MXPA00012066A - Acetylene derivatives as anti-inflammatory/analgesic agents - Google Patents

Abstract

The present invention relates to compounds of the formula wherein R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, X and Y are defined as in the specification, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the invention are useful in the treatment or alleviation of inflammation and other inflammation associated disorders, such as arthritis, colon cancer, and Alzheimer's disease in mammals, preferably humans, dogs, cats and livestock.

Description

ACETYLENE DERIVATIVES AS ANTI-INFLAMMATORY / ANALYZES AGENTS BACKGROUND OF THE INVENTION This invention relates to acetylene derivatives, treatment methods and pharmaceutical compositions for treatment of diseases mediated by cyclooxygenase. The compounds of this invention inhibit the biosynthesis of prostaglandins by intervening the action of the enzyme cyclooxygenase on arachidonic acid, and therefore are useful in the treatment or alleviation of inflammation, other disorders associated with inflammation, such as arthritis. , neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or cattle. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain and the signs and symptoms of arthritis due to its analgesic and anti-inflammatory activity. It is accepted that common NSAIDs work by blocking the activity of cyclooxygenase (COX), also known as prostaglandin G / H synthetase (PGHS), the enzyme that converts arachidonic acid into prostanoids. Prostaglandins, especially prostaglandin E2 (EPGE2), which is the predominant eicosanoid detected under conditions of inflammation, are mediators of pain, fever and other symptoms associated with inflammation. The inhibition of prostaglandin biosynthesis has been a therapeutic target for the discovery of anti-inflammatory drugs. The therapeutic use of conventional NSAIDs, however, is limited due to the side effects associated with the drug, including ulceration and renal toxicity. An alternative to NSAIDs is the use of corticosteroids; however, long-term therapy can also result in severe side effects. The use of NSAIDs in dogs and cats has been more limited than in humans, eg, only three of said NSAIDs have been approved by the Food and Drug Administration, Committee on Veterinary Medicine (FDA / CVM), for use in dogs in the United States, namely, ETOGESIC® (etolodac), ARQUEL® (meclofenamic acid) and RIMADYL® (carprofen). Consequently, there is less experience and knowledge in veterinary medicine about safety and efficacy issues around the use of NSAIDs in dogs. In veterinary medicine, for example, the most common indication for NSAIDs is the treatment of degenerative joint disease (DJD), which in dogs often results from a variety of developmental diseases, eg, hip dysphasia and osteochondrosis. , as well as a consequence of traumatic injuries to the joints. In addition to the treatment of chronic pain and inflammation, NSAIDs are also useful in dogs for the treatment of postsurgical acute pain, as well as for the treatment of associated clinical signs in osteoarthritis. Two forms of COX are known, a constitutive isoform (COX-1) and an inducible isoform (COX-2) of which expression is upregulated at sites of inflammation (Vane, JR, Mitchell, JA, Appleton, L Tomlinson, A; Bishop-Bailey, D; Croxtoll, J Willoughby, DA Proc. Natl-Acad, Sci. USA, 91, 2046). It is believed that COX-1 plays a physiological role and is responsible for gastrointestinal and renal protection. On the other hand, COX-2 seems to play a pathological role and is believed to be the predominant isoform present in inflammatory conditions. A pathological role for prostaglandins has been implicated in a number of human disease states including rheumatoid arthritis and osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular diseases, dysmenorrhea, preterm labor, nephritis, nephrosis, atherosclerosis, hypotension, shock, pain , cancer, and Alzheimer's disease. It is believed that compounds that selectively inhibit the biosynthesis of prostaglandins by intervening the induction phase of the COX-2 inducible enzyme and / or by intervening the activity of the COX-2 enzyme on arachidonic acid would provide alternates the use of NSAIDs or corticosteroids in that such compounds would exert anti-inflammatory effects without adverse side effects associated with the inhibition of COX-1. A variety of sulfonylbenzene compounds which inhibit COX have been disclosed in patent publications (WO 97/16435, WO / 14691, WO 96/19469, WO 96/36623, WO 96/03392, WO 96/03387, WO 97/727181, WO 96/936617, WO 96/19769, WO 96/08482, WO 95/00501 WO 95/15315, WO 95/155317, WO 95/15318, WO 97/13755, EP 0799523, EP 418845, and EP 554829). Especially important is International Publication No. WO 97/11704, which discloses pyrazole compounds optionally substituted by aryl.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of the formula: where n is one or two: X is CR7 or N; And it is CR8 or N; R1 is alkyl (CrC6) or -NH2; R 2 is hydrogen, halo (more preferably chloro or fluoro, and most preferably fluoro), alkyl (C Cß), alkenyl (C2-Ce), alkynyl (C2-Ce), alkoxy (C2-C6), alkylcarbonyl (C? -C6), formyl, formamidyl, cyano, nitro, -CO2H, alkoxycarbonyl (C? -C6), aminocarbonium, N-alkylaminocarbonyl (Ci-Ce), N, N- [(C? -C6) alkyl] 2-aminocarbonyl, N -alkylcarbonyl (C6-C? o), N, N- [aryl (C6-C? o)] 2-arninocarbonyl, N-alkyl (C? -C6) -N-arylaminocarbonyl (C6-C? o), aryl (Ce-Cι), aryloxy (Cβ-Cι), heteroaryl (C 2 -Cg), heteroaryloxy (C 2 -Cg), morpholinocarbonyl, alkoxycarbonylamino (Ci-Cβ) or alkylcarbonylamino (C 1 -C 9); wherein said R 2 alkyl group (C Cß) can optionally be substituted with one to three substituents independently selected from halo, hydroxyl, alkoxy (Ci-Cß), cyano, nitro, -CO 2 H, alkoxycarbonyl (Cr Cß), aminocarbonyl, N- alkylaminocarbonyl (Ci-Cß), N, N- [(Ci-C6) alkyl] 2-aminocarbonyl, N-arylaminocarbonyl (C6-C? 0), N, N- [aryl (C6-C? o)] 2-aminocarbonyl, N- alkyl (CrC6) -N-arylaminocarbonyl (C6-C? o), aryl (C6-C10), aryloxy (C6-C0), heteroaryl (C2-Cg), heteroaryloxy (C2-Cg), morpholinocarbonyl, alkoxycarbonylamino (C) Cß) or alkylcarbonylamino (Ci-Cß); R3 is hydrogen, halo (more preferably chloro or fluoro, and most preferably fluoro), alkyl (C6-6), alkenyl (C6), alkoxy (Ci-C3), alkylcarbonyl (C6C), formyl, formamidyl , cyano, nitro, -CO2H, alkoxycarbonyl (Ci-Cß), aminocarbonyl, N-alkylaminocarbonyl (C? -C6), N, N- [(C? -C6) alkyl] 2-aminocarbonyl, N-arylaminocarbonyl (C6-) C? O), N, N- [aryl (C6-C? O)] 2a -carbonyl, N -alkyl (C? -C6) -N-arylaminocarbonyl (Ce-Cio), aryl (C6-C10), aryloxy (C6-C? O), heteroaryl (C2-C9), heteroaryloxy (C2-Cg), morpholinocarbonyl, alkoxycarbonylamino (C-C) or alkyl (Ci-Ce-carbonylamino; alkyl (Ci-Cβ) can optionally be substituted with one to three substituents independently selected from halo, hydroxyl, alkoxy (CrCβ), cyano, nitro, -CO 2 H, alkoxycarbonyl (Cr Cβ), aminocarbonyl, N-alkylaminocarbonyl (Ci-Cβ) , N, N- [(Ci-C6) alkyl] 2-arninocarbonyl, N-arylaminocarbonyl (C6-C? O), N, N- [aryl (C6-C? O)] 2-aminocarbonyl, N-alkyl (CrCe) -N -arylaminocarbonyl (C6-C10), aryl (C6-C10), aryloxy, heteroaryl (C2-C9), heteroaryloxy (C2-C9), morpholinocarbonyl, alkoxycarbonylamino or (C6-6) alkylcarbonylamino; R4 is hydrogen, alkyl (CrC6), - (CH2) m-aryl (C6-C? 0), - (CH2) m-heteroaryl (C6-Cg), wherein m is an integer between 0 and 4; - (CH2) m-aryl (Ce-Cio), - (CH2) m-heteroaryl (Ce-Cg), can optionally be substituted with one to three substituents inde variously selected from halo (preferably fluoro or chloro); hydroxyl; mercapto; alkyl (C? -C6); (C -? - C6) alkoxy, optionally substituted with one to three halogen atoms (preferably fluoro); alkenyl (C2-Cß); (C2-C6) alkynyl; cyano; formyl: alkylcarbonyl (CrCß); alkyl (C2-Ce) - (C = O) -O; aminocarbonyl; N-alkylaminocarbonyl (C? -C6); N, N- [alkyl (Cr nitro; amino; alkylamino (C Cβ); [alkyl (CrC6)] 2 amino; or alkyl (C? -C6) -S-; wherein said R4 alkyl group (CrCe) can optionally be substituted with one to three substituents independently selected from halo, hydroxyl, alkoxy (CrCβ), cyano, nitro, alkoxycarbonyl (CrCβ), aminocarbonyl, N- (CrC 6) alkylaminocarbonyl, N, N- [alky (Cr N-arylaminocarbonyl (Ce- Cio), N, N- [aryl (C6-C? O)] 2-aminocarbonyl, N-alkyl (CrCeJ-N-arylaminocarbonyl (C6-C10), aryl (C6-C10), aryloxy (Ce-Cio), heteroaryl ( C2-C9), heteroaryloxy (C2-C9 morpholinocarbonyl, alkoxycarbonylamino (CrCβ), alkyl (CrCβ) carbonylamino or cycloalkylamino (d-Cβ); R is hydrogen, halo (more preferably chloro or fluoro, and most preferably fluoro), alkyl (CrC6), alkenyl (CrC6), (C2-C6) alkyl, alkoxy (Cr6), alkylcarbonyl (CrC3) formyl, formamidyl, cyano, nitro, -CO2H, alkoxycarbonyl (CrCβ) aminocarbonyl, N-alkylaminocarbonyl (CrC6), N, N- [alkyl (CrC6) ] 2-aminocarbonyl, N-arylaminocarbonyl (C6-C? 0), N, N- [aryl (C6-C? O)] 2-aminocarbonyl, N-alkyl (CrC6) -N-arylaminocarbonyl (Ce-Cio), aryl (C6-) C? O), aryl (C6-C o), aryloxy (C6-C? O), heteroaryl (C2-Cg), heteroaryloxy (C2-Cg), morpholinocarbonyl, alkoxycarbonylamino (CrC6) or alkylcarbonylamino (CrC6); wherein said R5 alkyl (CrCß) group can optionally be substituted with one to three substituents independently selected from halo, hydroxyl, akoxy (CrC6), cyano, nitro, -CO2H, alkoxycarboninyl (Cr Ce), aminocarbonyl, N-alkylaminocarbonyl (C Cß), N, N- [alkyl (Cr Ce)] 2-aminocarbonyl, N-arylaminocarbonyl (C6-C10), N, N- [aryl (Cß-C ?o)] 2-aminocarbonyl, N-alkyl (CrCe) -N- arylaminocarbonyl (Ce-Cio), aryl (C6-C? o), aryloxy, heteroaryl (C-Cg), heteroaryloxy (C2-C9), morpholinocarbonyl, alkoxycarbonylamino (CrCβ) or alkyl (CrCβ) carbonylamino; R6 is hydrogen, halo (more preferably chloro or fluoro, and most preferably fluoro), alkyl (CrC6), alkenyl (C2-C6), alkynyl (Cr C6), alkoxy (CrC6), alkylcarbonyl (CrC6), formyl, formamidyl , cyano, -CO2H, alkoxycarbonyl (CrCß), aminocarbonyl, N-alkylaminocarbonyl (Cr Cß), N, N- [(C6-C6) alkyl] 2-aminocarbonyl, N-arylaminocarbonyl (C6-C? o), N, N- [aryl (C6-C? o)] 2-aminocarbonyl, N-alkyl (CrCe) -N-arylaminocarbonyl (C6-Cio), aryl (C6-C? o), aryloxy (C6-C10), heteroaryl (C2) -C8), heteroaryloxy (C2-Cg), morpholinocarbonyl, alkoxycarbonylamino (d-Cß), or alkylcarbonylamino (d-C6); wherein said R6 alkyl (CrCe), which may optionally be substituted with one to three substituents selected from halo, hydroxyl, alkoxy (CrCß), cyano, nitro, -CO2H, alkoxycarbonyl (CrC6), aminocarbonyl, N-alkylaminocarbonyl ( d-Cß), N, N- [alkyl (CrC6)] 2-aminocarbonyl, N-arylaminocarbonyl (C6-C? o), N, N- [aryl (CrC6)] 2-aminocarbonyl, N, N- [aryl (C6 -C? O)] 2-aminocarbonyl, N-alkyl (CrC6) -N-arylaminocarbonyl (C6-C? 0), aryl (C6-C? O), aryloxy (Ce-Cio), heteroaryl (C2-C9), heteroaryloxy (C2-C9), morpholinocarbolino, alkoxycarbonylamino (d-Cß), or alkyl (d-C6) carbonylamino; R7 is hydrogen, halo (preferably fluoro or chloro); hydroxyl; mercapto; alkyl (d-Cß); alkoxy (CrC6) optionally substituted with one to three halogen atoms (preferably fluoro); alkenyl (C2-Ce); (C2-C6) alkynyl; cyano; formyl; alkylcarbonyl (CrCe); alkyl (d-C6) - (C = O) -O-; -CO2H; alkoxycarbonyl (CrC6); aminocarbonyl; N-alkylaminocarbonyl (d-Cß); N, N - [(alkylamino (CrCe)] 2-aminocarbonyl, nitro-amino; alkylamino (Cr Cβ); [alkyl (CrCe)] 2-amino, or alkyl (d-C6) -S-; wherein said R7 alkyl group (d) -Cß) can optionally be substituted by one to three substituents independently selected from halo, hydroxyl, alkoxy (CrC6), cyano, nitro, -CO2H, alkoxycarbonyl (d-Cß), aminocarbonyl, N-alkylaminocarbonyl (CrC6), N, N - [alkyl (Cr C2)] 2-aminocarbonyl, N-arylaminocarbonyl (C6-C0), N, N- [aryl (d-Ce)] 2-aminocarbonyl, N-alkyl (C? -Ce) -N-arylaminocarbonyl (C6-) C? 0), aryl (Cedo), aryloxy (Ce-Cio), heteroaryl (C2-Cg), heteroaryloxy (C2-Cg), morpholinocarbonyl (CrCe) or alkylcarbonylamino (CrC6); R8 is hydrogen; halo (preferably fluoro or chloro), hydroxyl, mercapto, alkyl (CrC6), alkoxy (CrCe) optionally substituted with one to three halogen atoms (preferably fluoro), alkenyl (d-Ce), (C2-C6) alkynyl, cyano, formyl, alkylcarbonyl ( CrC6); alky (CrC6) - (C = O) -O-; -CO H; alkoxycarbon nile (CrC6); aminocarbonyl; N-alkylaminocarbonyl (d-C6); N, N - [(alky (CrCe)] 2 aminocarbonyl, nitro; amino; alkylamino (CrC6); [alkyl (CrC6)] 2 amino, or alkyl (CrC6) -S-; wherein said group R8 alkyl (CrCß) it may optionally be substituted with one to three substituents independently selected from halo, hydroxyl, alkoxy (CrC6), cyano, nitro, -CO2H, alkoxycarbonyl (d-C6), aminocarbonyl, N-alkylaminocarbonyl (d-Cß), N, N- [(C-C2) alkyl] 2-aminocarbonyl, N-arylaminocarbonyl (C6-C? o), N, N- [(C6-C? o) aryl] 2-aminocarbonyl, N-alkyl (CrC6) -N-arylaminocarbonyl (C6-) C? O) arylaminocarbonyl, aryl (Cß-C 0), aryloxy (C6-C? O), heteroaryl (C2-C9), heteroaryloxy (C2-C9), morpholinocarbonyl, alkoxycarbonylamino (d-Cß) or alkyl (CrCe) -carbonylamino, and the pharmaceutically acceptable salts of such compounds The present invention also relates to pharmaceutically acceptable acid addition salts of compounds of the formula I. Acids which are used to prepare the acid addition salts of the above-mentioned base compounds of this invention are those that form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as the salts of hydrochloride, hydrobromide, iodohydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)] salts. The invention also relates to basic addition salts of the formula I. The chemical bases which can be used as reagents for preparing the pharmaceutically acceptable base salts of those compounds of the formula I which are acidic in nature are those which form base salts. non-toxic with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium and magnesium), ammonium, addition salts of water-soluble amines such as N-methylglucamine (meglumine), and the lower alkanoammonium and other pharmaceutically acceptable organic amine base salts. The compounds of this invention include all stereoisomers (examples, cis and trans isomers) and all optical isomers of the compounds of formula I (example, R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers. The compounds of the invention also exist in different tautomeric forms. This invention relates to all tautomers of formula I. The compounds of this invention may contain olefin-type double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. Unless otherwise indicated, the alkyl, referenced herein, as well as the alkyl moieties of other groups referenced herein (eg, alkoxy), may be linear or branched (such as metyl, ethyl, n-propyl, sopropyl , n-butyium, sobutyl, secondary butyl, tertiary butyl), and may also be cyclic (eg, cyclopropyl, or cyclobutyl); optionally substituted by 1 to 3 appropriate substituents as defined below such as fluoro, chloro, trifluoromethyl, alkoxy (d-Cß), aryloxy (C6-C? o), trifluoromethoxy, difluoromethoxy or alkyl (d-Cß). The phrase "each of said alkyl groups", as used herein, refers to any of the above alkyl moieties within a group such as alkoxy, alkenyl or alkylamino. Preferred alkyl groups include alkyl (d-d), more preferably methyl.

