Diarylethylene derivatives, method for their production and pharmaceutical composition based on them

 

(57) Abstract:

The present invention relates to diarylethylenes derivative of the formula I, in which the cycles a and b denote independently phenyl, naphthyl, heterocycle derived from 5-6 links and 1-4 heteroatoms derived saturated hydrocarbon cycle with 3-7 carbon atoms, at least one of the substituents X1X2, Y1or Y2necessarily mean the group-S(O)nR, in which n is an integer 0, 1 or 2; R is lower alkyl with 1 to 6 carbon atoms, a group-SO2NH2and is in the para-position, other means independently a hydrogen atom, halogen atom, lower alkyl with 1-6 carbon atoms, trifluoromethyl, lower-alkyl with 1-6 carbon atoms or X1and X2or Y1and Y2mean group methylendioxy, R1, R2, R3and R4denote independently a hydrogen atom, halogen atom, lower alkyl with 1-6 carbon atoms, lower halogenated with 1-6 carbon atoms, an aromatic radical selected from the group comprising phenyl, naphthyl, thienyl, furyl or pyridyl, or R1, R2or R3, R4mean oxygen atom, which have anti-inflammatory and analgesic properties, and t used in medicine. 3 S. and 8 C.p. f-crystals, 3 PL.

The present invention relates to diarylethylenes derivative of General formula (I) as new products.

One of the ways biotransformation of arachidonic acid is a cyclooxygenase, with the help of arachidonic acid is transformed into PGG2, then in PGH. The recent cloning and sequencing of cyclooxygenase helped to identify many species and, in particular, in humans, two isoenzyme MOR-1 and MOR-2. The first of these is a constitutive enzyme expressed in most tissues, whereas the second, expressed in some tissues such as the brain, induced mostly by a number of substances, in particular cytokines and mediators produced in the process of development of inflammatory reactions. Each of these enzymes has its role and the inhibition of MOR-1 and MOR-2 will cause different effects. Inhibition of MOR-1 will cause the reduction of prostaglandins involved in homeostasis, which can lead to side effects. Inhibition of MOR-2 will cause the reduction of prostaglandins produced in the process of inflammation. Therefore, selective inhibition of MOR-2 will allow you to get gocosmonaut to get such selective inhibition. Therefore, the compounds in question are of great interest for pharmacology due to the fact that they have anti-inflammatory and analgesic properties, excellently tolerated by the body at the level of the stomach. In particular, they will be used in the treatment of inflammatory processes and relief of pain.

For example, they can be used in the treatment of arthritis, namely rheumatoid arthritis, spondylitis, gouty arthritis, osteoarthritis, juvenile arthritis, autoimmune diseases, lupus erythematosus. They can also be used in the treatment of bronchial asthma, dysmenorhea, tendonitis, burstow, dermatological inflammation, such as psoriasis, eczema, burns, dermatitis, in the treatment of gastro-intestinal disease, Crohn's disease, gastritis, ulcerative colitis, for the prevention of cancer, particularly adenocarcinoma of the colon, for the prevention of neurodegenerative diseases, in particular Alzheimer's disease, for the prevention of sudden cerebral strokes, epilepsy and for the prevention of premature uterine birth.

Analgesic properties of these compounds allows them to be used in all kinds of pain symptoms, and have the research Institute of rheumatic diseases, pain cancer origin, as well as additional treatment in infectious diseases and fever.

The present invention relates also to a method for named products and their use in therapy.

Some derivatives described in the literature as having any abscopal selective properties of cyclooxygenase-2.

For example, you can name the compounds described in the application:

WO 9500501 A (Merck Frosst Canada Inc.)

WO 9415932 A (G. D. Searle et Co.)

WO 9608482 A (Merck et Co. Inc.)

Most of the compounds described in these applications as selective inhibitors of cyclooxygenase-2, is derived heterocycles with 5 atoms, substituted two aromatic rings are directly linked to the heterocycle and located on the two carbons adjacent to this heterocycle.

The applicant has unexpectedly found that derivatives bearing both aromatic rings of the same carbon, and these aromatic rings linked heterocycle are not directly, but via a double bond, have significant selective inhibitory properties of cyclooxygenase-2.

These diarylethylene derivatives distinguish analny radical

- nattily radical,

- derivative of the heterocycle with 5-6 units, including one heteroatom,

- derived saturated hydrocarbon cycle with 3-7 carbon atoms,

at least one of the substituents X1X2, Y1or Y2necessarily mean:

group-S(O)nR, in which n is an integer 0, 1 or 2, a R is lower alkyl with 1-6 carbon atoms,

group, - SO2NH2;

and is in the para-position,

other means independently

is a hydrogen atom,

is a halogen atom,

lower alkyl with 1-6 carbon atoms,

- trifluoromethyl,

the lowest 0-alkyl with 1-6 carbon atoms

or

X1and X2or Y1and Y2necessarily mean the group of methylendioxy,

R1, R2, R3and R4means independently

is a hydrogen atom,

is a halogen atom,

lower alkyl with 1-6 carbon atoms,

lowest halogenoalkane with 1-6 carbon atoms,

- aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl or pyridyl,

or

R1, R2or R3, R4mean oxygen atom.

