BG62808B1 - New diarylmethylidenfuran derivatives, method for their preparation and utilization as medicamentous forms - Google Patents

Abstract

The invention relates to diarylmethildenfuran derivatives with the formula where the meanings of the substitutents are listed in the description, and to their usage as medicamentous forms, in particular as antiphlogistic and analgetic means. 13 claims

Description

The invention relates to novel diarylmethylidene furan derivatives of general formula (I).

BACKGROUND OF THE INVENTION

One way to biotransform arachidonic acid is by using cyclooxygenase, which allows arachidonic acid to be converted to PGG2 and then to PGH2. A modern study on the cloning and sequencing (determination of the amino acid sequence) of cyclooxygenase shows the presence of two isoenzymes, COX-1 and COX-2, in some species, and in particular in humans. The first is a constitutive enzyme that is expressed in most tissues, while the second, which is expressed in few tissues, such as in the brain, can be induced in multiple tissues by different products, in particular through cytokines and mediators, obtained by inflammatory reaction. Each enzyme plays a different role and the inhibition (suppression) of COX-1 or COX-2 will not produce the same results. Inhibition of COX-1 leads to a decrease in prostaglandins involved in homeostasis, which may exacerbate side effects. Inhibition of COX-2 results in a decrease in the prostaglandins produced by the inflammatory process. Thus, the selective inhibition of COX-2 makes it possible to obtain an easily tolerated anti-inflammatory agent.

- 2 The compounds of the invention make it possible to achieve this selective inhibition. The compounds in question therefore have a very valuable pharmacological profile insofar as they have anti-inflammatory and analgesic properties and are at the same time extremely tolerable, in particular from the stomach. They are especially recommended for the treatment of inflammatory symptoms and for the treatment of pain.

For example, the use of arthritis, in particular rheumatoid arthritis, spondylitis, gouty arthritis, osteoarthritis and juvenile arthritis, autoimmune diseases and skin tuberculosis, may be used as an example for such use. The compounds may also be indicated for the treatment of bronchial asthma, dysmenorrhea, tendonitis, bursitis and dermatological inflammations such as psoriasis, eczema, burns and dermatitis. The compounds can also be used to treat gastrointestinal inflammation, Crohn's disease, gastritis and ulcerative (ulcerative) colitis, and to prevent cancer, especially colon adenocarcinoma, to prevent neurodegenerative diseases, in particular Alzheimer's disease, to prevent stroke and epilepsy and to prevent preterm birth.

These analgesic properties of the compounds allow them to be used for any symptoms of pain and especially for the treatment of myalgia. joint pain or neuralgia, toothache, shingles and migraines, as well as for the treatment of rheumatic complaints and pain due to cancer and for the further treatment of infectious and febrile conditions.

The invention also relates to a method for the preparation of said compounds as well as their use for treatment.

Some derivatives have been described in the literature and have been shown to have the ability to selectively inhibit cyclooxygenase-2. The compounds described in the following patent applications may be mentioned:

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

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

WO 96/08482 A (Merck and Co. Inc.).

In principle, most of the compounds described in these documents as selective cyclooxygenase-2 inhibitors are 5-membered heterocyclic derivatives substituted by two aromatic rings that are directly attached to the heterocycle and which are located on two adjacent heterocycles, carbon atom.

The applicant has surprisingly found that derivatives in which the two aromatic rings are at the same carbon atom (these two aromatic rings are not directly linked to the heterocycle but via an intermediate double bond) have an exceptional ability to selectively inhibit cyclooxygenase-2.

SUMMARY OF THE INVENTION

Said diarylmethylidene furan derivatives are of general formula (I):

formula (I)

- 4 in which the rings A and B represent separately: a phenyl radical, a naphthyl radical, a radical derived from a heterocycle containing 5 or 6 members having from 1 to 4 heteroatoms _; or a radical derived from a saturated hydrocarbon ring of from 3 to 7 carbon atoms;

as at least one of the substituents X ₁₅ X ₂ , Y-, or Υ ₂ must mean:

a group -S (O) _n -R in which η is an integer equal to 0, 1 or 2, and R is a lower alkyl radical of 1 to 6 carbon atoms or a lower haloalkyl radical of 1 to 6 carbon atoms or a group -SO ₂ NH ₂ ;

and is in a steam position, the other substituents being each independently: a hydrogen atom, a halogen atom, a lower alkyl radical of from 1 to 6 carbon atoms, a trifluoromethyl radical, or a lower alkyl radical of 1 to 6 carbon atoms;

or

X ₁ and X ₂ or Y ₁ and Y ₂ denote methylenedioxy group; and

R _1; R ₂ , R ₃ and R ₄ denote separately: a hydrogen atom, a halogen atom, a lower alkyl radical of 1 to 6 carbon atoms, a lower haloalkyl radical of 1 to 6 carbon atoms or an aromatic radical selected from the group consisting of phenyl , naphthyl, thienyl, furyl or pyridyl;

or either R ₃ R ₄ is an oxygen atom, or

R ₁ or R ₂ or R ₃ R ₄ together with the carbon atom to which they are attached ₇ form a saturated hydrocarbon ring of 3 to 7 carbon atoms.

In the description and claims, "lower alkyl" is intended to mean straight or branched chain hydrocarbons having from 1 to 6 carbon atoms. A lower alkyl radical is, for example, methyl, ethyl, propyl, isopropyl, butyl. isobutyl, t-butyl, pentyl, isopentyl, hexyl or isohexyl radical.

By "lower haloalkyl radical ¹ " is meant an alkyl radical of from 1 to 6 carbon atoms, in which from 1 to 7 hydrogen atoms are replaced by from 1 to 7 halogen atoms. A lower haloalkyl radical is, for example, a trifluoromethyl radical, a 2,2,2-trifluoroethyl radical, a pentafluoroethyl radical, a 2,2-difluoro-3,3,3-trifluoropropyl radical, a heptafluoropropyl radical, or chloromethylmethyl.

By "halogen" is meant a chlorine, bromine, iodine or fluorine atom.

The term "saturated hydrocarbon ring of 3 to 7 carbon atoms" is understood to be cyclopropane. cyclobutane, cyclopentane, cyclohexane or cycloheptane.

"Heterocycle-derived radical" means any aromatic ring containing from 1 to 4 heteroatoms in the ring, such as oxygen, nitrogen or sulfur.

Of these rings, particularly preferred are: pyridine, furan, thiophene, as well as pyrrole, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine. oxazoles, oxadiazoles, thiazoles and thiadiazoles.

The aforementioned derivatives of formula (I) may have asymmetric centers and / or may exist in the form of cis or trans compounds. The scope of the invention includes racemates and mixtures of cis and trans compounds, as well as optically active products, cis and trans derivatives, taken separately. These pure products can be

- 6 are obtained by methods known to those skilled in the art, in particular by chromatography, and in particular on chiral columns, in the case of optical isomers. This separation may, in some cases, be accomplished by ordinary recrystallization. Separation can take place both at the stage of preparation of the final product and at the preparation of the intermediate, in which case the rest of the synthesis will be subject to the stereochemistry of the molecule of the intermediate.

Preferred derivatives of the invention are those of formula (I) above, in which:

rings A and B represent separately:

a phenyl, naphthyl, pyridyl, furyl, thienyl or cyclohexyl radical;

at least one of the substituents Χ _η X ₂ , Υι or Y ₂ means a group SCH ₃ , SO ₂ CH ₃ or SO ₂ NH ₂ .

and the other substituents denote separately: a hydrogen atom, a halogen atom, a lower alkyl radical of 1 to 6 carbon atoms, a trifluoromethyl radical or a lower O-alkyl radical of 1 to 6 carbon atoms;

RtRs are an oxygen atom; and

R ₃ , R ₄ each denote a hydrogen atom or a lower alkyl radical having from 1 to 6 carbon atoms.

Within the scope of the present invention, it is preferred to use a compound of general formula (I) for which at least one of the following conditions is fulfilled:

- ring B is a phenyl radical,

- Χ-ι is a group of 4-SO ₂ CH ₃ or 4-SO ₂ NH ₂ ,

- X ₂ is a hydrogen atom,

- ring A is a phenyl or pyridyl radical,

- Y ₁ is a fluorine or chlorine atom or a methyl radical

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

- R.R. are an oxygen atom,

- R ₃ is a hydrogen atom and

- R ₄ is a hydrogen atom.

Of particular interest are the compounds of the invention with the following formulas:

(E) -3- [1- (4-fluorophenyl) -1- (4-methanesulfonyl phenyl) methyl de n] -dihydrofuran-2-one

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

(Z) -3- [1- (3,4-dichlorophenyl) -1- (4-methanesulfonylphenyl) methyl indene] dihydrofuran-2-one

CI

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

(Z) -4 - [(4-chloro-phenyl) - (2-xodych and drofuran-3-yl-den) methyl] benzenesulfonamide

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

F

According to the invention, the compounds of formula (I) can be synthesized as follows:

The acid chloride of formula (II):

CO-CI

- 9 in which A, Υτ and Υ ₂ have the meanings given above is reacted by Friedel-Crafts reaction with thioanisole to give a ketone of formula (III):

formula (III) in which A, Y-ι and Y ₂ have the meanings given above.

This ketone can also be obtained by a Grignard reaction: reacting a bromo-aromatic magnesium derivative which can be substituted with p-methylthiobenzonitrile.

This benzophenone is treated with a measure of metachloroperbenzoic acid, an oxidizing agent such as sodium perborate or hydrogen peroxide in the presence of a catalytic amount of molybdenum salts to give the derivative of formula (IV):

SO ₂ CH ₃ formula (IV) in which A, Y, and Y ₂ have the meanings given above.

The derivative of formula (IV) is reacted by a modified Reformat reaction with bromobutyrolactone of formula (V):

- 10 Br

formula (V) wherein R ₃ and R ₄ have the meanings defined above in the presence of magnesium and a small amount of methyl iodide to initiate the reaction to give the derivatives of formula (VI):

CH ₃ SO ₂ formula (VI) in which A, Υ _η Y ₂ , R ₃ and R ₄ have the meanings given above.

Finally, the derivatives of formula (VI) are dehydrated by heating in toluene, for example in the presence of p-toluenesulfonic acid or by treatment with trifluoroacetic anhydride in trifluoroacetic acid to give the compounds of formula (I):

formula (I)

- 11 in which B is a phenyl ring, X-, is a group 4-SO ₂ CH ₃ , X 2 θ ^{is a} parent atom, are an oxygen atom and A, Y ₂ , R 3 and I ₄ have the meanings defined above.

One embodiment of the preparation method involves treating the product of formula (III) or a derivative of formula (V) by the same method, including a modified Reformat reaction in the presence of magnesium and methyl iodide to initiate the reaction, or with lactones of formula (V '):

about if about

formula (V) wherein R ₃ and R ₄ have the meanings defined above in the presence of Ν, Ν-diethylaminomagnesium bromide, obtained by reacting NN-diethylamine with ethylmagnesium bromide, according to K. Sisido, N. Nozaki, 0. Kurihara, J. Am. Chem. Soc.,

TA, 6254 (1952) to give either the already dehydrated compound of formula (I) or the compound of formula (VI '):

formula (VI ') in which A, Y _and Y ₂ , R ₃ and R ₄ have the meanings given above.

The compounds of formula (VI ') are then dehydrated by treatment with trifluoroacetic anhydride and trifluoroacetic acid 12 to give the compounds of formula (I) below:

o b ₂ formula (I) in which B is a phenyl ring, X-] is a group 4-SCH ₃ , X ₂ is a hydrogen atom, R-, R ₂ are an oxygen atom and A, Υ _Ί . Y ₂ , R ₃ and R ₄ have the meanings given above.

The compound obtained in this embodiment is reacted with metachloroperbenzoic acid or with another oxidant, such as NaBO ₃ .4 H ₂ O, to give, depending on the amount of oxidant used, the compounds of formula (I):

formula (I) in which B is a phenyl ring, Xm is a group 4-SOCH ₃ when using one equivalent oxidant or group 4-SO ₂ CH ₃ if two equivalents of an oxidant are used, X ₂ is a hydrogen atom, R 2 are oxygen atom and A, Υ _η Y ₂ , R ₃ and R ₄ have the meanings given above.

Another embodiment of the process for preparing some compounds of formula (I) involves reacting a ketone of formula (III) with ethyl succinate, by the reaction of Stob, in tert-butanol in the presence of sodium or potassium t-butylate, such as the compounds of formula (VII) are prepared:

COOEt Coon

CH ₃ S formula (VII) in which A, Ϊ! and Y ₂ have the meanings given above.

Selective reduction of the ester group, for example with calcium borohydride obtained in situ from potassium borohydride and calcium chloride in ethanol or with sodium diethyldihydroaluminate in diethyl ether, gives, after lactonization of the resulting oxyacids, the derivatives of formula (VIII):

formula (VIII) in which A, Υτ and Υ ₂ have the meanings given above.

The derivatives of formula (VIII) can be oxidized as described above, then the SCH ₃ group can be converted to SOCH ₃ or SO ₂ CH ₃ depending on the amount of oxidant used to give the compounds of formula (I)

formula (I) in which B is a phenyl ring, Xi is a group SOCH ₃ or SO ₂ CH ₃ , X ₂ . R-ι and R ₂ are a hydrogen atom, R ₃ R ₄ is an oxygen atom and A, Yf and Y ₂ have the meanings defined above.

The derivatives of formula (VII) are reduced, for example, with lithium aluminum hydride in tetrahydrofuran to give the diols of formula (IX):

formula (IX) in which A, Yf and Y ₂ have the meanings given above.

These diols are dehydrated with sulfuric acid or by treatment in boiling toluene in the presence of p-toluenesulfonic acid with a Dean-Stark apparatus to give the compounds of formula (I):

formula I

- 15 in which A, Υτ and Υ ₂ have the meanings given above, B is a phenyl ring, Χ-ι is a group 4-SCH ₃ and X ₂ , R-ι, R ₂ , R ₃ and R ₄ are hydrogen atom.

