MXPA98006213A - Diphenylesthylenes as profarmacos for inhibitors of cyclooxygenes - Google Patents

Abstract

The invention comprises the novel compound of formula I, useful in the treatment of diseases mediated by cyclooxygenase-2, the invention also comprises certain pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases, comprising compounds of the formula

Description

DIPHENYLESTHYLENES AS PROFARMACOS FOR INHIBITORS OF CICL00XIGENASA-2 BACKGROUND OF THE INVENTION This invention relates to methods for treating cyclooxygenase-mediated diseases and to certain pharmaceutical compositions therefor. Anti-inflammatory drugs. Non-steroidal »exercise most of their anti-inflammatory activity. analgesic and antipyretic »and inhibit uterine contractions induced by the hormone» and certain types of cancer development »by inhibiting the prostaglandin G / H synthase. also known as cyclo-oxygenase. Initially, only one form of cyclooxygenase was known; this corresponded to cyclooxin-1 (COX-1) or the constitutive enzyme "as originally identified in bovine semen vesicles. More recently »the gene has been cloned and sequenced and characterized for a second inducible form of cyclooxygenase. Cyclooxygenase-2 (COX-2). initially of chickens »of murids and human sources. This enzyme is different from COX-1. which had been cloned »sequenced and characterized from various sources, including sheep» mouse and man. The second form of c-cloxygenase. COX-2 »is rapidly and easily inducible by several agents that include myogens» endotoxin, hormones, cytokines and growth factors. As the prostaglandins play physiological and pathological roles, it has been concluded that the constitut enzyme goes »COX-1. is responsible »to a large extent» for the endogenous basal release of prostaglandies and »accordingly. it is important in its physiological functions »such as the maintenance of the gastrointestinal integrity and in the renal blood flow. In contrast, it has been concluded that the inducible form »COX-2» is mainly responsible for the pathological effects of prostagland as, when rapid induction of the enzyme occurs in response to agents such as inflammatory agents. hormones »growth factors and cytokines. Thus, a selective inhibitor of C0X-2 will have anti-inflammatory properties. antipyretics and analgesics similar to a conventional non-steroidal anti-inflammatory drug; and in addition »it would inhibit uterine contractions induced by the hormone and would have potential effects against cancer» but it would have a diminished capacity to induce some of the side effects based on the mechanism. In particular »said compound would have a reduced potential for gastrointestinal toxicity» a reduced potential for renal side effects »and a reduced effect on bleeding times and. possibly »a weakened ability to induce asthma attacks in asthmatic subjects» sensitive to aspirin. Additionally, said compound will also inhibit the contraction of muscle l or induced by prostano- p ev or the synthesis of contractile prostanoids and, therefore, may be useful in the treatment of dysmenorrhoea, premature labor. asthma and alterations related to eosinophils. It will also be useful in the treatment of Alzheimer's disease; to decrease bone loss »particularly in post-enopausal women (ie» in the treatment of osteoporosis) and for the treatment of glaucoma. A brief description of the potential usefulness of cyclooxygenase-2 inhibitors is given in an article by John Vane »Nature, volume 367. pages 215-216» 1994 »and in an article published in Drug News and Perspecti ves» volume 7. pages 501-512 »1994. Many stilbene derivatives are known in the chemical literature. Toda and collaborators »in Chem. Commun. 1234-1235 (1984) describe the dialdehydes A; and diol B is described by Tsuji and coauthors »J. Am. Chem. Soc. 88. 1289-92 (1966). and the dio was prepared! C by Dhawau and coauthors »J. Qrg. Chem. 45 »922-924 (1980). The utility for these compounds is not described nor do they carry the R substituent of the present invention.

A B X = H Tsuji X = Ho Cl C X = ClDhawan Structure D is described as having utility for treating hyperlipsis by "Hashi oto and co-authors" in European patent application 424,541 (May 2, 1991). eno 1 to 5 atoms D These compounds (D) lack the second carbon X substituent of the present invention and have unrelated utility.

BRIEF DESCRIPTION OF THE INVENTION The invention comprises the novel compound of the formula I; as well as a method for treating diseases mediated by C0X-2 »which comprises administering to a patient in need of said treatment, a non-toxic, therapeutically effective amount, of a compound of formula I. These compounds are prodrugs that selectively inhibit C0X- 2 with respect to COX-1. The prodrugs are converted i vivo to the selective inhibitors.

The invention also comprises certain pharmaceutical compositions for the treatment of diseases mediated by COX-2, which comprise compounds of the formula I.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the invention comprises the novel compound of formula I "as well as a method for treating diseases mediated by COX-2. which comprises administering to a patient in need of such treatment "a non-toxic" therapeutically effective "amount of a compound of formula i: I or its pharmaceutically acceptable salts; wherein: X is (a) CH, 0H, < b > CHO, (C) CO, -S or (D) CONR - *.,; Y is (a) CH, (b) CH2ORβ is selected from the group consisting of: (a) S (0) 2CH; (b) S (0) 2IMH2, < C) S < 0) .J \ -HC < 0 > CF.- "? (d) S (0) ÍNH) CH_. (e) S (0) (NH) IMH. (f) S (0) (NH)? MHC (0) CF ,, »(g) P (0) (CH3) 0H, and (h) P (0) (CH3) NH2; each of R58 and R3 is independently selected from the group consisting of: (a) hydrogen; (b) halogen; (c) alkoxy of 1 to 6 carbon atoms; (d) alkyl of 1 to 6 carbon atoms; (e) C »(f) CFa (g) alkyl of 1 to 6 carbon atoms; and (h) N3; R- * is selected from the group consisting of: (a) hydrogen »(b) alkyl of 1 to 6 carbon atoms; and (c) benzyl mono-od-substituted "wherein the substituent is selected from: (1> hydrogen, (2) halogen, (3) alkyl of 1 to 6 carbon atoms, (4) alkoxy of 1 to 6 atoms of carbon, (5) alkylthio of 1 to 6 carbon atoms, (6) OH, (7) CN, and (B) CF3, or two R * 4 groups bound to the same N can form a ring of 5. 6 or 7-member "saturated" optionally containing a 0 or S atom or an additional I 1 atom, said IM atom being substituted with a hydrogen or an alkyl of 1 to 6 carbon atoms; a group consisting of: (a) alkyl of 1 to G carbon atoms, (b) mono- or disubstituted benzyl "wherein the substituent is selected from: (1) hydrogen, (2) halogen, (3) alkyl of 1 to 6 carbon atoms, (4) alkoxy of 1 to 6 carbon atoms. (5) alkylthio having from 1 to 6 carbon atoms »(6) OH, (7) CN, (8) CF3, and (9) CO - .R *. In a genus, the preferred compounds within this embodiment are those in which: RA is selected from the group consisting of: (a) S (0) 2CH3 »and (b) S (0) 2NH2; each of Rs and R3 is independently selected from the group consisting of: (1) hydrogen »(2) halogen» selected from the group consisting of fluorine, chlorine and bromine. In another genus, the preferred compounds within this embodiment are those in which: Y is CH3 or CH20-alkyl having 1 to 6 carbon atoms. Within this genus is the class of compounds in which: Y is CH 3 or CH 20 -alkyl of 1 to 6 carbon atoms; Rx is selected from the group consisting of: (a) S (0) 2CH3, (b) S (0) ßNH2, (C) S (0) 2NHC (0) CF3 »(d) S (0) NHCH-, , (e) S (0)? MHNH ..- ,, and (f) S (0) - \ IHNHC (0) CF3"and each of R2 and R3 is independently selected from the group consisting of: (a) hydrogen, (b) fluorine, chlorine and bromine »(c) alco? i of 1 to 4 carbon atoms. (d) alkylthio of 1 to 4 carbon atoms »(e) CN (f) CF3; and (g) alkyl of 1 to 4 carbon atoms. Within this class is the subclass of compounds in which each of R2 and R3 is independently selected from the group consisting of: (1) hydrogen; and (2) halogen; R- * is hydrogen or meth; and R-β is alkyl of 1 to 6 carbon atoms. In another genus, the preferred compounds within the above embodiment are those in which: X is C0 .., R **. Within this genus is the class of compounds in which: X is C02R "» and is methyl or CH20Rβ; RA is S (0) 2CH3; each of R2 and R3 is independently selected from the group consisting of: (a) hydrogen; and (b) halogen; R-4 is selected from the group consisting of: (a) hydrogen; and (b) alkyl of 1 to 6 carbon atoms; RE is selected from the group consisting of *. (a) alkyl of 1 to 6 carbon atoms; (b) mono- or di-substituted benzyl; wherein the substituent is selected from: (1) hydrogen »(2) halogen» (3) alkoxy of 1 to 6 carbon atoms; and (4) OH. Within this class is the subclass of compounds in which: X is C02R-S and is methyl or CH20Rs. RA is S (0) CH, each of Rβ and R3 is selected from the group consisting of: (a) hydrogen and (b) halogen; R- is selected from the group consisting of: (a) hydrogen »and (b) alkyl of 1 to 6 carbon atoms; R "5 is selected from the group consisting of: (a) alkyl of 1 to 6 carbon atoms, (b) mono- or di-substituted benzyl, wherein the substituent is selected from: (1) hydrogen, (2) halogen, (3) alkoxy of 1 to S carbon atoms, and (4) OH The compounds of tables II and III are illustrative of the invention For the purposes of description, alkyl is defined herein as linear, branched and cyclic structures, with the indicated number of carbon atoms Examples of alkyl are: ethyl, propyl, 2-propyl, secondary butyl and tertiary butyl, butyl, pentyl, hexyl, 1,1-dimeti leti Cyclopropyl »cyclobutyl» cyclopentyl and cyclohexyl Similarly, "alkoxy and alkylthio" means linear, branched and cyclic structures "with the indicated number of carbon atoms For the purposes of the present specification" when a definition appears twice, such as "R- *" in "CONR ** -. ", each occurrence must be considered independent of any other occurrence. Thus, in "" CO R - ^^ ", the groups" R- * "are not necessarily identical For the purposes of this specification, halogen means F, Cl, Br or I. The following abbreviations have the indicated meanings: AA = arachidonic acid, Ac = acetyl-. AIBN = 2,2-azobisisobutyrom "tri lo, Bn = benzyl CHO = ovaries of Chinese hamster, CMC = meto-p-toluensul fonate of 1-cyclohexy l-3- ( - orfo i oeti 1) carbodi ida, COX = ciel oox genasa, DBU = diazabicycloC5.4.03undec-7-ene, DMAP = 4- (d methylamino) pyridine, DMF = NIM-dimethylformamide. DMSO = dimethyl sulfoxide. Et ,, N = triethylamine »HBSS = balanced salt solution of HanKs» HEPES = N-C2-hydro ieti 1 -lpiperazi na-N ^ -cid 2-etansulonic3 »HB = human whole blood» KHMDS = hexa eti Idis lazano of potassium »LDA = diisoprop lithium lamide» LPS = 1 icarcardo. mCPBA = metachloroperbenzoic acid »MMPP = magnesium monoperoxyphthalate. Ms = methanesulfonyl = mesyl.