In the description and the claims under lower alkyl imply l is ropel, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl.

Under the halogen imply chlorine atom, bromine, iodine or fluorine.

Under saturated hydrocarbon cycle having 3 to 7 carbon atoms include cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane or Cycloheptane.

Under the derivatives of heterocycle mean all aromatic cycles containing ring heteroatom of nitrogen, oxygen, or sulfur.

Among these cycles are particularly preferred pyridine, furan, thiophene, and pyrrole, imidazole, pyrazole, pyrazin, pyrimidine, pyridazine, oxazole, akonadictl, thiazole, thiadiazole.

The above-mentioned derivatives of the formula (I) can represent the centers of asymmetry and/or may be in the form of derivatives of CIS or TRANS. The invention encompasses the racemic mixture, a mixture of compounds CIS and TRANS, but is also optically active products derived CIS and derivatives trance, taken separately. These pure products is carried out according to well-known specialists techniques, in particular, by chromatography on chiral columns, when talking about optical isomers. In some cases, this separation can be done by PR the synthesis, and in this case the continuation of the synthesis will correspond to the stereochemistry of a molecule of intermediate compounds.

Preferably, the derivatives according to the invention are derivatives of the above formula (I) in which:

Loops a and b denote independently a radical:

- phenyl,

- naphthyl,

- pyridyl,

- furyl,

- thienyl,

- cyclohexyl,

at least one of the substituents X1, X2, Y1or Y2necessarily mean the group S3, SO2CH3or SO2NH2,

other means independently:

is a hydrogen atom,

is a halogen atom,

lower alkyl with 1-6 carbon atoms,

- trifluoromethyl,

- lower O-alkyl with 1-6 carbon atoms

R1, R2mean oxygen atom,

R3, R4denote independently a hydrogen atom or a lower alkyl with 1-6 carbon atoms.

Preferably, in the framework of the present invention is used as a compound of formula (I), in which the at least one of the following conditions:

the cycle means phenyl,

- X1- group 4-SO2CH3or group 4-SO2NH2,

- X2is a hydrogen atom,

cycle a is phenyl or pyridyl,

- YB>1,R2is an oxygen atom,

- R3is a hydrogen atom,

- R4- the hydrogen atom.

Particularly preferred compounds according to the invention are derivatives of the formula (E)-3-[1-(4-forfinal)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

< / BR>
(Z)-3-[1-(4-chlorophenyl)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

< / BR>
(Z)-3-[1-(3,4-dichlorophenyl)-1-(4-methanesulfonyl)-methylidene] dihydrofuran-2-it,

< / BR>
(Z)-3-[1-(6-chloropyridin-3-yl)-1-(4-methanesulfonyl) methylidene] dihydrofuran-2-it,

< / BR>
(Z)-4-[(4-chlorophenyl)-(2-oxopiperidin-3-ilidene)methyl] benzosulfimide

< / BR>
(Z)-4-[(3-fluoro-4-were)-(2-oxopiperidin-3-ilidene)methyl] benzosulfimide

< / BR>
According to the invention the compounds of formula (I) can be synthesized as follows:

Using reaction Friedel-acid chloride of the acid of formula (II)

< / BR>
in which A, Y1and Y2defined above with thioanisole receive a ketone of formula (III)

< / BR>
in which A, Y1and Y2have the above values.

This ketone can be obtained also by using the Grignard reaction: the reaction of the magnesium-containing brominating derivative, which may be substituted on islote, perborate sodium or hydrogen peroxide in the presence of catalytic amounts of salts of molybdenum, get derivative of the formula (IV):

< / BR>
in which A, Y1and Y2have the above values.

Processing the derived formulas (IV) through reaction of the reformed, modified bromobutyrate formula (V)

< / BR>
in which R3and R4have the above meanings, in the presence of magnesium and a small amount under the conditions to initiate the reaction, get derivatives of the formula (VI):

< / BR>
in which A, Y1, Y2, R3and R4have the above values.

Dehydratase derivatives of the formula (VI) by heating in toluene, for example in the presence of paratoluenesulfonyl acid, or by treatment triperoxonane anhydride in triperoxonane acid, receive the compounds of formula (I):

< / BR>
which is a phenyl ring, X1- group 4-SO2CH3, X2is a hydrogen atom, R1, R2is an oxygen atom, a a, Y1, Y2, R3and R4have the above values.