Unless otherwise indicated, halogen includes fluoro, chloro, bromo or iodo, or fluoride, chloride, bromide or iodide. As used herein, the term "substituted haloalkyl" refers to an alkyl radical as described above substituted with one or more halogens including, but not limited to, chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2, 2-trichloroethyl, and the like; optionally substituted by 1 to 3 appropriate substituents as defined below such as fluoro, chloro, trifluoromethyl, alkoxy (CrC6), aryloxy (C6-C? o), trifluoromethoxy, difluoromethoxy or alkyl (CrC6). As used herein, the term "alkenyl" means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like, optionally substituted by 1 to 3 appropriate substituents as defined below such as fluoro, chloro, trifluoromethyl, alkoxy (d-Cß), aryloxy (C6) -C? O), trifluoromethoxy, difluoromethoxy or alkyl (CrC6). As used herein, the term "(C2-C6 alkynyl)" is used herein to refer to straight or branched chain radicals of hydrocarbons having a triple bond including, but not limited to, ethynyl, propynyl, butynyl, and the like; optionally substituted by 1 to 3 appropriate substituents as defined below such as fluoro, chloro, trifluoromethyl, alkoxy (d-Cß), aryloxy (Ce-Cio), trifluoromethoxy, difluoromethoxy or alkyl (CrC6).

As used herein, the term "carbonyl" (as used in phrases such as alkylcarbonyl or alkoxycarbonyl) refers to the binding of the > C = O with a second fraction such as an alkyl or amino group (ie, an amido group). The alkoxycarbonylamino refers to an alkylcarbamate group. The carbonyl group is also equivalently defined herein as (C = O). The alkylcarbonyl refers to groups such as acetamide. As used herein, the term "aryl" means aromatic radicals such as phenyl, naphthiio, tetrahydronaphthyl, indanyl and the like; optionally substituted by 1 to 3 appropriate substituents such as defined below as fiuoro, chloro, trifluoromethyl, (CrCe) alkoxy, (C6 ~ C? o) aryloxy, trifluoromethoxy, difluoromethoxy or alkyl (d-Ce). As used herein, the term "heteroaryl" refers to an aromatic heterocyclic group usually with a heteroatom selected from O, S and N in the ring. In addition to said heteroatom, the aromatic group may optionally have up to 4 N atoms in the ring. For example, the heteroaryl group includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolium (example, 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (example 1,2-thiazolyl, , 3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (eg, 1,3-triazolyl, 1,4-triazolyl), oxadiazolyl (exemplol, 2,3-oxadiazolyl), thiadiazolyl (example, 1, 3, 4-thiazolyl), etrazole, quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl and the like; optionally substituted by 1 to 3 appropriate substituents as defined below such as fluoro, chloro, trifluoromethyl, alkoxy (CrC6), aryloxy (C6-C? 0), trifluoromethoxy, difluoromethoxy or alkyl (d-Cß). Particularly preferred heteroaryl groups include pyridinyl, thienyl, furyl, thiazolyl and pyrazolyl (these heteroaryls are most preferred among the heteroaryls R4). "A suitable substituent" is intended to mean a chemically and pharmaceutically acceptable functional group, ie, a moiety that does not negate the inhibitory activity of the inventive compounds. Such appropriate substituents can be routinely selected by those skilled in the art. Illustrative examples of suitable substituents include, but are not limited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, hydroxyl groups, oxo groups, mercapto groups, alkylthio groups, alkoxyl groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkonium groups, aralkoxy groups or heteroaralkoxy, -CO2H groups, amino groups, alkyl and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups, dialkylaminocarbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arisulphonyl groups and the like. One embodiment of the present invention includes compounds of formula I, referred to as the arylsulfonyl group of compounds, wherein X and Y are both carbons. Another embodiment of the present invention includes compounds of the formula I, known as the group of pyridin-2-yl-sulfonyl compounds, wherein X is nitrogen and Y is carbon. Another embodiment of the present invention includes compounds of formula I, known as the group of pyridazin-2-yl-sulfonyl compounds, wherein X and Y are both nitrogen. Another embodiment of the present invention includes compounds of the formula I, known as the group of acetylene compounds, wherein R 4 is hydrogen. Another embodiment of the present invention includes compounds of formula I, known as the group of alkylacetylene compounds, wherein R 4 is alkyl (CrC 6). Another embodiment of the present invention includes compounds of the formula I, known as the group of arylacetylene compounds, wherein R4 is - (CH2) m-aryl (C8-C? O). Another embodiment of the present invention includes compounds of formula I, known as the group of heteroarylacetylene compounds, wherein R 4 is - (CH 2) m-heteroaryl (C 2 -Cg). Subgeneric moieties of the present invention of the group of arylsulfonyl elements are expressly contemplated by the present invention. Such subgeneric moieties with the group of arylsulfonyl compounds include the arylsulfonyl group in combination with each of the R4 groups (ie, acetylene-arylsulfonyl group, alkylacetylene-arylsulfonyl group, arylacetylene-arylsulfonyl group, and heteroarylacetylene-arylsulfonyl group). Subgeneric moieties of the present invention of the group of pyridin-2-yl-sulfonyl compounds are expressly contemplated in the present invention. Such subgeneric embodiments with the group of pyridin-2-yl-sulfonyl compounds include the pyridin-2-yl-sulfonyl group in combination with each of the R4 groups (ie, acetylene-pyridin-2-yl-sulfonyl group, alkylacetylene-pyridin-2-yl-sulfonyl, arylacetylene-pyridin-2-yl-sulfonyl group and heteroaryl-acetylene-pyridin-2-yl-sulfonyl group). Subgeneric moieties of the present invention of the group of pyridin-3-ylsulfonyl compounds are expressly contemplated by the present invention. Such subgeneric moieties within the group of pyridin-3-ylsulfonyl compounds include the pyridin-3-ylsulfonyl group in combination with each of the R4 groups (ie, acetylene-pyridin-3-ylsulfonyl group, alkylacetylene-pyridin-3-yl-sulfonyl, arylacetylene-pyridin-3-yl-suphonyl group and heteroarylacetylene-pyridin-3-ylsulfonyl group). Subgeneric moieties of the present invention of the group of pyridazin-2-ylsulfonyl compounds are expressly contemplated by the present invention. Such subgeneric moieties within the group of pyridazin-2-yl-sulfonyl compounds include the pyridazin-2-yl group in combination with each of the R4 groups (ie, acetylene-pyridazin-2-yl-sulfonyl group, alkylacetylene group). -pyridazin-2-yl-sulfonyl, arylacetylene-pyridazin-2-yl-sulfonyl group and heteroarylacetylene-pyridazin-2-yl-sulfonyl group). Preferred compounds of this invention are those of the formula (I) wherein X is CR7 and Y is nitrogen. Other preferred compounds of this invention are those of the formula (I) wherein X is nitrogen and Y is CR8.

Other preferred compounds of this invention are those of the formula (I) wherein X is CR7 and Y is CR8, more preferably wherein R7 and R8 are each independently selected from hydrogen, (d-C4) alkyl and halogen, more preferably hydrogen and methyl. Other preferred compounds of this invention are those of the formula (I) wherein R 1 is alkyl (CrC 6) (preferably methyl) or -NH 2. Other preferred compounds of this invention are those of the formula (I) wherein R 4 is hydrogen or optionally substituted alkyl (d-Cß), - (CH 2) m-aryl (C 6 -C 6) or - (CH 2) m- heteroaryl (C2-C9). The most preferred compounds are those wherein R4-acetylene is in the para or meta position, more preferably the R4-acetylene group is in the para position. The most preferred R4 groups are hydrogen and alkyl (CrC6). - (CH2) m-aryl (C6-C? O), - (CH2) m-heteroaryl (C2-Cg) optionally substituted are those optionally substituted with zero or a substituent selected from halo (preferably fluoro or chloro); hydroxyl; mercapto; alkyl (CrC6); alkoxy (d-Cß); alkoxy (d-Cß) optionally substituted with 1 to 3 halogen atoms (preferably fluoro); alkenyl (C2-C5); cyano; formyl; alkylcarbonyl (d-Cß); alkyl (CrC6) - (C = 0) -O- and alkoxycarbonyl (CrC6); more preferably between halo (preferably fluoro or chloro); hydroxyl; alkyl (d-Cß) and alkoxy (d-Cß) optionally substituted with 1 to 3 halogen atoms (preferably fluoro); most preferably being halo, alkyl (d-Cß) and alkoxy (d-C6).