MsO methanesulfonate = mesylate »NBS N-bromosuccium ni my da. NCS N-chlorosucc n mi a. NIS N-niosynthetic iodine »NSAID drug ant inf 1 non-steroidal amatorium» Oxone (R) potassium peroxymonosulfate »PCC pyridinium chlorochromate, PDC pyridinium dichromate. t. room temperature, rae. racém? co »Tf trifluoromethanesulfoni lo = triflyl, TFAA trifluoroacetic anhydride, TfO trifluoro-ethanesulfonate = triflate, THF tetrahydrofuran »TLC thin layer chromatography. TMPD N.N.N "," -tetrameti 1-p-feni lend a ina, Ts p-toluenesulfonyl = tosyl, TsO p-toluenesulfonate = tosylate »Tz 1H (or 2H) -tetra? Ol-5- lo, SO ^ Me methyl sulphona (also S02CH. S02NH. = Sulfonami a Abbreviations of alkyl group: Me Met lo, Et eti lo. n-Pr normal propyl i-Pr isoprop lo »n-Bu = but normal» i-Bu = isobut lo »s-Bu = secondary butyl» t-Bu = tertiary butyl »c-Pr = cyclopropyl, c-Bu = cyclobutyl, c-Pen = cyclopent, c-Hex = cyclohexyl.

Dose abbreviations: bid = bis i n die = 2 times daily qid = quater in die = 4 times daily, tid = ter i die = 3 times daily. Some of the compounds described herein contain one or more asymmetric centers and. in such a way can give rise to diastereomers and optical isomers. It is intended that the present invention comprises said possible racemic and resolved "enant omerically pure" diastereomers and their pharmaceutically acceptable salts.Some of the compounds described herein contain olefinic double bonds and "unless otherwise specified" are intended to include both the geometric isomers E and Z. The compound of formula I is useful for relieving pain »fever and inflammation in a variety of conditions including: rheumatic fever »symptoms associated with influenza or other viral infections, common cold, back and neck pain, dysmenorrhea, headache» dental pain, sprains and strains. iositis »neuralgia» synovitis »arthritis» including rheumatoid arthritis »degenerative joint diseases (osteoarthritis)» gout and ankylosing spondylitis »bursitis» burns. injuries after surgical and dental procedures. In addition, said compound can inhibit cellular neoplastic transformations and metastatic tumor growth. and therefore "can be used in the treatment of cancer. Compound 1 may also be useful in the treatment and / or prevention of prolific alterations mediated by cyclooxygenase, such as those that may occur in diabetic retinopathy and in tumor angiogenesis. Compound I, by virtue of its conversion in vivo to a COX-2 inhibitor, will also inhibit smooth muscle contraction, induced by prostanoids, by preventing the synthesis of contractile prostanoids and, therefore, may be useful in the treatment of dysmenorrhea, premature labor, asthma and alterations related to eosinophils. Its use will also be possible in the treatment of Alzheimer's disease, to reduce bone loss »particularly in postmenopausal women (ie in the treatment of osteoporosis) and for the treatment of glaucoma. The compounds of the formula I are prodrugs of selective COX-2 inhibitors, and exert their action by converting them to these active and selective COX-2 inhibitors. The active compounds formed from the compounds of the present invention are described in the following documents, which are thus incorporated by reference: WO 95/00501 »published on January 5, 1995; WO 95/188799, published July 13, 1995 and U.S. Patent 5,474,995, published December 12, 1995. In certain aspects, the compounds of the present invention have advantages over the compounds described in those documents, by virtue of improved pharmacokinetic profiles and / or safety profiles. A general description of the advantages and uses of prodrugs as pharmaceutically useful compounds is given in an article by Waller and George in Br. J. Clin. Pharmac. »Volume 2B» pages 497-507, 1989. »By way of illustration, the following compounds of the present invention are converted to the indicated selective COX-2 inhibitors.

