, carboxyl, C ₁-C ₆Tri haloalkyl is preferably trihalomethyl group, most preferably is trifluoromethyl, and cyano group;

Z ⁵Be selected from replacement and unsubstituted aryl.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the heterocyclic of describing in No. the 6153787th, the United States Patent (USP).This class heterocycle has the following general formula that shows in formula XVII and XVIII:

Wherein:

R ⁷⁹For single-, two-or the three-C that replaces _1-12Alkyl, or single-unsubstituted or single-, two-or the linear or ramose C of three-replacement _2-10Alkenyl, unsubstituted or single-, two-or three-the linear or ramose C that replaces _2-10Alkynyl, unsubstituted or single-, two-or the three-C that replaces _3-12Cycloalkenyl group, unsubstituted or single-, two-or the three-C that replaces _5-12Cycloalkynyl radical, wherein said substituent group is selected from:

(a) halo is selected from F, Cl, Br and I,

(b)OH，

(c)CF ₃，

(d) C _3-6Cycloalkyl,

(e)＝O，

(f) dioxolanes,

(g) CN; With

R ⁸⁰Be selected from:

(a)CH ₃，

(b)NH ₂，

(c)NHC(O)CF ₃，

(d)NHCH ₃；

R ⁸¹And R ⁸²Independently be selected from:

(a) hydrogen,

(b) C _1-10Alkyl;

Perhaps R ⁸¹And R ⁸²Form the saturated monocycle carbocyclic ring of 3,4,5,6 or 7 atoms with the carbon that they connected.

Formula XVIII is:

X ¹⁰Be fluorine or chlorine.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention be included in describe in No. the 6046217th, the United States Patent (USP) 2,3, the trisubstituted pyridines of 5-.This class pyridine or its pharmaceutically acceptable salt have the following general formula that shows in formula XIX:

Wherein:

X ¹¹Be selected from:

(a)O，

(b)S，

(c) key;

N is 0 or 1;

R ⁸³Be selected from:

(a)CH ₃，

(b)NH ₂，

(c)NHC(O)CF _a；

R ⁸⁴Be selected from:

(a) halo,

(b) C _1-6Alkoxyl,

(c) C _1-6Alkylthio group,

(d)CN，

(e) C _1-6Alkyl,

(f) C _1-6Fluoroalkyl,

(g)N ₃，

(h)-CO ₂R ⁹²，

(i) hydroxyl,

(j)-C(R ⁹³)(R ⁹⁴)-OH，

(k)-C _1-6Alkyl-CO ₂-R ⁹⁵,

(l) C _1-6Fluoroalkyloxy,

(m)NO ₂，

(n)NR ⁹⁶R ⁹⁷，

(o)NHCOR ⁹⁸；

R ⁸⁵-R ⁹⁸Independently be selected from

(a) hydrogen,

(b) C _1-6Alkyl;

Perhaps R ⁸⁵And R ⁸⁹, or R ⁸⁹And R ⁹⁰Form the carbocyclic ring of 3,4,5,6 or 7 atoms, perhaps R with the atom that they connected ⁸⁵And R ⁸⁷Be connected to form key.

An embodiment preferred of the Cox-2 selective depressant of formula XIX is that wherein X is a key.

Another embodiment preferred of the Cox-2 selective depressant of formula XIX is that wherein X is O.

Another embodiment preferred of the Cox-2 selective depressant of formula XIX is that wherein X is S.

Another embodiment preferred of the Cox-2 selective depressant of formula XIX is R wherein ⁸³Be CH ₃

Another embodiment preferred of the Cox-2 selective depressant of formula XIX is R wherein ⁸⁴Be halo or C _1-6Fluoroalkyl.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the diaryl bicyclic heterocycle class of describing in No. the 6329421st, the United States Patent (USP).This class diaryl bicyclic heterocycle and their pharmaceutically acceptable salt have the following general formula that shows in formula XX,

Wherein:

-A ⁵=A ⁶-A ⁷=A ⁸-be selected from:

(a)-CH＝CH-CH＝CH-，

(b)-CH ₂-CH ₂-CH ₂-C(O)-、-CH ₂-CH ₂-C(O)-CH ₂-、-CH ₂-C(O)-CH ₂-CH ₂-、-C(O)-CH ₂-CH ₂-CH ₂-，

(c)-CH ₂-CH ₂-C(O)-、-CH ₂-C(O)-CH ₂-、-C(O)-CH ₂-CH ₂-，

(d)-CH ₂-CH ₂-O-C(O)-、CH ₂-O-C(O)-CH ₂-、-O-C(O)-CH ₂-CH ₂-，

(e)-CH ₂-CH ₂-C(O)-O-、-CH ₂-C(O)-OCH ₂-、-C(O)-O-CH ₂-CH ₂-，

(f)-C(R ¹⁰⁵) ₂-O-C(O)-、-C(O)-O-C(R ¹⁰⁵) ₂-、-O-C(O)-C(R ¹⁰⁵) ₂-、-C(R ¹⁰⁵) ₂-C(O)-O-，

(g)-N＝CH-CH＝CH-，

(h)-CH＝N-CH＝CH-，

(i)-CH＝CH-N＝CH-，

(j)-CH＝CH-CH＝N-，

(k)-N＝CH-CH＝N-，

(l)-N＝CH-N＝CH-，

(m)-CH＝N-CH＝N-，

(n)-S-CH＝N-，

(o)-S-N＝CH-，

(p)-N＝N-NH-，

(q)-CH=N-S-and

(r)-N＝CH-S-；

R ⁹⁹Be selected from:

(a)S(O) ₂CH ₃，

(b)S(O) ₂NH ₂，

(c)S(O) ₂NHCOCF ₃，

(d)S(O)(NH)CH ₃，

(e)S(O)(NH)NH ₂，

(f)S(O)(NH)NHCOCF ₃，

(g) P (O) (CH ₃) OH and

(h)P(O)(CH ₃)NH ₂；

R ¹⁰⁰Be selected from:

(a) C _1-6Alkyl,

(b) C _3-7Cycloalkyl,

(c) single-or two-phenyl or naphthyl of replacing, wherein said substituent group is selected from:

(1) hydrogen,

(2) halo comprises F, Cl, Br, I,

(3) C _1-6Alkoxyl,

(4) C _1-6Alkylthio group,

(5)CN，

(6)CF ₃，

(7) C _1-6Alkyl,

(8)N ₃，

(9)-CO ₂H，

(10)-CO ₂-C _1-4Alkyl,

(11)-C(R ¹⁰³)(R ¹⁰⁴)-OH，

(12)-C (R ¹⁰³) (R ¹⁰⁴)-O-C _1-4Alkyl and

(13)-C _1-6Alkyl-CO ₂-R ¹⁰⁶

(d) single-or two-heteroaryl of replacing, wherein heteroaryl is the monocyclic aromatic ring of 5 atoms, described ring has hetero atom and optional 1,2 or 3 the other N atom for S, O or N; Perhaps heteroaryl is the monocycle of 6 atoms, and described ring has hetero atom and optional 1,2,3 or 4 the other N atom for N; Described substituent group is selected from:

(1) hydrogen,

(2) halo comprises fluorine, chlorine, bromine and iodine,

(3) C _1-6Alkyl,

(4) C _1-6Alkoxyl,

(5) C _1-6Alkylthio group,

(6)CN，

(7)CF ₃，

(8)N ₃，

(9)-C (R ¹⁰³) (R ¹⁰⁴)-OH and

(10)-C (R ¹⁰³) (R ¹⁰⁴)-O-C _1-4Alkyl;

(e) the benzo heteroaryl that comprises the benzo-fused analog of (d); R ¹⁰¹And R ¹⁰²For being present in-A ⁵=A ⁶-A ⁷=A ⁸-any locational substituent group, and independently be selected from:

(a) hydrogen,

(b)CF ₃，

(c)CN，

(d) C _1-6Alkyl,

(e)-Q ³, Q wherein ³Be Q ⁴, CO ₂H, C (R ¹⁰³) (R ¹⁰⁴) OH,

(f)-O-Q ⁴，

(g)-S-Q ⁴And

(h) optional replace:

(1)-C _1-5Alkyl-Q ³,

(2)-O-C _1-5Alkyl-Q ³,

(3)-S-C _1-5Alkyl-Q ³,

(4)-C _1-3Alkyl-O-C _1-3Alkyl-Q ³,

(5)-C _1-3Alkyl-S-C _1-3Alkyl-Q ³,

(6)-C _1-5Alkyl-O-Q ⁴,

(7)-C _1-5Alkyl-S-Q ⁴,

Wherein said substituent group is present on the alkyl chain, and described substituent group is C _1-3Alkyl, Q ³Be Q ⁴, CO ₂H, C (R ¹⁰³) (R ¹⁰⁴) OH, Q ⁴Be CO ₂-C _1-4Alkyl, tetrazolium-5-base or C (R ¹⁰³) (R ¹⁰⁴) O-C _1-4Alkyl;

R ¹⁰³, R ¹⁰⁴And R ¹⁰⁵Independently be selected from separately

(a) hydrogen,

(b) C _1-6Alkyl; Or

R ¹⁰³And R ¹⁰⁴Form the saturated monocycle carbocyclic ring of 3,4,5,6 or 7 atoms, perhaps two R on same carbon with the carbon that they connected ¹⁰⁵Group forms the saturated monocycle carbocyclic ring of 3,4,5,6 or 7 atoms;

R ¹⁰⁶Be hydrogen or C _1-6Alkyl;

R ¹⁰⁷Be hydrogen, C _1-6Alkyl or aryl;

X ⁷Be O, S, NR ¹⁰⁷, CO, C (R ¹⁰⁷) ₂, C (R ¹⁰⁷) (OH) ,-C (R ¹⁰⁷)=C (R ¹⁰⁷)-, C (R ¹⁰⁷)=N-,-N=C (R ¹⁰⁷).

Can be used as chemical compound that cyclooxygenase-2 inhibitor works and be included in the salt of describing the amino or amino 1,2,3-triazoles chemical compound that replaces of 5-in No. the 6239137th, the United States Patent (USP).Described salt belongs to the type of compounds of formula XXI:

Wherein:

R ¹⁰⁸For:

Wherein:

P is 0-2; M is 0-4; N is 0-5; X ¹³Be O, S, SO, SO ₂, CO, CHCN, CH ₂Or C=NR ¹¹³, R wherein ¹¹³Be hydrogen, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, two elementary alkyl amido or cyano group; R ¹¹¹And R ¹¹²Independent is halogen, cyano group, trifluoromethyl, low-grade alkane acidyl, nitro, low alkyl group, lower alkoxy, carboxyl, lower alkoxycarbonyl, trifluoromethoxy, acetylamino, lower alkylthio, low alkyl group sulfinyl, low alkyl group sulfonyl, trichloro-vinyl, trifluoromethylthio, trifluoromethyl sulphinyl base or trifluoromethyl sulfonyl; R ¹⁰⁹Be amino, list or two elementary alkyl amido, acetylamino, acetylimino-, urea groups, formamido, formamido or guanidine radicals; R ¹¹⁰Be carbamoyl, cyano group, carbazyl, amidino groups or N-hydroxyl amino formoxyl; Wherein said low alkyl group, the low alkyl group that contains, lower alkoxy and low-grade alkane acidyl contain 1-3 carbon atom.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the pyrazole derivatives of describing in No. the 6136831st, the United States Patent (USP).This pyrazol derivatives or its pharmaceutically acceptable salt have the following structural formula that shows in formula XXII:

Wherein:

R ¹¹⁴Be hydrogen or halogen, R ¹¹⁵And R ¹¹⁶Independent separately is hydrogen, halogen, low alkyl group, lower alkoxy, hydroxyl or lower alkanoyloxy;

R ¹¹⁷Be low-grade halogenated alkyl or low alkyl group;

R ¹⁴Be sulfur, oxygen or NH; With

Z ⁶Be lower alkylthio, low alkyl group sulfonyl or amino-sulfonyl.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the benzo sulfonamide of describing in No. the 6297282nd, the United States Patent (USP).This class benzo sulfonamide and their pharmaceutically acceptable salt have the following structural formula that shows in formula XXIII:

Wherein:

X ¹⁵Mean oxygen, sulfur or NH;

R ¹¹⁸Be optional undersaturated alkyl or alkoxyalkyl, its by halogen, alkoxyl, oxo or cyano group optional single-or polysubstituted or mix and replace, by halogen, alkyl, CF ₃, cyano group or alkoxyl optional single-or polysubstituted or mix cycloalkyl, aryl or the heteroaryl that replaces;

R ¹¹⁹And R ¹²⁰Mean hydrogen, optional how fluoric alkyl, aralkyl, aryl or heteroaryl or group (CH with being mutually independent ₂) _n-X ¹⁶Perhaps

R ¹¹⁹And R ¹²⁰Mean saturated, the partially or completely undersaturated heterocycle that contains one or more hetero atom N, O or S of 3-7 unit with the N-atom, it can be by oxo, alkyl, alkylaryl or aryl or group (CH ₂) _n-X ¹⁶The optional replacement;

X ¹⁶Mean halogen, NO ₂,-OR ¹²¹,-COR ¹²¹,-CO ₂R ¹²¹,-OCO ₂R ¹²¹,-CN ,-CONR ¹²¹OR ¹²²,-CONR ¹²¹R ¹²²,-SR ¹²¹,-S (O) R ¹²¹,-S (O) ₂R ¹²¹,-NR ¹²¹R ¹²²,-NHC (O) R ¹²¹,-NHS (O) ₂R ¹²¹

N means the integer of 0-6;

R ¹²³Mean straight chain or ramose alkyl, cycloalkyl, alkyl carboxyl, aryl, aralkyl, heteroaryl or heteroarylalkyl with 1-10 C-atom, its can by halogen or alkoxyl optional single-or polysubstituted or mix and replace;

R ¹²⁴Mean alkyl, alkoxyl, acyloxy or the alkoxy carbonyl of halogen, hydroxyl, straight chain or the ramose 1-6 of having a C-atom, it can be by halogen, NO ₂,-OR ¹²¹,-COR ¹²¹,-CO ₂R ¹²¹,-OCO ₂R ¹²¹,-CN ,-CONR ¹²¹OR ¹²²,-CONR ¹²¹R ¹²²,-SR ¹²¹,-S (O) R ¹²¹,-S (O) ₂R ¹²¹,-NR ¹²¹R ¹²²,-NHC (O) R ¹²¹,-NHS (O) ₂R ¹²¹Perhaps Polyfluoroalkyl optional single-or polysubstituted;

R ¹²¹And R ¹²²Mean hydrogen, alkyl, aralkyl or aryl with being mutually independent; With

M means the integer of 0-2.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in 3-phenyl-4-(4 (methyl sulphonyl) phenyl)-2-(5H)-Furanones of describing in No. the 6239173rd, the United States Patent (USP).This class 3-phenyl-4-(4 (methyl sulphonyl) phenyl)-2-(5H)-furanone or their pharmaceutically acceptable salt have the following structural formula that shows in formula XXIV:

Wherein:

X ¹⁷-Y ¹-Z ⁷-be selected from:

(a)-CH ₂CH ₂CH ₂-，

(b)-C(O)CH ₂CH ₂-，

(c)-CH ₂CH ₂C(O)-，

(d)-CR ¹²⁹(R ¹²⁹)-O-C(O)-，

(e)-C(O)-O-CR ¹²⁹(R ^129’)-，

(f)-CH ₂-NR ¹²⁷-CH ₂-，

(g)-CR ¹²⁹(R ^129’)-NR ¹²⁷-C(O)-，

(h)-CR ¹²⁸＝CR ^128’S-，

(i)-S-CR ¹²⁸＝CR ^128’-，

(j)-S-N＝CH-，

(k)-CH＝N-S-，

(l)-N＝CR ¹²⁸-O-，

(m)-O-CR ⁴＝N-，

(n)-N＝CR ¹²⁸-NH-，

(o)-N=CR ¹²⁸-S-and

(p)-S-CR ¹²⁸＝N-，

(q)-C(O)-NR ¹²⁷-CR ¹²⁹(R ^129’)-，

(r)-R ¹²⁷N-CH=CH-, prerequisite is R ₁₂₂Be not-S (O) ₂CH ₃,

(s)-CH=CH-NR ¹²⁷-, prerequisite is R ¹²⁵Be not-S (O) ₂CH ₃,

When side chain b is singly-bound for two keys and side chain a and c;

With

X ¹⁷-Y ¹-Z ⁷-be selected from:

(a)=CH-O-CH=and

(b)＝CH-NR ¹²⁷-CH＝，

(c)＝N-S-CH＝，

(d)＝CH-S-N＝，

(e)＝N-O-CH＝，

(f)＝CH-O-N＝，

(g)＝N-S-N＝，

(h)＝N-O-N＝，

When side chain a and c are singly-bound for two keys and side chain b;

R ¹²⁵Be selected from:

(a)S(O) ₂CH ₃，

(b)S(O) ₂NH ₂，

(c)S(O) ₂NHC(O)CF ₃，

(d)S(O)(NH)CH ₃，

(e)S(O)(NH)NH ₂，

(f)S(O)(NH)NHC(O)CF ₃，

(g) P (O) (CH ₃) OH and

(h)P(O)(CH ₃)NH ₂；

R ¹²⁶Be selected from:

(a) C _1-6Alkyl,

(b) C ₃, C ₄, C ₅, C ₆And C ₇Cycloalkyl,

(c) single-, two-or the three-phenyl or naphthyl that replaces,

Wherein said substituent group is selected from:

(1) hydrogen,

(2) halo,

(3) C _1-6Alkoxyl,

(4) C _1-6Alkylthio group,

(5)CN，

(6)CF ₃，

(7) C _1-6Alkyl,

(8)N ₃，

(9)-CO ₂H，

(10)-CO ₂-C _1-4Alkyl,

(11)-C(R ¹²⁹)(R ¹³⁰)-OH，

(12)-C (R ¹²⁹) (R ¹³⁰)-O-C _1-4Alkyl and

(13)-C _1-6Alkyl-CO ₂-R ¹²⁹

(d) single-, two-or the three-heteroaryl that replaces, wherein said heteroaryl is the monocyclic aromatic ring of 5 atoms, described ring has hetero atom and optional 1,2 or 3 the other N atom for S, O or N; Perhaps described heteroaryl is the monocycle of 6 atoms, and described ring has hetero atom and optional 1,2,3 or 4 the other N atom for N; Described substituent group is selected from:

(1) hydrogen,

(2) halo comprises fluorine, chlorine, bromine and iodine,

(3) C _1-6Alkyl,

(4) C _1-6Alkoxyl,

(5) C _1-6Alkylthio group,

(6)CN，

(7)CF ₃，

(8)N ₃，

(9)-C (R ¹²⁹) (R ¹³⁰)-OH and

(10)-C (R ¹²⁹) (R ¹³⁰)-O-C _1-4Alkyl;

(e) it comprises the benzo heteroaryl of the benzo-fused analog of (d);

R ¹²⁷Be selected from:

(a) hydrogen,

(b)CF ₃，

(c)CN，

(d) C _1-6Alkyl,

(e) hydroxyl C _1-6Alkyl,

(f)-C (O)-C _1-6Alkyl,

(g) optional replace:

(1)-C _1-5Alkyl-Q ⁵,

(2)-C _1-3Alkyl-O-C _1-3Alkyl-Q ⁵,

(3)-C _1-3Alkyl-S-C _1-3Alkyl-Q ⁵,

(4)-C _1-5Alkyl-O-Q ⁵, or

(5)-C _1-5Alkyl-S-Q ⁵,

Wherein said substituent group is present on the alkyl, and this substituent group is C _1-3Alkyl;

(h)-Q ⁵；

R ¹²⁸And R ^{128 '}Independently be selected from separately:

(a) hydrogen,

(b)CF ₃，

(c)CN，

(d) C _1-6Alkyl,

(e)-Q ⁵，

(f)-O-Q ⁵；

(g)-S-Q ⁵And

(h) optional replace:

(1)-C _1-5Alkyl-Q ⁵,

(2)-O-C _1-5Alkyl-Q ⁵,

(3)-S-C _1-5Alkyl-Q ⁵,

(4)-C _1-3Alkyl-O-C _1-3Alkyl-Q ⁵,

(5)-C _1-3Alkyl-S-C _1-3Alkyl-Q ⁵,

(6)-C _1-5Alkyl-O-Q ⁵,

(7)-C _1-5Alkyl-S-Q ⁵,

Wherein said substituent group is present on the alkyl, and this substituent group is C _1-3Alkyl and

R ¹²⁹, R ^{129 '}, R ¹³⁰, R ¹³¹And R ¹³²Independently be selected from separately:

(a) hydrogen,

(b) C _1-6Alkyl;

Perhaps R ¹²⁹And R ¹³⁰Or R ¹³¹And R ¹³²Form the saturated monocycle carbocyclic ring of 3,4,5,6 or 7 atoms with the carbon that they connected;

Q ⁵Be CO ₂H, CO ₂-C _1-4Alkyl, tetrazolium-5-base, C (R ¹³¹) (R ¹³²) (OH) or C (R ¹³¹) (R ¹³²) (O-C _1-4Alkyl);

Prerequisite is to be-S-CR as X-Y-Z ¹²⁸=CR ^{128 '}The time, R so ¹²⁸And R ^{128 '}Be not CF ₃

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the dicyclo carbonyl benzazolyl compounds of describing in No. the 6303628th, the United States Patent (USP).This class dicyclo carbonyl benzazolyl compounds or its pharmaceutically acceptable salt have the following structural formula that shows in formula XXV:

Wherein:

A ⁹Be C _1-6Alkylidene or-NR ¹³³-;

Z ⁸Be C (=L ³) R ¹³⁴Or SO ₂R ¹³⁵

Z ⁹Be CH or N;

Z ¹⁰And Y ²Independently be selected from-CH ₂-, O, S and-N-R ¹³³

M is 1,2 or 3;

Q and r independently are 0,1 or 2;

X ¹⁸Independently be selected from halogen, C _1-4Alkyl, halogenated C _1-4Alkyl, hydroxyl, C _1-4Alkoxyl, halogenated C _1-4Alkoxyl, C _1-4Alkylthio group, nitro, amino, list-or two-(C _1-4Alkyl) amino and cyano group;

N is 0,1,2,3 or 4;

L ³Be oxygen or sulfur;

R ¹³³Be hydrogen or C _1-4Alkyl;

R ¹³⁴Be hydroxyl, C _1-6Alkyl, halogenated C _1-6Alkyl, C _1-6Alkoxyl, halogenated C _1-6Alkoxyl, C _3-7Cycloalkyloxy, C _1-4Alkyl (C _3-7Cycloalkyloxy) ,-NR ¹³⁶R ¹³⁷, C _1-4Alkyl phenyl-O-or phenyl-O-, described phenyl independently is selected from halogen, C by 1-5 _1-4Alkyl, hydroxyl, C _1-4The substituent group of alkoxyl and nitro is optional to be replaced;

R ¹³⁵Be C _1-6Alkyl or halogenated C _1-6Alkyl; With

R ¹³⁶And R ¹³⁷Independently be selected from hydrogen, C _1-6Alkyl and halogenated C _1-6Alkyl.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the benzimidazole compound of describing in No. the 6310079th, the United States Patent (USP).This class benzimidazole compound or its pharmaceutically acceptable salt have the following structural formula that shows in formula XXVI:

Wherein:

A ¹⁰For being selected from the heteroaryl of 5-unit monocyclic aromatic ring, it has the hetero atom and the optional individual N atom except described hetero atom of 1-3 that contains that are selected from O, S and N, perhaps for being selected from the heteroaryl of 6-unit monocyclic aromatic ring, it has a N atom and the optional individual N atom except described N atom of 1-4 that contains; And described heteroaryl is connected on the nitrogen-atoms on the benzimidazole by the carbon atom on the heteroaryl ring;

X ²⁰Independently be selected from halo, C ₁-C ₄Alkyl, hydroxyl, C ₁-C ₄Alkoxyl, halogenated C ₁-C ₄The C that alkyl, hydroxyl replace ₁-C ₄Alkyl, (C ₁-C ₄Alkoxyl) C ₁-C ₄Alkyl, halogenated C ₁-C ₄Alkoxyl, amino, N-(C ₁-C ₄Alkyl) amino, N, N-two (C ₁-C ₄Alkyl) amino, [N-(C ₁-C ₄Alkyl) amino] C ₁-C ₄Alkyl, [N, N-two (C ₁-C ₄Alkyl) amino] C ₁-C ₄Alkyl, N-(C ₁-C ₄Alkanoyl) amino, N-(C ₁-C ₄Alkyl) (C ₁-C ₄Alkanoyl) amino, N-[(C ₁-C ₄Alkyl) sulfonyl] amino, the halogenated C of N-[( ₁-C ₄Alkyl) sulfonyl] amino, C ₁-C ₄Alkanoyl, carboxyl, (C ₁-C ₄Alkoxyl) carbonyl, carbamoyl, [N-(C ₁-C ₄Alkyl) amino] carbonyl, [N, N-two (C ₁-C ₄Alkyl) amino] carbonyl, cyano group, nitro, sulfydryl, (C ₁-C ₄Alkyl) sulfo-, (C ₁-C ₄Alkyl) sulfinyl, (C ₁-C ₄Alkyl) sulfonyl, amino-sulfonyl, [N-(C ₁-C ₄Alkyl) amino] sulfonyl and [N, N-two (C ₁-C ₄Alkyl) amino] sulfonyl;

X ²¹Independently be selected from halo, C ₁-C ₄Alkyl, hydroxyl, C ₁-C ₄Alkoxyl, halogenated C ₁-C ₄The C that alkyl, hydroxyl replace ₁-C ₄Alkyl, (C ₁-C ₄Alkoxyl) C ₁-C ₄Alkyl, halogenated C ₁-C ₄Alkoxyl, amino, N-(C ₁-C ₄Alkyl) amino, N, N-two (C ₁-C ₄Alkyl) amino, [N-(C ₁-C ₄Alkyl) amino] C ₁-C ₄Alkyl, [N, N-two (C ₁-C ₄Alkyl) amino] C ₁-C ₄Alkyl, N-(C ₁-C ₄Alkanoyl) amino, N-(C ₁-C ₄Alkyl)-N-(C ₁-C ₄Alkanoyl) amino, N-[(C ₁-C ₄Alkyl) sulfonyl] amino, the halogenated C of N-[( ₁-C ₄Alkyl) sulfonyl] amino, C ₁-C ₄Alkanoyl, carboxyl, (C ₁-C ₄Alkoxyl) carbonyl, carbamoyl, [N-(C ₁-C ₄Alkyl) amino] carbonyl, [N, N-two (C ₁-C ₄Alkyl) amino] carbonyl, N-carbamoyl amino, cyano group, nitro, sulfydryl, (C ₁-C ₄Alkyl) sulfo-, (C ₁-C ₄Alkyl) sulfinyl, (C ₁-C ₄Alkyl) sulfonyl, amino-sulfonyl, [N-(C ₁-C ₄Alkyl) amino] sulfonyl and [N, N-two (C ₁-C ₄Alkyl) amino] sulfonyl;

R ¹³⁸Be selected from hydrogen,

By the C of the optional straight or branched that replaces of 1-3 substituent group ₁-C ₄Alkyl, wherein said substituent group independently is selected from halo, hydroxyl, C ₁-C ₄Alkoxyl, amino, N-(C ₁-C ₄Alkyl) amino and N, N-two (C ₁-C ₄Alkyl) amino,

By the optional C that replaces of 1-3 substituent group ₃-C ₈Cycloalkyl, wherein said substituent group independently is selected from halo, C ₁-C ₄Alkyl, hydroxyl, C ₁-C ₄Alkoxyl, amino, N-(C ₁-C ₄Alkyl) amino and N, N-two (C ₁-C ₄Alkyl) amino,

By the optional C that replaces of 1-3 substituent group ₄-C ₈Cycloalkenyl group, wherein said substituent group independently is selected from halo, C ₁-C ₄Alkyl, hydroxyl, C ₁-C ₄Alkoxyl, amino, N-(C ₁-C ₄Alkyl) amino and N, N-two (C ₁-C ₄Alkyl) amino,

By the optional phenyl that replaces of 1-3 substituent group, wherein said substituent group independently is selected from halo, C ₁-C ₄Alkyl, hydroxyl, C ₁-C ₄Alkoxyl, halogenated C ₁-C ₄The C that alkyl, hydroxyl replace ₁-C ₄Alkyl, (C ₁-C ₄Alkoxyl) C ₁-C ₄Alkyl, halogenated C ₁-C ₄Alkoxyl, amino, N-(C ₁-C ₄Alkyl) amino, N, N-two (C ₁-C ₄Alkyl) amino, [N-(C ₁-C ₄Alkyl) amino] C ₁-C ₄Alkyl, [N, N-two (C ₁-C ₄Alkyl) amino] C ₁-C ₄Alkyl, N-(C ₁-C ₄Alkanoyl) amino, N-[(C ₁-C ₄Alkyl) (C ₁-C ₄Alkanoyl)] amino, N-[(C ₁-C ₄Alkyl) sulfonyl] amino, the halogenated C of N-[( ₁-C ₄Alkyl) sulfonyl] amino, C ₁-C ₄Alkanoyl, carboxyl, (C ₁-C ₄Alkoxyl) carbonyl, carbamoyl, [N-(C ₁-C ₄Alkyl) amino] carbonyl, [N, N-two (C ₁-C ₄Alkyl) amino] carbonyl, cyano group, nitro, sulfydryl, (C ₁-C ₄Alkyl) sulfo-, (C ₁-C ₄Alkyl) sulfinyl, (C ₁-C ₄Alkyl) sulfonyl, amino-sulfonyl, [N-(C ₁-C ₄Alkyl) amino] sulfonyl and [N, N-two (C ₁-C ₄Alkyl) amino] sulfonyl; With

Heteroaryl is selected from:

Has a hetero atom and an optional 5-unit monocyclic aromatic ring that contains 1-3 the N atom except described hetero atom that is selected from O, S and N; Perhaps have a N atom and optional 6 yuan of monocyclic aromatic rings that contain 1-4 the N atom except described N atom; With

Described heteroaryl is selected from X by 1-3 ²⁰Optional replacement of substituent group;

R ¹³⁹And R ¹⁴⁰Independently be selected from:

Hydrogen,

Halo,

C ₁-C ₄Alkyl,

By the optional phenyl that replaces of 1-3 substituent group, wherein said substituent group independently is selected from halo, C ₁-C ₄Alkyl, hydroxyl, C ₁-C ₄Alkoxyl, amino, N-(C ₁-C ₄Alkyl) amino and N, N-two (C ₁-C ₄Alkyl) amino,

Perhaps R ¹³⁸And R ¹³⁹Can form C with the carbon atom that they connect ₃-C ₇Cycloalkyl ring;

M is 0,1,2,3,4 or 5; With

N is 0,1,2,3 or 4.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the benzazolyl compounds of describing in No. the 6300363rd, the United States Patent (USP).This class benzazolyl compounds and their pharmaceutically acceptable salt have the following structural formula that shows in formula XXVII:

Wherein:

L ⁴Be oxygen or sulfur;

Y ³Be direct key or C ₁-C ₄Alkylidene;

Q ⁶For:

(a) C _1-6Alkyl or halogenated C _1-6Alkyl, described alkyl is reached 3 most and independently is selected from hydroxyl, C _1-4Alkoxyl, amino and list-or two-(C _1-4Alkyl) An Ji substituent group is optional replaces,

(b) being reached 3 most independently is selected from hydroxyl, C _1-4Alkyl and C _1-4The optional C that replaces of the substituent group of alkoxyl _3-7Cycloalkyl,

(c) phenyl or naphthyl, described phenyl or naphthyl are reached 4 most and independently are selected from the optional replacement of following substituent group, comprising: (c-1) halo, C _1-4Alkyl, halogenated C _1-4Alkyl, hydroxyl, C _1-4Alkoxyl, halogenated C _1-4Alkoxyl, S (O) _mR ¹⁴³, SO ₂NH ₂, SO ₂N (C _1-4Alkyl) ₂, amino, single-or two-(C _1-4Alkyl) amino, NHSO ₂R ¹⁴³, NHC (O) R ¹⁴³, CN, CO ₂H, CO ₂(C _1-4Alkyl), C _1-4Alkyl-OH, C _1-4Alkyl-OR ¹⁴³, CONH ₂, CONH (C _1-4Alkyl), CON (C _1-4Alkyl) ₂With-the O-Y-phenyl, described phenyl independently is selected from halo, C by 1 or 2 _1-4Alkyl, CF ₃, hydroxyl, OR ¹⁴³, S (O) _mR ¹⁴³, amino, single-or two-(C _1-4Alkyl) the optional replacement of substituent group amino and CN;

(d) mono-cyclic aromatic group of 5 atoms, described aromatic group has a hetero atom that is selected from O, S and N and optionally contains the most nearly 3 N atoms except described hetero atom, and described aromatic group by the most nearly 3 independently be selected from following substituent group replacement:

(d-1) halo, C _1-4Alkyl, halogenated C _1-4Alkyl, hydroxyl, C _1-4Alkoxyl, halogenated C _1-4Alkoxyl, C _1-4Alkyl-OH, S (O) _mR ¹⁴³, SO ₂NH ₂, SO ₂N (C _1-4Alkyl) ₂, amino, single-or two-(C _1-4Alkyl) amino, NHSO ₂R ¹⁴³, NHC (O) R ¹⁴³, CN, CO ₂H, CO ₂(C _1-4Alkyl), C _1-4Alkyl-OR ¹⁴³, CONH ₂, CONH (C _1-4Alkyl), CON (C _1-4Alkyl) 2, phenyl and single-, two-or the three-phenyl that replaces, wherein said substituent group independently is selected from halo, CF ₃, C _1-4Alkyl, hydroxyl, C _1-4Alkoxyl, OCF ₃, SR ¹⁴³, SO ₂CH ₃, SO ₂NH ₂, amino, C _1-4Alkyl amino and NHSO ₂R ¹⁴³

(e) mono-cyclic aromatic group of 6 atoms, described aromatic group has a hetero atom for N and contains the most nearly 3 atoms except described hetero atom with optional, and described aromatic group is by the most nearly 3 substituent groups replacements that independently are selected from above group (d-1);

