SK137598A3 - Novel furan diarylmethylidene derivatives, method for their preparation and therapeutical uses thereof - Google Patents

Abstract

Furan diarylmethylidene derivatives of formula (I) and the therapeutical use thereof, particularly as anti-inflammatory and antalgic medicaments are disclosed.

Description

FURAN DIARYL METHYLIDENE DERIVATIVES, METHOD OF PREPARATION, PHARMACEUTICAL FORM AND THERAPEUTIC USE

Technical field

The invention relates to diarylmethylidene furan derivatives having anti-inflammatory and analgesic properties, to a process for the preparation of these compounds, to pharmaceutical compositions containing the compounds and to the use of the compounds according to the invention for therapeutic purposes.

BACKGROUND OF THE INVENTION

One of the arachidonic acid biotransformation conversion systems is the cyclooxygenase pathway by which arachidonic acid is transformed into PGG2 and then to PGH2. Recently, work on cyclooxygenase cloning and sequencing has shown that there are two isoenzymes, COX-1 and COX-2, which occur in some animal species and in particular in humans. The first represents a constitutive enzyme that is expressed in most tissues, while the second, which is expressed only in some tissues, such as brain tissue, is inducible in most tissues by many different products, especially cytokines and mediators produced during the inflammatory reaction. Each of these enzymes plays a different role, and inhibition of COX-1 or COX-2 does not have the same consequences. Inhibition of COX-1 causes a decrease in prostaglandins involved in homeostasis, which may cause side effects. Inhibition of COX-2 causes a decrease in prostaglandins produced in inflammatory conditions. From the above, it is evident that inhibition of COX-2 allows a good toleration of the anti-inflammatory process to be induced.

SUMMARY OF THE INVENTION

The compounds of the present invention allow the above selective inhibition to be achieved. The compounds according to the invention thus exhibit a very valuable pharmacological profile because they exhibit anti-inflammatory and analgesic properties and are exceptionally well tolerated, especially in the gastric region. In particular, these compounds have been indicated for the treatment of inflammatory conditions and for the treatment of pain.

31075 / H

Examples of their use include the treatment of arthritis, in particular rheumatoid arthritis, spondilitis, gout arthritis, osteoarthritis and juvenile arthritis, autoimmune diseases and lupus erythematosus. These compounds have also been indicated for the treatment of bronchial asthma, dysmenorrhea, tendinitis, bursitis and dermatological inflammatory conditions such as psoriasis, eczema, burns and dermatitis. The compounds of the present invention may also be used for the treatment of gastrointestinal inflammation, Crohn's disease, gastritis and ulcerative colitis, for the prevention of tumors, especially colon adenocarcinoma, for the prevention of neurodegenerative diseases, especially Alzheimer's disease, for the prevention of stroke and epilepsy and .

The analgesic properties of these compounds allow them to be applied to all symptoms of pain, in particular for the treatment of myalgia, articular pain or neuralgia, for tooth pain, for the treatment of herpes zoster and migraine, for the treatment of rheumatic complications and cancer-related pain, they can be used for the overall treatment of infections and febrile conditions.

The present invention also encompasses processes for preparing the compounds and their use as therapeutic agents.

Certain derivatives are described in the prior art literature and are said to exhibit selective 2cyclooxygenase inhibitory properties. These compounds are described in the following International Patent Applications PCT:

- WO 95 00501 A (Merck Frosst Canada Inc.),

- WO 94 15932 A (G. D. Searle and Co.),

WO 96 08482 (Merck & Co., Inc).

In general, most of the compounds described in these prior art documents as 2-cyclooxygenase inhibitors are five-membered heterocyclic derivatives substituted with two aromatic rings, which are bonded directly to the heterocycle and are situated on two carbon atoms adjacent to the heterocycle. .

Unexpectedly, it has been found that these derivatives having two aromatic rings on the same carbon atom (wherein the two aromatic rings are attached to the heterocycle not directly but via a double bond) exhibit significant selective 231075 / H cyclooxygenase inhibitory properties .

The diarylmethylidene furan derivatives of the present invention can be characterized by the following formula (I):

* in which:

* rings A and B independently represent:

- a phenyl group,

- naphthyl group,

a heterocycle radical containing from 5 to 6 members and containing from 1 to 4 heteroatoms, or

- a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms, * at least one of X 1, X ₂ , Y 1 or Y ₂ is necessarily:

- a -S (O) _n -R group in which n represents an integer of 0, 1 or 2 and R represents a lower alkyl group having 1 to 6 carbon atoms or a lower haloalkyl group having 1 to 6 carbon atoms, or

- the group -SO ₂ NH ₂ , which group is located in the para position and the other of these substituents independently of one another mean:

- a hydrogen atom,

- halogen atom,

- a lower alkyl group having 1 to 6 carbon atoms,

a trifluoromethyl group, or

- a lower O-alkyl group having 1 to 6 carbon atoms, or X 1 and X ₂ or Y 1 and Y ₂ represent methylenedioxy and R 1, R ₂ , R ₃ and R ₄ independently of one another mean:

- a hydrogen atom,

31075 / H

- halogen atom,

- a lower alkyl group having 1 to 6 carbon atoms,

a lower haloalkyl group having 1 to 6 carbon atoms, or

an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl, or R ₁ R ₂ or R ₃ R ₄ are an oxygen atom, or R ₁ R ₂ or R ₃ R ₄ together with the carbon atom to which they are attached form a saturated hydrocarbon ring containing 3 to 7 carbon atoms.

In the specification and claims, the term lower alkyl refers to a linear or branched hydrocarbon chain containing from 1 to 6 carbon atoms. Examples of a lower alkyl group include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl.

The term "lower haloalkyl" as used herein refers to an alkyl group having 1 to 6 carbon atoms in which 1 to 7 hydrogen atoms have been replaced by 1 to 7 halogen atoms. Examples of the lower haloalkyl group include, for example, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2-difluoro-3,3,3-trifluoropropyl, heptafluoropropyl, chloromethyl or bromomethyl.

By halogen in the description of the present invention is meant a chlorine, bromine, iodine or fluorine atom.

The term saturated C 3 -C 7 hydrocarbon ring refers to cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane.

The term heterocycle-derived moiety refers to any aromatic ring containing one to four heteroatoms in its ring: nitrogen, oxygen or sulfur.

Among these rings, pyridine, furan, thiophene and pyrrole, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, oxazole, oxadiazole, thiazole and thiadiazole are particularly preferred.

The aforementioned derivatives of formula (I) may be asymmetric

31075 / H centers and / or may exist in the form of yew or trans derivatives. Both racemates and mixtures of these yt and trans compounds are within the scope of the present invention, but optically active products and yt derivatives and trans derivatives themselves are also within the scope of the present invention. These pure products can be obtained by methods well known to those skilled in the art, in particular the chromatographic procedure, in particular using chiral columns in the case of optical isomers. Separation of individual substances can also be accomplished in certain cases by simple recrystallization. This separation can also be carried out either with the final product or with an intermediate of the synthesis process, in which case the further synthesis process must be carried out with respect to the stereochemistry in the intermediate molecule.

Preferred derivatives of the present invention are those of formula (I) wherein:

* rings A and B independently of one another mean:

- a phenyl group,

- naphthyl group,

- a pyridyl group,

- furyl group,

a thienyl group, or

a cyclohexyl group;

at least one of X 1, X ₂ , Y 1 or Y ₂ is necessarily SCH 3, SO ₂ CH ₃ or SO ₂ NH ₂ , the other substituents being independently of one another:

- a hydrogen atom,

- halogen atom,

- a lower alkyl group having 1 to 6 carbon atoms,

a trifluoromethyl group, or

- a lower O-alkyl group having 1 to 6 carbon atoms, * R 1 R ₂ represents an oxygen atom, and * R ₃ and R 4 independently represent a hydrogen atom or a lower alkyl group containing 1 to 6 carbon atoms.

Within the scope of the present invention, it is preferred to use compounds of the above formula (I) for which at least one is satisfied

31075 / H from the following conditions:

- ring B represents a phenyl group,

- X 1 is 4-SO 2 CH 3 or 4-SO 2 NH 2,

- X ₂ represents a hydrogen atom,

- ring A represents a phenyl group or a pyridyl group,

- Y 1 represents a fluorine atom, a chlorine atom or a methyl group,

- Y 2 represents a hydrogen atom, a fluorine atom or a chlorine atom,

- R1R2 represents an oxygen atom,

- R3 represents a hydrogen atom and

- R ₄ represents a hydrogen atom.

Particularly preferred compounds of the present invention are derivatives of the following structural formulas:

(E) -3- [1- (4-fluorophenyl) -1- (4-methanesulfonyl-phenyl) methylidene] dihydrofuran-2-one;

(Z) -3- [1- (4-Chlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one:

(Z) -3- [1- (3,4-dichlorophenyl) -1- (4-methanesulfonyl-phenyl) methylidene] dihydrofuran-2-

31075 / H (Z) -3- [1- (6-chloropyridin-3-yl) -1- (4-methanesulfonylphenyl) methylidene] dihydorfuran-2-one:

(Z) -4- [4-Chloro-phenyl) - (2-oxodihydrofuran-3-ylidene) -methyl] -benzenesulfonamide:

(Z) -4 - [(3-fluoro-4-methyl-phenyl) - (2-oxodihydrofurán-3-ylidene) methyl] -benzenesulfonamide:

According to the present invention, the compounds of formula (I) may be prepared as follows.

Friedel-Crafts reaction of the acid chloride of formula II:

yl

Y,

CO - C1 (ΙΌ

31075 / H in which A, Y-1 and Y ₂ have the same meaning as defined above, with a thioanisole, a ketone of formula III is obtained:

wherein A, Y, Y 1 and Y ₂ have the same meaning as defined above.

This ketone can also be prepared by a Grignard reaction, i.e. a reaction using a bromo-aromatic magnesium derivative which may be optionally substituted with p-methylthiobenzonitrile.

Treatment of the benzophenone so obtained with an oxidizing agent such as metachloroperbenzoic acid, sodium perborate or hydrogen peroxide in the presence of a catalytic amount of a molybdenum salt provides a derivative of the formula IV:

(IV) wherein A, Y 1 and Y ₂ have the same meanings as defined above.

Treatment of the thus obtained derivative of the formula IV using a modified Reformat reaction with a bromobutyrolactone of the formula

IN:

31075 / H wherein R ₃ and R ₄ are as stated above, in the presence of magnesium and a small amount of methyl iodide to initiate the reaction, the obtained compound of formula VI:

(VI) wherein A, Y 1, Y ₂ , R 3 and R ₄ have the same meaning as previously described.

Finally, dehydration of the thus obtained derivative of general formula (VI) is carried out by heating in toluene, for example in the presence of paratoluenesulfonic acid, or by treatment with trifluoroacetic anhydride in trifluoroacetic acid, to give a compound of general formula (I):

in which:

B is a phenyl ring,

X1 is 4-SO2CH3,

X ₂ represents a hydrogen atom,

R ₁ R ₂ represents an oxygen atom and

A, Y 1, Y ₂ , R 3 and R ₄ have the same meaning as above.

One alternative method of this process is to treat a compound of formula III either with a derivative of formula V using the same method including a modified Reformat reaction, in the presence of magnesium and methyl iodide to initiate the reaction, or with a lactone of formula V '

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Ο * 3 ~ Κ ₄ (V ') wherein R 3 and R 4 are as defined above, in the presence of N N -diethylaminomagnesium bromide prepared by reaction of N, N-diethylamine with ethylmagnesium bromide, following the procedure of K. Sisido, H. Nozaki, O. Kurihara, J. Am. Chem. Soc., 74, 6254 (1952) to prepare either a dehydrated compound of formula I or a compound of formula VII ':

ch ₃ s

Y

Y,

(VII ') wherein A, Y-Y, Y ₂ , R 3 and R ₄ have the same meaning as previously defined.

This compound of formula VII 'is then dehydrated by treatment with trifluoroacetic anhydride and trifluoroacetic acid to give a compound of formula I:

where:

B is a phenyl ring,

Xi is a _4-SCH3, X ₂ is H,

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R 1 R 2 represents an oxygen atom and

A, Υι. Y 2, R 3 and R 4 have the same meaning as above.

Treatment of the compound thus prepared according to this alternative method with metachloroperbenzoic acid or another oxidizing agent such as NaBO ₃ . 4H ₂ O, is obtained depending on the amount of the oxidizing agent, compound of Formula I:

in which:

B is a phenyl ring,

X 1 is a _4-3 SOC in case of using one equivalent of oxidizing agent and a 4-SO2CH3 in the case of using two equivalents of oxidant.

X ₂ represents a hydrogen atom,

R 1 R 2 represents an oxygen atom and

A, Y-1, Y 2, R 3 and R ₄ have the same meaning as above.

Another alternative process for the preparation of compounds of formula (I) consists in treating the ketone compound of formula (III) with ethyl succinate, i.e., carrying out a Stobbe reaction, in tert-butanol in the presence of sodium or potassium tert-butoxide.

Y,

COOEt (VII)

CH, S

COOH in which A, Y 1 and Y ₂ the same as defined above.

3Ι075Ή

By selective reduction of the ester group, for example using calcium borohydride, obtained in situ by the reaction of potassium borohydride and calcium chloride in ethanol, or using sodium diethyldihydroaluminate in diethyl ether, a derivative of the general formula VIII is obtained after lactonization of the hydroxy acid:

(VIII) wherein A, Y 1 and Y _{2 have the} same meaning as previously defined.

This derivative of formula (VIII) is then oxidized in the same manner as described above, whereby the SCH ₃ group is converted to SPCH ₃ or SO ₂ CH ₃ , depending on the amount of oxidizing agent used to give a compound of formula (I):

Xt is the group ₃ or group SOC SO2CH _3,

X ₂ , R 1 and R ₂ are hydrogen,

R ₃ R ₄ represents an oxygen atom and

A, Y ₁ and Y ₂ have the same meaning as above.

Reduction of a derivative of formula VII, for example, using lithium aluminum hydride in tetrahydrofuran, yields a diol of formula IX:

(IX)

31075 / H wherein A, Y1 and Y2 have the same meaning as previously defined.

Dehydration of the diol using sulfuric acid or refluxing in the presence of paratoluenesulfonic acid using a Dean-Stark apparatus yields a compound of formula I:

in which:

A, Y1 and Y2 have the same meaning as defined above,

B is a phenyl ring,

X 1 represents a 4-SCH 3 group and

X ₂ , R 1, R ₂ , and R 3, R 4 are hydrogen.

Treatment of this derivative with an oxidizing agent in the same manner as above gives the corresponding derivative in which X1 is 4-SOCH3 or 4-SO2CH3 depending on the amount of oxidizing agent used.