Optionally substituted and preferred alkyl groups (CrCe) are those optionally substituted with 1 to 3 substituents (preferably a single substituent) independently selected from halo, hydroxyl, alkoxy (d-Cß), cyano, nitro, -C02H, alkoxycarbonyl (d-C6) ), aryl (Ce-Cio), aryloxy (Ce-Cio), heteroaryl (C2-C9) and heteroaryloxy (CrC6), more preferably halo, hydroxyl, alkoxy (d-Cß) and aryloxy (d-C6), most preferably preferable being halo and alkoxy (CrC6). Other preferred compounds of this invention are those of the formula (I) wherein R5 is H or methyl. Other preferred compounds of this invention are those of the formula (I) wherein R6 is CF3 or CF2H. Other preferred compounds of this invention are those of the formula (I) wherein R3 is hydrogen, halo (more preferably chloro or fluoro, most preferably being fluoro), alkyl (CrC6), alkenyl (CrC6), alkoxy (d-Cß) ), alkylcarbonyl (d-Cß), formyl (d-Cß), formamidyl, cyano, nitro, -CO2H, alkoxycarbonyl (d-Cß), aminocarbonyl, N-alkylaminocarbonyl (CrC6), N, N - [(alkyl (CrC6 )] 2-aminocarbonyl, N-arylaminocarbonyl (CrC6), N, N- [aryl (CrC6)] 2 aminocarbonyl, N-alkyl (CrC6) -N-arylaminocarbonyl (Cr C6), aryl (CrC6), aryloxy (C6-C) 0), heteroaryl (C2-C9), heteroaryloxy (C2-C8), morpholinocarbonyl, alkoxyaminocarbonyl (d-Cß) or alkyl (CrCe) -carbonylamino Examples of preferred compounds of the formula I are the following: 4- [5 - (4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -benzenesulfonamide, 4- [5- (3-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -benzenesulfonamide, - [5- (4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -2-fluoro-benzenesulf namide, 2-aminonosulfonyl-5- [5- (4-ethynyl-phenyl) -3-trifluoromethyl-1-pyrolol-1-yl] -pyridine, 2-aminosulfonyl-5- [ 5- (3-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 2-methylsulfonyl-5- [5- (4-ethynyl-phenyl) -3- trifluoromethyl-pyrazol-1-yl] -pyridine, 5-methylsulfonyl-2- [5- (4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyrid Na, 2-aminosulfonyl-5- [5- (3-ethynyl-4-methoxyphenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 5-methylsulfonyl-2- [5- (4-ethynyl-phenyl) -3 -difluoromethyl-pyrazol-1-yl] -pyridine, 4- [5- (3-ethynyl-4-methoxy-phenyl) -3-dichlorophenol-pyrazol-1-yl] -benzenesulfonamide, 5- (4 -etinyl-phenyl) -3-trifluoromethyl-1- (4-methylsulfonylphenyl) -pyrazol, and 4- (5- (3-ethynyl-phenyl) -3-trifluoromethyl-1- (4-methylsulfonylphenyl) -pyrazol, and - (5- (3-ethynyl-4-methoxy-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -2-fluoro-benzenesulfonamide Other compounds of the formula I include the following: 4- [5- (3-methyl-4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -benzenesulfonamide, 4- [5- (3-fluoro-4-ethynyl-phenyl) -3-trifluoromethyl-p-aceol-1-yl] -benzenesulfonamide, 4- [5- (3-chloro-4-ethynyl-phenyl) -3-trifluoromethyl-pyrrazol-1-yl] -benzenesulfonamide, 5- (3-methyl-4-ethynyl-phenyl) -1- (4-methylsulfonylphenyl) -3-trifluoromethyl-pyrazole, 5- (3 -fluoro-4-ethynyl-phenyl) -1- (4-methylsulfonylphenyl) -3-trifluoromethyl-pyrazole, 5- (3-chloro-4-ethynyl-phenyl) -1- (4-methylsulfonylphenyl) -3-trifluoromethyl- pyrazole, 5-methylsulfonyl-2- [5- (3-methyl-4-ethynyl-phenyl) ~ 3-trifluoromethyl-pyrrazol-1-yl] -pyridine, 5-methylsulfonyl-2- [5 - (3-fluoro-4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 5-methylsulfonyl-2- [5- (3-chloro-4-ethylene-phenyl) - 3-trifluoromethyl-pyrrazol-1-yl] -pyridine, 2-methylsulfonyl-5- [5- (3-methyl-4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyridine , 2-methylsulfonyl-5- [5- (3-chloro-4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 2-methylsulfonyl-5- [5- (3-fluoro-4 -ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 2-aminosulfonyl-5- [5- (3-methyl-4-ethynyl-phenyl) -3-tr ifluoromethyl-pyrazol-1-yl] -pyridine, 2-aminosulfonyl-5- [5- (3-fluoro-4-etyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 2-am N-sulphonyl-5- [5- (3-chloro-4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 5-aminosulfonyl-2- [5- (3-methyl) -4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 5-aminosulfoniI-2- [5- (3-fluoro-4-ethynyl-phenyl) -3-trifluoromethyl-pyrazole-1- il] -pyridine, 5-aminosulfonyl-2- [5- (3-chloro-4-ethynyl-phenyl] -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 5-aminosulfonyl-2- [5- (4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 4- [5- (3-methyl-4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -2-fluoro-benzenesulfonamide, 4- [5- (3-fluoro-4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -2-fluoro-benzenesulfonamide, 5- [3-ethynyl] 4- (1, 3-thiazol-4-yl) -phenyl] -3-trifluoromethyl-1- (4-methylsulfonylphenyl) -pyrazol, 5- [3-ethynyl-4- (furan-2-yl) - phenyl] -3-trifluoromethyl-1- (4-methylsulfonylphenyl) -pyrazol, 5- [3-ethynyl-4- (furan-2-yl) -phenyl] -3-trifluoromethyl-1- (4-aminosul fonylphenyl) -pyrazol 5- [3-ethynyl-4- (1,3-thiazol-4-yl) -phenyl] -3-trifluoromethyl-1 - [2- (5-methylsulfonyl) -pyridyl] -pyrazol, 5- [3-ethynyl-4- (1, 3-tizol-4-yl) -phenyl] -3-trifluoromethyl-1 - [5- (2-methylsulfonyl) -pyridyl] -pyrazine 5- [3- ethynyl-4- (furan-2-yl) phenyl] -3-trifluoromethyl-1- [2- (5-methylsulfonyl) -pyridyl-pyrazole, 5- [3-ethynyl-4- (furan-2-yl) phenyl] -3-trifluoromethyl-1- [5- (2-methylsulfonyl) -pyridyl-pyrazol 5- [3-ethynyl-4- (1,3-thiazol-4-yl) -phenyl] -3-trifluoromethyl-1- [2- (5-aminosu-butyl) -pyridyl] -pyrazol, 5- [3-ethynyl-4- (1,3-thiazol-4-yl) -phenyl] -3-trifluoromethyl-1 - [5-82-aminonosulfonyl) -pyridyl] -p-maleol, 5- [3-ethynyl-4- (furan-2-yl) -phenyl] -3-trifluoromethyl-1- [2 - (5-aminosulfonyl) -pyridyl] -pyrazol, 5- [3-ethynyl-4- (furan-2-yl) -phenyl] -3-trifluoromethyl-1- [5- (2-aminosulfonyl) -pyridyl] - pyrazole, 5- [3-ethynyl-4- (furan-2-yl) -phenyl] -3-trifluoromethyl-pyrazol-1-yl] -2-fluoro-benzenesulfonamide, and 5- [3-ethynyl-4] - (1,3-thiazol-4-yl) -phenyl] -3-trifluoromethyl-pyrazol-1-yl] -2-fluoro-benzenesulfonamide. The present invention also relates to a pharmaceutical composition for the treatment of a condition selected from the group consisting of arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), fever (including rheumatic fever and fever associated with influenza and other viral infections), common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, Organ transplant toxicity, cachexia, allergic reactions, contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin's disease; aplastic anemia, skin cancer and familial adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal injury, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, disease periodontal, bullous epidermolysis, osteoporosis, loosening of artificial joint implants, atherosclerosis (including rupture of atherosclerotic plaque), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, ischemia cerebral, head trauma, spinal cord injury, neuralgia, neurodegenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain (including lower back pain and neck pain) , headache and toothache), gingivitis, cerebral amyloid angiopathy, increased cognition, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, ocular degeneration, conjunctivitis, abnormal healing of wounds, dislocations or muscle or joint strains, tendonitis, disorders of skin (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes (including type I and II diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor invasion, tumor growth, metastasis, corneal scarring, scleritis, immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats), sepsis, preterm labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease, Rickettsial infections ( such as Lyme disease, Eryhchiosis), protozoan diseases (such it is like malaria, giardia, coccidia), reproductive disorders (preferably in cattle) and septic shock in a mammal, preferably a human, cat, cattle, or a dog, comprising an amount of a compound of formula I or a pharmaceutically salt acceptable thereof, effective in such treatment and a pharmaceutically acceptable vehicle.