Oxidation of these derivatives with an oxidant as described above yields corresponding derivatives in which Xm is a group of 4-SOCH ₃ or 4-SO ₂ CH ₃ , depending on the amount of oxidant used.

Other embodiments may be used to prepare the compounds of formula (I).

By reacting ketones of formula (IV) with ethyl succinate, by the reaction of Stob, in tert-butanol in the presence of, for example, sodium or potassium tert-butylate, the compounds of formula (X) are obtained:

COOEt - Coon formula (X) in which A, Υτ and Υ ₂ have the meanings given above.

After this time selective reduction of the acid group, for example by reaction with borane or with borane / methylsulfide complex in tetrahydrofuran or diethyl ether, the alcoholic esters of formula (XI) are obtained:

CH ₃ SO ₂ formula (XI)

- 16 in which A, Y ·, and Y ₂ have the meanings given above.

These alcoholic esters of formula (XI) or even alcoholic acids, obtained by hydrolysis of the ester functional group with sodium hydroxide in boiling ethanol, are cyclized by heating in an aromatic solvent, such as toluene, in the presence of p-toluenesulfonic acid, to give the compounds of formula (I):

formula (I) in which A, Υ! and Υ ₂ have the meanings given above, B is a phenyl ring, Xm is a group 4-SO ₃ CH ₃ . X ₂ , R ₃ and R ₄ are a hydrogen atom and R- (R ₂ is an oxygen atom.

The compounds of formula (XII) in which A, Y ₁ and Υ ₂ have the meanings defined above can be obtained analogously to the following reaction scheme, in which Ph is a phenyl group and Z is the McBr radical when A is phenyl ring and Li when A is a pyridyl ring:

z - A

PhCH ₂ S - - CN + [A ||

Υ. Υ ₂

Υ.

PhCH ₂ S (B)

- 17 ^γ, χ ^Υζ 4ς ^Α 1

4-NHSO ₂ ethyl succinate

------------------- ►

COOEt

--COOH formula (XII)

An option involving the preparation of diarylketone (B) used in the above reaction scheme by reacting benzyl mercaptan PhCH ₂ SH with fluorodyrylketone in dimethylformamide in the presence of sodium hydride or sodium carbonate:

The compounds of formula (XII) are treated in the same manner as the compounds of formula (X) to give the compounds of formula (I):

formula (I)

- 18 in which B is a phenyl ring, X is a group 4-SO ₂ NHt-Bu, X ₂ , R 3 ^and

R ₄ is a hydrogen atom, θ ^{3 is an} oxygen atom and A, Υ, and Υ ₂ have the meanings given above.

By reacting these derivatives with a strong acid such as concentrated sulfuric acid, trifluoroacetic acid or by heating them in toluene in the presence of p-toluenesulfonic acid, the compounds of formula (I) are obtained in which B is a phenyl ring, Χ _Ί is the group 4SO ₂ NH ₂ , X ₂ , R ₃ and R ₄ are a hydrogen atom, R- | R ₂ are an oxygen atom and A, Υϊ and Υ ₂ have the meanings given above.

The compounds of formula (I) as defined above are inhibitors of cyclooxygenase-2 and have a very good anti-inflammatory and analgesic action, together with excellent tolerability, in particular of the stomach.

These actions allow them to be used for treatment and hence the invention also relates to medicaments containing the compounds of formula (I) above.

The invention also includes a pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of formula (I) as given above, optionally together with a pharmaceutically acceptable excipient, vehicle or carrier.

These compositions may be administered orally, rectally, parenterally, transdermally (through the skin), ophthalmic, nasal or ear.

The compositions may be solid or liquid and may be in the form of dosage forms commonly used in human medicine, such as ordinary or coated tablets, gelatin capsules, granules, suppositories, injectables, transdermal systems, eye drops,

- 19 aerosols and sprays and ear drops. They are prepared by conventional methods. The active ingredient, representing a pharmaceutically effective amount of at least one compound of formula (I) given above, can be mixed with excipients commonly used in pharmaceutical compositions such as talc, arabic gum, lactose, starch, magnesium stearate , polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, aqueous or non-aqueous vehicles, animal or vegetable fats, glycols, various wetting agents, dispersants or emulsifiers, silicone gels. certain polymers or copolymers, preservatives, flavorings and coloring agents.

The invention also relates to a pharmaceutical composition having an anti-inflammatory and analgesic action, which can be used in particular as a preferred treatment for inflammatory processes and pain, and which contains a pharmaceutically effective amount of at least one compound of formula (I), together with a pharmaceutically acceptable excipient , vehicle or carrier. According to one embodiment of the invention, a pharmaceutical composition is prepared with an anti-inflammatory and analgesic action, which is specifically intended for the preferred treatment of various inflammatory processes and pain.

In one embodiment, the composition is formulated as gelatin capsules or as tablets containing a dose of 1 mg to 1000 mg or as injectable preparations containing a dose of 0.1 mg to 500 mg. The compositions may be formulated as suppositories, ointments, creams, gels, aerosol preparations, transdermal preparations or patches.

The invention also relates to a method of treating mammals in which a therapeutically effective amount of at least

- 20 one compound of formula (I) given above is administered to a mammal. According to one embodiment of this method of treatment, the compound of formula (I), either alone or together with a pharmaceutically acceptable excipient, is formulated as gelatin capsules or as tablets containing a dose of 1 mg to 1000 mg for oral administration, as injectable preparations, containing a dose of 0.1 mg to 500 mg or as suppositories, ointments, creams, gels or aerosols.

This method provides, in particular, a preferred treatment for inflammatory processes and pain.

In the treatment of humans or animals, the compounds of formula (I) may be administered alone or together with a pharmaceutically acceptable excipient in any form, in particular orally, in the form of gelatin capsules or tablets, or parenterally as injectable solutions. Other forms of administration, such as suppositories, ointments, creams, gels or aerosol preparations, may also be considered.

As will be apparent from the pharmacological tests provided at the end of the description, the compounds of the invention may be administered to treat humans in the above-mentioned indications, orally, in the form of tablets or gelatin capsules containing a dose of 1 mg to 1000 mg or parenterally, as injectable preparations containing a dose of 0.1 mg to 500 mg, in one or more daily dosage units for adults of an average weight of 60-70 kg.

In the treatment of animals, the daily dose is between 0.1 mg and 100 mg / kg.

Further features and advantages of the invention will become apparent from the following examples, which in no way limit the invention, but are given by way of illustration only.

EXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

Example 1: 4-Fluoro-4'-methylthiobenzophenone

Formula (III): A = phenyl, Y ₁ = 4-F, Y ₂ = Η

86.4 g of aluminum trichloride are added in portions, at a temperature between 0 ° C and 5 ° C, to a solution of 70 g (0.564 mol) of thioanisole and 90.2 g (0.654 mol) of 4-fluorobenzoyl chloride in 500 ml of dichloromethane. When the addition is complete, bring the mixture to room temperature and reflux for 2 hours. After cooling, the reaction mixture was poured into an ice / dilute hydrochloric acid mixture and the organic phase was poured, then dried over magnesium sulfate and evaporated in vacuo to give a residue which crystallized from diisopropyl ether. 118 g of 4-fluoro-4'-methylthiobenzophenone are obtained, m.p. 88 ° C.

Example 2: 4-Fluoro-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Y ₁ = 4-F, Y ₂ = Η g 70% 3-chloroperbenzoic acid is added portionwise, at a temperature between 0 ° C and 5 ° C, to a solution of 25 g (0.1015 mol) of 4-fluoro-4'-methylthiobenzophenone obtained in Example 1 in 350 ml of dichloromethane. The mixture was stirred for 30 minutes at 0 ° C and then brought to room temperature and stirred for 2.5 hours. The resulting precipitate was filtered off, washed with dilute sodium hydroxide solution and dissolved in dichloromethane. The resulting organic phase was dried over magnesium sulfate and evaporated in vacuo to give an oil which crystallized from diisopropyl

- 22 ethers. 24.6 g of 4-fluoro-4'-methanesulfonylbenzophenone are obtained, m.p. 136 ° C.

Example 3: 3- [1- (4-Fluorophenyl) -1-hydroxy-1- (4-methanesulfonylphenyl) methyl] dihydrofuran-2-one

Formula (IV): A = phenyl, Y, = 4-F, Y ₂ = H, R ₃ = R ₄ = Η

Magnesium chips (3.5 g) were covered with anhydrous tetrahydrofuran and a few drops of iodomethane were added. As soon as the reaction begins, a mixture of 24.6 g of 4fluoro-4'-methanesulfonylbenzophenone and 8.1 ml of α-bromo-y-butyrolactone in 250 ml of anhydrous tetrahydrofuran is added dropwise to maintain the boiling point slowly. When the addition is complete, the reaction mixture is cooled and poured into a mixture of ice and 10% dilute sulfuric acid. The organic phase was extracted with tetrahydrofuran, washed with saturated sodium bicarbonate solution and then dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was chromatographed on silica gel with a mixture of 9/1 dichloromethane / acetone to give 7 g of 3- [1- (4-fluorophenyl) -1-hydroxy-1- (4-methanesulfonylphenyl) methyl] dihydrofuran -2-one in the form of amorphous beige powder, which is used as such in the next step.

Example 4: (E) -3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) ethyl ethyl] dihydrofuran-2-one (E) isomer: formula (I): A = B = phenyl, Y-, = 4-F, X ₂ = Y ₂ = H, Xm = 4-SO ₂ CH ₃ , RtR ₂ = 0, R ₃ = R ₄ = Η

A few mg of toluene-4-sulfonic acid were added to a solution of 7 g of 3- [1- (4-fluorophenyl) -1-hydroxy-1- (4-methanesulfonylphenyl) methyl] dihydrofuran-2-one prepared in Example

- 23 3, in 100 ml of toluene and the mixture is refluxed for 10 hours on a Dean-Stark attachment. The solvent was then evaporated to dryness in vacuo and the residue chromatographed using a mixture of 9/1 dichloromethane / acetone as eluent to give an oil which was chromatographed with tert-butyl methyl ether as eluant to give 2.9 g of (E ) -3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (second eluting product) as crystals which melt at 187-9 ° C. 1.5 g of (7) -3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (first eluted product) are separated as crystals which melt at 157- 158 ° C.

Example 5: 4-Chloro-4'-methylthiobenzophenone

Formula (111): A = phenyl, Y, = 4-Cl, Y ₂ = H

It was obtained by the method described in Example 1. The crystals were melted at 134 ° C.

Example 6: 3- [1- (4-Chlorophenyl) -1-hydroxy-1- (4-methylthiophenyl) methyl] dihydrofuran-2-one

Formula (IV '): A = phenyl, Υ- = 4-CI, Y ₂ = H, R ₃ = R ₄ = Η

A few drops of iodomethane were added to 5.9 g of magnesium chips coated with anhydrous tetrahydrofuran. As soon as the reaction begins, a mixture of 17 g of 4-chloro-4'-methylthiobenzophenone and 12.6 ml of α-bromo-y-butyrolactone in 300 ml of anhydrous tetrahydrofuran is added dropwise to maintain the boiling point slowly. When the addition is complete, the mixture is stirred at room temperature for 1.5 hours and cooled with an ice bath. Saturated ammonium chloride solution was added and the mixture was stirred and decanted. The organic phase was dried over magnesium sulfate and evaporated in vacuo to afford an oily residue which, after chromatography on silica gel in dichloromethane, gave 8.5 g of 3- [1- (4-chlorophenyl) -1hydroxy-1- (4- methylthio phenyl) methyl] breathing and drofuran-2-one as an oil, which is used crude in the next step.

Example 7: 3- [1- (4-Chlorophenyl) -1- (4-methylthiophenyl) methylidene] dihydrofuran-2-one

Formula (I): A = B = phenyl, X! = 4-CI, X ₂ = Υ-ι = H,

Y ₂ = 4-SCH ₃ , R- | R ₂ = O, R ₃ = R ₄ = Η

5.2 g of trifluoroacetic anhydride and 3.8 ml of trifluoroacetic acid are added to a solution of 8.6 g of 3- [1- (4-chlorophenyl) -

1-hydroxyl-1- (4-methyl thiophenyl) methyl] dihydrofuran-2-one obtained in Example 6 in 100 ml of dichloromethane. The mixture was stirred at room temperature for 4 hours, then diluted with water and decanted. The organic phase was dried over magnesium sulfate and evaporated in vacuo to give 7.5 g of 3- [1- (4-chlorophenyl) -1- (4-methylthiophenyl) methylidene] dihydrofuran-2one as an oil, which is used as such in the next stage.

Example 8: (Z) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonylphenyl) methyl and lene] dihydrofuran -2-one (Z) isomer: formula (I): A = B = phenyl, Υτ = 4-0, Xm = Υ ₂ = H, X ₂ = 4-SO ₂ CH ₃ , = 0, R ₃ = R ₄ = Η g sodium perborate trihydrate are added to a solution of 9.5 g 3- [1- (4-Chlorophenyl) -1- (4-methylthiophenyl) methylidene] dihydrofuran-2-one obtained in Example 7 in 120 ml of acetic acid. The mixture was heated at 40-50 ° C for 5 hours, then cooled. The resulting crystals were filtered off, washed with water and chromatographed on silica gel in dichloro-25 methane / acetone (99/1) to give 4.1 g (Z) -3- [1- (4-chlorophenyl) -1- ( 4-Methanesulfonylphenyl) methylidene] dihydrofuran-2-one (first eluted product) as crystals of m.p. 197199 ° C.

Isolation of the second eluting product gave 2.5 g (E) -3 [1- (4-chlorophenyl) -1- (4-methanesulphonylphenyl) methyl ethyl] n] dihydrofuran-2-one, as crystals m.p. t. 211-212 ° C.

Example 9: 3-Fluoro-4'-methylthiobenzophenone

Formula (III): A = phenyl, Yt = 3-F, Υ ₂ = Η

Obtained according to the method described in Example 1. of crystals 76 ° C.