E jemp l o Pro-Armaco Fármaco Activo. Re erence By virtue of its in vivo conversion to a compound with high inhibitory activity against COX-2 and / or a specificity for COX-2 with respect to COX-1, compound I will prove useful as an alternative to conventional NSAIDs, Particularly when said non-steroidal anti-inflammatory drugs may be contraindicated, such as in patients with peptic ulcers »gastritis, regional enteritis» col tis ulcerante »vertically or with a recurrent history of gastrointestinal lesions; gastrointestinal bleeding »alterations in coagulation. including anemia »such as hypoprothrombine ia» hemophilia or other bleeding problems; kidney diseases; the circumstances prior to surgery or the ingestion of anticoagulants. The pharmaceutical compositions of the present invention comprise a compound of the formula I as an active ingredient or a pharmaceutically acceptable salt thereof and may also contain a pharmaceutically acceptable carrier. optionally »other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to the salts prepared from non-toxic, "pharmaceutically acceptable" bases including the inorganic bases and the organic bases. Salts derived from inorganic bases include those of aluminum »ammonium, calcium» copper, ferric »ferrous» lithium »magnesium, manganic salts. manganosas of potassium, of sodium »of zinc and the like. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts. The salts derived from non-toxic organic bases are pharmaceutically acceptable. they include salts of primary amines. secondary and tertiary, substituted amines "which include the naturally occurring substituted amines; cyclic amines, such as arginine »betaine. caffeine »choline» N.N-dibenc leti lendiamine. diethylamine. 2-diethyl laminoethanol. 2- dimeti inoethanol »ethanolamine. ethylenediamine. N-eti l orfol ina »N-eti Ipiperidina» glucamine. glucosamine »histidine. idrabami na »isopropi la ina. lysine »meti Iglucamine. morfol na »piperazine. p pen * dina polyamine resins, prscaine. purines, theobromine. triet lam a, trimet lamina, triprop lamina, tro etamina and the like; and the ion exchange resins, basic. It should be understood that in the discussion of the methods of treatment that follow, references to the compounds of the formula I should also include the pharmaceutically acceptable salts. The compound of formula I is useful for alleviating pain, fever and inflammation in a variety of conditions, including rheumatic fever »symptoms associated with influenza or other viral infections; the common cold »back and neck pain, dysmenorrhea» headache, dental pain, sprains and strains, myositis, neuralgia, synovitis, arthritis »including rheumatoid arthritis, joint degenerative diseases (osteoarthritis), gout and ankylosing spondylitis; b > ursitis. Burns. injuries after surgical and dental procedures. Further. said compound can inhibit cellular neoplastic transformations and metastatic tumor growth and can therefore be used in the treatment of cancer. Compound I may also be useful in the treatment and / or prevention of cyclooxygenase-mediated proliferative disorders, such as those that may occur in diabetic retinopathy and in tumor angiogenesis. Compound I will also inhibit the contraction of smooth muscle, induced by prostanoids, by preventing "O synthesis of contractile prostanoids and, therefore, may be useful in the treatment of dysmenorrhea, preterm labor, asthma and eosinophil-related disorders. It will also be useful in the treatment of Alzheimer's disease, and for the prevention of bone loss (treatment of osteoporosis) and to treat glaucoma. By virtue of the high activity against COX-2 and / or the high specificity for COX-2 of the inhibitor derived from I "with respect to COX-1, compound I will prove useful as an alternative for conventional IMSAIDs, in Particularly when said non-steroidal anti-inflammatory prodrugs may be contraindicated, for example in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverculitis or with a recurrent history of gastrointestinal lesions: gastrointestinal bleeding, coagulation disorders including anemia, such as hypoprotrame, hemof lau other bleeding problems; kidney diseases, those prior to surgery or the ingestion of anticoagulants. Similarly, compound I will be useful as a partial or complete substitute for conventional NSAIDs, in preparations where they are currently co-administered with other agents or ingredients. Thus, in other aspects, the invention comprises pharmaceutical compositions for treating COX-2 mediated diseases, such as those defined above comprising a non-toxic, therapeutically effective amount of the compound of formula I, as defined above. top »and one or more ingredients, such as another analgesic, including acetaminophen or phenacetin; an enhancer, including caffeine; an antagonist of H3, aluminum or magnesium hydroxide, if ethicone, a decongestant, which includes: phenylephrine, phenopropanolamine, pseudofedrine, oxy etazol ine »epinephrine» naphazoline »xi eta etazol ina, propi 1 hexedrine or levo-deoxy edrina; an antitussive, including codeine, hydrocodone, caramiphen, carbetapentane or dextrametor n; a prostaglandin, including misoprostol »enprostil, rioprostil. ornoprostol or rosaprostol; a diuretic; a sedative or non-sedating antihistamine. Additionally the invention comprises a method for treating cyclooxygenase-mediated diseases comprising: administering to a patient in need of such treatment, a therapeutically effective, non-toxic amount of the compound of formula I, optionally co-administered with one or more of ingredients such as those mentioned immediately above. For the treatment of any of these cyclooxygenase-mediated diseases, compound I can be administered orally, topically, parenterally, med spray before inhalation or rectally, in dosage unit formulations containing carriers, adjuvants and conventional vehicles. non-toxic caceously acceptable. The term parenteral, as used herein, includes subcutaneous injections, intravenous injection. intramuscular »ntrasternal or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans. As indicated above, the pharmaceutical compositions for treating diseases mediated by COX-2, as defined. they may optionally include one or more of the ingredients mentioned in the above list. The pharmaceutical compositions containing the active ingredient may also be in a form suitable for oral use, for example, as tablets, candies, troches, aqueous or oily suspensions, powders or dispersible granules, emulsions »hard or soft capsules, or syrups or elixirs . The compositions intended for oral use can be prepared according to any method known in the art. for the manufacture of pharmaceutical compositions and said compositions may contain one or more agents selected from the group consisting of sweetening agents and flavoring agents. coloring agents and preservatives, in order to provide pharmaceutically elegant and palatable preparations. The tablets contain the active ingredient in admixture with pharmaceutically acceptable excipients. non-toxic, which are suitable for the manufacture of tablets. For example, those excipients may be inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.; granulating or disintegrating agents, for example, corn starch or alginic acid; agglutinating agents »for example» starch, gelatin or acacia gum; and lubricating agents »for example, magnesium stearate, stearic acid or talc. The tablets may not be coated or may be coated by known techniques, to delay disintegration and absorption in the gastrointestinal tract and, thereby, provide a sustained action over a longer period. For example, a time-retarding material, such as glyceryl monostearate or glyceryl distearate, may be employed. They can also be coated by the technique described in US Patents 4,256,108, 4,166,452 and 4,265,874, to form osmotic therapeutic tablets to control the release. Formulations for oral use may also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, eg, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules. in which the active ingredients are mixed with water or miscible solvents. such as propylene glycol. PEG and ethanol. or with an oily medium. for example. peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Said excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl Ipirrol donut, gum tragacanth and acacia gum; the dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with alcohols long-chain aliphatics, for example, heptadecaeti lenoxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as polyoxyethoniumoleyate monooleate lensorbitol, or condensation products of ethylene oxide with partial esters fatty acid derivatives and hexitol anhydrides, for example, polyethylether monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents »one or more flavoring agents and one or more sweetening agents» such as sucrose, saccharin or aspartame . Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil; or in a mineral oil, such as liquid paraffin. Oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those noted above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti oxidant, such as ascorbic acid. Dispersible powders and granules, suitable for the preparation of an aqueous suspension by the addition of water, provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suitable suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweeteners, flavors and coloring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures thereof. Emulsifying agents can be fossados that occur in nature. for example »soybean lecithin and esters or partial esters, fatty acid derivatives and hexitol anhydrides. for example, sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example, polyethylene monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents, for example. glycerol. propylene glycol. sorbitol or sucrose. Said formulations may also contain a surfactant, a preservative and flavoring and coloring agents. The compositions of the invention may also be in the form of an injectable aqueous or oleaginous suspension. sterile. This suspension can be formulated according to the known technique, using the suitable dispersing or wetting agents that have been mentioned above. The sterile injectable preparation can also be an injectable, sterile solution or suspension in a non-toxic diluent or solvent, parenterally acceptable, for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents, which may be employed, are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols can also be used. Additionally »fixed» sterile »oils are used as solvent or suspension medium. For this purpose, any fixed, soft oil, including synthetic mono- or diglycerides, can be used. In addition »fatty acids» such as oleic acid »have utility in the preparation of injectables. Compound I can also be administered in the form of suppositories for rectal administration of the drug.