The present invention also relates to a pharmaceutical composition for the treatment of a disorder or condition that can be treated by selectively inhibiting COX-2 in a mammal, preferably a human, cat, cattle or dog, comprising an effective amount of a compound of selective inhibition of COX-2 of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The present invention also relates to a method for treating a condition selected from the group consisting of arthritis (including osteoarthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), fever (including rheumatic fever and fever associated with influenza and other viral infections), common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, transplant toxicity of organs, cachexia, allergic reactions, contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin's disease; aplastic anemia) , cancer skin and familial adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticuitis, recurrent gastrointestinal injury, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, bullous epidermolysis, osteoporosis, loosening of artificial joint implants, atherosclerosis (including rupture of atherosclerotic plaque), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neurodegenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain (including lower back pain and neck pain, head and toothache), gingivit is, cerebral amyloid angiopathy, increased cognition, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, ocular degeneration, conjunctivitis, abnormal wound healing, muscle or joint dislocations or sprains, tendonitis, skin disorders (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes (including type I and II diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor invasion, tumor growth, metastasis, corneal scarring, scleritis, immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats), sepsis, preterm labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease, Rickettsial infections (such as Lyme disease) , Erlichiosis), protozoan diseases (such as malaria, giardia, coccidia), reproductive disorders (preferably in cattle) and septic shock in a mammal, preferably a human, cat, cattle or a dog, comprising administering to said mammal an amount of a compound of the formula I or a pharmaceutically acceptable salt of the same effective to treat such condition. The present invention also relates to a method for treating a disorder or condition that can be treated or prevented by selectively inhibiting COX-2 in a mammal, preferably a human, cat, cattle or dog, comprising administering to a mammal in need of such treatment of an effective amount of a COX-2 selective inhibiting compound of formula I or a pharmaceutically acceptable salt thereof. This method also relates to a method or a pharmaceutical composition for treating inflammatory diseases and processes comprising the administration of a compound of the formula I of this invention or its salt to a mammal including a human, cat, cattle or dog, wherein said diseases and inflammatory processes are as defined above, and said inhibitory compound is used in combination with one or more therapeutically active agents under the following conditions: A) wherein a joint is seriously inflamed as well as also at the same time by bacteria, fungi, protozoa, and / or viruses, said inhibitory compound is administered in combination with one or more antibiotic, antifungal, antiprotozoal, and / or antiviral therapeutic agents; B) where a multiple treatment for pain and inflammation is desired, said inhibitory compound is administered in combination with inhibitors of other inflammation mediators, comprising one or more elements independently selected from the group consisting essentially of: (1) NSAID's (2) Hi receptor antagonists; (3) antagonists of the quinine receptors Bi and B2; (4) prostaglandin inhibitors selected from the group consisting of the PGD-, PGF-PGI2- receptor antagonists; and PGE; (5) thromboxane A2 inhibitors (AXA2-); (6) inhibitors of 5-, 12- and 15-lipoxygenase; (7) leukotriene inhibitors LTC4-, LTD ^ LTE, and LTB-; (8) PAF receptor antagonists; (9) gold in the form of an aurothio group together with one or more hydrophilic groups; (10) immunosuppressive agents selected from the group consisting of cyclosporin, azathioprine, and methotrexate; (11) anti-inflammatory glucocorticoids; (12) penicillamine; (13) hydroxychloroquine; (14) anti-gout agents including colchicine; xanthine oxidase inhibitors including allopurinol; and uricosuric agents selected from probenecid, sulfinpyrazone, and benzbromarone; C) where older mammals are being treated for disease conditions, syndromes and symptoms found in geriatric mammals, said inhibitory compound is administered in combination with one or more elements independently selected from the group consisting essentially of: (1) cognitive therapeutics to counteract loss and memory deterioration. (2) antihypertensive and other cardiovascular drugs aimed at balancing the consequences of atherosclerosis, hypertension, myocardial ischemia, angina, congestive heart failure, and myocardial infarction, selected from the group consisting of: a. diuretics; b. vasodilators; c. β-adrenergic receptor antagonists; d. angiotensin-II conversion enzyme inhibitors (ACE-inhibitors), alone or optionally together with inhibitors of neutral endopeptidase; and. antagonists of angiotensin-ll receptors; F. renin inhibitors; g. calcium channel blockers; h. sympatholytic agents; i. a2-adrenergic agonists; j. antagonists of a-adrenergic receptors; and k. inhibitors of HMG-CoA reductase (anti-hypercholesterolemic); (3) antineoplastic agents selected from: a. Antimitotic drugs selected from: i. vinca alkaloids selected from: [1] vinblastine, and [2] vincristine; (4) growth hormone secretagogues; (5) strong analgesics; (6) local and systemic anesthetics; and (7) H2 receptor antagonists, proton pump inhibitors, and other gastroprotective agents. The term "treat", as used herein, refers to reversing, alleviating, inhibiting progress, or avoiding the disorder or condition to which that term is applied, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, refers to the act of treating, "treating" as defined immediately before. The term "livestock" as used herein refers to domesticated quadrupeds, including those bred for meat and other by-products, eg, a bovine animal including cattle and other members of the Bos genus, a porcine animal including domestic pigs and other members of the family. genus Sus, an ovine animal including sheep and other members of the genus Ovis, domestic goats and other members of the genus Capra; domesticated quadrupeds being bred for specialized tasks such as use as a beast of burden, eg, an equine animal including domestic horses and other members of the Equidae family, genus Equus, or for search or guard duties, eg, a canine animal including domestic dogs and other members of the genus Canis; and domesticated quadrupeds reared primarily for recreational purposes, eg, members of Equus and Canis, as well as a feline animal including domestic cats and other members of the Felidae family, genus Felis. "Pets" as used here refers to dogs and cats. As used here, the term "dogs" denotes any member of the species Canis famillaris, of which there are a large number of different breeds. Although laboratory determinations of biological activity may have been carried out using a particular breed, it is contemplated that the inhibitory compounds of the present invention will be found useful in treating pain and inflammation in any of these numerous breeds. Dogs represent a particularly preferred class of patients since they are well known to be very susceptible to chronic inflammatory processes such as osteoarthritis and degenerative joint disease, which in dogs often results from a variety of developmental diseases, eg, hip dysphasia and osteochondrosis, as well as from traumatic injuries to the joints. Conventional NSAIDs, if used in canine therapy, have the potential to generate serious adverse gastrointestinal reactions and other adverse reactions including toxicity to the kidneys and liver. Gastrointestinal effects such as simple or multiple ulcerations, including perforation and hemorrhaging of the esophagus, stomach, duodenum or small and large intestine, are usually debilitating, but can often be severe or even fatal. The term "treating reproductive disorders (preferably in cattle)" as used herein refers to the use of the COX-2 inhibitors of the invention in mammals, preferably livestock animals (cows, pigs, sheep, goats or horses) during the estrus cycle to control the moment of the onset of oestrus blocking the uterine signal for lysis of the corpus luteum, that is, prostaglandins of the F-series, then removing the inhibition when the onset of estrus is desired. There are means where it is useful to control or synchronize the moment of estrus, especially when it is going to perform artificial insemination or embryo transfer. Such use also includes increasing the survival rate of embryos in pregnant females. Blocking the release of the F-series prostaglandins may have several beneficial actions including reduction of uterine contractions, increase of uteroplacental blood flow, pregnancy recognition support, and extension of corpus luteum lysis at the time estrus will occur if the animal would not have been pregnant (around day 21 of pregnancy). Such treatment also nullifies the effects of stress on reproduction. For example reductions in fertility caused by excessive heat, negative balance of energy and other stress factors which have a component mediated by COX-2, such as stress-induced abortion such as heat, transport, asinamiento, palpation, infection, etc. Such treatment is also useful to control the moment of delivery, which is accompanied by the release of prostanglandins from the F-series that lead to lysis of the corpus luteum. Inhibition of COX-2 would block the onset of premature labor in livestock animals, allowing breeding time to mature before birth. There are also ways in which controlling the moment of delivery is a useful tool for managing pregnant females. The present invention also includes isotopically labeled compounds, which are identical to those named in formula I, but by the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 3P, 35S, 18F and 36CI, respectively. The compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those in which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug testing and / or distribution of substrate tissues. Tritiated isotopes, namely 3H, and carbon-14, 14C, are particularly preferred for their ease of preparation and detection. In addition, replacement with heavier isotopes such as deuterium, i.e., 2H, may provide certain therapeutic and diagnostic advantages resulting in greater metabolic stability, for example increased half-life in vivo or reduced dosage requirements and, therefore, may be preferred in some circumstances. The isotopically labeled compounds of the formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples and preparations below., replacing an isotopically labeled reagent available with a non-isotopically labeled reagent. This invention also encompasses pharmaceutical compositions containing prodrugs of the compounds of the formula I. This invention also includes methods for treating or preventing disorders that can be treated or prevented by selective inhibition of COX-2 comprising administration of prodrugs of the compounds of the invention. Formula I. Compounds of the formula I having free amino, amido, hydroxyl, carboxylic acid, sulfonamide or carboxylic ester (especially alkyl -S- and alkyl- (S = O) -) groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently linked through peptide bonds or free amino, hydroxyl or acid groups carboxylic acid of compounds of the formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosin, isodemosin, 3-methylhistidine, norvaline, β-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserin, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters are covalently linked to the above substituents of formula I through the side chain of the carbonyl-carbon prodrug. Prodrugs also include metabolically labile groups such as esters, acetates, mercaptans and sulfoxides. One of ordinary skill in the art will appreciate that the compounds of the invention are useful for treating a diverse set of diseases. One of ordinary skill in the art will also appreciate that when the compounds of the invention are used in the treatment of a specific disease, the compounds of the invention can be combined with various existing therapeutic agents used for that disease. For the treatment of rheumatoid arthritis, the compounds of the invention can be combined with agents such as TNF-alpha inhibitors such as anti-TNF monoclonal antibodies and in immunoglobulin molecules of TNF receptors (such as Enbrel, low-dose methotrexate, lefunimide, hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold The compounds of the invention may also be used in combination with existing therapeutic agents for the treatment of osteoarthritis Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents (from here hereinafter NSAIDs) such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors. such as celecoxib and refecoxib, a and intra-articular therapies such as corticosteroids and hyaluronic acids such as hyalgan and sinvisc. The active ingredient of the present invention can be administered in combination with inhibitors of other mediators of inflammation, which comprises one or more members selected from basically the classes of such inhibitors and examples thereof which include metalloproteinase inhibitors. matrix, aggrecanase inhibitors, TACE inhibitors, leukotriene receptor antagonists, inhibitors of the release and processing of IL-1, IL-1 ra, Hi receptor antagonists, quinine receptor antagonists Bi and B; prostaglandin inhibitors such as PGD-, PGF-, PGI2-, and PGE receptor antagonists; thromboxane A2 inhibitors (TXA2-); inhibitors of 5- and 12-lipoxygenase; leukotriene inhibitors LTC4-, LTU ^ LTE, and LTB4; antagonists of two PAF receptors; gold in the form of an aurothio group together with several hydrophilic groups; immunosuppressive agents, eg, cyclosporin, azathioprine, and methotrexan; anti-inflammatory glucocorticoids; penicillamine; hydroxychloroquine; anti-gout agents, eg, colchicine, xanthine oxidase inhibitors, eg, allopurinol, and uricosuric agents, eg, probenecid, sulfinpyrazone, and benzbromarone. The compounds of the present invention may also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, ethopocide, taxol, taxotere, and alkaloids, such as vincristine, and antimetabolites such as methotrexate The compounds of the present invention can also be used in combination with antihypertensive and cardiovascular drugs aimed at balancing the consequences of atherosclerosis, including hypertension, myocardial ischemia including angina, congestive heart failure, and myocardial infarction, selected from vasodilators such as hydralazine, antagonists. of beta-adrenergic receptors such as propanolol, calcium channel blockers such as nifenipine, alpha 2-adrenergic antagonists such as clonidine, alpha-adrenergic receptor antagonists such as prazosin, and HMG-CoA reductase inhibitors ( anti-hypercholesterolemic) such as lovastatin or atorvastatin. The active ingredient of the present invention may also be administered in combination with one or more other antibiotic, antifungal, antiprotozoal, antiviral or therapeutic therapeutics. The compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as L-dopa, requip, mirapex, MAOB inhibitors such as selegine and rasagiline, common inhibitors such such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine antagonists, depamine agonists and neuronal nitric oxide synthetase inhibitors), and anti-Alzheimer's drugs such as donepezil, tacrine, inhibitors of COX-2, propentofilina or metifronato. The compounds of the present invention can also be used in combination with osteroporosis agents such as roloxifene, Iasofoxifene, droloxifene, or fosomax and immunosuppressive agents such as FK-506 and rapamycin. The present invention also relates to the formulation of the active agents of the present invention alone or with one or more therapeutic agents which are to form the desired combination, including wherein said different drugs have variable half lives, creating controlled release forms. of said drugs with different release times achieving relatively uniform dosing; or, in the case of non-human patients, a medicated feed dosage form, wherein said drugs used in the combination are present together in the mixture in said feed composition. In addition, co-administration is provided according to the present invention in which the combination of drugs is achieved by simultaneous administration of said drugs to be given in combination; including coadministration by means of different dosage forms and administration routes; the use of combinations according to different but regular and continuous dosing schedules by which the desired plasma levels of said involved drugs are maintained in the treated patient, even when the individual drugs making up said combination are not being administered to said patient simultaneously.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the formula I can be prepared according to the following reaction and discussion schemes. Unless otherwise indicated, R1 to R8, X and n in the reaction and discussion schemes that follow are as defined above.

SCHEME 1 SCHEME 2 Scheme 1 illustrates an even method of synthesizing compounds of formula I. With reference to scheme 1, a compound of formula I is prepared from a compound of formula II, wherein L 1 is bromine or iodine, by reaction with a trimethylxylyl acetylide of the formula (Me) 3- - Si = R 4 in the presence of a catalyst, a base and a solvent. Palladium is the preferred catalyst (for example, ((CeH5) 3P) Pd or Pd2 (dba) 3), where dba refers to dibenzylidene acetone. A catalytic amount of Cul is usually used for the reaction. Suitable bases include alkyl amines such as triethylamine. Suitable solvents for the aforesaid reaction including acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone, preferably dimethylformamide. This reaction is conveniently carried out between about 20 ° C and 160 ° C, preferably between about 60 ° C and 130 ° C. The compound of the formula II is prepared by the reaction of a compound of the formula III with a compound of the formula (prepared according to the methods of scheme 2 or commercially available or prepared by methods known to those of ordinary skill in the art) under acidic, neutral, or basic conditions preferably in the presence of an acid or the acid salt of the compound of the formula VI in an appropriate solvent. Suitable solvents include alcohols, such as ethanol, methanol, propanol, isopropanol, trifluoromethanol or butanol; dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA) or N, N-methyl-2-pyrrolidone (NMP), preferably an alcohol, most preferably ethanol, trifluoromethanol, or Sopropanol Suitable acids include hydrochloric acid, trifluoroacetic acid, acetic acid, and sulfuric acid. This reaction is generally carried out at a temperature between about 0 ° C and about 140 ° C, is preferred at about the reflux temperature of the polar solvent. The compound of the formula III is prepared from a compound of the formula IV by reaction with a compound of the formula OR II V L- C-R3 where L is a leaving group, in the presence of a base and solvent. Examples of compounds of formula V include ester or ether equivalents such as acylimidazole, dialkylamine and dialkylacetal, preferably ester and acylimidazole. Suitable bases include potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydride (NaH), sodium methoxide, potassium-tert-butoxide, lithium diisopropylamine, pyrrolidinone and piperidine, preferably sodium methoxide, these reactions can are carried out in a solvent such as di (alkyl) ether (preferably dimethyl ether), tetrahydrofuran (THF), methanol, dichloromethane, methyl tert-butyl ether, dimethylformamide (DMF), dimethylacetamide (DMA) or DMSO, preferably dimethoxyethane ( DME). The reaction temperatures may be in the range between about 0 ° C and 150 ° C, preferably between about 20 ° C and about 25 ° C. The compounds of the formula IV are commercially available or can be prepared by methods well known to those with common experience in the state of the art. The compounds of the formula III can be prepared by the method described in Aust. J. Chem. 1977, 30, 229 and Heterocycles. 1990, 31, 1951 and which are incorporated by reference. The pyrazole regio isomeric (la ') can also be prepared from the corresponding 1,3-diketone and heteroarylhydrazine according to other methods well known in the state of the art. Scheme 2 refers to the preparation of compounds of formula VI which are intermediate compounds used in scheme 1. With reference to scheme 2, the compounds of formula VI are prepared from compounds of formula VII by reaction with hydrazine in the presence of a polar solvent. Suitable solvents include alcohols, such as ethanol, methanol, propanol or butanol; methyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA) or N, N-methyl-2-pyrrolidone (NMP), preferably an alcohol, most preferably. This reaction is generally carried out at a temperature between about 0 ° C and about 140 ° C, preferably at about the reflux temperature of the polar solvent. Preferably the product is isolated as a salt, such as a hydrochloride salt.

The compound of the formula VII is prepared from a compound of the formula VIII by the reaction of an oxidizing reagent in the presence of a solvent. Suitable oxidants include meta-chloroperbenzoic acid, hydrogen peroxide, sodium perborate, or Oxone (Oxone is preferred). Suitable solvents or solvent mixtures include methanol-water, dioxane-water, tetrahydrofuran-water, methylene chloride, or chloroform, preferably methanol-water. Suitable temperatures for the aforesaid reaction are in the range between about 0 ° C and about 60 ° C, preferably the temperature can be between about 20 ° C and about 25 ° C (ie, room temperature). The reaction is complete between about 0.5 and 24 hours, preferably about 16 hours. The compound of the formula VIII is prepared from a compound of the formula IX by reaction with a methyl disulfide or alkylthiosulfonate of the formula R1S-L, wherein L is alkylthio or methyl sulfonate, in the presence or absence of a base in a polar solvent. Suitable bases include, alkyl lithium such as n-butyllithium, and suitable solvents include ether, benzene and THF. This reaction is generally carried out at a temperature between -78 ° C and 0 ° C for about 1 to 8 hours. Unless otherwise indicated, the pressure of each of the above reactions is not critical. Generally, the reactions will be carried out at a pressure between one and three atmospheres approximately. Preferably at ambient pressure (approximately one atmosphere). The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various organic and inorganic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of formula I from the reaction mixture as a pharmaceutically acceptable salt and then simply convert the latter to a basic compound. free by treatment with an alkaline reagent, and subsequently converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the compound with a base with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in an appropriate organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid is obtained. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, ie, salts containing pharmaceutically acceptable anions, such as hydrochloride salts, hydrobromide, acid, acetate, lactate, citrate or citrate acid, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [ie 1-1'- methylene.bis- (2-hydroxy-3-naphthoate)]. Those compounds of formula I which are also acidic in nature, for example, wherein R2, R4 and R5 or R6 include a -COOH, tetrazole or other acidic fraction are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal salts or alkaline earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents for preparing the pharmaceutically acceptable basic salts of this invention are those which form non-toxic basic salts with the acidic compounds described herein of the formula I. These non-toxic basic salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, these can also be prepared by mixing lower alkanolic solutions of the acidic compounds with the alkali metal alkoxide, and then evaporating the remaining solution to dryness in the same manner as above. In either case, the stoichiometric amounts of the reagents are preferably employed with the aim of ensuring the integrity of the reaction and maximum yield of the product.METHOD FOR EVALUATING BIOLOGICAL ACTIVITIES The activity of the compounds of the formula (I) of the present invention was shown by the following tests.