Example 10: 3-Fluoro-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Υτ = 3-F, Υ ₂ = Η

Obtained by the method described in Example 2. of crystals 106 ° C.

Example 11: 3-Ethoxycarbonyl-4- (3-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Y, = 3-F, Y ₂ = H

35.5 g (0.1275 mol) of 3-fluoro-4'-methanesulfonylbenzophenone prepared in Example 10 were added portionwise to a solution of 15.7 g (0.140 mol) of potassium tert-butylate in 100 ml of tert-butanol. The mixture was stirred and 32 ml (0.191 mol) of ethyl succinate were added dropwise rapidly. The mixture was heated to reflux for 30 minutes and cooled, 1 N hydrochloric acid was added to obtain pH 1 and the mixture was extracted with tert-butyl methyl ether. The organic phase was treated with 2% sodium hydroxide solution and the mixture was decanted. The aqueous phase was acidified with 1 N hydrochloric acid and extracted with tert-butyl methyl ether. The organic phase was dried over magnesium sulfate and evaporated in vacuo to give 39.2 g of 3-ethoxycarbonyl-4- (3-fluoro-phenyl) -4- (4-ethane sulfonyl-phenyl) -3-butenoic acid. as a thick oil which is used as such in the next step.

Example 12: Ethyl 3- (3-fluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Yt = 3-F, Υ ₂ = Η

15.5 ml (0.155 mol) of the borane / methylsulfide complex were added dropwise to a solution of 31.5 g (0.0775 mol) of 3ethoxycarbonyl-4- (3-fluorophenyl) -4- (4-methanesulfonylphenyl) -

3-butenoic acid obtained in Example 11 in 90 ml of anhydrous tetrahydrofuran. The mixture was stirred at room temperature for 8 hours and 23.5 ml of methanol were added dropwise. The mixture was evaporated to dryness in vacuo and the residue was dissolved in ethyl acetate and then treated with an aqueous solution of 7.6 g of potassium carbonate. The organic phase was decanted and then dried over magnesium sulfate, evaporated to dryness in vacuo to give 29.3 g of ethyl 3- (3-fluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) - 2-propenoate as a viscous oil, which is used as such in the next step.

Example 13: (Z) -3- [1- (3-fluorophenyl) -1- (4-methanesulfonylphenyl) methyl day] dihydrofuran-2-one (Z) isomer: formula (I): A = B = phenyl, Yt = 3-F, X ₂ = Υ ₂ = Η, X! = 4-SO ₂ CH ₃ , F ^ Rg = 0, R ₃ = R ₄ = Η

3.3 g of sodium hydroxide dissolved in 10 ml of water were added to a solution of 29.3 g of ethyl 3- (3-fluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate prepared in Example 12, in 50 ml ethanol and the mixture was refluxed for 2 hours. After evaporation to dryness, the residue was dissolved in water, acidified with 1 N hydrochloric acid and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and evaporated in vacuo to give an oily residue. The oil was solubilized in 150 ml of toluene and 10 mg of p-toluenesulfonic acid was added. The mixture was refluxed and the separated water was removed with a Dean-Stark apparatus. After cooling, the mixture was washed with water, the organic phase was dried over magnesium sulfate and evaporated in vacuo and the residue was chromatographed on silica in tert-butyl methyl ether to give 4 g (Z) -3- [1- ( 3fluorophenyl) -1- (4-methanesulfonylphenyl) methyl iden] dihydrofuran-2-one (second elution product) as crystals which melt at 153-154 ° C.

Example 14: 3,4-Dichloro-4'-methylthiobenzophenone

Formula (III): A is phenyl, = 3-Cl, Y ₂ = 4-Cl

Obtained according to the method described in Example 1. of crystals 100 ° C.

Example 15: 3,4-Dichloro-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Y, = 3-Cl, Y ₂ = 4-Cl

Obtained by the method described in Example 2. of crystals 158 ° C.

Example 16: 3-Ethoxycarbonyl-4- (3,4-dichlorophenyl) -4- (4methylsulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Y, = 3-Cl, Y ₂ = 4-Cl

- 28 Obtained by the method described in Example 11. The oil was used as obtained in the next step.

Example 17: Ethyl 3- (3,4-Dichlorophenyl) -3- (4-methylsulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Y ₇ = 3-CI, Y ₂ = 4-CI

It was obtained by the method described in Example 12. The oil was used as obtained in the next step.

Example 18: (d) -3- [1- (3,4-Dichlorophenyl) -1- (4-methanesulfonyl and phenyl) methyl] dihydrofuran-2-one (Z) isomer: Formula (I): A = B = phenyl, Y ₇ = 3-CI, Y ₂ = 4-CI, X ₂ = H, X, = 4-SO ₂ CH ₃ , = O, R ₃ = R ₄ = Η

Obtained by the method described in Example 13. Chromatograph in dichloromethane / acetone (99/1). The first eluted product. M.P. of crystals 195-197 ° C.

After isolation of the second eluting product by chromatography, the (E) -3- [1- (3,4-dichlorophenyl) -1 (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one isomer is obtained as crystals of mp. t. Mp 163-164 ° C.

Example 19: 3-Chloro-4'-methylthiobenzophenone

Formula (III): A = phenyl, Y ₇ = 3-CI, Y ₂ = Η

Obtained according to the method described in Example 1. of crystals at 70 ° C.

Example 20: 3-Chloro-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Yi = 3-CI, Y ₂ = Η

Obtained by the method described in Example 2. of crystals 140 ° C.

-29 Example 21: 3-Ethoxycarbonyl-4- (3-chlorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Y, = 3-Cl, Y ₂ = H Prepared according to the method described in Example 11. The oil was used as obtained in the next step.

Example 22: Ethyl 3- (3-chlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Υτ = 3-CI, Υ ₂ = Η Obtained by the method described in Example 12. The oil is used as obtained in the next step.

Example 23: (Ζ) -3- [1- (3-chlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (Ζ) isomer: formula (I): A = B = phenyl, Υτ = 3-CI, X ₂ = Υ ₂ = Η,

Xm = 4-SO ₂ CH ₃ = 0, R ₃ = r ₄ = h

Obtained by the method described in Example 13. Chromatograph in dichloromethane / acetone (99/1). The first eluted product. M.P. of crystals 147-149 ° C.

After isolation of the second eluting product by chromatography, the (E) -3- [1- (3-chlorophenyl) -1- (4methanesulfonylphenyl) methylidene] dihydrofuran-2-one isomer is obtained. in the form of crystals of m.p. 170-172 ° C.

Example 24: 4-methylthiobenzophenone

Formula (III): A = phenyl, Y ₁ = Y ₂ = H

Obtained according to the method described in Example 1. of crystals 84 ° C.

- 30 Example 25: 4-Methanesulfonylbenzophenone

Formula (IV): A = phenyl, Y ₁ = Y ₂ = H

Obtained by the method described in Example 2. of crystals 150 ° C.

Example 26: 3-Ethoxycarbonyl-4-phenyl-4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Y ₁ = Y ₂ = Η Obtained by the method described in Example 11. The oil was used as obtained in the next step.

Example 27: Ethyl 3-phenyl-3- (4-methanesulfonylphenyl) -2- (2hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Y, = Y ₂ = H Prepared according to the method described in Example 12. The oil was used as obtained in the next step.

Example 28: (E) -3- [1-Phenyl-1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (E) isomer: Formula (I): A = B = phenyl, Υ _Ί = Υ ₂ = Η, X ₂ = H,

X, = 4-SO ₂ CH ₃ , = 0, R ₃ = R ₄ = H

Obtained by the method described in Example 13. Chromatograph on silica gel in dichloromethane / acetone (99/1). The first eluted product. M.P. of crystals 135-137 ° C.

After isolation of the second eluting product by chromatography, the (2) -3- [1-phenyl-1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one isomer is obtained as crystals of m.p. 206-208 ° C.

- 31 Example 29: 5,5-dimethyl-3- [1- (4-fluorophenyl) -1-hydroxy-1- (4-methyl and lthiophenyl) methyl] dihydrofuran-2-one

Formula (VI '): A = phenyl, Y-] = 4-F, Y ₂ = H, R ₃ = R ₄ = CH ₃

7.5 ml of bromoethane are added dropwise to a suspension of

2.4 g of magnesium chips in anhydrous diethyl ether. When the addition is complete, the mixture is cooled to 0 ° C and 10.5 m dropwise added. Ν, Ν-diethylamine. The reaction mixture was stirred for 1 hour at room temperature, then heated to reflux for 15 minutes and cooled with an ice / sodium chloride bath. A solution of 12.3 g of 4fluoro-4'-methylthiobenzophenone was added dropwise. obtained in Example 1 and 5.7 g of 4,4 dimethylbutyrolactone in 50 ml of anhydrous tetrahydrofuran and the temperature was maintained between 0 ° C and 5 ° C. The mixture was heated at reflux for 2 hours, cooled and treated with 100 ml of 10% sulfuric acid solution. After extraction with diethyl ether, the organic phase was dried over magnesium sulfate and evaporated in vacuo to give 4.8 g of 5.5 dimethyl-3- [1- (4-fluorophenyl) -1-hydroxy-1- (4-methylthiophenyl) methyl] dihydrofuran-2-one as crystals of m.p. 185 ° C.

Example 30: 5,5-Dimethyl-3- [1- (4-fluorophenyl) -1- (4-methylthiophenyl) methyl day] dihydrofuran-2-one (E) isomer: formula (I): A = B = phenyl , Yt = 4-F, Υ ₂ = X ₂ = H, X ₁ = 4-SCH ₃ , RiR, = O, R ₃ = R ₄ = CH ₃ (Z) isomer: formula (I): A = B = phenyl, Υ-, = 4-F, Y ₂ = X ₂ = H,

Y, = 4-SCH ₃ , R t R ₂ = O, R ₃ = R ₄ = CH ₃

Obtained by the method described in Example 4 from the derivative of Example 29.

The two isomers were separated by fractional crystallization into a diisopropyl ether / pentane mixture:

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

(2) -5,5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-methylthio phenyl) methylidene] dihydrofuran-2-one, m.p. 160 ° C.

Example 31: (E) -5,5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methyl] dihydrofluoro-2-one (E) isomer: formula (I): A = B = phenyl, Y-ι = 4-F, Y ₂ = X ₂ = H, χ ₁ = 4-SO ₂ CH ₃ , R- | R ₂ = O, R ₃ = R ₄ = CH ₃

1.9 g of sodium perborate trihydrate were added to a solution of 2 g (E) -5,5-dimethyl-3- [1- (4-fluorophenyl) -1- (4-methylthiophenyl) methylidene] dihydrofuran-2-one obtained in Example 30, in 15 ml of acetic acid. The mixture was heated at 45 ° C for 3 hours and the resulting crystals filtered hot, chromatographed on silica gel using the dichloromethane / acetone mixture (9/1) as the eluent to give 1.2 g (E) -5.5- dimethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one as crystals of m.p. 175 °.

Example 32: 5-Ethyl-3- [1- (4-fluorophenyl) -1-hydroxy-1- (4methylthiophenyl) methyl] dihydrofuran-2-one

Formula (IV '): A = phenyl, Yt = 4-F. Y ₂ = H, R ₃ = C ₂ H ₅ , R ₄ = H

It was prepared by the method described in Example 29 of γ-caprolactone. M.P. of crystals 150 ° C.

Example 33: 5-Ethyl-3- [1- (4-fluorophenyl) -1- (4-methylthiophenyl) ethyl day] dihydrofuran-2-one (E) isomer: formula (I): A = B = phenyl, Y, = 4-F, Y ₂ = X ₂ = H,

X, = 4-SCH ₃ , R ^ = 0, R ₃ = C ₂ H ₅ , R ₄ = Η

- 33 (Z) isomer: formula (I): A = B = phenyl, Χ-ι = 4-F, Y ₂ = X ₂ = H, Υι = 4-SCH ₃ , R ^, = 0, R ₃ = C ₂ H ₅ , R ₄ = Η

It was prepared by the method described in Example 4 from the derivative of Example 29. The mixture of the two isomers, (E) and (Ζ), was used as obtained in the next step.

Example 34: (E) -5-ethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) ethyl day] dihydrofuran-2-one (E) isomer: Formula (I): A = B = phenyl, Υτ = 4-F, X ₂ = Υ ₂ = H,

X ₁ = 4-SO ₂ CH ₃ = 0, R ₃ = C ₂ H ₅ , R ₄ = H

Obtained by the method described in Example 31. The isomer (E) -

5-ethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonyl phenyl) methyl indene] dihydrofuran-2-one was purified by chromatography on silica gel in dichloromethane / acetone (99/1), at which produces crystals of m.p. 134-136 ° C. (first eluted product).

After isolation of the second eluting product by chromatography, the (2) -5-ethyl-3- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one isomer is obtained as crystals with so. 176-177 ° C.

Example 35: 5-Methyl-3- [1- (3-chlorophenyl) -1-hydroxy-1- (4methylthiophenyl) methyl] dihydrofuran-2-one

Formula (IV '): A = phenyl, Yt = 3-Cl, Y ₂ = H, R ₃ = CH ₃ , R ₄ = H Prepared by the method described in Example 6 of 3-chloro-4'-methylthiobenzophenone and a -bromo-y-valerolactone. The amorphous powder is used as obtained in the next step.

34 Example 36: 5-Methyl-3- [1- (3-chlorophenyl) -1- (4-methylthiophenyl) methylidene] dihydrofuran-2-one (Z) isomer: formula (I): A = B = phenyl, Ut = 3-CI, X ₂ = B ₂ ⁼ H,

X ₁ = 4-SCH3. = O, R ₃ = CH ₃ , R ₄ = H (E) isomer: formula (I): A = B = phenyl, Υί = C-Cl, X ₂ = B ₂ = H.

Xm = 4-SCH3 = 0, R ₃ = CH ₃ , R ₄ = H

It was prepared by the method described in Example 4 from the derivative of Example 35. The mixture of the two isomers was used, as obtained, as an oil, in the next step.

