MXPA98008174A - New derivatives of diarylemetilidene furanicos, methods of preparation and their use terapeut - Google Patents

Abstract

The present invention relates to diarylmethylidene furan derivatives of formula (I) and their use in therapeutics, especially as medicaments with anti-inflammatory and antialgic properties.

Description

NEW DERIVATIVES OF FURANIC DIARYLEMETILIDENE, METHODS OF PREPARATION AND Sü THERAPEUTIC USE The present invention relates, as novel products, to the diarylmethylidene furan derivatives of general formula (I). One of the biotransformation pathways of arachidonic acid is the cyclooxygenase pathway; This allows the transformation of arachidonic acid into PGG2 then into PGH2. Recent work on the cloning and sequencing of cyclooxygenase makes it possible to highlight two COX-1 and COX-2 isoenzymes within many species and in humans in particular. The first is a constitutive enzyme, expressed in most tissues, while the second, which is expressed in some tissues such as the brain, can be induced in most tissues by numerous products, in particular by cytokines and mediators. produced in the course of the inflammatory reaction. Each enzyme plays a different role and the inhibition of COX-l or COX-2 will cause consequences that are not identical. The inhibition of COX-1 will cause a decrease in the prostaglandins that participate in homeostasis in which it can cause side effects. The inhibition of COX-2 will cause a decrease of the prostaglandins produced in the inflammation situation. Thus, the selective inhibition of COX-2 allows a well-tolerated anti-inflammatory agent to be obtained. The compounds of the invention make it possible to obtain this selective inhibition. Consequently, the compounds in question present a very interesting pharmacological profile insofar as they are endowed with anti-inflammatory and analgesic properties while being remarkably well tolerated, especially at the gastric level. They will be particularly indicated for the treatment of inflammatory phenomena and for the treatment of pain. It can be mentioned, for example, its use in the treatment of arthritis, especially rheumatoid arthritis, spondylarthritis, arthritis of gout, osteoarthritis, juvenile arthritis, autoimmune diseases, lupus erythematosus. They will be equally indicated for the treatment of bronchial asthma, dysmenorrhea, tendonitis, bursitis, dermatological inflammations such as psoriasis, eczema, burns, dermatitis. They can also be used for the treatment of gastrointestinal inflammations, Crohn's disease, gastritis, ulcerative colitis, the prevention of cancer, especially colon adenocarcinoma, the prevention of neurodegenerative diseases, particularly Alzheimer's disease, the prevention of attacks, epilepsy and the prevention of premature uterine labor.

Its anti-allergic properties also allow its use in all painful symptoms especially in the treatment of muscle, joint or nerve pain, dental pain, areas and migraines, in the treatment of rheumatic diseases, cancerous pains, but also in the manner of complementary treatments in infectious and febrile states. The present invention also relates to the process for the preparation of these products and their applications in therapy. Certain derivatives are described in the literature as having selective inhibitory properties of cyclooxygenase-2. Mention may be made, for example, of the compounds described in the following patent applications: WO 95 00501 A (Merck Frosst Canada Inc.) WO 94 15932 A (GD Searle and Co.) WO 96 08482 A (Merck and Co. Inc.) In a general manner, most of the compounds described in these documents as selective inhibitors of cyclooxygenase-2 are the derivatives of 5-atom heterocycles, substituted by two aromatic nuclei directly attached to the heterocycle and are found on two adjacent carbon atoms. of this heterocycle. The Applicant has discovered, surprisingly, that the derivatives have the two nuclei on the same carbon, these two aromatic nuclei that are linked to the heterocycle but not directly but by means of a double bond, possess the selective inhibitory properties of the cyclooxygenase- 2 notable. These furanic diarylmethylidene derivatives are characterized in that they correspond to the general formula (I): Formula (I) in which: Cycles A and B independently represent: - a phenyl radical - a naphthyl radical - a radical derived from a heterocycle having from 5 to 6 Cctdenas and possessing from 1 to 4 heteroatoms - a radical derived of a saturated hydrocarbon cycle having from 3 to 7 carbon atoms at least one of the substituents X, X2, [or Y2] necessarily represents: - a group -S (0) nR in which n is an integer equal to O, l or 2 and R is a lower alkyl radical of 1 to 6 carbon atoms, a halogen radical lower alkyl of 1 to 6 carbon atoms, - a group -SO2NH2; and is in the para position, the others independently represent - the hydrogen atom - a halogen atom - a lower alkyl radical of 1 to 6 carbon atoms - a trifluoromethyl radical, - an O-lower alkyl radical of 1 to 6 atoms carbon or also Xj and X2 or Y1 and Y2 represent a methylene dioxy group, Rj, R2, R3 and R4 independently represent - the hydrogen atom - a halogen atom - a lower alkyl radical of 1 to 6 carbon atoms, - a lower haloalkyl radical of 1 to 6 carbon atoms, - an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl or pyridyl, or also R¡R2 or R3R4 represent an oxygen atom or Rlf R2 or R3, R4, together form with the carbon atom to which they are attached a saturated hydrocarbon cycle having from 3 to 7 carbon atoms. In the description and the claims, the lower alkyl is a hydrocarbon chain having 1 to 6 carbon atoms, linear or branched. A lower alkyl radical is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary thiobutyl, pentyl, isopentyl, hexyl, isohexyl radical. By radical halo-lower alkyl, it is meant an alkyl radical of 1 to 6 carbon atoms whose 1 to 7 hydrogen atoms are substituted by 1 to 7 halogen atoms. A haloalkyl radical radical is, for example, a trifluoromethyl radical, a 2,2,2-trifluoroethyl radical, a pentafluoroethyl radical, a 2,2-difluoro-3,3,3-trifluoropropyl radical, a heptafluoropropyl radical, a chloromethyl or bromomethyl radical. Halogen is understood as a chlorine, bromine, iodine or fluorine atom. By saturated hydrocarbon cycle having from 3 to 7 carbon atoms, it is meant cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane. By a radical derived from a heterocycle, all the aromatic rings having one to four heteroatoms in the nucleus are understood: nitrogen, oxygen or sulfur. Among these cycles, pyridine, furan, thiophene, and also pyrrole, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, an oxazole, oxadiazole, thiazole, thiadiazole will be particularly preferred. The aforementioned derivatives of formula (I) may have centers of asymmetry and / or be in the form of cis or trans derivatives. The invention covers racemic, mixtures of cis and trans compounds but also optically active products, cis derivatives and trans derivatives taken independently. The production of these pure products will be carried out according to methods known to the person skilled in the art, in particular by chromatography, especially on chiral columns when optical isomers are active. This separation can also be done in certain cases by simple recrystallization. It can be done either on the final product, or on a synthesis intermediary, in this case the continuation of the synthesis will respect the stereochemistry of the intermediate molecule. Advantageously, the derivatives according to the invention are the aforementioned derivatives of formula (I) in which: Cycles A and B independently represent a radical: phenyl-naphthyl-pyridyl-furyl-thienyl-cyclohexyl at least one of the substituents Xlf X2, Yi or Y2 necessarily represents a SCH3 group, SO2CH3 or S02NH2, the others independently represent: - the hydrogen atom - a halogen atom - a lower alkyl radical of 1 to 6 carbon atoms - a trifluoromethyl radical - an O-lower alkyl radical of 1 to 6 carbon atoms RjR2 represent an oxygen atom R3, R4 independently represent the hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms. Advantageously, within the framework of the present invention, a compound of formula (I) will be used in which, at least one of the following conditions is carried out: - cycle B represents a phenyl radical - Xt represents group 4-SO2CH3 or the group 4-SO2NH2 - X2 represents the hydrogen atom - cycle A represents a phenyl or pyridyl radical - Yi represents the fluorine atom, the chlorine atom or a methyl radical - Y2 represents the hydrogen atom, the fluorine atom or the chlorine atom - RjR2 represents an oxygen atom - R3 represents the hydrogen atom - R4 represents the hydrogen atom Particularly preferred compounds of the invention are the derivatives of the formula: (E) -3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] -dihydro-furan-2-one (Z) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydro-furan-2-one (Z) -3- [1- (3,4-Dichlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] -dihydro-furan-2-one (Z) -3- [1- (6-chloropyridin-3- il) -1- (4-methanesulfonylphenyl) methylidene] -dihydro-furan-2-one (Z) -4- [(4-chlorophenyl) - (2-oxo-dihydro-furan-3-ylidene) -methyl] benzenesulfonamide (Z) -4- [(3-f luoro-4-methylphenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] -benzenesulfone one way According to the invention, the compounds of formula (I) can be synthesized in the following manner: For a Friedel and Crafts reaction of the acid chloride of formula (II) Formula (II) in which A, Yj and Y2 are defined as above in the present about thioanisole, the ketone of formula (III) will be obtained Formula (III) in which A, Y < and Y2 are defined as above in the present. This ketone can also be obtained by means of a Grignard reaction: magnesium reaction of a bromoaromatic derivative which can be substituted, on the p-thiomethyl-benzo-nitrile.

By treating this ketone by an oxidizing agent such as for example metachloroperbenzoic acid, sodium perborate or hydrogen peroxide in the presence of a catalytic amount of molybdenum salts, the derivative of formula (IV) will be obtained.

Formula (IV) in which A, Yj and Y2 are defined as previously in the present. By treating the derivative of formula (IV) by a modified Reformatsky reaction with a bromobutyrolactone of formula (V) Formula (V) in which R3 and R4 are defined as above, in the presence of magnesium and a small amount of methyl iodide to prime the reaction, there will be obtained the derivatives of formula (VI) in which A, Y { , Y2, and R4 are defined as hereinbefore. Finally, by dehydration of the derivatives of formula (VI) by heating in toluene for example in the presence of paratoluenesulfonic acid or by treatment with trifluoroacetic anhydride in trifluoroacetic acid, the compounds of formula (I) will be obtained: wherein B represents a phenyl nucleus, Xt represents a group 4-SO2CH3, X2 represents the hydrogen atom, RtR2 the oxygen atom and A, Y1 (Y12-R3 and R4 are as defined hereinbefore. preparation consists in treating the product of formula (III) either by the derivative of formula (V) according to an identical Reformatsky reaction method modified in the presence of magnesium and methyl iodide to prime the reaction, either by lactones of formula (V) Formula (V) in which, R 3 and R 4 are defined as above, in the presence of N, N-diethylamino magnesium bromide, prepared by the action of N, N-diethylamine on ethyl-magnesium bromide, according to the reference: K. Sisido, H. Nozaki, O. Kurihara J. Am. Chem. Soc., 74, 6254 (1952) to conduct either the already dehydrated compounds of formula (I), or the compounds of formula (VI *) Formula (VI1) in which A, Yt, Y2, R3 and R4 are defined as previously herein. The compounds of formula (VI ') are then dehydrated by treatment with trifuoroacetic anhydride and trifluoroacetic acid to give the compounds of formula (I) hereinafter: Formula (I) in which B represents a phenyl nucleus, Xt represents a group 4 -SCH3, X2 represents the hydrogen atom, R ^ 2 the oxygen atom and A, Y1 (Yμ R3 and R4 are defined as hereinabove. The treatment of the compound thus obtained according to this variant, by meta chloroperbenzoic acid or by another oxidant such as NaB03, 4H20 will lead according to the amount of oxidant used to the compounds of formula (I) Formula (I) in which B represents a phenyl nucleus, X ^ represents a 4-SOCH3 group for an oxidant equivalent or a 4-SO2CH3 group for two equivalents of oxidant, X7 represents the hydrogen atom, R1R2 the oxygen atom and A, Y1 (Y2, R3 and R are defined as above in the present.

Another variant of the preparation of certain compounds of formula (I) is to treat a ketone of formula (III) by ethyl succinate according to the reaction of Stobbe in tertiary butanol in the presence of sodium or potassium tertiary butylate, for example, for driving to the compounds of formula (VII) Formula (VII) in which A, Y < and Y2 are defined as above in the present. Selective reduction of the ester function, for example the calcium borohydride obtained on site from potassium borohydride and calcium chloride in ethanol or dihidroaluminato diethyl sodium in ethyl ether lead after lactonization of hydroxyacids obtained derivatives of formula (VIII). Y, Formula (VIII) in which A, Y < and Y2 are defined as above in the present. The derivatives of formula (VIII) can be oxides as previously described, the group SCH3 is now transformed into group SOCH3 or S02CH3 according to the amount of oxidizing agent used, to lead to the compounds of formula Formula (I) in which B represents the phenyl nucleus, and represents the group 4-SOCH3 or the group 4-SO2CH3, X2, Rj and R2 represent the hydrogen atom, R3R4 the oxygen atom and A, Y1 (Y2 The reduction of the derivatives of formula (VII) by means of lithium aluminum double hydride in tetrahydrofuran, for example, will lead to the diols of formula (IX) Formula (IX) in which A, Y and Y2 are defined as above in the present. The dehydration of these diols by sulfuric acid or by a reflux treatment of toluene in the presence of paratoluenesulfonic acid with a Dean Stark apparatus will make it possible to obtain the compounds of formula (I) Formula (I) in which A, Yt and Y2 are defined as above in the present, B represents the phenyl nucleus, Xj represents the group 4-SCH3, X2, R1; R2, R3, R4 represent the hydrogen atom. By treating these derivatives with an oxidizing agent as described above, the corresponding derivatives will be obtained where Xt represents the group 4-SOCH3 or 4-SO2CH3 according to the amount of oxidant used. Other preparation variants of the compounds of formula 1 can be used. The reaction of the ketones, compounds of formula (IV), with ethyl succinate according to the Stobbe reaction in tertiary butanol in the presence of sodium or potassium tertiary butylate example, will lead to the compounds of formula (X): Formula (X) in which A, Y < and Y2 are defined as above in the present. The selective reduction this time, of the acid function, for example by the action of borane or borane / methyl sulfide complex in terahydrofuran or ethyl ether, will lead to the alcohol esters of Formula (XI): Formula (XI): in which A, Yt and Y are defined as previously in the present. These esters Alcohols of formula (XI) or the corresponding acids alcohols obtained by hydrolysis of the ester function with sodium hydroxide in ethanol to reflux, be cyclized by heating in an aromatic solvent such as toluene, for example, in the presence of paratoluenesulfonic acid to obtain compounds of formula (I): Formula (I): wherein A, Yj and Y2 are defined as above in the present, B represents the phenyl nucleus, Xj represents the group 4-SCH3, X2, R3, and R4 represent the hydrogen atom and RjR2 represent the oxygen atom. In an analogous manner, it will be possible to prepare the compounds of Formula (XII) in which A, Y1 # Y2 have the same meaning as hereinabove, according to the scheme of following rections in which Ph represents a phenyl group and Z represents a MgBr radical when A is a phenyl nucleus and Li when A is a pyridyl nucleus,Formula (XII) A variant consists in preparing the diarylketone (B) used in the above reaction scheme, by the action of benzylmercaptan PhCl ^ Sh on a fluorodiaryl ketone in dimethylformamide in the presence of sodium hydride or sodium carbonate.