R ¹⁴¹For hydrogen or independently be selected from hydroxyl, OR ¹⁴³, nitro, amino, list-or two-(C _1-4Alkyl) amino, CO ₂H, CO ₂(C _1-4Alkyl), CONH ₂, CONH (C _1-4Alkyl) and CON (C _1-4Alkyl) the optional C that replaces of 2 substituent group _1-6Alkyl;

R ¹⁴²For:

(a) hydrogen,

(b) C _1-4Alkyl,

(c)C(O)R ¹⁴⁵，

R wherein ¹⁴⁵Be selected from:

(c-1) C _1-22Alkyl or C _2-22Alkenyl, described alkyl or alkenyl are reached 4 most and independently are selected from the optional replacement of following substituent group, comprising:

(c-1-1) halo, hydroxyl, OR ¹⁴³, S (O) _mR ¹⁴³, nitro, amino, list-or two-(C _1-4Alkyl) amino, NHSO ₂R ¹⁴³, CO ₂H, CO ₂(C _1-4Alkyl), CONH ₂, CONH (C _1-4Alkyl), CON (C _1-4Alkyl) ₂, OC (O) R ¹⁴³, thienyl, naphthyl and following formula group:

With

(c-2) C _1-22Alkyl or C _2-22Alkenyl, described alkyl or alkenyl are chosen wantonly by 5-45 halogen atom and are replaced,

(c-3)-Y ⁵-C _3-7Cycloalkyl or-Y ⁵-C _3-7Cycloalkenyl group, described cycloalkyl or cycloalkenyl group are reached 3 most and independently are selected from the optional replacement of following substituent group:

(c-3-1) C _1-4Alkyl, hydroxyl, OR ¹⁴³, S (O) _mR ¹⁴³, amino, single-or two-(C _1-4Alkyl) amino, CONH ₂, CONH (C _1-4Alkyl) and CON (C _1-4Alkyl) ₂,

(c-4) phenyl or naphthyl, described phenyl or naphthyl independently is selected from the optional replacement of following substituent group by the most nearly 7 (preferably most reaching 7):

(c-4-1) halo, C _1-8Alkyl, C _1-4Alkyl-OH, hydroxyl, C _1-8Alkoxyl, halogenated C _1-8Alkyl, halogenated C _1-8Alkoxyl, CN, nitro, S (O) _mR ¹⁴³, SO ₂NH ₂, SO ₂NH (C _1-4Alkyl), SO ₂N (C _1-4Alkyl) ₂, amino, C _1-4Alkyl amino, two-(C _1-4Alkyl) amino, CONH ₂, CONH (C _1-4Alkyl), CON (C _1-4Alkyl) ₂, OC (O) R ¹⁴³Most reach 3 with quilt and independently be selected from halo, C _1-4Alkyl, hydroxyl, OCH ₃, CF ₃, OCF ₃, CN, nitro, amino, list-or two-(C _1-4Alkyl) amino, CO ₂H, CO ₂(C _1-4Alkyl) and CONH ₂The optional phenyl that replaces of substituent group,

(c-5) as the mono-cyclic aromatic group of above definition at (d) and (e), described aromatic group by the most nearly 3 be selected from independently that following substituent group is optional to be replaced:

(c-5-1) halo, C _1-8Alkyl, C _1-4Alkyl-OH, hydroxyl, C _1-8Alkoxyl, CF ₃, OCF ₃, CN, nitro, S (O) _mR ¹⁴³, amino, single-or two-(C _1-4Alkyl) amino, CONH ₂, CONH (C _1-4Alkyl), CON (C _1-4Alkyl) ₂, CO ₂H and CO ₂(C _1-4Alkyl) and-the Y-phenyl, described phenyl by the most nearly 3 independently be selected from halogen, C _1-4Alkyl, hydroxyl, C _1-4Alkoxyl, CF ₃, OCF ₃, CN, nitro, S (O) _mR ¹⁴³, amino, single-or two-(C _1-4Alkyl) amino, CO ₂H, CO ₂(C _1-4Alkyl), CONH ₂, CONH (C _1-4Alkyl) and CON (C _1-4Alkyl) ₂Optional replacement of substituent group,

(c-6) group of following formula:

X ²²Be halo, C _1-4Alkyl, hydroxyl, C _1-4Alkoxyl, halogenated C _1-4Alkoxyl, S (O) _mR ¹⁴³, amino, single-or two-(C _1-4Alkyl) amino, NHSO ₂R ¹⁴³, nitro, halogenated C _1-4Alkyl, CN, CO ₂H, CO ₂(C _1-4Alkyl), C _1-4Alkyl-OH, C _1-4Alkyl OR ¹⁴³, CONH ₂, CONH (C _1-4Alkyl) or CON (C _1-4Alkyl) ₂

R ¹⁴³Be C _1-4Alkyl or halogenated C _1-4Alkyl;

M is 0,1 or 2; N is 0,1,2 or 3; P is 1,2,3,4 or 5; Q is 2 or 3; Z ¹¹Be oxygen, sulfur or NR ¹⁴⁴With

R ¹⁴⁴Be hydrogen, C _1-6Alkyl, halogenated C _1-4Alkyl or-Y ⁵-phenyl, described phenyl is reached 2 most and independently is selected from halo, C _1-4Alkyl, hydroxyl, C _1-4Alkoxyl, S (O) _mR ¹⁴³, amino, single-or two-(C _1-4Alkyl) amino, CF ₃, OCF ₃, CN and nitro optional replacement of substituent group;

Prerequisite is to work as X ²²During for hydrogen, formula-Y ⁵The group of-Q is not methyl or ethyl;

L ⁴Be oxygen;

R ¹⁴¹Be hydrogen; With

R ¹⁴²Be acetyl group.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the aryl phenyl hydrazides class of describing in No. the 6077869th, the United States Patent (USP).This class aryl phenyl hydrazides has the following structural formula that shows in formula XXVIII:

Wherein:

X ³³And Y ⁶Be selected from hydrogen, halogen, alkyl, nitro, amino or other the functional group that contains aerobic and sulfur, for example hydroxyl, methoxyl group and methyl sulphonyl.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in 2-aryloxy group, the 4-aryl furan of describing in No. the 6140515th, the United States Patent (USP)-2-ketone.This class 2-aryloxy group, 4-aryl furan-2-ketone or their pharmaceutical salts have the following structural formula that shows in formula XXIX:

Wherein:

R ¹⁴⁶Be selected from SCH ₃,-S (O) ₂CH ₃With-S (O) ₂NH ₂

R ¹⁴⁷Be selected from OR ¹⁵⁰, single or two-phenyl or pyridine radicals of replacing, wherein said substituent group is selected from methyl, chlorine and F;

R ¹⁵⁰Be phenyl or pyridine radicals unsubstituted or single or two-replacement, wherein said substituent group is selected from methyl, chlorine and F;

R ¹⁴⁸For H, by 1-3 F, Cl or the optional C that replaces of Br group _1-4Alkyl; With

R ¹⁴⁹For hydrogen, by 1-3 F, Cl or the optional C that replaces of Br group _1-4Alkyl, prerequisite are R ¹⁴⁸And R ¹⁴⁹Inequality.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the bi-aromatic compounds of describing in No. the 5994379th, the United States Patent (USP).This class bi-aromatic compounds or its pharmaceutically acceptable salt, ester or tautomer have the following structural formula that shows in formula XXX:

Wherein:

Z ¹³Be C or N;

Work as Z ¹³During for N, R ¹⁵¹Expression H or do not exist, perhaps as described below with R ¹⁵²Connect:

Work as Z ¹³During for C, R ¹⁵¹Expression H, R ¹⁵²For having the part of following feature:

(a) it is the linear chain that contains 3-4 atom of 0-2 two keys, and it can take a kind of reverse configuration of energy stabilization, and if the existence of two key, this key exists with cis-configuration,

(b) it is lipophilic, except atom is directly connected in ring A, itself or lipotropy or right and wrong are lipophilic and

(c) with the interior configuration plane that has an energy stabilization of extremely about 15 degree of ring A;

Perhaps R ¹⁵¹And R ¹⁵²Combine, represent condensing in the ring D of ring A of 5-or 6-unit's aromatics or non-aromatics, described ring D contains 0-3 hetero atom that is selected from O, S and N;

Described ring D is lipophilic, and except atom was directly connected in ring A, it was that lipotropy or right and wrong are lipophilic, and can obtain the configuration plane of an energy stabilization in described ring D and extremely about 15 degree of ring A;

Described ring D is selected from following R by one ^aFurther replace, comprising: C _1-2Alkyl ,-OC _1-2Alkyl ,-NHC _1-2Alkyl ,-N (C _1-2Alkyl) ₂,-C (O) C _1-2Alkyl ,-S-C _1-2Alkyl and-C (S) C _1-2Alkyl;

Y ⁷Expression N, CH or C-OC _1-3Alkyl, and work as Z ¹³During for N, Y ⁷Also can represent carbonyl;

R ¹⁵³Expression H, Br, Cl or F; With

R ¹⁵⁴Expression H or methyl.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention be included in describe in No. the 6028202nd, the United States Patent (USP) 1,5-diaryl pyrazole azole.This class 1,5-diaryl pyrazole and their pharmaceutically acceptable salt have the following structural formula that shows in formula XXXI:

Wherein:

R ¹⁵⁵, R ¹⁵⁶, R ¹⁵⁷And R ¹⁵⁸Independently be selected from hydrogen, C _1-5Alkyl, C _1-5Alkoxyl, phenyl, halo, hydroxyl, C _1-5Alkyl sulphonyl, C _1-5Alkylthio group, three halo C _1-5Alkyl, amino, nitro and 2-quinolyl methoxyl group;

R ¹⁵⁹Be hydrogen, C _1-5Alkyl, three halo C _1-5The phenyl of alkyl, phenyl, replacement, wherein phenyl substituent is halogen, C _1-5Alkoxyl, three halo C _1-5Alkyl or nitro, perhaps R ¹⁵⁹Be the heteroaryl of 5-7 unit ring, wherein at least one annular atoms is nitrogen, sulfur or oxygen;

R ¹⁶⁰Be hydrogen, C _1-5Alkyl, phenyl C _1-5The phenyl C of alkyl, replacement _1-5Alkyl, wherein phenyl substituent is halogen, C _1-5Alkoxyl, three halo C _1-5Alkyl or nitro, perhaps R ¹⁶⁰Be C _1-5The phenyloxycarbonyl of alkoxy carbonyl, phenyloxycarbonyl, replacement, wherein phenyl substituent is halogen, C _1-5Alkoxyl, three halo C _1-5Alkyl or nitro;

R ¹⁶¹Be C _1-10The C of alkyl, replacement _1-10Alkyl, wherein said substituent group are halogen, three halo C _1-5Alkyl, C _1-5Alkoxyl, carboxyl, C _1-5Alkoxy carbonyl, amino, C _1-5Alkyl amino, two C _1-5Alkyl amino, two C _1-5Alkyl amino C _1-5Alkyl amino, C _1-5Alkyl amino C _1-5Alkyl amino or contain the heterocycle of 4-8 annular atoms, wherein one or more annular atomses are nitrogen, oxygen or sulfur, wherein said heterocycle can be by C _1-5Alkyl is optional to be replaced; Perhaps R ¹⁶¹(wherein phenyl substituent is one or more C for the phenyl of phenyl, replacement _1-5Alkyl, halogen, C _1-5Alkoxyl, three halo C _1-5Alkyl or nitro), perhaps R ¹⁶¹For having the heteroaryl of 5-7 annular atoms, wherein one or more atoms are nitrogen, oxygen or sulfur, condensed heteroaryl, and the first aromatic ring of wherein one or more 5-7 condenses in this heteroaryl; Perhaps

R ¹⁶¹Be NR ¹⁶³R ¹⁶⁴, R wherein ¹⁶³And R ¹⁶⁴Independently be selected from hydrogen and C _1-5Alkyl, perhaps R ¹⁶³And R ¹⁶⁴Can form the heteroaryl ring of 5-7 unit ring with described nitrogen, wherein one or more annular atomses are nitrogen, sulfur or oxygen, and wherein said heteroaryl ring can be by C _1-5Alkyl is optional to be replaced;

R ¹⁶²Be hydrogen, C _1-5Alkyl, nitro, amino and halogen.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the imidazoles that the 2-that describes in No. the 6040320th, the United States Patent (USP) replaces.Imidazoles that this class 2-replaces and their pharmaceutically acceptable salt have the following structural formula that shows in formula XXXII:

Wherein:

R ¹⁶⁴Be phenyl, heteroaryl, wherein heteroaryl contains 5-6 annular atoms, perhaps

The phenyl that replaces;

Wherein said substituent group independently is selected from one or more C _1-5Alkyl, halogen, nitro, trifluoromethyl and nitrile;

R ¹⁶⁵Be phenyl, heteroaryl, wherein said heteroaryl contains 5-6 annular atoms,

The heteroaryl that replaces;

Wherein said substituent group independently is selected from one or more C _1-5Alkyl and halogen, the perhaps phenyl of Qu Daiing,

Wherein said substituent group independently is selected from one or more C _1-5Alkyl, halogen, nitro, trifluoromethyl and nitrile;

R ¹⁶⁶Be hydrogen, SEM, C _1-5Alkoxy carbonyl, aryloxycarbonyl, aryl C _1-5Alkoxy carbonyl, aryl C _1-5Alkyl, phthalimido C _1-5Alkyl, amino C _1-5Alkyl, diaminourea C _1-5Alkyl, succinimido C _1-5Alkyl, C _1-5Alkyl-carbonyl, aryl carbonyl, C _1-5Alkyl-carbonyl C _1-5Alkyl, aryloxycarbonyl C _1-5Alkyl, heteroaryl C _1-5Alkyl, wherein heteroaryl contains 5-6 annular atoms, perhaps the aryl C of Qu Daiing _1-5Alkyl,

Wherein aryl substituent independently is selected from one or more C _1-5Alkyl, C _1-5Alkoxyl, halogen, amino, C _1-5Alkyl amino and two C _1-5Alkyl amino;

R ¹⁶⁷Be (A ¹¹) _n-(CH ¹⁶⁵) _q-X ²⁴, wherein:

A ¹¹Be sulfur or carbonyl;

N is 0 or 1;

Q is 0-9;

X ²⁴Be selected from hydrogen, hydroxyl, halogen, vinyl, acetenyl, C _1-5Alkyl, C _3-7Cycloalkyl, C _1-5Alkoxyl, phenoxy group, phenyl, aryl C _1-5Alkyl, amino, C _1-5Alkyl amino, nitrile, phthalimido, acylamino-, phenylcarbonyl group, C _1-5Alkyl amino-carbonyl, phenyl amino carbonyl, aryl C _1-5Alkyl amino-carbonyl, C _1-5Alkylthio group, C _1-5Alkyl sulphonyl, phenyl sulfonyl,

The sulfonamido that replaces,

Wherein said sulfonyl substituent group is selected from C _1-5Alkyl, phenyl, aralkyl C _1-5Alkyl, thienyl, furyl and naphthyl;

The vinyl that replaces,

Wherein said substituent group independently is selected from one or more fluorine, bromine, chlorine and iodine,

The acetenyl that replaces,

Wherein said substituent group independently is selected from one or more fluorine, bromine, chlorine and iodine,

The C that replaces _1-5Alkyl,

Wherein said substituent group is selected from one or more C _1-5Alkoxyl, tri haloalkyl, phthalimido and amino,

The phenyl that replaces,

Wherein said phenyl substituent independently is selected from one or more C _1-5Alkyl, halogen and C _1-5Alkoxyl,

The phenoxy group that replaces,

Wherein said phenyl substituent independently is selected from one or more C _1-5Alkyl, halogen and C _1-5Alkoxyl,

The C that replaces _1-5Alkoxyl,

Wherein alkyl substituent is selected from phthalimido and amino,

The aryl C that replaces _1-5Alkyl,

Wherein said alkyl substituent is a hydroxyl,

The aryl C that replaces _1-5Alkyl,

Wherein said phenyl substituent independently is selected from one or more C _1-5Alkyl, halogen and C _1-5Alkoxyl,

The acylamino-that replaces,

Wherein said carbonyl substituted base is selected from C _1-5Alkyl, phenyl, aryl C _1-5Alkyl, thienyl, furyl and naphthyl,

The phenylcarbonyl group that replaces,

Wherein said phenyl substituent independently is selected from one or more C _1-5Alkyl, halogen and C _1-5Alkoxyl,

The C that replaces _1-5Alkylthio group,

Wherein said alkyl substituent is selected from hydroxyl and phthalimido,

The C that replaces _1-5Alkyl sulphonyl,

Wherein said alkyl substituent is selected from hydroxyl and phthalimido,

The phenyl sulfonyl that replaces,

Wherein said phenyl substituent independently is selected from one or more bromines, fluorine, chlorine, C _1-5Alkoxyl and trifluoromethyl,

Prerequisite is:

If A ¹¹Be sulfur and X ²⁴Be not hydrogen, C _1-5Alkyl amino-carbonyl, phenyl amino carbonyl, aryl C _1-5Alkyl amino-carbonyl, C _1-5Alkyl sulphonyl or phenyl sulfonyl, q must be equal to or greater than 1 so;