Example 37: (2) -5-methyl-3- [1- (3-chlorophenyl) -1- (4-methanesulfonylphenyl) methyl] dihydrofuran-2-one (Z) isomer: formula (I): A = B = phenyl, Ut = C-Cl, X ₂ = B ₂ = H,

X, = 4-SO _£ CH ₃ , R ₄ R ₂ = 0, R ₃ = CH ₃ R ₄ = H Obtained by the method described in Example 31. The isomer (Z) -

5-Methyl-3- [1- (3-chlorophenyl) -1- (4-methanesulfonyl phenyl) methyl] dihydrofuran-2-one was purified by chromatography on silica gel using a dichloromethane / acetone mixture (99 / 1) as eluent to give amorphous powder (first eluted product).

Isolation of the second eluting product by chromatography afforded the (E) -5-methyl-3- [1- (3-chlorophenyl) -1- (4-methanesulfonyl phenyl) methyl] dihydrofuran ran-2-one isomer , in the form of crystals of m.p. Mp 164-165 ° C.

Example 38: 2-Chloro-5- (4-methylthiobenzoyl) pyridine

Formula (III): A = 3-pyridyl. B-, = 6-CI, Y ₂ = H

Obtained according to the method described in Example 1. of crystals 145 ° C.

- 35 Example 39: 2-Chloro-5- (4-methanesulfonylbenzoyl) pyridine

Formula (IV): A = 3-pyridyl, Yt = 6-CI, Υ ₂ = Η

A solution of 34.6 g of 2-chloro-5- (4-methylthiobenzoyl) pyridine obtained in Example 38 and 42 g of sodium perborate trihydrate in 250 ml of acetic acid was heated at 45 ° C for 4 hours. The resulting crystals were filtered hot, washed with water and dried to give 32.6 g of 2-chloro-5- (4-methanesulfonylbenzoyl) pyridine as crystals of m.p. 170 ° C.

Example 40: 4- (6-Chloropyridin-3-yl) -3-ethoxycarbonyl-4 (4-methylsulfonylphenyl) -3-butenoic acid

Formula (X): A = 3-pyridyl, Yt = 6-Cl, Υ ₂ = Η

Obtained according to the method described in Example 11 from the derivative of Example 39. The amorphous solid was used as obtained in the next step.

Example 41: Ethyl 3- (6-chloropyridin-3-yl) -2- (2-hydroxyethyl) -3- (4-methylsulfonylphenyl) -2-propenoate

Formula (XI): A = 3-pyridyl. Y ₁ = 6-CI, Y ₂ = Η

Obtained by the method described in Example 12 from the derivative of Example 40. The amorphous solid is used as obtained in the next step.

Example 42: (N) -3- [1- (6-chloropyridin-3-yl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (N) isomer: Formula (I): A = 3- pyridyl, B = phenyl, Υτ = 6-CI, Χ ₂ = Υ ₂ = H, X _{1 =} 4-SO ₂ CH ₃ , R ₁ R ₂ = O, R ₃ = R ₄ = Η

It is obtained by the method described in Example 13 from the derivative of Example 41.

The 36 (Z) isomer is obtained in the form of crystals of m.p.

172-174 ° C by chromatography on a dichloromethane / acetone mixture (5/1) and subsequent crystallization from an acetone / ethyl ether mixture.

The (E) -3- [1- (6-chloro-pyridin-3-yl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one isomer is obtained pure as crystals, m.p. 198-199 ° C by crystallization from acetone and subsequent chromatography of the crude mixture of the two isomers.

Example 43: 3-Ethoxycarbonyl-4- (4-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Y, = 4-F, Y ₂ = H

This was obtained by the method described in Example 11 of 4-fluoro-4'-methanesulfonylbenzophenone obtained in Example 2. The oil was used as obtained in the next step.

Example 44: 4- [1- (4-Fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one

Formula (I): A = B = phenyl, Xf = 4-SO ₂ CH ₃ , X ₂ = Y ₂ = Η,

Υι = 4-F, R.R2 = H, R ₃ R ₄ = O

13.6 g of powdered anhydrous calcium chloride were added to a solution of 3-ethoxycarbonyl-4- (4-fluorophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid obtained in Example 43 in 500 ml of ethanol. The mixture was stirred at room temperature and a solution of 7.5 g of sodium borohydride in a mixture of 1.5 g of potassium hydroxide, 10 ml of water and 10 ml of ethanol was added dropwise under ice bath cooling. After standing at room temperature for 4 hours, the reaction mixture was cooled to 0 ° C and a 6 N hydrochloric acid solution was added dropwise thereto. After extraction with dichloromethane, organ

The 37th phase was dried over magnesium sulfate and evaporated in vacuo and the residue was crystallized from isopropyl ether. The crystals obtained were recrystallized from methanol to give 5 g of 4- [1- (4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one as a mixture (50/50) of the two isomers, (E) and (Z), in the form of crystals of m.p. 160-164 ° C.

Example 45: 3-methyl-4'-methylthiobenzophenone

Formula (III): A = phenyl, Yt = 3-CH ₃ , Y ₂ = H

Obtained according to the method described in Example 1. of crystals 46-47 ° C.

Example 46: 3-methyl-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, B ₁ = 3-CH ₃ , B ₂ = H

Obtained by the method described in Example 2. of crystals 150 ° C.

Example 47: 3-Ethoxycarbonyl-4- (3-methylphenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Ut = 3-CH ₃ , Y ₂ = H

Obtained by the method described in Example 11 from the derivative of Example 46. The oil was used as obtained in the next step.

Example 48: Ethyl 3- (3-methylphenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, B! = 3-CH ₃ , B ₂ = H

Obtained according to the method described in Example 12 from the derivative of Example 47. The oil was used as obtained in the next step.

38 Example 49: (Z) -3- [1- (3-methylphenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (Z) isomer: Formula (I): A = B = phenyl, Y ₁ = 3-CH ₃ , X ₂ =

Υ ₂ = n, X ₁ = 4-SO ₂ CH ₃ , RR, = O, R ₃ = R ₄ = Η

Obtained by the method described in Example 13 from the derivative of Example 48.

Purify by chromatography on silica gel in a mixture of dichloromethane / acetone (99/1). The first eluted product in the form of crystals, m.p. 166 ° C.

Example 50: 3,4-Difluoro-4'-methylthiobenzophenone

Formula (III): A = phenyl, Yt = 3-F. Y ₂ = 4-F

Obtained according to the method described in Example 1. of the crystals 96 ° C.

Example 51: 3,4-Difluoro-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Yt = 3-F. Y ₂ = 4-F

Obtained by the method described in Example 2 from the derivative of Example 50. of crystals 120 ° C.

Example 52: 3-Ethoxycarbonyl-4- (3,4-Difluorophenyl) -4 (4-methanesulfonylphenyl) -3-butenoic acid of formula (X): A = phenyl, Y ₁ = 3-F, Y ₂ = 4-F

Obtained according to the method described in Example 11 from the derivative of Example 51. The oil was used in the next step as obtained.

Example 53: Ethyl 3- (3,4-difluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Yt = 3-F, Y ₂ = 4-F

- 39 Obtained by the method described in Example 12 from the derivative of Example 52. The oil was used in the next step as obtained.

Example 54: (d) -3- [1- (3,4-Difluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (Z) isomer: formula (I): A = B = phenyl, Yt = 3-F, Y ₂ = 4-F, X, = 4-SO ₂ CH ₃ , X ₂ = H, RtRs = 0, R ₃ = R ₄ = H

Obtained by the method described in Example 13 from the derivative of Example 53.

Purify by chromatography on silica gel in a mixture of dichloromethane / acetone (99/1). The first eluted product in the form of crystals, m.p. 148 ° C.

Example 55: 4-Benzylthiobenzonitrile

A mixture of 37.2 g of benzyl mercaptan, 36.3 g of 4-fluorobenzonitrile and 42 g 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 dissolved in water and petroleum ether. The resulting crystals were filtered and washed with water and petroleum ether to give 46 g of 4-benzylthiobenzonitrile as crystals of m.p. 85 ° C.

Example 56: 4-Benzylthio-4'-fluorobenzophenone

A solution of 44 ml of 4-bromo-1-fluorobenzene in 300 ml of anhydrous diethyl ether was added dropwise to a suspension of 9.6 g of magnesium chips in 20 ml of anhydrous diethyl ether. When the addition is complete, the mixture is stirred for several minutes at room temperature and a solution of 46 g of 4-benzylthiobenzonitrile is added dropwise. obtained in Example 55, in 400 ml anhydrous

- 40 tetrahydrofuran. The diethyl ether was distilled off and the mixture was refluxed for 3 hours, then cooled with ice. A solution of 6 N hydrochloric acid (400 ml) was added dropwise and the mixture was refluxed for 6 hours. Water and dichloromethane were added, the organic phase was decanted, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diisopropylether to give 48 g of 4-benzylthio-4'-fluorobenzophenone as crystals of m.p. 96 ° C.

Example 57: 4-tert-Butylaminosulfonyl-4'-fluorobenzophenone

Chlorine was bubbled to saturation (36 g) in a solution of 43 g of 4-benzylthio-4'-fluorobenzophenone obtained in Example 56 in 300 ml of acetic acid cooled to 0 ° C. The mixture was stirred for 2 hours at room temperature, then poured into ice-cold water and extracted with dichloromethane. The organic phase was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 47 g of an oil which was dissolved in 100 ml of 1,2-dichloroethane. This solution was added dropwise to a solution of 50 ml of tert-butylamine in 300 ml of 1,2-dichloroethane. The mixture was heated at 80 ° C for one hour, cooled and washed with water and then with dilute hydrochloric acid. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 25 g of 4-tert-butylaminosulfonyl-4'fluorobenzophenone as crystals of m.p. 160 ° C.

Example 58: 3-Ethoxycarbonyl-4- (4-tert-butylaminosulfonylphenyl) -4- (4-fluorophenyl) -3-butenoic acid

- 41 Formula (XII): A = phenyl, Υ, = 4-F, Y ₂ = Η

It is obtained by the method described in Example 11 of the derivative of Example 57 using 2 equivalents of potassium tert-butylate. The amorphous powder is used in the next step as obtained.

Example 59: Ethyl 3- (4-tert-butylaminosulfonylphenyl) -3 (4-fluorophenyl) -2- (2-hydroxyethyl) -2-propenoate

Obtained by the method described in Example 12 from the derivative of Example 58.

The resulting oil was dissolved in diethyl ether and the crystals formed were dried to give the pure isomer (Ζ) -βτπΛ 3- (4-tert-butylaminosulfonylphenyl) -3- (4-fluorophenyl) -2- (2-hydroxyethyl) - 2-propenoate in the form of crystals of m.p. 152 ° C. The filtrate was evaporated in vacuo to give an oily residue corresponding to the isomer ethyl (E) -3- (4-tert-butylaminosulfonylphenyl) -3- (4-fluorophenyl) -2- (2-hydroxyethyl) -2-propenoate, which is used as obtained in the next step.

Example 60: (E) -4 - [(4-fluorophenyl) - (2-oxodihydrofuran3-ylidene) methyl] benzenesulfonamide (E) isomer: formula (I): A = B = phenyl, Υ ·, = 4-F. Υ ₂ = X ₂ = H, X ₁ = 4-SO ₂ NH ₂ , R ₇ R ₂ = 0, R ₃ = R ₄ = H

Ethyl (E) -3- (4-tert-butyl aminosulfonyl phenyl) -3- (4-fluorophenyl) -2- (2-hydroxyethyl) -2-propenoate (10 g) obtained in Example 59 , was dissolved in 20 ml of ethanol and a solution of 2 g of sodium hydroxide in 10 ml of water was added. The mixture was refluxed for two hours. After evaporation to

- 42 dry, the residue is dissolved in water, acidified with 1 N hydrochloric acid and then extracted with dichloromethane. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was added portionwise to 500 ml of concentrated sulfuric acid. The mixture was stirred at room temperature for 15 minutes and poured into ice-cold water, the resulting crystals filtered with diethyl ether and then dissolved in 100 ml of warm acetone. To the resulting solution was added 50 ml of diethyl ether and the crystals formed were filtered, dried and 6 g of (E) -3- [1- (4-aminosulfonylphenyl) -1- (4-fluorophenyl) methylidene] dihydrofuran-2- were obtained it in the form of crystals of m.p. 202 ° C.

Example 61: (d) -4 - [(4-fluorophenyl) - (2-oxodihydrofuran-3-yl) methyl] benzenesulfonamide (Z) isomer: formula (I): A = B = phenyl, Y ₁ = 4-F, X ₂ = Y ₂ = H, Y ₁ = 4-SO ₂ NH _2j RiR ₂ = O, R ₃ = R ₄ = Η

It is obtained by the method described in Example 60 of the (Ζ) isomer obtained in Example 59. The crystals obtained have a m.p. 222 ° C.

Example 52: 4-Chloro-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Υ-, = 4-Cl, Y ₂ = H Prepared according to the method described in Example 39 of the derivative of Example 5. M.p. of the crystals obtained 176 ° C.

Example 63: (2) -3-Ethoxycarbonyl-4- (4-chlorophenyl) -4- (4methanesulfonyl) -3-butenoic acid

Formula (X): A = phenyl, Y ₁ = 4-CI, Y ₂ = Η

To a suspension of 20 g of 4-chloro-4'-methanesulfonylbenzophenone prepared in Example 62, in 100 ml of tert-butanol were added immediately 7.2 g of sodium t-butylate at room temperature. The suspension was heated at 40 ° C and a solution of 16.9 ml of ethyl succinate in 20 ml of tert-butanol was added over 10 minutes. The temperature was maintained at 55 ° C for 30 minutes, then decreased to 35-40 ° C; 140 ml of cold water are added and the mixture is 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 filtered, washed with water and dried in vacuo to give 20.2 g (2) -3-ethoxycarbonyl-4 (4-chlorophenyl) -4- (4-methanesulfonyl) -3-butenoic acid,

HPLC showed a purity of 81.6%, 12.1% (E) isomer. Recrystallization from propan-2-ol gave 14 g (7) -3-ethoxycarbonyl-4- (4-chlorophenyl) -4- (4-methanesulfonyl) -3-butenoic acid, with HPLC showing a purity of 96.1% and a content of 0.7% (E ) isomer, in the form of crystals of m.p. 183 ° C.