In vitro assays Human cell-based COX-1 assay Human peripheral blood obtained from healthy volunteers was diluted 1/10 with a 3.8% sodium citrate solution. The immediate platelet-rich plasma obtained was washed with 0.14 M sodium chloride containing 12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA. The platelets were then washed with platelet buffer (Hanks buffer (without calcium) containing 0.2% BSA and 20 mM Hepes). Finally, washed human platelets (HWP) were suspended in the platelet buffer at the concentration of 2.85 x 108 cells / ml and washed at room temperature until use. The suspension of HWP (aliquots of 70 μl, 2.0 x 107 cells / ml) was placed in a 96-well plate with U-bottom and aliquots of 10 μm of 12.6 mM calcium chloride were added. The platelets were incubated with A23187 (final 10 μM, Sigma) with the test compound (0.1-100 μM) dissolved in DMSO (final concentration, less than 0.01%) at 37 ° C for 15 minutes. The reaction was stopped by the addition of EDTA (final 7.7 mM) and TxB2 in the quantified supernatant by the use of a radioimmunoassay kit (Amersham) according to the manufacturer's procedure.

COX-2 Assay Based on Human Cells The COX-2 assay based on human cells was carried out or as previously described (Moore, Inflam. Res., 45. 54, 1996). Endothelial cells from the confluent human umbilical vein (HUVECs, Morinaga) in a 36 well plate with flat bottom were washed with 80 ml of RPM1640 containing 2% FBS and incubated with hIL-1beta (final concentration 300 U / ml, R & amp; amp;; D Systems) at 37 ° C for 24 hours. After washing, the activated HUVECs were incubated with the test compound (final concentration, 0.1 nM-1uM) dissolved in DMSO (final concentration, less than 0.01%) at 37 ° C for 20 minutes and stimulated with A23187 (final concentration 30 mM) in Hanks buffer containing 0.2% BSA, 20 mM Hepes at 37 ° C for 15 minutes, 6-Keto-PFG, stable metabolite of FGIZ. In the supernatant, they were quantified using the radioimmunoassay method (antibody, mandatory diagnosis, SPA, Arnetrsham).

Canine in vitro tests The following canine-based COX-1 and COX-2 assays have been reported in Ricketts, Inhibition Evaluation Selective Canine Cyclooxyguase 1 and 2 using Carprofen and other non-steroidal anti-inflammatory drugs, American Journal of Research Veterinary, 59 (11), 1441-1446.

Protocol for the evaluation of canine COX-1 activity The test drug compounds were solubilized and diluted the day before the test with 0.1 ml of DMSO / 9.9 ml of Hank's balanced salt solution (HBSS), and stored overnight at 4 ° C. On the day of the trial, coded blood was drawn from a donor dog, centrifuged at 190 x g for 25 minutes at room temperature, and the resulting rich plasma in packs was then transferred to a new tube for further procedures. The packets were washed by centrifugation at 1500 x g for ten minutes at room temperature. The platelets were washed with platelet buffer comprising Hank buffer (calcium free) with 0.2% bovine serum albumin (BSA) and 20 nM HEPES. The platelet samples were then adjusted to 1.5 x 10 7 / MI, after which 50 μl of calcium ionophore (A23187) was added together with the calcium chloride solution to 50 μl of dilution of the test drug compound in plates to produce the final concentrations of 1.7 μM A23187 and 1.26 mM Ca. Then, 100 μL of canine platelets were added and the samples were incubated at 37 ° C for 15 minutes, after which the reaction was stopped by adding 20 μL of 77 mM EDTA. The plates were then centrifuged at 2000 x g for 10 minutes at 4 ° C, after which 50 μl of supernatant was assayed for thromboxane B2 (TXB2) by enzyme immunoassay (ElA). The pg / ml of TBX2 was calculated from the standard line included on each plate, from which it was possible to calculate the percentage of inhibition of COX-1 and the IC50 values for the compounds of the test drug.

Protocol for the evaluation of canine COX-2 activity A canine histocytoma cell line (macrophage type) from the American-type culture collection designated as DH82 was used to configure the protocol to evaluate COX-inhibition activity. 2 of several test drug compounds. 10 μg / ml of LPS were added to these cells, after which the cultures were incubated overnight. The same dilutions of the test drug compounds as described above for the COX-1 protocol were used for the COX-2 assay and were prepared the day before the assay was performed. Cells were harvested from culture vessels by scraping, and then washed with minimal Eagle's medium (MEM) combined with 1% fetal bovine serum, centrifuged at 1500 rpm for two minutes, and adjusted to a concentration of 3.2 x. 105 cells / ml.

To 50 μl of dilution of the test drug was also added μl of the cell suspension to give a final concentration of 1.6 x 10 5 cells / ml. The test sample suspensions were incubated for 1 hour and then centrifuged at 1000 rpm for 10 minutes at 4 ° C, after which aliquots of 50 μl of each test drug sample were released onto the ElA plates. The ElA was performed to determine prostaglandin E2 (PGE2), and the pg / ml concentration of PGE2 was calculated from the standard line included on each plate. From these data it was possible to calculate the percentage inhibition of COX-2 and the IC50 values for the test drug compounds. Repeated investigations of inhibition of COX-1 were made over the course of several months. The results are averaged, and a simple proportion of COX-1: COX2 is calculated. Complete blood tests for COX-1 and COSX-2 are known in the state of the art such as the methods described in C. Brideau, A Complete Human Blood Test for Clinical Evaluation of Biochemical Efficacy of Cyclooxygenase Inhibitors, Research of Inflammation, Vol. 45, pp. 68-79 (1996). These methods can be applied with feline, canine or human blood as needed.

In vivo assays Carrageenan induced foot edema in rats Sprague-Dawley male rats (5 weeks old, Charles River Japan) were fasted overnight. It was extracted to a line using a marker above the ankle on the right hind paw and the volume of the paw (VO) was measured by water displacement using a plethysmometer (Muromachi). The animals were orally given a vehicle (0.1% methyl cellulose or 50% Tween 80) or a test compound (2.5 ml per 100 g body weight). One hour later, the animals were injected intradermally with? carrageenan (0.1 ml of 1% w / v suspension in saline, Zushikagaku) in the right hind paw (Winter, Proc. Soc. Exp. Biol. Med. 111, 544, 1962; Lombardino, Arzneim. Forsch., 25, 1629, 1975) and three hours later, the volume of the paw (V3) was measured and the increase in volume (V3-V0) was calculated. Since the maximum inhibition obtainable with classical NSAIDs is 60-70%, the ED30 values were calculated.

Gastric ulceration in rats Gastric ulcerogenicity of the test compound was evaluated by a modification of the conventional method (Ezer, J.

Pharm. Pharmacol., 28, 655, 1976; Cashin., J. Pharm. Pharmacol., 29, 330-336, 1977). Male Sprague-Dawley rats (5 weeks old, Charles River Japan), fasted overnight, were orally given a vehicle (0.1% methyl cellulose or 5% Tween 80) or a compound of test (1 ml per 100 g of body weight). Six hours later, the animals were sacrificed by cervical dislocation. The stomachs were removed and inflated with 1% formalin solution (10 ml). Stomachs were opened by cutting along the greater curvature. The incidence of ulceration was calculated from the number of rats that showed at least one gastric ulcer or hemorrhagic erosion (including acchimosis). The animals did not have access to food or water during the experiment.

Ex VO determinations of canine whole blood of COX-1 and COX-2 activity inhibition The inhibitory potency in vivo of a test compound against COX-1 and COX-2 can be evaluated using an ex vivo procedure on canine whole blood . Three dogs were sacrificed dosed with 5 mg / kg of test compound administered by 0.5% methylcellulose vehicle priming and three dogs were not treated. A blood sample at zero hour was collected from all the dogs in the study before dosing, followed by collections of blood samples at 2 and 8 hours after dosing. The test tubes were prepared containing 2 μL of (A) calcium ionophore A23187 giving a final concentration of 50 μM, which stimulates the production of thromboxane B2 (TXB2) for determination of the activity of COX-1; or from (B) lipopolysaccharide (LPS) to give a final concentration of 10 μg / ml, which stimulates the production of prostaglandin E2 (PEG2) for determination of COX-2 activity. Test tubes with unstimulated vehicle were used as controls. A blood sample of 500 μL was added to each of the test tubes described above, after which they were incubated at 37 ° C for one hour in the case of test tubes containing calcium ionophore, and throughout the night in the case of test tubes containing LPS. After incubation, 10 μL of EDTA was added to give a final concentration of 0.3% for the purpose of preventing plasma coagulation which sometimes occurs after liquefying frozen plasma samples. The incubated samples were centrifuged at 4 ° C and the resulting plasma sample of 200 μL was collected and stored at -20 ° C in 96-well polypropylene plates. In order to complete the end points for this study, enzyme immunoassay kits (ElA) available from Cayman were used to measure the production of TXB and PGE2, using the competitive competitor binding principle with antibody and the determination of endpoint by colorimetry The plasma samples were diluted to approximate the range of standard quantities that would be supplied in a diagnostic or research tool kit, ie. 1/500 for TXB2 and 1/750 for PGE2. The data presented in Table 2 show how the percentage inhibition of COX-1 and COX-2 activity is calculated based on their zero-hour values. The data are expressed as averages of treatment groups in pg / ml of TXB2 and PGE2 produced by the sample. The plasma dilution was not included in said data values. The data in Table 2 shows that, in this illustration, at the 5 mg / kg dose there was significant inhibition of COX-2 at both time points. The data in Table 2 also show that at the 5 mg / kg dose there was no significant inhibition of COX-1 activity at the time points involved. Therefore, the data in Table 2 clearly demonstrate that in the dosage concentration of 5 mg / kg this compound possesses good COX-2 selectivity.

TABLE 2 The inhibition of COX is observed when the percentage of measured inhibition is higher than that measured for untreated controls. The percentage of inhibition in the previous table is calculated in a direct way according to the following equation:% inhibition (2 hours) = (PGE at t = 0) - (PGE2 at t = 2) / (PGE at t = 0) Data analysis Statistical software packages were used to Macintosh, SYSTAT (SYSTAT, INC.) And StatView (Abacus Concepts, Inc.) Differences between the treated group of the test compound and the control group were tested using ANOVA. The IC50 values (ED30) were calculated from the equation for the logarithmic linear regression line of concentration (dose) vs percentage of inhibition. Most of the compounds prepared in the working examples described hereinafter were tested by means of at least one of the methods described above, and showed IC50 values of 0.001 μM to 3 μM with respect to the inhibition of COX-2 e? canine or human trials. The selectivity of COX-2 can be determined by the ratio in terms of IC50 value of inhibition of COX-1 to inhibition of COX-2. In general, it can be said that a compound showing a COX-2 / COX-1 inhibition ratio greater than 5 has a good COX-2 selectivity. The compounds of the formula (I) of this invention can be administered through oral, parenteral, anal, buccal, or topical routes to mammals (including humans, dogs, cats, horses, and cattle).