Other alternative processes for the preparation of the compound of formula (I) may also be used.

For example, by reacting a ketone compound of formula IV with ethyl succinate using a Stobbe reaction, which is carried out in tertiary butanol in the presence of tert. of potassium or sodium butoxide, a compound of formula X is obtained:

(X)

31075 / H wherein A, Y 1 and Y 2 have the same meaning as previously defined.

Reduction of the acid group, this time by selective reduction, carried out, for example, by reaction with borane or borane / methylsulfide complex in tetrahydrofuran or diethyl ether, yields an alcohol / ester of formula XI:

(XI) wherein A, Y 1 and Y ₂ have the same meaning as previously defined.

The alcohol / ester compound of formula XI, or even the corresponding alcohol / acid compound obtained by hydrolyzing the ester function with sodium hydroxide in ethanol at reflux, is then cyclized by heating in an aromatic solvent such as toluene in the presence of, for example, paratoluenesulfonic acid. to give a compound of formula I:

in which:

A, Y 1 and Y ₂ are as defined above,

B is a phenyl ring,

X 1 represents a 4-SO 2 CH 3 group,

X ₂ , R 3 and R ₄ represent a hydrogen atom and R, R ₂ represent an oxygen atom.

The compound of formula XII, in which A, Yt and _Y2 are the same

31075 / H meaning as defined above can be prepared in an analogous manner according to the following reaction scheme wherein Ph is phenyl and T is a residue

MgBr when A is a phenyl group or Li when A is a pyridyl ring:

Alternatively, the diaryl ketone of formula (B) used in the above reaction scheme is prepared by reacting benzyl mercaptan PhCbhSH with fluorodiaryl ketone in dimethylformamide in the presence of sodium hydride or sodium carbonate according to the following scheme:

O (B)

The compound of formula XII thus obtained is then treated in the same manner as the compound of formula X to give a compound of formula I:

31075 / H in which:

B is a phenyl ring,

X-ι denotes the group 4-SO2BHt-Bu,

X 2, R 5 and R ₄ represent a hydrogen atom,

R 1 R 2 represents an oxygen atom and

A, Y-1 and Y 2 have the same meanings as above.

Treatment of the derivative with a strong acid, such as concentrated sulfuric acid, trifluoroacetic acid, or by heating the compound in toluene in the presence of paratoluenesulfonic acid, provides a compound of formula I wherein:

B is a phenyl ring,

X 1 is a 4-SO ₂ NH _2,

X 2, R 3 and R ₄ are hydrogen,

R 1 R 2 represents an oxygen atom and

A, Y-1 and Y 2 have the same meanings as defined above.

These compounds of formula (I) as defined above are 2-cyclooxygenase inhibitors and exhibit very good anti-inflammatory and analgesic activity, which is also associated with excellent tolerance, especially gastric tolerance.

These properties of the compounds of the present invention entitle them to be used as therapeutically active agents, and all products based on the compounds of formula (I) above, for example in the form of medicaments, are also within the scope of the present invention.

Accordingly, the present invention also encompasses pharmaceutical compositions comprising an effective pharmaceutical amount of at least one compound of Formula I, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or carrier material.

The pharmaceutical compositions can be administered by buccal, rectal, parenteral, transdermal, ophthalmic, basal or auricular routes.

The compositions may be in the form of a solid or a liquid, and may be formulated in any of the pharmaceutical forms commonly used in the art.

31075 / H in human medicine, such as simple or coated tablets, gelatin capsules, granules, suppositories, injectables, transdermal systems, eye drops, aerosols and sprays and ear drops. These compositions may be prepared by any of the methods well known and used. The active ingredient represented by a pharmaceutically effective amount of at least one compound of formula (I) as defined above is combined with excipients commonly used in pharmaceutical compositions such as talc, acacia, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives. , cocoa butter, semisynthetic glycerides, aqueous or non-aqueous vehicle, fats of animal or natural origin, glycols, various wetting agents, dispersants or emulsifying agents, silicone gels, certain polymers or copolymers, preservatives, flavoring agents and coloring agents.

The present invention also relates to pharmaceutical compositions having anti-inflammatory and analgesic efficacy, which can be used, in particular, as beneficial agents in the treatment of inflammatory conditions and pain, characterized in that they contain a pharmaceutically effective amount of at least one compound of formula I as defined above, in a pharmaceutically acceptable excipient, vehicle or carrier material. According to one embodiment, a pharmaceutical composition having anti-inflammatory or analgesic activity is prepared, which is used in particular as a beneficial agent in the treatment of various inflammatory and pain conditions.

According to a variant of the pharmaceutical composition, the composition is formulated in a gelatin capsule or tablet containing an effective dose in the range of 1 milligram to 1000 milligrams, or in the form of a preparation for injection comprising an effective dose in the range of 0.1 milligram to 500 milligrams. It is also possible to use a formulation formulated in a suppository, ointment, cream, gel, aerosol formulation, transdermal formulation or patch.

The present invention also provides a method for the therapeutic treatment of a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of at least one compound of formula I as described above. , either alone or in conjunction

31075 / H with a pharmaceutically acceptable excipient, formulated into a gelatin capsule or tablet containing a dose of 1 milligram to 1000 milligrams for oral administration, or a preparation for injection containing a dosage of 0.1 milligram to 500 milligrams, or a suppository, ointment, cream, gel or aerosol formulation.

In particular, this procedure allows the effective treatment of inflammatory and pain conditions.

In the case of therapeutic compositions intended for the treatment of humans and animals, the compounds of formula I as defined above may be administered as such or in combination with a physiologically acceptable excipient and in any form, particularly suitable for oral administration such as a gelatin capsule or tablet, or parenterally. administration, such as a solution for injection. Other administration forms, such as suppositories, ointments, creams, gels or aerosol formulations, may also be recommended.

From the pharmacological tests listed below at the end of the Example section, it is clear that the compounds of the present invention can be administered as therapeutic agents in human medicine for the above indications orally in the form of tablets or gelatin capsules containing a dose of active ingredient in the range from 1 milligram to 1000 milligrams, or parenterally in the form of injectables containing an effective dose in the range of 0.1 milligrams to 500 milligrams, in the form of one or more daily unit dosage forms for an adult patient having an average weight of 60 to 70 kilograms.

For therapeutic agents administered to animals, the daily dose may range from 0.1 milligram to 100 milligrams per kilogram.

DETAILED DESCRIPTION OF THE INVENTION

The furandiarylmethylidene derivatives, process for their preparation, pharmaceutical compositions, their use and the effects of the compounds of the present invention will be further elucidated by means of specific examples, which are, however, illustrative and not limiting.

31075 / H

Example 1

Preparation of 4-fluoro-4'-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Y = 4 - F, _Y2 = H

86.4 grams of aluminum chloride were added in portions at a temperature ranging from 0 ° C to 5 ° C to a solution containing 70 grams (0.5654 mol) of thioanisole and 90.2 grams (0.654) mol) of 4-fluorobenzoyl chloride in 500 ml of dichloromethane. Upon completion of the addition, the reaction mixture was brought back to room temperature and then heated at reflux for 2 hours. After cooling, the mixture was transferred to ice / dilute hydrochloric acid, the organic phase was decanted, dried over magnesium sulphate and evaporated in vacuo to a residue which was crystallized from diisopropyl ether. by the procedure, the desired 4-fluoro-4'-methylthiobenzophenone was prepared. Yield: 118 grams,

Melting point: 88 ° C.

Example 2

Preparation of 4-fluoro-4'-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, = 4 - F, _Y2 = H

87 grams of 70% 3-chloroperbenzoic acid, which was gradually added portionwise at a temperature ranging from 0 ° C to 5 ° C, to a solution containing 25 grams (0.1015 mol) of 4-fluoro 4'-methylthiobenzophenone, prepared as described in Example 1, in 350 ml of dichloromethane. The reaction mixture was then stirred at 0 ° C for 30 minutes and then brought back to room temperature and stirred for 2 hours and 30 minutes. The precipitate thus obtained was filtered off, washed with dilute sodium hydroxide solution and then dissolved with magnesium sulfate and evaporated in vacuo to give an oil which was recrystallized from diisopropyl ether,

31075 / H to give the desired 4-fluoro-4'-methanesulfonylbenzophenone.

Yield: 24.6 grams.

Melting point: 136 ° C.

Example 3

Preparation of 3- [1- (4-fluorophenyl) -1-hydroxy-1- (4-methanesulfonylphenyl) methyl] dihydrofuran-2-one.

Compound of formula (VI):

A = phenyl, Y = 4-F, _Y2 = H, R ₃ = R ₄ = H

In this procedure, the magnesium nozzles were covered with anhydrous tetrahydrofuran, and a few drops of iodomethane were added. Immediately as the reaction started, a mixture containing 24.6 grams of 4-fluoro-4'-methanesulfonylbenzophenone and 8.1 milliliters of α-bromo-γ-butyrolactone in 250 milliliters of anhydrous tetrahydrofuran was added dropwise while keeping the reaction mixture under gentle reflux. condenser. Upon completion of the addition, the reaction product was cooled and then transferred to a mixture of ice and a 10% dilute sulfuric acid solution. The organic phase was then extracted with tetrahydrofuran, washed with saturated sodium bicarbonate solution and then dried over magnesium sulfate. After evaporation of the solvent, the residue is chromatographed on silica gel, eluting with dichloromethane / acetone 9/1 to give 3- [1- (4-fluorophenyl) -1-hydroxy-1- (4-Methanesulfonylphenyl) methyl] dihydrofuran-2-one in the form of an amorphous beige powder, which was used immediately as it was obtained for the next procedure.

Yield: 7 grams.

Example 4

Preparation of (E) -3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(E) isomer;

compound of formula (I):

A = B = phenyl, Y ₁ = 4-F, X ₂ = Y ₂ = H, Χ _Ί = 4-SO ₂ CH ₃ ,

31075 / H

R1R2-O, R3-R4-Η.

Several milligrams of toluene-4-sulfonic acid was added to a solution containing 7 grams of 3- [1- (4-fluorophenyl) -1-hydroxy-1- (4-methanesulfonylphenyl) methyl] dihydrofuran-2-one, prepared as described in the Example. 3, in 100 ml of toluene, and the reaction mixture was then refluxed for 10 hours in a Dean-Stark apparatus. The solvent was evaporated to dryness under vacuum and the residue was chromatographed, eluting with dichloromethane / acetone 9/1 to give an oil which was chromatographed using t-. of butyl methyl ether as the eluent, and 2.9 g of (E) -3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (second eluted product) were prepared as above. ) in the form of crystals having a melting point ranging from 187 ° C to 189 ° C. (Z) -3- [1- (4-Fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (first eluted product) was obtained as crystals with a melting point ranging from 157 to 158 ° C.

Example 5

Preparation of 4-chloro-4'-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Y1 = 4-Cl, Y2 = H.

This compound was prepared in the same manner as in Example 1. Crystals: melting point 134 ° C.

Example 6

Preparation of 3- [1- (4-chlorophenyl) -1-hydroxy-1- (4-methylthiophenyl) methyl] dihydrofuran-2-one.

Compound of formula (VII '):

A = phenyl, Y = 4 - Cl, _Y2 = H, R ₃ = R ₄ = H

According to this embodiment, a few drops of iodomethane were added to the

5.9 grams of magnesium shavings covered with anhydrous tetrahydrofuran. Immediately after starting the reaction, a mixture containing 17 grams of 4-chloro-4'-methylthiobenzophenone and 12.6 ml of α-bromo-γ-butyrolactone in 300 ml was added dropwise.

31075 / H anhydrous tetrahydrofuran was added dropwise and the reaction mixture was kept under gentle reflux. Upon completion of the addition, the reaction mixture was stirred at room temperature for 1 hour and 30 minutes and then cooled in an ice bath. Saturated ammonium chloride solution was added to the reaction mixture, which was stirred and then decanted. The organic phase was dried over magnesium sulphate and evaporated in vacuo to give an oily residue which was chromatographed on silica gel, eluting with dichloromethane to give 3- [1- (4-chlorophenyl)]. -1-hydroxy-1- (4-methylthiophenyl) methyl] dihydrofuran-2-one as an oil, which was then used in the crude state as obtained for the next procedure.

Yield: 8.5 g.

Example 7

Preparation of 3- [1- (4-chlorophenyl) -1- (4-methylthiophenyl) methylidene] dihydrofuran-2-one. Compound of formula (I):

A = B = phenyl, X = 4-Cl, X ₂ = Yi = H, _Y2 = _4-SCH3,

R | ₂ = R 0, R ₃ = R 4 = H

5.2 grams of trifluoroacetic anhydride and 3.8 milliliters of trifluoroacetic acid were added to a solution containing 8.6 grams of 3- [1- (4-chlorophenyl) -1-hydroxy-1- (4-methylthiophenyl) methyl] -dihydrofuran-2-one, prepared as described in Example 6, in 100 mL of dichloromethane. The reaction mixture was stirred at room temperature for 4 hours and then diluted with water and decanted. The organic phase was dried over magnesium sulphate and evaporated in vacuo to give 3- [1- (4-chlorophenyl) -1- (4-methylthiophenyl) methylidene] -dihydrofuran-2-one as an oil which was then used in the state in which it was obtained for the next procedure.

Yield: 7.5 grams.

Example 8

Preparation of (Z) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydro-3107H-furan-2-one.

(Z) isomer:

Compound of formula (I):

A = B = phenyl, Y _n = 4-Cl, Y ₂ = X 1 = H, X ₂ = SO ₂ CH ₃ ,

RiR ₂ = H, R ₃ = R ₄ = H

11 grams of sodium perborate trihydrate was added to a solution containing 9.5 grams of 3- [1- (4-chlorophenyl) -1- (4-methylthiophenyl) methylidene] dihydrofuran-2-one prepared as described in Example 7, in 120 ml acetic acid. The reaction mixture was stirred at 40 to 50 ° C for 5 hours and cooled. The crystals formed were filtered off, washed with water and then chromatographed on silica gel, eluting with dichloromethane / acetone (99/1) to give (Z) -3- [1- (4-chlorophenyl) as eluent. -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (eluted first product) as crystals.

Yield: 4.1 grams.

Melting point: 197-199 ° C.

The second product was isolated by elution to give (E) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one as crystals of melting point 211 mp 212 ° C. Yield: 2.5 g.

Example 9

Preparation of 3-fluoro-4'-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Y @ 3 = F, _Y2 = H

This compound was prepared in the same manner as in Example 1. Crystals; melting point: 76 ° C.

Example 10

Preparation of 3-fluoro-4'-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, Y-1 = 3-F, Y ₂ = H.

31075 / H

This compound was prepared in the same manner as in Example 2. Crystals: melting point: 106 ° C.

Example 11

3-Ethoxycarbonyl-4- (3-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid.