The compounds of formula (XII) will be treated as the compounds of formula (X) to lead to the compounds of formula (I) Formula (I) in which B represents a phenyl nucleus, Xt represents the group 4-S0NHt-Bu, X2, 3 and R4 represent the hydrogen atom, RtR2 represents the oxygen atom and A, Y < Y2 are defined as above in the present. By treating these derivatives with a strong acid such as for example concentrated sulfuric acid, trifluoroacetic acid or by heating in toluene in the presence of paratoluenesulfonic acid, the compounds of formula (I) in which B represents the phenyl nucleus, X, will be obtained. represents the group 4-S02NH2, X > R3 and R4 represent the hydrogen atom, RjR2 represents the oxygen atom and A, Y1 and Y2 are defined as above. The compounds of formula (I) as defined above are inhibitors of cyclooxygenase-2 and are endowed with a very good anti-inflammatory and analgesic activity associated with an excellent tolerance in particular gastric. These properties justify their application in therapy and the invention also has the object, as drugs, of products as defined by formula (I) above. Thus, the invention also covers a pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as defined above, optionally incorporated in a pharmaceutically acceptable excipient, carrier or carrier. These compositions can be administered orally, rectally, parenterally, transdermally, ocularly, nasally or via the atrium. These compositions can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine, such as, for example, plain tablets or pills, capsules, granules, suppositories, injectable preparations, transdermal systems, eye drops, aerosols and sprays and ear drops. They are prepared according to the usual methods. The active principle, constituted by a pharmaceutically effective amount of at least one compound of formula (I) defined as hereinabove can be incorporated into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, stearate magnesium, polyvidone, cellulose derivatives, cocoa cream, semi-synthetic glycerides, aqueous or non-aqueous vehicles, grease bodies of animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, aromas and colors. The invention also covers a pharmaceutical composition with anti-inflammatory and analgesic activity which makes it possible especially to treat inflammatory phenomena and pain favorably, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) mentioned above in a pharmaceutically excipient, carrier or carrier. acceptable. According to one embodiment, a pharmaceutical composition with anti-inflammatory and analgesic activity is prepared, which makes it possible in particular to treat different inflammations and pain favorably. According to a variant embodiment, a composition formulated in the form of capsules or tablets dosed from 1 milligram to 1000 milligrams or in the form of injectable preparations dosed from 0.1 milligram to 500 milligrams is prepared. It is also possible to use formulations in the form of suppositories, ointments, creams, gels, aerosol preparations, transdermal preparations or plasters.

The invention also covers a method of therapeutic treatment of mammals, characterized in that a therapeutically effective amount of at least one compound of formula (I) as defined above is administered to this mammal. According to a variant embodiment of this treatment method, the compound of formula (I), either alone, or in association with a pharmaceutically acceptable excipient, is formulated in capsules or tablets dosed from 1 milligram to 1000 milligrams for administration orally, or in the form of injectable preparations dosed from 0.1 milligrams to 500 milligrams or also in the form of suppositories, ointments, creams, gels or aerosol preparations. This procedure makes it possible especially to treat inflammatory phenomena and pain favorably. In human and animal therapeutics, the compounds of formula (I) can be administered alone or in association with a physiologically acceptable excipient in any form, in particular orally in the form of capsules or tablets or parenterally in the form of an injectable solution. Other forms of administration such as suppositories, ointments, creams, gels or aerosol preparations can also be considered. As will clearly be pointed out from the pharmacological tests given at the end of the description, the compounds according to the invention can be administered in human therapeutics with the aforementioned indications orally in the form of tablets or capsules dosed from 1 milligram to 1000 milligrams or by parenterally in the form of injectable preparations dosed from 0.1 milligrams to 500 milligrams in one or more daily doses for an adult of average weight of 60 to 70 kilograms. In animal therapy, the usable daily dose is between 0.1 milligram and 100 milligrams per kilogram. Other features and advantages of the invention will be better understood with the following reading of some non-limiting examples, but given by way of illustration. Example 1: 4-fluoro-4 * -thiomethylbenzophenone Formula (III): A = phenyl, Y 1 = 4-F, Y 2 = HA a solution of 70 grams (0.564 moles) of thioanisole and 90.2 grams (0.654 moles) of chloride of 4-fluorobenzoyl in 500 milliliters of dichloromethane are added in portion 86.4 grams of aluminum trichloride at a temperature comprised between 0 ° C and 5 ° C. After the addition is complete, the mixture is brought to room temperature then heated to reflux for 2 hours. After cooling, the reaction medium is emptied into a mixture of ice / dilute hydrochloric acid and the organic phase is decanted and then dried over magnesium sulfate and evaporated under vacuum to produce a residue which is crystallized from isopropyl ether and gives 118 grams of 4-fluoro-4-thiomethylbenzophenone with a melting point of 88 ° C. Example 2: 4-Fluoro-4'-methanesulfenylbenzophenone Formula (IV): A = phenyl, Yt = 4-F, Y2 = HA a solution of 25 grams (0.1015 moles) of 4-fluoro-4'-thiomethylbenzophenone, prepared in Example 1, in 350 milliliters of dichloromethane are added in portions 87 grams of 70% 3-chloroperbenzoic acid, at a temperature between 0 ° C and 5 ° C. The mixture is then stirred at 0 ° C for 30 minutes, then returned to room temperature and stirred for 2 hours 30 minutes. The precipitate obtained is centrifuged and washed with a dilute sodium hydroxide solution then dissolved in dichloromethane. The organic phase thus obtained is dried over magnesium sulphate and evaporated under vacuum to give an oil which crystallizes from the isopropyl ether and gives 24.6 grams of 4-fluoro-4'-methanesulfonylbenzophenone with a melting point of 136 ° C. Example 3: 3 - [1- (4-fluorophenyl) -1-hydroxy-1- (4-methanesulfonylphenyl) methyl] -dihydro-furan-2 -one Formula (VI): A = phenyl, Y 1 = 4- F, Y2 = H, R3 = R4 = H The magnesium in flakes (3.5 grams is recovered by anhydrous tetrahydrofuran and a few drops of iodomethane are added.) Since the reaction begins, a mixture of 24.6 grams of 4-fluoro-4 '- Methanesulfonylbenzophenone and 8.1 milliliters of a-bromo-β-butyrolactone in 250 milliliters of anhydrous tetrahydrofuran are added dropwise in order to maintain a slight reflux., the reaction medium is cooled and then emptied onto a mixture of ice and 10% diluted sulfuric acid. The organic phase is extracted with tetrahydrofuran and washed with a saturated solution of sodium bicarbonate, then dried over magnesium sulfate. After evaporation of the solvent, the obtained residue is chromatographed on silica gel with a mixture of dichloromethane 9 / acetone 1 to give 7 grams of 3- [1- (4-fluorophenyl) -1-hydroxy-1 - (4 - methanesulfonylphenyl) methyl] -dihydro-furan-2 -one in the form of an amorphous beige powder used in that form for the continuation. Example 4: (E) -3- [4-fluorophenyl) -1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2 -one Isomer (E): Formula (I): A = B = phenyl, Y1 = 4-F, X2 = Y2 = H, X, = 4-S02CH3, R1R2 = 0, R3 = R4 = HA a solution of 7 grams of 3- [1- (4-fluorophenyl) -1-hydroxy-1- (4-methanesulfonylphenyl) methyl] -dihydro-furan-2-one prepared in Example 3, in 100 milliliters of toluene, some milligrams of 4-toluenesulfonic acid are added and the mixture is heated at reflux for 10 hours with a Dean Stark The solvent is then evaporated to dryness under vacuum and the residue is chromatographed in a dichloromethane mixture. 9 / acetone 1 as eluent to give an oil which is chromatographed on methyl tertiary butyl ether as eluent to give 2.9 grams of (E) -3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) - methylidene] -dihydro-furan-2-one (second product eluted) in the form of crystals with a melting point of 187.9 ° C. 1.5 grams of (Z) -3- [1- (4-fluorophenyl) -1-methanesulfonylphenyl) methylidene] -dihydro-furan-2-one (first eluate) are recovered in the form of crystals with a melting point of 157 -158 ° C. Example 5: 4-chloro-4 -thiomethylbenzophenone Formula (III): A = phenyl, Y ^ -Cl, Y2 = H Prepared according to the mode of operation of example 1. Crystals with melting point 134 ° C. Example 6: 3 - [1- (4-chlorophenyl) -1- (methylthiophenyl) ethyl] -dihydro-furan-2-one Formula (VI '): A = phenyl, Y 1 = 4-C1, Y 2 = H, R 3 = R4 = HA 5.9 grams of magnesium in flakes coated with anhydrous tetrahydrofuran, a few drops of iodomethane are added. Since the reaction is started, a mixture of 17 grams of 4-chloro-4'-thiomethylbenzophenone and 12.6 milliliters of Q-bromo-butyrolactone in 300 milliliters of anhydrous tetrahydrofuran is added dropwise so that there is a slight reflux. After the addition is complete, the mixture is stirred at room temperature for 1 hour 30 minutes then cooled by an ice bath. A saturated solution of ammonium chloride is then added and the mixture is stirred, then decanted. The organic phase is dried over magnesium sulfate and evaporated in vacuo to give an oily residue which is then chromatographed on silica gel in dichloromethane giving 8.5 grams of 3- [1- (4-chlorophenyl) -1-hydroxy-1- (4-thiomethyl enyl) methyl] -dihydro-furan-2-one in the form of a crude oil used for continuation. Example 7: 3- [1- (4-chlorophenyl) -1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2-one Formula (I): A = B = phenyl, Y1 = 4-C1, Y2 = X! = H, X2 = 4-SCH3, R1R2 = 0, R3 = R4 HA a solution of 8.6 grams of 3- [1- (4-chlorophenyl) -1-hydroxy-1- (4-thiomethylphenyl) -methyl ] -dihydro-furan-2-one prepared in Example 6, in 100 milliliters of dichloromethane are added 5.2 grams of trifluoroacetic anhydride and 3.8 milliliters of trifluoroacetic acid. The mixture is stirred at room temperature for 4 hours then diluted in water and decanted. The organic phase is dried over magnesium sulfate and evaporated in vacuo to give 7.5 grams of 3- [1- (4-chlorophenyl) -1- (4-thiomethylphenyl) methylidene] -dihydro-furan-2-one in the form of oil used as is for the continuation. Example 8: (Z) -3 - [l- (4-Chlorophenyl) -1- (4-methanesulphonylphenyl) -methylidene] -dihydro-furan-2-ene Isomer (Z): Formula (I). A = B = phenyl, Yt = 4C1, Y2 = X? H, X2, = 4 - S02CH3, R ^ 2 = 0, R3 = R4 = HA a solution of 9.5 grams of 3- [1- (4-chlorophenyl) -1- (4-thiomethylphenyl) methylidene] -dihydro-furan -2-Oxygenated in Example 7, in 120 milliliters of acetic acid, 11 grams of sodium perborate trihydrate are added. The mixture is heated at 40-50 ° C for 5 hours then cooled. The crystals formed are centrifuged, washed in water, chromatographed on silica gel in a dichloromethane / acetone 99/1 mixture to give 4.1 grams of (Z) -3- [1- (4-chlorophenyl) -1- (4 -methanesulfonylphenyl) methylidene] -dihydro-furan-2 -one (first product eluted) in the form of crystals with a melting point of 197-199 ° C. The isolation of the second eluted product makes it possible to obtain 2.5 grams of (E) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2-one in the form of crystals with melting point 211-212 ° C. Example 9: 3-Fluoro-4'-thiomethylbenzophenone Formula (III): A = phenyl, Y ^ -F, Y 2 = H Prepared according to the mode of operation of example 1 Crystals with melting point 76 ° C. Example 10: 3-fluoro-4 • -methanesulfonylbenzophenone Formula (IV): A = phenyl, Y ^ -F, Y2 = H Prepared according to the mode of operation of example 2. Crystals with melting point 106 ° C. Example 11: 3-Ethoxycarbonyl-4- (3-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = phenyl, Y ^ -F, Y2 = HA a solution of 15.7 grams ( 0.140 moles) of potassium tertiary butylate in 100 milliliters of tertiary butanol are added per portion 35.5 grams (0.1275 moles) of 3-fluoro-4'-methanesulfonylbenzophenone prepared in the example . The mixture is stirred and 32 milliliters (0.191 mol) of ethyl succinate are added dropwise, at a rapid rate.