One of the embodiments is that the product of formula (III) process or a derivative of formula (V) with the initiation of the reaction, or the lactones of the formula (V')

< / BR>
in which R3and R4have the above meanings, in the presence of bromide N, N-diethylaminophenyl obtained by exposure to N,N-diethylamino on bromide of etermine, according to information reference: K. Sisido, H. Nozaki, O. Kurihara J. Am. Chem. Soc., 74, 6254 (1952) to receive either already digidrirovannye the compounds of formula (I) or the compounds of formula (VI')

< / BR>
in which A, Y1, Y2, R3and R4have the above values.

Then the compounds of formula (VI') dehydration using triperoxonane anhydride and triperoxonane acid to obtain the compounds of formula (I):

< / BR>
in which In - phenyl ring, X1- group 4-S3, X2is a hydrogen atom, R1, R2is an oxygen atom, a a, Y1, Y2, R3and R4have the above values.

Processing the thus obtained compound with metallocarboranes acid or other oxidizing agent, for example Pavo3, 4H2Oh, will, depending on the used amount of oxidant, to compounds of formula (I)

< / BR>
in which In - phenyl ring, X1- group 4-S3for one equivalent of the oxidizing agent or group 4-SO2 is A, Y1, Y2, R3and R4have the above values.

Another option for obtaining compounds of formula (I) is that processes the ketone of formula (III) with ethylsuccinate according to the reaction of Stobbe in tert-butanol in the presence of tert-butyl sodium or potassium hydroxide, to obtain the compounds of formula (VII)

< / BR>
in which A, Y1and Y2have the above values.

Selective recovery of ester, for example, calcium borohydride, obtained in situ from potassium borohydride and calcium chloride in ethanol, or in diethyldithiocarbamate sodium in ethyl ether, leads after lactonization received hydroxy acids, derivatives of the formula (VIII).

< / BR>
in which A, Y1and Y2have the above values.

Derivatives of the formula (VIII) can be oxidized as described above, the group S3turns into a group S3or SO2CH3depending on the used amount of the oxidizing agent, to obtain the compounds of formula (I)

< / BR>
in which In - phenyl ring, X1- group 4-S3or group 4-SO2CH3, X2, R1and R2is a hydrogen atom, R3, R4- at the uly (VII) using dual lithium aluminum hydride, for example, in tetrahydrofuran results in diodes of the formula (IX)

< / BR>
in which A, Y1, Y2have the above values.

Dehydration of these diodes using sulfuric acid or by boiling toluene under reflux in the presence of paratoluenesulfonyl acid with the device Dina stark allows to obtain the compounds of formula (I)

< / BR>
in which A, Y1and Y2have the above meanings, In - phenyl ring, X1- group 4-S3, X2, R1, R2, R3, R4means a hydrogen atom.

Treating these derived oxidant as described above, receive the corresponding derivatives in which X1means group 4-S3or group 4-SO2CH3depending on the used amount of oxidant.

You can use other ways to produce compounds of formula I.

The reaction of ketones, compounds of formula (IV) with ethylsuccinate according to the reaction of Stobbe carried out in tert-butanol in the presence of tert-butyl sodium or potassium, leading, for example, to obtain compounds of the formula (X):

< / BR>
in which A, Y1and Y2have the above values.

In the RAS/metilsulfate in tetrahydrofuran or ethyl ether leads to the production of esters, containing an alcohol group of the formula (XI):

< / BR>
in which A, Y1and y2have the above values.

These esters containing an alcohol group of the formula (XI), or the corresponding acid containing an alcohol group, obtained by hydrolysis of ester with sodium hydroxide in ethanol by boiling under reflux, cyclist by heating in an aromatic solvent such as toluene, for example, in the presence of paratoluenesulfonyl acid to obtain the compounds of formula (I):

< / BR>
in which A, Y1, Y2have the above meanings, In the phenyl nucleus, X1- group 4-SO2CH3, X2, R3and R4means a hydrogen atom, a R1, R2the oxygen atom.

The compounds of formula (XII) in which A, Y1, Y2have the abovementioned meanings, can be obtained according to reaction scheme, in which Ph means a phenyl group, a Z means the radical MDG, when a is phenyl, and a radical Li, when a is pyridyl.

< / BR>
Another option is to get diarylethene (C) used in the preceding reaction scheme, by influencing benzylmercaptan PhCh2SH on foldericon in dimethylformamid the unity of formula (X), to obtain the compounds of formula (I):

< / BR>
in which In - phenyl ring, X1 is a group 4-SO2NHt-Bu, X2, R3and R4is a hydrogen atom, R1, R2is an oxygen atom, a a, Y1and Y2have the above values.

Processing these derivatives of a strong acid, for example concentrated sulfuric acid, triperoxonane acid or by heating in toluene in the presence of paratoluenesulfonyl acid, receive the compounds of formula (I), in which In - phenyl ring, X1- group 4-SO2NH2, X2, R3and R4is a hydrogen atom, R1, R2is an oxygen atom, and A, Y1and Y2have the above values.