Compound of formula (X):

A = phenyl, Υ _Ί = 3 - F, Y ₂ = H.

35.5 grams (0.1275 mol) of 3-fluoro-4'-methanesulfonylbenzophenone prepared as described in Example 10 was added portionwise to a solution containing 15.7 grams (0.140 mol) of potassium t-butoxide. in 100 ml of t-butanol. The reaction mixture was stirred and 32 ml (0.191 mol) of ethyl succinate was added dropwise at high speed. The reaction mixture was heated to reflux for 30 minutes and then cooled, water and 1N hydrochloric acid solution were added to adjust the pH to 1, and the reaction mixture was extracted with t-butyl methyl ether. The organic phase was treated with 2% sodium hydroxide solution and the resulting mixture was decanted. The aqueous phase was acidified with 1 N hydrochloric acid solution and then extracted with t-butyl methyl ether. The organic phase was dried over magnesium sulphate and evaporated in vacuo to give 3-ethoxycarbonyl-4- (3-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid as a thick oil which was used in the oil. the state in which it was obtained for the next procedure.

Yield: 39.2 grams.

Example 12

Preparation of 3- (3-fluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, Y-1 = 3-F, Y ₂ = H.

15.5 ml (0.155 mol) of borane / methyl sulfide complex was added dropwise to a solution which

31075 / H contained 31.5 grams (0.0775 mol) of 3-ethoxycarbonyl-4- (3-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid, prepared as described in Example 11, in 90 milliliters of anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 8 hours, then 23.5 ml of methanol was added dropwise. The reaction mixture was evaporated to dryness in vacuo and the residue taken up in ethyl acetate and treated with an aqueous solution containing 7.6 grams of sodium carbonate. The organic phase was decanted and washed with magnesium sulfate, then evaporated to dryness in vacuo to give the desired 3- (3-fluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester. in the form of a viscous oil, which was then used as it was for the next process.

Yield: 29.3 grams.

Example 13

Preparation of (Z) -3- [1- (3-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

"A = B = phenyl, Υ _Ί = 3 - F, X ₂ = Y ₂ = H, X t = 4-SO ₂ CH ₃ ,

RiR ₂ ⁼ 0, R 3 - R 4 - H.

3.3 g of sodium hydroxide was dissolved in 10 ml of water, and this solution was added to a solution containing 29.3 g of 3- (3-fluorophenyl) -3- (4-methanesulfonylphenyl) -2- ( 2-hydroxyethyl) -2-propene, prepared as described in Example 12, in 50 ml of ethanol and heated at reflux for 2 hours. After evaporation to dryness, the residue was taken up in water, acidified with 1N hydrochloric acid solution and then extracted with dichloromethane. The organic phase was dried over magnesium sulphate and evaporated in vacuo to give an oily residue. The oil was solubilized in 150 ml of toluene and 10 mg of pratoluenesulfonic acid was added. The reaction mixture was heated to reflux and the resulting water was removed with the aid of

31075 / H

Dean-Stark equipment. After cooling, the mixture is washed with water, the organic phase is dried over magnesium sulphate and evaporated in vacuo and the residue is chromatographed on silica gel, eluting with t-butyl methyl ether, to give the desired (Z) -3- [ 1- (3-Fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (second eluted product) as crystals.

Yield: 4 g.

Melting point: 153-154 ° C.

* Example 14

Preparation of 3,4-dichloro-4'-methylthiobenzophenone.

s

Compound of formula (III):

A = phenyl, Y ·, = 3 - Cl, _Y2 = 4 - Cl.

This compound was prepared in the same manner as in Example 1. Crystals; melting point: 100 ° C.

Example 15

Preparation of 3,4-dichloro-4'-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, Yt = 3-Cl, Y ₂ = 4-Cl.

This compound was prepared in the same manner as in Example 2.

WITH

The crystals; melting point: 158 ° C.

Example 16

3-Ethoxycarbonyl-4- (3,4-dichlorophenyl) -4- (4-methylsulfonylphenyl) -3-butyric acid.

Compound of formula (X):

A = phenyl, Y = 3 - Cl, _Y2 = 4 - Cl.

This compound was prepared in the same manner as in Example 11.

The product was obtained in the form of an oil which was used as such for the next stage.

31075 / H

Example 17

Preparation of 3- (3,4-dichlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl Y ₁ = 3-Cl, Y ₂ = 4-Cl.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 18

Preparation of (Z) -3- [1- (3,4-dichlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

A = B = phenyl, Yt = 3 - Cl, _Y2 = 4-Cl, X ₂ = H,

X 1 = 4-SO ₂ CH ₃ , R, R ₂ = O, r ₃ = r ₄ = h.

This compound was prepared in the same manner as in Example 13. Chromatography with dichloromethane / acetone 99/1 gave the title compound as the first eluted product.

crystals; melting point: 195-197 ° C.

The second product was isolated by chromatography to give (E) -3- [1- (3,4-dichlorophenyl) -1- (4-methanesulfonylphenyl) -methylidene] dihydrofuran-2-one as crystals of m.p. 163-164 ° C.

Example 19

Preparation of 3-chloro-4'-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Y 1 = 3 - Cl, Y ₂ = H.

This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 70 ° C.

31075 / H

Example 20

Preparation of 3-chloro-4'-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, Yt = 3 - Cl, _Y2 = H

This compound was prepared in the same manner as in Example 2.

The crystals; melting point: 140 ° C.

Example 21

3-Ethoxycarbonyl-4- (3-chlorophenyl) -4- (4-methanesulfonylphenyl) -3-butyric acid.

Compound of formula (X):

A = phenyl, Y = 3 - Cl, _Y2 = H

This compound was prepared in the same manner as in Example 11. The product was obtained as an oil, which was used as such for the next stage.

Example 22

Preparation of 3- (3-chlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, Υ _Ί = 3 - Cl, Y ₂ = H.

This compound was prepared in the same manner as in Example 12. The product was obtained as an oil, which was used as such for the next step.

Example 23

Preparation of (Z) -3- [1- (3-chlorophenyl) -1- (4-methanesulfonylphenylmethylidene) dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

A = B = phenyl, = 3-Cl, X ₂ = Y ₂ = H, Χ _Ί = 4-SO ₂ CH ₃ ,

R | ₂ = R 0, R ₃ = R ₄ = H

This compound was prepared in the same manner as described above

31075 / H in Example 13. Chromatography using 99/1 acetone dichloromethane gave the first eluted product.

crystals; melting point 147-149 ° C.

The second product was isolated by elution with a chromatographic method to give (Z) -3- [1- (3-chlorophenyl) -1- (4-methanesulfonylphenylmethylidene) dihydrofuran-2-one.

crystals; melting point 170-172 ° C

Example 24

Preparation of 4-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Y, = Y ₂ = H

This compound was prepared in the same manner as in Example 1. Crystals; melting point: 84 ° C.

Example 25

Preparation of 4-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, Y 1 = Y ₂ = H.

This compound was prepared in the same manner as in Example 2.

The crystals; melting point: 150 ° C.

Example 26

3-Ethoxycarbonyl-4-phenyl-4- (4-methanesulfonylphenyl) -3-butenoic acid.

Compound of formula (X):

A = phenyl, Y 1 = Y ₂ = H.

This compound was prepared in the same manner as in Example 11.

The product was obtained in the form of an oil which was used as such for the next stage.

31075 / H

Example 27

Preparation of 3-phenyl-3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, Y, = Y ₂ = H.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 28

Preparation of (E) -3- [1- (phenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2one.

(E) isomer:

Compound of formula (I):

A = B = phenyl, Y ₁ = Y ₂ = H, X ₂ = H, X ₁ = 4-SQ ₂ CH ₃ ,

R1R2 = 0, R ₃ = R ₄ = H

This compound was prepared in the same manner as in Example 13. Chromatography on silica gel using 99/1 acetone dichloromethane gave the first eluted product. crystals; melting point 135-137 ° C.

Isolation of the second product by elution afforded the (Z) -3- [1- (phenyl) 1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one isomer.

crystals; mp 206-208 ° C.

Example 29 i

Preparation of 5,5-dimethyl-3- [1- (4-fluorophenyl) -1-hydroxy-1- (4-methylthiophenyl) methyl] dihydrofuran-2-one.

Compound of formula (VII '):

A = phenyl, Y = 4-F, _Y2 = H, R ₃ = R ₄ = CH ₃

7.5 ml of bromomethane was added dropwise to a suspension containing 2.4 grams of magnesium shavings in anhydrous diethyl ether. Upon completion of the addition, the reaction mixture was cooled to 0 ° C

31075 / H was added dropwise 10.5 ml of Ν, Ν-diethylamine. The reaction mixture was stirred at room temperature for 1 hour and then heated at reflux for 15 minutes, then cooled in an ice bath with sodium chloride. A solution containing 12.3 grams of 4-fluoro-4'-methylthiobenzophenone prepared as described in Example 1 and 5.7 grams of 4,4-dimethylbutyrolactone in 50 ml of anhydrous tetrahydrofuran was slowly added dropwise at the temperature of the reaction mixture. was maintained between 0 ° C and 5 ° C. The reaction mixture was heated at reflux for 2 hours, cooled and treated with 100 ml of 10% sulfuric acid. After extraction with diethyl ether, the organic phase was dried over magnesium sulphate and evaporated in vacuo to give 5,5-dimethyl-3- [1-4-fluorophenyl) -1-hydroxy-1- (4-methylthiophenyl) methyl] dihydrofuran. 2-one in the form of crystals.

Yield: 4.8 g.

Melting point: 185 ° C.

Example 30

Preparation of 5,5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-methylthiophenyl) methylidene] dihydrofuran-2-one.

(E) isomer:

Compound of formula (I):

A = B = phenyl, Y = 4-F, _Y2 = _X2 = H, _X1 = _4-SCH3,

R 1 ⁼ R 2 ⁼ O, R 3 ⁼ R 4 ⁼ CH 3.

(Z) isomer:

Compound of formula (I):

A = B = phenyl, X 1 = 4-F, X ₂ = Y ₂ = H, Y 2 -SCH 3,

R 1 = R 2 ⁼ O, R 3 = R 4 = ch ₃ .

The compounds were prepared in the same manner as in Example 4 using the derivative of Example 29.

The two isomers were prepared by fractional crystallization in a mixture of diisopropyl ether and pentane.

(E) -5,5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-methylthiophenyl) methylidene] dihydrofuran-2-one. Melting point: 98 ° C.

31075 / H (Z) -5,5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-methylthiophenyl) methylidene] dihydrofuran-2-one. Melting point: 160 ° C.

Example 31

Preparation of (E) -5,5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(E) isomer:

Compound of formula (I):

A = B = phenyl, Y 1 = 4-F, X ₂ = Y ₂ = H, X ₁ = 4-SO ₂ CH ₃ ,

R1R2 ⁼ 0, R ₃ = R ₄ = CH _third

1.9 grams of sodium perborate trihydrate was added to a solution containing 2 grams of (E) -5,5-dimethyl-3- [1- (4-fluorophenyl) -1 (4-methylthiophenyl) methylidene] dihydrofuran- 2-one, prepared as described in Example 30, in 15 ml acetic acid. The reaction mixture was heated at 45 ° C for 3 hours and then the crystals formed were hot filtered and subjected to silica gel column chromatography using dichloromethane / acetone 9/1 as eluent. prepared the desired (E) -5,5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one as crystals.

Yield: 1.2 grams

Melting point: 175 ° C.

Example 32

5-Ethyl-3- [1- (4-fluorophenyl) -1-hydroxy-1- (4-methylthiophenyl) methyl] dihydrofuran-2-one.

Compound of formula (VII '):

A = phenyl, Y = 4-F, _Y2 = H, R ₃ = C ₂ H _5,

R ₄ = H.

This compound was prepared in the same manner as in Example 29 using N-caprolactone.

The crystals; melting point: 150 ° C.

31075 / H Ί

Example 33

5-Ethyl-3- [1- (4-fluorophenyl) -1- (4-methylthiophenyl) methylidene] dihydrofuran-2-one.

(E) isomer:

Compound of formula (1): A = B = phenyl, Y = 4 - F, X ₂ = Y ₂ = H, Xi = 4-SCH3 R1R2 ⁼ 0, R3 = C2H5, r ₄ = h. (Z) isomer: Compound of formula (I): A = B = phenyl, _X1 = 4 - F, X ₂ = Y ₂ = H, Yt = 4-SCH 3, RiR ₂ ⁼ 0, R3 = C2H5, r ₄ = h. These compounds were prepared by the same method as described above

in Example 32. The mixture of the two isomers (E) and (Z) was then used to proceed as obtained.

Example 34

Preparation of (E) -5-ethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(E) isomer:

Compound of formula (I):

A = B = phenyl, Y 1 = 4-F, X ₂ = Y ₂ = H, X 1 -SC 1 CH 3.

R1R2 ⁼ 0, R3 ⁼ C2H5, _R4 = H,

This compound was prepared in the same manner as in Example 31. The (E) -5-ethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one isomer was purified by chromatography silica gel, eluting with dichloromethane / acetone 99/1 to give the crystals (first eluting product).

Melting point: 134-136 ° C.

The second product was isolated by chromatography to give (Z) -5-ethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one as crystals.

Melting point: 176-177 ° C.

31075 / H

Example 35

5-Methyl-3- [1- (3-chlorophenyl) -1-hydroxy-1- (4-methylthiophenyl) methyl] dihydrofuran-2-one.

Compound of formula (VII '):

A = phenyl, Y 1 = 3-Cl, Y ₂ = H, R ₃ = CH ₃ ,

R ₄ = H.

This compound was prepared in the same manner as in Example 6 using 3-chloro-4'-methylthiobenzophenone and α-bromo-Vvalerolactone.

The amorphous powder obtained was used for the next procedure as obtained.

Example 36

Xi = _4-SCH3,

5-Methyl-3- [1- (3-chlorophenyl) -1- (4-methylthiophenyl) methylidene] dihydrofuran-2-one.

I (Z) isomer:

Compound of formula (I):

A = B = phenyl, Y 1 = 3-Cl, X ₂ = Y ₂ = H,

R ₁ = 2, r ₃ = ch ₃ , r ₄ = h.

(E) isomer:

Compound of formula (I):

A = B = phenyl, X = 3 - Cl, _X2 = _Y2 = H,

R ₁ = 2, r ₃ = ch ₃ , r ₄ = h.

Yl = _4-SCH3,

The compounds were prepared as described in Example 4, using a derivative prepared according to Example 35. A mixture of the two isomers was obtained as an oil, which was then used as such for the next step.

Example 37

(Z) -5-methyl-3- [1- (3-chlorophenyl) -1- (4-methanesulfonylphenyl) methyl] dihydrofuran-2-one.