Example 64: Ethyl (d) -3- (4-chlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Y ·, = 4-Cl, Y ₂ = H

To a solution of 350 g of (7) -3-ethoxycarbonyl-4- (4-chlorophenyl) -4- (4-methanesulfonyl) -3-butenoic acid obtained in Example 63, 1.5 L of THF was added dropwise at good stirring, 120 ml borane / dimethyl sulfide complex. At the end of the addition, the solution was stirred at room temperature for 2.5 hours. The excess borane is hydrolyzed with 100 ml of methanol and 100 ml of water. After evaporation of the solvent in vacuo, the residue was crystallized in water, filtered and washed with water to give ethyl (2) -3- (4-chlorophenyl) -3- 44 (4-methanesulfonyl-phenyl) -2- (2 -hydroxyethyl) -2-propenoate as wet crystals, which are used as such in the next step. Drying these crystals and recrystallizing them from propan-2-ol gave ethyl (S) -3- (4-chlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate in type of crystals with HPLC purity 98.3% and m.p. 128 ° C.

Example 65: (R) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one

Formula (I): A = B = phenyl, Y, = 4-Cl, X ₂ = Y ₂ = H,

X ₁ = 4-SO ₂ CH ₃ , R- | R ₂ = 0, R ₃ = R ₄ = H

The wet product of Example 64 was refluxed in 1.5 L of toluene in the presence of 1 g of p-toluenesulfonic acid. Water and ethanol were removed using a Dean-Stark apparatus and then about 1 L of toluene was evaporated. The temperature was lowered to room temperature, the crystals obtained were filtered off and washed with insignificant amount of butan-2-one, dried to give 261.5 g (Z) -3- [1- (4-chlorophenyl) -1- (4-methanesul background yl phenyl) methyl iden] dihydrofuran-2one in the form of crystals of m.p. 188-190 ° C.

Example 56: 3,5-Dichloro-4'-methylthiobenzophenone

Formula (III): A = phenyl, Y, = 3-Cl, Y ₂ = 5-Cl

Obtained according to the method described in Example 1. of the resulting crystals 108 ° C.

Example 57: 3,5-Dichloro-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Υ-, = 3-Cl, Y ₂ = 5-Cl

- 45 Obtained according to the method described in Example 39. 200 ° C crystals obtained.

Example 68: (2) -3-Ethoxycarbonyl-4- (3,5-dichlorophenyl) -4 (4-methanesulfonylphenyl) -3-butenoic acid (Z) isomer: Formula (X): A = phenyl, Yt = 3- CI, Y ₂ = 5-CI

Obtained by the method described in Example 11. of the crystals obtained was 180 ° C.

Example 69: Ethyl (N) -3- (3,5-dichlorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate (Z) isomer: Formula (XI): A = phenyl , Y-, = 5-CI, Y ₂ = 5-CI

It was obtained by the method described in Example 12. The oil was used as obtained in the next step.

Example 70: (Ζ) -3- [1- (3,5-dichlorophenyl) -1- (4-methanesulfonylphenyl) methyl day] dihydrofuran-2-one (Ζ) isomer: Formula (I): A = B = phenyl , Υ _Ί = 5-CI, Y ₂ = 5-CI X ₁ = 4-30 ₂ CH _g . X ₂ = H, F ^ Rs = 0, R ₃ = R ₄ = Η

Obtained according to the method described in Example 65. of the crystals obtained 114 ° C.

Example 71: 2,4-Difluoro-4'-methylthiobenzophenone

Formula (III): A = phenyl, Ut = 2-F, Y ₂ = 4-F

Obtained according to the method described in Example 1. 98 ° C crystals obtained.

Example 72: 2,4-Difluoro-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Ut = 2-F, Y ₂ = 4-F

- 46 Obtained according to the method described in Example 39. of the crystals obtained is 160 ° C.

Example 73: 3-Ethoxycarbonyl-4- (2,4-difluorophenyl) -4 (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Y ₁ = 2-F, Y ₂ = 4-F

Obtained according to the method described in Example 11. The oil was used as obtained in the next step.

Example 74: Ethyl 3- (2,4-difluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Y-, = 2-F, Y ₂ = 4-F

It was obtained by the method described in Example 12. The oil was used as obtained in the next step.

Example 75: (Z) -3- [1- (2,4-difluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran -2-one (Z) isomer: formula (I): A = B = phenyl, Y, = 2-F, Y ₂ = 4-F χ ₁ = 4-SO ₂ CH ₃ , X ₂ = H, F ^ Rs = 0, R ₃ = R ₄ = Η

Obtained according to the method described in Example 65. The resulting product was purified by chromatography in a dichloromethane / acetone mixture (10 / 0.3). M.P. of the crystals obtained 140 ° C.

Example 76: 3,5-Difluoro-4'-methylthiobenzophenone

Formula (III): A = phenyl, Y-, = 3-F, Y ₂ = 5-F

Obtained according to the method described in Example 1. 90 ° C crystals obtained.

Example 77: 3,5-Difluoro-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Υί = 3-F, Y ₂ = 5-F

- 47 Obtained according to the method described in Example 39. of the crystals obtained 152 ° C.

Example 78: 3-Ethoxycarbonyl-4- (3,5-difluorophenyl) -4 (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Y ₁ = 3-F, Y ₂ = 5-F

Obtained according to the method described in Example 11. The oil was used as obtained in the next step.

Example 79: Ethyl 3- (3,5-difluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Y ₄ = 3-F, Y ₂ = 5-F

It was obtained by the method described in Example 12. The oil was used as obtained in the next step.

Example 80: (Z) -3- [1- (3,5-difluorophenyl) -1- (4-methanesulfonylphenyl) ethyl ethyl] dihydrofuran-2-one (Z) isomer: Formula (I): A = B = phenyl, Yt = 3-F, Y ₂ = 5-F

X, = 4-SO ₂ CHc. X ₂ = H, = 0, R ₃ = R ₄ = H

Obtained according to the method described in Example 65. The resulting product was purified by chromatography in a dichloromethane / acetone mixture (10 / 0.3). M.P. of the obtained crystals 162 ° C.

Example 81: 4-methyl-4'-methylthiobenzophenone

Formula (III): A = phenyl, Y, = 4-CH ₃ , Y ₂ = H

Obtained according to the method described in Example 1. of the crystals obtained 96 ° C.

Example 82: 4-methyl-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Y, = 4-CH ₃ , Y ₂ = H

- 48 Obtained according to the method described in Example 39. of the crystals obtained was 180 ° C.

Example 83: 3-Ethoxycarbonyl-4- (4-methylphenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Yt = 4-CH ₃ , Y ₂ = H

Obtained according to the method described in Example 11. The oil was used as obtained in the next step.

Example 84: Ethyl 3- (4-methylphenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Υ _Ί = 4-CH ₃ , Y ₂ = H

It was obtained by the method described in Example 12. The oil was used as obtained in the next step.

Example 85: (E) -3- [1- (4-methylphenyl) -1- (4-methanesulfonylphenyl) methyl day] dihydrofuran-2-one (E) isomer: Formula (I): A = B = phenyl, Υτ = 4-CH ₃₁ Y ₂ = H X! = 4-SO ₂ CH ₃ . X ₂ = H, R- | R ₂ = O, R ₃ = R ₄ = Η

Obtained according to the method described in Example 65. The resulting product was purified by chromatography in a dichloromethane / acetone mixture (10 / 0.3). M.P. of the crystals obtained 222 ° C.

Example 86: 3-Bromo-4'-methylthiobenzophenone

Formula (III): A = phenyl, Y. = 3-Br, Y ₂ = H

Obtained according to the method described in Example 1. 90 ° C crystals obtained.

Example 87: 3-Bromo-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Y ₅ = 3-Br, Y ₂ = H

- 49 Obtained according to the method described in Example 39. of the obtained crystals 170 ° C.

Example 88: 3-Ethoxycarbonyl-4- (3-bromophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Y, = 3-Br, Y ₂ = H

Obtained according to the method described in Example 11. The oil was used as obtained in the next step.

Example 89: Ethyl-3- (3-bromophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Υ-ι = C-Br, Y ₂ = H

It was obtained by the method described in Example 12. The oil was used as obtained in the next step.

Example 90: (Ζ) -3- [1- (3-bromophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (Ζ) isomer: Formula (I): A = B = phenyl, Υ · , = 3- Br, Y ₂ = H X. = 4-SO ₂ CH ₃ . X ₂ = H, RR, = 0, R ₃ = R ₄ = Η

Obtained according to the method described in Example 65. The resulting product was purified by chromatography in a dichloromethane / acetone mixture (10 / 0.3). M.P. of the obtained crystals 162 ° C.

Example 91: 3-Chloro-4-fluoro-4'-methylthiobenzophenone

Formula (III): A = phenyl, Yt = 3-CI, Y ₂ = 4-F

Obtained according to the method described in Example 1. of the crystals obtained 116 ° C.

- 50 Example 92: 3-chloro-4-fluoro-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Y ₁ = 3-CI, Y ₂ = 4-F

Obtained according to the method described in Example 39. of the crystals obtained 146 ° C.

Example 93: 3-Ethoxycarbonyl-4- (3-chloro-4-fluorophenyl) 4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Yt = 3-CI, Y ₂ = 4-F

Obtained according to the method described in Example 11. The oil was used as obtained in the next step.

Example 94: Ethyl 3- (3-chloro-4-fluorophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Yt = 3-CI, Y ₂ = 4-F

It was obtained by the method described in Example 12. The oil was used as obtained in the next step.

Example 95: (Z) -3- [1- (3-chloro-4-fluorophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (Z) isomer: Formula (I): A = B = phenyl, Yt = 3-CI, Y ₂ = 4-F X ₁ = 4-SO ₂ CH ₃ , X ₂ = H, F ^ Rs = 0, R ₃ = R ₄ = H

Obtained according to the method described in Example 65. The resulting product was purified by chromatography in a dichloromethane / acetone mixture (10 / 0.3). M.P. of the obtained crystals 123 ° C.

Example 96: 4-Bromo-4'-methylthiobenzophenone

Formula (III): A = phenyl, Y ₁ = 4-Br, Y ₂ = H

Obtained according to the method described in Example 1. of the crystals obtained 148 ° C.

- 51 Example 97: 4-Bromo-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl,?! = 4-Br, Y ₂ = H

Obtained according to the method described in Example 39. of the crystals obtained 188 ° C.

Example 98: 3-Ethoxycarbonyl-4- (4-bromophenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Υ-] = 4-Br, Y ₂ = H

Obtained according to the method described in Example 11. The oil was used as obtained in the next step.

Example 99: Ethyl 3- (4-bromophenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Y ₁ = 4-Br, Y ₂ = H

It was obtained by the method described in Example 12. The oil was used as obtained in the next step.

Example 100: (d) -3- [1- (4-bromophenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (Ζ) isomer: formula (I): A = B = phenyl, Yi = 4-Br, Y ₂ = H

X! = 4-SO ₂ CH ₃ , X ₂ = H, R, R ₂ = 0, R ₃ = R ₄ = Η

Obtained according to the method described in Example 65. The resulting product was purified by chromatography in a dichloromethane / acetone mixture (10 / 0.3). M.P. of the crystals obtained 204 ° C.

Example 101: 2- (4-Methylthiobenzoid) furan

Formula (III): A = 2-furyl, Y ₁ = Y ₂ = H

Obtained according to the method described in Example 1. of the crystals obtained 86 ° C.

- 52 Example 102: 2- (4-Methanesulfonylbenzoyl) furan

Formula (IV): A = 2-furyl, Y, = Υ ₂ = Η

Obtained according to the method described in Example 39. of the crystals obtained 112 ° C.

Example 103: 3-Ethoxycarbonyl-4- (furan-2-yl) -4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = 2-furyl, Y, = Y ₂ = H

It was obtained by the method described in Example 11. The oil was used in the next step as obtained.

Example 104: Ethyl 3- (furan-2-yl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = 2-furyl, Y, = Y ₂ = H

It was obtained by the method described in Example 12. The oil was used in the next step as obtained.

Example 105: (2) -3- [1- (furan-2-yl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (Ζ) isomer: formula (I): A = 2-furyl, B = phenyl, Υ ₄ = Υ ₂ = H X, = 4-SO ₂ CH _s . X ₂ = H, R-jR ₂ = 0, R ₃ = R ₄ = Η

Obtained according to the method described in Example 65. The resulting product was purified by chromatography in a dichloromethane / acetone mixture (10 / 0.3). M.P. of the obtained crystals 170 ° C.

Example 106: (4-methylthiobenzoyl) cyclohexane

Formula (III): A = cyclohexyl, Υτ = Υ ₂ = Η

Obtained according to the method described in Example 1. of the crystals obtained is 110 ° C.

53 Example 107: 2- (4-Methanesulfonylbenzoyl) cyclohexane

Formula (IV): A = 2-cyclohexyl, Y ₁ = Y ₂ = Η

Obtained according to the method described in Example 39. of the crystals obtained 116 ° C.

Example 108: 3-Ethoxycarbonyl-4-cyclohexyl-4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = cyclohexyl, Y, = Y ₂ = H

It was obtained by the method described in Example 11. The oil was used in the next step as obtained.

Example 109: Ethyl 3-cyclohexyl-3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = cyclohexyl, Ϊ! = Y ₂ = H

It was obtained by the method described in Example 12. The oil was used in the next step as obtained.

Example 110: (d) -3- [1-cyclohexyl-1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (Ζ) isomer: formula (I): A = cyclohexyl, B = phenyl, Υτ = Υ ₂ = H

X! = 4-SO ₂ CH ₃ , X ₂ = H, R- | R ₂ = 0, R ₃ = R ₄ = Η

Obtained according to the method described in Example 65. of the crystals obtained 148 ° C.