If A ¹¹For sulfur and q are 1, X so ²⁴Can not think C _1-2Alkyl;

If A ¹¹For carbonyl and q are 0, X so ²⁴Can not think vinyl, acetenyl, C _1-5Alkyl amino-carbonyl, phenyl amino carbonyl, aryl C _1-5Alkyl amino-carbonyl, C _1-5Alkyl sulphonyl or phenyl sulfonyl,

If A ¹¹Be carbonyl, q is 0 and X ²⁴Be H, so R ¹⁶⁶Be not SEM (2-trimethyl silyl) ethoxyl methyl);

If n be 0 and q be 0, X so ²⁴Can not think hydrogen.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention be included in describe in No. the 6083969th, the United States Patent (USP) 1,3-and 2,3-diaryl cycloalkanes and and cyclenes and pyrazoles.This class 1,3-and 2,3-diaryl pyrazole azole compounds and their pharmaceutically acceptable salt, ester and prodrug forms have the following general formula that shows in formula XXXIII and XXXIV:

Wherein:

R ¹⁶⁸And R ¹⁶⁹Independently be selected from hydrogen, halogen, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, nitro, amino, hydroxyl, trifluoro ,-S (C ₁-C ₆) alkyl ,-SO (C ₁-C ₆) alkyl and-SO ₂(C ₁-C ₆) alkyl; And this condensed part M is selected from the cyclohexyl of the optional replacement with following formula and the group of suberyl:

, or

Wherein:

R ¹⁷⁰Be selected from hydrogen, halogen, hydroxyl and carbonyl;

Perhaps R ¹⁷⁰And R ¹⁷¹Form together and be selected from-OCOCH ₂-,-ONH (CH ₃) COCH ₂-,-OCOCH.dbd. and-part of O-;

R ¹⁷¹And R ¹⁷²Independently be selected from hydrogen, halogen, hydroxyl, carbonyl, amino, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl ,=NOH ,-NR ¹⁷⁴R ¹⁷⁵,-OCH ₃,-OCH ₂CH ₃,-OSO ₂NHCO ₂CH ₃,=CHCO ₂CH ₂CH ₃,-CH ₂CO ₂H ,-CH ₂CO ₂CH ₃,-CH ₂CO ₂CH ₂CH ₃,-CH ₂CON (CH ₃) ₂,-CH ₂CO ₂NHCH ₃,-CHCHCO ₂CH ₂CH ₃,-OCON (CH ₃) OH ,-C (COCH ₃) ₂, two (C ₁-C ₆) alkyl and two (C ₁-C ₆) alkoxyl;

R ¹⁷³Be selected from hydrogen, halogen, hydroxyl, carbonyl, amino, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl and the optional carboxyl phenyl that replaces, wherein the substituent group on carboxyl phenyl is selected from halogen, hydroxyl, amino, (C ₁-C ₆) alkyl and (C ₁-C ₆) alkoxyl;

Perhaps R ¹⁷²And R ¹⁷³Form together and be selected from-O-and following part

R ¹⁷⁴Be selected from hydrogen, OH ,-OCOCH ₃,-COCH ₃(C ₁-C ₆) alkyl; With

R ¹⁷⁵Be selected from hydrogen, OH ,-OCOCH ₃,-COCH ₃, (C ₁-C ₆) alkyl ,-CONH ₂With-SO ₂CH ₃

Prerequisite is

If M is cyclohexyl, R so ¹⁷⁰-R ¹⁷³Cannot all be hydrogen.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention be included in describe in No. the 6306890th, the United States Patent (USP) derived from the esters of indole alkanol with derived from the new amide-type of indolyl amide.This compounds has the following general formula that shows in formula XXXV:

Wherein:

R ¹⁷⁶Be C ₁-C ₆Alkyl, C ₁-C ₆Branch's alkyl, C ₄-C ₈Cycloalkyl, C ₁-C ₆Hydroxy alkyl, ramose C ₁-C ₆The C that hydroxy alkyl, hydroxyl replace ₄-C ₈Aryl, primary, the second month in a season or uncle C ₁-C ₆Alkyl amino, primary, the second month in a season or the ramose C of uncle ₁-C ₆Alkyl amino, primary, the second month in a season or uncle C ₄-C ₈Arylamino, C ₁-C ₆Alkyl carboxylic acid, ramose C ₁-C ₆Alkyl carboxylic acid, C ₁-C ₆Arrcostab, ramose C ₁-C ₆Arrcostab, C ₄-C ₈Aryl, C ₄-C ₈Aryl carboxylic acid, C ₄-C ₈Aryl ester, C ₄-C ₈The C that aryl replaces ₁-C ₆Alkyl, C ₄-C ₈Heterocyclylalkyl or in ring, contain aryl, the alkyl C that replace or that aryl replaces of O, N or S ₄-C ₈Heterocyclylalkyl or in ring, contain the aryl of O, N or S, perhaps their halogenated variant, wherein halogen is chlorine, bromine, fluorine or iodine;

R ¹⁷⁷Be C ₁-C ₆Alkyl, C ₁-C ₆Ramose alkyl, C ₄-C ₈Cycloalkyl, C ₄-C ₈Aryl, C ₄-C ₈The C that aryl replaces ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Ramose alkoxyl, C ₄-C ₈Aryloxy group or their halogenated variant, perhaps R ¹⁷⁷Be halo, wherein halogen is chlorine, fluorine, bromine or iodine;

R ¹⁷⁸Be hydrogen, C ₁-C ₆Alkyl or C ₁-C ₆Ramose alkyl;

R ¹⁷⁹Be C ₁-C ₆Alkyl, C ₄-C ₈Aroyl, C ₄-C ₈Aryl, C ₄-C ₈Heterocyclylalkyl or in ring, contain the aryl of O, N or S, C ₄-C ₈The C that aryl replaces ₁-C ₆Alkyl, alkyl C that replace or that aryl replaces ₄-C ₈Heterocyclylalkyl or in ring, contain the aryl of O, N or S, the C that alkyl replaces ₄-C ₈The C that aroyl or alkyl replace ₄-C ₈Aryl or their halogenated variant, wherein halogen is chlorine, bromine or iodine;

N is 1,2,3 or 4; With

X ²⁵Be O, NH or N-R ¹⁸⁰, R wherein ¹⁸⁰Be C ₁-C ₆Alkyl or C ₁-C ₆Ramose alkyl.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the pyridazinone compound of describing in No. the 6307047th, the United States Patent (USP).This class pyridazinone compound or its pharmaceutically acceptable salt, ester or prodrug have the following structural formula that shows in formula XXXVI:

Wherein:

X ²⁶Be selected from O, S ,-NR ¹⁸⁵,-NOR ^aWith-NNR ^bR ^c

R ¹⁸⁵Be selected from alkenyl, alkyl, aryl, aryl alkyl, cycloalkenyl group, cycloalkenyl alkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical and Heterocyclylalkyl;

R ^a, R ^bAnd R ^cIndependently be selected from alkyl, aryl, aryl alkyl, cycloalkyl and cycloalkyl-alkyl;

R ¹⁸¹Be selected from alkenyl; alkoxyl; alkoxyalkyl; the Alkoximino alkoxyl; alkyl; the alkyl-carbonyl alkyl; the alkyl sulphonyl alkyl; alkynyl; aryl; aromatic yl alkenyl; alkoxy aryl; aryl alkyl; aromatic yl polysulfide yl; the aryl halide substituted alkyl; the aryl hydroxy alkyl; aryloxy group; the aryloxy group haloalkyl; the aryloxy group hydroxy alkyl; aryl alkyl carbonyl; carboxyalkyl; the cyano group alkyl; cycloalkenyl group; cycloalkenyl alkyl; cycloalkyl; cycloalkyl-alkyl; the cycloalkylidene alkyl; halogenated alkenyl; the halogenated alkoxy hydroxy alkyl; haloalkyl; the halo alkynyl; heterocyclic radical; the heterocyclic radical alkoxyl; the heterocyclic radical alkyl; the heterocyclyloxy base; hydroxy alkyl; the oxyimino alkoxyl;-(CH ₂) _nC (O) R ¹⁸⁶,-(CH ₂) _nCH (OH) R ¹⁸⁶,-(CH ₂) _nC (NOR ^d) R ¹⁸⁶,-(CH ₂) _nCH (NOR ^d) R ¹⁸⁶,-(CH ₂) _nCH (NR ^dR ^c) R ¹⁸⁶,-R ¹⁸⁷R ¹⁸⁸,-(CH ₂) _nC CR ¹⁸⁸,-(CH ₂) _n[CH (CX ^{26 '} ₃)] _m(CH ₂) _pR ¹⁸⁸,-(CH ₂) _n(CX ^{26 '} ₂) _m(CH ₂) _pR ¹⁸⁸With-(CH ₂) _n(CHX ^{26 '}) _m(CH ₂) _mR ¹⁸⁸

R ¹⁸⁶Be selected from hydrogen, alkenyl, alkyl, alkynyl, aryl, aryl alkyl, cycloalkenyl group, cycloalkyl, halogenated alkenyl, haloalkyl, halo alkynyl, heterocyclic radical and heterocyclic radical alkyl;

R ¹⁸⁷Be selected from alkylene group, alkylidene, halogenated alkylene group and halogenated alkylidene;

R ¹⁸⁸Be selected from hydrogen, alkenyl, alkyl, alkynyl, aryl, aryl alkyl, cycloalkyl, cycloalkenyl group, haloalkyl, heterocyclic radical and heterocyclic radical alkyl;

R ^dAnd R ^eIndependently be selected from hydrogen, alkenyl, alkyl, alkynyl, aryl, aryl alkyl, cycloalkenyl group, cycloalkyl, haloalkyl, heterocyclic radical and heterocyclic radical alkyl;

X ^{26 '}Be halogen;

M is the integer of 0-5;

N is the integer of 0-10; With

P is the integer of 0-10; With

R ¹⁸², R ¹⁸³And R ¹⁸⁴Independently be selected from hydrogen; alkenyl; alkoxyalkyl; the Alkoximino alkoxyl; the Alkoximino alkyl; alkyl; alkynyl; the alkyl-carbonyl alkoxyl; alkyl-carbonyl-amino; the alkyl-carbonyl-amino alkyl; aminoalkoxy; aminoalkyl carbonyl oxygen base alkoxyl; the amino carbonyl alkyl; aryl; aromatic yl alkenyl; aryl alkyl; aromatic yl polysulfide yl; carboxyalkyl carbonyl oxygen base alkoxyl; cyano group; cycloalkenyl group; cycloalkyl; the cycloalkylidene alkyl; the halo alkenyloxy; halogenated alkoxy; haloalkyl; halogen; heterocyclic radical; the hydroxy alkoxy base; the oxyimino alkoxyl; the oxyimino alkyl; the sulfydryl alkoxyl; nitro; phosphono (phosphonato) alkoxyl, Y ⁸And Z ¹⁴

Prerequisite is R ¹⁸², R ¹⁸³Or R ¹⁸⁴In one be necessary for Z ¹⁴, another prerequisite is R ¹⁸², R ¹⁸³Or R ¹⁸⁴In only one be Z ¹⁴,

Z ¹⁴Be selected from:

With

X ²⁷Be selected from S (O) ₂, S (O) (NR ¹⁹¹), S (O), Se (O) ₂, P (O) (OR ¹⁹²) and P (O) (NRR ¹⁹³R ¹⁹⁴);

X ²⁸Be selected from hydrogen, alkenyl, alkyl, alkynyl and halogen;

R ¹⁹⁰Be selected from alkenyl, alkoxyl, alkyl, alkyl amino, alkyl-carbonyl-amino, alkynyl, amino, cycloalkenyl group, cycloalkyl, dialkyl amido ,-NHNH ₂With-NCHN (R ¹⁹¹) R ¹⁹²

R ¹⁹¹, R ¹⁹², R ¹⁹³And R ¹⁹⁴Independently be selected from hydrogen, alkyl and cycloalkyl, perhaps R ¹⁹³And R ¹⁹⁴The nitrogen that connects with their forms and contains 1 or 2 and be selected from O, S and NR ¹⁸⁸Heteroatomic 3-6 unit ring;

Y ⁸Be selected from-OR ¹⁹⁵,-SR ¹⁹⁵,-C (R ¹⁹⁷) (R ¹⁹⁸) R ¹⁹⁵,-C (O) R ¹⁹⁵,-C (O) OR ¹⁹⁵,-N (R ¹⁹⁷) C (O) R ¹⁹⁵,-NC (R ¹⁹⁷) R ¹⁹⁵With-N (R ¹⁹⁷) R ¹⁹⁵

R ¹⁹⁵Be selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthio alkyl, alkynyl, cycloalkenyl group, cycloalkenyl alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aryl alkyl, heterocyclic radical, heterocyclic radical alkyl, hydroxy alkyl and NR ¹⁹⁹R ²⁰⁰With

R ¹⁹⁷, R ¹⁹⁸, R ¹⁹⁹And R ²⁰⁰Independently be selected from hydrogen, alkenyl, alkoxyl, alkyl, cycloalkenyl group, cycloalkyl, aryl, aryl alkyl, heterocyclic radical and heterocyclic radical alkyl.

The material that can be used as cyclo-oxygenase-2 selective depressant of the present invention is included in the benzene sulfinyl amine derivative of describing in No. the 6004948th, the United States Patent (USP).This class benzene sulfinyl amine derivative and pharmaceutically acceptable salt thereof have the following structural formula that shows in formula XXXVII:

This:

A ¹²Mean oxygen, sulfur or NH;

R ²⁰¹Mean by halogen, alkyl, CF ₃Or the optional list of alkoxyl-or polysubstituted cycloalkyl, aryl or heteroaryl;

D ⁵Mean the group of formula XXXVIII or XXXIX:

Or

R ²⁰²And R ²⁰³Mean hydrogen, optional how fluoric alkyl, aralkyl, aryl or heteroaryl or group (CH independently of one another ₂) _n-X ²⁹Perhaps

R ²⁰²And R ²⁰³Mean 3-to 7-unit with the N-atom, saturated, partially or completely undersaturated, as to contain one or more hetero atom N, O or S heterocycle, it can be by oxo, alkyl, alkylaryl or aryl or group (CH ₂) _n-X ²⁹Optional replacement, R ^{202 '}Mean hydrogen, optional how fluoric alkyl, aralkyl, aryl or heteroaryl or group (CH ₂) _n-X ²⁹

Wherein:

X ²⁹Mean halogen, NO ₂,-OR ²⁰⁴,-COR ²⁰⁴,-CO ₂R ²⁰⁴,-OCO ₂R ²⁰⁴,-CN ,-CONR ²⁰⁴OR ²⁰⁵,-CONR ²⁰⁴R ²⁰⁵,-SR ²⁰⁴,-S (O) R ²⁰⁴,-S (O) ₂R ²⁰⁴,-NR ²⁰⁴R ²⁰⁵,-NHC (O) R ²⁰⁴,-NHS (O) ₂R ²⁰⁴

Z ¹⁵Mean-CH ₂-,-CH ₂-CH ₂-,-CH ₂-CH ₂-CH ₂-,-CH ₂-CH=CH-,-CH=CH-CH ₂-,-CH ₂-CO-,-CO-CH ₂-,-NHCO-,-CONH-,-NHCH ₂-,-CH ₂NH-,-N=CH-,-NHCH-,-CH ₂-CH ₂-NH-,-CH=CH-,＞N-R ²⁰³,＞C=O,＞S (O) _m

R ²⁰⁴And R ²⁰⁵Mean hydrogen, alkyl, aralkyl or aryl independently of one another;

N is the integer of 0-6;

R ²⁰⁶For can by halogen or alkoxyl optional single-or polysubstituted straight chain or ramose C _1-4-alkyl, perhaps R ²⁰⁶Mean CF ₃With

M means the integer of 0-2;

Prerequisite is if R ²⁰⁶Mean CF ₃, A ¹²Do not represent O.

The Cox-2 selective depressant that is used for the inventive method and compositions can be included in United States Patent (USP) No. 6169188; No. 6020343; No. 5981576 ((methyl sulphonyl) benzofurane ketone); No. the 6222048th, United States Patent (USP) (diaryl-2-(5H)-furanone); United States Patent (USP) No. 6057319 (3; 4-diaryl-2-hydroxyl-2, the 5-dihydrofuran); No. the 6046236th, United States Patent (USP) (carbocyclic ring sulfonamide); No. the 6002014th, United States Patent (USP) and No. 5945539 (oxazole derivant) and No. 6359182 (C-nitroso compound) middle chemical compound of describing of United States Patent (USP).

Can be provided for cyclo-oxygenase-2 selective depressant of the present invention by any source, as long as described cyclo-oxygenase-2 selective depressant is acceptable pharmaceutically.The cyclo-oxygenase-2 selective depressant can separate and purification obtains or can synthesize and obtain from natural origin.The cyclo-oxygenase-2 selective depressant should have quality and purity conventional in the trade of medicinal product purposes.

In the compositions and methods of the invention, except that cyclo-oxygenase-2 selective depressant and PPAR alfa agonists, also can there be other chemical compound.For example, can choose wantonly and have chemical compound such as p38MAP kinases.Believe that the p38MAP kinases can make the transactivation of PPAR α phosphorylation and increase ligand-dependent.Referring to for example Barger, P.M. etc., J.Biol.Chem., Sept.27, (2001).