The above compounds of formula (I) are inhibitors of cyclooxygenase-2 and possess good anti-inflammatory and pain-soothing activity along with excellent tolerance, in particular gastric.

Thanks to these properties, they can be used in therapy. Therefore, an object of the present invention as medicines are products defined by the above formula (I).

The object of the invention is also a pharmaceutical composition, characterized in that it on the uly (I) optionally included in excipient, binder or pharmaceutically acceptable carrier.

These compositions can be assigned for oral administration, rectal, parenteral, percutaneous, ocular, nazalnam or auricular way.

They can be solid or liquid and can represent all the pharmaceutical forms currently used in medicine, such as pills and simple index, gelatin capsules, granules, suppositories, injectable preparations, percutaneous system, lotions for the eyes, aerosols and sprays and ear drops. Methods of receiving the usual and well-known. The active principle consisting of a pharmaceutically effective amount of at least one of the above compounds of formula (I), may be included in used in these pharmaceutical compositions excipients. It can be talc, gum Arabic, lactose, starch, magnesium stearate, polyvidone, derivatives of cellulose, cocoa butter, semi-synthetic triglycerides, aqueous or non-aqueous binder, fats of animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, some polymers and copolymers, preservatives, fragrances and dyes. the Commissioner action providing, in particular, a favorable effect in the treatment of inflammation and pain, characterized in that it comprises a pharmaceutically effective amount of at least one compound of a specified formula (I), introduced in excipient, binder or pharmaceutically acceptable carrier. According to the method of execution, receive pharmaceutical composition with anti-inflammatory and analgesic effect, allowing, in particular, to safely treat a variety of inflammation and pain.

According to one variant of implementation get the composition is formulated as gelatin capsules or tablets with a dosage of 1 mg to 1000 mg, or in the form of injections with a dosage of 0.1 mg to 500 mg. you Can also use the formulation in the form of suppositories, ointments, creams, gels, aerosol preparations, percutaneous drugs or patches.

The invention relates also to a method of therapeutic treatment of mammals, characterized in that the mammal is prescribed therapeutically effective amount of at least one compound of the above formula (I). According to one variant of implementation of this method, the compound of formula (I) or on the Ah with a dosage of 1 mg to 1000 mg for oral administration, or injected drugs with dosage ranging from 0.1 mg to 500 mg, or in the form of suppositories, ointments, creams, gels or aerosols.

This method allows, in particular, successfully treat inflammation and pain.

When therapeutic treatment of human and animal compounds of formula (I) can be prescribed alone or in combination with physiologically acceptable excipients in any pharmaceutical form, in particular oral route in the form of gelatin capsules or tablets or parenterally in the form of solutions for injection. Can be considered for other purposes, such as suppositories, ointments, creams, gels and aerosol preparations.

Of the pharmacological tests, presented in the end of the description, it is seen that in the treatment of a person with the above indications compounds according to the invention can be assigned in the form of gelatin capsules or tablets with a dosage of 1 mg to 1000 mg for oral administration or in the form of injections with a dosage of 0.1 mg to 500 mg for once or several times per day for an adult weighing 60-70 kg for receiving parenteral.

In the treatment of animals used daily doses ranging from 0.1 mg to 100 mg per kilogram.< examples which do not limit the invention, as shown in the illustration.

EXAMPLE 1

4-fluoro-4'-methylthioinosine

Formula (III): A=phenyl, Y1=4-F, Y2=H

To a solution of 70 g (0,564 mol) of thioanisole and 90.2 g (0,654 mol) of 4-perbendaharaan in 500 ml of dichloromethane added in portions to 86.4 g of trichloride aluminum at a temperature of from 0oWith up to 5oC. After the addition the mixture is brought to room temperature, then heated under reflux for 2 hours. After cooling, the reaction medium is poured into a mixture of ice/dilute hydrochloric acid, and the organic phase is decanted, dried over magnesium sulfate and evaporated in vacuo to obtain a residue, which crystallized in isopropyl ether and give 118 g of 4-fluoro-4'-methyldibenzothiophene with a melting point of 88oC.

EXAMPLE 2

4-fluoro-4'-methysulfonylmethane

Formula (IV): A= phenyl, Y1=4-F, Y2=H

To a solution of 25 g (0,1015 mole) of 4-fluoro-4'-methyldibenzothiophene obtained in example 1 in 350 ml dichloromethane added in portions 87 g of 70% aqueous solution of 3-chloroperbenzoic acid at a temperature of from 0oWith up to 5oC. the mixture is Then stirred at 0oC for 30 minutes, the t and washed in a dilute solution of sodium hydroxide, then dissolved in dichloromethane. The organic phase is dried over magnesium sulfate and evaporated in vacuum to obtain an oil, which crystallized in isopropyl ether and gives to 24.6 g of 4-fluoro-4'-methysulfonylmethane with a melting point of 136oC.