The mixture is then heated under reflux for 30 minutes, cooled and added with water and IN hydrochloric acid in order to obtain a pH equal to 1 and then extracted with methyl tertiary butyl ether. The organic phase is treated with a 2 percent sodium hydroxide solution and the mixture is decanted. The aqueous phase is acidified by IN hydrochloric acid and then extracted with tertiary butyl methyl ether. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give 39.2 grams of 3-ethoxycarbonyl-4- (3-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid in the form of a viscous oil. Used as is for the continuation. Example 12: Ethyl 3- (3-fluorophenyl) -3- (4-methanesulfonylphenyl) -2- (hydroxyethyl) -2-propenate Formula (XI): A = phenyl, Y1 = 3-F, Y2 = HA a solution of 31.5 grams (0.0775 moles) of acid 3-Ethoxycarbonyl-4- (3-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic, prepared in Example 11, in 90 milliliters of anhydrous tetrahydrofuran, 15.5 milliliters are added dropwise. (0.155 moles) of borane / methyl sulfide complex. The mixture is stirred at room temperature for 8 hours and 23.5 milliliters of methanol are added dropwise. The mixture is evaporated to dryness in vacuo and the residue is taken up in ethyl acetate, then treated with an aqueous solution of 7.6 grams of potassium carbonate. The organic phase is decanted then dried over magnesium sulfate and evaporated to dryness in vacuo to give 29.3 grams of 3- (3-fluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate of ethyl in the form of a viscous oil used as is for the continuation. Example 13: (Z) -3- [1- (3-fluorophenyl) -1- (4-methanesulfonyl-phenyl) -methylidene] -dihydro-furan-2-one Isomer (Z): Formula (I): A = B-phenyl, Y = 3-F, X2 = Y2 = H, Xt = 4S02CH3, RjR2 = 0, R3 = R4 = HA a solution of 29.3 grams of 3- (3-fluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2 Ethylpropenate prepared in Example 12, in 50 milliliters of ethanol, 3.3 grams of soda in solution in 10 milliliters of water are added and the mixture is heated under reflux for 2 hours. After evaporation to dryness, the residue is taken up in water and acidified with IN hydrochloric acid, then extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated in vacuo to give an oily residue. The oil is solubilized in 150 milliliters of toluene and 10 milligrams of paratoluenesulfonic acid are added. The mixture is heated to reflux and the water formed is removed by a Dean Stark. After cooling the mixture is washed in water, the organic phase is dried over magnesium sulphate, evaporated in vacuo and the residue chromatographed on silica in tertiary butyl methyl ether to give 4 grams of (Z) -3- [ l- (3-fluorophenyl) -1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2-one (second product eluted) in the form of crystals with a melting point of 153-154 ° C. Example 14: 3,4-dichloro-4'-methobenzophenone Formula (III): A = phenyl, Y ^ -Cl, Y2 = 4-Cl Prepared according to the mode of operation of example 1 Crystals of melting point at 100 ° C . Example 15: 3,4-dichloro-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y ^ -Cl, Y2 = 4-Cl Prepared according to the mode of operation of example 2. Crystals of melting point at 158 ° C C. Example 16: 3-Ethoxycarbonyl-4- (3,4-dichlorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid. Formula (X): A = phenyl, Y { = 3-Cl, Y2 = 4-C1 Prepared according to the mode of operation of example 11. Oil used as is for the continuation. Example 17: Ethyl (3, 4-dichlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate.

Formula (XI): A-phenyl, Y2 = 4-C1 Prepared according to the operating mode of example 12. Oil used as is for the continuation. Example 18: (Z) -3- ti- (3, 4-dichlorophenyl) -1- (4-methanesulfonyl-phenyl) methylidene] -dihydro-furan-2 -one Isomer (Z): Formula (I): A = B = phenyl, Yx = 3-Cl, Y2 = 4 -C1, X2 = H, X1 = 4-S02CH3, R! R2 = 0, R3 = R4 = H Prepared according to the mode of operation of example 13. Chromatography in a mixture of dichloromethane / acetone (99/1), first product eluted Crystals of melting point at 195-197 ° C. After chromatography, the isolation of the second eluted product makes it possible to obtain the (E) -3- [1- (3,4-dichlorophenyl) -l- (4-methanesulfonylphenimethylidene] -dihydro-furan-2-one isomer in the form of crystals with melting point 163-6 164 ° C. Example 19: 3-chloro-4 -thiomethylbenzophenone Formula (III): A = phenyl, Y 1 = 3-C1, Y 2 = H Prepared according to the mode of operation of the example 1. Crystals of melting point at 70 ° C. Example 20: 3-chloro-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y 1 = 3-C1, Y 2 = H Prepared according to the mode of operation of example 2 .

Crystals of melting point at 140 ° C. Example 21: 3-Ethoxycarbonyl-4- (3-chlorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid. Formula (X): A = phenyl, Yt = 3-Cl, Y 2 = H Prepared according to the mode of operation of example 11. Oil used as is for the continuation. Example 22: Ethyl 3- (chlorophenyl) -3- (4-m-ethanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate. Formula (XI): A = phenyl, Y1 = 3-C1, Y2 = H Prepared according to the operating mode of example 12. Oil used as is for the continuation. Example 23: (Z) -3- ti- (3-chlorophenyl) -1- (4-methanesulfonyl-phenyl) -methylidene] -dihydro-furan-2 -one Isomer (Z): Formula (I): A = B -phenyl, Y, = 3-Cl, X2 = Y2 = H, X { = 4-S02CH3, R1R2 = 0, R3 = R4 = H Prepared according to the mode of operation of example 13. Chromatography in a dichloromethane / acetone (99/1) mixture, first eluted product. Crystals of melting point at 147-149 ° C. The isolation of the second eluted product leads to the compound (E) -3- [1- (3-chlorophenyl) -1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2-one under the forra of crystals with a fusion 170-172 ° C. Example 24: 4-thiomethylbenzophenone Formula (III): A = phenyl, Y 1 = Y 2 = H Prepared according to the mode of operation of example 1. Crystals of melting point at 84 ° C. Example 25: 4-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y 1 = Y 2 = H Prepared according to the mode of operation of example 2. Crystals of melting point at 150 ° C. Example 26: 3-Ethoxycarbonyl-4-phenyl-4- (4-methanesulfonylphenyl) -3-butenoic acid. Formula (X): A = phenyl, Y1 = Y2 = H Prepared according to the mode of operation of example 11. Oil used as is for the continuation. Example 27: 3-phenyl-3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-ethylpropenate Formula (XI): A = phenyl, Yj = Y2 = H Prepared according to the mode of operation of the example 12. Oil used as is for the continuation. Example 28: (E) -3 - [1- Phenyl-1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2-one Isomer (E): Formula (I): A = B = phenyl, Y? = Y2 = H, X2 = H, X { = 4-S02CH3, R1R2 = 0, R3 = R4 = H Prepared according to the mode of operation of example 13. Chromatography on silica gel in a dichloromethane / acetone (99/1) mixture, first eluted product. Crystals of melting point at 135-137 ° C.

The isolation of the second eluted product makes it possible to obtain the (Z) -3- [1-phenyl-1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2-one isomer in the form of crystals with a melting point of 206- 208 ° C. Example 29: 5,5-Dimethyl-3-ti- (4-fluorophenyl) -1-hydroxy-1- (4-thiomethylphenyl) methyl] -dihydro-furan-2-one Formula (VI '): A = phenyl, Y1 = 4-F, Y2 = H, R3 = R4 = CH3 To a suspension of 2.4 grams of magnesium in flakes in anhydrous ethyl ether 7.5 milliliters of bromoethane are added dropwise. At the end of the addition, the mixture is cooled to 0 ° C and 10.5 milliliters of N, N-diethylamine are added dropwise. The reaction medium is stirred at room temperature for 1 hour, then heated to reflux for 15 minutes and cooled by an ice-bath and sodium chloride. A solution of 12.3 grams of 4-fluoro-4'-iomethylbenzophenone, prepared in Example 1, and 5.7 grams of 4,4-dimethylbutyrolactone in 50 milliliters of anhydrous tetrahydrofuran are added dropwise maintaining a temperature between 0 ° C and 5 ° C. ° C. The mixture is then refluxed for 2 hours, cooled and treated with 100 milliliters of a 10 percent sulfuric acid solution. After extraction of the ethyl ether, the organic phase is dried over magnesium sulfate and evaporated under vacuum to give 4.8 grams of 5,5-dimethyl-3- [1- (4-fluorophenyl) -1-hydroxy-1- ( 4-thiomethylphenyl) me il] -dihydro-furan-2-anephenol forms crystals with a melting point of 185 ° C.

Example 30: 5, 5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-thiomethyl-phenyl) methylidene] -dihydro-furan-2 -one Isomer (E): Formula (I): A = B = phenyl, Y1 = 4-F, Y2 = X2 = H, X1 = 4-SCH3, R1R2 = 0, R3 = R4 = CH3 Isomer (Z): Formulad): A = B = phenyl, X1 = 4- F, X2 = Y2 = H, Y1 = 4-SCH3, RjR2 = 0, R3 = R4 = CH3 Prepared according to the mode of operation of example 4 from the derivative of example 29. The two isomers are separated by fractional crystallization in a mixture of isopropyl ether / pentane: ( E) -5,5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-thiomet ilphenyl) -methylidene] -dihydro-furan-2-one, mp 98 ° C. (Z) -5,5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-thiomethylphenyl) -methylidene] -dihydro-furan-2-one, melting point 160 ° C.

Example 31: (E) -5,5-dimethyl-3-ti- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] -dihydro-furan-2-one Isomer (E): Formulad): A = B = phenyl, Yj = 4-F, X2 = Y2 = H, X1 = 4-S02CH3, R1R2 = 0, R3 = R4 = CH3 To a solution of 2 grams of (E) -5,5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-thiomethylphenyl) -methylidene] -dihydro-furan-2-one prepared in Example 30, in 15 milliliters of acetic acid are added 1.9 grams of sodium perborate trihydrate. The mixture is heated for 3 hours at 45 ° C and the crystals formed are centrifuged with heat and chromatographed on silica gel in a dichloromethane / acetone mixture (9/1) as eluent, to give 1.2 grams of (E) -5 , 5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] -dihydro-furan-2-one in the form of crystals with a melting point of 175 ° C. Example 32: 5-ethyl-3 - [1- (4-fluorophenyl) -1-hydroxy-1- (4-thiomethylphenyl) methyl] -dihydro-furan-2-one Formula (VI1): A = phenyl, Y 1 = 4-F, Y2 = H, R3 = C2H5, R4 = H Prepared according to the mode of operation of Example 29 from? -caprolactone Crystals with a melting point of 150 ° C. Example 33: 5-Ethyl-3- [1- (4-fluorophenyl) -1- (4-thiomethylphenyl) -methylidene] -dihydro-furan-2 -one Isomer (E): Formulad): A = B = phenyl, Y ^ -F, X2 = Y2 = H, X1 = 4-SCH3, R ^^ O, R3 = C2H5R4 = H Isomer (Z): Formulad): A = B = phenyl, X? = 4-F, X2 = Y2 = H, Y1 = 4-SCH3, R1R2 = 0, R3 = C2H5, R4 = H Prepared according to the mode of operation of example 4 from the derivative of example 32. The mixture of two isomers (E) and (Z) is used as is for the continuation. Example 34: (E) -5-Ethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2 -one Isomer (E): Formula (I ): A = B = f enyl, Y ^ -F, X2 = Y2 = H, X1 = 4-S02CH3, R1R2 = 0, R3 = C2H5R4 = H Prepared according to the mode of operation of example 31.

The (E) -5-ethyl-3 - [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2-one isomer is purified by chromatography on silica gel in a mixture of dichloromethane / acetone (99/1), in the form of crystals with a melting point of 134 to 136 ° C (first product eluted). The isolation of the second product eluted after chromatography makes it possible to obtain (Z) -5-ethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2-one in the form of crystals with a melting point of 176-177 ° C. Example 35: 5 -methyl-3 - [1- (3-chlorophenyl) -1-hydroxy-1- (4-thiomethylphenyl) -methyl] -dihydro-furan-2-one Formula (VI1): A = phenyl, Y ^ -Cl, Y2 = H, R3 = CH3, R4 = H Prepared according to the mode of operation of Example 6 from 3-chlorophenyl-4'-thiomethylbenzophenone and a-bromo-β-valerolactone. Amorphous powder used as is for the continuation; Example 36: 5-methyl-3- [1- (3-chlorophenyl) -1 (4-thiomethylphenyl) -methylidene] -dihydro-furan-2-one Isomer (Z): Formula (I): A = B = phenyl , Y ^ -Cl, X2 = Y2 = H, X1 = 4-SCH3, R1R2 = 0, R3 = CH3, R = H Isomer (E): Formulad): A = B = phenyl, X ^ -Cl, X2 = Y2 = H, Y1 = 4-SCH3, R! R2 = 0, R3 = CH3, R4 = H Prepared according to the mode of operation of example 4 from the derivative of example 35. The mixture of the two isomers is used as is. for continuation in the form of oil. Example 37: (Z) -5-Methyl-3-11- (3-chlorophenyl) -1 (4-methanesulfonylphenyl) -methyl] -dihydro-furan-2-one Isomer (Z): Formulad): A = B = phenyl, Y ^ Cl, X2 = Y2 = H, X ^ -SO ^ I ^, RtR2 = 0, R3 = CH3, R = H Prepared according to the mode of operation of Example 31. The (Z) -5 isomer -met il -3- [1- (3-chlorofenyl) -1- (4-methanesulfonylphenyl) methyl] -dihydro-furan-2-one is purified by chromatography on silica gel in a dichloromethane / acetone mixture (99 / 1) as eluent in the form of an amorphous powder (first eluted product). The isolation of the second eluted product makes it possible to obtain the (E) -5-methyl-3- [1- (3-chlorophenyl) -1- (4-methanesulfonylphenyl) -methyl] -dihydro-furan-2-one isomer in the form of crystals with a melting point of 164-165 ° C. Example 38: 2-Chloro-5- (4-thiomethylbenzoyl) pyridine Formula dll): A = 3-pyridyl, Y! = 6-Cl, Y2 = H Prepared according to the mode of operation of example 1. Crystals with a melting point of 145 ° C.