(Z) isomer:

31075 / H

Compound of Formula (I): A = B = phenyl, Y 1 = 3-Cl, R 1 R 2 = O, R 3 -CH 3,

_X2 = _Y2 = HR ₄ = H,

X ₁ = 4-SO2CH3,

This compound was prepared in the same manner as in the Example

31. The (Z) -5-methyl-3- [1- (3-chlorophenyl) -1- (4-methanesulfonylphenyl) methyl] dihydrofuran-2-one isomer was purified by silica gel chromatography using as eluent 99/1 dichloromethane / acetone mixture to give an amorphous powder (first eluted product).

The second product was isolated by elution to give (E) -5-methyl-3- [1- (3-chlorophenyl) -1- (4-methanesulfonylphenyl) methyl] dihydrofuran-2-one as crystals.

Melting point: 164-165 ° C.

Example 38

Preparation of 2-chloro-5- (4-methylthiobenzoyl) pyridine.

Compound of formula (III)

A = 3-pyridyl, Y1 = 6-Cl,

Y ₂ = H.

This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 145 ° C.

Example 39

Preparation of 2-chloro-5- (4-methanesulfonylbenzoyl) pyridine.

Compound of formula (IV):

A = 3 - pyridyl, Y1 = 6 - Cl, _Y2 = H

A solution containing 34.6 grams of 2-chloro-5- (4-methylthiobenzoyl) -pyridine prepared as described in Example 38 and 42 grams of sodium perborate in 250 ml of acetic acid was heated. for 4 hours at 45 ° C. The crystals were hot filtered, washed with water and dried to give the desired 2-chloro-5- (4-methanesulfonylbenzoyl) pyridine as crystals.

Yield: 32.6 grams.

31075 / H

Melting point: 170 ° C.

Example 40

4- (6-Chloropyridin-3-yl) -3-ethoxycarbonyl-4- (4-methanesulfonylphenyl) -3-butyric acid.

Compound of formula (X):

A = 3-pyridyl, Yt = 6 - Cl, _Y2 = H

This compound was prepared in the same manner as in Example 11 using the derivative obtained in Example 39.

An amorphous solid that was used to proceed as obtained.

Example 41

Preparation of 3- (6-chloropyridin-3-yl) -2-hydroxyethyl) -3- (4-methylsulfonylphenyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = 3-pyridinyl, Y = 6 - Cl, _Y2 = H

This compound was prepared in the same manner as in Example 12 using the derivative obtained in Example 40.

An amorphous solid that was used to proceed as obtained.

Example 42

Preparation of (Z) -3- [1- (6-chloropyridin-3-yl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

A = 3-pyridyl, B = phenyl, Υ _Ί = 6-Cl, X ₂ = Y ₂ = H,

X = 4-SO ₂ CH ₃ , R ₁ R ₂ = O, R ₃ = R ₄ = H.

This compound was prepared in the same manner as in Example 13 using the derivative obtained in Example 41.

The (Z) -isomer was obtained as crystals having a melting point of 172-174 ° C by a chromatographic method using as eluent

31075 / H 5/1 dichloromethane / acetone followed by crystallization with acetone / ethyl ether.

The (E) -3- [1- (6-chloropyridin-3-yl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one isomer was obtained in pure form as crystals of melting point. from 198 ° C to 199 ° C by crystallization from acetone prior to chromatographic work-up of the crude mixture of the two isomers.

Example 43

3-Ethoxycarbonyl-4- (4-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butyric acid.

Compound of formula (X):

A = phenyl, Υ _Ί = 4 - F, Y ₂ = H.

This compound was prepared in the same manner as in Example 11, starting from 4-fluoro-4'-methanesulfonylbenzophenone prepared as in Example 2.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 44

Preparation of 4- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2one.

Compound of formula (I):

A = B = phenyl, _X1 = _{4-SO2 CH3, X2} = _Y2 = H, Y ·, = 4-F,

R 1 R 2 = H, R 3 R 4 ⁼ O.

13.6 grams of powdered anhydrous calcium chloride was added to a solution containing 3-ethoxycarbonyl-4- (4-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid, prepared as described in Example 43, in 500 milliliters of ethanol. The reaction mixture was stirred at room temperature and a solution containing 7.5 grams of sodium borohydride in a mixture containing 1.5 grams of sodium hydroxide, 10 ml of water and 10 ml of ethanol was added dropwise while cooling in ice bath. After 4 hours at room temperature, the reaction medium was cooled

31075 / H to 0 ° C, then a solution of 6 N hydrochloric acid was added dropwise. After extraction with dichloromethane, the organic phase was dried over magnesium sulphate and evaporated in vacuo and the residue was crystallized from isopropyl ether. The crystals were recrystallized from methanol to give 5 grams of the desired 4- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one as a mixture (50/50 ratio). of the two isomers (E) and (Z).

crystals; melting point: 160-164 ° C.

Example 45

Preparation of 3-methyl-4'-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Y 1 = 3-CH _3, Y ₂ = H.

This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 46-47 ° C.

Example 46

Preparation of 3-methyl-4'-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, Y 1 = 3-CH ₃ , Y ₂ = H.

This compound was prepared in the same manner as in Example 2.

The crystals; melting point: 150 ° C.

Example 47

3-Ethoxycarbonyl-4- (3-methylphenyl) -4- (4-methanesulfonylphenyl) -3-butyric acid.

Compound of formula (X):

A = phenyl, = 3-CH ₃ , Y ₂ = H.

This compound was prepared in the same manner as in Example 11, starting from the derivative prepared as in Example 46.

31075 / H

The product was obtained in the form of an oil which was used as such for the next stage.

Example 48

Preparation of 3- (3-methylphenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, Y 1 = 3-CH ₃ , Y ₂ = H.

This compound was prepared in the same manner as in Example 12, starting from the derivative prepared as in Example 47.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 49

(Z) -3- [1- (3-methylphenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

A = B = phenyl, Y 1 = 3-CH ₃ , X ₂ = Y ₂ = H, Xt = 4-SO ₂ CH ₃ ,

R ₁ ⁼ R ₂ ⁼ O, R 3 ⁼ R 4 ⁼ H.

This compound was prepared in the same manner as in Example 13, starting from the derivative prepared according to the procedure of Example 48.

The product was purified by silica gel chromatography, eluting with dichloromethane / acetone (99/1). The first eluted product was in the form of crystals with a melting point of 166 ° C.

Example 50

Preparation of 3,4-difluoro-4'-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Y = ι-3 - F, _Y2 = 4 - F

This compound was prepared in the same manner as described above

31075 / H in Example 1.

The crystals; melting point: 96 ° C.

Example 51

Preparation of 3,4-difluoro-4'-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, Y = ι-3 - F, _Y2 = 4 - F

This compound was prepared in the same manner as in Example 2, starting from the derivative prepared as in Example 50. The product was obtained as crystals with a melting point of 120 ° C.

Example 52

3-Ethoxycarbonyl-4- (3,4-difluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid.

Compound of formula (X):

A = phenyl, Y = 3 - F, _Y2 = 4-F.

This compound was prepared in the same manner as in Example 11, starting from the derivative prepared as in Example 51.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 53

Preparation of 3- (3,4-difluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, γ ₁ = 3 - F, Y ₂ = 4 - F.

This compound was prepared in the same manner as in Example 12, starting from the derivative prepared according to the procedure of Example 52.

The product was obtained in the form of an oil which was used as such for the next stage.

31075 / H

Example 54

(Z) -3- [1- (3,4-Difluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

A = B = phenyl, Y = 3-F, _Y2 = 4-F, X = 4-SO ₂ CH _3,

X ₂ = H, R ₁ R ₂ = o, r ₃ = r ₄ = h.

This compound was prepared in the same manner as in Example 13, starting from the derivative prepared according to the procedure of Example 53.

The product was purified by silica gel chromatography, eluting with dichloromethane / acetone (99/1). The first eluted product was in the form of crystals having a melting point of 148 ° C.

Example 55

Preparation of 4-benzylthiobenzonitrile.

A mixture containing 37.2 grams of benzyl mercaptan, 36.3 grams of 4-fluorobenzonitrile and 42 grams of potassium carbonate in 700 ml of 2-butanone was heated at reflux for 7 hours. The solvent was evaporated in vacuo and the residue was taken up in a mixture of water and petroleum ether. The formed crystals were filtered and washed with water and petroleum ether to give the desired 4-benzylthiobenzonitrile as crystals.

Yield: 46 grams.

Melting point: 85 ° C.

Example 56

Preparation of 4-benzylthio-4'-fluorobenzophenone.

A solution containing 44 ml of 4-bromo-1-fluorobenzene in 300 ml of anhydrous diethyl ether was added dropwise to a suspension containing 9.6 grams of magnesium shavings in 20 ml of anhydrous diethyl ether. Upon completion of the addition, the reaction was quenched

31075 / H was stirred for several minutes at room temperature and a solution containing 46 grams of 4-benzylthiobenzonitrile, prepared as described in Example 55, in 400 ml of anhydrous tetrahydrofuran was added dropwise. The diethyl ether was distilled off and the reaction mixture was heated at reflux for 3 hours and then cooled with ice. A 6 N hydrochloric acid solution (400 ml) was added dropwise and the reaction mixture was heated to reflux for 6 hours. After addition of water and dichloromethane, the organic phase was separated by decantation, dried over magnesium sulphate and then evaporated in vacuo. The residue was crystallized from diisopropyl ether to give the desired 4-benzylthio-4'-fluorobenzophenone as crystals.

Yield: 48 grams.

Melting point: 96 ° C.

Example 57

Preparation of 4-t-butylaminosulfonyl-4'-fluorobenzophenone.

Chlorine was bubbled until saturated (36 grams) with a solution containing 43 grams of 4-benzylthio-4'-fluorobenzophenone, prepared as described in Example 5, in 300 ml of acetic acid cooled to 0 ° C. The reaction mixture was stirred at room temperature for 2 hours, poured into ice water and extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulphate and evaporated under vacuum to give 47 grams of an oil which is dissolved in 100 ml of 1,2-dichloroethane. This solution was then added dropwise to a solution containing 50 ml of t-butylamine in 300 ml of 1,2-dichloroethane. The resulting reaction mixture was heated at 80 ° C for 1 hour, cooled and washed with water and then with dilute aqueous hydrochloric acid. The organic phase was then dried over magnesium sulphate and evaporated in vacuo. The residue was crystallized from diethyl ether to give the desired 4-t-butylaminosulfonyl-4'-fluorobenzophenone as crystals as described above. Yield: 25 grams.

31075 / H

Melting point: 160 ° C.

Example 58

3-Ethoxycarbonyl-4- (4-t-butylaminosulfonylphenyl) -4- (4-fluorophenyl) -3-butyric acid.

Compound of formula (XII):

A = phenyl, γ ₁ = 4 - F, Y ₂ = H.

This compound was prepared in the same manner as in Example 11, starting from a derivative prepared according to the procedure of Example 57 and 2 equivalents of potassium tert-butoxide.

The product was obtained from an amorphous powder, which was used for the next stage as obtained.

Example 59

Preparation of 3- (4-t-butylaminosulfonylphenyl) -3- (4-fluorophenyl) -2 (2-hydroxyethyl) -2-propenoic acid ethyl ester.

This compound was prepared in the same manner as in Example 12, starting from the derivative prepared as in Example 58.

The oil was taken up in diethyl ether and the resulting crystals were dried to give the pure isomer of (Z) -3- (4-t-butylaminosulfonylphenyl) -3- (4-fluorophenyl) -2- (2-hydroxyethyl) -2-ethyl ester. -propene in the form of crystals with a melting point of 152 ° C. The filtrate was evaporated in vacuo to give an oily residue corresponding to the (E) -3- (4-t-butylaminosulfonylphenyl) -3- (4-fluorophenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester, which was then used to proceed in the state in which it was obtained.

Example 60

Preparation of (E) -4 - [(4-fluorophenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide.

(E) isomer:

Compound of formula (I):

A = B = phenyl, Y = 4-F, Y ₂ = X ₂ = H, Xt = 4-SO ₂ NH ₂ ,

31075 / H

R1R2 - H, R 3 - R ₄ - Η.

Ethyl (E) -3- (4-t-butylaminosulfonylphenyl) -3- (4-fluorophenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester (10 grams) was prepared according to the procedure of of Example 59, which was dissolved in 20 ml of ethanol, and a solution containing 2 grams of sodium hydroxide in 10 ml of water was added. The reaction mixture was then heated at reflux for 2 hours. After evaporation of the reaction mixture to dryness, the residue was taken up in water, acidified with 1 N hydrochloric acid solution and then extracted with dichloromethane. The organic phase was dried over magnesium sulphate and then evaporated under vacuum. The resulting residue was added portionwise to 500 mL of concentrated sulfuric acid. The mixture was stirred for 15 minutes at room temperature and then poured into ice water and the crystals were filtered off and washed with diethyl ether and then transferred to 100 ml of warm acetone. 50 ml of diethyl ether was added to the solution thus obtained, and the formed crystals were filtered off and dried to give the desired (E) -3 [1- (4-aminosulfonylphenyl) -1- (4-fluorophenyl) methylidene] dihydrofuran-2. -one in the form of crystals.

Yield: 6 grams.

Melting point: 202 ° C.

Example 61

Preparation of (Z) -4 - [(4-fluorophenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide.

(Z) isomer:

Compound of formula (I):

A = B = phenyl, X = 4-F, _X2 = _Y2 = H, _Y1 = 4-SO ₂ NH _2,

R ₁ R ₂ = O, r ₃ = r ₄ = h.

This compound was prepared in the same manner as in Example 60, starting from the (Z) -isomer prepared according to the procedure of Example 59.

Crystals: melting point: 222 ° C.

31075 / H

Example 62

Preparation of 4-chloro-4'-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, = 4 - Cl, _Y2 = H

This compound was prepared in the same manner as in Example 39, starting from the procedure of Example 5.

The crystals; melting point: 176 ° C.

Example 63

(Z) -3-Ethoxycarbonyl-4- (4-chlorophenyl) -4- (4-methanesulfonyl) -3-butenoic acid

Compound of formula (X):

A = phenyl, Y = 4 - Cl, _Y2 = H

A suspension containing 20 grams of 4-chloro-4'-methanesulfonylbenzophenone prepared as described in Example 62 in 100 milliliters of t-butanol was added to which 7.2 grams of sodium t-butoxide was added as a one-time addition. addition was performed at room temperature. The suspension was heated to 40 ° C and a solution containing 16.9 ml of ethyl succinate in 20 ml of t-butanol was added over 10 minutes. The temperature was maintained at 55 ° C for 30 minutes and then adjusted to 35-40 ° C, then 140 ml of cold water was added and the reaction mixture was stirred for 30 minutes. The solution was filtered and the crystals were washed with water. The aqueous alcoholic phase was washed twice with 75 ml of toluene and then acidified with concentrated hydrochloric acid. The crystals were collected by filtration, washed with water and dried in vacuo to give (Z) -3-ethoxycarbonyl-4- (4-chlorophenyl) -4- (4-methanesulfonyl) -3-butenoic acid.