These compositions can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at ordinary temperatures, but liquid at the rectal temperature; and therefore »is based on the rectum to release the drug. These materials are cocoa butter and poli eti lengl icoles. For topical use, creams, ointments, gels are used. solutions or suspensions »etc., which contain the compound of formula I (for the purposes of this application, the topical application will include mouth rinses and gargles). Topical formulations can consist "generally" of a pharmaceutical carrier. a cosolvent »an emulsifier» a penetration enhancer »a preservative system and an emollient. Dosage levels in the range of 0.01 mg to about 140 mg / kg of body weight per day are useful in the treatment of the conditions indicated above or »alternatively» around 0.5 mg to about 7 g per patient »per day . For example, inflammation can be treated effectively by administering about 0.01 to 50 mg of the compound per kilogram of body weight per day or. alternatively, about 0.5 mg to 3.5 g per patient, per day. The amount of active ingredient that can be combined with the carrier materials to produce a single dose form will vary, depending on the host treated and the .8 particular mode of administration. For example. A formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compound with an appropriate and convenient amount of carrier material, which may vary from about 5 to 95% of the total composition. Dosage unit forms will generally contain between about 1 mg to 500 mg of an active ingredient, typically 25 mg, 50 g, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg. However, it will be understood that the specific dose level for a particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, administration time, route of administration, administration, the rate of excretion »the combination of drug and the severity of the disease that is undergoing therapy. The compounds of the present invention can be prepared according to the following methods.

METHOD A The treatment of a ketal l and a bistrimeti Icetenoacetal 2, with a suitable Lewis acid, such as TiCl. * Or Eta "" BF3 in an appropriate solvent, such as methylene chloride provides an adduct 3 with a diastereomeric mixture. The esterification of 3 with CH2N2 »followed by a treatment with a base, such as DBU, gives rise to a mixture of 5 and 6, which is separated by chromatography on silica gel. Oxidation of 5 with MMPP or mCPBA produces the desired product.

£ MMPP METHOD B Hydrolysis of the ester 7 with a base, such as LiOH or NaOH in an aqueous solvent mixture, such as THF / water or MeOH / water, yields the desired carboxylic acid 8. 8 METHOD C The treatment of carboxylic acid 8 with oxalyl chloride, followed by an appropriate amine, produces the desired amide 9.

Q.

METHOD D A difeni 1-lactone 10 is reduced to the dio! 11, by a suitable reducing agent »such as diisobutyl aluminum hydride or lithium aluminum hydride» in an appropriate solvent »such as toluene» hexane, tetrahydrofuran or ether. The diol 11 is alkylated with an alkyl halide or a benzyl halide, in the presence of a base such as NaH or KOBut. This alkylation gives rise to the desired isomer 12 and the undesirable isomer 13, which is separated by chromatography or crystallization. Compound 12 is oxidized to aldehyde 14 by a reagent such as manganese dioxide. Subsequent oxidation of 14 with NaC102 produces the acid 15. Alternatively, 12 can be oxidized with Cr "" - ß reagents directly to the acid 15. The 15-base treatment generates salt 16. Esters 17 can be prepared by reacting 15 with an alkylating agent in the presence of a base. The methyl ester of 15 is conveniently prepared on a small scale by reaction of 15 with diazo ethane in ether.

MnO5 25 R- * = alkyl of 1 to 6 carbon atoms or substituted benzyl, METHOD E A diphenylmaleic anhydride 18 can be reduced to the diol 11 with suitable hydride reducing agents, such as diisobutyl aluminum hydride or lithium aluminum hydride. Solvents, such as toluene, tetrahydrofuran or ether, or a mixture thereof, are suitable for reduction, METHOD F The 2,3-diphenicmaleic anhydride 18 can be prepared by the Fields CJ method. Org. Chem. »Volume 55» pages 5165-5170 (1990); US 4,596.8671 wherein a phenylacetic acid 19 is reacted with a fa-oxophene lactic acid 20 (preferably its potassium salt) in acetic anhydride. A sequence of multiple steps up to IB, from feni lacetoni tri, such as 21 and 22, is described by Smith and co-authors in J. Org. Chem., Volume 55, pages 3351-3362 (1990). Florac and collaborators in Tetrahedron, volume 46 »pages 445-452 (1990) describe another synthesis of 18 in several steps, starting with alpha-bromopheni lacetohydrazides 23 and 24.

(Florac) Some lactones 10 are shown in Table I, from which the compounds of the present invention can be prepared according to method D. In Table II and III, representative compounds of the present invention are shown (structures la and Ib). ).

TABLE I Lactone TABLE I (continued) Lactone 25 TABLE I (continued) Lactone 25 TABLE I (continued) Lactone 25 TABLE I (continued) ona 25 TABLE I (continued) Lactone 25 TABLE I (continued) a 25 TABLE I (continued) tona TABLE I (continued) Lactone 25 TABLE I (continued) Lactone 25 TABLE I (continued) Lactone 25 TABLE I (continued) Lactone twenty TABLE II the COMPOSITE R2 R = »X Y 1 H H CH2OH CH3 2 H H CH2OH CH2OMe 3 H H CHO CH 3 4 H H C02H CH3 H H C02Me CH3 6 H H C02Na CH3 7 H H CHO CH 2? 8 H H C02H CH2OMe 9 H H C02Me CH2OMe H H C02Na CH2OMe 11 H F CH2OH CH3 12 H F CHO CH -.OMe 13 H F C02Me CH3 14 H F C02H CH3 H F C02Na CH3 16 F F C02H CH3 17 F F C02Me CH3 18 F F C02Me CH20Me 19 F F COa? Ma CH2OMe F F CH2OH CH3 TABLE III Ib COMPOSITE R5 * "R3 X Y 21 H H CH2OH CH3 22 H H CH2OH CH2OMe 23 H H CHO CH 3 24 H H C02H CH3 H H C02Me CH3" 26 H H C02Na CH3 27 H H CHO CH 2OMe 28 H H C02H CH2OMe 29 H H C02Me CH2OMe H H C02Na CH2OMe 31 H F CH2OH CH3 32 H F CHO CH 2OMe 33 H F C02Me CH3 34 H F C02H CH3 H F C02Na CH3 ANALYSIS TO DETERMINE THE BIOLOGICAL ACTIVITY The compound of formula I can be tested using the following analyzes to determine its inhibitory activity of cyclooxygenase-2.

INHIBITION OF THE ACTIVITY OF CICLOOXIQENASA The compounds are tested as inhibitors of cyclooxygenase activity in cyclooxygenase analysis in whole cells. Both analyzes measure the synthesis of prostaglandin to E2 in response to arachidonic acid using a radioinoneanalysis. In these analyzes »100% activity is defined as the difference between the synthesis of prostaglandin E2 in the absence and in the presence of arachidonate.

Analysis in whole cells For cyclooxygenase analyzes, osteosarcoma cells are cultured in 1 ml of multipurpose medium (Nunclon) from 24 concavities to confluence (1-2 x 10a cells concavity) .U-937 cells are grown in centrifuge flasks and resuspend at a final density of 1.5 x 10ß cells / ml in multiplates (Nunclon) of 24 concavities.After washing and re-suspending the osteosarcoma and U-937 cells in 1 ml of HBSS », 1 μl of a DMSO solution of the test compound "or the DMSO vehicle, and mix the samples gently, carry out all analyzes in triplicate, then incubate the samples for 5 or 15 minutes at 37 ° C before adding the acid Arachidonic acid is prepared (peroxide-free, Cayman Chemical) as a 10 mM master solution in ethanol and is further diluted 10 times in HBSS. An aliquot of 10 μl of this diluted solution is added to the cells to give the cells a final concentration of arachidonic acid of 10 μM. Control samples are incubated with vehicle ethanol instead of arachidonic acid. The samples are gently mixed again and incubated for another 10 minutes at 37 ° C. For the osteosarcoma cells, the reactions are then stopped by the addition of 100 μl of HCl, with mixing and by rapid elimination of the solution from the monolayers of cells. For U-937 cells. the reactions are stopped by the addition of 100 μl of IN HCl with mixing. The samples are then neutralized by adding 100 μl of IN NaOH and the levels of PGEJB are measured by radioimmunoanalysis.

Analysis in whole cells for COX-2 and COX-1. using transfected CHO cell lines.