Example 39: 2-chloro-5- (4-methanesulfonylbenzoyl) pyridine Formula (IV): A = 3-pyridyl, Y ^ d-Cl, Y2 = H A solution of 34.6 grams of 2-chloro-5- (4- thiome ilbenzoyl) pyridine prepared in Example 38 and 42 grams of sodium perborate trihydrate in 250 milliliters of acetic acid is heated for 4 hours at 45 ° C. The crystals formed are centrifuged with heat, washed in water and dried to give 32.6 grams of 2-chloro-5- (4-methanesulfonylbenzoyl) -pyridine in the form of crystals with a melting point of 170 ° C. Example 40: 4- (6-Chloropyridin-3-yl) -3-ethoxycarbonyl-4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = 3-pyridyl, Y ^ d-Cl, Y2 = H Prepared according to the mode of operation of example 11 from the derivative of example 39. Amorphous solid used as is for the continuation. Example 41: Ethyl 3- (6-chloropyridin-3-yl) -2- (2-hydroxyethyl) -3- (4-methanesulfonylphenyl) -2-propenate Formula (XI): A = 3-pyridyl, Y1 = 6 -C1, Y2 = H Prepared according to the mode of operation of example 12 from the derivative of example 40. Amorphous solid used as is for the continuation. Example 42: (Z) -3- (6-chloropyridin-3-yl) -1- (4-methanesulfonyl-1-phenyl) methylidene] -dihydro-furan-2-one Isomer (Z): Formulad): A = 3- pyridyl, B = phenyl, Y ^ d-Cl, X2 = Y2 = H, Xj = 4-S02CH3, R ^^ O, R3 = R4 = H Prepared according to the mode of operation of example 13 from the derivative of example 41 The (Z) isomer is obtained by chromatography in a dichloromethane / acetone mixture (5/1) after crystallization in a mixture of acetone / ethyl ether in the form of crystals with a melting point of 172-174 ° C. The (E) -3- [1- (6-chloropyridin-3-yl) -1- (4-methanesulfonylphenyl) methylidene] -dihydro-furan-2-isomer is obtained by crystallization from acetone, before chromatography of the crude mixture of the two isomers, in the form of crystals with a melting point of 198-199 ° C. Example 43: 3-Ethoxycarbonyl-4- (4-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = 3-phenyl, Y 1 = 4-F, Y 2 = H Prepared as the mode of operation of example 11 from the 4-fluoro-4'-methanesulfonyl benzophenone prepared in example 2. Oil used as is for the continuation. Example 44: 4 [1- (4-fluorophenyl) -1 (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2-one Formula (I): A = B-phenyl, X? = 4-S02CH3, X2 = Y2 = H Y { = 4-F, RtR2 = H, R3R4 = 0 To a solution of 3-ethoxycarbonyl-4- (4-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid, prepared in Example 43, in 500 milliliters of ethanol are added 13.6 grams of anhydrous calcium chloride powder. The mixture is stirred at room temperature and 7.5 grams of sodium borohydride in solution in a mixture composed of 1.5 grams of potassium, 10 milliliters of water and 10 milliliters of ethanol, are added dropwise by cooling by an ice bath. After 4 hours at room temperature, the reaction mixture is cooled to 0 ° C and a solution of 6N hydrochloric acid is added dropwise. After extraction in dichloromethane, the organic phase is dried over magnesium sulfate, evaporated in vacuo and the residue is crystallized from isopropyl ether. The crystals obtained are recrystallized from methanol to give 5 grams of 4 [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2-one in the form of a mixture (50/50 ) of the two isomers (E) and (Z), crystals of melting point 160-164 ° C. Example 45: 3-methyl-4'-thiomethylbenzophenone Formula (III): A = phenyl, Y { = 3-CH3, Y2 = H Prepared according to the mode of operation of example l. Crystals with a melting point of 46-47 ° C. Example 46: 3-methyl-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y! = 3-CH3, Y2 = H Prepared according to the mode of operation of example 2.

Crystals with a melting point of 150 ° C. Example 47: 3-Ethoxycarbonyl-4- (3-methylphenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = phenyl, Y 1 = 3CH 3, Y 2 = H Prepared according to the mode of operation of the example 11, from the derivative of example 46. Oil used as is for the continuation. Example 48: 3- (3-methylphenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propeny to ethyl Formula (XI): A = phenyl, Y1 = 3-CH3, Y2 = H Prepared according to the mode of operation of example 12 from the derivative of example 47. Oil used as is for the continuation. Example 49: (Z) -3- [1- (3-Methylphenyl) -1- (4-methanesulfonyl-phenyl) -methylidene] -dihydro-furan-2-one Isomer (Z): Formulad): A = B = phenyl, Y! = 3CH3, X2 = Y2 = H, X1 = 4-S02CH3, R! R2 = 0, R3 = R4 = H Prepared according to the mode of operation of example 13, from the derivative of example 48. Purified by chromatography on silica gel in a dichloromethane / acetone (99/1) mixture, first eluate, in the form of crystals with a melting point of 166 ° C. Example 50: 3,4-difluoro-4'-thiomethylbenzophenone Formula (III): A = phenyl, Y = 3-F, Y 2 = 4-F Prepared according to the mode of operation of example 1. Crystals of melting point of 96 ° C. Example 51: 3,4-difluoro-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y ^ -F, Y2 = 4-F Prepared according to the mode of operation of example 2 from the derivative of example 50. Crystals of melting point of 120 ° C. Example 52: 3-Ethoxycarbonyl-4- (3,4-difluorophenyl) -4- (methanesulfonylphenyl) -3-butenoic acid Formula (X): A = phenyl, Y ^ -F, Y2 = 4-F • Prepared according to operation mode of example 11 from the derivative of example 51. Oil used as is for the continuation. Example 53: Ethyl 3- (-3-difluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate Formula (XI): A = phenyl, Yt = 3-F, Y2 = 4-F Prepared according to the mode of operation of example 12 from the derivative of example 52. Oil used as is for the continuation. Example 54: (Z) -3- [1- (3,4 -difluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] -dihydro-furan-2 -one Isomer (Z): Formulad): A = B = phenyl , Yj = 3-F, Y2 = 4-F, X1 = 4-S02CH3, X2 = H, RjR ^ O, R3 = R4 = H Prepared according to the mode of operation of example 13, from the derivative of example 53. Purified by chromatography on silica gel in a dichloromethane / acetone (99/1) mixture, first eluted product, melting point crystals of 148 ° C. Example 55: 4-thiobenzylbenzonitrile A mixture of 37.2 grams of benzyl mercaptan, 36.3 grams of 4-fluorobenzonitrile and 42 grams of potassium carbonate in 700 milliliters of 2-butanone is brought to reflux for 7 hours. The solvent is evaporated under vacuum, the residue is recovered in water and in petroleum ether. The crystals formed are centrifuged, washed in water and in petroleum ether to give 46 grams of 4-thiobenzylbenzonitrile in the form of crystals with a melting point of 85 ° C. Example 56: 4-thiobenzyl-4'-fluorobenzophenone To a suspension of 9.6 grams of magnesium in flakes in 20 milliliters of anhydrous ethyl ether is added dropwise a solution of 44 milliliters of 4-bromo-1-fluorobenzene in 300 milliliters of anhydrous ethyl ether. After the end of the addition the mixture is stirred a few minutes at room temperature and a solution of 46 grams of 4-thiobenzylbenzonitrile, prepared in Example 55, in 400 milliliters of anhydrous tetrahydrofuran is added dropwise. The ethyl ether is distilled and the mixture is refluxed for 3 hours then cooled by ice. A solution of 6N hydrochloric acid (400 milliliters) is added dropwise and the mixture is brought to reflux for 6 hours. After the addition of water and dichloromethane, the organic phase is decanted and dried over magnesium sulfate, then evaporated in vacuo. The residue is crystallized from the isopropyl ether to give 48 grams of 4-benzylthio-4'-fluorobenzophenone in the form of crystals with a melting point of 96 ° C. Example 57: Tertiary-4-butyl-aminosulfonyl-1-4'-fluorobenzophenone In a solution of 43 grams of 4-thiobenzyl-4'-fluorobenzophenone prepared in Example 56, in 300 milliliters of acetic acid cooled to 0 ° C., the chlorine is immersed until saturation (36 grams). The mixture is stirred for 2 hours at room temperature then poured into ice water and extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and evaporated in vacuo to give 47 grams of an oil which is dissolved in 100 milliliters of 1,2-dichloroethane. This solution is added dropwise to a solution of 50 milliliters of tertiary butyl amine in 300 milliliters of 1,2-dichloroethane. The mixture is heated for one hour at 80 ° C, cooled and washed with water, then with dilute hydrochloric acid. The organic phase is dried over magnesium sulphate and evaporated in vacuo. The residue is crystallized from the ethyl ether to give 25 grams of tertiary-4-butyl-aminosulfonyl-4'-fluorobenzophenone in the form of crystals with a melting point of 160 ° C.

Example 58: 3-Ethoxycarbonyl-4- (4-butyl tertiary-aminosulfonylphenyl) -4- (4-fluorophenyl) -3-butenoic acid Formula (XII): A = phenyl, Yt = 4-F, Y2 = H Prepared according to the mode of operation of example 11, from the derivative of example 57 using 2 equivalents of tertiary potassium butylate. Amorphous powder used as is for the continuation.