In an embodiment of the inventive method, need the patient of prevention or treatment pain, inflammation or the disease relevant with PPAR alfa agonists and cyclo-oxygenase-2 selective depressant or the treatment of its prodrug with inflammation.In one embodiment, with a certain amount of PPAR alfa agonists and a certain amount of Cox-2 selective depressant treatment patient, wherein the amount of the amount of PPAR alfa agonists and Cox-2 selective depressant provides the dosage of the combination that is enough to constitute effective dose or the combination of amount together.Described effective dose can effectively be measured for the treatment or the prevention of inhibition of pain or inflammation.

In another embodiment of the inventive method, use the treatment of PPAR alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug to need the patient of prevention or treatment cardiovascular disease or disorder.In one embodiment, treat described patient with a certain amount of PPAR alfa agonists and a certain amount of Cox-2 selective depressant, wherein the amount of the amount of PPAR alfa agonists and Cox-2 selective depressant provides the dosage or the amount of the combination that is enough to constitute effective dose together.Described effective dose can be for suppressing effectively amount of cardiovascular disorder or treatment of diseases or prevention.

In another embodiment of the inventive method, use the treatment of PPAR alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug to need the patient of prevention or treatment cancer.In one embodiment, treat described patient with a certain amount of PPAR alfa agonists and a certain amount of Cox-2 selective depressant, wherein the amount of the amount of PPAR alfa agonists and Cox-2 selective depressant provides the dosage or the amount of the combination that is enough to constitute effective dose together.Described effective dose can be for suppressing effectively amount of treatment for cancer or prevention.

In another embodiment of the inventive method, use the treatment of PPAR alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug to need the patient of prevention or treatment Alzheimer.In one embodiment, treat described patient with a certain amount of PPAR alfa agonists and a certain amount of Cox-2 selective depressant, wherein the amount of the amount of PPAR alfa agonists and Cox-2 selective depressant provides the dosage or the amount of the combination that is enough to constitute effective dose together.Described effective dose can effectively be measured for the treatment or the prevention that suppress Alzheimer.

" effective dose " means the dosage that gives the patient or effective amount and to patient's administration frequency as used herein, and this can be by one of ordinary skill in the art by using known technology and being easy to determine by observe the result who obtains under similar environment.One of ordinary skill in the art is by using known technology and can being easy to determine to give patient's dosage or effective amount and to patient's administration frequency by observe the result who obtains under similar environment.When definite effective dose or dosage, diagnostician on duty need consider multiple factor, includes, but is not limited to: the character of the effect effectiveness of the chemical compound of use and persistent period, the disease of being treated and seriousness and the patient's that treated sex, age, body weight, health status and individual reactive and other correlation circumstance.

Term " treatment effectively " refers to chemoprophylaxis or improves severity of disease, avoids the ability of general relevant with other therapies harmful side effect simultaneously.Term " treatment effectively " is interpreted as being equal to term " to treatment, prevention or inhibition effectively ", both all refer to the amount of each used in conjoint therapy medicine, this therapy is treated easier the reach seriousness of improving cancer, Alzheimer, cardiovascular disease or pain and inflammation and the purpose that reduces sickness rate than single medicine itself, avoids the general harmful side effect relevant with other therapies simultaneously.

Those those skilled in the art will know the ThePharmacological Basis of Therapeutics according to Goodman and Goldman, Ninth Edition (1996), and Appendix II, the guide of 1707-1711 page or leaf also can be determined dosage.

In the method for the invention, when with the administration of cyclo-oxygenase-2 selective depressant, the amount of employed PPAR alfa agonists should be enough to constitute the effective dose of this combination.Preferably the dosage that should make up constitutes effectively amount of treatment.

And the combination of Cox-2 selective depressant is used for the amount of the employed PPAR alfa agonists of single-dose treatment preferably between the about 0.01mg-200mg of every kg weight in patients.More preferably described amount is between about 0.1mg/kg-50mg/kg, even more preferably about 1mg/kg-20mg/kg, and still more preferably about 1mg/kg-10mg/kg.

Administration frequency will be decided according to the half-life of PPAR alfa agonists molecule.If PPAR alfa agonists molecule has the short half-life (for example about 2-10 hour), it may be necessary giving one or more dosage every day.Perhaps,, only be necessary every day, give once weekly, perhaps even per 1 or gave once in 2 months if PPAR alfa agonists molecule has the long half-life (for example about 2-15 days).Preferred administration frequency is to give the patient dosage described above once a day.

In order to calculate and to represent administration frequency, do not consider administration frequency, based on average magnitude every day, calculate all dosage in this expression.For example, per composition of once taking a 100mg dosage in two days should be expressed as 50mg/ days administration frequency.Similarly, the administration frequency of wherein taking 50mg every day for twice should be expressed as 100mg/ days administration frequency.

In order to calculate the administration frequency of the inventive method, suppose that adult body weight is 70kg.

When with the administration of PPAR alfa agonists, the amount that is used for the Cox-2 selective depressant of the inventive method can be the amount that is enough to constitute the combination of effective dose.This amount preferably should be enough to provide the treatment effective dose of described combination.This treatment effective dose also can be described as the treatment or the prevention effective dose of the combination of inhibition of pain or inflammation at this, perhaps for suppressing effectively amount of cardiovascular disorder or treatment of diseases or prevention, perhaps being to suppress treatment for cancer or the effective amount of prevention, perhaps is treatment or the effective amount of prevention that suppresses Alzheimer.

In the method for the invention, the amount of Cox-2 selective depressant that is used for new Therapeutic Method is preferably in the scope of the body weight (mg/ days kg) of about 0.01-100 mg/day/kg of patient, more preferably in the scope of about 0.1-50mg/ days kg, even more preferably in the scope of about 1-20mg/ days kg.

When the Cox-2 selective depressant comprised rofecoxib, preferred employed amount was in the scope of about 0.15-1.0mg/ days kg, and even more preferably in the scope of about 0.18-0.4mg/ days kg.

Examine in former days when the Cox-2 selective depressant comprises relying on, preferred employed amount is in the scope of about 0.5-5mg/ days kg, and even more preferably in the scope of about 0.8-4mg/ days .kg.

When the Cox-2 selective depressant comprised celecoxib, preferred employed amount was in the scope of about 1-10mg/ days kg, even more preferably in the scope of about 1.4-8.6mg/ days kg, and still more preferably in the scope of about 2-3mg/ days kg.

When the Cox-2 selective depressant comprised valdecoxib or parecoxib sodium, preferred employed amount was in the scope of about 0.1-3mg/ days kg, and even more preferably in the scope of about 0.3-1mg/kg.

In the inventive method and the present composition, can be with PPAR alfa agonists and Cox-2 selective depressant administering drug combinations.The weight rate of amount that preferably gives patient's the amount of PPAR alfa agonists and Cox-2 selective depressant is between about 0.0001: 1-20000: in 1 the scope, more preferably between about 0.02: 1-200: in 1 the scope, even more preferably between about 0.05: 1-10: in 1 the scope.

Can be the combination that the form of the new therapeutic combination in the scope of the invention provides PPAR alfa agonists and Cox-2 selective depressant it is believed that.The relative quantity of each composition in therapeutic combination can change, and can change as described in just by above.Above-mentioned PPAR alfa agonists and Cox-2 selective depressant can be provided with the form of therapeutic combination, thereby by single dose, single injection or single capsule, for example or the most nearly 4 or more a plurality of single dose form provide the preferred amounts of each composition.

When new compositions provides with pharmaceutically acceptable carrier, form Pharmaceutical composition.Pharmaceutical composition of the present invention relates to and is suitable for preventing or treat pain, inflammation and/or the disease relevant with inflammation or is suitable for prevention or treatment cardiovascular disease or disorder, perhaps be suitable for prevention or treatment cancer, perhaps be suitable for preventing or treating the compositions of Alzheimer.Pharmaceutical composition comprises pharmaceutically acceptable carrier, PPAR alfa agonists and cyclo-oxygenase-2 selective depressant.

Pharmaceutically acceptable carrier includes, but is not limited to normal saline, Ringer's solution, phosphate solution or buffer, buffer saline and other carrier known in the art.Pharmaceutical composition also can comprise stabilizing agent, antioxidant, coloring agent and diluent.Thereby select pharmaceutically acceptable carrier and additive messenger drug to reduce to minimum, and the usefulness of chemical compound is not eliminated or is suppressed to the degree of failing to respond to any medical treatment with the side effect of chemical compound.

Term " effective dose on the pharmacology " means the physiology who just is not studied tissue, system, animal or people that person or clinicist probe into or the medicine that medical science is replied or the amount of pharmaceutical formulation of bringing out.This amount can be for effectively measuring on the therapeutics.

Term " pharmaceutically acceptable " means the noun of the modification that is applicable to medicinal product as used herein.Pharmaceutically acceptable cation comprises metal ion and organic ion.Preferred metal ion includes, but is not limited to suitable alkali metal salt, alkali salt and other physiology and goes up acceptable metal ion.Illustrative ion comprises aluminum, calcium, lithium, magnesium, potassium, sodium and the zinc of common valence state.Preferred organic ion comprises protonated tertiary amine and quaternary ammonium cation, and part comprises trimethylamine, diethylamine, N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, ethylenediamine, Mai Geluming (N-methylglucosamine) and procaine.Illustrative pharmaceutically acceptable acid includes, but is not limited to hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, sulphuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, acetone acid, oxalacetic acid, fumaric acid, propanoic acid, aspartic acid, glutamic acid, benzoic acid etc.

Be also contained in the combination of the present invention is isomeric forms and the tautomer and the pharmaceutically acceptable salt of PPAR alfa agonists and cyclo-oxygenase-2 selective depressant.Be equipped with illustrative pharmaceutically acceptable salt from following processed with acid, comprise: formic acid, acetic acid, propanoic acid, succinic acid, glycolic, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, acetone acid, aspartic acid, glutamic acid, benzoic acid, ortho-aminobenzoic acid, methanesulfonic acid, stearic acid, salicylic acid, right-hydroxy benzoic acid, phenylacetic acid, mandelic acid, pamoic acid (pamoic acid), methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, the 2-ethylenehydrinsulfonic acid, sulfanilic acid, the cyclohexyl sulfamic acid, alginic acid (algenic), beta-hydroxy-butanoic acid, galactosaccharic acid and galacturonic acid.

The suitable pharmaceutically acceptable base addition salts of The compounds of this invention comprises metal cation salt and organic ion salt.Preferred metal cation salt includes, but is not limited to suitable alkali metal (Ia group) salt, alkali salt (IIa group) salt and other physiology and goes up acceptable metal ion.Can prepare this class salt from the ion of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.Preferred organic salt can be from tertiary amine and quaternary ammonium salt preparation, and part comprises trimethylamine, diethylamine, N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, ethylenediamine, Mai Geluming (N-methylglucosamine) and procaine.Those skilled in the art use corresponding The compounds of this invention by conventional method, can prepare all above salt.

Method of the present invention and combination are used for (but being not limited to) prevention, suppress and treatment intravital pain of patient and/or inflammation, and are used for the treatment of inflammation related disease, for example are used for the treatment of pain and headache as analgesic, perhaps are used for the treatment of heating as antipyretic.For example, combination of the present invention can be used for treatment of arthritis, includes, but is not limited to rheumatoid arthritis, vertebral arthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematosus (sle) and juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis.This class combination of the present invention can be used for treating asthma, bronchitis, menstruation cramp, tendinitis, bursitis, connective tissue damage or disease and the disease relevant with skin, for example psoriasis, eczema, burn and dermatitis.

Combination of the present invention also can be used for treating gastroenteropathy, inflammatory bowel disease, gastric ulcer, the varicose of the stomach pulse pipe, Ke Langshi disease, gastritis, the irritable bowel trace integration ulcerative colitis of seeking peace for example, and can be used for prevention or treatment cancer, for example colorectal carcinoma.Combination of the present invention can be used for treating the inflammation in disease and the symptom, for example herpes simplex infection, HIV, pulmonary edema, renal calculus, slight wound, wound healing, skin wound healing, vaginitis, candidiasis, the lumbar spine dislocation, lumbar spine arthritis, angiopathy, migraine, the sinus frontalis headache, tension headache, toothache, polyarteritis nodosa, thyroiditis, aplastic anemia, Hokdkin disease, scleroderma, rheumatic fever, type i diabetes, type ii diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, the Paget Cotard, polymyositis, gingivitis, anaphylaxis, the swelling that the damage back takes place, myocardial ischemia etc.

Compositions with new combination also can be used for treating ophthalmic diseases, for example the acute injury of retinitis, retinal degeneration, conjunctivitis, uveitis, eye photophobia and ocular tissue.Described compositions also can be used for treating respiratory inflammation, for example with viral infection diseases associated and cystic fibrosis of the pancreas.Said composition also can be used for treating some central nervous system disease, for example comprises the cortex dementia of Alzheimer.Combination of the present invention also as anti-inflammatory agent, for example is used for the treatment of arthritis.

Term " pain, inflammation or inflammation related disease " and " disease of cyclo-oxygenase-2 mediation " are intended to include, but is not limited to above-mentioned various symptom or disease as used herein.

Existing several animal models, they are suitable for the prevention of pain and inflammation and the evaluation of treatment.Referring to for example Winter etc. at Proc.Soc.Exp.Biol.Med., among the 111:544 (1962) to the description of rat carrageenan toes swelling test; With description in Pain 32:77 (1988) such as Hargreaves to the inductive analgesic test of rat carrageenan.

The scorching model of joint of animal is also by Stuart, and J. describes among the 2:199 (1984) at Ann.Rev.Immunol.Chinn, K.S. etc., Lipids, 32 (9): 979-988 (1997) has described in the rat body that essential fatty acid lacks by the inductive arthritis of food arachidonic acid adjuvant.

The animal model of Alzheimer has been described in No. the 6310048th, the United States Patent (USP) of Kumar, wherein with SAM P8 mouse test medicine to the anabolic effect of amyloid-beta with to presenting the effect of the seriousness of the similar symptom of Alzheimer with those.

The inventive method comprises the disease that treats and/or prevents cyclo-oxygenase-2 mediation in patient's body, and wherein this method comprises treating with the compound or its salt of the PPAR alfa agonists of treatment effective dose and any cyclo-oxygenase-2 selective depressant of describing to suffer from or the patient of the described disease of easy infection in the application's book.The disease that mediates when cyclo-oxygenase-2 is inflammation, arthritis, pain or adstante febre, and this method is useful especially.

Can be used for prevention, treatment or suppress cancer at this method and composition of describing as method and composition of the present invention.Method and composition of the present invention preferably can be used for the treatment of, prevention or suppress comprise optimum and malignant tumor in being formed on ND and shift in neoplasia, and also comprise acral-lentiginous melanoma, actinic keratosis, adenocarcinoma, adenocystic carcinoma, adenoma, sarcoadenoma, adenoid squamous cell carcinoma, astrocytoma, carcinoma of Bartholin, basal cell carcinoma, breast carcinoma, bronchial adenocarcinoma, the blood capillary cancer, carcinoid, cancer, carcinosarcoma, the cavity, cancer of biliary duct, chondrosarcoma, choroid plexus papilloma/cancer, renal cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, the endometrial stroma sarcoma, adenocarcinoma of endometrium, the ependyma cancer, last dermoid cancer, Ewing's sarcoma, the fibrous layer cancer, local knot shape hypertrophy, gastrinoma, germinoma, glioblastoma, glucagonoma, the vascular cell tumor, hemangioendothelioma, hemangioma, adenoma of liver, the adenoma of liver disease, hepatocarcinoma, insuloma, last Intradermal neoplasia, squamous cell neoplasia between epithelium, the wellability squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, malignant lentigo, malignant melanoma, malignant mesothe, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelium, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelium adenocarcinoma, nodular melanoma, oat-cell carcinoma, oligodendroglioma, osteosarcoma, the pancreas polypeptide, the serious adenocarcinoma of mamillary, pinealocyte, pituitary tumor, plasmocytoma, false sarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, the serosity cancer, small cell carcinoma, the soft tissue cancer, GHIF secretion tumor, squamous cell carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, the tunica uvea melanoma, verrucous carcinoma, the vasoactive intestinal polypeptide tumor, wall differentiation cancer and dimension Mu Shi tumor.

Existing several animal models, they are suitable for the prevention of cancer or the evaluation of treatment.Petrik for example, M.B. etc. be at J.Nutr., and 130 (10): the purposes of having described the model that Apc (Min/+) mice takes place as the test intestinal neoplasms among the 2434-2443 (2000).Desaulniers, D. etc., Environ Health Perspect, Jul:109 (2001) have described the rat that suffers from the mastocarcinoma that methyl-nitroso-urea (MNU) the causes purposes as subjects.Moser, A.R. etc. in Cancer Tes.61 (8): 3480-3485 (2001), described the Apc (min) that suffers from the mastocarcinoma that ethylnitrosourea (ENU) causes /+mice is as the purposes of subjects.