Chinese hamster ovary (CHO) cell lines that had been stably transfected with a pCDNAIII eukaryotic expression vector containing human COX-1 or COX-2 cDNA for analysis are used. These cell lines are CHOChCOX-i: and CHOChCOX-2-3, respectively. For the analyzes of cyclooxygenase, CHOChCOX-1 cells are harvested from suspension cultures and CHOChC0X-2"l cells, prepared by tri-peptization of adherent cultures; centrifugation (300 xg, 10 minutes) and washed once in HBSS containing 15 mM HEPES, pH 7.4 »and resuspended in HBSS» 15 M HEPES »pH 7.4» at a cell concentration of 1.5 x 10ß cells / ml. It dissolves the drugs that are going to be tested »in DMSO at 66.7 times the highest concentration of the test drug. Compounds are typically tested at 8 concentrations, in duplicate »using serial dilutions in 3-fold series» in DMS «O» of the highest drug concentration. Pre-incubate cells (0.3 x 10ß cells in 200 μl) with 3 μl of the test drug or DMSO vehicle "for 15 minutes" at 37 ° C. The working solutions of peroxide-free AA (5.5 μM and 100 μM AA for CHOChCOX-lD and CHOChCOX-21 .. analyzes) are prepared by diluting to 10 times the AA solution concentrated in ethanol. in HBSS containing 15 mM HEPES. pH 7.4. Then the cells are challenged in the presence or absence of the drug, with the solution of AA / HBSS. to produce a final concentration of 0.5 μM AA in the CHOChCOX-l "] analysis and a final concentration of 10 μM in the CHChC0X-23 analysis.The reaction is terminated by the addition of 10 μl of HCl liM» followed by neutralization with 20 μl of 0.5N NaOH The samples are centrifuged at 300 xg at 4 ° C for 10 minutes and an aliquot of the clarified supernatant is diluted appropriately for the determination of the PGE2 levels using an immunoanalysis linked to enzyme for PGE2 (PGE enzyme immunoassay kit - correlated »Assay Designs» Inc.) Cyclooxygenase activity is determined in the absence of test compounds »as the difference in PGE ... levels of the challenged cells with arachidonic acid against PGE3 levels in cells challenged in a fictitious manner with ethanol vehicle The inhibition of P6E- synthesis by the test compounds is calculated as a percentage of the activity in of the drug against activity in the positive control samples.

Analysis of COX-1 activity from U937 cell microsomes.

Pellets of U937 cells are formed by centrifugation at 500 x g for 5 minutes »and they are washed once with phosphate-regulated salt and the pellet is re-formed. The cells are resuspended in homogenization buffer consisting of 0.1 M Tris-HCl. pH 7.4, 10 M EDTA, 2 μg / ml leupeptin, 2 μg / ml soybean trypsin inhibitor »2 μg / ml aprotinin and 1 mM phene fluoride Imeti Isulfoni lo.

The cell suspension is treated sonically, four times for 10 seconds, and centrifuged at 10,000 x g for 10 minutes at 4 ° C. The supernatant is centrifuged at 100,000 x g for 1 hour at 4 ° C. The microscopic 100,000 x g pellet is resuspended in 0.1 M Tris-HCl, pH 7.4, 10 mM EDTA, at approximately 7 mg protein / ml, and stored at -0 ° C. The microsomal preparations are thawed immediately before use, subjected to a sonic treatment and then diluted to a protein concentration of 125 μg / ml in 0.1 M Tris-HCl buffer, pH 7.4, containing 10 mM of EDTA 0.5 mM phenol. 1 mM of reduced glutathione and 1 μM of he atina. The analyzes are carried out in duplicate in a final volume of 250 μl. Initially, 5 μl of DMSO vehicle or drug in DMSO is added. to 20 μl of 0.1M Tris-HCl buffer, pH 7.4, containing 10 mM of ETA, in concavities of a polypropylene titration plate, with 96 deep concavities. Then 200 μl of the microsomal preparation is added and preincubated for 15 minutes at room temperature before adding 25 μl of 1M arachidonic acid in 0.1 M Tris-HCl and 10 mM EDTA. pH 7.4. The samples are incubated for 40 minutes at room temperature and then the reaction is stopped by adding 25 μl of IN HCl. The samples are neutralized with 25 μl of IN NaOH before quantification of the PGE content; -. using radioimmunoanalysis (Dupont-EN or Amersham analysis equipment). , Cyclooxygenase activity is defined as the difference in PGE.- levels, in samples incubated in the presence of arachidonic acid and vehicle ethanol.

Analysis of the activity of purified human COX-2 The enzyme activity is measured using a chrogenic analysis which is based on the oxidation of N, N, N ', γ -tetramethi-p-eni-1-endiamine (TMPD) during the reduction of PGG2 to PGH2. COX-2 (Copeland and coauthors (1994), Proc. Nati Acad. Sei., 91. 11202-11206). Recombinant human COX-2 is purified from Sf9 cells, as described above (Percival and co-authors ( 1994) Arch. Biochem. Biophys .. 15. 111-118) The analysis mixture (180 μl) contains 100 mM sodium phosphate, pH 6.5, 2 M genapol X-100, 1 μM hematin. mg / ml gelatin 80-100 units of purified enzyme (one unit of enzyme is defined as the amount of enzyme needed to produce a change in O. D of 0.001 / min at 610 nm) and 4 μl of test compound in DMSO The mixture is preincubated at room temperature (22 ° C) for 15 minutes, before starting the enzymatic reaction by the addition of 20 μl of a sonically treated solution of 1 M arachidonic acid ico (AA) and 1 mM of TMPD in the analysis regulator (without enzyme or haematin). Enzymatic activity is measured by estimating the initial oxidation rate of TMPD during the first 36 seconds of the reaction. A non-specific reaction rate is observed in the absence of enzyme (0.007-0.010 0. D./min) and subtracted from the calculation of the percent inhibition. The IC50 values are derived from the least squared, 4-parameter, non-linear regression analysis diagram of the logarithmic dose against the percentage of inhibition.

AN LYSIS OF HUMAN WHOLE BLOOD Exposition Whole human blood provides a medium rich in proteins and cells, suitable for the study of the biochemical effectiveness of anti- inflammatory compounds, such as selective COX-2 inhibitors. Studies have shown that normal human blood does not contain the COX-2 enzyme. This is consistent with the observation that COX-2 inhibitors have no effect on the production of PGE2 in normal blood. These inhibitors are active only after incubation of whole human blood with LPS, which induces COX-2. This analysis can be used to evaluate the inhibitory effect of selective COX-2 inhibitors on the production of PGE2. Likewise, platelets in whole blood contain a large amount of COX-1 enzyme. Immediately after blood coagulation, platelets are activated by means of a mechanism mediated by thrombin. This reaction results in the production of thromboxane B2 (TxB2) by activation of COX-I. Thus, the effect of test compounds on TxB2 levels, after blood coagulation, can be examined and used as an indicator of COX-1 activity. Accordingly, the degree of selectivity for the test compound can be determined by measuring the levels of PGE2 after the induction of LPS (COX-2) and TxB2 after blood coagulation (COX-1), in the same analysis.

The method A. CQX-2 (production of PGE., »Induced by LPS) Fresh blood is collected in heparinized tubes, by venepuncture in male and female volunteers. The subjects had no apparent inflammatory conditions, and had not taken any NSAIDs for at least 7 days prior to blood collection. Plasma is immediately obtained from a 2 ml aliquot of blood for use as a blank reference (basal levels of PGE.-., »). The remaining blood is incubated with LPS (100 μg / ml final concentration, Sigma Chem., TtL-2630) of E. coli; diluted in O.i? of BSA (saline regulated with phosphate) for 5 minutes at room temperature. Incubate with 500 μl of blood with 2 μl of vehicle (DMSO) or 2 μl of a test compound, at final concentrations ranging from 10 nM to 30 μM for 24 hours at 37 ° C. At the end of the incubation, the blood is centrifuged at 12,000 x g for 5 minutes to obtain plasma. An aliquot of 100 μl of plasma is mixed with 400 μl of methanol to precipitate the protein. The supernatant is obtained and analyzed for PGE, ..., using a radioimmunoanalysis device (Amersham, RPA «630) after converting PGE2 to its methyl oximate derivative, according to the manufacturer's procedure.