Example 59: Ethyl 3- (4-butyl tertiary -aminosulfonylphenyl) -3- (fluorophenyl) -2- (2-hydroxyethyl) -2-propenate Prepared according to the mode of operation of example 12, from the derivative of example 58 The oil obtained is recovered in the ethyl ether and the crystals formed are dried to give the (Z) -3- (4-tertiary butyl-aminosulfonylphenyl) -3- (4-fluorophenyl) -2- (2-hydroxyethyl) isomer -2-pure ethylpropenate in the form of crystals with a melting point of 152 ° C. The filtrate is evaporated under vacuum to give an oily residue corresponding to the (E) -3- (4-butyl tertiary-aminosulfonylphenyl) -3- (4-fluorophenyl) -2- (2-hydroxyethyl) -2-ethylpropenate isomer. used as is for the continuation. Example 60: (E) -4- [(4-fluorophenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfonamide Isomer (Z): Formula (I): A = B = phenyl, Yj = 4-F, Y2 = X2 = H, X1 = 4-S02? JH2, RtR2 = 0, R3 = R4 = H The (E) -3- (4-butyl tertiary-aminosulfonylphenyl) -3- (4-fluorophenyl) -2- (2-hydroxyethyl) -2-ethyl propenate (10 grams), prepared in Example 59, is put into solution in 20 milliliters of ethanol and 2 grams of soda in solution in 10 milliliters of water are added. The mixture is heated at reflux for 2 hours. After evaporation in the dry state, the residue is recovered by water and acidified with IN hydrochloric acid, then extracted with dichloromethane. The organic phase is dried over magnesium sulphate then evaporated in vacuo. The residue is added in portions to 500 milliliters of concentrated sulfuric acid. The mixture is stirred for 15 minutes at room temperature then poured into ice water, the crystals formed are centrifuged and washed in ethyl ether, then recovered in 100 milliliters of warm acetone. To the obtained solution 50 milliliters of ethyl ether are added and the crystals formed are centrifuged and dried to give 6 grams of (E) -4- [(4-fluorophenyl) - (2-oxo-dihydro-furan-3-ylidene ) methyl] benzenesulfonamide in the form of crystals with melting point of 202 ° C Example 61: (Z) -4- [(fluorophenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfone ida Isomer ( Z): Formulad): A = B = phenyl, X1 = 4-F, X2 = Y2 = H, Y1 = 4-S02NH2, RjR2 = 0, R3 = R4 = H Prepared according to the mode of operation of Example 60, a from the isomer (Z) prepared in example 59. Crystals of melting point of 222 ° C. Example 62: 4-chloro-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y ^ -Cl, Y2 = H Prepared according to the mode of operation of example 39, from the derivative of example 5. Crystals fusion of 176 ° C. Example 63: (Z) -3-Ethoxycarbonyl-4- (4-chlorophenyl) -4- (4-methanesulfonyl) -3-butenoic acid Formula (X): A = phenyl, Y1 = 4-C1, Y2 = HA a suspension of 20 grams of 4-chloro-4'-methanesulfonylbenzophenone, prepared in Example 62, in 100 milliliters of tertiary butanol are added in one portion 7.2 grams of tertiary sodium butylate at room temperature. The suspension is heated to 40 ° C and a solution of 16.9 milliliters of ethyl succinate in 20 milliliters of tertiary butanol is added in 10 minutes. The temperature is maintained at 55 ° C during minutes, then return to 35-40 ° C; 140 milliliters of cold water are added and the mixture is stirred for 30 minutes. The solution is filtered and the crystals are washed in water. The hydroalcoholic phase is washed twice with 75 milliliters of toluene, then acidified by concentrated hydrochloric acid. The crystals are centrifuged, washed with water and dried in vacuo to give 20.2 grams of (Z) -3-ethoxycarbonyl-4- (chlorophenyl) -4- (4-methanesulfonyl) -3-butenoic acid, liquid chromatography purity High performance (HPLC): 81.6 percent, 12.1 percent isomer (E). The recrystallization in 2-propanol allows obtaining 14 grams of (Z) 3-ethoxycarbonyl-4- (4-chlorophenyl) -4- (methanesulphonyl) -3-butenoic acid of high performance liquid chromatography purity: 96.1 percent which It contains 0.7 percent isomer (E), in the form of crystals with a melting point of 183 ° C. Example 64: (Z) -3- (4-chlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-ethylpropenate Formula (XI): A = phenyl, Y? = 4-Cl, Y2 = HA a solution of 350 grams of (Z) -3-ethoxycarbonyl-4- (4-chlorophenyl) -4- (methanesulfonylphenyl) -3-butenoic acid, prepared in Example 63, in 1.5 liters of tetrahydrofuran are added dropwise and under good agitation 120 milliliters of borane / methyl sulfide complex. At the end of the addition, the solution is stirred for 2.5 hours at room temperature. The excess borane is hydrolyzed by 100 milliliters of methanol and 100 milliliters of water. After evaporation under vacuum of the solvent, the residue is organized in water, filtered, washed in water to give (Z) -3- (4-chlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2 -hydroxyethyl) -2-ethyl propenate in the form of wet crystals, used as such for the next step. By drying these crystals and recrystallizing from 2-propanol, ethyl (Z) -3- (4-chlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate is obtained. in the form of high performance liquid chromatography purity crystals of 98.3 percent and melting point of 128 ° C. Example 65: (Z) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2-one Formula (I): A = B = phenyl, Y1 = 4 -C1, X2 = Y2 = H X1 = 4-S02CH3, R! R2 = 0, R3 = R4 = H The wet product of Example 64 is refluxed in 1.5 liters of toluene in the presence of 1 gram of toluenesulfonic acid. Water and ethanol are removed with the aid of a Dean Starck, and approximately 1 liter of toluene is evaporated. After returning to room temperature the crystals formed are centrifuged and washed with a minimum amount of 2-butanone, then dried to obtain 261.5 grams of (Z) -3 - [1- (4-chlorophenyl) -l- (4 - methanesulfonylphenyl) methylidene] -dihydro-furan-2-one in the form of crystals with a melting point of 108 ° C. Example 66: 3, 5-dichloro-4'-thiomethylbenzophenone Formula (III): A = phenyl, Y 1 = 3-C1, Y 2 = 5-C1 Prepared according to the mode of operation of example 1. Crystals of melting point of 188 -190 ° C. Example 67: 3,5-dichloro-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y 1 = 3-C1, Y 2 = 5-C1 Prepared according to the mode of operation of example 39. Mink-point crystals of 200 ° C. Example 68: Acid (Z) -3-ethoxycarbonyl-4- (3,5-dichlorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic Isomer (Z): Formula (X): A = phenyl, Y. { . = 3-Cl, Y2 = 5-C1 Prepared according to the mode of operation of example 11. Crystals of melting point of 180 ° C. Example 69: (Z) -3- (3,5-dichlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-ethyl propenate Isomer (Z): Formula (XI): A = phenyl, Yj = 3-Cl, Y2 = 5-Cl Prepared according to the operation mode of example 12. Oil used as is for the continuation. Example 70: (Z) -3- [1- (3,5-dichlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydro-furan-2 -one Isomer (Z): Formula (I): A = B = phenyl, Yj = 3-Cl, Y2 = 5-C1 X1 = 4-S02CH3, X2 = H, RjR2 = 0, R3 = R4 = H Prepared according to the mode of operation of example 65. Crystals of melting point 114 ° C. Example 71: 2,4-difluoro-4'-thiomethylbenzophenone Formula (III): A = phenyl, Y? = 2-F, Y2 = 4-F Prepared according to the mode of operation of example l. Melting point crystals 98 ° C. Example 72: 2,4-difluoro-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y 1 = 2-F, Y 2 = 4-F Prepared according to the mode of operation of example 39, Melting point crystals 160 ° C. Example 73: 3-Ethoxycarbonyl-4- (2,4-difluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = phenyl, Yt = 2-F, Y2 = 4-F Prepared according to the mode of operation of example 11. Oil used as is for the continuation. Example 74: Ethyl 3- (2, 4-difluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate Formula (XI): A = phenyl, Y! = 2-F, Y2 = 4-F Prepared according to the operation mode of example 12. Oil used as is for the continuation. Example 75: (Z) -3 - [1 - (1,4-difluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydro-furan-2 -one Isomer (Z): Formula (I): A = B = phenyl, Yj = 2-F, Y2 = 4-F, X1 = 4-S02CH3, X2 = H, R! R2 = 0, R3 = R4 = H Prepared according to the mode of operation of Example 65, purified by chromatography in a dichloromethane / acetone mixture (10 / 0.3). Crystals of melting point 140 ° C. Example 76: 3, 5-difluoro-4'-thiomethylbenzophenone Formula (III): A = phenyl, Y ^ -F, Y2 = 5-F Prepared according to the mode of operation of example 1.

Crystals of melting point 90 ° C. Example 77: 3, 5-difluoro-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y ^ -F, Y2 = 5-F Prepared according to the mode of operation of example 39. Crystals of melting point 152 ° C . Example 78: 3-Ethoxycarbonyl-4- (3, 5-difluorophenyl) -4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = phenyl, Y1 = 3-F, Y2 = 5-F Prepared according to the mode of operation of example 11. Oil used as is for the continuation. Example 79: Ethyl 3- (3, 5-difluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate Formula (XI): A = phenyl, Yt = 3-F, Y2 = 5-F Prepared according to the operation mode of example 12. Oil used as is for the continuation. Example 80: Z) -3- [1- (3, 5-difluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] -dihydro-furan-2-one Isomer (Z): Formulad): A = B = phenyl, Y1 = 3-F, Y2 = 5-F X1 = 4-S02CH3, X2 = H, R ^ -O, R3 = R4 = H Prepared according to the mode of operation of Example 65, purified by chromatography in a dichloromethane / acetone (10 / 0.3). 162 ° C melting point crystals.

Example 81: 4-methyl-4'-thiomethylbenzophenone Formula (III): A = phenyl, Y! = 4-CH 3, Y 2 = H Prepared according to the mode of operation of example 1. Crystals of melting point of 96 ° C. Example 82: 4-methyl-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y 1 = 4-CH 3, Y 2 = H Prepared according to the mode of operation of example 39. Crystals of melting point of 180 ° C. Example 83: 3-Ethoxycarbonyl-4- (4-methylphenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = phenyl, Y1 = 4-CH3, Y2 = H Prepared according to the mode of operation of example 11. Oil used as is for the continuation. Example 84: Ethyl 3- (4-methylphenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate Formula (XI): A = phenyl, Y ^ -CI ^, Y2 = H Prepared according to the operation mode of example 12. Oil used as is for the continuation. Example 85: (E) -3- [1- (4-Methylphenyl) -1- (4-methanesulfonylphenyl) methylidene] -dihydro-furan-2 -one Isomer (E): Formula (I): A = B = phenyl, Y1 = 4-CH3, Y2 = H, X1 = 4-S02CH3, X2 = H, R! R2 = 0, R3 = R4 = H Prepared according to the mode of operation of Example 65, purified by chromatography in a dichloromethane mixture / acetone (10 / 0.3). Crystals with a melting point of 222 ° C. Example 86: 3-bromo-4'-thiomethylbenzophenone Formula (III): A = phenyl, Y 1 = 3-Br, Y 2 = H Prepared according to the mode of operation of example 1. Crystals of melting point of 90 ° C. Example 87: 3-bromo-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Yt = 3-Br, Y 2 = H Prepared according to the mode of operation of example 39. Crystals of melting point 170 ° C. Example 88: 3-Ethoxycarbonyl-4- (3-bromophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = phenyl, Y 1 = 3-Br, Y 2 = H Prepared according to the mode of example operation 11. Oil used as is for the continuation. Example 89: Ethyl 3- (3-bromophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate Formula (XI): A = phenyl, Y, = 3-Br, Y2 = H Prepared according to the mode of operation of example 12. Oil used as is for the continuation. Example 90: (Z) -3 - [1- (3-Bromophenyl) -1- (4-methanesulfonyl-phenyl) -methylidene] -dihydro-furan-2-one Isomer (Z): Formula (I): A = B = phenyl, Y ^ -Br, Y2 = H, X1 = 4-S02CH3, X2 = H, R1R2 = 0, R3 = R4 = H Prepared according to the mode of operation of Example 65 purified by chromatography in a dichloromethane / acetone (10 / 0.3). 162 ° C melting point crystals. Example 91: 3-chloro-4-fluoro-4'-ethylthiobenzophenone Formula (III): A = phenyl, Y1 = 3-C1, Y2 = 4-F Prepared according to the mode of operation of example 1. Crystals of melting point of 116 ° C. Example 92: 3-chloro-4-fluoro-4 'methanesulfonylbenzophenone Formula V): A = phenyl, Yj-3-Cl, Y 2 = 4-F Prepared according to the mode of operation of example 39. Crystals of melting point of 146 ° C. Example 93: 3-Ethoxycarbonyl-4- (3-chloro-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = phenyl, Y1 = 3-C1, Y2 = 4-F Prepared according to the mode of operation of example 11. Oil used as is for the continuation. Example 94: Ethyl 3- (3-chloro-4-fluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate Formula (XI): A = phenyl, Y1 = 3-C1 , Y2 = 4-F Prepared according to the operating mode of example 12.

Oil used as is for the continuation. Example 95: (Z) -3- [1- (3-Chloro-4-fluorophenyl) -1- (4-methanesulfonylphenyl) -methylidene] -dihydro-furan-2-one Isomer (Z): Formulad): A = B = phenyl, Y ^ -Cl, Y2 = 4-F, X1 = 4-S02CH3, X2 = H, RtR2 = 0, R3 = R4 = H Prepared according to the mode of operation of Example 65 purified by chromatography in a dichloromethane / acetone mixture (10 / 0.3). Crystals with a melting point of 123 ° C. Example 96: 4-bromo-4 '-methylthiobenzophenone Formula (III): A = phenyl, Y 1 = 4-Br, Y 2 = H Prepared according to the mode of operation of example 1. Crystals of melting point of 148 ° C. Example 97: 4-bromo-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y 1 = 4-Br, Y 2 = H Prepared according to the mode of operation of example 39. Crystals of melting point 188 ° C. Example 98: 3-Ethoxycarbonyl-4- (4-bromophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = phenyl, Y 1 = 4-Br, Y 2 = H Prepared according to the mode of operation of example 11. Oil used as is for the continuation. Example 99: Ethyl 3- (4-bromophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate Formula (XI): A = phenyl, Y ^ -Br, Y2 = H Prepared according to the operation mode of example 12. Oil used as is for the continuation. Example 100: (Z) -3- ti- (4-bromophenyl) -1- (4-methanesulfonyl-phenyl) methylidene] -dihydro-furan-2-one Isomer (Z) -. Formula (I): A = B = phenyl, Y ^ -Br, 2 = H, X1 = 4-S02CH3, X2 = H, R! R2 = 0, R3 = R4 = H Prepared according to the mode of operation of Example 65 , purified by chromatography in a dichloromethane / acetone mixture (10 / 0.3). Crystals of melting point 204 ° C. Example 101: 2- (4-thiomethyl-benzoyl) furan Formula (III): A = 2-furyl, Yt = Y 2 = H Prepared according to the mode of operation of example l. Crystals of melting point 86 ° C. Example 102: 2- (4-methanesulfonylbenzoyl) furan Formula (IV): A = 2-furyl, Y? = Y2 = H Prepared according to the mode of operation of example 39. Crystals of melting point 112 ° C. Example 103: 3-Ethoxycarbonyl-4- (furan-2-yl) 4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = 2-furyl, Y? = Y2 = H Prepared according to the mode of operation of example ll. Oil used as is for the continuation.