EXAMPLE 3

3-[1-(4-forfinal)-1-hydroxy-1-(4-methanesulfonyl)methyl]dihydrofuran-2-he

Formula (IV): A=phenyl, Y1=4-F, Y2=H, R3=R4=H

Shavings of magnesium (3.5 g) cover anhydrous tetrahydrofuran and add a few drops of iodomethane. As soon as the reaction started, is added dropwise a mixture of 24.6 g of 4-fluorescent-4'-methysulfonylmethane and 8.1 ml-bromo-butyrolactone 250 ml of anhydrous tetrahydrofuran, to support light reflux. After adding the reaction medium is cooled, then poured into a mixture of ice/10% aqueous solution of sulfuric acid. The organic phase is extracted in tetrahydrofuran and washed with saturated sodium bicarbonate solution, then dried over magnesium sulfate. After evaporation of the solvent, the obtained residue chromatographic on silica gel with elution of a mixture of dichloromethane/acetone (9/1) to obtain 7 g of 3-[1-(4-forfinal)-1-hydroxy-1-(4-methanesulfonyl)methyl] dihydrofuran-2-on�)-3-[1-(4-forfend)-1-(4-methanesulfonyl phenyl)-methylidene] dihydrofuran-2-he

The isomer (S): Formula (I): a=b=phenyl, Y1=4=F, X2=Y2=H, X1=4-SO2CH3, R1, R2=0, R3=R4=H.

To a solution of 7 g of 3-[1-(4-forfinal)-1-hydroxy-1-(4-methanesulfonyl)methyl] dihydrofuran-2-she obtained in example 3 in 100 ml of toluene, add a few mg of 4-toluensulfonate acid and the mixture heated under reflux for 10 hours with an instrument Dean-stark. The solvent is then evaporated to dryness in vacuo and the residue chromatographic when the elution of a mixture of dichloromethane/acetone (9/1) to obtain the oil, which elute tert-butylmethylether to obtain 2.9 g (E)-3-[1-(4-forfinal)-1- (4-methanesulfonyl)methylidene] dihydrofuran-2-it (second suirvey product) in the form of crystals with a melting point 187-9oC. Recuperat 1.5 g (Z)-3-[1-(4-forfinal)-1-(4-methanesulfonyl)methylidene]dihydrofuran-2-it (first suirvey product) in the form of crystals with a melting point 157-158oC.

EXAMPLE 5

4-hdor-4'-meridiansoth

Formula (III): A=phenyl, Y1=4-Cl, Y2=H.

Receive according to the method of example 1.

Crystals with a melting point of 134oC.

EXAMPLE 6

3-[1-(4-(chlorophenyl)-1-hydroxy-1-(4-BR> To 5.9 g magnesium turnings covered with anhydrous tetrahydrofuran, add a few drops of iodomethane. As soon as the reaction starts, add one drop of a mixture of 17 g of 4-chloro-4'-methyldibenzothiophene and 12.6 ml-bromo-butyrolactone in 300 ml of anhydrous tetrahydrofuran, to support light reflux. After the addition the mixture is stirred at room temperature for 1 hour and 30 minutes, then cooled in an ice bath. Then add a saturated solution of ammonium chloride and the mixture is stirred, then decanted. The organic phase is dried over magnesium sulfate and evaporated in vacuum to obtain an oily residue, which after chromatography on silica gel with elution with dichloromethane gives 8.5 g of 3-[1-(4-chlorophenyl)-1-hydroxy-1-(4-methylthiophenyl)methyl] dihydrofuran-2-it is in the form of oil, is further used in crude form.

EXAMPLE 7

3-[1-(4-chlorophenyl)-1-(4-methylthiophenyl)meta-Liden]dihydrofuran-2-he

Formula (I): a=b=phenyl, Y1=4-Cl, Y2=X1=H, X2=4-S3, R1, R2=0, R3=R4=N

To a solution of 8.6 g of 3-[ 1-(4-chlorophenyl)-1-hydroxy-1-(4-methylthiophenyl)methyl]dihydrofuran-2-it, obtained in example 6 in 100 ml of dichloromethane 5,2 g triperoxonane anhydride and 3.8 ml of the water and decanted. The organic phase is dried over magnesium sulfate and evaporated in vacuum to obtain 7.5 g of 3-[1-(4-chlorophenyl)-1-(4-methylthiophenyl)methylidene] dihydrofuran-2-it is in the form of an oil used as is in the future.

EXAMPLE 8

(Z)-3-[1-(4-chlorophenyl)-1-(4-methanesulfonyl)methylidene]-dihydrofuran-2-he

The isomer (Z): Formula (I): a=b=phenyl, Y1=4=Cl, Y2=X1=H, X2=4-SC2CH3, R1, R2=0, R3=R4=N.