Yield: 20.2 grams.

HPLC purity: 81.6%, containing 12.1% of the (E) -isomer.

Recrystallization from 2-propanol gave (Z) -3-ethoxycarbonyl-4- (4-chlorophenyl) -4- (4-methanesulfonyl) -3-butenoic acid.

31075 / H

Yield: 14 grams.

HPLC purity: 96.1%, containing 0.7% of the (E) -isomer,

The crystals; melting point: 183 ° C.

Example 64

Preparation of (Z) -3- (4-chlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, = 4 - Cl, _Y2 = H

A solution containing 350 grams of (Z) -3-ethoxycarbonyl-4- (4-chlorophenyl) -4- (4-methanesulfonyl) -3-butene, prepared as described in Example 63, in 1.5 liters of tetrahydrofuran to which a solution of 120 ml of borane / dimethylsulfide complex was slowly added dropwise with good stirring. At the end of the addition, the solution was stirred for 2.5 hours at room temperature. The borane residue was then hydrolyzed by the addition of 100 ml of methanol and 100 ml of water. After evaporation of the solvent in vacuo, the residue was crystallized with water, filtered and washed with water to give (Z) -3- (4-chlorophenyl) -3- (4-methanesulfonylphenyl) -2-ethyl ester. - (2-Hydroxyethyl) -2-propene in the form of wet crystals, which were then used as received for the next procedure. Drying these crystals and recrystallizing them from 2-propanol gave (Z) -3- (4-chlorophenyl) -3 (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester as crystals.

HPLC purity: 98.3%

Melting point: 128 ° C.

Example 65

Preparation of (Z) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

Compound of formula (I):

A = B = phenyl, Yt = 4-Cl, X ₂ = Y ₂ = H, Χ _Ί = 4-SO ₂ CH ₃ ,

R @ 1 - R @ ₂ = o, r @ ₃ = r @ ₄ = h.

The wet product obtained by the procedure of Example 64 was heated at room temperature

31075 / H at reflux in 1.5 L of toluene in the presence of 1 gram of paratoluenesulfonic acid. Water and ethanol were then removed using a Dean Stark apparatus and then about 1 liter of toluene was evaporated. After adjusting the temperature to room temperature, the crystals thus obtained were filtered and washed with a minimum amount of 2-butanone, then dried to give the desired (Z) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonylphenyl). -methylidene] dihydro-furan-2-one in the form of crystals.

Yield: 261.5 grams

Melting point: 188-190 ° C.

Example 66

Preparation of 3,5-dichloro-4-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Υ _Ί = 3 - Cl, Y ₂ = 5 - Cl.

This compound was prepared in the same manner as in Example 1.

Crystals: melting point: 108 ° C.

Example 67

Preparation of 3,5-dichloro-4-methanesulfonylbenzophenone.

Compound of formula (VI):

A = phenyl, Y = 3 - Cl, _Y2 = 5 - Cl.

This compound was prepared in the same manner as in Example 39.

Crystals: melting point: 200 ° C.

Example 68

(Z) -3-ethoxycarbonyl-4- (3,5-dichlorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid.

(Z) isomer:

Compound of formula (X):

A = phenyl, Y = 3 - Cl, _Y2 = 5-CI.

This compound was prepared in the same manner as described above

31075 / H in Example 11.

The crystals; melting point: 180 ° C.

Example 69

Preparation of (Z) -3- (3,5-dichlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

(Z) isomer:

Compound of formula (XI):

A = phenyl, Y = 3 - Cl, _Y2 = 5 - CL

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 70

Preparation of (Z) -3- [1- (3,5-dichlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

A = B = phenyl, Yt = 3-Cl, Y ₂ = 5-Cl, Xi = 4-SO ₂ CH ₃ ,

X ₂ = H, RiR ₂ = 0, R ₃ = R ₄ = H

This compound was prepared in the same manner as in Example 65.

The crystals; melting point: 114 ° C.

Example 71

Preparation of 2,4-difluoro-4-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, γ ₁ = 2 - F, _Y2 = 4 - F

This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 98 ° C.

3I075 / H

Example 72

Preparation of 2,4-difluoro-4-methylsulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, _Y1 = 2 - F, _Y2 = 4 - F

This compound was prepared in the same manner as in Example 99.

The crystals; melting point: 160 ° C.

Example 73

3-Ethoxycarbonyl-4- (2,4-difluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid.

Compound of formula (X):

A = phenyl, Y 1 = 2 - F, Y ₂ = 4 - F.

This compound was prepared in the same manner as in Example 11.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 74

Preparation of 3- (2,4-Difluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, _Y1 = 2 - F, _Y2 = 4 - F

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 75

(Z) -3- [1- (2,4-Difluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

31075 / H

A = B-phenyl, Y = 2-F, Y ₂ = 4-F, _{Ί Ί} = 4-SO ₂ CH ₃ ,

X ₂ = H, r ₁ r ₂ = o, r ₃ = r ₄ = h.

This compound was prepared in the same manner as in Example 65 and purified by chromatography using a 10 / 0.3 mixture of dichloromethane and acetone as eluent.

The crystals; melting point: 140 ° C.

Example 76

Preparation of 3,5-difluoro-4-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Y _} = 3-F, Y ₂ = 5-F.

This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 90 ° C.

Example 77

Preparation of 3,5-difluoro-4-methanesulfonylbenzophenone.

Compound of Formula (IV);

A = phenyl, Υ _Ί = 3 - F, Y ₂ = 5 - F.

This compound was prepared in the same manner as in Example 39.

The crystals; melting point: 152 ° C.

Example 78

3-Ethoxycarbonyl-4- (3,5-difluorophenyl) -4- (4-methanesulfonylphenyl) -3-butyric acid.

Compound of formula (X):

A = phenyl, Y = 3 - F, _Y2 = 5 - F

This compound was prepared in the same manner as in Example 11.

The product was obtained in the form of an oil which was used as such for the next stage.

31075 / H

Example 79

Preparation of 3- (3,5-difluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, _Y1 = 3 - F, _Y2 = 5-F.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 80

Preparation of (Z) -3- [1- (3,5-difluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

A = B = phenyl, Yt = 3-F, Y ₂ = 5-F, Xt = 4-SO ₂ CH ₃ ,

X ₂ = H, R ₁ = 2, R ₃ = R 4 = H.

This compound was prepared in the same manner as in Example 65 and purified by chromatography using a 10 / 0.3 mixture of dichloromethane and acetone as eluent.

The crystals; melting point: 162 ° C.

Example 81

Preparation of 4-methyl-4-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, _{Y1 = 4-CH3, Y2} = H

This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 96 ° C.

Example 82

Preparation of 4-methyl-4-methanesulfonylbenzophenone.

Compound of formula (IV):

31075 / H

A = phenyl, Y = _{4-CH3, Y2} = H

This compound was prepared in the same manner as in Example 39.

The crystals; melting point: 180 ° C.

Example 83

3-Ethoxycarbonyl-4- (4-methylphenyl) -4- (4-methanesulfonylphenyl) -3-butyric acid.

Compound of formula (X):

A = phenyl, Y 1 = 4-CH ₃ , Y ₂ = H.

This compound was prepared in the same manner as in Example 11.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 84

Preparation of 3- (4-Methylphenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, Y = 4 - _{CH3, Y2} = H

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 85

Preparation of (E) -3- [1- (4-methylphenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(E) isomer:

Compound of formula (I):

A = B = phenyl, ^ = 4-O ^, Y ₂ = H, X 1 = 4-SO ₂ CH ₃ ,

X ₂ = H, R ₁ = 2, r ₃ = r ₄ = h.

This compound was prepared in the same manner as described above

31075 / H in Example 65, which was purified by chromatography using a 10 / 0.3 mixture of dichloromethane and acetone as eluent.

The crystals; melting point: 222 ° C.

Example 86

Preparation of 3-bromo-4'-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Y = 3 - Br, _Y2 = H

This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 90 ° C.

Example 87

Preparation of 3-bromo-4'-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, Y = 3 - B r, Y ₂ = H,

This compound was prepared in the same manner as in Example 39.

The crystals; melting point: 170 ° C.

Example 88

3-Ethoxycarbonyl-4- (3-bromophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid. I

Compound of formula (X):

A = phenyl, Y = 3 - B r, Y ₂ = H,

This compound was prepared in the same manner as in Example 11.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 89

Preparation of 3- (3-bromophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

31075 / H

Compound of formula (XI):

A = phenyl, Υ _Ί = 3 - Br, Y ₂ = H.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 90

Preparation of (Z) -3- [1- (3-bromophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

A = B-phenyl, Y 1 = 3-Br, Y ₂ = H, X 1 = 4-SO ₂ CH ₃ ,

X ₂ = H, R ₁ R ₂ = O, R ₃ = R ₄ = H.

This compound was prepared in the same manner as in Example 65 and purified by chromatography using 10: 0.3 dichloromethane: acetone as eluent.

The crystals; melting point: 162 ° C.

Example 91

Preparation of 3-chloro-4-fluoro-4'-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Y 1 = 3 - Cl, Y ₂ = 4 - F.

This compound was prepared in the same manner as in Example 39.

The crystals; melting point: 140 ° C.

Example 92

Preparation of 3-chloro-4-fluoro-4'-methanesulfonylbenzophenone.

Compound of Formula (IV);

A = phenyl, Y 1 = 3 - Cl, Y ₂ = 4 - F.

This compound was prepared in the same manner as in Example 39.

31075 / H

The crystals; melting point: 146 ° C.

Example 93

3-Ethoxycarbonyl-4- (3-chloro-4-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butyric acid.

Compound of formula (X):

A = phenyl, Y = 3 - Cl, _Y2 = 4 - F

This compound was prepared in the same manner as in Example 11.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 94

Preparation of 3- (3-chloro-4-fluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, Y _n = 3 - Cl, _Y2 = 4-F.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 95

(Z) -3- [1- (3-Chloro-4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

A = B = phenyl, Y 1 = 3-Cl, Y ₂ = 4-F, X t = 4-SO ₂ CH ₃ ,

X ₂ = H, R ₁ R ₂ = O, r ₃ = r ₄ = h.

This compound was prepared in the same manner as in Example 65 and purified by chromatography using a 10 / 0.3 mixture of dichloromethane and acetone as eluent.

The crystals; melting point: 123 ° C.

31075 / H

Example 96

Preparation of 4-bromo-4'-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Y = 4 - Br, _Y2 = H

This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 148 ° C.

Example 97

Preparation of 4-bromo-4'-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, _Y1 = 4 - Br, _Y2 = H

This compound was prepared in the same manner as in Example 39.

The crystals; melting point: 188 ° C.

Example 98

3-Ethoxycarbonyl-4- (4-bromophenyl) -4- (4-methanesulfonylphenyl) -3-butyric acid.

Compound of formula (X):

A = phenyl, Υ _Ί = 4 - Br, Y ₂ = H.

This compound was prepared in the same manner as in Example 11.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 99

Preparation of 3- (4-bromophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, Υ _Ί = 4 - Br, Y ₂ = H.

This compound was prepared in the same manner as in Example 12.

31075 / H

The product was obtained in the form of an oil which was used as such for the next stage.

Example 100

Preparation of (Z) -3- [1- (3-bromophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

compound of of formula (I) A = B = phenyl, Yi = 4-Br, y ₂ = h, Xi = 4-SO ₂ CH ₃ x ₂ = h, RiR ₂ = 0 R ₃ = R ₄ = H

This compound was prepared in the same manner as in Example 65 and purified by chromatography using a 10 / 0.3 mixture of dichloromethane and acetone as eluent.

The crystals; melting point: 204 ° C.

Example 101

Preparation of 2- (4-methylthiobenzoyl) furan.

Compound of formula (III):

A = 2-furyl, Y 1 = Y ₂ = H.

h This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 86 ° C.

Example 102

Preparation of 2- (4-methanesulfonylbenzoyl) furan.

Compound of formula (IV):

A = 2 - furyl, Y 1 = Y ₂ = H.

This compound was prepared in the same manner as in Example 39.

The crystals; melting point: 112 ° C.

Example 103

Preparation of 3-ethoxycarbonyl-4- (furan-2-yl) -4- (4-methanesulfonylphenyl) -3-butene

31075 / H acid.

Compound of formula (X):

A = 2-furyl, γ _{1 =} γ ₂ = Η.

This compound was prepared in the same manner as in Example 11.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 104

Preparation of 3- (furan-2-yl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = 2-furyl, Y _{1 =} Y ₂ = H.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 105

Preparation of (Z) -3- [1- (furan-2-yl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

A = 2-furyl, B = phenyl, Y 1 = Y ₂ = H, Χτ = 4-SO ₂ CH ₃ ,

X ₂ = H ^ 2 = 0, R ₃ = R ₄ = H

This compound was prepared in the same manner as in Example 65 and purified by chromatography using a 10 / 0.3 mixture of dichloromethane and acetone as eluent.

The crystals; melting point: 170 ° C.

Example 106

Preparation of (4-methylthiobenzoyl) cyclohexane.

Compound of formula (III):

31075 / H

A = cyclohexyl, Y1 = Y2 = H.

This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 110 ° C.

Example 107

Preparation of (4-methanesulfonylbenzoyl) cyclohexane.

Compound of formula (IV):

A = cyclohexyl, Y1 = Y2 = H.

This compound was prepared in the same manner as in Example 39.

The crystals; melting point: 116 ° C.

Example 108

3-Ethoxycarbonyl-4-cyclohexyl-4- (4-methanesulfonylphenyl) -3-butenoic acid.

Compound of formula (X):

A = cyclohexyl, Y1 = Y2 = H.

This compound was prepared in the same manner as in Example 11.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 109

Preparation of 3-cyclohexyl-3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = cyclohexyl, Y-Y = Y ₂ = H.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

31075 / H

Example 110

Preparation of (Z) -3- [1-cyclohexyl-1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

A = cyclohexyl, B = phenyl, Y = _Y2 = H, X = ι-4-SO ₂ CH _third

X ₂ = H, RiR ₂ = 0, R ₃ = R ₄ = H

This compound was prepared in the same manner as in Example 65.

The crystals; melting point: 148 ° C.

Example 111

Preparation of 3-fluoro-4-methyl-4'-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Υ _Ί = 3 - F, Y ₂ = 4 - CH ₃ .