Example 104: Ethyl 3- (furan-2-yl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate Formula (XI): A = 2 -furyl, Y = Y2 = H Prepared according to the operation mode of example 12. Oil used as is for the continuation. Example 105: (Z) -3- [1-furan-2-yl) -1- (4-methanesulfonylphenyl) -methylidene] dihydro-furan-2 -one Isomer (Z): Formula (I): A = 2- furyl, B = phenyl, Y1 = Y2 = H, X1 = 4S02CH3, X2 = H, R! R2 = 0; R3 = R4 = H Prepared according to the mode of operation of Example 65, purified by chromatography in a dichloromethane / acetone mixture (10 / 0.3). Crystals of melting point 170 ° C. Example 106: (4-thiomethylbenzoyl) cyclohexane Formula (III): A = cyclohexyl, Y! = Y 2 = H Prepared according to the mode of operation of example 1. Crystals of melting point 110 ° C. Example 107: (4-methanesulfonylbenzoyl) cyclohexane Formula (IV): A = cyclohexyl, Yj = Y2 = H Prepared according to the mode of operation of example 39. Crystals of melting point 116 ° C. Example 108: 3-Ethoxycarbonyl-4-cyclohexyl-4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): a = cyclohexyl, Yj = Y2 = H Prepared according to the mode of operation of example 11. Oil used as which for the continuation. Example 109: Ethyl 3-cyclohexyl-3- (4-methanesulfonylphenyl) -2 - (2-hydroxyethyl) -2-propenate Formula (XI): A = cyclohexyl, Yt = Y2 = H Prepared according to the mode of operation of the example 12. Oil used as is for the continuation. Example 110: (Z) -3- [1-Cyclohexyl-1- (4-methanesulfonylphenyl) -methylidene] dihydro-furan-2-one Isomer (Z): Formula (I): A = cyclohexyl, B = phenyl, Y 1 = Y2 = H, X1 = 4-S02CH3, X2 = H, RjR2 = 0, R3 = R4 = H Prepared according to the mode of operation of example 65. Crystals of melting point 148 ° C. Example 111: 3-Fluoro-4-methyl-4'-thiomethyl-benzophenone Formula (III): A = phenyl, Y { = 3-F, Y2 = 4-CH3 To a suspension of 6.4 grams of magnesium in flakes in 5 milliliters of anhydrous ethyl ether is added dropwise a solution of 50 grams of 4-bromo-2-fluorotoluene in 150 milliliters of ether ethyl anhydrous. At the end of the addition, the mixture is stirred 30 minutes then a solution of 4-thiomethyl-benzonitrile in 200 milliliters of anhydrous tetrahydrofuran is added. The ethyl ether is distilled and the mixture is heated under reflux for 4 hours. After returning to room temperature, 300 milliliters of 6N hydrochloric acid are added dropwise. The mixture is heated under reflux for 6 hours then cooled to room temperature and extracted with isopropyl ether. The organic phase is dried over magnesium sulphate and then evaporated to dry. The residue is crystallized from ethyl ether to give 25 grams of 3-fluoro-4-methyl-4'-thiomethyl benzophenone in the form of crystals of melting point 94 ° C. Example 112: 3-Fluoro-4-methyl-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y > = 3-F, Y2 = 4-CH3 Prepared according to the mode of operation of example 39. Crystals of melting point 170 ° C. Example 113: Acid (Z) -3-ethoxycarbonyl-4- (3-fluoro-4-methylphenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = phenyl, Y { = 3-F, Y2 = 4-CH3 Prepared according to the mode of operation of example 11, purified by treating the crude mixture of the two isomers (E) and (Z) with 1 equivalent of D- (+) -a- methylbenzylamine in 5 volumes of ethyl acetate. The crystals formed are removed (salt of isomer (E)) and the filtrate is acidified by dilute hydrochloric acid, decanted and evaporated in vacuo to give an oil corresponding to the (Z) isomer containing less than 5 percent isomer (E) Example 114: (Z) -3- (3-f luoro-4-m-methylf-ß-nyl) -3- (4-methanesulfonyl-f-enyl) -2- (2-hydroxyethyl) -2-ethylpropenate Formula (XI) : A = phenyl, Y { = 3-F, Y2 = 4-CH3 Prepared according to the mode of operation of example 12 Oil used as is for the continuation. Example 115: (Z) -3- [1- (3-f luoro-4-methyl-1-enyl) -1- (4-methanesulfonyl-phenyl) -methylidene] -dihydro-furan-2-one Isomer (Z): Formula (I ): A = B = phenyl, Y1 = 3-F, Y2 = 4-CH3, X1 = 4-S02CH3, X2 = H, R ^ -O, R3 = R4 = H Prepared according to the mode of operation of Example 65 Crystals of melting point 169-170 ° C. Example 116: 4-trifluoromethyl-4'-thiomethyl-benzophenone Formula (III): A = phenyl, Y? = 4-CF3, Y2 = H Prepared according to the mode of operation of example 1. Crystals of melting point 139 ° C. Example 117: 4-trifluoromethyl-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Yt = 4-CF3, Y2 = H Prepared according to the mode of operation of example 39. Crystals of melting point 138 ° C. Example 118: 3-Ethoxycarbonyl-4- (4-trifluoromethylphenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = phenyl, Y { = 4-CF3, Y2 = H Prepared according to the mode of operation of example 11. Oil used as is for the continuation. Example 119: Ethyl 3- (4-trifluoromethylphenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenate Formula (XI): A = phenyl, Y! = 4-CF3, Y2 = H Prepared according to the operating mode of example 12. Oil used as is for the continuation. Example 120: (E) -3- [1- (4-trifluoromethylphenyl) -1- (4-methanesulfonylphenyl) methylidene] -dihydro-furan-2-one Isomer (E): Formula (I): A = B = phenyl, Y1 = 4-CF3, Y2 = H, X1 = 4-S02CH3, X2 = H, R! R2 = 0, R3 = R4 = H Prepared according to the mode of operation of example 65, purified by chromatography in a mixture of dichloromethane / acetone (10 / 0.3). Crystals melting point 188-189 ° C. Example 121: 4-thiobenzyl-4'-chlorobenzophenone Prepared according to the mode of operation of example 56 from 4-bromochlorobenzene and 4-thiobenzylbenzonitrile prepared in example 55. Crystals of melting point 134 ° C. Example 122: Tertiary-4-butyl-aminosul-foni 1-4'-chlorobenzophenone Prepared according to the mode of operation of example 57. Crystals of melting point 163 ° C. Example 123: 3-Ethoxycarbonyl-4- (4-butyl tertiary-aminosulfonyl phenyl) -4- (4-chlorophenyl) -3-butenoic acid Formula (XII): A = phenyl, Y { = 4-Cl, Y2 = H Prepared according to the operation mode of example 58. Oil used as is for the continuation. Example 124: (Z) -3- (4-butyl tertiary-aminosulfonyl) -3- (4-chlorophenyl) -2- (2-hydroxyethyl) -2-ethyl propenate Prepared according to the mode of operation of example 12.

The oil obtained is recovered in ethyl ether and the crystals formed are centrifuged (E-isomer). The filtrate is concentrated in vacuo and the residue is taken up in crystallized petroleum ether to give the (Z) -isomer in the form of crystals with a melting point of 120 ° C. Example 125: (Z) -4- [(4-chlorophenyl) -2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfonamide Formula (I): A = B = phenyl, Y1 = 4-C13, Y2 = H, X1 = 4-S02NH2, X2 = H, R1R2 = 0, R3 = R4 = H A solution of 10 grams of (Z) -3- (4-butyl tertiary-aminosulfonylphenyl) 3- (4-chlorophenyl) -2 Ethyl (2-hydroxyethyl) -2-propenate prepared in Example 124, in 80 milliliters of trifluoroacetic acid is heated at reflux for 15 hours. After evaporation under vacuum of the solvent, the residue is taken up in dichloromethane. The organic phase is washed with water then dried over magnesium sulfate and evaporated in vacuo to give an oil which crystallizes from a mixture of acetone / isopropyl ether to give 3.9 grams of (Z) -4- (4-chlorophenyl) - (2-Oxo-dihydro-furan-3-ylidene) -methyl] benzenesulfonamide in the form of crystals with a melting point of 187-189 ° C. Example 126: 4-thiobenzyl-3'-fluoro-4"-methylbenzophenone Prepared according to the mode of operation of example 56 from 4-bromo-2-fluorotoluene Crystals of melting point 122 ° C. Example 127: 4- tertiary-aminosulfonyl-3'-fluoro-4'-methylbenzophenone butyl Prepared according to the procedure of example 57. Melting point crystals 132 ° C. Example 128: (Z) -3-Ethoxycarbonyl-4- (4-) acid tertiary-aminosulfonylphenyl) -4- (3-fluoro-4-methylphenyl) -3-butenoicbutyl Formula (XII): A = phenyl, Y { = 3-F, Y2 = 4-CH3 Prepared according to the mode of operation of Example 58, the obtained oil is recovered in tertiary butyl methyl ether and the crystals formed are centrifuged to give the (E) isomer of melting point 96 °. C. The filtrate is concentrated in vacuo to give the (Z) isomer in the form of an oil used as such for continuation. Example 129: (Z) -3- (4-butyl tertiary-aminosulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -2- ethyl propenate Prepared according to the mode of operation of the Example 12 from the isomer (Z) of the acid of example 128. Oil used as is for the continuation. Example 130: (Z) -4- [(3-Fluoro-4-methylphenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfonamide Formula (I): A = B = phenyl, Y ^ - F, Y2 = 4-CH3, X1 = 4-S02NH2, 2 = H, R ^ -O, R3 = R4 = H Prepared according to the mode of operation of example 125. Crystals of melting point 170-172 ° C. Example 131: 4-thiobenzyl-4'-fluoro-3'-ethylbenzophenone Prepared according to the mode of operation of example 56 from 5-bromo-2-fluorotoluene. Crystals of melting point 123 ° C. Example 132: 4-tertiary butyl-aminosulfonyl-4-fluoro-3'-methylbenzo-phenone Prepared according to the mode of operation of example 57. Crystals of melting point 108 ° C. Example 133: (Z) -3-Ethoxycarbonyl-4- (4-butyl tertiary-aminosulfonylphenyl) -4- (4-fluoro-3-methylphenyl) -3-butenoic acid Formula (XII): A = phenyl, Y. { . = 3-CH3, Y2 = 4-F Prepared according to the operation mode of example 58, the obtained oil is recovered in methyl tertiary butyl ether (isomer (E)). The filtrate is evaporated in vacuo to give the isomer (Z) in the form of oil used as is for the continuation. Example 134: (Z) -3- (4-butyl tertiary-aminosulfonyl-phenyl) -3- (4-fluoro-3-methylphenyl) -2- (2-hydroxyethyl) -2-ethylpropenate Prepared according to the mode of operation of the example 12. Crystals of melting point 128 ° C. Example 135: (Z) -4- [(4-Fluoro-3-methylphenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfonamide Formula (I): A = B = phenyl, Y! = 3-CH3, Y2 = 4-F, X1 = 4-S02NH2, X2 = H, R1R2 = 0, R3 = R4 = H Prepared according to the operating mode of example 125. Melting point crystals 228-229 ° C . Example 136: (E) -3- (4-butyl tertiary-aminosulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -3-ethylpropenate Prepared according to the mode of operation of the Example 12, from the isomer (E) of the acid of example 128. Oil used as is for the continuation. Prepared according to the mode of operation of example 12. Example 137: Acid (E) -3- (4-bu tyl tertiary-aminosulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -3-propenoic A solution of 16 grams of (E) -3- (4-butyl tertiary-aminosulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -3-ethyl propenate , prepared in Example 136, in 50 milliliters of ethanol, containing 3 grams of soda and 5 milliliters of water, heated at reflux for 2 hours. The mixture is concentrated in vacuo, taken up in water, washed with ethyl ether, then acidified with dilute hydrochloric acid and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, then evaporated dry in vacuo to give a residue that crystallizes from isopropyl ether to give 7.6 grams of (E) -3- (4-tertiary butyl-aminosulfonylphenyl) -3- acid. (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -3-propenoic acid in the form of crystals of melting point 160 ° C. Example 138: (E) -2- [1- (4-tertiary butyl aminosulfonylphenyl) -1- (3-f luoro-4-methylphenyl) methylidene] butane-1,4-diol To a solution of 7.8 grams of acid (E) -3- (4-Butyl-tertiary-aminosulfonyl-phenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -3-propenoic prepared to Example 137, in 50 milliliters of anhydrous tetrahydrofuran is 5 milliliters of borane / methyl sulfide complex are added dropwise, the mixture is stirred 6 hours at room temperature then 10 milliliters of methanol are added dropwise. The mixture is concentrated under vacuum, it is recovered with an aqueous solution of potassium carbonate and extracted with ethyl ether. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give 6.3 grams of (E) -2- [1- (4-tertiary butyl-aminosulfonylphenyl) -1- (3-fluoro-4-methylphenyl) methylidene] butane-l, 4-diol in the form of crystals of melting point 106 ° C. Example 139: (E) -4- [(3-Fluoro-4-methylphenyl) - (tetrahydrofuran-3-ylidene) methyl] benzenesulfonamide Formula (I): A = B = phenyl, Xt = 3-F, X2 = 4-CH3, Y1 = 4-S02 H2, Y2 = H, R1 = R2 = R3 = R = H A solution of 6.3 grams of (E) -2- [1- (4-butyl tertiary-aminosulfonylphenyl) - 1- (3-f luoro-4-methylphenyl) methylidene] butane-1,1-diol prepared in Example 138 in 75 milliliters of trifluoroacetic acid is heated at reflux for 10 hours. The solvent is concentrated in vacuo and the residue is taken up in a dilute sodium hydroxide solution, washed with dichloromethane, then acidified with dilute hydrochloric acid and extracted with dichloromethane. The organic phases are combined and dried over magnesium sulphate, then evaporated in vacuo. The residue is organized in methyl tertiary butyl ether to give 4 grams of (E) -4- [(3-fluoro-4-methylphenyl) - (tetrahydro-furan-3-ylidene) methyl] benzenesulfonamide in the form of crystals melting point 174-176 ° C. Example 140: 4-thiobenzyl-3'-chloro-4'-fluorobenzophenone Prepared according to the mode of operation of example 56, starting from 4-bromo-2-chlorofluorobenzene. Melting point crystals 102 ° C, Example 141: 4-tertiary butyl-aminosulfonyl-3-chloro-4'-fluorobenzophenone Prepared according to the mode of operation of example 57.