Example 111: 3-Fluoro-4-methyl-4'-methylthiobenzophenone

Formula (III): A = phenyl, Yt = 3-F, Y ₂ = 4-CH ₃

A solution of 50 g of 4-bromo-2-fluorotoluene in 150 ml of anhydrous diethyl ether was added dropwise to a suspension of 6.4 g of magnesium chips in 5 ml of anhydrous diethyl ether. At the end of the addition, the mixture was stirred for 30 minutes and then stirred

- 54 added a solution of 4-methylthiobenzonitrile in 200 ml of anhydrous tetrahydrofuran. The diethyl ether was distilled off and the mixture was refluxed for 4 hours. The temperature was brought back to room temperature and 300 ml of 6 N hydrochloric acid were added dropwise. The mixture was then refluxed for 6 hours, cooled to room temperature and extracted with diisopropyl ether. The organic phase was dried over magnesium sulfate and evaporated to dryness. The residue was crystallized from diethyl ether to give 25 g of 3-fluoro-4-methyl-4'-methylthiobenzophenone as crystals of m.p. 94 ° C.

Example 112: 3-Fluoro-4-methyl-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Yt = 3-F, Y ₂ = 4-CH ₃

Obtained according to the method described in Example 39. of the obtained crystals 170 ° C.

Example 113: (d) -3-Ethoxycarbonyl-4- (3-fluoro-4-methylphenyl) -4- (4-methane sulfone and phenyl) -3-butyric acid

Formula (X): A = phenyl, Yt = 3-F, Y ₂ = 4-CH ₃

It was obtained by the method described in Example 11. The product was purified by treating the crude mixture of the two isomers (E) and (Z) with 1 equivalent of O- (+) -a-methylbenzylamine in 5 volumes of ethyl acetate. The resulting crystals were separated ((E) isomer salt) and the filtrate was acidified with dilute hydrochloric acid, separated and evaporated in vacuo to give an oil corresponding to the (Z) isomer containing less than 5% (E) isomer.

- 55 Example 114: Ethyl (r) -3- (3-fluoro-4-methylphenyl) -3- (4methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Y-ι = 3-F, Y ₂ = 4-CH ₃ Obtained by the method described in Example 12. The oil was used in the next step as obtained.

Example 115: (2) -3- [1- (3-fluoro-4-methylphenyl) -1- (4-methanesulfonylphenyl) ethyl de n] dihydrofuran-2-one (Z) isomer: formula (I): A = B = phenyl, Yt = 3-F, Y ₂ = 4-CH ₃

X, = 4-SO ₂ CH ₃ , X ₂ = H, R. R ₂ = 0, R ₃ = R ₄ = Η Obtained according to the method described in Example 65. of the obtained crystals 169-170 ° C.

Example 116: 4-Trifluoromethyl-4'-methylthiobenzophenone

Formula (III): A = phenyl, Yt = 4-CF ₃ , Y ₂ = Η

Obtained by the method described in Example 1.T.T. of the crystals obtained 139 ° C.

Example 117: 4-Trifluoromethyl-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Υτ = 4-CF ₃ , Y ₂ = Η

Obtained according to the method described in Example 39. of the crystals obtained 138 ° C.

Example 118: 3-Ethoxycarbonyl-4- (3-trifluoromethylphenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = phenyl, Υτ = 4-CF ₃ , Y ₂ = Η

Obtained by the method described in Example 11. The resulting oil was used in the next step without further treatment.

- 56 Example 119: Ethyl 3- (4-trifluoromethylphenyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = phenyl, Y-. = 4-CF ₃ , Y ₂ = Η

It was obtained by the method described in Example 12. The oil was used in the next step as obtained.

Example 120: (E) -3- [1- (4-Trifluoromethylphenyl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one (E) isomer: formula (I): A = B = phenyl. Υτ = 4-CF ₃ , Y ₂ = Η

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

Obtained by the method described in Example 65, purified by chromatography on a dichloromethane / acetone mixture (10 / 0.3). M.P. of crystals obtained 188189 ° C.

Example 121: 4-Benzylthio-4'-chlorobenzophenone

This was obtained by the method described in Example 56 of 4-bromochlorobenzene and 4-benzylthiobenzonitrile, obtained in example 55. of the crystals obtained 134 ^: C.

Example 122: 4-tert-Butylaminosulfonyl-4'-chlorobenzophenone

Obtained according to the method described in Example 57. of the crystals obtained 163 ° C.

Example 123: 3-Ethoxycarbonyl-4- (4-tert-butylaminosulfonylphenyl) -4- (4-chlorophenyl) -3-butenoic acid

Formula (XII): A = phenyl, Y, = 4-CI, Υ ₂ = Η

- 57 Obtained by the method described in Example 58. The resulting oil was used in the next step without further treatment.

Example 124: Ethyl (2) -3- (4-tert-butylaminosulfonylphenyl) -3- (4-chlorophenyl) -2- (2-hydroxyethyl) -2-propenoate

Obtained by the method described in Example 12. The resulting oil was dissolved in diethyl ether. and the crystals formed are filtered off (E isomer). The filtrate was concentrated in vacuo and the residue was dissolved in petroleum ether and then crystallized to give the (Z) isomer as crystals, m.p. 120 ° C.

Example 125: (2) -4 - [(4-chlorophenyl) - (2-oxodihydrofuran3-ylidene) methyl] benzenesulfonamide

Formula (I): A = B = phenyl. Y ^ = 4-CI, Υ ₂ = Η

X! = 4-SO ₂ NH ₂ , X ₂ = H, F ^ Rs = O, R ₃ = R ₄ = H

A solution of 10 g of ethyl N- (3- (4-tert-butylaminosulfonylphenyl) -3- (4-chlorophenyl) -2- (2-hydroxyethyl) -2-propenoate obtained in Example 124 in 80 ml of trifluoroacetic acid refluxed for 15 hours. After evaporation of the solvent in vacuo, the residue was dissolved in dichloromethane. The organic phase was washed with water and then dried over magnesium sulfate and evaporated in vacuo to give an oil which crystallized from a mixture of acetone / diisopropyl ether to give 3.9 g (Ζ) -4 - [(4-οοροφβΗil ) - (2-Oxodihydrofuran-3-ylidene) methyl] benzenesulfonamide in the form of crystals of m.p. 187-189 ° C.

- 58 Example 126: 4-Benzylthio-3'-fluoro-4'-methylbenzophenone

It was prepared by the method described in Example 56 from 4-bromo-2fluorotoluene. M.P. of the crystals obtained 122 ° C.

Example 127: 4-tert-Butylaminosulfonyl-3'-fluoro-4'methylbenzophenone

Obtained according to the method described in Example 57. of the crystals obtained 132 ° C.

Example 128: (d) -3-Ethoxycarbonyl-4- (4-tert-butylaminosulfonylphenyl) -4- (3-fluoro-4-methylphenyl) -3-butenoic acid

Formula (XII): A = phenyl, Y ₁ = 3-F, Y ₂ = CH ₃ Obtained by the method described in Example 58. The resulting oil was dissolved in tert-butyl methyl ether and the crystals formed were filtered to give ( E) the isomer of m.p. 96 ° C. The filtrate was concentrated in vacuo to give the (Z) isomer as an oil, which was used as obtained in the next step.

Example 129: Ethyl (2) -3- (4-tert-butylaminosulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -2-propenoate

This was obtained by the method described in Example 12 from the (Z) isomer of acid obtained in Example 128. The oil was used as obtained in the next step.

Example 130: (R) -4 - [(3-fluoro-4-methylphenyl) - (2-oxodihydrofuran -3-or day) methyl] benzenesulfone amide

Formula (I): A = B = phenyl,% = 3-F, Y ₂ = CH ₃

- 59 χ ₁ = 4-SO ₂ NH ₂ , X ₂ = H, = 0, R ₃ = R ₄ = H

Obtained according to the method described in Example 125. of the obtained crystals 170-172 ° C.

Example 131: 4-Benzylthio-4'-fluoro-3'-methylbenzophenone

It was prepared by the method described in Example 56 from 5-bromo-2fluorotoluene. M.P. of the obtained crystals 123 ° C.

Example 132: 4-tert-Butylaminosulfonyl-4'-fluoro-3'methylbenzophenone

Obtained according to the method described in Example 57. of the resulting crystals 108 ° C.

Example 133: (R) -3-Ethoxycarbonyl-4- (4-tert-butylaminosulfonylphenyl) -4- (4-fluoro-3-methylphenyl) -3-butenoic acid

Formula (XII): A = phenyl, Ut = 3-CH ₃ , Y ₂ = 4-F

Obtained according to the method described in Example 58. The resulting oil was dissolved in tert-butyl methyl ether and the crystals formed after separation gave the (E) isomer. The filtrate was evaporated in vacuo to give the (Z) isomer as an oil, which was used as obtained in the next step.

Example 134: Ethyl (r) -3- (4-tert-butylaminosulfonylphenyl) -3- (4-fluoro-3-methylphenyl) -2- (2-hydroxyethyl) -2-propenoate

It is obtained by the method described in Example 12. The crystals obtained have a m.p. 128 ° C.

- 60 Example 135: (2) -4 - [(4-fluoro-3-methylphenide) - (2-oxodihydrofuran-3-ylidene) methyl] benzenesulfonamide

Formula (I): A = B = phenyl, Υ-ι = 3- CH ₃ , Y ₂ = 4-F,

Xm = 4-SO ₂ NH ₂ , X ₂ = H, F ^ Rs = O, R ₃ = R ₄ = Η

Obtained according to the method described in Example 125. of the crystals obtained 228-229 ° C.

Example 136: Ethyl (E) -3- (4-tert-butylaminosulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Obtained by the method described in Example 12 from the (E) isomer of the acid obtained in Example 128. The oil was used as obtained in the next step.

Example 137: (E) -3- (4-tert-Butylaminosulfonylphenyl) -3 (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid

A solution of 16 g of ethyl (E) -3- (4-tert-butylaminosulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2- (2-hydroxyethyl) -2-propenoate prepared in Example 136, c 50 ml of ethanol containing 3 g of sodium hydroxide and 5 ml of water are refluxed for 2 hours. The mixture was concentrated in vacuo, dissolved in water, washed with diethyl ether and acidified with dilute hydrochloric acid, then extracted with dichloromethane. The organic phase was dried over magnesium sulfate and evaporated to dryness in vacuo to give a residue which crystallized in diisopropyl ether to give 7.6 g (E) -3- (4-tert-butylaminosulfonylphenyl) -3- (3-fluoro -4-methylphenyl) -2- (2-hydroxyethyl) -2-propenoic acid as crystals of m.p. 160 ° C.

- 61 Example 138: (E) -2- (1- (4-tert-butylaminosulfonylphenyl) -1- (3-fluoro-4-methylphenyl) methyl day] butane -1,4-DIO d

To a solution of 7.8 g (E) -3- (4-tert-butylaminosulfonylphenyl) -3- (3-fluoro-4-methyl-phenyl) -2- (2-hydroxyethyl) -2-propenoic acid prepared in Example 137 in 50 ml of anhydrous tetrahydrofuran were added dropwise 5 ml of borane / dimethyl sulfide complex. The mixture was stirred for 6 hours at room temperature and then 10 ml of methanol were added dropwise. The mixture was concentrated in vacuo, dissolved in aqueous potassium carbonate solution and extracted with diethyl ether. The organic phase was dried over magnesium sulfate and evaporated in vacuo to give 6.3 g (E) -2- (1- (4-tert-butylaminosulfonylphenyl) -1- (3-fluoro-4methylphenyl) methylidene] butane- 1,4-diol as crystals, mp 106 ° C.

Example 139: (E) -4 - [(3-fluoro-4-methylphenyl) - (tetrahydrofuran-3-ylidene) methyl] benzenesulfonamide

Formula (I): A = B = phenyl, Xm = C-F, X ₂ = CH ₃

Y ₁ = 4-SO ₂ NH ₂ , Y ₂ = H, R 1 = R ₂ = R ₃ = R ₄ = H

A solution of 6.3 g (E) -2- [1- (4-tert-butylaminosulfonylphenyl) -1- (3-fluoro-4-methyl phenyl) methyl and day] butane-1,4-diol obtained in Example 138, in 75 ml of trifluoroacetic acid was refluxed for 10 hours. After concentrating the solvent in vacuo, the residue was dissolved in dilute sodium hydroxide solution, washed with dichloromethane, acidified with dilute hydrochloric acid and extracted again with dichloromethane. The organic phases are combined and dried over magnesium sulfate and then evaporated in vacuo. A residue is obtained which crystallizes in

62 tert-butyl methyl ether to give 4.0 g (E) -4 - [(3-fluoro-4methylphenyl) - (tetrahydrofuran-3-ylidene) methyl] benzenesulfonamide as crystals of m.p. 174-176 ° C.

Example 140: 4-Benzylthio-3'-chloro-4'-fluorobenzophenone

It was prepared by the method described in Example 56 from 4-bromo-2chlorofluorobenzene. M.P. 102 ° C crystals obtained.

Example 141: 4-tert-Butylaminosulfonyl-3'-chloro-4'-fluorobenzophenone

Obtained according to the method described in Example 57. of the resulting crystals 108 ° C.

Example 142: 3-Ethoxycarbonyl-4- (4-tert-butylaminosulfonylphenyl) -4- (3-chloro-4-fluorophenyl) -3-butenoic acid

Formula (XII): A = phenyl, Y, = 3-Cl, Y ₂ = 4-F

Obtained by the method described in Example 58. The resulting oil was used directly in the next step.