In general, these compounds are preferably administered to humans in doses in the range between 0.01 mg and 100 mg per kg of body weight per day, although variations will necessarily occur depending on the weight, sex and condition of the subject treated, the condition of the disease treated and the particular route of administration chosen. However, a dosage level that is in the range between 0.1 mg and 10 mg of body weight per day, of single or divided dosage is more preferably used in humans for the treatment of the aforementioned diseases. These compounds are most desirably administered to said non-human mammals, such as, for example, dogs, cats, horses or cattle in an amount, expressed as mg per kg of body weight of said member per day, in a range between 0.01 mg. / kg approximately 20.0 mg / kg / day, preferably between 0.1 mg / kg approximately 12.0 mg / kg / day, more preferably between 0.5 mg / kg and approximately 10.0 mg / kg / day, and most preferably between 0.5 mg / kg. kg and 8.0 mg / kg / day approximately. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the foregoing routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, ie they can be combined with several inert pharmaceutically acceptable carriers in the form of tablets, capsules, lozenges, troches, candies, powders, sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such vehicles include solid fillers or diluents, sterile aqueous media, and various non-toxic organic solvents, etc. In addition, the oral pharmaceutical compositions may be appropriately sweetened and / or flavored. In general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels in the range between 5% and 70% by weight, preferably between 10% and 50% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine can be used together with various disintegrants such as starch and preferably corn starch, potato or tapioca, alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type can also be used as fillers in gelatin capsules; Preferred materials in this connection also include lactose or lactin as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if desired, emulsifying and / or suspending agents as well, together with such diluents. as water, ethanol, propylene glycol, glycerin and various compositions thereof. A preferred composition for dogs comprises an ingestible liquid peroral dosage form selected from the group consisting of a solution, suspension, emulsion, inverse emulsion, elixir, extract, tincture, and concentrate, optionally to be added to the drinking water of the treated dog. Any of these liquid dosage forms, when formulated according to methods well known in the art, can be administered directly to the treated dog, or they can be added to the drinking water of the treated dog. The concentrated liquid form, on the other hand, is formulated to be first added to a given amount of water, from which an amount of aliquot can be extracted for direct administration to the dog or in addition to the drinking water of the dog. A preferred composition provided delayed, sustained, and / or controlled release of said selective COX-2 antiinflammatory inhibitor. Such preferred compositions include all these dosage forms which produces >; 80% inhibition of COX-2 isoenzyme activity and produce a plasma concentration of said inhibitor of at least three times IC50 of COX-2 for at least four hours; preferably for at least 8 hours; more preferably for at least 12 hours; even more preferably for at least 16 hours; even more preferably for at least 20 hours; and most preferably for at least 24 hours. Preferably, those which produce > are included within the dosage forms described above; 80% inhibition of COX-2 isoenzyme activity and produce a plasma concentration of inhibitor of at least 5 times IC50 of COX-2 for at least four hours, preferably for at least 8 hours, more preferably for at least 12 hours hours, even more preferably for at least 20 hours, and most preferably for at least 24 hours. More preferably, the above-described dosage forms which produce > 90% inhibition of COX-2 isoenzyme activity results in a plasma concentration of said inhibitor of at least 5 times IC50 of COX-2 for at least four hours, preferably for at least 8 hours, more preferably for at least 12 hours hours, even more preferably for at least 20 hours, most preferably for at least 24 hours. For parenteral administration, solutions of a compound of the present invention may be employed in sesame oil or peanut or in aqueous propylene glycol. The aqueous solutions should be appropriately buffered (preferably pH> 8) if necessary and the liquid diluent first rendered sotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular, subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this can preferably be done by creams, jellies, gels, pastes, ointments and the like, according to standard pharmaceutical practice. The compounds of the formula (I) can also be administered in the form of suppositories for rectal or vaginal administration of active ingredient. These compounds can be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at room temperature (e.g., 10 ° C to 32 ° C) but liquid at rectal temperature melts in the rectum or vagina to release the active ingredient . Such materials are polyethylene glycols, cocoa butter, suppository and wax. For buccal administration, the composition can take the form of tablets or lozenges formulated in conventional manner. For transdermal administration, transdermal patches prepared according to well known drug release technology, can be prepared and applied to the mammalian skin, preferably a human or a dog, to be treated, where the active ingredient by reason of its characteristics of Formulated solubility migrates through the epidermis and into the dermal layers of the skin where it is absorbed as part of the general circulation, eventually providing systemic distribution of the active ingredient over an extended and desired period of time. Also included are the implants which are placed under the epidermal layer of the skin, that is, between the epidermis and the dermis of the skin of the treated patient. Such an implant will be formulated according to well-known principles and materials commonly used in this delivery technology, and may be prepared in such a manner as to provide controlled, sustained, and / or delayed release of the active ingredient in the systemic circulation of the patient. Such subepidermal (subcuticular) implants provide the same ease of installation and release efficiency as transdermal patches, but without the limitation of being subjected to degradation, damage or accidental removal as a consequence of being exposed on the upper layer of the patient's skin.

EXAMPLES The following examples contain detailed descriptions of the methods of preparation of the compounds of the formula (I). These detailed descriptions fall within the scope of the invention and serve to exemplify the general synthetic methods described above which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended to restrict the scope of the present invention. The invention is illustrated in the following non-limiting examples in which, unless otherwise stated; all operations were carried out at room temperature, that is, in the range of 18-25 ° C; the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure with a bath up to 60 ° C; the reactions were monitored by thin layer chromatography (tic) and the reaction times are given for illustration only; the given melting points (m.p.) are not corrected (the polymorphism can produce different melting points); the structure and purity of all isolated compounds were ensured by at least one of the following techniques: tic (plates precoated with Merck 60 F-254 silica gel), mass spectrometry, nuclear magnetic resonance (NMR), infrared spectroscopy (IR) ). The IR data was obtained on an FTIR 8200 (SHIMAZU spectrometer). The returns are given for illustrative purposes only. Flash column chromatography was carried out using silica gel 60 (mesh size 230-400 ASTM). The low resolution mass spectral data (El) were obtained on a Automass 120 mass spectrometer (JEOL). The liquid chromatography data was collected on a Liquid Chromatography / Hewlett Packard 1100 mass selective detector (LC / MSD). The analysis was performed on a Luna C-18 column with dimensions of 3.0x150 mm. The flow rate was 0.425 ml / min running at a 50% gradient of 0.1% aqueous formic acid and 50% acetonitrile to 100% acetonitrile in 15 minutes. The ionization type for the mass spectrometer mass detector was atmospheric pressure electroatomization in the positive ion mode with a 50 volt shredder voltage. NMR data were determined at 270 MHz (JEOL JNM-LA spectrometer) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unless otherwise indicated, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); Conventional abbreviations used are: s = simple, d = doublet, t = triplet, q = quadruple, m = multiple, br. = width, etc. The following abbreviations are used: THF: tetrahydrofuran CH2CI2: dichloromethane NaHCO3: sodium bicarbonate HCl: hydrogen chloride MgSO4: magnesium sulfate Na SO4: sodium sulfate DME: dimethoxyethane n-BuLi: n-butylithium DMF: dimethylformamide EXAMPLE 1 5- Mßt¡lsulfonil-2-r5- (4-acetHenylphenyl) -3-trifluoromethyl-1 H-pyrazole-1-pyridine Step 1: 5-Methylsulfonyl-2- [5- (4-acetylenylphenyl) -3-trifluoromethyl-1 H -pyrazol-1-illpyridine 4,4,4-Trifluoro-1- (4-bromophenyl) 1,3-butanedione (600 mg) (prepared according to the method of Thjomas D. Penning, J. Med. Chem., 1997, 40, 1347-1365.) And 2-hydrazino-5- (methylsulfonyl) pyridine hydrochloride (420 mg) were mixed with ethanol (40 ml), and the resulting solution was refluxed for 3 days. Upon cooling, white precipitates emerged. The white precipitates were collected by filtration and purified by flash chromatography using 70:30 methylene chloride and hexane to yield the title compound (450 mg).

Step 2: 5-Methylsulfonyl-2- [5- (4-acetylenyl-pheny] -3-trifluoromethyl-1 H -pyrazole-1-pyridine 5-methylsulfonyl-2- [5- (4-bromophenyl) -3 -trifluoromethyl-1 H-pyrazol-1-ylpyridine (230 mg). Cul (5 mg), Pd (PPh3) 4 (30 mg) were mixed in triethylamine (2.5 ml), followed by the addition of trimethylsilyl acetylene (0.182 ml), and the reaction mixture was heated at 80 ° C for 2 hours. hours. TLC in 1: 1 ethyl acetate / hexane showed complete conversion of the initial material to the product. The solvent was removed under vacuum to produce the crude product.

This crude material was then dissolved in methanol (2.5 ml), followed by the addition of potassium carbonate (20 mg). The reaction mixture was stirred at room temperature for 30 minutes. After filtration, the solvent was removed in vacuo to give the crude product which was purified by flash chromatography using 70:30 methylene chloride / hexane to yield the title compound (41 mg). The following examples were prepared by a procedure analogous to that of Example 1, except where indicated. 70 EXAMPLE 14 5- (4-Ethylphenyl) -1-r4- (methylsulfonyl) phenyl-3- (trifluoromethyl) -1H-pyrazole Step 1: 5- (4-Bromophenyl) -1- [4-methylsulfonyl] pheny1-3- (trifluoromethyl) -1H-pyrazole. A mixture of 1- (4-bromophenyl) -4,4,4-trifluoro-1,3-butanedione (890 mg, 3.0 mmol, Jones, John RJ Chem. Soc. Perkin Trans. 2. 11, 1231 ( 1975)) and 4-methylsulfonylhydrazine hydrochloride (735 mg, 3.3 mmol, S. Akol, Eur. J. Med. Chem. Chim. Ther .. 223 (1984)) in ethanol (15 ml) was heated to reflux temperature. for 5 hours. The mixture was concentrated and ethyl acetate (50 ml) was added and washed with water, brine and dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography, eluted with ethyl acetate / hexane (1: 4) to yield the title compound (1.3 g, amount). H-NMR (CDCl 3) d 7.97 (d, J = 8.9 Hz, 2H), 7.55-7.51 (m, 4H), 7.11 (d, J = 8.9 Hz, 2H), 6.80 (s, 1 H), 3.08 ( s, 3H).

Step 2: 1-r 4 - (methylsulfonyl) -phenyl-3- (trifluoromethyl) -5- [4-r (trimethylsilyllethenphen-1 H-pyrazole.) To a mixture of 5- (4-bromophenyl) -1- [ 4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -l H-pyrazole (670 mg, 1.5 mmol), from step 1), triethylamine (10 ml) and dimethylformamide (2 ml), copper iodide (15 ml) was added. mg, 0.08 mmol), bis (triethylphosphine) palladium (II) chloride (105 mg, 0.15 mmol) and (triethylsilyl) acetylene (221 mg, 2.25 mmol) at room temperature. The mixture was stirred for 4 h at room temperature and concentrated. The concentrate was diluted with water (30 ml) and extracted with ethyl acetate (20 ml x 3), dried (MgSO) and concentrated in vacuo. The residue was ethyl acetate / hexane (1: 4) to yield the title compound (353 mg, 52%). 1 H-NMR (CDCl 3) d 7.84 (d, J = 8.7 Hz, 2 H), 7.51 (d, J = 8.7 Hz, 2 H), 7.46 (d, J = 8.6 Hz, 2 H), 7.18 (d, J = 8.6 Hz, 2H), 6.80 (s, 1H), 3.06 (s, 3H), 0.25 (s, 9H).

Step 3: 5- (4-ethynylphenyl) -1 - [4- (methylsulfonyl) phen.p-3- (trifluoromethyl-1H-pyrazole) A mixture of 1- (4-methylsulfonyl] -3- (trifluoromethyl) - 5- [4 - [(Trimethylsilyl) ethyl] phenyl] -1H-pyrazol (345 mg, 0.77 mmol, from step 3) and potassium carbonate (530 mg, 3.8 mmol) in methanol (10 ml) was stirred for 4 hours. The mixture was concentrated and water (30 ml) was added and it was extracted with ether (20 ml x 3), dried (MgSO) and concentrated in vacuo, the residue was purified by flash chromatography, eluted with ethyl acetate. ethyl / hexane (1: 3) to yield the solid bank The solid was washed with hexane to yield the title compound (216 mg, 72%). 1 H-NMR (CDCl 3) d 7.96 (d, J = 8.6 Hz, 2H ), 7.55-7.49 (m, 4H), 7.20 (d, J = 8.2 Hz, 2H), 6.81 (s, 1 H), 3.19 (s, 1 H), 3.08 (s, 3H). Calculated for C19H13N2O2F3S: C, 58.4; H, 3.36; N, 7.18, Found: C, 58.73; H, 365; N, 6.93 The following components were prepared using HSS techniques.

EXAMPLE 15 1-r4- (Methylsulfonyl) phenin-5-r4- (phenylethynyl) phenin-3-trifluoromethyl-1H-pyridol To a stirred solution of 1- [4- (methylsulfonyl) phenyl] -5- [4-bromophenyl] -3-trifluoromethyl-1 H-pyrazole (445 mg, 1 mmol) and phenylacetylene (102 mg, 1 mmol) in pyrrolidine (2 ml) was added tetrakis (triphenylphosphine) palladium (35 mg) under a nitrogen atmosphere, and the mixture was heated at 80 ° C for 1 hour. After cooling, the volatilities were removed by evaporation. The residue was purified by flash chromatography (S02), eluted with ethyl acetate / hexane (1: 3) to yield the title compound (0.4 g, 86% yield). Melting point: 170-172 ° C, MS (El): 466 (M *) EXAMPLE 16 5-l4- (1 -hexin-1-yl) pheny1-1-r4- (methylsulfonyl) phenyl1-3-trifluoromethyl-1 H-pyrazole The title compound was prepared according to the procedure of Example 15 using 1-hexin in exchange for phenylacetylene. Melting point: 96-98 ° C, MS (El): 446 (M *) EXAMPLE 17 5-r4- (5-Hydroxy-1 -pentin-1-yl) -phenyl-1-r4- (methylsulfonyl) -phenip-3-trifluoromethyl-1H-pyrazole The title compound was prepared according to the procedure of Example 1 using 4-pentin-1-ol in exchange for phenylacetylene. Melting point: 97-90 ° C, MS (El): 448 (M *) 74 EXAMPLE 18 5-r4- (3-hydroxy-1-propin-1-yl) phen.p-1 -r4- (methylsulfoni) P-3-trifluoromethyl-1 H-pyrazole The title compound was prepared according to the procedure of Example 1 using propargyl alcohol in exchange for phenylacetylene. MS (El): 420 (M *) EXAMPLE 19 5-r4- (3-methoxy-1-propin-1 -i-Phenill-1-r4- (methylsulfonyl) phenyl-1-3-trifluorornethyl-1H-pyrazole The title compound was prepared according to the procedure of Example 1 using phenyl-acetylene methylpropargyl ether. MS (El): 434 (M *) EXAMPLE 20 5-l4- (3- (pyrrolidin-1-yl) -1-propyl-1-iH-enylM-r4- (methylsulfonyl) -pheniphenin-3-trifluoromethyl-1H-pyrazole The title compound was prepared according to the procedure of Example 1 using propargyl bromide in exchange for phenylacetylene. MS (El): 473 (M *) 75 1 H-NMR (CDCl 3) d; 7.95 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.79 ( s, 1H), 3.64 (s, 2H), 3.07 (s, 3), 2.72-2.65 (m, 4H), 1.88-1.82 (m, 4H).

EXAMPLE 21 5-r4- (2- (2-pyridyl) Ttin-1 -n-phenffl-1 -r4- (methylsulfonyl) phen.p-3-trifluoromethyl-1H-pyrazole The title compound was prepared according to the procedure of Example 1 using 2-pyridylacetylene instead of phenylacetylene. MS (El): 467 (M *) PREPARATION 1 Preparation of 3-pyridyl hydrazines Step 1: 3-nitro-6 - (methylto) pyridine 2-mercapto-5-nitro pyridine (20.0 g, 128 mmol) was suspended in water / ethanol (43 ml / 13 ml). Sodium carbonate monohydrate (17.49 g, 141 mmol), dissolved in 86 ml of the above mixture was added and the mixture was stirred at room temperature for 1 hour. The solid was filtered and washed with water and ethanol to deliver the title compound in quantitative production.