Crystals of melting point 108 ° C. Example 142: 3-Ethoxycarbonyl-4- (4-butyl tertiary-aminosulfonylphenyl) -4- (3-chloro-4-fluorophenyl) -3-butenoic acid Formula (XII): A = phenyl, Y ^ -Cl, Y2 = 4-F Prepared according to the operation mode of example 58. Oil used as is for the continuation. Example 143: (Z) -4- [(3-chloro-4-fluorophenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfonamide Formula (I): A = B = phenyl, Yt = 3 -Cl, Y2 = 4-F, X1 = 4-S02NH2, 2 = H, R ^ -O, R3 = R4 = HA a solution of 17 grams of 3-ethoxycarbonyl-4- (4-tertiary butyl-aminosulfonylphenyl) acid 4- (3-chloro-4-fluorophenyl) -3-butenoic prepared in example 142 in 150 milliliters of tetrahydrofuran are added dropwise 7 milliliters of borane / methyl sulfide complex. The mixture is stirred 6 hours at room temperature then 30 milliliters of ethanol are added dropwise. After the addition of an aqueous solution of potassium carbonate, the mixture is extracted into dichloromethane. The organic phase is dried and evaporated in vacuo. The residue (13.8 grams) is recovered in 30 milliliters of ethanol containing a solution of 3 grams of soda in 10 milliliters of water and the mixture is heated at 70 ° C for 3 hours. The solvents are concentrated in vacuo and the residue is recovered in water; The aqueous phase is washed with ethyl ether, acidified with hydrochloric acid and extracted with dichloromethane, dried over magnesium sulphate and evaporated in vacuo. The residue is taken up in ethyl ether and the crystals obtained are centrifuged to give 3 grams of (E) -3- (4-tertiary butyl-aminosulfonylphenyl) -3- (3-fluoro-4-chlorophenyl) -2- (2) acid. -hydroxyethyl) -3-propenoic acid (melting point 180 ° C). The filtrate is concentrated in vacuo and the residue is recovered in 60 milliliters of trifluoroacetic acid. The mixture is heated under reflux for 17 hours then concentrated in vacuo. The residue is recovered with a dilute solution of sodium hydroxide and extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then evaporated in vacuo to give 2 grams of (Z) -4- [(3-chloro-4-fluorophenyl) - (2-oxo-dihydro-furan-3-ylidene) met. il] -benzenesulfonamide in the form of crystals of melting point 244-246 ° C. Example 144: 4-thiobenzyl-3'-fluoro-4'-methoxybenzophenone Prepared according to the mode of operation of example 56 from 4-bromo-2-fluoroanisole. Crystals of melting point 125 ° C. Example 145: 4-tertiary butyl-aminosulfonyl-3'-fluoro-4'-methoxybenzo-phenone Prepared according to the mode of operation of example 57. Crystals of melting point 136 ° C. Example 146: (Z) -3-Ethoxycarbonyl-4- (4-butyl tertiary-aminosulfonylphenyl) -4- (3-fluoro-4- * methyclophenyl) -3-benzoic acid Formula (II): A = phenyl, Y. { = 3-F, Y2 = 4-0 Me Prepared according to the mode of operation of Example 58, the obtained oil is recovered by tertiary butyl methyl ether to give the (Z) isomer in the form of amorphous crystals used as is for the continuation.

Example 147: (Z) -3- (4-butyl tertiary-aminosulfonylphenyl) -3- (3-fluoro-4-methoxyphenyl) -2- (2-hydroxyethyl) -2-ethylpropenate Prepared according to the mode of operation of the example 12. Oil used as is for the continuation. Example 148: (Z) -4- [(3-Fluoro-4-methoxyphenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfonamide Formula (I): A = B = phenyl, Yj = 3 -F, Y2 = 4-0Me, X1 = 4-S02NH2, X2 = H, R1R2 = 0, R3 = R4 = H Prepared according to the operating mode of example 125. Crystals of melting point 149-150 ° C. Example 149: 3- (4-fluorobenzoyl) pyridine To a suspension of 140 grams of nicotinic acid chloride hydrochloride in 500 milliliters of fluorobenzene, cooled to 0 ° C, 280 grams of aluminum chloride are added in portions. The mixture is refluxed for 6 hours then cooled and poured onto ice. After addition of soda to pH = 8, the mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then evaporated under vacuum. The residue crystallized from a pentane / isopropyl ether mixture to give 108.5 grams of 3- (4-fluorobenzoyl) pyridine in the form of crystals of melting point 91 ° C. Example 150: 3- (4-thiobenzyl-benzoyl) pyridine To a solution of 43 grams of benzylmercaptan in 500 milliliters of N, N-dimethylformamide is added 14 grams of 60 percent sodium hydride. The mixture is stirred 20 minutes at room temperature and 70 grams of 3- (4-fluorobenzoyl) pyridine are added, prepared in example 149. The mixture is heated 8 hours at 80 ° C then concentrated in vacuo and the residue recovered with water. The crystals formed are centrifuged, dissolved in dichloromethane, the solution is dried over magnesium sulfate and concentrated in vacuo. The residue crystallizes from a mixture of pentane / isopropyl ether to give 81 grams of 3- (4-thiobenzyl-benzoyl) pyridine in the form of crystals of melting point 102 ° C. Example 151: 3- (4-tertiary butyl io-aminosul foni 1 -benzoyl) pyridine Prepared according to the mode of operation of example 57. Melting point crystals 179 ° C. Example 152: (Z) -3-Ethoxycarbonyl-4- (4-butyl-tertiary-amino-sulfonyl-phenyl) -4- (3-pyridyl) -3-butenoic acid Formula (XII): A = 3-pyridyl, Yi = Y2 = H Prepared according to the mode of operation of Example 58, the oil obtained is recovered in hot ethyl acetate, the crystals formed are centrifuged (isomer (E) of melting point 209 ° C). The filtrate is evaporated and the residue is recovered with crystallized pentene to give the (Z) isomer in the form of crystals of melting point 195 ° C. Example 153: (Z) -3- (4-butyl tertiary-aminosulfonylphenyl) -3- (3-pyridyl) -2- (2-hydroxyethyl) -2-ethyl propenate Prepared according to the mode of operation of example 12. Crystals amorphous used as is for the continuation. Example 154: (Z) - [(3-pyridyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfonamide Formula (I): A = 3-pyridyl, B = phenyl, Xj = 4- S02NH2 , X2 = H, Y1 = Y2 = H, R1R2 = 0, R3 = R4 = H Prepared according to the mode of operation of example 125. Crystals of melting point 219-220 ° C. Example 155: 3-chloro-4-methoxy-4'-thiomethylbenzophenone Formula (III): A = phenyl, Y 1 = 3-C1, Y 2 = 4-0Me Prepared according to the mode of operation of example 1. Melting point crystals 100 ° C. Example 156: 3-chloro-4-methoxy-4'-methanesulfonylbenzophenone Formula (IV): A = phenyl, Y ^ -Cl, Y2 = 4-0Me Prepared according to the mode of operation of example 39. Melting point crystals 164 ° C.

Example 157: (Z) -3-Ethoxycarbonyl-4- (3-chloro-4-methoxyphenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid Formula (X): A = phenyl, Y ^ -Cl, Y2 = 4-0Me Prepared according to the mode of operation of example 11, the oil obtained is recovered in ether and the crystals formed are centrifuged to give the isomer (Z) in the form of crystals of melting point .179 ° C. Example 158: (Z) -3- (3-chloro-4-methoxyphenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -3-ethylpropenate Formula (XI): A = phenyl, Y ^ -Cl, Y2 = 4-0Me Prepared according to the mode of operation of example 12. Crystals of melting point 102 ° C. Example 159: (Z) -3- ti- (3-chloro-4-methoxyphenyl) -1- (4-methane sulfonylphenyl) methylidene] -dihydro-furan-2 -one Formula (I): A = B = phenyl, Y ^ -Cl, Y2 = 4-OMe, X1 = 4-S02CH3, X2 = H, RtR2 = 0, R3 = R4 = H Prepared according to the mode of operation of example 65. Crystals of melting point 177 ° C. Example 160: 2- (4-thiomethyl-benzoyl) thiophene Formula (III): A = 2-thienyl, Yj = Y 2 = H Prepared according to the mode of operation of example 1. Crystals of melting point 60 ° C.

Example 161: 2- (4-methanesulfonylbenzoyl) thiophene Formula (IV): A = 2-thienyl, Y > = Y2 = H Prepared according to the mode of operation of example 39. Crystals of melting point 140 ° C. Example 162: (E) -3-Ethoxycarbonyl-4- (4-methanesulfonylphenyl) -4- (2-thienyl) -3-butenoic acid Formula (X): A = 2-thienyl, Y1 = Y2 = H Prepared according to mode of operation of example 11. Crystals of melting point 120 ° C. Example 163: (E) -3- (4-methanesulfonylphenyl) -3- (2-thienyl) -2-hydroxyethyl) -3-ethylpropenate Formula (XI): A = 2-thienyl, Y! = Y2 = H Prepared according to the mode of operation of example 12. Crystals of melting point 116 ° C. Example 164: (E) -3- [1- (4-methanesulfonylf enyl) -1- (2-thienyl) methylidene] -dihydro-furan-2-one Formula (I): A = 2-thienyl, B = phenyl , Y? = Y2 = H, X1 = 4-S02CH3, X2 = H, RjR2 = 0, R3 = R4 = H Prepared according to the mode of operation of example 65. Crystals of melting point 246 ° C. Example 165: 4- (2-naphthoyl) thiomethyl-benzene Formula (III): A = 2-naphthyl, Y { = Y2 = H Prepared according to the operation mode of example l. Melting point crystals 98 ° C.

Example 166: 4- (2-naphthoyl) methanesulfonylbenzene Formula (IV): A = 2-naphthyl, Y! = Y2 = H Prepared according to the mode of operation of example 39. Crystals of melting point 150 ° C. Example 167: Acid-3-ethoxycarbonyl-4 - (2 -naphyl) -4- (4-methanesulfonylphenyl) -3-butenoic Formula (X): A = 2-naphthyl, Y { = Y2 = H Prepared according to the mode of operation of example 11. Oil used as is for the continuation. Example 168: Ethyl 3- (2-naphthyl) -3- (4-methanesulfonylphenyl) -2 - (2-hydroxyethyl) -2-propenate Formula (XI): A = 2-naphthyl, Y? = Y2 = H Prepared according to the operation mode of example 12. Oil used as is for the continuation. Example 169: (Z) -3- [1- (2-naphthyl) - (4-methanesulfonylphenyl) methylidene] dihydro-furan-2-one Formula (I): A = 2-naphthyl, B = phenyl, Yj = Y2 = H, X1 = 4-S02CH3, X2 = H, R ^ 2 = 0, R3 = R4 = H Prepared according to the mode of operation of Example 65, purified by chromatography in a dichloromethane / acetone mixture (10 / 0.3). Crystals of melting point 244 ° C. Example 170: 3, 5-dichloro-4'-fluorobenzophenone A mixture of 50 grams of 3,5-dichlorobenzoyl chloride and 150 milliliters of fluorobenzene is cooled to 0 ° C and 65 grams of aluminum trichloride are added per portion. The mixture is then stirred at room temperature for 2 hours then under reflux for 4 hours. After cooling, the mixture is poured onto an ice / dilute hydrochloric acid mixture and extracted in dichloromethane. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 59 grams of 3,5-dichloro-4'-fluorobenzophenone in the form of crystals with a melting point of 65 ° C. Example 171: 3, 5-dichloro-4'-thiobenzylbenzophenone Prepared according to the mode of operation of Example 150, starting with 3,5-dichloro-4'-fluorobenzophenone prepared in example 170. Melting point crystals 80 ° C. Example 172: 4-butyl tertiary-aminosulfonyl-3 ', 5'-dichlorobenzophenone Prepared according to the mode of operation of Example 57, starting from 3,5-dichloro-4'-thiobenzylbenzophenone prepared in Example 171 Crystals melting point 144 ° C. Example 173: 3-Ethoxycarbonyl-4- (4-butyl tertiary-aminosulfonylphenyl) -4- (3,5-dichlorophenyl) -3-butenoic acid Formula (XII): A = phenyl, Yt = 3-Cl, Y 2 = 5 -Cl Prepared according to the operation mode of example 58.