To a solution of 9.5 g of 3-[1-(4-chlorophenyl)-1- (4-methylthiophenyl)methylidene] dihydrofuran-2-she obtained in example 7, in 120 ml acetic acid is added 11 g digidrirovannoe sodium perborate. The mixture is heated at 40-50oC for 5 hours, then cooled. Formed crystals are centrifuged, washed with water, then chromatographic on silica gel with elution of a mixture of dichloromethane/acetone (99/1) to obtain 4.1 g (Z)-3-[1-(4-chlorophenyl)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-it is in the form of crystals with a melting point 197-199oC.

The selection of the second lirovannomu product allows to obtain 2.5 g (E)-3-[1-(4-chlorophenyl)-1-(4-methanesulfonyl)-methylidene] dihydrofuran-2-it is in the form of crystals with a melting point 211-212oC.

Premphase method of example 1.

Crystals with a melting point of 76oC.

EXAMPLE 10

4-fluoro-4'-methysulfonylmethane

Formula (IV): A=phenyl, Y1=3-F, Y2=H.

Receive according to the method of example 2.

Crystals with a melting point of 106oC.

EXAMPLE 11

3-etoxycarbonyl-4-(3-forfinal)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=3-F, Y2=H

To a solution of 15.7 g (0,140 mol) of potassium tert-butylate in 100 ml of tert-butanol add portions of 35.5 g (0,1275 mole) of 4-fluoro-4'-methysulfonylmethane obtained in example 10. The mixture is stirred and quickly added dropwise 32 ml (0,191 mole) of ethylsuccinate. The mixture is then heated under reflux for 30 minutes, cool and add water and 1N hydrochloric acid to get pH 1, then extracted into tert-butylmethylether. The organic phase is treated with 2% potassium hydroxide solution and the mixture is decanted. The aqueous phase is acidified with 1N hydrochloric acid, then extracted into tert-butylmethylether. The organic phase is dried over magnesium sulfate and evaporated in vacuum to get about 39.2 g of 3-etoxycarbonyl-4-(3-forfinal)-4-(4-methanesulfonyl)-3-butenova acid in the form of a thick oil used shall yl)-2-ethylpropane

Formula (XI): A=phenyl, Y1=3-F, Y2=H.

To a solution of 31.5 g (0,0775 mole) 3-etoxycarbonyl-4-(3-forfinal)-4-(4-methanesulfonyl)-3-butenova acid obtained in example 11, in 90 ml of anhydrous tetrahydrofuran was added drop of 15.5 ml (0,155 mole) of borane complex/metilsulfate. The mixture is stirred at room temperature for 8 hours and add one drop of 23.5 ml of methanol. The mixture is evaporated to dryness in vacuo, the residue treated with ethyl acetate, then treated with an aqueous solution of 7.6 g of potassium carbonate. The organic phase is decanted, dried over magnesium sulfate and evaporated to dryness in vacuo to obtain 29.3 g of 3-(3-forfinal)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane in the form of viscous oils used in this form in the future.

EXAMPLE 13

(Z)-3-[1-(3-forfinal)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-F, X2=Y2=H, X1=4-SO2CH3, R1, R2=0, R3=R4=N

To a solution of 29.3 g of 3-(3-forfinal)-3-(4-methanesulfonyl) -2-(2-hydroxyethyl)-2-ethylpropane obtained in example 12, 50 ml ethanol, added 3.3 grams of sodium hydroxide in solution in 10 ml of water and the mixture is heated with hydrochloric acid, then extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated in vacuum to obtain an oily residue. The oil is dissolved in 150 ml of toluene and add 10 mg paratoluenesulfonyl acid. The mixture is heated under reflux and the water formed is removed by means of the device Dina stark. After cooling, the mixture is washed with water, the organic phase is dried over magnesium sulfate, evaporated in vacuo, and the residue chromatographic on silica with elution tert-butylmethylether to obtain 4 g (Z)-3-[1-(3-forfinal)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-it (second suirvey product) in the form of crystals with a melting point 153-154oC.

EXAMPLE 14

3,4-dindar-4'-methylthioinosine

Formula (III): A=phenyl, Y1=3-Cl, Y2=4-Cl.

Receive according to the method of example 1.

Crystals with a melting point of 100oC.

EXAMPLE 15

3,4-dichloro-4'-methysulfonylmethane

Formula (IV): A= phenyl, Y1=3-Cl, Y2=4-Cl.

Receive according to the method of example 2.

Crystals with a melting point of 158oC.

EXAMPLE 16

3-etoxycarbonyl-4-(3,4-dichlorophenyl)-4- (4-methanesulfonyl example 11.

The oil used is, as is in the future.

EXAMPLE 17

3-(3,4-dichlorophenyl)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane

Formula (XI): A=phenyl, Y1=3-Cl, Y2=4-C1

Receive according to the method of example 12.

The oil used in this form in the future.

EXAMPLE 18

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

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-Cl, Y2=4-Cl, X2=H, X1=4-SO2CH3, R1, R2=0, R3=R4=H.

Receive according to the method of example 13.