Example 143: (2) -4 - [(3-chloro-4-fluorophenyl) - (2-oxodihydrofuran-3-yl day) methyl] benzene sulfone amide d

Formula (I): A = B = phenyl, Y ₁ = 3-CI, Y ₂ = 4-F,

X ₁ = 4-SO ₂ NH ₂ , X ₂ = H, F ^ Ro = O, R ₃ = R ₄ = Η

To a solution of 17 g of 3-ethoxycarbonyl-4- (4-tert-butylaminosulfonylphenyl) -4- (3-chloro-4-fluorophenyl) -3-butenoic acid obtained in Example 142 in 150 ml of tetrahydrofuran was added to drops of 7 ml borane / dimethyl sulfide complex. The mixture was stirred for 6 hours at room temperature and then 30 ml of ethanol were added dropwise. Aqueous solution was added

- 63 of potassium carbonate and the mixture is extracted with dichloromethane. The organic phase was dried and evaporated in vacuo. The residue (13.8 g) was dissolved in 30 ml of ethanol containing a solution of 3 g of sodium hydroxide in 10 ml of water and the mixture heated at 70 ° C for 3 hours. The solvent was evaporated in vacuo and the residue was dissolved in water; The aqueous phase was washed with diethyl ether, acidified with hydrochloric acid and extracted with dichloromethane, then dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in diethyl ether and the crystals obtained were filtered to give 3 g (E) -3- (4-tert-butylaminosulfonylphenyl) -3- (3-fluoro-4-chlorophenyl) -2- (2-hydroxyethyl) ) -3-propenoic acid (mp 180 ° C). The filtrate was concentrated in vacuo and the residue was dissolved in 60 ml of trifluoroacetic acid. The mixture was refluxed for 17 hours, then concentrated in vacuo. The residue was dissolved in dilute sodium hydroxide solution and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and evaporated in vacuo to give 2 g (Z) -4 - [(3-chloro-4-fluorophenyl) - (2-oxodihydrofuran-3-ylidene) methyl] benzenesulfonamide as crystals of m.p. Mp 244-246 ° C.

Example 144: 4-Benzylthio-3'-fluoro-4'-methoxybenzophenone

It was prepared by the method described in Example 56 from 4-bromo-2fluoroanisole. M.P. 125 ° C crystals obtained.

Example 145: 4-tert-Butylaminosulfonyl-3'-fluoro-4methoxybenzophenone

- 64 Obtained according to the method described in Example 57. of the crystals obtained 136 ° C.

Example 146: (d) -3-Ethoxycarbonyl-4- (4-tert-butylaminosulfonylphenyl) -4- (3-fluoro-4-methoxyphenyl) -3-butenoic acid

Formula (XII): A = phenyl, Ϊ! = 3-F, Y ₂ = 4-OMe

Obtained by the method described in Example 58. The resulting oil was dissolved in tert-butyl methyl ether. The (Ζ) isomer is obtained as amorphous crystals, which are used as obtained in the next step.

Example 147: Ethyl (r) -3- (4-tert-butylaminosulfonylphenyl) -3- (3-fluoro-4-methoxyphenyl) -2- (2-hydroxyethyl) -2-propenoate

It is obtained by the method described in Example 12. The resulting oil is used directly in the next step.

Example 148: (2) -4 - [(3-fluoro-4-methoxyphenyl) - (2-oxodicylic acid 3-yl day) methyl] benzene sulfonamide

Formula (I): A = B = phenyl. Y, = 3-F, Υ ₂ = 4-OMe, χ ₁ = 4-SO ₂ NH ₂ , X ₂ = H, R ^ = 0, R ₃ = R ₄ = Η

Obtained according to the method described in Example 125. of the crystals obtained 149-150 ° C.

Example 149: 3- (4-Fluorobenzoyl) pyridine

To a suspension of 140 g of nicotinic acid chloride hydrochloride in 500 ml of fluorobenzene cooled to 0 ° C was added in portions 280 g of aluminum chloride. The mixture was refluxed for 6 hours, cooled and poured onto ice.

- 65 Sodium hydroxide was added to bring the pH to 8 and the mixture was extracted with dichloromethane. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from a pentane / diisopropyl ether mixture to give 108.5 g of 3- (4-fluorobenzoyl) pyridine as crystals, m.p. 91 ° C.

Example 150: 3- (4-Benzylthiobenzoyl) pyridine

To a solution of 43 g of benzyl mercaptan in 500 ml of N, N-dimethylformamide was added 14 g of 60% sodium hydroxide. The mixture was stirred for 20 minutes at room temperature and 70 g of 3- (4-fluorobenzoyl) pyridine obtained in Example 149 were added. The mixture was heated at 80-C for 8 hours, concentrated in vacuo and the residue dissolved in water. The crystals formed were filtered, dissolved in dichloromethane and the solution was dried over magnesium sulfate, then concentrated in vacuo. The residue was crystallized from a pentane / diisopropyl ether mixture to give 81 g of 3- (4-benzylthiobenzoyl) pyridine as crystals of m.p. 102-C.

Example 151: 3- (4-tert-Butylaminosulfonylbenzoyl) pyridine

Obtained according to the method described in Example 57. of the crystals obtained 179 ° C.

Example 152: (2) -3-Ethoxycarbonyl-4- (4-tert-butylaminosulfonylphenyl) -4- (3-pyridyl) -3-butenoic acid

Formula (XII): A = pyridyl. Y, = Υ ₂ = Η

This was obtained by the method described in Example 58. The resulting oil was dissolved in hot ethyl acetate and the crystals formed, representing the (E) isomer, m.p. 209 ° C, filtered.

The filtrate was evaporated and the residue was dissolved in pentane, then crystallized to give the (Z) isomer as crystals, m.p. 195 ² p.

Example 153; Ethyl (N) -3- (4-tert-butylaminosulfonylphenyl) -3- (3-pyridyl) -2- (2-hydroxyethyl) -2-propenoate

It is obtained by the method described in Example 12. The resulting amorphous crystals are used directly in the next step.

Example 154: (2) - [(3-pyridyl) - (2-oxodihydrofuran-3-ylidene) ethyl] benzenesulfonamide

Formula (I): A = 3-pyridyl, B = phenyl, X! = 4-SO ₂ NH ₂ , χ ₂ = Η, Ύ, = Y ₂ = H, R, R ₂ = O, R ₃ = R ₄ = Η Obtained according to the method described in Example 125. of the crystals obtained 219-220 ° C.

Example 155: 3-Chloro-4-methoxy-4'-methylthiobenzophenone

Formula (III): A = phenyl, Y! = C-Cl, Υ ₂ = 4-OMe

Obtained as described in Example 1. M.p. of the crystals obtained is 100 ° C.

Example 156: 3-Chloro-4-methoxy-4'-methanesulfonylbenzophenone

Formula (IV): A = phenyl, Y, = 3-Cl, Y ₂ = 4-OMe

Obtained as described in Example 39. of the crystals obtained 164 ° C.

Example 157: (2) -3-Ethoxycarbonyl-4- (3-chloro-4-methoxyphenyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid

- 67 Formula (X): A = phenyl, Υτ = 3-CI, Y ₂ = 4-OMe

Obtained as described in Example 11, the resulting oil being dissolved in ether and the crystals formed were filtered to give the (Z) isomer as crystals, m.p. 179 ° C.

Example 158: Ethyl (r) -3- (3-chloro-4-methoxyphenyl) -3- (4methanesulfonylphenyl) -2- (2-hydroxyethyl) -3-propenoate

Formula (XI): A = phenyl, Y ₁ = 3-Cl, Y ₂ = 4-OMe

Obtained as described in Example 12. m.p. 102 ° C crystals obtained.

Example 159: (d) -3- [1- (3-chloro-4-methoxyphenyl) -1- (4-methanesulfonylphenyl) methyl day] dihydrofuran-2-one

Formula (I): A = B = phenyl. Y ₃ = 3-CI, Y ₂ = 4-OMe,

X, = 4-SO ₂ CH ₃ , X ₂ = H, R-, R ₂ = 0, R ₃ = R ₄ = H

Obtained according to the method described in Example 65. of the crystals obtained 177 ° C.

Example 160: 2- (4-methylthiobenzoyl) thiophene

Formula (III): A = 2-thienyl. Y-, = Y ₂ = H

Obtained as described in Example 1. M.p. 60 ° C crystals obtained.

Example 161: 2- (4-Methanesulfonylbenzoyl) thiophene

Formula (IV): A = 2-thienyl, Y ₁ = Y ₂ = Η

Obtained as described in Example 39. of the crystals obtained 140 ° C.

- 68 Example 162: (E) -3-Ethoxycarbonyl-4- (4-methanesulfonylphenyl) -4- (2-thienyl) -3-butenoic acid

Formula (X): A = 2-thienyl, Υ, = Υ ₂ = Η Prepared as described in Example 11. M.p. of the crystals obtained 120 ° C.

Example 163: Ethyl (E) -3- (4-methanesulfonylphenyl) -3- (2-thienyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = 2-thienyl, = Υ ₂ = Η Prepared as described in Example 12. M.p. of the crystals obtained 116 ° C.

Example 164: (E) -3- [1- (4-Methanesulfonylphenyl) -1- (2-thienyl) methyl day] dihydrofuran-2-one

Formula (I): A = 2-thienyl, B = phenyl, Υ-ι = Υ ₂ = Η, χ ₁ = 4-SO ₂ CH ₃ , X ₂ = H, R, R ₂ = 0, R ₃ = R ₄ = Η Obtained as described in Example 65. m.p. of the crystals obtained 246 ° C.

Example 165: 4- (2-Naphthoyl) methylthiobenzene

Formula (III): A = 2-naphthyl, Y-, = Y ₂ = H Prepared as described in Example 1. M.p. 98 ° C crystals obtained.

Example 166: 4- (2-Naphthoyl) methanesulfonylbenzene

Formula (IV): A = 2-naphthyl, Υ ₃ = Υ ₂ = Η

Obtained as described in Example 39. of the crystals obtained is 150 ° C.

- 69 Example 167: 3-Ethoxycarbonyl-4- (2-naphthyl) -4- (4-methanesulfonylphenyl) -3-butenoic acid

Formula (X): A = 2-naphthyl, Y- = Y ₂ = H

Obtained as described in Example 11. The oil was used as obtained in the next step.

Example 168: Ethyl 3- (2-naphthyl) -3- (4-methanesulfonylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Formula (XI): A = 2-naphthyl, Yt = Y ₂ = H

Obtained as described in Example 12. The oil was used as obtained in the next step.

Example 169: (S) -3- [1- (2-Naphthyl) -1- (4-methanesulfonylphenyl) methyl day] breathing drofu ran-2-one

Formula (I): A = 2-naphthyl, B = phenyl, Υ _Ί = Υ ₂ = Η,

X, = 4-SO ₂ CH ₃ , X _£ = HRR, = 0, R ₃ = R ₄ = H

Obtained as described in Example 65, the product was purified by chromatography on a dichloromethane / acetone mixture (10 / 0.3). M.P. of the crystals obtained was 244 ° C.

Example 170: 3,5-Dichloro-4'-fluorobenzophenone

A mixture of 50 g of 3,5-dichlorobenzoyl chloride and 150 ml of fluorobenzene was cooled to 0 ° C and 65 g of aluminum trichloride were added portionwise. The mixture was stirred at room temperature for 2 hours and then refluxed for 4 hours. After cooling, the mixture was poured into ice / dilute hydrochloric acid and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and evaporated to dryness to give 59 g of 3,5-dichloro-4'-fluorobenzophenone as crystals of m.p. 65 ° C.

- 70 Example 171: 3,5-Dichloro-4'-benzylthiobenzophenone

Obtained as described in Example 150 from 3,5-dichloro-4'-fluorobenzophenone obtained in Example 170. of the crystals obtained 80 ° C.

Example 172: 4-tert-Butylaminosulfonyl-3 ', 5'-dichlorobenzophenone

Obtained as described in Example 57 from 3,5-dichloro-4'-benzylthiobenzophenone prepared in Example 171. of the obtained crystals 144 ° C.

Example 173: 3-Ethoxycarbonyl-4- (4-tert-butylaminosulfonylphenyl) -4- (3,5-dichlorophenyl) -3-butenoic acid

Formula (XII): A = phenyl, Ϊ! = 3-CI, Y ₂ = 5-CI

Obtained as described in Example 58. The resulting oil was used directly in the next step.

Example 174: Ethyl 3- (4-tert-butylaminosulfonylphenyl) 3- (3,5-dichlorophenyl) -2- (2-hydroxyethyl) -2-propenoate

Obtained as described in Example 12. The resulting oil was used directly in the next step.

Example 175: (2) -4 - [(3,5-Dichlorophenyl) - (2-oxodihydrofuran-3-or-day) methyl] benzene sulfone amide (Ζ) isomer: Formula (XII): A = B = phenyl, Y ₄ = 3-CI, Y ₂ = 5-CI X, = 4-SO ₂ NH ₂ , X ₂ = H, R- | R ₂ = o, r ₃ = r ₄ = h

Obtained by the method described in Example 65. The crystals obtained were chromatographed on silica gel in dichloromethane / acetone (9/1) to give (Z) -4 - [(3,5-dichlorophenyl) - after recrystallization from acetic acid. (2-Oxodihyd-71 rofuran-3-ylidene) methyl] benzenesulfonamide in the form of crystals of m.p. 217 ° C.

Example 176; 3-chloro-4-fluorobenzophenone

Obtained as described in Example 170. of the crystals obtained 76 ° C.

Example 177: 3-chloro-4'-benzylthiobenzophenone

Obtained as described in Example 150 from 3-chloro-4'fluorobenzophenone prepared in Example 176. M.P. 90 ° C crystals obtained.

Example 178: 4-tert-Butylaminosulfonyl-3'-chlorobenzophenone

Obtained as described in Example 57 from 3'-chloro-4'-benzylthiobenzophenone obtained in Example 177. M.p. 128 ° C crystals obtained.

Example 179: 3-Ethoxycarbonyl-4- (4-tert-butylaminosulfonylphenyl) -4- (3-chlorophenyl) -3-butenoic acid

Formula (XII): A = phenyl, Y, = 3-Cl, Y ₂ = H

Obtained as described in Example 58. The resulting oil was used directly in the next step.