Compositions described here and method can be used for (but being not limited to) prevention, treatment or need to suppress the patient's of this kind prevention, treatment or inhibition cardiovascular disease or disorder.This class disease and disorder also can refer to " cardiovascular/metabolic disease and disorder " or " CVMDs " at this.Compositions described here is preferred for preventing, treating or need to suppress the patient's of this kind prevention, treatment or inhibition the cardiovascular disease relevant with inflammation with method.Described compositions and method can be used for preventing coronary artery disease, aneurysm, arteriosclerosis, atherosclerosis (comprising the heart transplantation atherosclerosis), myocardial infarction, thromboembolism, apoplexy, thrombosis (comprising venous thrombosis), angina pectoris (comprising the instability angina pectoris), the coronary pluques inflammation, the inflammation that antibacterial is brought out (comprising the inflammation that chlamydiaceae brings out), viral-induced inflammation and the inflammation relevant with operation process, for example blood vessel grafting comprises coronary bypass, revascularization procedure comprises angioplasty, graft is fixed, endarterectomy or other invasive diagnosis technical method (comprise tremulous pulse, vein and blood capillary).

Existing several animal models, the evaluation of the prevention of the cardiovascular disease that they are suitable for comprising that prevention of arterial is atherosis.Referring to for example Stehbens, Prog.Card.Dis., XXIX, 1007-28 (1986) and Zhang etc., Science, 258:468-71 (1992).

Roselear etc. (Arterioscle.Thromb.Vasc.Biol., 16,1013-18 (1996)) have described and have been used for atherosclerotic ApoE mouse model.Under the dosage of 20mg/kg, described cyclooxygenase-2 inhibitor is activated in the atherosis damage of prevention of arterial.Hasty, A.H. etc., J.Biol.Chem., 276 (40): 37402-37408 (2001) described two mutant mices (LDLR-/-; Ob/ob) as the purposes of hypercholesterolemia, hypertriglyceridemia and atherosclerotic test model.

As mentioned above, embodiment of the present invention comprise the Pharmaceutical composition that is used for angiocardiopathy preventing, and said composition comprises the PPAR alfa agonists of the treatment effective dose that makes up with at least a pharmaceutically acceptable carrier, adjuvant or diluent and other active component (if desired) and the combination of cyclo-oxygenase-2 selective depressant.Commercial use, clinical evaluation and clinical before have a large amount for the treatment of cardiovascular diseases in the exploitation, they can be selected for combination of the present invention, by combination medicine therapy angiocardiopathy preventing.This class medicine can be selected from the medicine of the main catalogue of (but being not limited to) several classes for one or more kinds, be lipid lowerers, comprise ibat inhibitor, nicotinic acid, his spit of fland, CETP inhibitor and cholic acid chelating agent, antioxidant (comprising vitamin E and probucol), IIbIIIa antagonist (comprising xemilofiban and orbofiban), aldosterone inhibitor (comprising spironolactone and epoxymexrenone), AII antagonist (comprising losartan), beta blocker, aspirin, loop diuretic and ACE inhibitor.

Particularly, combination of the present invention is used for the treatment of disease or the disorder by the activity mediation of PPAR α.The disease or the disorderly example of the activity mediation by PPAR α include, but is not limited to hyperglycemia, hyperlipemia, atherosclerosis, ischemic heart disease, with old and feeble diseases associated, lipid metabolism is unusual, insulin resistance, chronic inflammatory disease, atherosclerotic easy susceptibility, tumor takes place, hepatocarcinoma takes place, atheromatous disease, diabetes, hyperglycemia, obesity, hyperlipemia, hypertriglyceridemia, hypercholesterolemia, the HDL level that raises, the blood vessel retinitis, the irritable bowel trace integration is levied, pancreatitis, abdominal obesity, the adipose cell tumor, the adipose cell cancer, liposarcoma, insulin resistance is the disease of the cause of disease, X syndrome, ovarian hyperandrogenism, obesity, tangier's disease, type ii diabetes, angiopathy and skin wound healing.

Term " treatment " or " medical treatment " mean mitigation symptoms, eliminate temporary or the persistency cause of disease in essence, perhaps prevent or the symptom that slows down apparent.Term " treatment " comprises the cause of disease that alleviates, eliminates following disease or prevents following disease, comprising: cancer, Alzheimer, cardiovascular disease or disorder or pain and/or with the inflammation of disease described here or disorderly relevant (but being not limited to).Except that the treatment that is used for the people, these combinations also are used for the treatment of mammal, comprise horse, dog, cat, rat, mice, sheep, pig etc.

The term " patient " that is used for the treatment of purpose comprises to be needed this kind prevention or suffers from cancer, Alzheimer, cardiovascular disease or pain, inflammation and/or anyone or animal patient of the disease of any known and inflammation-related.Described patient is generally mammal." mammal " conduct is term as used herein, refer to classify as mammiferous any animal, comprise people, poultry and feed lot animal, and zoo, the motion animal raising or Gong view and admire, for example dog, horse, cat, cattle etc., preferably mammal behaviour.

For method of the present invention, described patient is anyone or animal patient, and be preferably need prevent and/or treat cancer, Alzheimer, cardiovascular disease or pain, inflammation and/or with the curee of the disease of inflammation-related.Described patient can be the human patients under the risk of the disease (for example those diseases described above) that is in cancer, Alzheimer, cardiovascular disease or pain and/or inflammation or acquisition and inflammation-related.Under the risk that described patient can be in owing to inherited genetic factors, inherent life style, diet, be exposed to the reagent that causes disease, be exposed to pathogen reagent etc.

Pharmaceutical composition of the present invention can be through intestinal and parenterai administration.That parenterai administration comprises is subcutaneous, in the intramuscular, intradermal, breast, intravenous administration and other medication known in the art.Intestinal canal administration comprises solution, tablet, Kronocap, enteric coating capsule and syrup.When administration, described Pharmaceutical composition can give at body temperature or near under the body temperature.

Term " therapeutic alliance ", " administration altogether ", " together administration " or " treatment altogether ", when the purposes of definition cyclo-oxygenase-2 selective depressant medicine and PPAR alfa agonists, be intended to be included in and give each medicine in a continuous manner providing in the therapeutic scheme of useful effect of drug regimen, and be also intended to comprise in simultaneously mode basically and give these medicines jointly, for example or repeatedly with each medicine with the single capsule of fixed ratio or doser with these active component, capsule or doser separately gives, capsule that wherein separates or doser can be taken simultaneously together, perhaps take in the time durations that is enough to accept from the useful effect of two kinds of composition medicines of combination.

Although combination of the present invention can be included in the effective time of each corresponding composition and give PPAR alfa agonists composition and cyclo-oxygenase-2 selective depressant composition, but preferably give both corresponding compositions simultaneously, and more preferably give both corresponding composition with single transmission dosage.

Specifically, combination of the present invention can orally give, but for example as the form of tablet, coated tablet, coated tablet, lozenge, dragee, aqueous or oiliness suspensoid dispersion powder or granule, Emulsion, hard or soft capsule or syrup or elixir.Any method according to preparation Pharmaceutical composition known in the art can prepare the compositions that is used for oral use, this based composition can contain one or more kinds ofly be selected from following reagent, comprising: for sweeting agent, correctives, coloring agent and the antiseptic of pharmaceutically good and agreeable to the taste preparation are provided.Tablet comprises and the pharmaceutically acceptable mutually blended active component of excipient that is suitable for preparing tablet of non-toxicity.These excipient can be for example inert diluent, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example corn starch or alginic acid; Binding agent, for example starch, gelatin or arabic gum, and lubricant, for example magnesium stearate, stearic acid or Pulvis Talci.Tablet can for the plain sheet of coating not or can be by known technology with its coating postponing disintegrate and the absorption in gastrointestinal tract, thereby continuous action in long-time is provided.For example, can adopt the time-delay material, for example glyceryl monostearate or glycerol distearate.

The preparation that is used for oral use also can be used as wherein with active component and for example blended hard gelatin capsule existence of calcium carbonate, calcium phosphate or Kaolin of inert solid diluent, perhaps conduct is wherein with active component itself, perhaps with water or for example Perle existence of Oleum Arachidis hypogaeae semen, liquid paraffin or mixed with olive oil of oily medium.

Can prepare the active component aqueous suspension that contains and be suitable for preparing the mixed with excipients of aqueous suspension.This class excipient is a suspending agent, for example sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinylpyrrolidone, Tragacanth and arabic gum; Dispersant or wetting agent can be the phospholipid of natural origin, lecithin for example, the perhaps condensation product of alkylidene epoxide and fatty acid, Myrj 45 for example, the perhaps condensation product of oxirane and long-chain fatty alcohol, heptadecyl Oxyranyle spermol for example, perhaps oxirane be derived from the condensation product of the part ester of fatty acid and hexitol, octadecanoic acid ester of polyethylene glycol for example, perhaps oxirane be derived from the condensation product of the part ester of fatty acid and hexitol anhydride, polyoxyethylene sorbose monooleate for example.

Aqueous suspension also can contain one or more kinds of antiseptic, and for example, ethyl or n-pro-pyl be right-hydroxybenzoate, one or more kinds of coloring agent, and one or more kinds of correctives or one or more kinds of sweeting agent, for example sucrose or glucide.

Can be suspended in for example Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois or mineral oil preparation oiliness suspensoid in the liquid paraffin for example of omega-fatty acid, vegetable oil by making active component.Described oiliness suspensoid can contain thickening agent, for example Cera Flava, hard paraffin or spermol.

Can add sweeting agent (aforesaid those) and correctives so that agreeable to the taste oral formulations to be provided.By add antioxidant for example ascorbic acid can protect these compositionss anticorrosion.

Be suitable for preparing the dispersible powders agent of aqueous suspension and granule and providing and dispersant or wetting agent, suspending agent and one or the blended active component of more kinds of antiseptic by adding entry.Suitable dispersant or wetting agent and suspending agent mentioned by top those illustrate.Also can there be other excipient, for example sweeting agent, correctives and coloring agent.

With sweeting agent for example glycerol, sorbitol or sucrose, can prepare the syrup and the elixir that comprise new compositions.This class preparation also can contain demulcent, antiseptic and correctives and coloring agent.

Also can in non-intestinal or subcutaneous or vein or intramuscular or breastbone or by infusion techniques, give combination of the present invention with the form of sterile water for injection or oiliness (olagenous) suspensoid.According to known technology, adopt wetting agent and dispersive those reagent of suspending agent or other the acceptable agents mentioned above being suitable for making, can prepare this class suspensoid.Described sterilization ejection preparation also can be sterilizing injecting solution or the suspension in atoxic non-intestinal acceptable diluent or solvent, for example as the solution in 1,3 butylene glycol.Spendable described acceptable vehicle and solvent are water, Ringer's mixture and isotonic sodium chlorrde solution.In addition, the fixedly oil that generally will sterilize is as solvent or suspension media.For this purpose, can adopt and comprise synthetic single-or the fixedly oil of any gentleness of two glyceride.In addition, can find the purposes of n-3 polyunsaturated fatty acid in the preparation injection.

The present invention's combination also can give by suction with the aerosol of nebulizer or the form of solution, perhaps to give by the suppository form rectum that medicine and suitable non-irritating excipient (it is solid at normal temperatures but is liquid under rectal temperature, therefore can be in rectum fusion to discharge medicine) be mixed with.This class excipient is cocoa butter and Polyethylene Glycol.

New compositions also can be with the form topical administration of cream, unguentum, gellant, collyrium, solution or suspensoid.

Daily dose can change in very wide scope, and to each concrete case, can be adjusted to scheme separately.Usually, for adult's administration, if suitable daily dose described above is although when convenient, can surmount determined preferred range.Described daily dose can be used as single dose or each divided dose gives.

Various transmission systems comprise for example capsule, tablet and gelatine capsule.

The present invention also comprises and is applicable to the kit that carries out with the method for described treatment, prevention or inhibition.In one embodiment, described kit comprises and contains above determined one or first dosage form of the PPAR alfa agonists of more kinds of forms and contain above determined one or more kinds of cyclo-oxygenase-2 selective depressant or second dosage form of its prodrug, and they exist with the amount that is enough to carry out method of the present invention.First dosage form and second dosage form preferably are configured for treating together, prevention or inhibition of pain, inflammation or with the disease of inflammation-related, or cardiovascular disease or disorder, or cancer, or the treatment effective dose of each chemical compound of Alzheimer.

Following examples have been described embodiment of the present invention.Those skilled in the art can clearly understand other embodiment in this claim scope after having considered description of the present invention disclosed herein or practice.This description only is an exemplary illustration with the specified scope and spirit of the present invention of claim of embodiment after for embodiment.In these embodiments, except as otherwise noted, all percentage ratios all are weight percentage.

Comparing embodiment 1

Present embodiment shows the preparation of celecoxib.

Step 1:1-(4-aminomethyl phenyl)-4,4,4-trifluoro butane-1, the preparation of 3-diketone.

According to the disclosure that in No. the 5760068th, United States Patent (USP), provides, under argon, with 4 '-(5.26g 39.2mmol) is dissolved in the methanol of 25mL methyl acetophenone, is added in 12mL (52.5mmol) Feldalat NM in the methanol (25%) then.Mixture was stirred 5 minutes, add 5.5mL (46.2mmol) Trifluoroacetic Acid Ethyl Ester then.Reflux after 24 hours, make mixture be cooled to room temperature, concentrate.Add 100mL 10%HCl, with 4 * 75mL ethyl acetate extraction mixture.Through MgSO ₄Dry extract filters and concentrates, and obtains 8.47g (94%) brown oil, and it need not be further purified and can carry out.

Step 2:4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] preparation of benzsulfamide.

To the diketone that derives from step 1 in the 75mL dehydrated alcohol (4.14g, 18.0mmol) in, add 4-sulfoamido (sulphonamido) hydrazinobenzene hydrochloride salt of 4.26g (19.0mmol).Under argon, reactant liquor was refluxed 24 hours.After being cooled to room temperature, filter, concentrated reaction mixture obtains the 6.13g orange solids.With the solid recrystallization, obtaining 3.11g (8.2mmol, 46%) is the product of light yellow solid, 157-159 ℃ of fusing point (mp) with dichloromethane/hexane; C ₁₇H ₁₄N ₃O ₂SF ₃Calculating form: C, 53.54; H, 3.70; N, 11.02.This forms measured value: C, 53.17; H, 3.81; N, 10.90.

Embodiment 2

The preparation that present embodiment has been set forth the preparation method of composition that contains celecoxib and fenofibrate and contained the Pharmaceutical composition of described combination.

Fenofibrate can be from Abbott Laboratories, North Chicago, and IL is with trade name TRICOR ^Obtain.Celecoxib can by described in the comparing embodiment 1 preparation, perhaps from Pharmacia Corporation, Peapack, NJ is with trade name CELEBREX ^Obtain.

Laboratory grind or mixing arrangement in (this device be suitable for tight mixed-powder do not produce basically simultaneously to shear or do not produce be enough to degrade the temperature of two kinds of chemical compounds), (160g is as TRICOR by making fenofibrate ^Derive from Abbott Laboratories) and 4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide (200g, according to preparation in the comparing embodiment 1, perhaps derive from Pharmacia Corporation, Peapack, NJ) mix mutually, can form therapeutic combination of the present invention.After the mixing, being combined to form of celecoxib and pioglitazone is enough to produce the therapeutic combination of about 1000 personal single dosage forms.Each single dosage form contains the fenofibrate of the 160mg that has an appointment and the celecoxib of about 200mg.

If desired, solid carrier and other material can be mixed to form Pharmaceutical composition mutually with therapeutic combination, then the Pharmaceutical composition that is generated is for example formed the human capsule by conventional scrotiform apparatus for converting, wherein each capsule contains fenofibrate and the 200mg celecoxib of 160mg.

Perhaps, fenofibrate and celecoxib can be dissolved in the liquid-carrier, for example, the normal-salt aqueous solution is to form man-rated Pharmaceutical composition.The single dose of human liquid pharmaceutical composition should be is enough to provide the pioglitazone of 160mg and the volume of 200mg celecoxib.

Can form the treatment and the Pharmaceutical composition of the combination of the PPAR alfa agonists that contains any cyclo-oxygenase-2 selective depressant described above and any source by similar approach.

Embodiment 3

The therapeutic combination of present embodiment elaboration fenofibrate and celecoxib improves the evaluation of the biopotency of pain and inflammation.

The therapeutic combination that contains fenofibrate and celecoxib by preparation described in the embodiment 2.By rat carrageenan toes swelling test with measure the biopotency of compositions by the inductive analgesic test of rat carrageenan.

Rat carrageenin toes swelling test:

Basically press (Proc.Soc.Exp.Biol.Med., 111,544 (1962)) described material, reagent and methods such as Winter and carry out carrageenin toes swelling test.Select every group of male Sprague-Dawley rat, so that average weight is approaching as far as possible.Tested preceding 16 hours, and, freely drank water the rat fasting.Oral (1mL) gives the chemical compound that rat is suspended in the embodiment 2 in the carrier intermediate that contains 0.5% methylcellulose and 0.025% surfactant, perhaps only independent orally give rat carrier intermediate.After 1 hour, give a sufficient pawl vola 1% solution of carrageenin/sterile saline (0.9%) of injection 0.1mL down, it is long-pending to measure the sufficient corpus unguis of having injected with the displaced volume tracer that connects the pressure transmitter that has digital indicating gage then.The injection carrageenin is measured the volume of sufficient pawl after 3 hours once more.The average foot pawl swelling degree of Drug therapy treated animal and the average foot pawl swelling degree of placebo treatment treated animal are compared, measure percentage ratio suppression ratio (Otterness and the Bliven of swelling then, LaboratoryModels for Testing NSAIDS, in NSAID (non-steroidal anti-inflammatory drug) (J.Lombardino edits, 1985)).This percent inhibition shows in the method the percentage ratio reduction rate with respect to the matched group toes volume of being measured.Think that now these data can show that the combination of fenofibrate and celecoxib can provide effective anti-inflammatory activity.