A suspension containing 6.4 grams of magnesium shavings in 5 milliliters of anhydrous diethyl ether was added, and a solution containing 50 grams of 4-bromo-2-fluorotoluene in 150 milliliters of anhydrous diethyl ether was carefully added dropwise. At the end of the addition, the reaction mixture was stirred for 30 minutes, and a solution of 4-methylthiobenzonitrile in 200 mL of anhydrous tetrahydrofuran was added. The diethyl ether was distilled off and the mixture was heated to reflux for 4 hours. After adjusting the temperature of the product to room temperature, 300 mL of 6 N hydrochloric acid solution was added dropwise. The reaction mixture was heated at reflux for 6 hours, cooled to room temperature and extracted with diisopropyl ether. The organic phase was dried over magnesium sulphate and then evaporated to dryness. The residue was crystallized from diethyl ether to give the desired 3-fluoro-4-methyl-4'-methylthiobenzophenone as crystals.

Yield: 25 grams.

Melting point: 94 ° C.

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Example 112

Preparation of 3-fluoro-4-methyl-4'-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, Y = 3-F, Y ₂ = 4-CH ₃ .

This compound was prepared in the same manner as in Example 39.

The crystals; melting point: 170 ° C.

Example 113

(Z) -3-ethoxycarbonyl-4- (3-fluoro-4-methylphenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid.

Compound of formula (X):

A = phenyl, Y = 3 - F, _Y2 = 4-CH _third

This compound was obtained in the same manner as in Example 11, which was purified by treating the crude mixture containing both the (E) and (Z) isomer with the equivalent of D - (+) - α-methylbenzylamine in 5 volumes of ethyl acetate. The obtained crystals were removed ((E) -isomeric salt) and the filtrate was acidified with dilute hydrochloric acid solution, separated and evaporated in vacuo to give the corresponding (Z) -isomer containing less than 5% of the (E) -isomer.

Example 114

Preparation of (Z) -3- (3-fluoro-4-methylphenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, Y = 3-F, Y ₂ = 4-CH ₃ .

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 115

Preparation of (Z) -3- [1- (3-fluoro-4-methylphenyl) -1- (4-methanesulfonylphenyl) methylidene] -3755H dihydrofuran-2-one.

(Z) isomer:

Compound of formula (I):

A = B = phenyl, Yi = 3-F, _Y2 = 4-CH _3, Xi = 4-SO ₂ CH ₃ x ₂ = h, R ₂ iR = 0, R ₃ = R ₄ = H This the compound was prepared by the same as described above in Example 65.

The crystals; melting point: 169-170 ° C.

Example 116

4-Trifluoromethyl-4'-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Υ _Ί = 4 - CF ₃ , Y ₂ = H.

This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 139 ° C.

Example 117

Preparation of 4-trifluoromethyl-4'-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, = 4-CF ₃ , Y ₂ = H.

This compound was prepared in the same manner as in Example 39.

The crystals; melting point: 138 ° C.

Example 118

3-Ethoxycarbonyl-4- (4-trifluoromethylphenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid.

Compound of formula (X):

A = phenyl, _{Y1 = 4-CF3, Y2} = H.

This compound was prepared in the same manner as in Example 11.

The product was obtained as an oil which was used as such for the next stage

31075 / H as obtained.

Example 119

Preparation of 3- (4-Trifluoromethylphenyl) -3- (4-methanesulfonylphenyl) 2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, Y = 4 - CF _3, Y 2 = H,

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 120

(E) -3- [1- (4-Trifluoromethylphenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

(E) isomer:

Compound of formula (I):

A = B = phenyl, Yt = 4-CF ₃ , Y ₂ = H, Xt = 4-SO ₂ CH ₃ ,

X ₂ = H, R t R ₂ = O, R ₃ = R ₄ = H.

This compound was prepared in the same manner as in Example 65 and purified by chromatography using a 10 / 0.3 mixture of dichloromethane and acetone as eluent.

The crystals; melting point: 188-190 ° C.

Example 121

Preparation of 4-benzylthio-4'-chlorobenzophenone.

This compound was prepared in the same manner as in Example 56, starting from 4-bromochlorobenzene and 4-benzylthiobenzonitrile prepared according to Example 55.

crystals; melting point 134 ° C.

Example 122

Preparation of 4-t-butylaminosulfonyl-4'-chlorobenzophenone.

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This compound was prepared in the same manner as in Example 57.

The crystals; melting point: 163 ° C.

Example 123

3-Ethoxycarbonyl-4- (4-t-butylaminosulfonylphenyl) -4- (4-chlorophenyl) -3-butyric acid.

Compound of formula (XII):

A = phenyl, Υ _Ί = 4 - Cl, Y ₂ = H.

This compound was prepared in the same manner as in Example 58.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 124

Preparation of (Z) -3- (4-t-butylaminosulfonylphenyl) -3- (4-chlorophenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

This compound was prepared in the same manner as in Example 12. The oil thus obtained was taken up in diethyl ether and the crystals obtained were filtered off with the ((E) -isomer). The filtrate was concentrated under reduced pressure and the residue was taken up in petroleum ether where, after crystallization, the (Z) isomer was obtained as crystals with a melting point of 120 ° C.

Example 125

Preparation of (Z) -4 - [(4-chlorophenyl) - (2-oxo-dihydro-furan-3-ylidene) methyl] benzenesulfonamide.

Compound of formula (I):

A = B = phenyl, Y _{1 =} 4-Cl, Y ₂ = H, X 1 = 4-SO ₂ CH ₃ ,

X ₂ = H, r ₁ r ₂ = o, r ₃ = r ₄ = h.

A solution containing 10 grams of (Z) -3- (4-t-butylaminosulfonylphenyl) -3- (4-chlorophenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester, prepared as described in Example 124, was used. in 80 ml of trifluoroacetic acid and the solution was heated to boiling point below

31075 / H reflux condenser for 15 hours. After evaporation of the solvent in vacuo, the residue was taken up in dichloromethane. The organic phase was washed with water and dried over magnesium sulphate and evaporated in vacuo to give an oil which crystallized from acetone / diisopropyl ether to give (Z) -4 - [(4-chlorophenyl) - ( 2-Oxodihydrofuran-3-ylidene) methyl] benzenesulfonamide as crystals.

Yield: 3.9 grams.

Melting point: 187-189 ° C.

Example 126

Preparation of 4-benzylthio-3'-fluoro-4'-methylbenzophenone.

This compound was prepared in the same manner as in Example 56, starting from 4-bromo-2-fluorotoluene. The crystals; melting point: 122 ° C.

Example 127

Preparation of 4-t-butylaminosulfonyl-3'-fluoro-4'-methylbenzophenone.

This compound was prepared in the same manner as in Example 57.

The crystals; melting point: 132 ° C.

Example 128

(Z) -3-ethoxycarbonyl-4- (4- t -butylaminosulfonylphenyl) -4- (3-fluoro-4-methylphenyl) -3-butenoic acid.

Compound of formula (XII):

A = phenyl, Y 1 = 3-F, Y ₂ = 4-CH ₃ .

This compound was prepared in the same manner as in Example 58 where the oil was transferred to t-butyl methyl ether and the crystals formed were collected by filtration to give the (E) -isomer with a melting point of 96 ° C. The filtrate was concentrated in vacuo to give the (Z) -isomer as an oil, which was then used as it was.

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Example 129

(Z) -3- (4-t-Butylaminosulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

This compound was prepared in the same manner as in Example 12, starting from the (Z) -isomer of the acid of Example 128.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 130

(Z) -4 - [(3-Fluoro-4-methylphenyl) - (2-oxodihydrofuran-3-ylidene) methyl] benzenesulfonamide.

Compound of formula (I):

A = B = phenyl, Y 1 = 3-F, Y ₂ = 4-CH ₃ , X 1 = 4-SO ₂ NH ₂ ,

X ₂ = H, R ₁ = 2, r ₃ = r ₄ = h.

This compound was prepared in the same manner as in Example 125.

The crystals; melting point: 170-172 ° C.

Example 131

Preparation of 4-benzylthio-4'-fluoro-3'-methylbenzophenone.

This compound was prepared in the same manner as in Example 56, starting with 5-bromo-2-fluorotoluene. The crystals; melting point: 123 ° C.

Example 132

Preparation of 4-t-butylaminosulfonyl-4'-fluoro-3'-methylbenzophenone.

This compound was prepared in the same manner as in Example 57.

The crystals; melting point: 108 ° C.

Example 133

Preparation of (Z) -3-ethoxycarbonyl-4- (4- t -butylaminosulfonylphenyl) -4- (4-fluoro-331075 / H methylphenyl) -3-butenoic acid.

Compound of formula (XII):

A = phenyl, Y 1 = 3-CH ₃ , Y ₂ = 4-F.

This compound was prepared in the same manner as in Example 58 where the oil was transferred to t-butyl methyl ether and the crystals formed were filtered to give the (E) -isomer with a melting point of 96 ° C. The filtrate was evaporated in vacuo to give the (Z) isomer as an oil, which was then used as it was.

Example 134

(Z) -3- (4-t-Butylaminosulfonylphenyl) -3- (4-fluoro-3-methylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

This compound was prepared in the same manner as in Example 12.

The crystals; melting temperature; 128 [deg.] C.

Example 135

(Z) -4 - [(4-Fluoro-3-methylphenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide.

Compound of formula (I):

A = B = phenyl, Y = 3-CH ₃ , Y ₂ = 4-F, X-1 = 4-SO ₂ NH ₂ ,

X ₂ = H, RiR ₂ = 0, R ₃ = R ₄ = H

This compound was prepared in the same manner as in Example 125.

The crystals; melting point: 228-229 ° C.

Example 136

(E) -3- (4-t-Butylaminosulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -3-propenoic acid ethyl ester.

This compound was prepared in the same manner as in Example 12, starting from the (E) -isomer of the acid of Example 128.

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The product was obtained in the form of an oil which was used as such for the next stage.

Example 137

(E) -3- (4-t-Butylaminosulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -3-propenoic acid.

A solution containing 16 grams of (E) -3- (4-t-butylaminosulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -3-propenoic acid ethyl ester, prepared from according to the procedure of Example 136, in 50 ml of ethanol containing 3 g of sodium hydroxide and 5 ml of water, and the solution was heated at reflux for 2 hours. The reaction mixture was concentrated in vacuo, taken up in water, washed with diethyl ether, and acidified with dilute hydrochloric acid solution and extracted with dichloromethane. The organic phase is dried over magnesium sulphate and evaporated to dryness in vacuo to give a residue which crystallizes from diisopropyl ether to give (E) -3- (4-t-butylaminosulfonylphenyl) -3- (3-fluoro). 4-methylphenyl) -2- (2-hydroxyethyl) -3-propenoic acid in the form of crystals.

Yield: 7.6 grams

Melting point: 160 ° C.

Example 138

Preparation of (E) -2- [1- (4-t-butylaminosulfonylphenyl) -1- (3-fluoro-4-methylphenyl) methylidene] butane-1,4-diol.

A solution containing 7.8 grams of (E) -3- (4-t-butylaminosulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -3-propenoic acid, which was prepared in accordance with the procedure of Example 137 in 50 ml of anhydrous tetrahydrofuran, to which 5 ml of borane / dimethylsulfide complex was added dropwise. The reaction mixture was stirred for 6 hours at room temperature and then 10 ml of methanol was added slowly dropwise. The mixture was concentrated in vacuo, the product was taken up in aqueous potassium carbonate solution and extracted with diethyl ether. The organic phase was dried with magnesium sulfate and

31075 / H evaporated in vacuo to give the desired product, (E) -2- [1- (4-t-butylaminosulfonyilphenyl) -1- (3-fluoro-4-methylphenyl) methylidene] butane-1,4 diol, in the form of crystals.

Yield: 6.3 g.

Melting point: 106 ° C.

Example 139

Preparation of (E) -4 - [(3-Fluoro-4-methylphenyl) - (tetrahydrofuran-3-ylidene) methyl] benzenesulfonamide.

Compound of formula (I):

A = B = phenyl, = 3-F, X ₂ = 4-CH ₃ , Y 1 = 4-SO ₂ NH ₂ ,

Y ₂ = H, R 1 = R ₂ = R ₃ = R ₄ = H.

A solution containing 6.3 grams of (E) -2- [1- (4-t-butylaminosulfonylphenyl) -1- (3-fluoro-4-methylphenyl) methylidene] butane-1,4-diol, which was prepared, was used. according to the procedure of Example 138, in 75 ml of trifluoroacetic acid, and the solution was heated under reflux for 10 hours. The solvent was concentrated in vacuo and the residue was taken up in dilute sodium hydroxide solution, washed with dichloromethane and acidified with dilute hydrochloric acid solution and extracted with dichloromethane. The organic phases were then combined and dried over magnesium sulphate and evaporated in vacuo. The residue thus obtained was crystallized from tert-butyl methyl ether to give the desired product, (E) -4 - [(3-fluoro-4-methylphenyl) - (tetrahydrofuran-3-ylidene) methyl] benzenesulfonamide, as crystals.

Yield: 4 g.

Melting point: 174-176 ° C.

Example 140

Preparation of 4-benzylthio-3'-chloro-4'-fluorobenzophenone.

This compound was prepared according to the procedure of Example 56, starting from 4-bromo-2-chlorofluorobenzene.

The product was obtained as crystals with a melting point of 102 ° C.

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Example 141

Preparation of 4-t-butylaminosulfonyl-3'-chloro-4'-fluorobenzophenone.

This compound was prepared in the same manner as in Example 57.

The crystals; melting point: 108 ° C.

Example 142

3-Ethoxycarbonyl-4- (4-t-butylaminosulfonylphenyl) -4- (3-chloro-4-fluorophenyl) -3-butenoic acid.

Compound of formula (XII):

A = phenyl, = 3 - Cl, _Y2 = 4 - F

This compound was prepared in the same manner as in Example 58.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 143

Preparation of (Z) -4 - [(3-chloro-4-fluorophenyl) - (2-oxo-dihydrofuran-3ylidene) methyl] benzenesulfonamide.