Step 2: 3-Nitro-6- (methylsulfonyl) pyridine 3-nitro-6- (methylthio) pyridine (22.0 g, 129.3 mmol) was dissolved in acetone (140 ml). Sulfuric acid (2N, 230 ml) was added dropwise to the above solution to form a watery slurry. Potassium permanganate (KmnO) (26.5 g, 168.1 mmol, dissolved in 500 mL of H O) was added to the above mixture by drip. The resulting mixture was stirred at room temperature overnight. The solid was filtered and stirred with a hot mixture of ethanol / methanol (10/1). The insoluble salt was filtered, the filtrate was concentrated to give a pale yellow solid. The crude product was recrystallized from ethanol to replace the title compound (17.8 g, 70%).

Step 3: 3-amino-6- (methylsulfonyl D-pyridine 3-nitro-6- (methylsulfonyl) pyridine (10 g, 49.5 mmol) was suspended in water (200 ml) Iron powder (5.0 g, 89.3 mmol) and acetic acid (0.5 ml) were added to the above mixture.The mixture, which resulted, was heated at reflux for 2 hours.The reaction was monitored by thin layer chromatography (ethyl acetate / hexane, 1/1). The reaction mixture was then cooled to room temperature and the saturated solution of sodium bicarbonate (NaHCO3) (100 ml) was added to the mixture Ethyl acetate (200 ml) was added to the above mixture and the resulting mixture was stirred at room temperature. ambient temperature for 30 minutes The mixture was filtered through Celite® and the organic layer was collected.The aqueous layer was extracted with ethyl acetate (200 ml x 3) .The organic extractions were combined and dried over sodium sulfate. The solvent was removed under reduced pressure to deliver the 3-am No-6- (methylsulfonyl) pyridine (6 g, 70.5%).

Step 4: 5-hydrazino-2- (methylsulfonyl) pyridine To a solution of 3-amino-6- (methylsulfonyl) pyridine (3.72 g, 21.6 mmol) in concentrated hydrochloric acid (30 ml), sodium nitrite (1.78 g) was added. g, 25.7 mmoles) in water (20 ml) by dripping at ~ 10 ° C at 15 ° C and the mixture was stirred for 2 hours between -10 ° C and 5 ° C (note: the reaction was monitored by layer chromatography. thin to ensure that all the initial material was consumed). Tin chloride dihydrate (20 g, 88.6 mmol) in concentrated hydrochloric acid (30 ml) was added dropwise at -5 ° C. The mixture was stirred for 1 hour at 5 ° C and then left overnight. The mixture was basified with aqueous sodium hydroxide (pH = 9) with ice cooling, tetrahydrofuran (200 ml) was added and stirred for 30 minutes. The mixture was filtered by Celite® and the filtrate was extracted with tetrahydrofuran (200 ml x 3). The organic extraction was combined and dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound (3.2 g, 78.8%). 5-hydrazino-2- (methylsulfonyl) pyridine was dissolved in HCl-methanol (10%, 30 ml) and the volatilities were removed under reduced pressure. The residue was washed with ether and used directly in the next step without further purification. 1 H-NMR (DMSO-e) d; 8.40-8.37 (m, 1 H) 7.96 (d, J = 8.6 Hz, 1 H), 7.55-7.45 (m, 1 H), 3.19 (s, 3H).

PREPARATION 2 Preparation of 2-pyridyl hydrazines Step 1: 2-Hydrazino-5- (methylsulfonyl) pyridine 5-methylthio-2-bromopyridine hydrochloride To a solution of 2,5-dibromopyridine (23.4 g, 0.099 moles) in ether (500 ml), n-BuL was added (1.52 M in n-hexane, 68 mL, 0.10 mmol) was dripped at -78 ° C and the mixture was stirred for 1 hour at the temperature. Dimethyl disulfide (9.8 ml, 0.11 mmol) was slowly added at -78 ° C and the mixture was stirred for 1 hour at that temperature and further 1 hour at 0 ° C. The mixture was quenched with 1 N aqueous HCl (200 ml) and extracted with ether (100 ml x 2), dried over magnesium sulfate (MgSO 4), and concentrated in vacuo to yield the title compound (18.9 g, 94%). 1 H-NMR (CDCl 3) d; 824 (dd, J = 0.8, 2.5 Hz, 1 H) 7.43 (dd, J = 2.8, 8.4 Hz, 1 H), 7.38 (dd, J = 0.8, 8.4 Hz, 1 H), 2.50 (s, 3H) .

Step 2: 5-Methylsulfonyl-2-bromopyridine To a solution of 5-methylthio-2-bromopyridine from step 1 (18.9 g, 0.093 mmol) in methylene chloride (600 ml), m-chloroperbenzoic acid (48 g) was added. , 0.19 moles) at 0 ° C and the mixture was stirred for 2 hours at room temperature. Aqueous saturated Na 2 S 3 (200 mL) was added and stirred for 15 minutes and the organic phase was separated and washed with saturated aqueous sodium bicarbonate (NaHCO 3) (200 mL), dried (MgSO 4), and concentrated in vacuo to give produce the title compound (20.9 g, 96%). 1 H-NMR (CDCl 3) d; 8.91 (d, J = 2.6 Hz, 1 H), 8.06 (dd, J = 2.6, 8.4 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 3.12 (s, 3H).

Step 3: 2-Hydrazine-5- (methylsulfonyl) pyridine hydrochloride A mixture of 5-methylsulfonyl-2-bromopyridine from step 2 (20.9 g, 0.088 moles) and anhydrous hydrazine (5.6 ml, 0.18 moles) in ethanol ( 200 ml) was refluxed for 4 hours. Then cooled to room temperature and concentrated. The residual solid was washed with saturated aqueous NaHC? 3. (300 ml) and water (100 ml) and collected by filtration to give a pale yellow solid (9.6 g). The solid was treated with 10% methanolic HCl (80 ml) and the precipitate was collected by filtration to yield the title compound (9.8 g, 50%). 1 H-NMR (DMSO-de) d; 8.54 (s, 1 H), 7.99 (d, J = 8.9 Hz, 1 H), 6.94 (d, J = 8.9 Hz, 1 H), 3.20 (s, 3H). (Hydrazine proton was not detected). 80 PREPARATION 3 2-fluoro-4-hydrazino-benzenesulfonamide Step 1: n- (3-fluoro-4-sulfamoyl-phen-0-acetamide Chlorosulphonic acid (200 ml, 3 moles) was added in a 1 liter, three neck container, followed by the addition of N- portions ( 3-fluoro-phenyl) -acetamide (91.8 g, 600 mmol) in an ice-water bath The reaction mixture was heated to 70 ° C and 5 hours, and then cooled to room temperature. The reaction mixture was diluted with methylene chloride (300 ml), and the resulting mixture was poured into 1 liter of crushed ice. The aqueous layer was extracted with methylene chloride (2 x 400 ml), and the combined organic layers were concentrated to about 300 ml in vacuo. The residue was cooled in an ice-water bath, and 28% ammonia (120 ml) was added slowly over 1 hour, and the temperature in the reaction vessel was maintained between 0 ° C and 10 ° C. The white precipitate was formed, and was collected by filtration dried under high vacuum (71.0 g, 51%).

Step 2: 4-amino-2-fluoro-benzenesulfonamide To a stirred solution of sodium hydroxide (120 g 3 moles) in water (500 ml) was added? - (3-fluoro-4-sulfamoyl-phenyl) -acetamide ( 69.7 g, 300 mmol). The reaction mixture was stirred at reflux temperature for 3 hours. The solution was then cooled to room temperature, and the pH was adjusted to 6 by the addition of a 5N HCl solution. The majority of the solvent was removed under vacuum, and the product was precipitated. The product was collected by filtration and dried under vacuum at 60 ° C (32 g, 56%).

Step 3: Salt of 2-fluoro-4-hydrazino-benzenesulfonamide hydrochloride To a stirred suspension of 4-amino-2-fluoro-benzenesulfonamide (15.2 g, 80 mmol) in concentrated hydrochloric acid solution (180 ml) was added slowly NaNO2 (5.8 g, 84 mmol) in water (180 ml), while maintaining the internal temperature between -15 ° C and 20 ° C in a dry ice / acetonitrile bath. After the reaction mixture was stirred at -20 ° C for 30 minutes, a solution of tin hydrochloride (SnC ^) (90.3 g, 400 mmol) in concentrated hydrochloric acid solution (100 ml) was added dropwise, and the Reaction mixture temperature was maintained between -5 ° C and -10 ° C with ice / methanol bath. stirring was continued at -10 ° C for 1 hour and then at room temperature for 4 hours. The pH of the solution was adjusted to 8 by the addition of a 5N solution of NaOH at 0 ° C, and the precipitate was removed by filtration through Celite. The aqueous layer was extracted with THF (3 x 600 mL), and the combined organic layers were washed with brine, dried over MgDo 4, and concentrated in vacuo. The residue was dissolved in 10% methanolic HCl solution, followed by stirring at room temperature for 1 hour, the title compound was collected by filtration (12.5 g, 65%). 82 PREPARATION 4 2-sulfamyl-5-hydrazino-pyridine hydrochloride salt Step 1: 2-sulfamyl-5-amino-pyridine N- (6-mercapto-pyridin-3-yl) -acetamide (30 g, 17.3 mmol) was dissolved in cold concentrated hydrochloric acid solution (225 mL), followed by ice water addition (50 ml). Chloride was bubbled into the solution, and the temperature was maintained below 10 ° C. The solution turned dark brown first, and the chlorination was finished after three hours when the temperature did not rise further and the color of the solution became clear. The reaction was diluted with ice and water (1.2 kg) while maintaining the temperature below 10 ° C. The product, 5-acetylamino-oyrridine-2-sulfonyl chloride, was collected by filtration and air dried. This was then suspended in chloroform (CHCl3) (200 ml), followed by the addition of 30% ammonia solution (100 ml), and the resulting reaction mixture was stirred for 2 hours. The solvent was removed under vacuum to yield a black solid, 2-sulfamyl-5-acetyleminopyridine. 2-sulfamyl-5-acetylamine-pyridine was dissolved in 0.85 N NaOH solution (500 ml), and the resulting solution was stirred at reflux temperature for 3.5 hours. After cooling to room temperature, the reaction mixture was extracted with 3: 1 CHCI13 / MeOH solution (3 x 200 ml). The aqueous layer was neutralized to pH 7, and the water was removed in vacuo to give the crude product which was recrystallized from water to yield the title compound (21.6 g, 70%). 83 Step 2: Salt of 2-sulfamyl-5-hydrazino-pyridine hydrochloride To a solution of 2-sulfamyl-5-amino-pyridine (3 g) in concentrated hydrochloric acid solution (23 ml) was added Na 2 ( 1.4 g, 20 mmol) in water (23 ml) while maintaining the temperature between -5 ° C and 0 ° C. After the reaction mixture was stirred at 0 ° C for 1.5 hours, SnCl 2 (19 g) was added in concentrated hydrochloric acid solution (25 ml), the resulting reaction mixture was stirred at 0 ° C for 1 hour, then at Room temperature throughout the night. The pH of the reaction solution was adjusted to 8 by addition of NaOH (24 g) in water (30 ml), followed by the addition of THF (200 ml). After stirring at room temperature for 30 minutes, the reaction mixture was filtered through Celite®. The aqueous layer was extracted with THF (3 X 200 ml) and ethyl acetate (2 x 200 ml). The combined organic layers were dried with sodium sulfate (NaSO 4), and concentrated in vacuo. The product was dissolved in 10% HC0I in ethanol (50 ml), and the solvent was removed in vacuo to yield the title compound (2.5 9) -

Claims (3)