The inductive analgesic test of rat carrageenan:

Basically press the analgesic test that (Pain, 32,77 (1988)) described material, reagent and methods such as Hargreaves adopt rat carrageenan.Adopt the male Sprague-Dawley rat of before rat carrageenan toes swelling test having been described to carry out.Injection carrageenin after 3 hours is put into rat and is had the special P LEXIGLAS of high-intensity lamp as the lamella lucida of radiant heat source ^In the container, thermal source can be placed under the floor.After initial 20 minutes, begin to carry out thermostimulation to the sufficient pawl of injection or to the sufficient pawl that its offside is not injected.Shrink back the cut-out light time when sufficient pawl, photoelectric cell will be closed lamp and timer.Measuring rat then shrinks back its time of sufficient pawl.Measure the latent time of shrinking back (showing) of matched group and medication therapy groups, and measure the percentage ratio suppression ratio that hyperpathia foot pawl is shunk back with stopwatch.Think that now this result can show that the combination of fenofibrate and celecoxib is groaned effective analgesic activities is provided.

Embodiment 4

The evaluation of the biopotency of the mouse arthritis that the therapeutic combination treatment of present embodiment elaboration fenofibrate and celecoxib is collagen-induced.

The therapeutic combination that contains fenofibrate and celecoxib by preparation described in the embodiment 2.By inducing and estimate the biopotency that collagen-induced mouse arthritis is measured compositions.

By [J.Stuart, Annual Rev.Immunol., 2,199 (1984)] described in, in 0 day, by the chicken-II Collagen Type VI (CII) of injection 50 μ g in complete Freunds adjuvant (Sigma), bring out arthritis in the male DBA/1 mice body age in week at 8-12 at the tail root.With compound become 0.5% methylcellulose (Sigma, St.Louis, Mo.) and the suspension in 0.025% polysorbas20 (Sigma).Separately or as the combination of the therapeutic combination in embodiment 2, described give cyclooxygenase-2 inhibitor (celecoxib, as described in the comparing embodiment 1) and fenofibrate (with trade name TRICOR ^Derive from Abbott Laboratories, NorthChicago, IL).Beginning in the 20th day gives chemical compound non--arthritis animal with the 0.1ml volume through conduit behind the collagen injection, continues every day to carry out, till final evaluation in the 55th day.The 50 μ g collagens (CII) that were used in the 21st day in the incomplete Freunds adjuvant excite animal.Then weekly with the incidence rate of joint of animal inflammation and seriousness evaluation several times up to the 56th day.Any animal that will have erythema or swelling is all counted arthritis.Press P.Wooley etc. at Trans.Proc., described in 15,180 (1983), adopt the mark of 0-3 that every sufficient pawl (largest score 12/ mice) is carried out the scoring of seriousness.Measure the incidence rate of joint of animal inflammation and the seriousness of viewed arthritic animal.By the swelling or the erythema of observing sufficient pawl or toes, on the bore hole level, determine arthritic incidence rate.Measure seriousness with following guide.In brief, show four normal foot pawls, the animal that does not promptly have erythema or swelling is cited as 0 fen.Any erythema or the swelling of toes or sufficient pawl are chosen as 1 fen.Swelling or distortion on the whole sufficient pawl bore hole level are cited as 2 fens.Ankylosis are cited as 3 fens.

The histology of foot pawl:

The bore hole measurement result of-arthritis animal non-for confirming can be carried out histology.[R.Jonsson, J.Immunol.Methods, 88,109 (1986)] as previously mentioned, the animal of putting to death when experiment is finished foot pawl is extractd, and is fixing, deliming matter.By standard method, with the sample embedding, cut into slices and dye with hematoxylin and eosin with paraffin.Painted fragment is carried out cellular infiltration, synovial fluid propagation and cartilage corrode detection.

Think that now this result can show that the combination of cyclo-oxygenase-2 selective depressant and PPAR alfa agonists fenofibrate can effectively treat collagen-induced arthritis in the mice body.

Now think and embodiment 3 and 4 can be reappeared the compositions that contains any PPAR alfa agonists and any cyclo-oxygenase-2 selective depressant combination described here, the result shows that this combination can provide effective anti-inflammatory activity, effective analgesic activities, and can effectively treat collagen-induced arthritis in the mice body.

Embodiment 5

Present embodiment is set forth being combined in of celecoxib and fenofibrate and is alleviated the arthritic effectiveness that adjuvant brings out in the rat body.

The combination that can prepare celecoxib and fenofibrate by the method for in embodiment 2, describing.By Chinn, K.S. etc. are at Lipids, and 32 (9): the method for describing among the 979-988 (1997) can be tested the effectiveness of described combination.

Think that now can find that the present invention makes up can alleviate the arthritis that adjuvant brings out in the rat body effectively.In fact, the combination of be sure oing to comprise any or more kinds of PPAR alfa agonists described here and any or more kinds of cyclo-oxygenase-2 selective depressants described here also is effective to such purpose.

Embodiment 6

Present embodiment is set forth the effectiveness of PPAR alfa agonists and cyclo-oxygenase-2 selective depressant treatment of cancer with combinations.

The combination that can prepare any or more kinds of PPAR alfa agonists described here and any or more kinds of cyclo-oxygenase-2 selective depressants described here by the method for in embodiment 2, describing.Can test the following effectiveness of described combination by the method for in No. the 6242196th, United States Patent (USP), describing:

A. the minimizing of body fat glucagonoma volume;

B. the inhibitory action of leukocyte cell proliferation; With

C. prostate gland cancer cell inhibition of proliferation effect.

Think that now can find that the present invention makes up can reduce body fat glucagonoma volume effectively, suppresses the leukocyte cell proliferation and suppress prostate gland cancer cell propagation.

Embodiment 7

Present embodiment is set forth the effectiveness that is combined in intestinal canal tumour in prevention or treatment Apc (Min/+) the mice body of celecoxib and fenofibrate.

The combination that can prepare celecoxib and fenofibrate by the method for in embodiment 2, describing.By Petrik, M.B.H. etc. are at J.Nutr., and the method for describing among the 130:2434-2443 (2000) can be measured the described effectiveness that intestinal canal tumour forms in prevention or minimizing Apc (Min/+) the mice body that is combined in.

Think that now can find that the present invention makes up can effectively prevent or reduce the intravital tumor of this type of mice and form.In fact, the combination of be sure oing to comprise any or more kinds of PPAR alfa agonists described here and any or more kinds of cyclo-oxygenase-2 selective depressants described here also is effective to this purpose.

Embodiment 8

Present embodiment is set forth the effectiveness of combination prevention or the interior breast hypertrophy of treatment Apc (Min/+) mice body and the tumor formation of celecoxib and fenofibrate.

The combination that can prepare celecoxib and fenofibrate by the method for in embodiment 2, describing.Pass through Moser, A.R. wait at Cancer Res., 61 (8): the method that 3480-3485 (2001) (being used for the cancer that ethylnitrosourea (ENU) brings out) describes, can measure the effectiveness that described combination prevention or the interior breast hypertrophy of treatment mice body and tumor form, perhaps pass through Deasulniers, D. wait at Environ.Health Perspect., 109 (7): 739-747 (2001), the method that (being used for the cancer that methyl-nitroso-urea (MNU) brings out) describes can be measured the effectiveness that described combination prevention or treatment breast hypertrophy and tumor form in the rat body.

Think that now can find that the present invention makes up can effectively prevent or treat in mice and the rat body mastocarcinoma development.In fact, the combination of be sure oing to comprise any or more kinds of PPAR alfa agonists described here and any or more kinds of cyclo-oxygenase-2 selective depressants described here also is effective to such purpose.

Embodiment 9

Present embodiment shows that PPAR alfa agonists and the combination of cyclo-oxygenase-2 selective depressant are effective to the cardiac function that improves in the myocardial infarction.

The combination that can prepare any or more kinds of PPAR alfa agonists described here and any or more kinds of cyclo-oxygenase-2 selective depressants described here by the method for in embodiment 2, describing.By Saito, T. etc. are at Biochem.and Biophys.Res.Communic., and the method for describing among the 273:772-775 (2000) can be tested the effectiveness that described combination improves the cardiac function in the myocardial infarction.Believe and to find that of the present invention being combined in the cardiac function that improves in the myocardial infarction is effective.

Embodiment 10

Present embodiment is set forth the effectiveness in hypercholesterolemia, hypertriglyceridemia and the atherosclerosis in prevention or the treatment mice body that is combined in of celecoxib and fenofibrate.

The combination that can prepare celecoxib and fenofibrate by the method for in embodiment 2, describing.By Hasty, A.H. etc. are at J.Biol.Chem., and 276 (40): the method for describing among the 37402-37408 (2001), can test hypercholesterolemia, hypertriglyceridemia and atherosclerotic effectiveness in described combination prevention or the treatment mice body.The two sudden change of this method employing LDLR-/-; The ob/ob mice is as animal pattern.

Think that now can find that the present invention makes up can effectively prevent and/or treat hypercholesterolemia, hypertriglyceridemia and atherosclerosis in the mice body.In fact, the combination of be sure oing to comprise any or more kinds of PPAR alfa agonists described here and any or more kinds of cyclo-oxygenase-2 selective depressants described here also is effective to such purpose.

Embodiment 11

Present embodiment is set forth the effectiveness that reduces in the human body risk of cardiovascular diseases that is combined in of celecoxib and fenofibrate.

The combination that can prepare celecoxib and fenofibrate by the method for in embodiment 2, describing.By Robins, S.J. is at J.Cardiovascular Risk, and the method for describing in any list of references of quoting in the table of announcing among the 8:195-201 (2001) 1 can be tested the effectiveness of described combination.

Think that now can find that the present invention makes up can reduce the human body cardiovascular disease risk effectively.In fact, the combination of be sure oing to comprise any or more kinds of PPAR alfa agonists described here and any or more kinds of cyclo-oxygenase-2 selective depressants described here also is effective to such purpose.

Embodiment 12

Present embodiment is set forth the effectiveness in the diabetes in prevention or the treatment rat body that is combined in of celecoxib and fenofibrate.

The combination that can prepare celecoxib and fenofibrate by the method for in embodiment 2, describing.By Shibata, T. etc. are at Br.J.Pharmacol., and 130 (3): the method for describing among the 495-504 (2000), the effectiveness that can test described combination prevention or treatment Zucker diabetes fat rat (ZDF) type ii diabetes.

Now think and to find that the present invention makes up the type ii diabetes that can effectively prevent and/or treat rat.In fact, the combination of be sure oing to comprise any or more kinds of PPAR alfa agonists described here and any or more kinds of cyclo-oxygenase-2 selective depressants described here also is effective to such purpose.

Embodiment 13

Present embodiment is set forth the effectiveness in the Alzheimer in prevention or the treatment mice body that is combined in of celecoxib and fenofibrate.

The combination that can prepare celecoxib and fenofibrate by the method for in embodiment 2, describing.By the method for in No. the 6310048th, the United States Patent (USP) of Kumar, describing, can test described combination prevention or treatment SAM P8 mice amyloid beta protein generation and accumulative ability and prevention or alleviate the ability of Alzheimer-type symptom.

Now think and to find that the present invention makes up the Alzheimer that can effectively prevent and/or treat mice.In fact, the combination of be sure oing to comprise any or more kinds of PPAR alfa agonists described here and any or more kinds of cyclo-oxygenase-2 selective depressants described here also is effective to such purpose.Alzheimer, 6310048 of Kumar.

All lists of references of in the application's book, quoting, include, but is not limited to, all papers, publication, patent, application for patent, video, textbook, report, handwritten book, pamphlet, books, the Internet email, magazine article, periodical etc., this by reference integral body be attached in this description.Only be used to summarize the opinion that their author makes in this discussion, do not allow any list of references to constitute prior art list of references.The applicant keeps the accuracy of challenge institute citing document and the right of appropriateness.

In sum, it should be noted that to draw several advantage of the present invention, and can obtain other favourable result.

Because under scope situation of the present invention, can make various variations to above method and composition, therefore all examples that are included in the above description should be only as illustrative illustration, and does not have the meaning of qualification.

Claims (59)

1. patient's prevention, treatment or inhibition of pain, inflammation that is used in the treatment of this kind of needs, prevention or inhibition, or inflammation related disease, or cancer, or Alzheimer, or cardiovascular disease or disorderly method, this method comprises with peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug treats described patient.

2. the process of claim 1 wherein that described method is used for treating pain, inflammation or inflammation related disease the patient of the treatment of this kind of needs, prevention or inhibition.

3. the method for claim 1, wherein said peroxisome proliferation-activated receptors-alfa agonists comprises and is selected from following material: WY-14643, can activate medium chain and the long-chain fatty acid of PPAR α, fiber acid derivative, the special class of shellfish, clofibrate, clofibride, fenofibrate, bezafibrate, ciprofibrate, beclofibrate (beclobrate), etofibrate, simfibrate, gemfibrozil, can activate the Arylthiazolidinedionderivatives derivatives of PPAR α, pioglitazone, bezafibrate (bezafibrate), (-) DRF2725, BM-17.0744, can activate the omega-3-fatty acid of PPAR α, 22 carbon caproic acids, JTT-501, trichloroacetic esters, the dichloroacetic acid ester, DHEA-S, can activate the unsaturated C:18 fatty acid of PPAR α, arachidonic acid, leukotriene B4, can activate the fatty aryl compound of PPAR α, and composition thereof.

4. the method for claim 1, wherein said peroxisome proliferation-activated receptors-alfa agonists comprises and is selected from following material: WY-14643, can activate medium chain and the long-chain fatty acid of PPAR α, fiber acid derivative, the special class of shellfish, clofibrate, clofibride, fenofibrate, bezafibrate, ciprofibrate, beclofibrate (beclobrate), etofibrate, simfibrate, gemfibrozil, bezafibrate (bezafibrate), (-) DRF2725, BM-17.0744, can activate the omega-3-fatty acid of PPAR α, JTT-501, trichloroacetic esters, the dichloroacetic acid ester, DHEA-S, can activate the unsaturated C:18 fatty acid of PPAR α, arachidonic acid, leukotriene B4, can activate the fatty aryl compound of PPAR α, and composition thereof.

5. the process of claim 1 wherein that described peroxisome proliferation-activated receptors-alfa agonists comprises the special class of shellfish.

6. the method for claim 1, wherein said peroxisome proliferation-activated receptors-alfa agonists comprises the chemical compound that is selected from WY-14643, clofibrate, clofibride, fenofibrate, bezafibrate, ciprofibrate, beclofibrate (beclobrate), etofibrate, simfibrate, gemfibrozil, and composition thereof.

7. the process of claim 1 wherein that described peroxisome proliferation-activated receptors-alfa agonists comprises the chemical compound that is selected from (-) DRF2725, BM-17.0744,22 carbon caproic acids, JTT-501, and composition thereof.