Compound of formula (I):

A = B = phenyl, Υ _Ί = 3-Cl, Y ₂ = 4-F, Xt = 4-SO ₂ NH ₂ ,

X ₂ = H, RiR ₂ = 0, R ₃ = R ₄ = H

A solution containing 17 grams of 3-ethoxycarbonyl-4- (4-t-butylaminosulfonylphenyl) -4- (3-chloro-4-fluorophenyl) -3-butenoic acid, prepared as described in Example 142, in 150 ml of tetrahydrofuran was used. 7 ml of borane / dimethylsulfide complex was added dropwise to the solution. The reaction mixture was stirred for 6 hours at room temperature and 30 ml of ethanol were added dropwise. After addition of aqueous potassium carbonate solution, the reaction mixture was extracted with dichloromethane. The organic phase was then dried and evaporated in vacuo. The residue (13.8 g) was added to 30 ml of ethanol containing a solution of 3 g of sodium hydroxide in 10 ml of water and

The 31075 / H reaction mixture was then heated at 70 ° C for 3 hours. The solvents were evaporated in vacuo and the residue was taken up in water, the aqueous phase washed with diethyl ether, acidified with hydrochloric acid and extracted with dichloromethane, dried over magnesium sulphate and evaporated in vacuo. The residue was taken up in diethyl ether and the obtained crystals were filtered to give 3 grams of (E) -4- (t-butylaminosulfonylphenyl) -3- (3-fluoro-4-chlorophenyl) -2- (2-hydroxyethyl) -3-propenoic acid (melting point 180 ° C). The filtrate was concentrated in vacuo and the residue was taken up in 60 ml of trifluoroacetic acid. The thus obtained reaction mixture was heated at reflux for 17 hours and then concentrated in vacuo. The residue was taken up in dilute sodium hydroxide solution and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and evaporated in vacuo to give (Z) -4 - [(3-chloro-4-fluorophenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] -benzenesulfonamide, in the form of crystals.

Yield: 2 g.

Melting point: 244-246 ° C.

Example 144

Preparation of 4-benzylthio-3'-fluoro-4'-methoxybenzophenone.

This compound was prepared in the same manner as in Example 56, starting from 4-bromo-2-fluoroanisole. The crystals; melting point: 125 ° C.

Example 145

Preparation of 4-t-butylaminosulfonyl-3'-fluoro-4'-methoxybenzophenone.

This compound was prepared in the same manner as in Example 57.

The crystals; melting point: 136 ° C.

Example 146

(Z) -3-Ethoxycarbonyl-4- (4- t -butylaminosulfonylphenyl) -4- (3-fluoro-431075 / methoxyphenyl) -3-butenoic acid.

Compound of formula (XII):

A = phenyl, Y = 3 - F, _Y2 = 4 - OMe.

This compound was prepared in the same manner as in Example 58, whereupon the oil was transferred to t-butyl methyl ether to give the (Z) -isomer as amorphous crystals, which were used for the next stage as obtained.

Example 147

(Z) -3- (4-t-Butylaminosulfonylphenyl) -3- (3-fluoro-4-methoxyphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 148

(Z) -4 - [(3-Fluoro-4-methoxyphenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide.

Compound of formula (I):

A = B = phenyl, Y 1 = 3-F, Y ₂ = 4-OMe, X 1 = 4-SO ₂ NH ₂ ,

X ₂ = H, R 1 = R ₂ = O, R ₃ = R ₄ = H.

This compound was prepared in the same manner as in Example 125.

The crystals; melting point: 149-150 ° C.

Example 149

Preparation of 3- (4-fluorobenzoyl) pyridine.

A suspension containing 140 grams of nicotinic chloride hydrochloride in 500 ml of fluorobenzene was cooled to 0 ° C and 280 grams of aluminum chloride was added portionwise. The reaction mixture was heated at reflux for 6 hours, cooled, then poured onto

31075 / H ice. After the addition of sodium hydroxide added to adjust the pH to 8, the reaction mixture was extracted with dichloromethane. The organic phase was dried over magnesium sulfate and then evaporated in vacuo. The residue was crystallized from pentane / diisopropyl ether to give the desired 3- (4-fluorobenzoyl) pyridine as crystals.

Yield: 108.5 grams

Melting point: 91 ° C.

Example 150

Preparation of 3- (4-benzylthiobenzoyl) pyridine.

A solution containing grams of benzyl mercaptan in 500 ml of Ν, Ν-dimethylformamide was added to which 14 grams of 60% sodium hydroxide solution was added. The reaction mixture was stirred for 20 minutes at room temperature and 70 grams of 3- (4-fluorobenzoyl) pyridine prepared as described in Example 149 was added. The reaction mixture was heated at 80 ° C for 8 hours. then concentrated in vacuo and the residue taken up in water. The crystals were filtered off, dissolved in dichloromethane and the solution was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized in pentane / diisopropyl ether to give the desired 3- (4-benzylthiobenzoyl) pyridine as crystals.

Yield: 81 grams.

Melting point: 102 ° C.

Example 151

Preparation of 3- (4-t-butylaminosulfonylbenzoyl) pyridine.

This compound was prepared in the same manner as in Example 57.

The crystals; melting point: 179 ° C.

Example 152

Preparation of (Z) -3-ethoxycarbonyl-4- (4- t -butylaminosulfonylphenyl) -4- (3-pyridyl) -331075 / H butenoic acid.

Compound of formula (XII):

A = 3-pyridyl, Y 1 = Y 2 -H.

This compound was prepared in the same manner as in Example 58 by placing the oil in hot ethyl acetate and filtering the crystals to give the (E) isomer with a melting point of 209 ° C. The filtrate was evaporated and the residue was taken up in pentane, where the (Z) -isomer crystallized as crystals with a melting point of 195 ° C.

Example 153

Preparation of (Z) -3- (4-t-butylaminosulfonylphenyl) -3- (3-pyridyl) -2 (2-hydroxyethyl) -2-propenoic acid ethyl ester.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of amorphous crystals, which were used for the next stage as obtained.

Example 154

Preparation of (Z) - [(3-pyridyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide.

Compound of formula (1): A = 3-pyridyl, B = phenyl, X 1 = 4-SO ₂ NH ₂ , X ₂ = H, Y 1 = Y ₂ = H, R 1 = R ₂ = 0, R ₃ = R ₄ = H This compound was prepared by the same as described above

in Example 125.

The crystals; melting point: 219-220 ° C.

Example 155

Preparation of 3-chloro-4-methoxy-4'-methylthiobenzophenone.

Compound of formula (III):

A = phenyl, Y1 = 3 - Cl, _Y2 = 4 - OMe.

This compound was prepared in the same manner as in Example 1.

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The crystals; melting point: 100 ° C.

Example 156

Preparation of 3-chloro-4-methoxy-4'-methanesulfonylbenzophenone.

Compound of formula (IV):

A = phenyl, Y 1 = 3-Cl, Y ₂ = 4-OMe.

This compound was prepared in the same manner as in Example 39.

The crystals; melting point: 164 ° C.

Example 157

(Z) -3-ethoxycarbonyl-4- (3-chloro-4-methoxyphenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid.

Compound of Formula (X);

A = phenyl, = 3 - Cl, _Y2 = 4 - OMe.

This compound was prepared in the same manner as in Example 11, the oil thus obtained was transferred to ether and the crystals obtained were filtered off to give the (Z) -isomer as crystals having a melting point of 179 ° C.

Example 158

Preparation of (Z) -3- (3-chloro-4-methoxyphenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -3-propenoic acid ethyl ester.

Compound of formula (XI):

A = phenyl, Y 1 = 3-Cl, Y ₂ = 4-OMe.

This compound was prepared in the same manner as in Example 12.

The crystals; melting point: 102 ° C.

Example 159

Preparation of (Z) -3- [1- (3-chloro-4-methoxyphenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

Compound of formula (I):

31075 / H

A = B = phenyl, Y 1 = 3-Cl, Y ₂ = 4-OMe, Xt = 4-SO ₂ CH ₃ ,

X ₂ = H, R ₁ = R ₂ = 0, R ₃ = R ₄ = H

This compound was prepared in the same manner as in Example 65.

The crystals; melting point: 177 ° C.

Example 160

Preparation of 2- (4-methylthiobenzoyl) thiophene.

Compound of formula (III):

A = 2-thienyl, Υ _Ί = Y ₂ = H

This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 60 ° C.

Example 161

Preparation of 2- (4-methanesulfonylbenzoyl) thiophene.

Compound of formula (IV):

A = 2-thienyl, Y 1 = Y ₂ = H.

This compound was prepared in the same manner as in Example 39.

The crystals; melting point: 140 ° C.

Example 162

(E) -3-ethoxycarbonyl-4- (4-methanesulfonylphenyl) -4- (2-thienyl) -3-butenoic acid.

Compound of formula (X):

A = 2-thienyl, Y 1 = Y ₂ = H.

This compound was prepared in the same manner as in Example 11.

The crystals; melting point: 120 ° C.

Example 163

Preparation of (E) -3- (4-methanesulfonylphenyl) -3- (2-thienyl) -2- (231075 / hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = 2-thienyl, Υ _Ί = Y ₂ = H.

This compound was prepared in the same manner as in Example 12.

The crystals; melting point: 116 ° C.

Example 164

Preparation of (E) -3- [1- (4-methanesulfonylphenyl) -1- (2-thienyl) methylidene] dihydrofuran-2one.

Compound of formula (I):

A = 2-thienyl, B = phenyl, Y = _Y2 = H, Xt = 4-SO ₂ CH _3,

X ₂ = H, R 1 = R ₂ = O, R ₃ = R ₄ - = H.

This compound was prepared in the same manner as in Example 65.

The crystals; mp 246 ° C.

Example 165

Preparation of 4- (2-naphthoyl) methylthiobenzene.

Compound of formula (III):

A = 2-thienyl, Y = Y ₂ = H.

This compound was prepared in the same manner as in Example 1.

The crystals; melting point: 98 ° C.

Example 166

Preparation of 4- (2-naphthoyl) methanesulfonylbenzene

Compound of formula (IV):

A = 2-naphthyl, Y 1 = Y ₂ = H.

This compound was prepared in the same manner as in Example 39.

The crystals; melting point: 150 ° C.

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Example 167

3-Ethoxycarbonyl-4- (2-naphthyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid.

Compound of formula (X):

A = 2-naphthyl, = Y ₂ = H _.;

This compound was prepared in the same manner as in Example 11.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 168

Preparation of 3- (2-naphthyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

Compound of formula (XI):

A = 2-naphthyl, Y 1 = Y ₂ = H.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 169

Preparation of (Z) -3- [1- (2-naphthyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one.

Compound of formula (I):

A = 2-naphthyl, B = phenyl, Y-Y = Y ₂ = H, X 1 -SO 2 CH 3,

X ₂ = H, R ₁ = R ₂ = O, R ₃ = R ₄ = H.

This compound was prepared in the same manner as in Example 65 and purified by chromatography using a 10 / 0.3 mixture of dichloromethane and acetone as eluent.

The crystals; melting point: 244 ° C.

Example 170

Preparation of 3,5-dichloro-4'-fluorobenzophenone.

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The mixture containing 50 grams of 3,5-dichlorobenzoyl chloride and 150 ml of fluorobenzene was cooled to 0 ° C and 65 grams of aluminum chloride was added in portions. The reaction mixture was then stirred at ambient temperature for 2 (

The reaction mixture was heated at reflux for 4 hours. After cooling, the mixture was poured onto a mixture of ice and dilute hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then evaporated to dryness to give the desired 3,5-dichloro-4'-fluorobenzophenone as crystals.

Yield: 59 grams.

Melting point: 65 ° C.

Example 171

Preparation of 3,5-dichloro-4'-benzylthiobenzophenone.

This compound was prepared in the same manner as in Example 150, starting from 3,5-dichloro-4'-fluorobenzophenone prepared as in Example 170.

The crystals; melting point: 80 ° C.

Example 172

Preparation of 4-t-butylaminosulfonyl-3 ', 5'-dichlorobenzophenone.

This compound was prepared in the same manner as in Example 57 starting from 3,5-dichloro-4'-benzylthiobenzophenone prepared as in Example 171.

The crystals; melting point: 144 ° C.

Example 173

3-Ethoxycarbonyl-4- (4-t-butylaminosulfonylphenyl) -4- (3,5-dichlorophenyl) 3-butenoic acid.

Compound of formula (XII):

A = phenyl, Y! = 3-Cl, Y ₂ = 5-Cl.

This compound was prepared in the same manner as described above

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The product was obtained in the form of an oil which was used as such for the next stage.

Example 174

Preparation of 3- (4-t-butylaminosulfonylphenyl) -3- (3,5-dichlorophenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 175

Preparation of (Z) -4 - [(3,5-dichlorophenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide.

(Z) isomer:

Compound of formula (I):

A = B = phenyl Y 1 = 3-Cl, Y ₂ = 5-Cl, X ₁ = 4-SO ₂ NH ₂ ,

X ₂ = H, RiR ₂ = 0, R ₃ = R ₄ = H

This compound was prepared in the same manner as in Example 65. The obtained crystals were chromatographed on silica gel, eluting with dichloromethane / acetone 9/1, to give the desired (Z) after recrystallization from acetic acid. 4 - [(3,5-dichlorophenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide as crystals.

Melting point: 217 ° C.

Example 176

Preparation of 3-chloro-4'-fluorobenzophenone.

This compound was prepared in the same manner as in Example 170.

The crystals; melting point: 76 ° C.

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Example 177

Preparation of 3-chloro-4'-benzylthiobenzophenone.

This compound was prepared in the same manner as in Example 150 starting from 3-chloro-4'-fluorobenzophenone prepared as in Example 176.

The crystals; melting point: 90 ° C.

Example 178

Preparation of 4-t-butylaminosulfonyl-3'-chlorobenzophenone.

This compound was prepared in the same manner as in Example 57, starting from 3'-chloro-4'benzylthiobenzophenone prepared as in Example 177.

The crystals; melting point: 128 ° C.

Example 179

3-Ethoxycarbonyl-4- (4-t-butylaminosulfonylphenyl) -4- (3-chlorophenyl) -3-butyric acid.

Compound of formula (XII):

A = phenyl, Y = 3 - Cl, _Y2 = H.

This compound was prepared in the same manner as in Example 58.

The product was obtained in the form of an orange oil, which was used for the next step as obtained.

Example 180

Preparation of 3- (4-t-butylaminosulfonylphenyl) -3- (3-chlorophenyl) -2 (2-hydroxyethyl) -2-propenoic acid ethyl ester.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

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Example 181

Preparation of (Z) -4 - [(3-chlorophenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide.

(Z) isomer:

Compound of formula (I):

A = B = phenyl, = 3-Cl, _Y2 = H, Xt = 4-SO ₂ NH _2,

X ₂ = H ^ 2 = 0, R ₃ = R ₄ = H

This compound was prepared in the same manner as in Example 65 and purified by silica gel chromatography using 10/1 dichloromethane / acetone as eluent.

crystals; melting point: 178 ° C.

Example 182

Preparation of 4-fluoro-3'-methylbenzophenone.

This compound was prepared in the same manner as in Example 170.

The crystals; melting point: 50 ° C.

Example 183

Preparation of 4-benzylthio-3'-methylbenzophenone.

This compound was prepared in the same manner as in Example 150, starting from 4-fluoro-3'-methyl-benzophenone, prepared according to Example 182.