Oil used as is for the continuation. Example 174: Ethyl 3- (4-butyl tertiary-aminosulfonylphenyl) -3- (3,5-dichlorophenyl) -2- (2-hydroxyethyl) -2-propenate Prepared according to the mode of operation of example 12. Oil used which for the continuation. Example 175: (Z) -4- [(3,5-Dichlorophenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide Isomer (Z): Formula (I): A = B = phenyl, = 3 -Cl, Y2 = 5-C1, X1 = 4-S02NH2, X2 = H, R ^ 2 = 0, R3 = R4 = H Prepared according to the mode of operation of example 65. The obtained crystals are chromatographed on silica gel in a dichloromethane / acetone mixture (9/1) to give after recrystallization from acetic acid, (Z) -4-t ( 3,5-dichlorophenyl) - (2-oxo-dihydro-furan-3-yl-idene) -methyl] -benzenesulfonamide in the form of crystals of melting point 217 ° C. Example 176: 3-chloro-4 • -fluorobenzophenone Prepared according to the mode of operation of example 170. Crystals of melting point 76 ° C. Example 177: 3-Chloro-4'-thiobenzylbenzophenone Prepared according to the mode of operation of Example 150 starting from 3-chloro-4'-fluorobenzophenone prepared in Example 176. Crystals of melting point 90 ° C.

Example 178: Tertiary-4-butyl-aminosulfonyl-3'-chlorobenzophenone Prepared according to the mode of operation of example 57 from 3'-chloro-4'-thiobenzylbenzophenone, prepared in example 177. Melting point crystals 128 ° C. Example 179: 3-Ethoxycarbonyl-4- (4-butyl tertiary-aminosulfonyl phenyl) -4- (3-chlorophenyl) -3-butenoic acid Formula (XII): A = phenyl, Y { = 3-Cl, Y2 = H Prepared according to the procedure of example 58. Orange oil used as is for the continuation. Example 180: 3- (4-butyl tertiary-aminosulfonylphenyl) -3 (3-chlorophenyl) -2- (2-hydroxyethyl) -2-ethylpropenate Prepared according to the mode of operation of example 12. Oil used as is for the continuation. Example 181: (Z) -4- [(3-chlorophenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfonamide Isomer (Z): Formula (I): A = B = phenyl, Y1 = 3-Cl, Y = H, X1 = 4-S02NH2, X2 = H, RjR2 = O, R3 = R4 = H Prepared according to the mode of operation of Example 65, purified by chromatography on silica gel with a dichloromethane / acetone (10/1).

The crystals melting point 178 ° C. Example 182: 4-Fluoro-3'-methylbenzophenone Prepared according to the mode of operation of example 170. Crystals of melting point 50 ° C. Example 183: 4-thiobenzyl-3'-methylbenzophenone Prepared according to the mode of operation of example 150, starting from 4-fluoro-3'-methylbenzophenone, prepared in example 182. Crystals of melting point 98 ° C. Example 184: Tertiary-4-butyl-aminosul-fon-1 -3'-methylbenzophenone Prepared according to the procedure of Example 57, starting from 4-thiobenzyl-3'-methylbenzophenone, prepared in example 183. Melting point crystals 116 ° C. Example 185: 3-Ethoxycarbonyl-4- (4-butyl tertiary-aminosulfonyl phenyl) -4- (3-methylphenyl) -3-bute oic acid Formula (XII): A = phenyl, Y ^ -Ci ^, Y2 = H Prepared according to the mode of operation of example 58. Oil used as is for the continuation. Example 186: Ethyl 3- (4-butyl tertiary-aminosulfonylphenyl) -3- (3-methylphenyl) -2- (2-hydroxyethyl) -2-propenate Prepared according to the mode of operation of example 12.

Oil used as is for the continuation. Example 187: (Z) -4- [(3-methylphenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfonamide Isomer (Z): Formula (I): A = B = phenyl, Yt = 3-CH3, Y2 = H, X1 = 4-S02NH2, X2 = H, RLR2 = 0, R3 = R4 = H Prepared according to the mode of operation of example 65. The oil obtained is chromatographed on silica gel with a dichloromethane / acetone mixture (10/1) to give (Z) -4 - [(3-methylphenyl) - (2 - oxo-dihydro-furan-3-ylidene) methyl] benzene sulfonamide in the form of crystals of melting point 166 ° C. Example 188: 3-chloro-4-methoxy-4'-thiobenzylbenzophenone Prepared according to the mode of operation of example 56 from 2-chloro-4-bromoanisole. Crystals of melting point 115 ° C. Example 189: Tertiary-4-butyl-aminosulfonyl-3'-chloro-4'-methoxybenzo-phenone Prepared according to the mode of operation of example 57 from 3-chloro-4-methoxy-4'-thiobenzylbenzophenone. Crystals with a melting point of 120 ° C. Example 190: 3-Ethoxycarbonyl-4- (4-butyl tertiary-amino sulfonylphenyl) -4- (3-chloro-4-methoxyphenyl) -3-butenoic acid Formula (XII): A = phenyl, Y1 = 3-C1, Y2 = 0Me Prepared according to the operating mode of example 58. Oil used as is for the continuation.

Example 191: 3- (4-butyl tertiary-aminosulfonylphenyl) -3- (3-chloro-4-methoxyphenyl) -2- (2-hydroxyethyl) -2- ethyl propenate Prepared according to the mode of operation of example 12. Oil Used as is for the continuation. Example 192: (Z) -4- [(3-chloro-4-methoxyphenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfonamide and (E) -4- [3-chloro-4- methoxyphenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfonamide Formula (I): A = B = phenyl, Y? = 3-Cl, Y2 = 4-0Me, X1 = 4-S02NH2, X2 = H, R ^ 2 = 0, R3 = R4 = H Prepared according to the mode of operation of Example 65. The oil obtained is chromatographed on a silica with a dichloromethane / acetone mixture (10/1) to give a mixture of (E) and (Z) -4- [(3-chloro-4-methoxyphenyl) - (2-oxo-dihydro-furan-3) -ylidene) methyl] benzenesulfonamide in the form of amorphous crystals. PHARMACOLOGY The anti-inflammatory activity of the compounds of the examples was evaluated according to the carrageenan edema method and the antalgic activity according to the kaolin arthritis method. Methods Anti-inflammatory activity: The anti-inflammatory activity is evaluated in the rat by the carrageenan edema test. The product is administered orally at a rate of 2.5 milliliters / 100 grams (n = 6 animals per dose) 2 hours 30 minutes after an oral water overload (2.5 milliliters / 100 grams), one hour after administration of the product , the edema is induced by subcutaneous injection planting an aqueous solution of carrageenan at 2 percent. The results are expressed in the form of ID 50, doses in milligrams / kilogram that induce 50 percent decrease in edema volume, calculated by linear regression using the volume of maximum edema obtained for each product tested. Analgesic activity: The analgesic activity is evaluated in the rat by the kaolin arthritis test. Thirty minutes after the intra-articular administration of an aqueous suspension of kaolin at 10 percent, the product is administered orally at a rate of 1 milliliter / 100 grams (n = 10 animals per dose). The results are expressed in the form of DE5g, dose in mg / kg that induces the 50 percent decrease in the maximum levels obtained in the control lot, calculated by linear regression.

Inhibition of enzymatic activities COX-l and COX-2 The studied molecule is previously incubated for 10 minutes at 25 ° C with 2 units of COX-1 (enzyme purified from seminal vesicles of sheep) or 1 unit of COX-2 (enzyme purified from lamb placenta). Arachidonic acid (6 μM for COX-1, 4 μM for COX-2) is added to the reaction medium and incubation is carried out for 5 minutes at 25 ° C. at the end of the incubation, the enzymatic reaction is stopped by an addition of IN HCl and the produced PGE2 is dosed by EIA. The results are expressed in the form of CI5o, concentration in nM corresponding to 50 percent inhibition of the maximum enzymatic activity on COX-1 and COX-2 (n = 1 to 4 determinations).

TOLERANCE Gastric tolerance: The study of gastric tolerance is performed in the CD Charles River rat strain that weighs 110 to 150 grams. The animals are subjected to a water diet 24 hours before the administration of the product or vehicle only orally at a rate of 1 milliliter / 100 grams (n = 6 animals per dose). Six hours after administration, the animals are sacrificed, the stomachs are raised and opened according to the large curvature. The number of points and hemorrhagic furrows per stomach identified macroscopically allows to establish an index of ulceration (0: no injury, 1: 1 to 2 injuries, 2: 3 to 4 injuries, 3: 5 to 8 injuries, 4: 9 to 16 lesions, 5: more than 17 lesions) and estimate the 50 percent ulcer dose (DU50 = dose expressed in mg / kg that induces 4 to 5 lesions).

TOXICOLOGY The first toxicology studies carried out show that the products of the examples do not induce any harmful effect after the oral absorption of the rat doses up to 300 mg / kg.

Claims (13)

1. l. Diarylmethex ideno franian derivatives characterized by responding to the general formula (I):
2. Formula (I) in which: Cycles A and B independently represent: - a phenyl radical - a naphthyl radical - a radical derived from a heterocycle having from 5 to 6 chains and possessing from 1 to 4 heteroatoms - a radical derived of a saturated hydrocarbon cycle having from 3 to 7 carbon atoms at least one of the substituents X1; X2, Y] or Y2 necessarily represents: - a group -S (0) nR in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical of 1 to 6 carbon atoms, a radical halogen lower alkyl of 1 to 6 carbon atoms, - a group -SO2NH2; and is in the para position, the others independently represent - the hydrogen atom - a halogen atom - a lower alkyl radical of 1 to 6 carbon atoms - a trifluoromethyl radical, - an O-lower alkyl radical of 1 to 6 atoms of carbon. Xj and X2 or Yj and Y2 represent a methylene dioxy group, Rj, R2, R3 and R4 independently represent - the hydrogen atom - a halogen atom - a lower alkyl radical of 1 to 6 carbon atoms, - a halo- lower alkyl of 1 to 6 carbon atoms, - an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl or pyridyl, or else RjR2 or R3R4 represent an oxygen atom or R1 (R2 or R3, R4, they form together with the carbon atom to which they are attached a saturated hydrocarbon cycle having from 3 to 7 carbon atoms 2. Derivatives of the formula (I) according to claim 1, characterized in that: cycles A and B independently represent a radical: - phenyl-naphthyl-pyridyl-furyl-thienyl-cyclohexyl, at least one of the substituents X1 # X2, IO and Y2 necessarily represents a group SCH3, SO2CH3 or S02NH2, the others independently represent: - the hydrogen atom - a halogen atom - a lower alkyl radical of 1 to 6 carbon atoms - a trifluoromethyl radical - an O-lower alkyl radical of 1 to 6 carbon atoms.
3. 3. Derivatives according to claim 1 or 2, characterized in that cycle B represents a phenyl radical.
4. 4. Derivatives according to claim 1 or 2, characterized in that cycle A represents a phenyl radical. or pyridyl.
5. 5. Derivatives according to any of claims 1 to 4, characterized in that X-i represents the group 4-S02CH or the group 4-S02NH2 and X2 represents the hydrogen atom.
6. 6. Derivatives according to any of claims 1 to 5, characterized in that 'Y! represents the fluorine atom, the chlorine atom or a methyl radical and Y2 represents the hydrogen atom, the fluorine atom or the chlorine atom.
7. 7. Derivatives according to any of claims 1 to 6, characterized in that R ^ represents the oxygen atom and R3 and R4 each represent a hydrogen atom.
8. 8. Derivatives according to claim 1, characterized in that they are selected from among the compounds of formula; (E) -3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] -dihydro-furan-2-one (Z) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydro-furan-2-one (Z) -3- [1- (3,4-Dichlorophenyl) -1- (4-methanesulfonyl phenyl) methylidene] -dihydro-furan-2 -one (Z) -3- [1- (6-chloropyridin-3-yl) -1- (4-methanesulfonyl) enyl) methylidene] -dihydro-furan-2 -one (Z) -4- [(4-chlorophenyl) - (2-oxo-dihydro-furan-3-ylidene) -methyl] benzenesulfonamide (Z) -4- [(3-Fluoro-4-methylphenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] -benzenesulfonamide
9. 9. Process for the preparation of the compounds of formula (I) according to any of claims 1 to 8, characterized in that it comprises the reaction of a ketone of formula in which A, B, X! X2, Yi and Y2 are as defined in claim 1, with an alkyl succinate of formula wherein R 'is a lower alkyl radical of 1 to 6 carbon atoms, optimally the ethyl radical, according to the conditions of the condensation reaction of Stobbe in the presence of an alcoholic in particular the tertiary sodium or potassium butoxide or a hydride such as sodium hydride in an alcoholic solvent such as tertiary butanol or toluene , the selection of the condensing agent and the solvent may allow to direct the reaction towards a particular isomer, to lead to the acid ester derivatives of formula wherein A, B, X X2, Yj and Y2, are as defined in claim 1; the selective reduction of the acid function of the mentioned acidic ester derivatives, for example by the action of a borane in the tetrahydrofuran to lead to the alcohol esters of formula wherein A, B, X1 (X2, Yj and Y2, are as defined in claim 1, after the cyclization of these alcohol esters by heat, for example in toluene in the presence of paratoluenesulfonic acid
10. 10. Pharmaceutical composition , characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as defined in any of claims 1 to 8, optionally incorporated in a pharmaceutically acceptable excipient, carrier or carrier
11. 11. Pharmaceutical composition of anti-inflammatory activity and antialgic, characterized in that it contains a pharmaceutically effective amount of a compound of formula (I) as defined in any of claims 8, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or carrier
12. 12. Pharmaceutically useful composition in the prevention of cancer , in particular colon adenocarcinoma, the prevention of neurodegenerative diseases, particularly Alzheimer's disease, the prevention of infarction or, epilepsy and the prevention of premature uterine labor.
13. 13. Pharmaceutical composition according to claim 10 or 11 characterized in that it is presented in the form of capsules, of tablets dosed from 1 milligram to 1000 milligrams or in the form of metered injection preparations from 0.1 milligram to 500 milligrams.