B. COX-l (Coagulation induced T Ba production Fresh blood is collected in vacuum containers that do not contain anticoagulants. Aliquots of 500 μl are immediately transferred to siliconized microcentrifuge tubes, pre-loaded with 2 μl of DMSO or of a test compound, at final concentrations ranging from 10 nM to 30 μM.

Vortex is formed in the tubes and incubated at 37 ° C for one hour to allow the blood to clot. At the end of the incubation, the serum is obtained by centrifuging (12,000 x g for 5 minutes). An aliquot of 100 μl of serum is mixed with 400 μl of methanol to precipitate the protein. The supernatant is obtained and analyzed for TxB2, using an enzyme immunoassay kit (Cayman, 8 519031), according to the manufacturer's instructions.

ANALYSIS OF EDEMA IN THE FRONT OF THE RAT Protocol Male Sprague-Dawley rats (150-200 g) were fasted overnight and orally administered either a vehicle (1% Methocel or 5% Tween 80) or a test compound. One hour later a line is drawn using a permanent marker at the level above the ankle on a front leg, to define the area of the leg to be monitored. The volume of the leg (VO) is measured using a plethysmometer (Ugo-Basile, Italy), based on the principle of water displacement. Then animals are injected subplantarmente 60 μl of solution to IX of carrageenin in saline (FMC Corp, Maine) in the paw, using an insulin syringe, with a 25-gauge needle (ie, 500 μg of carrageenan per leg) . Three hours later the volume of the paw (V3) is measured and the increase in the volume of the paw (V3 - VO) is calculated. The animals are sacrificed by asphyxiation with CO .. and the absence or presence of stomach lesions is noted. The data is compared with the vehicle control values and the inhibition percentage is calculated. All treatment groups are coded to eliminate the deviation of the observer.

GASTROPATIA INDUCED BY NSAID IN RATS Exhibition The main side effect of conventional NSAIDs is their ability to produce gastric lesions in man. It is believed that this action is caused by the inhibition of Cox-1 in the gastrointestinal tract. Rats are particularly sensitive to the actions of IMSAIDs. In fact »rat models have been commonly used» in the past »to assess the gastrointestinal side effects of current conventional NSAIDs. In the present analysis, gastrointestinal damage induced by NSAID is observed by measuring fecal axCr excretion after systemic injection of red blood cells labeled with axC. The excretion of fecal Cr is a well-established and sensitive technique for detecting gastrointestinal integrity in animals and man.

Methods It is administered orally to male Sprague Dawley rats (150-200 g> a test compound either once (acute dosing) or b.i.d. for 5 days (chronic dosing). Immediately after administration of the last dose »the rats are injected through the caudal vein» with 0.5 ml of red blood cells marked with ß «LCr» from a donor rat.The animals are placed idly in metabolism cages »with food and water ad 1 The stool is collected over a period of 48 hours and the faecal excretion of a Cr is calculated as the percentage of the total injected dose.Red blood cells marked with Cr are prepared using the following procedures. of blood in heparinized tubes through the vena cava of a donor rat.The plasma is removed by centrifugation and refilled with equal volume of HBSS.The red cells are incubated with 400 Ci of sodium chromate81 for 30 minutes at 37 ° C. the incubation is washed twice the red blood cells with 20 ml of HBS to eliminate the chromate * "1 of free sodium. Finally the red blood cells are reconstituted in 10 ml of HBSS and 0.5 ml of the solution (about 20 Ci) is injected per rat.

GASTROPATIA WITH PROTEIN LOSS IN SPIDER MONKEYS Exposition Gastropathy with protein loss (manifested as the appearance of circulating cells and plasma proteins in the gastrointestinal tract (SI)) is a "significant and dose-limiting" adverse response for normal non-steroidal anti-inflammatory drugs (NSAIDs) . It can be determined quantitatively by intravenous administration of ßa-CrCl .. ,, solution. This isotopic ion can bind avidly to the cells and serum globins and the endoplasmic reticulum of the cell. The measurement of the radioactivity that appears in the feces collected during 24 hours after the administration of the isotope, thus provides a sensitive and quantitative indication of gastropathy with protein loss.

Methods Groups of male spider monkeys (0.8 to 1.4 kg) are treated by administration in the feeding of 1% Methocel 1 or 5 '/, TweenBO in water vehicles (3 ml7 kg, bid) or test compounds at doses of 1 to 100 mg / kg bid for five days. IV-Cr (5 Ci / kg in 1 ml / kg of phosphate buffered saline (PBS)) is administered intravenously one hour after the last dose of drug / vehicle, and the stool is collected for 24 hours in a metabolism cage and the Cr excreted is determined by gamma-ray counting. The venous blood is sampled one hour and 8 hours after the last drug dose, and the drug concentrations in the plasma are measured by RP-HPLC.

LEVELS IN THE RAS PLASMA Oral pharmacokinetics in rats PROCEDURE: Animals are housed, fed and cared for in accordance with the guidelines of the Canadian Council for Animal Care. Male Sprague Dawley rats (325-375 g) are fasted on the night before each study of the PO blood level. The rats are placed on the restrictor one at a time and the box is firmly secured. The zero blood sample is obtained by cutting a small piece (1 mm or less) from the tip of the tail. Then the tail moves with a firm but moderate movement, from the top to the bottom, to draw blood. Approximately 1 ml of blood is collected in a heparinized vacuum vessel tube. The compounds are prepared as required, in a normal dosage volume of 10 ml / kg and administered orally by passing them through a 16 gauge, 7.62 cm delivery needle into the stomach. Subsequent bleeds are collected in the same manner as zero bleed, except that there is no need to trim the tail again. The tail is cleaned with a piece of gauze and tapped to extract "as described above" into appropriately marked tubes. Immediately after sampling the blood is centrifuged, separated, placed in clearly labeled bottles and stored in a freezer until analyzed. The typical time points for the determination of levels in rat blood, after dosing PO. They are: O. 15 minutes. 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours. After bleeding at the 4 hour time point, feed is provided to the rats ad 1 ibi tum. Water is given at all times during the study.

The vehicles The following vehicles can be used in the determination of the rat blood level PO: PEG 200/300/400 restricted to 2 ml / kg. Methocel? .5 * / .- l.o? 10 ml / kg 5% Tween 80 10 ml / kg The compounds for the blood levels of PO can be in the suspension form. For better dissolution the solution can be placed in a sonic treatment apparatus for about 5 minutes.

Intravenous pharmacodynamics in rats. PROCEDURE: Animals are housed, fed and cared for in accordance with the Canadian Animal Care Council Guidelines. Male Sprague Dawley rats (325-375 g) are placed in plastic shoe box cages, with a suspended floor, a cage top, a bottle of water and food. The compound is prepared as required, in a normal dosage volume of 1 ml / kg. The rats are bled for the zero blood sample and dosed under sedation with C0_. The rats "one by one, are placed in a chamber of CO, barley" and are collected as soon as they have lost their reflex of righteousness. Then the rats are placed on a restriction board; a nasal cone with C02 supply is placed on the snout and the rats are restrained to the board with elastics. With the use of forceps and scissors the jugular vein is exposed and the zero sample is taken "followed by a measured dose of compound that is injected into the jugular vein. Light digital pressure is applied to the injection site and the nasal cone removed. The time is noted. This constitutes the zero hour point. You take the minute bleeding by cutting a piece (1-2 mm) from the tip of the tail. Then the tail is struck with a firm but gentle movement from the top of the tail to the bottom to extract the blood from the tail. Approximately 1 ml of blood is collected in a heparinized collection bottle. Then he takes the next blood samples in the same way. except that there is no need to trim the tail again. The glue is cleaned with a piece of gauze and bled as described above, to the appropriately marked tubes. Typical time points for the determination of rat blood levels »after dosing I. V.» are: 0.5 min, 15 min, 30 min, 1 h, 2 h, 6 h; or 0.5 mi, 30 mi »1 h. 2 h. 4h »6h.