The crystals; melting point: 98 ° C.

Example 184

Preparation of 4-t-butylaminosulfonyl-3'-methylbenzophenone.

This compound was prepared in the same manner as in Example 57, starting from 4-benzylthio-3'-methylbenzophenone, prepared according to Example 183.

The crystals; melting point: 116 ° C.

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Example 185

3-Ethoxycarbonyl-4- (4-t-butylaminosulfonylphenyl) -4- (3-methylphenyl) -3-butyric acid.

Compound of formula (XII):

A = phenyl, Y 1 = 3-CH ₃ , Y ₂ = H.

This compound was prepared in the same manner as in Example 58.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 186

Preparation of 3- (4-t-butylaminosulfonylphenyl) -3- (3-methylphenyl) 2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

This compound was prepared in the same manner as in Example 58.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 187

Preparation of (Z) -4 - [(3-methylphenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide.

(Z) isomer:

Compound of formula (1): A = B = phenyl, Y 1 = 3-CH ₃ , y ₂ = h, Xi = 4-SO ₂ NH ₂ x ₂ = h, r ₁ r ₂ = o, r ₃ = r ₄ = h.

This compound was prepared in the same manner as in Example 65. The oil was chromatographed on silica gel, eluting with dichloromethane / acetone (10/1) to give (Z) -4- [(3-methylphenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide in the form of crystals.

Melting point: 166 ° C.

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Example 188

Preparation of 3-chloro-4-methoxy-4'-benzylthiobenzophenone.

This compound was prepared in the same manner as in Example 56, starting with 2-chloro-4-bromoanisole. The crystals; melting point: 115 ° C.

Example 189

Preparation of 4-t-butylaminosulfonyl-3'-chloro-4'-methoxybenzophenone.

This compound was prepared in the same manner as in Example 57, starting with 3-chloro-4-methoxy-4'-benzylthiophenone.

The crystals; melting point: 120 ° C.

Example 190

3-Ethoxycarbonyl-4- (4-t-butylaminosulfonylphenyl) -4- (3-chloro-4-methoxyphenyl) -3-butenoic acid.

Compound of Formula (XII);

A = phenyl, Y = 3 - Cl, _Y2 = OMe.

This compound was prepared in the same manner as in Example 58.

The product was obtained in the form of an oil which was used as such for the next stage.

Example 191

Preparation of 3- (4-t-butylaminosulfonylphenyl) -3- (3-chloro-4-methoxyphenyl) -2- (2-hydroxyethyl) -2-propenoic acid ethyl ester.

This compound was prepared in the same manner as in Example 12.

The product was obtained in the form of an oil which was used as such for the next stage.

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Example 192

(Z) -4 - [(3-Chloro-4-methoxyphenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide and (E) -4 - [(3-Chloro-4-methoxyphenyl)] - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide.

Compound of formula (I):

A = B = phenyl, _{η η} = 3-Cl, Y ₂ = 4-OMe, X, = 4-SO ₂ NH ₂ , x ₂ = h, r ₁ r ₂ = o, r ₃ = r ₄ = h.

This compound was prepared in the same manner as in Example 65. The oil was chromatographed on silica gel using 10/1 dichloromethane / acetone as eluent to give (E) and (Z). 4 - [(3-chloro-4-methoxyphenyl) - (2-oxo-dihydrofuran-3-ylidene) methyl] benzenesulfonamide as amorphous crystals.

Pharmacological tests

The anti-inflammatory activity of the compounds of the above examples was evaluated by the carrageenin-induced edema method and the analgesic activity was evaluated by the kaolin-induced arthritis test.

techniques

Anti-inflammatory efficacy:

Anti-inflammatory efficacy was evaluated in rats using the carrageenin-induced edema test. The product was administered orally at 2.5 ml / 100 grams (n = 6 animals per dose) 2 hours and 30 minutes after oral hyperhydration (2.5 ml / 100 grams). One hour after product administration, edema was induced by plantar subcutaneous injection of a 2% carrageenin solution. The results obtained are expressed as an ID value of ₅ o. that is, the dose in milligrams / kilogram that produced a 50% decrease in edema volume, calculated by linear regression using the maximum edema volume obtained for each product tested.

Analgesic efficacy:

Analgesic efficacy was evaluated in rats by the kaolin-induced arthritis test. In this test, thirty minutes after intra-articular administration was 10

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A 1% aqueous suspension of kaolin administered product, orally in an amount of 1 milliliter / 100 grams (n = 10 animals per dose). The results obtained are expressed as DE ₅₀ values, i.e. doses in milligrams / kilogram, which produce a 50% decrease in the maximum record in the control group, as calculated by the linear regression method.

The results obtained are shown in the following table.

Example Anti-inflammatory efficacy ID ₅₀ (mg / kg) Analgesic efficacy DE ₅₀ (mg / kg) 4 (E isomer) 1.8 7.6 8 (E isomer) > 30 - 8 and 65 (Z isomers) 3.7 2.1 13 (Z isomer) 3.9 14.1 18 (Z isomer) > 30 6.1 23 (Z isomer) 9.3 7.2 28 (E isomer) 10.1 26.1 31 (E isomer) 3.1 14.2 34 (E isomer) - 38.8 49 (Z isomer) > 30 > 30 54 (Z isomer) > 30 10.8 60 (E isomer) 1.7 20.9 70 (Z isomer) 5.5 21.5 75 (Z isomer) 4.6 - 80 (Z isomer) 4.8 5.8 85 (E isomer) > 30 > 30 90 (Z isomer) 17.2 - 95 (Z isomer) 1.6 5.8 100 (Z isomer) 3.6 - 125 (Z isomer) 1.8 8.5 130 (Z isomer) 2.0 2.4 135 (Z isomer) 3.3 6.1 143 (Z isomer) 0.7 6.4

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Inhibition of COX-1 and COX-2 enzymatic activities:

The test molecule was pre-incubated for 10 minutes at 25 ° C with 2 U COX-1 (purified ram semen) or 1 U COX-2 (purified placenta sheep). Arachidonic acid (6 μΜ for COX-1, 4μΜ for COX-2) was added to the reaction medium and incubated for 5 minutes at 25 ° C. Upon completion of the incubation, the enzymatic reaction was stopped by addition of 1 N hydrochloric acid solution and produced by PGE2 was detected by the EIA method.

The results obtained are expressed as an IC ₅₀ value, concentration in nM, corresponding to a 50% inhibition of the maximum enzymatic activity of COX-1 and COX-2 (n = 1 to 4 assays).

The results are shown in the following table.

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Example Inhibition of COX-2 IC ₅₀ (nM) Inhibition of COX-1 IC ₅₀ (nM) selectivity ratio COX-1 / COX-2 4 (E) 674 + 46 (n = 3) > 300,000 > 445 8 or 65 (W) 182 ± 25 (N = 4) 171875 ± 22193 (N = 4) 944 13 (Z) 610 > 100,000 > 164 18 (Z) 132 + 32 (n = 2) 73200 555 23 (E) 627 > 100,000 > 159 28 (E) 18354 > 10,000 > 0.5 31 (E) 780 > 100,000 > 128 34 (E) 694 > 100,000 > 144 49 (Z) 418 > 100,000 > 239 54 (Z) 710 > 100,000 > 141 60 (E) 296 + 107 (n = 2) 81000 274 70 (Z) 225 > 100,000 > 444 80 (Z) 518 > 100,000 > 193 85 (E) 350 > 100,000 > 286 90 (Z) 458 > 100,000 > 218 95 (Z) 205 ± 35 (N = 2) 309500 ± 27500 (N = 2) 1510 100 (Z) 166 62000 373 125 (Z) 60 2525 ± 1312 (n = 2) 42 130 (Z) 131 + 19 (n = 2) 45730 349 135 (Z) 245 + 76 (n = 2) 19700 80 143 (Z) 73 12700 174

tolerance

Gastric tolerance:

Gastric tolerance was studied in Charles River rats of CD weight in the range of 110 to 150 grams. These animals were kept on

31075 / H water diet for 24 hours prior to oral administration of the product or vehicle alone in an amount of 1 milliliter / 100 grams (n = 6 animals per dose). Six hours after administration, the animals were killed, their stomach removed and opened along another curvature. The number of haemorrhagic sites and furrows in the stomach, identified macroscopically, made it possible to determine the ulceration index (0 means no lesion, 1 means 1 to 2 lesions, 2 means 3 to 4 lesions, 3 means 5 to 8 lesions, 4 means 9 to 16 lesions, 5 (more than 17 lesions) and further allowed to estimate a 50% ulcerigenic dose (UD50 means a dose causing 4-5 lesions, expressed in milligrams / kilogram).

Example UD50 (confidence limit) mg / kg 4 (E - isomer) > 1000 8 or 65 (Z-isomer) > 1000 125 (Z - isomer) > 1000 indomethacin 8.3 (5.8 to 11.8)

toxicology

The first toxicological studies performed showed that the products of the above examples did not produce adverse effects in rats after oral absorption of doses ranging up to 300 milligrams / kilogram.

Claims (13)

1. Diarylmethylidene furan derivatives of the general formula I (I) in which: * rings A and B independently represent: - a phenyl group, - naphthyl group, a residue derived from a heterocycle of 5 to 6 members and containing 1 to 4 heteroatoms, or - a radical derived from a saturated hydrocarbon ring containing from 3 to 7 carbon atoms, * at least one of the substituents Χ _Ί , X ₂ , Y 1 or Y ₂ necessarily means: - a -S (O) _n -R group in which n is an integer of 0, 1 or 2 and R represents a lower alkyl group having 1 to 6 carbon atoms or a lower haloalkyl group having 1 to 6 carbon atoms, or - the group -SO2NH2, which group is located in the para position and the other of these substituents independently of one another mean: - a hydrogen atom, - a halogen atom - a lower alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, or 31075 / H - a lower O-alkyl of 1 to 6 carbon atoms, * or X, and X ₂ and Yi and _Y2 represent methylenedioxy, and R *, R _2, R ₃ and R ₄ each independently of one another: - a hydrogen atom, - halogen atom, - a lower alkyl group having 1 to 6 carbon atoms, lower haloalkyl having 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl, or R ₁ R ₂ or R ₃ R ₄ are an oxygen atom, or R ₁ R ₂ or R ₃ R ₄ together with the carbon atom to which they are attached form a saturated hydrocarbon ring containing from 3 to 7 carbon atoms. The diarylmethylidene furan derivatives of the general formula I according to claim 1, wherein * rings A and B independently of one another mean: - a phenyl group, - naphthyl group, - a pyridyl group, - furyl group, a thienyl group, or a cyclohexyl group; • at least one of the substituents X _1, X ₂ , Yt or Y ₂ is necessarily a group SCH ₃ , SO ₂ CH ₃ or SO ₂ NH ₂ , the other substituents being independently of one another: - a hydrogen atom, - halogen atom, - a lower alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, or - a lower O-alkyl group having 1 to 6 carbon atoms; * R 1 R ₂ represents an oxygen atom and * R ₃ and R ₄ independently represent a hydrogen atom or a lower alkyl group containing 1 to 6 carbon atoms. 31075 / H A compound of formula I according to claim 1 or 2, wherein ring B is a phenyl group. A compound of formula I according to claim 1 or 2, wherein ring A is a phenyl or pyridyl group. A compound of formula I according to any one of claims 1 to 4, wherein X 1 is 4-SO ₂ CH ₃ or 4-SO ₂ NH ₂ and X ₂ is hydrogen. A compound of formula I as claimed in any one of claims 1 to 5, wherein Y 1 represents a fluorine atom, a chlorine atom or a methyl group and Y ₂ represents a hydrogen atom, a fluorine atom or a chlorine atom. The diarylmethylidene furan derivatives of the general formula I according to any one of claims 1 to 6, wherein R 1 -R ₂ represents an oxygen atom and R ₃ and R ₄ each represent a hydrogen atom. The diarylmethylidene furan derivatives of the formula I according to claim 1, selected from the group consisting of: (E) -3- [1- (4-fluorophenyl) -1- (4-methanesulfonyl-phenyl) methylidene] dihydrofuran-2-one; (Z) -3- [1- (4-Chlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one: (Z) -3- [1- (3,4-Dichlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-231075 / H (Z) -3- [1- (6-chloropyridin-3-yl) - 1- (4-methanesulfonyl-phenyl) methylidene] dihydrofurán2-one: (Z) -4- [4-Chloro-phenyl) - (2-oxodihydrofuran-3-ylidene) -methyl] -benzenesulfonamide; (Z) -4 - [(3-fluoro-4-methyl-phenyl) - (2-oxodihydrofurán-3-ylidene) methyl] -benzenesulfonamide: 31075 / H A process for the preparation of a compound of the formula I according to any one of claims 1 to 8, characterized in that a ketone of the formula: wherein A, B, X 1, X ₂ , Y 1 and Y _{2 have the} same meaning as in claim 1, with an alkyl succinate of the general formula; ch ₂ -COOR ' CH ₂ -COOR 'in which: R 'represents a lower alkyl group having 1 to 6 carbon atoms, preferably an ethyl group, under Stobbe condensation conditions, in the presence of an alkoxide, in particular in the presence of sodium or potassium tert-butoxide, or a hydride such as sodium hydride in an alcoholic solvent such as tert-butanol or an aromatic solvent such as toluene, the choice of the condensing agent and solvent allowing the reaction to direct the reaction to obtain a particular isomer, thereby obtaining an acid ester derivative of the formula: 31075 H in which A, B, X, X _2, Y ₂ and Y the meanings indicated in Claim 1, by selective reduction of the acid function of the above ester / acids, e.g., by treatment with borane in tetrahydrofuran, to give the alcohol ester of the formula: ·? wherein A, B, X _{1 (} X ₂ , Y 1, Y _{2 have the} same meaning as in claim 1, followed by cyclization of the ester alcohol by heating, for example in toluene in the presence of paratoluenesulfonic acid. 10. A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of the formula I ^! I as defined in any one of claims 1 to 8, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or carrier material. Pharmaceutical composition having anti-inflammatory and analgesic activity, characterized in that it comprises a pharmaceutically effective amount of at least ^{5 of} a compound of the formula I as defined in any one of claims 1 to 8, W optionally incorporated in a pharmaceutically acceptable excipient, vehicle or carrier material. A pharmaceutical composition useful for the prevention of tumors, in particular adenocarcinoma or colon cancer, for the prevention of neurodegenerative diseases, in particular Alzheimer's disease, for the prevention of stroke and epilepsy and for the prevention of premature labor. Pharmaceutical composition according to claim 10 or 11, characterized in that it is in the form of a gelatin capsule or tablet containing a dose of 1 milligram to 1000 milligrams, or in the form of an injectable preparation containing 0.1 milligrams to 500 milligrams.