Example 180: Ethyl 3- (4-tert-butylaminosulfonylphenyl) 3- (3-chlorophenyl) -2- (2-hydroxyethyl) -2-propenoate

Obtained as described in Example 12. The resulting oil was used directly in the next step.

- 72 Example 181: (2) -4 - [(3-chlorophenyl) - (2-oxodihydrofuran-3-day) methyl] benzenesulfone amide (Z) isomer: formula (XII): A = B = phenyl, 3-CI , Υ ₂ = Η,

X ₁ = 4-SO ₂ NH ₂ , X ₂ = H, RR, = O, R ₃ = R ₄ = Η Obtained by the method described in Example 65. The resulting product was chromatographed on silica gel in dichloromethane / acetone (10 / 1). M.P. of the crystals obtained 178 ° C.

Example 182: 4-Fluoro-3'-methylbenzophenone

Obtained as described in Example 170. of the crystals obtained is 50 ° C.

Example 183: 4-Benzylthio-3'-methylbenzophenone

Obtained as described in Example 150 from 4-fluoro 3'-methylbenzophenone obtained in Example 182. M.p. 98 ° C crystals obtained.

Example 184: 4-tert-Butylaminosulfonyl-3'-methylbenzophenone

Obtained as described in Example 57 from 4-benzylthio 3'-methylbenzophenone obtained in Example 183. m.p. of the crystals obtained 116 ° C.

Example 185: 3-Ethoxycarbonyl-4- (4-tert-butylaminosulfonylphenyl) -4- (3-methylphenyl) -3-butenoic acid

Formula (XII): A = phenyl, Υί = 3-CH ₃ , Y ₂ = H

Obtained as described in Example 58. The resulting oil was used directly in the next step.

- 73 Example 186: Ethyl 3- (4-tert-butylaminosulfonylphenyl) 3- (3-methylphenyl) -2- (2-hydroxyethyl) -2-propenoate

Obtained as described in Example 12. The resulting oil was used directly in the next step.

Example 187: (d) -4 - [(3-methylphenyl) - (2-oxodihydrofuran3-ylidene) methyl] benzenesulfonamide (Z) isomer: Formula (I): A = B = phenyl, Υ _π = 3-CH ₃ , Y ₂ = H,

X ₁ = 4-SO ₂ NH ₂ X; = N. R- | R ₂ = 0, R ₃ = R ₄ = Η

Obtained by the method described in Example 65. The resulting oil was chromatographed on silica gel in dichloromethane / acetone (10/1) to give (S) -4 - [(3-methylphenyl) (2-oxodihydrofuran-3- methylene) benzenesulfonamide in the form of crystals of m.p. 166 ° C.

Example 188: 3-Chloro-4-methoxy-4'-benzylbenzophenone

Obtained as described in Example 56 from 2-chloro-4bromoanisole. M.P. of the crystals obtained 11 ^ C.

Example 189: 4-tert-Butylaminosulfonyl-3'-chloro-4'-methoxybenzophenone

Obtained as described in Example 57 from 3-chloro-4-methoxy-4'-benzylthiobenzophenone. of the crystals obtained 120 ° C.

Example 190: 3-Ethoxycarbonyl-4- (4-tert-butylaminosulfonylphenyl) -4- (3-chloro-4-methoxyphenyl) -3-butenoic acid

Formula (XII): A = phenyl, Y, = 3-Cl, Y ₂ = OMe,

- 74 Obtained as described in Example 58. The resulting oil was used directly in the next step.

Example 191: Ethyl 3- (4-tert-butylaminosulfonylphenyl) 3- (3-chloro-4-methoxy phenyl) -2- (2-hydroxy ethyl) -2-prop is no

It is obtained by the method described in Example 12. The resulting oil is used directly in the next step.

Example 192: (R) -4 - [(3-chloro-4-methoxyphenyl) - (2-oxodihydrofuran-3-ylidene) methyl] benzenesulfonamide and (E) -4 [(3-chloro-4- methoxyphenyl) - (2-oxodicyclofuran-3-ylidene) methyl] benzene sulfonamide

Formula (I): A = B = phenyl, Y ^ = 3-CI, Υ ₂ = 4-OMe,

X, = 4-SO ₂ NH ₂ , X ₂ = H, = 0, R ₃ = R ₄ = H

Obtained by the method described in Example 65. The resulting oil was chromatographed on silica gel in dichloromethane / acetone (10/1). to give a mixture of (E) and (Z) -4 - [(3-chloro-4-methoxyphenyl) - (2-oxodi-furan-3-ylidene) methyl] benzenesulfonamide as amorphous crystals.

PHARMACOLOGY

The anti-inflammatory action of the compounds prepared in the examples is established by the carrageenan edema method and the analgesic action is evaluated by the kaolin arthritis method.

- 75 Methods

Anti-inflammatory action:

The anti-inflammatory effect was evaluated in rats by the carrageenan edema test. The product was administered orally at a dose of 2.5 ml / 100 g (η = 6 animals per dose) for 2 h and 30 min after hyperhydrogenation (2.5 ml / 100 g); One hour after product administration, edema was induced by plantar subcutaneous injection with 2% aqueous carrageenin solution. Results are expressed as IC _50, the dose mg / kg, which produced a 50% reduction in the volume of edema was calculated by linear regression using the maximum volume of edema was obtained for each test product.

Analgesic action:

The analgesic effect was tested in rats by a kaolin arthritis test. Thirty minutes after intra-articular administration of a 10% aqueous suspension of kaolin, the product was administered orally at a dose of 1 ml / 100 g (η = 10 animals per dose). The results are presented as DE ₅₀ , the dose in mg / kg, which causes a 50% reduction of said maximum in the control group, calculated by linear regression.

an example anti-inflammatory action ID ₅₀ (mg / kg) analgesic action DE _SO (mg / kg) 4 (E isomer) 1.8 7.6 8 (E isomer) > 30 - 8 and 65 (Z isomer) 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

- 77 Inhibition of the enzymatic activity of COX-1 and COX-2

The test molecule was incubated for 10 minutes at 25 ° C with 2 U COX-1 (purified ram seed enzyme) or 1 U COX-2 (purified placental enzyme). Arachidonic acid (6 μΜ for COX1, 4 μΜ for COX-2) was added to the reaction medium and the incubation was carried out for 5 minutes at 25 ° C. After incubation is complete, the enzymatic reaction is terminated by the addition of 1 N hydrochloric acid and the resulting PGE2 is determined by ΕΙΑ.

The results are presented by IC ₅₀ , the concentration in nM corresponding to 50% inhibition of maximal enzyme activity against COX-1 and COX-2 (n = 1 to 4 determinations).

an example inhibition of COX-2 1C ₅₀ (nM) inhibition of COX-1 1C ₅₀ (nM) selectivity COX-1 / COX-2 ratio 4 (E) 674 ± 46 (n = 3) > 300,000 > 445 8 or 65 (Z) 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

- 79 tolerability

Stomach tolerance:

Gastric tolerance was tested in Charles River rats, strain CD, weighing 110 to 150 g. Animals were left in water only 24 hours before oral administration of the product or only excipient at a dose of 1 ml / 100 g (n = 6 animals per each dose). Six hours after taking the product, the animals are killed, their stomachs are removed and the greater curvature is opened. The number of hemorrhagic points and grooves for each stomach, determined with a microscope, allows to determine the index of ulceration (ulcer formation) (0: no lesions; 1: 1 to 2 lesions; 2: 3 to 4 lesions; 3: 5 up to 8 lesions; 4: 9 to 16 lesions; 5: more than 17 lesions), as well as to establish a 50% ulcerogenic dose (UD ₅₀ = dose causing 4 to 5 lesions, expressed in mg / kg).

an example UD ₅₀ (confidence limit) mg / kg 4 (E isomer) > 1000 8 or 65 (Z isomer) > 1000 125 (Z isomer) > 1000 indomethacin 8.3 (5.8 - 11.8)

toxicology

The first toxicological studies performed showed that the products obtained in the examples had no adverse effect on rats after oral ingestion of doses in the range up to 300 mg / kg.

Claims (13)

1. Diarylmethylidene furan derivatives of general formula (I): formula (I) wherein the rings A and B are each independently: a phenyl radical, a naphthyl radical, a radical derived from a heterocycle containing 5 or 6 members having from 1 to 4 heteroatoms, or a radical derived from a saturated hydrocarbon ring of 3 up to 7 carbon atoms; as at least one of the substituents Χι, X ₂ , Υ _Ί or Υ ₂ must mean: a group -S (O) _n -H in which η is an integer equal to 0, 1 or 2 and R is a lower alkyl radical of 1 to 6 carbon atoms or a lower haloalkyl radical of 1 to 6 carbon atoms or a group -SO ₂ NH ₂ ; and is positioned in a steam place, the other substituents being each independently: a hydrogen atom, a halogen atom, a lower alkyl radical of 1 to 6 carbon atoms, a trifluoromethyl radical or a lower 0 alkyl radical of 1 to 6 carbon atoms; or X ·, and X ₂ or Υ-ι and Y ₂ denote methylenedioxy group; and R ₁₅ R ₂ , R ₃ and R ₄ mean separately: - a hydrogen atom, a halogen atom, a lower alkyl radical of from 1 to 6 carbon atoms, a lower haloalkyl radical of from 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl. furyl or pyridyl; or R ^ s or R ₃ R ₄ are an oxygen atom, or R ₁ or R ₃ R ₄ together with the carbon atom to which they are attached form a saturated hydrocarbon ring of 3 to 7 carbon atoms. 2. The derivatives of formula (I) according to claim 1, wherein: rings A and B denote separately: a phenyl radical, a naphthyl radical, a pyridyl radical, a furyl radical, a thienyl radical or a cyclohexyl radical; and at least one of the substituents Χ _1Ί X ₂ , Υτ or Υ ₂ must mean a group SCH ₃ , SO ₂ CH ₃ or SO ₂ NH ₂ , and the rest mean: a hydrogen atom, a halogen atom, a lower alkyl radical of up to 6 carbon atoms, a trifluoromethyl radical or a lower O-alkyl radical of 1 to 6 carbon atoms; R ^ a is an oxygen atom; and R ₃ , R ₄ are each a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms. 3. Derivatives according to claim 1 or 2, in which ring B is a phenyl radical. 4. Derivatives according to claim 1 or 2, in which ring A is a phenyl or pyridyl radical. 5. Derivatives according to any one of claims 1 to 4, in which X- is a group of 4-SO ₂ CH ₃ or 4-SO ₂ NH ₂ and X ₂ is a hydrogen atom. Derivatives according to any one of claims 1 to 5, wherein Y is a fluorine or chlorine atom or a methyl radical and Y ₂ is a hydrogen, fluorine or chlorine atom. 7. Derivatives according to any one of claims 1 to 6, in which they are an oxygen atom and R ₃ and R _{4 each} represent a hydrogen atom. 8. The derivatives according to claim 1 selected from the compounds of the formulas: (E) -3- [1- (4-fluorophenyl) -1- (4-methanesulphonylphenyl) methyl den] breath and drofuran-2-one (Z) -3- [1- (4-chlorophenyl) ) -1 - (4-methanesul background yl phenyl) methyl πάθη] breath and drofuran-2-one CHgSOg _ N / ((Z) -3- [1- (3,4-dichlorophenyl) -1- (4-methanesulfonylphenyl) methyl and dene] C) - 83 (Z) -3- [1- (6-chloropyridin-3-yl) -1- (4-methanesulfonylphenyl) methylidene] dihydrofuran-2-one CH ₃ SO ₂ . (Z) -4 - [(4-chlorophenyl) - (2-oxodihydrofuran-3-ylidene) methyl] benzenesulfonamide (Z) -4 - [(3-fluoro-4-methylphenyl) - (2-oxodihydrofuran-3ylidene) methyl ] benzenesulfonamide A process for the preparation of compounds of formula (I) according to any one of claims 1 to 8, characterized in that the ketone of formula: - 84 in which A, B, X _1s X ₂ , Y ₁ and Y ₂ have the meanings defined in claim 1, reacted with an alkyl succinate of the formula: CH ₂ -COOR ' CH ₂ -COOR 'in which R' is a lower alkyl radical of 1 to 6 carbon atoms, is optionally an ethyl radical under the condensation reaction of Stob, in the presence of an alkoxide, in particular sodium or potassium tert-butylate , or hydride. such as sodium hydride, in an alcoholic solvent such as tert-butanol, or in an aromatic solvent such as toluene, the choice of the condensing agent and the solvent allowing the reaction to be directed to the preparation of a particular isomer to give acid ester derivatives of the formula : -COOH COOEt in which A, B, X-t, X ₂ , Υτ and Υ ₂ have the meanings defined in claim 1; the acid functional group of said esters is selectively reduced, for example by the use of borane in tetrahydrofuran, to give ester alcohols of the formula: COOEt - 85 wherein A, B, X _n X ₂ , Y ₁ and Y ₂ have the meanings defined in claim 1; and then these ester alcohols are cyclized by heating, for example in toluene, in the presence of p-toluenesulfonic acid. A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 8, optionally together with a pharmaceutically acceptable excipient, vehicle or carrier. 11. A pharmaceutical composition having an anti-inflammatory and analgesic action, characterized in that _? that it contains a pharmaceutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 8, optionally together with a pharmaceutically acceptable excipient, vehicle or carrier. 12. A pharmaceutical composition for the prevention of cancer, in particular of adenocarcinoma of the colon, for the prevention of neurodegenerative diseases, in particular for Alzheimer's disease, for the prevention of stroke and epilepsy, and for the prevention of preterm birth, characterized in that ₇ that it contains a pharmaceutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 8, optionally together with a pharmaceutically acceptable excipient, vehicle or carrier. A pharmaceutical composition according to claim 10 or 11, characterized in that it is in the form of gelatin capsules or tablets containing a dose of 1 mg to 1000 mg or in the form of an injection preparation containing a dose of 0.1 mg to 500 mg .