The vehicles The following vehicles can be used in IV blood rat level determinations: dextrose 1 ml / kg Molecusol at 255 μl ml / kg DMSO (dimethyl sulfoxide) restricted to a dose volume of 0.1 ml per animal. PEG 200: Not more than 60%. mixed with A0% sterile water - 1 ml / kg With dextrose you can add sodium bicarbonate or sodium carbonate, if the solution is cloudy. For analysis, the aliquots are diluted with an equal volume of acetonitrile and centrifuged to remove the protein precipitate. The supernatant is injected directly onto a C-18 HPLC column with UV detection. Quantification is performed in relation to a sample of chopped blood with a known amount of drug. The bioavailability is determined (F) by comparing the area under the curve (AUS). i. v. against p. and.

AUCpo DOSISiv? x x lOO'í AU iv DOSISpo Elimination speeds are calculated from the following relationship: DOSISi v (mg / kg) Cl = AYCiv The units of Cl are ml / h-kg (milliliters per hour per i achieved).

BIOLOGICAL DATA REPRESENTATIVE The compounds of the present invention are prodrugs of the COX-2 inhibitors and are thus useful in the treatment of COX-2 mediated diseases. as those listed above. The degree of conversion of these compounds to the active COX-2 inhibitors can be seen in the representative results shown below. The levels in the plasma indicated are the maximum concentrations in the rat plasma of the active COX-2 inhibitor »observed when treating the rat with an oral dose of 20 mg / kg of the prodrug indicated.

TABLE IV Example Levels in the plasma (uM) * 1 1.0 * The maximum concentration in the plasma of the corresponding lactone »observed in rats» when orally administered 20 mg / kg of the indicated prodrug. The invention will now be illustrated by the following non-limiting examples "in which" unless otherwise indicated: (i) all operations were carried out at room temperature "ie at a temperature in the range of 18 to 25 ° C; (ii) evaporation of the solvent was carried out using a rotary evaporator at reduced pressure (600-4,000 pascais: 4.5-30 mm Hg) with a bath temperature up to 60 ° C; (iii) the course of the reactions was followed by thin layer chromatography (TLC) and the reaction times are given only for illustration; (iv) the melting points are not corrected; and "d" indicates decomposition; the melting points given are those obtained for the materials prepared as described; the polymorphism can result in the isolation of materials with different melting points in some preparations; (v) the structure and purity of all final products were assured by at least one of the following techniques: TLC »mass spectrometry, nuclear magnetic resonance (NMR) spectrometry, or microanalytical data; (vi) yields are given only as an illustration; (vii) when they appear, the NMR data are in the form of delta values (¿) for the main diagnostic protons, given in parts per million (ppm) in relation to tetrameti Isi la or (TMS) as an internal standard, determined at 300 MHz or 400 MHz, using the indicated solvent; The conventional abbreviations used for the signal form are: s = a single band; d = double band; t = triple band; m = multiple bands; br = broad; etc.; in addition, "Ar" means an aromatic signal; (viii) chemical symbols have their usual meanings; The following abbreviations have also been used: v (volume). w (weight), p. and. (Boiling point); p. F. (melting point); 1 (liters); mi (milliliters); g (grams); mg (milligrams; mol (moles); mmol (millimoles), eq (equivalents).

EXAMPLE 1 (E) -3- (4-Methylsulfonyl) feni 1-2-phenyl-1-but-2-enoic acid methyl ester Step 1: 2-Methoxy-3- (4-methyllio) enyl-2-phenyl-1-butanoic acid methyl ester.

To a solution of 2.9 g, 13.7 mmol, of 1- (1-dimethoxy-1-yl) -4-methyl-1-thiobenzene in 100 ml of methylene chloride, cooled to -78 ° C, a solution of 13.7 ml was added dropwise. , 1 M of Ti l ^ in methylene chloride, followed by 4. 6 g, 16.4 mmol of (2,2-bis-trimeti lei 1 i loxi vini 1) benzene, prepared according to the procedure published by Ainsworth, J. Organomet. Chem., 1972, 46, 73). The reaction mixture was stirred at -78 ° C for two hours and quenched with regulator solution at pH 7 (60 ml of NaH2PO_ / Na2HPO.- »). The mixture was extracted with 3 x 50 ml of methylene chloride. The extracts were combined, dried over magnesium sulfate and concentrated. The residue was dissolved in 50 ml of ether and treated with an excess of CH 2 N 2 in ether. Evaporation of the ether yielded the crude title compound, as a diastereomeric mixture.

Step 2: Methyl ester of (E) and (Z) -3- (4-methylsul onyl) phenyl 1-2-phenyl-1-but-2-enoic acid 0.62 g of the crude product from step 1 was dissolved in 10 ml of methanol at 0 ° C. A solution of 4.0 ml, 0.75 M of Oxone in water was added dropwise, and the mixture was stirred at 0 ° C for 10 minutes and at room temperature for two hours. The mixture was then diluted with 10 ml of water and extracted with 3 x 20 ml of methylene chloride. The extracts were combined, dried over magnesium sulfate and concentrated. The residue was dissolved in 10 ml of acetonitrile and treated with 0.51 ml of DBU. The mixture was then heated at reflux for 22 hours and cooled to room temperature. The solvent was evaporated and the residue was purified by chromatography on silica gel. Elution with 9: 1 hexane / ethyl acetate first provided the E-isomer (0.25 g) as a white solid. NMR with (400 MHz, CDCl.,) Or 7.69 (2H, d), 7.20 (2H, d), 7.11 (3H, m), 6.96 (2H,). 3.78 (3H, s), 2.97 (3H, e), 2.34 (3H, s). Continuous elution with 4: 1 hexane / ethyl acetate gave 0.35 g of the Z isomer, as a white solid. NMR with - «- H (400 MHz, CDCl ,,) or 7.92 (2H, d). 7.48 (2H, d). 7.41 (2H; m). 7.33 (3H, m>, 3.44 (3H, s), 3.07 (3H, s), 2.01 (3H, S).

EXAMPLE 2 Aci or (E) -3- (4-meti Isul om * 1) feni 1-2-phenyl but-2-enoic A mixture of 258 mg of the methyl ester of (E) -3- (4-meth i 1 sul foni 1) -phenyl 1-2-ene-but-2-enoic acid and 98 mg was heated at reflux for two hours. of LiOH-H20 in 5 ml of dioxane and 5 ml of water. The reaction mixture was then cooled to room temperature, acidified with 1N HCl to pH about 1, and extracted with 50 ml of EtOAc. The ethyl acetate layer was dried over sodium sulfate and concentrated. Crystallization in 1: 1 hexane / ethyl acetate product 200 mg of the title acid, as a white solid. NMR with AH (400 MHz, CDCl- ,.) or 7.69 (2H.D), 7.19 (2H, d). 7.13 (3H; m), 6.98 (2H.m), 2.97 (3H.s); 2.47 (3H, s).

EXAMPLE 3 (E) -2- (4-chlorophenyl) -3- (4-ethylsulfonyl) -phi-l-2-enoic acid methyl ester NMR with H (400 MHz, acetone-dβ)? 7.76 (2H, d>, 7.36 (2H, d), 7.06 (2H,), 6.90 (2H, m), 3.76 (3H, s), 3.05 (3H, s), 2.36 (3H, s).

EXAMPLE 4 (E) -3- (4-Methylsulfon * 1) pheny1-morphol in-4-i 1-2-phenyl-butyl-2-en-l- or a The title compound was prepared according to the procedures described in method C.

NMR with JH (400 MHz, CDCl-,) or 7.73 (2H, d), 7.28 (2H, d), 7.13 (3H, m), 7.01 (2H, m), 3.72 (2H,), 3.64 (2H, m), 3.42 < 4H, bs), 3.00 (3H, s), 2.21 (3H, s).

EXAMPLE 5 Acid (E) -4-methox? -3- (4-methy1sul on? 1 in? 1) -2-fem'lbutenoic acid The title compound was prepared according to the procedures described in method D. NMR with ^ -H (400 MHz, acetone-dß) or 7.75 (2H »), 7.42 (2H, d), 7.15 (5H, m) , 4.55 (2H, s), 3.30 (3H, s), 3.05 (3H, s).