84 NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula where n is one or two X is CR7 or N; And it is CR8 or N; R1 is alkyl (d-C6) or -NH2; R2 is hydrogen, halo (more preferably chloro or fluoro, and most preferably fluoro), alkyl (d-Cß), alkenyl (C2-C6), alkynyl (O d, (C2-C6) alkoxy, alkylcarbonyl (d-Cß) ), formyl, formamidyl, cyano, nitro, -Co2, akoxycarbonyl (d-Cß), aminocarbonyl, N-alkylaminocarbonyl (CrCß), N, N- [alkyl (dd ^ aminocarbonyl, N-arylaminocarbonyl (Ce-Cio), N , N- [aryl (C6-C? O)] 2a? T? Inocarbonyl, N-alkyl (CrC6) -N-arylaminocarbonyl (C6-C? 0), aryl (Ce-Cio), aryloxy (C6-C? o), heteroaryl (C2-Cg), heteroaryloxy (C2-Cg), morpholino-carbonyl, alkoxycarbonylamino (d-Cß) or alkylcarbonylamino (C1-C9), wherein said R2 alkyl group (CrC6) can optionally be substituted with one to three substituents independently selected from halo, hydroxyl, N-alkylaminocarbonyl (d-Cß), cyano, nitro, -CO2H, alkoxycarbonyl 85 (CrCe), aminocarbonyl, N-alkylaminocarbonyl (d-Cß), N, N- [alkyl ( CrC6)] 2 aminocarbonyl, N-arylaminocarbonyl (Ce-Cio), N, N- [aryl (C6-C? O) 2-aminocarbonyl, N-alkyl (CrC6) -N-arylaminocarbonyl (Ce-Cio), aryl (Ce-Cio), aryloxy (Ce-Cio), heteroaryl (C2-Cg), heteroaryloxy (C2-C9), morpholine- carbonyl, alkoxycarbonylamino (CrCß) or alkyl-carbonylamino (d-Cß); R3 is hydrogen, halo (more preferably chloro or fluoro, and most preferably fluoro), alkyl (CrC6), alkoxy (CrC6), alkylcarbonyl, formyl, formamidyl, cyano, nitro-CO2H, alkoxycarbonyl (CrC6), aminocarbonyl, N- (alkylaminocarbonyl (CrC6), N, N- [alkyl (CrC6)] 2-aminocarbonyl, N-arylaminocarbonyl (C8-C? 0), N, N- [aryl (C6-C? o)] 2-aminocarbonyl, N-alkyl (d) -C6) -N-arI-aminocarbonyl (C6-C? 0), aryl (C6-C? 0), aryloxy (C6-C10), heteroaryl (C2-C9), heteroaryloxy (C2-C9), morpholino-carbonyl , alkoxycarbonylamino (d-C6) or alkyl-carbonylamine, wherein said R3 alkyl group (d-Cß) can optionally be substituted with one to three substituents independently selected from halo, hydroxyl, alkoxy (d-Cß), cyano, nitro, -CO2H, alkoxycarbonyl (CrC6), aminocarbonyl, N-alkylaminocarbonyl (d-Cß), N, N- [N-arylaminocarbonyl (C6-C10) alkyl, N, N- [aryl (C? -C-C? O)]. 2-aminocarbonyl, N-alkyl (CrC6) -N-arylaminocarbonyl (C6-C? 0), aryl (C6-C? O), aryloxy (C6-C? O), heteroaryl (C2-Cg), heteroaryloxy (C2-Cg), morpholino-carbonyl, alkoxycarbonylamino or alkyl (CrCe) -carbonylamino; R 4 is hydrogen, alkyl (d-Cß), heteroaryl (CH 2) m- (C 6 -Cg), wherein m is an integer from 0 to 4; wherein said - (CH2) m-aryl (Ce-Cio), - (CH2) m-heteroaryl (C2-Cg) can optionally be substituted with one to three substituents 86 independently selected from halo (preferably fluoro or chloro); hydroxyl; mercapto; alkyl (CrC6); optionally substituted with one to three halogen atoms (preferably fluoro); alkenyl (C2-C6); (C2-C6) alkynyl; cyano; formyl; alkylcarbonyl (d-d); alkyl (CrC6); alkyl (d-d) - (C = O) -; aminocarbonyl; N-alkylaminocarbonyl (d-C6); N, N- [(CrC6)] 2 aminocarbonyl; nitro; Not me; alkylamino (d-d); [alkyl (CrC6)] 23 amino; or alkyl (dd -S- wherein said R4 alkyl (dd) group may optionally be substituted with one to three substituents independently selected from halo, hydroxyl, (C? -C6) alkoxy, cyano, nitro, alkoxycarbonyl (dd), aminocarbonyl , N- (C? -C6)] 2-aminocarbonyl, N-arylaminocarbonyl (Cedo), N, N- [(C6-C? O) aryl] 2-aminocarbonyl, N-alkyl (Crd) -N-arylaminocarbonyl (C6-C? o), aryl (d-Cio), aryloxy (d-Cio), heteroaryl (C2-C9), heteroaryloxy (C2-C9), morpholino-carbonyl, alkoxycarbonylamino (dd), alkyl-carbonylamino (dd) or cycloalkylamino; is hydrogen, halo (more preferably chloro or fluoro, and most preferably fluoro), alkyl (dd), alkenyl (CrC6), alkynyl (dd), alkoxy (dd), alkylcarbonyl (CrCe) formyl, formamidyl, cyano, nitro, -CO2H, alkoxycarbonyl (dd) aminocarbonyl, N-alkylaminocarbonyl (dd), N, N- [alkyl (Cr Ce) 2-aminocarbonyl, N-arylaminocarbonyl (C6-C? O), N, N- [aryl (dC? O) ] 2-aminocarbonyl, N-alkyl (C? -Ce) -N-arylaminocarbonyl (C6-C? O), aryloxy (C6-C? O), heteroaryl (C-Cg), heteroaryloxy (C2-Cg), morpholino-carbonyl, alkoxycarbonylamino (d-d) or alkylcarbonylamino (d-d); wherein said R 5 alkyl (dd) group can optionally be substituted with one to three substituents independently selected from halo, hydroxyl, alkoxy, (dd), cyano, nitro, -CO 2 H, alkoxycarboninyl (CrCβ), aminocarbonyl, N-alkylaminocarbonyl ( CrC6), N, N- [alkyl (CrC6)] 2-aminocarbonyl, N-arylaminocarbonyl (C6-C? 0), N, N- [aryl (C6-C? O)] 2-aminocarbonyl, N-alkyl (d-C6) -N-arylaminocarbonyl (C6-C? 0), aryl (C6-C? 0), aryloxy (Ce-Cio), heteroaryl (C2-Cg), heteroaryloxy (C-Cg), morpholino-carbonyl, akoxycarbonylamino (d-) C6) or alkyl (CrC6) -carbonylamino; R6 is hydrogen, halo (more preferably chloro or fluoro, and most preferably fluoro), alkyl (CrC6), alkenyl (C2-d), alkoxy (CrCe), alkylcarbonyl (dd), formyl, formamidyl, cyano -CO2H, alkoxycarbonyl (dd), aminocarbonyl, N-alkylaminocarbonyl (CrC6), N, N- [alkyl N-arylaminocarbonyl (d-Cio), N, N- [aryl (dC? o)] 2-aminocarbonyl, N-alkyl (CrC6) -N -arylaminocarbonyl (C6-C? 0), aryl (Ce-Cio), aryloxy (C6-C? o), heteroaryl (C2-C9), heteroaryloxy (C2-C9), morpholino-carbonyl, acloxycarbonylamino (CrC6) or alkylcarbonylamino (dd); wherein said R6 alkyl (dd) can optionally be substituted with one to three substituents selected from halo, hydroxyl, cyano, nitro, -CO2H, akoxycarbonyl (dd), aminocarbonyl, N-alkylaminocarbonyl (dd), N, N- [alkyl (Crd ^ aminocarbonyl, N-arylaminocarbonyl (C6-C? O), N, N- [aryl (d-Ciojfcaminocarbonyl, N, N- [aryl N-alkyl (CrCe) -N-arylaminocarbonyl (C6-C? 0) , aryl (C6-C? 0), aryloxy (Ce-C? o), heteroaryl (C2-C9), heteroaryloxy (C2-Cg), morpholino-carbonyl, alkoxycarbonylamino Crd) or alkyl-carbonylamino (dd); R7 is hydrogen, halo (preferably fluoro or chloro), hydroxyl, mercapto, alkyl (CrCe), alkoxy (Crd) optionally substituted with one to three halogen atoms (preferably fluoro): alkenyl (C2-C6) alkynyl (C2-C6) ); cyano; formyl; alkylcarbonyl (CrC6); alkyl (CrC6) - (C = O) -O-; -CO2H; alkoxycarbonyl (CrCe); aminocarbonyl; N-alkylaminocarbonyl (CrC6); N, N [(alkyl (CrC6 )] 2-aminocarbonyl, nitro; amino; alkylamino (CrCe); [alkyl (CrC6)] 2-amino; or alkyl (Crd) -S-; Wherein said R7 alkyl group (CrC6) can optionally be substituted by one to three substituents independently selected from halo, hydroxyl; alkoxy (dd), cyano, nitro, -CO2H, alkoxycarbonyl (CrC6), aminocarbonyl, N-alkylaminocarbonyl (d-C6), N; N- [alkyl (dd ^ aminocarbonyl, N-arylaminocarbonyl (C6-C? o), N, N- [aryl (C6-C? 0)] 2-aminocarbonyl, N-alkyl (d-C6) -N-arylaminocarbonyl (C6-C? O), aryl (C6-C? 0), aryloxyI (C6-C) o), heteroaryl (C2-Cg), heteroaryloxy (C2-Cg), morpholino-carbonyl, alkoxycarbonylaminoCrd) or alkyl-carbonylamino (CrCe); R8 is hydrogen; halo (preferably fluoro or chloro); hydroxyl; mercapto; alkyl (CrC6); alkoxy (CrCe) optionally substituted with one to three halogen atoms (preferably fluoro); alkenyl (d-d); alkynyl (d-d); cyano; formyl; Aquilcarbonium (CrCe); alkyl (CrCe) - (C = O) -O-; CO H; alkoxycarbonyl (CrC6); aminocarbonyl; N-alkylaminocarbonyl (CrCe); N, N- [alkyl (dC) aminocarbonyl; nitro; amino; alkylamino (CrC6); [alkyl (CrCe)] 2-amino; or alky (CrC6) -S- wherein said group R8 alkyl (CrC6) can optionally to be substituted with one to three substituents independently selected from halo, hydroxyl, alkoxy (Crd), cyano, nitro, -CO2H, alkoxycarbonyl (dd), aminocarbonyl, N-alkylaminocarbonyl (CrCe), N, N- [alkyl (Cr 89-aminocarbonyl, N-arylaminocarbonyl (C6-C10), N, N- [aryl (C6-C? O)] 2-aminocarbonyl, N-alkyl (CrC6) -N-arylaminocarbonyl (C6-C? O) arylaminocaronyl, aryl (dC o), aryloxy (C6-C? 0), heteroaryl (C2-Cg), heteroaryloxy (C2-Cg), morpholino-carbonyl, alkoxycarbonylamino (CrC6), or alkyl (CrCe), carbonylamino; or a pharmaceutically acceptable salt of such compounds

2. A compound according to claim 1 wherein X is CR7 and Y is nitrogen

3. A compound according to claim 1 wherein X is nitrogen and Y is CR8. Composed in accordance with the reivi ndication 1 where X is CR7 and Y is CR8. 5. A compound according to claim 1 wherein R4-acetylione is in the meta or para position and R4 is hydrogen. 6. A compound according to claim 1 wherein R5 is H or methyl and R6 is CF3 or CF2H. 7. A compound according to claim 1 wherein R3 is hydrogenhalo, alkyl (dd), alkenyl (dd), alkynyl (dd), alkoxy (dd), alkylcarbonyl, formyl, formamidyl, cyano, nitro, -CO2H, alkoxycarbonyl (d-C6), aminocarbonyl, N- (CrC6) -alkylaminocarbonyl, N, N- [alkyl (CrC6)] 2 aminocarbonyl, N-arylaminocarbonyl (C6-C? o), N, N- [aryl (C6-C? o)] 2-aminocarbonyl, N-alkyl ( CrCe) -N-arylaminocarbonyl (C6-C? O), aryl (C6-90 Cio), aryloxy (C6-C o), heteroaryl (C2-Cg), heteroaryloxy (C2-Cg), morpholinocarbonyl, alkoxycarbonyl amine (CrCe) or alkyl-carbonylamino. 8. A compound according to claim 1 wherein said compound is selected from the group consisting of: 4- [5- (4-ethynyl-phenyl) -3-trifluoromethyl-pyrazole-1-yl- benzenesulfonamide, 4- [5- (3-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -benzenesulfonamide, 4- [5- (4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl ] -2-fluoro-benzenesulfonamide, 2-aminosulfonyl-5- [5- (4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 2-aminosulfonyl-5- [5- ( 3-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 2-methylsulfonyl-5- [5- (4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-l] -pyridine , 5-methylsulfonyl-2- [5- (4-ethynyl-phenyl) -3-trifluoromethyl-pyrazol-1-yl-pyridine, 2-aminosulfonyl-5- [5- (3-ethynyl-4- methoxy-phenyI) -3-trifluoromethyl-pyrazol-1-yl] -pyridine, 5-methylsulfonyl-2- [5- (4-ethynyl-phenyl) -3-difluoromethyl-pyrazol-1-yl] -pyridine, 4- [5- (3-ethynyl-4-methoxy-phenyl) -3-difluorophenyl-pyrazol-1-yl] -benzenesulfonamide, 5- (4-ethynyl-phenyl) -3-trifluoromethyl-1- (4-methylisulfonylphenyl) - pyre zol, and 4- [5- (3-ethynyl-4-methoxy-phenyl) -3-trifluoromethyl-pyrazol-1-yl] -2-fluoro-benzenesulfonamide. 9. A pharmaceutical composition for the treatment of a condition selected from the group consisting of arthritis, fever, common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, episemia, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, contact hypersensitivity, cancer, 91 tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal injury, gastrointestinal bleeding , coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis, aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), periarteritis nodosa, fal cardiac congestive, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neurodegenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, gingivitis cerebral amyloid angiopathy, increased cognition, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, ocular degeneration, conjunctivitis, abnormal healing of wounds, dislocations or muscle or joint strains, tendonitis, skin disorders, myasthenia gravis , polymyositis, myositis, bursitis, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases, sepsis, preterm labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet syndrome, hypersensitivity , kidney disease, infection is Rickettsiales, protozoal diseases, reproductive disorders and septic shock in a mammal, comprising an amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, effective in such treatments and pharmaceutically acceptable carrier. 10. The use of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a condition selected from the group consisting of arthritis, fever, common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions , contact hypersensitivity, cancer, tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal injury, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neurodegenerative disorders, autoimmune disorders, disease Huntingtonm disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, gingivitis, cerebral amyloid angiopathy, increased cognition, myotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, ocular degeneration, conjunctivitis, abnormal wound healing , dislocations 93 or muscle or joint strains, tendinitis, skin disorders, myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases, sepsis , premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet syndrome, hypersensitivity, kidney disease, Rickettsial infections, protozoal diseases, reproductive disorders and septic shock in a mammal.