8. the process of claim 1 wherein that described peroxisome proliferation-activated receptors-γ comprises the chemical compound with following structure:

Wherein

Ar ¹For (1) arlydene or

(2) inferior heteroaryl,

Wherein arlydene and inferior heteroaryl are selected from R by 1-4 ^aOptional replacement of group;

Ar ²For the aryl of (1) neighbour-replacement or

(2) heteroaryl of neighbour-replacement,

Wherein said ortho-substituent is selected from R;

And aryl and heteroaryl independently are selected from R by 1-4 ^aGroup optional further replace; X and Y independently are O, S, N-R ^bOr CH ₂

Z is O or S;

N is 0-3;

R is selected from halogen and C for (1) by 1-4 _3-6The optional C that replaces of the group of cycloalkyl _3-10Alkyl,

(2) C _3-10Alkenyl, or

(3) C _3-8Cycloalkyl;

R ^aBe (1) C _1-5Alkanoyl,

(2) C _1-5Alkyl,

(3) C _2-15Alkenyl,

(4) C _2-15Alkynyl,

(5) halogen,

(6)OR ^b，

(7) aryl, or

(8) heteroaryl,

Wherein said alkyl, alkenyl, alkynyl and alkanoyl are selected from R by 1-5 ^cOptional replacement of group, and described aryl and heteroaryl are selected from R by 1-5 ^dOptional replacement of group;

R ^bBe (1) hydrogen,

(2) C _1-10Alkyl,

(3) C _2-10Alkenyl,

(4) C _2-10Alkynyl,

(5) aryl,

(6) heteroaryl,

(7) aryl C _1-15Alkyl,

(8) heteroaryl C _1-5Alkyl,

(9) C _1-5Cycloalkyl,

(10) C _3-8Cycloalkyl,

Wherein alkyl, alkenyl, alkynyl independently are selected from R by 1-4 ^cOptional replacement of substituent group, and cycloalkyl, aryl and heteroaryl independently are selected from R by 1-4 ^dOptional replacement of substituent group; Or

R ^cBe (1) halo,

(2) aryl,

(3) heteroaryl,

(4)CN，

(5)NO ₂，

(6)OR ^f，

(7) S (O) _mR ^f, m=0,1 or 2, condition is when m is 1 or 2, R ^fBe not H;

(8)NR ^fR ^f，

(9)NR ^fCOR ^f，

(10)NR ^fCO ₂R ^f，

(11)NR ^fCON(R ^f) ₂，

(12) NR ^fSO ₂R ^f, condition is R ^fBe not H,

(13)COR ^f，

(14)CO ₂R ^f，

(15)CON(R ^f) ₂，

(16)SO ₂N(R ^f) ₂，

(17) OCON (R ^f) ₂, or

(18) C _3-8Cycloalkyl,

Wherein said cycloalkyl, aryl and heteroaryl are by 1-3 halogen or C _1-6The group of alkyl is optional to be replaced;

R ^dFor (1) is selected from R ^cGroup,

(2) C _1-10Alkyl,

(3) C _2-10Alkenyl,

(4) C _2-10Alkynyl,

(5) aryl C _1-10Alkyl, or

(6) heteroaryl C _1-10Alkyl,

Wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl independently are selected from R ^eOptional replacement of group;

R ^eBe (1) halogen,

(2) amino,

(3) carboxyl,

(4) C _1-4Alkyl,

(5) C _1-4Alkoxyl,

(6) hydroxyl

(7) aryl,

(8) aryl C _1-4Alkyl, or

(9) aryloxy group;

R ^fBe (1) hydrogen,

(2) C _1-10Alkyl,

(3) C _2-10Alkenyl,

(4) C _2-10Alkynyl,

(5) aryl,

(6) heteroaryl,

(7) aryl C _1-15Alkyl,

(8) heteroaryl C _1-15Alkyl,

(9) C _1-15Alkanoyl;

(10) C _3-8Cycloalkyl;

Wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkanoyl and cycloalkyl are selected from R by 1-4 ^eOptional replacement of group;

Or its pharmaceutically acceptable salt.

9. the process of claim 1 wherein that described peroxisome proliferation-activated receptors-alfa agonists comprises chemical compound with following formula or their salt:

Wherein m is 0-20, R ⁶Be selected from hydrogen and

And R ⁸Be selected from

Wherein y is 0,1 or 2, and each alk is independently for hydrogen or comprise the alkyl of 1-6 carbon atom, each R group independently be hydrogen, halogen, cyano group ,-NO ₂, phenyl, comprise the straight or branched alkyl or the fluoro-alkyl of 1-6 carbon atom, and it can comprise hetero atom, and for example nitrogen, oxygen or sulfur and Qi Ke comprise functional group for example ketone or ester, the cycloalkyl that comprises 3-7 carbon atom, two R groups that perhaps are connected in adjacent carbon atom can form aliphatic series or aromatic ring or multiple loop systems with the carbon atom that they connected, and wherein each ring that is described has no more than 3 alk groups.

10. the method for claim 9, wherein said peroxisome proliferation-activated receptors-alfa agonists comprise and be selected from following chemical compound, the salt of described chemical compound, and composition thereof:

2-(4-(2-(1-(4-biphenyl ethyl)-3-cyclohexyl urea groups) ethyl) thiophenyl)-2 Methylpropionic acid,

2-(4-(2-(1-(2-(4-morpholino phenyl) ethyl-3-cyclohexyl urea groups) ethyl) thiophenyl)-2 Methylpropionic acid;

2-(4-(2-(1-(cyclohexane extraction butyl)-3-cyclohexyl urea groups) ethyl) thiophenyl)-2 Methylpropionic acid;

2-(4-(2-(1-heptyl-3-(2,4 difluorobenzene base) urea groups) ethyl) thiophenyl)-2 Methylpropionic acid;

2-(4-(2-(1-(2-chloro-4-(2-trifluoromethyl) phenyl methyl)-3-(cyclohexyl) urea groups) ethyl) thiophenyl)-2 Methylpropionic acid.

11. the process of claim 1 wherein that described Therapeutic Method comprises with the described patient of compounds for treating who is selected from p38MAP kinases and PPAR alpha inhibitor.

12. the process of claim 1 wherein that described cyclo-oxygenase-2 selective depressant or its prodrug have the cyclo-oxygenase-2 IC that is less than about 0.2 μ mol/L ₅₀

13. the method for claim 11, wherein said cyclo-oxygenase-2 selective depressant or its prodrug have the cyclo-oxygenase-1IC at least about 1 μ mol/L ₅₀

14. the process of claim 1 wherein that described cyclo-oxygenase-2 selective depressant is selected from celecoxib, weary examine former times, deracoxib, rofecoxib, support and examine former times, parecoxib, chlorine U.S.A and examine former times, SD-8381, ABT-963, BMS-347070 and NS-398.

15. the method for claim 14, wherein said cyclo-oxygenase-2 selective depressant are selected from celecoxib, weary examine former times, deracoxib, rofecoxib, support and examine former times, parecoxib and chlorine U.S.A and examine former times.

16. the method for claim 15, wherein said cyclo-oxygenase-2 selective depressant are selected from celecoxib, weary former times and the parecoxib examined.

17. the process of claim 1 wherein that described cyclo-oxygenase-2 selective depressant comprises celecoxib.

18. the method for claim 2, wherein a certain amount of peroxisome proliferation-activated receptors-alfa agonists and a certain amount of cyclo-oxygenase-2 selective depressant or its prodrug are configured for treating together, the effective dose of prevention or inhibition of pain, inflammation or the disease relevant with inflammation.

19. the process of claim 1 wherein that the amount of described peroxisome proliferation-activated receptors-alfa agonists is between every kg weight in patients about 0.1-50mg/ days.

20. the method for claim 19, the amount of wherein said cyclo-oxygenase-2 selective depressant or its prodrug is between every approximately kg weight in patients 0.01-100mg/ days.

21. the method for claim 20, the amount of wherein said cyclo-oxygenase-2 selective depressant or its prodrug is between every kg weight in patients about 1-20mg/ days.

22. the process of claim 1 wherein that the weight rate of amount of the amount of peroxisome proliferation-activated receptors-alfa agonists of giving described patient and cyclo-oxygenase-2 selective depressant or its prodrug is between about 0.02: 1-200: in 1 the scope.

23. the method for claim 22, the weight rate of amount that wherein gives described patient's the amount of peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug is between about 0.05: 1-10: in 1 the scope.

24. the method for claim 2, wherein said pain, inflammation or inflammation related disease are selected from headache, heating, arthritis, rheumatoid arthritis, vertebral arthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematosus (sle), adolescence arthritis, asthma, bronchitis, the menstruation cramp, tendinitis, bursitis, connective tissue damage or disease, the disease relevant with skin, psoriasis, eczema, burn, dermatitis, gastroenteropathy, inflammatory bowel disease, gastric ulcer, the varicose of the stomach pulse pipe, the Ke Langshi disease, gastritis, the irritable bowel trace integration is levied, ulcerative colitis, cancer, colorectal carcinoma, herpes simplex infection, HIV, pulmonary edema, renal calculus, slight wound, wound healing, vaginitis, candidiasis, the lumbar spine dislocation, lumbar spine arthritis, angiopathy, migraine, the sinus frontalis headache, tension headache, toothache, polyarteritis nodosa, thyroiditis, aplastic anemia, Hokdkin disease, scleroderma, rheumatic fever, type i diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, the Paget Cotard, polymyositis, gingivitis, anaphylaxis, the swelling that the damage back takes place, myocardial ischemia, ophthalmic diseases, retinitis, retinopathy, conjunctivitis, uveitis, the eye photophobia, the acute injury of ocular tissue, respiratory inflammation, nervous system disease, cortex dementia and Alzheimer.

25. the method for claim 2, wherein said pain, inflammation or inflammation related disease are ophthalmic diseases or ocular injury.

26. the method for claim 25, wherein said ophthalmic diseases or ocular injury are selected from the acute injury of retinitis, retinopathy, conjunctivitis, uveitis, eye photophobia, ocular tissue.

27. the method for claim 24, wherein said pain, inflammation or inflammation related disease are arthritis.

28. the method for claim 27, wherein said arthritis are osteoarthritis.

29. the method for claim 27, wherein said arthritis are rheumatoid arthritis.

30. the process of claim 1 wherein that described patient is animal.

31. the method for claim 30, wherein said patient behaves.

32. the process of claim 1 wherein that described treatment step comprises that every day is to give described patient's peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant in one or more dosage enteral or the non-intestinal.

33. the method for claim 32, wherein said peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant are given described patient basically simultaneously.

34. the method for claim 32, wherein said peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant are given described patient successively.

35. a method that is used for the treatment of or prevents to have the disease of inflammatory component in needs treatments or prevention have the patient of disease of inflammatory component, this method comprises peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its pharmaceutically acceptable salt or the prodrug that gives described patient treatment effective dose.

36. one kind be used for the treatment of, the compositions of prevention or inhibition of pain, inflammation or inflammation related disease, it comprises peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug.

37. the compositions of claim 36.It also comprises the chemical compound that is selected from p38MAP kinases and PPAR alpha inhibitor.

38. the compositions of claim 36, wherein said compositions is used for the treatment of and needs to treat, the patient of prevention or inhibition of pain, inflammation or inflammation related disease, and wherein the dosage of compositions comprises a certain amount of peroxisome proliferation-activated receptors-alfa agonists and a certain amount of cyclo-oxygenase-2 selective depressant or its pharmaceutically acceptable salt or prodrug, and both constitute the treatment or the prevention of inhibition of pain or inflammation together and effectively measure.

39. a Pharmaceutical composition, it comprises peroxisome proliferation-activated receptors-alfa agonists, cyclo-oxygenase-2 selective depressant or its prodrug, and pharmaceutically acceptable excipient.

40. kit that is applicable to treatment, prevention or inhibition of pain, inflammation or inflammation related disease, described kit comprises first dosage form that contains peroxisome proliferation-activated receptors-alfa agonists and second dosage form that contains cyclo-oxygenase-2 selective depressant or its prodrug, and they exist with the amount of the combination of compounds that contains being used for the treatment of of treatment effective dose, prevention or inhibition of pain, inflammation or inflammation related disease.

41. comprising with peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its pharmaceutically acceptable salt or prodrug, a patient treatment for the treatment of like this, preventing or suppress at needs, prevention or suppress cardiovascular disease or disorderly method, this method treat described patient.

42. the method for claim 61, wherein said cyclo-oxygenase-2 selective depressant are selected from celecoxib, weary examine former times, deracoxib, rofecoxib, support and examine former times, parecoxib, chlorine U.S.A and examine former times, SD-8381, ABT-963, BMS-347070 and NS-398.

43. the method for claim 42, wherein said cyclo-oxygenase-2 selective depressant are selected from celecoxib, weary examine former times, deracoxib, rofecoxib, support and examine former times, parecoxib and chlorine U.S.A and examine former times.

44. the method for claim 43, wherein said cyclo-oxygenase-2 selective depressant are selected from celecoxib, weary former times and the parecoxib examined.

45. the method for claim 41, wherein said cyclo-oxygenase-2 selective depressant comprises celecoxib.

46. the method for claim 41, wherein said cardiovascular disease or disorder are selected from coronary artery disease, aneurysm, arteriosclerosis, atherosclerosis, the heart transplantation atherosclerosis, myocardial infarction, thromboembolism, apoplexy, thrombosis, venous thrombosis, angina pectoris (comprising the instability angina pectoris), the coronary pluques inflammation, the inflammation that antibacterial is brought out, the inflammation that chlamydiaceae brings out, viral-induced inflammation, the inflammation relevant with operation process, blood vessel grafting, coronary bypass, revascularization procedure, angioplasty, graft is fixed, endarterectomy and relate to tremulous pulse with other, the inflammation that the invasive surgical of vein and blood capillary is relevant.

47. one kind is used for the treatment of, prevents or suppress cardiovascular disease or disorderly compositions, it comprises peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug.

48. one kind is applicable to treatment, prevention or suppresses cardiovascular disease or disorderly kit, wherein said kit comprises first dosage form that contains peroxisome proliferation-activated receptors-alfa agonists and second dosage form that contains cyclo-oxygenase-2 selective depressant or its prodrug, and they exist with the amount that contains the chemical compound that is used for the treatment of, prevents or suppress angiopathy or disorder for the treatment of effective dose.

49. comprising with peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its pharmaceutically acceptable salt or prodrug, treatment, prevention or suppress method for cancer among the patient who treats like this, prevents or suppress at needs, this method treat described patient.

50. the method for claim 49, wherein said cyclo-oxygenase-2 selective depressant are selected from celecoxib, weary examine former times, deracoxib, rofecoxib, support and examine former times, parecoxib, chlorine U.S.A and examine former times, SD-8381, ABT-963, BMS-347070 and NS-398.

51. the method for claim 50, wherein said cyclo-oxygenase-2 selective depressant are selected from celecoxib, weary examine former times, deracoxib, rofecoxib, support and examine former times, parecoxib and chlorine U.S.A and examine former times.

52. the method for claim 51, wherein said cyclo-oxygenase-2 selective depressant are selected from celecoxib, weary former times and the parecoxib examined.

53. the method for claim 49, wherein said cyclo-oxygenase-2 selective depressant comprises celecoxib.

54. the method for claim 49, wherein said cancer is selected from ND, benign tumor forms, neoplasia in the transfer, malignant tumor forms, acral-lentiginous melanoma, actinic keratosis, adenocarcinoma, adenocystic carcinoma, adenoma, sarcoadenoma, adenoid squamous cell carcinoma, astrocytoma, carcinoma of Bartholin, basal cell carcinoma, breast carcinoma, colon cancer, bronchial adenocarcinoma, blood capillary, carcinoid, cancer, carcinosarcoma, the cavity, cancer of biliary duct, chondrosarcoma, choroid plexus papilloma/cancer, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, the endometrial stroma sarcoma, adenocarcinoma of endometrium, ependymoma, last dermoid tumor, Ewing's sarcoma, the fibrous layer tumor, local knot shape hypertrophy, gastrinoma, germinoma, glioblastoma, glucagonoma, the vascular cell tumor, hemangioendothelioma, hemangioma, adenoma of liver, the adenoma of liver disease, hepatocarcinoma, insuloma, last Intradermal neoplasia, squamous cell neoplasia between epithelium, the wellability squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, malignant lentigo, malignant melanoma, malignant mesothe, medulloblastoma, medulloepithelioma, melanoma, the meninges cancer, carcinoma mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelium adenocarcinoma, nodular melanoma, oat-cell carcinoma, oligodendroglioma, osteosarcoma, pancreas polypeptide tumor, the serious adenocarcinoma of mamillary, pinealocytoma, pituitary tumor, plasmocytoma, false sarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, the serosity cancer, small cell carcinoma, the soft tissue cancer, GHIF secretion tumor, squamous cell carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, the tunica uvea melanoma, verrucous carcinoma, the vasoactive intestinal polypeptide tumor, wall differentiation cancer and dimension Mu Shi tumor.

55. a compositions that is used for the treatment of, prevents or suppress cancer, it comprises peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug.

56. kit that is applicable to treatment, prevention or suppresses cancer, wherein said kit comprises first dosage form that contains peroxisome proliferation-activated receptors-alfa agonists and second dosage form that contains cyclo-oxygenase-2 selective depressant or its prodrug, and they exist with the amount that is used for the treatment of, prevents or suppress the chemical compound of cancer that contains the treatment effective dose.

57. prevention among the patient who prevents like this, treats or suppress at needs, treatment or inhibition are by the disease of the activity inducement of PPAR α or the method for disorder, this method comprises the combination that gives described patient's peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its prodrug, and wherein two kinds of amount of substances constitute the effective dose of combination together.

58. the method for claim 57, wherein disease or the disorder by the activity inducement of PPAR α is selected from hyperglycemia, hyperlipemia, atherosclerosis, the ischemic heart disease, with old and feeble diseases associated, lipid metabolism is unusual, insulin resistance, chronic inflammatory disease, atherosclerotic easy susceptibility, tumor takes place, hepatocarcinoma takes place, atheromatous disease, diabetes, hyperglycemia, obesity, hyperlipemia, hypertriglyceridemia, hypercholesterolemia, the HDL level that raises, atherosclerosis, the blood vessel retinitis, the irritable bowel trace integration is levied, pancreatitis, abdominal obesity, the adipose cell cancer, the adipose cell tumor, liposarcoma, insulin resistance is the disease of the cause of disease, X syndrome, ovarian hyperandrogenism, obesity, tangier's disease, type ii diabetes, angiopathy and skin wound healing.

59. a method for the treatment of, prevent or suppress Alzheimer in the patient of the treatment of this kind of needs, prevention or inhibition, this method comprises with the salt of peroxisome proliferation-activated receptors-alfa agonists and cyclo-oxygenase-2 selective depressant or its pharmaceutically acceptable hands or prodrug treats described patient.