Claims (17)

1. NOVELTY OF THE INVENTION CLAIMS or their pharmaceutically acceptable salts, characterized in that X is (a) CH 2 OH; (b) CHO; (c) C02R- », or (d) CONR-» 2; Y is (a) CH3 »or (b) CH2ORβ; R is selected from the group consisting of: (a) S (0) 2CH3, (b) S (0) 2NH2, (OS (0) 2NHC (0) CF3, (d) S (0) (NH) CH3, (e) S (0) (NH) NH2, (f) S (O) (H) NHC (O) CF3, (g) P (0) (CH3) OH, and (h) P (0) (CH3 ) NH2, each of Rz and R = »is independently selected from the group consisting of (a) hydrogen, (b) halogen, (c) alkoxy of 1 to 6 carbon atoms, (d) alkylthio of 1 to 6 atoms carbon, (e) CN, (f) CF3, (g) alkyl of 1 to 6 carbon atoms, and (h) N3; R- * is selected from the group consisting of: (a) hydrogen, (b) alkyl of 1 to 6 carbon atoms and (c) mono- or disubstituted benzyl, in which the substituent is selected from: (1) hydrogen, (2) halogen, (3) alkyl of 1 to 6 carbon atoms. 4) alkoxy of 1 to 6 carbon atoms, (5) alkylthio of 1 to 6 carbon atoms, (6) OH, (7) CN "and (8) CF3, or two R- * groups together, attached to it N. can form a saturated ring of 5, 6 or 7 members, optionally containing a 0 or S atom or an atom of additional N, said N atom is substituted with a hydrogen or alkyl of 1 to 6 carbon atoms; Rβ is selected from the group consisting of: (a) alkyl of 1 to 6 carbon atoms. (b) benzyl mono- or disusti tuido. wherein the substituent is selected from: (1) hydrogen, (2). halogen »(3) alkyl of 1 to 6 carbon atoms» (4) alkoxy of 1 to 6 carbon atoms »(5) alkylthio of 1 to 6 carbon atoms» (6) OH, (7) CN, (8) ) CF3; and (9) CO ^ R- *.
2. 2. A compound according to claim 1 »further characterized in that Y is CH3 or CH20-alkylo? from 1 to 6 carbon atoms.
3. 3. A compound according to claim 1 »further characterized in that Y is CHa or CH20-alkyl of 1 to 6 carbon atoms; Rx is selected from the group consisting of: (a) S (0) 2CH3, (b) S (0) 2NH2, (c) S (0) 2NHC (0) CF3, (d) S (0) (NH) CH3, (e) S (0) (NH) NH2, and (f) S (0) (NH) NHC (0) CF3; and each of R * and R3 is independently selected from the group consisting of (a) hydrogen, (b) fluorine, chlorine and bromine; (c) alkoxy of 1 to 4 carbon atoms. < d) alkylthio of 1 to 4 carbon atoms, (e) CN, (f) CFa, and (g) alkyl of 1 to 4 carbon atoms.
4. 4. - A compound in accordance with the claim

   3. further characterized in that each of Rz and R3 is independently selected from the group consisting of (1) hydrogen; and (2) allogen; R is hydrogen or methyl; and RB is alkyl of 1 to 6 carbon atoms.
5. 5. A compound in accordance with the claim 4, further characterized in that R is selected from the group consisting of (a) S (0) 2CH3 and (b) S (0) 2NH2; each of R2 and RS is selected from the group consisting of (1) hydrogen (2) halogen selected from the group consisting of fluorine, chlorine and bromine.
6. 6. A compound according to claim 1 »further characterized in that X e3 C0., R- *"; 7.- A compound according to the rei indication 1 »further characterized because X is C02R- '; Y is methyl or CH20Rβ; Rx is S (0) 2CH3; each of Rz and R3 is independently selected from the group consisting of (a) hydrogen and (b) halogen; R-4 is selected from the group consisting of (a) hydrogen and (b) alkyl of 1 to 6 carbon atoms: Rβ is selected from the group consisting of (a) alkyl of 1 to 6 carbon atoms »(b) mono- or disubstituted benzyl» wherein the substituent is selected from: (1) hydrogen »(2) halogen» (3) alkoxy of 1 to 6 carbon atoms, and (4) OH B.- A compound of the formula la: characterized because: R2 R3 X Y 1 H H CH2OH CH3 2 H H CH2OH CH2OMe 3 H H CHO CH 3 4 H H C02H CH3 5 H H C02Me CH3 6 H H C02Na CH3
7. 7 H H CHO CH 2OMe
8. 8 H H C02H CH2OMe 9 H H C02Me CH2OMe 10 H H CO-gNa CH2OMe 11 H F CH2OH Ha ' 12 H F CHO CH 2OMe 13 H F C02Me CH3 14 H F C02H CH3 15 H F C02Na CH3 16 F F C02H CH3 17 F F C02Me CH3 18 F F C02Me CH2OMe 19 F F C02Na CH2OMe 20 F F CH, OH CHa
9. 9. - A compound of the formula Ib: Ib R * R3 XY 1 HH CH2OH CH3 2 HH CH2OH CH2OMe 3 HH CHO CH3 4 HH C02H CH3 5 HH C02Me CH3 6 HH C02Na CH3 7 HH CHO CH 2OMe 8 HH C02H CH2OMe 9 HH C02Me CH2OMe 10 HH C02Na CH2OMe 11 HF CH2OH CH3 12 HF CHO CH 2OMe 13 HF C02Me CH3 14 HF C02H CH3 15 HF C02Na CH3
10. 10. - A compound according to claim 1, characterized in that it is selected from: (a) methyl ester of (E) -3- (4-methyl Isulfoni 1) feni 1-2-fem "lbut-2- enoic (b) (E) -3- (4-methylsulfoni 1) phenyl 1-2-phenyl-buty-2-enoic acid ((E) -2- (4-f luorofeni 1) methyl ester) -3- (4-methyl Isulfoni 1) phenyl-but-2-enoic; (d) (E) -3- (4-methyl-1-sulfonyl) -phi 1-1-morphol in-4-i 1-2- fem "1 but-2-en-l-one; and (e) acid < E) -4-methaxy-3- (4-methylsulfon" Ifeni 1) -2-phenyl-1-butenoic.
11. Pharmaceutical for treating an inflammatory disease susceptible to being treated with a non-steroidal anti-inflammatory agent, characterized in that it comprises: a non-toxic, therapeutically effective amount of a compound according to any one of claims 1 to 10, and a pharmaceutically carrier acceptable.
12. 12. - A pharmaceutical composition for treating diseases mediated by cyclogenase »advantageously treated with an active agent that selectively inhibits COX-2 in preference to COX-1» characterized in that it comprises: a therapeutically effective amount. non-toxic of a compound according to any of the rei indications 1 to 10 and a pharmaceutically acceptable carrier.
13. 13. The use of a compound according to claim 1 »and in combination with a pharmaceutically acceptable carrier» in the manufacture of a medicament for treating an inflammatory disease »capable of being treated with a non-steroidal anti-inflammatory agent.
14. 14. The use of a compound according to claim 1, in the manufacture of a medicament for treating diseases mediated by cyclo-oxygenase. advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX-1.
15. 15. An anti-inflammatory pharmaceutical composition. characterized in that it comprises an acceptable anti-inflammatory amount, of a compound of the formula (I) as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or a pharmaceutically acceptable salt of the same, in association with a pharmaceutically acceptable carrier.
16. 16. The use of a compound of the formula (I) as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or of a pharmaceutically acceptable salt thereof, in the treatment of diseases mediated by cyclo-oxygenase. advantageously treated by an agent that selectively inhibits COX-2 in preference to COX-1.
17. 17. The use of a compound of the formula (I). as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or of a pharmaceutically acceptable salt of the "meme" in the manufacture of a medicament for the treatment of an inflammatory disease. susceptible to being treated with a non-steroidal anti-inflammatory agent.