Chromatographic when the elution of a mixture of dichloromethane/acetone (99/1), the first suirvey product.

Crystals with a melting point 195-197oC.

During chromatography, the selection of the second lirovannomu product allows to obtain the isomer (E)-3-[1-(3,4-dichlorophenyl)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-it is in the form of crystals with a melting point of 163-164oC.

EXAMPLE 19

4-chloro-4'-methylthioinosine

Formula (III): A=phenyl, Y1=3-Cl, Y2=H.

Receive according to the method of example 1.

Crystals with a melting point of 70oC.

PR is according to the method of example 2.

Crystals with a melting point of 140oC.

EXAMPLE 21

3-etoxycarbonyl-4-(3-chlorophenyl)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=3-Cl, Y2=H.

Receive according to the method of example 11.

The oil used in this form in the future.

EXAMPLE 22

3-(3-chlorophenyl)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane

Formula (XI): A=phenyl, Y1=3-Cl, Y2=H

Receive according to the method of example 12.

The oil used in this form in the future.

EXAMPLE 23

(Z)-3-[1-(3-chlorophenyl)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-Cl, X2=Y2=H, X1-4-SO2CH3, R1, R2=0, R3=R4=H.

Receive according to the method of example 13.

Chromatographic when the elution of a mixture of dichloromethane/acetone (99/1), the first suirvey product.

Crystals with a melting point 147-149oC.

The selection of the second lirovannomu product during chromatography allows to obtain compound (E)-3-[1-(3-harfe-nil)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-it is in the form of crystals with point PL is/SUB>=H.

Receive according to the method of example 1.

Crystals with a melting point of 84oC.

EXAMPLE 25

4-methysulfonylmethane

Formula (IV): A=phenyl, Y1=Y2=H

Receive according to the method of example 2.

Crystals with a melting point of 150oC.

EXAMPLE 26

3-etoxycarbonyl-4-phenyl-4-(4-methanesulfonyl)-3-butenova acid

Formula (X ): A=phenyl, Y1=Y2=H.

Receive according to the method of example 11.

The oil used in this form in the future.

EXAMPLE 27

3-phenyl-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane

Formula (XI): A=phenyl, Y1=Y2=H.

Receive according to the method of example 12.

The oil used is, as is in the future.

EXAMPLE 28

(E)-3-[1-phenyl-1-(4-methanesulfonyl)methylidene]-dihydrofuran-2-he

The isomer (S): formula (I): a=b=phenyl, Y1=Y2=H, X2=N, X1=4-SO2CH3, R1, R2= 0, R3=R4=H.

Receive according to the method of example 13.

Chromatographic on silica gel with elution of a mixture of dichloromethane/acetone (99/1), the first suirvey product.

Crget isomer (Z)-3-[1-phenyl-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-it is in the form of crystals with a melting point 206-208oC.

EXAMPLE 29

5,5-dimethyl-3-[1-(4-forfinal)-1-hydroxy-1-(4-methylthiophenyl)methyl] dihydrofuran-2-he

Formula (VI'): A=phenyl, Y1=4-F, Y2=H, R3=R4=CH3< / BR>
To a suspension of 2.4 g magnesium turnings in anhydrous ethyl ether is added dropwise 7.5 ml of brometane. Once added, the mixture is cooled to 0oWith and 10.5 ml of N,N-diethylamine added dropwise. The reaction medium is stirred for one hour at room temperature, then 15 minutes, heated under reflux and cooled in an ice bath of ice and sodium chloride. Add drop by drop a solution of 12.3 g of 4-fluoro-4'-methyldibenzothiophene obtained in example 1, and 5.7 g of 4,4-dimethylbutylamine in 50 ml of anhydrous tetrahydrofuran, maintaining the temperature from 0oWith up to 5oC. the mixture is Then refluxed for 2 hours, cooled and treated with 100 ml of a 10% solution of sulfuric acid. After extraction with ethyl ether, the organic phase is dried over magnesium sulfate and evaporated in vacuum to obtain 4.8 g of 5,5-dimethyl-3-[1-(4-forfinal)-1-hydroxy-1-(4-methylthiophenyl)methyl]dihydrofuran-2-it is in the form of crystals of melting point 185oC.

EXAMPLE 30

5,5-dimethyl-3-[1-(4-forfinal)SUB>=H, X1=4-SCH3, R1R2=0, R3=R4=CH3.

The isomer (Z): Formula (I): a=b=phenyl, X1=4-F, X2=Y2=H, Y1=4-SCH3, R1, R2= 0, R3=R4=CH3.

Receive according to the method of example 4 from a derivative of example 29.

Both isomers split by fractional crystallization in a mixture of isopropyl ether/pentane:

(E)-5,5-dimethyl-3-[1-(4-forfinal)-1- (4-methylthiophenyl)methylidene] dihydrofuran-2-it, melting point 98oC.

(Z)-5,5-dimethyl-3-[1-(4-forfinal)-1-(4-methylthiophenyl)-methylidene] dihydrofuran-2-it, melting point 160oC.

EXAMPLE 31

(E)-5,5-dimethyl-3-[1-(4-forfinal)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

The isomer (S): Formula (I): a=b=phenyl, Y1=4-F, X2=Y2=H, X1=4-SO2CH3, R1, R2=0, R3=R4=CH3.

To a solution of 2 g of (E)-5,5-dimethyl-3-[1-(4-forfinal)-1-(4-methylthiophenyl)methylidene]dihydrofuran-2-she obtained in example 30, in 15 ml of acetic acid are added to 1.9 g digidrirovannoe sodium perborate. The mixture is heated for 3 hours at 45oWith the formed crystals are centrifuged at heating and chromatographic on silicagel hilfer) methylidene] dihydrofuran-2-it is in the form of crystals with a melting point of 175oC.

EXAMPLE 32

5-ethyl-3-[1-(4-forfinal)-1-hydroxy-1-(4-methylthiophenyl)-methyl]dihydrofuran-2-he

Formula (VI'): A=phenyl, Y1=4-F, Y2=H, R3=C2H5, R4=H.

Receive according to the method of example 29 from-caprolactone.

Crystals with a melting point of 150oC.

EXAMPLE 33

5-ethyl-3-[1-(4-forfinal)-1-(4-methylthiophenyl)methylidene] -dihydrofuran-2-he

The isomer (S): Formula (I): a=b=phenyl, Y1=4-F, X2=Y2=H, X1=4-SCH3, R1, R2= 0, R3=C2H5, R4=H.

The isomer (Z): Formula (I): a=b=phenyl, X1=4-F, X2=Y2=H, Y1=4-SCH3, R1, R2= 0, R3=C2H5, R4=H.

Receive according to the method of example 4 from a derivative of example 29. A mixture of the two isomers (E) and (Z) is used as such in the future.

EXAMPLE 34

(E)-5-ethyl-3-[1-(4-forfinal)-1-(4-methanesulfonyl)methylidene]dihydrofuran-2-he

The isomer (S): Formula (I): a=b=phenyl, Y1=4-F, X2=Y2=H, X1=4-SO2CH3, R1, R2=0, R3=C2H5, R4=H.

Receive according to the method of example 31. Isomer (E)-5-ethyl-3-[1-(4-forfinal)-1-(4-methanesulfonyl) is n (99/1) and obtained as crystals with a melting point 134-136o(First suirvey product).

The selection of the second lirovannomu product during chromatography allows to obtain (Z)-5-ethyl-3-[1-(4-forfinal)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-it is in the form of crystals with a melting point of 176-177oC.

EXAMPLE 35

5-methyl-3-[1-(4-chlorophenyl)-1-hydroxy-1-(4-methylthiophenyl)-methyl]dihydrofuran-2-he

Formula (VI'): A=phenyl, Y1=3-Cl, Y2=N, R3=CH2, R4=H.

Receive according to the method of example 6 from 3-chloro-4'-methyldibenzothiophene and-bromo-valerolactone.

Amorphous powder used in the future.

EXAMPLE 36

5-methyl-3-[1-(3-chlorophenyl)-1-(4-methylthiophenyl)methylidene] dihydrofuran-2-he

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-Cl, X2=Y2=H, X1=4-SCH3, R1, R2= 0, R3=CH3, R4=H.

The isomer (S): Formula (I): a=b=phenyl, X1=3-Cl, X2=Y2=H, X1=4-SCH3, R1, R2= 0, R3=CH3, R4=H.

Receive according to the method of example 4 of the derivative of example 35. A mixture of the two isomers used in the form of butter.

EXAMPLE 37

(Z)-5-methyl-3-[1-(3-chlorophenyl)-1-(4-methanesulfonyl)methyl]digid R1, R2=0, R3=CH3, R4=H.

Receive according to the method of example 31. The isomer (Z)-5-methyl-3-[1-(3-chlorophenyl)-1-(4-methanesulfonyl)methyl] dihydrofuran-2-he purified chromatographically on silica gel with elution of a mixture of dichloromethane/acetone (99/1) as amorphous powder (first suirvey product).

The selection of the second lirovannomu product allows to obtain the isomer (E)-5-methyl-3-[1-(3-chlorophenyl)-1- (4-methanesulfonyl)methyl] dihydrofuran-2-it is in the form of crystals with a melting point of 164-165oC.

EXAMPLE 38

2-chloro-5-(4-methylthiophenyl)pyridine

Formula (III): A=3-pyridyl, Y1=6-Cl, Y2=N.

Receive according to the method of example 2.

Crystals with a melting point of 150oC.

EXAMPLE 39

2-chloro-5-(4-methansulfonate)pyridine

Formula (IV): A=3-pyridyl, Y1=6-Cl, Y2=H.

A solution of 34.6 g of 2-chloro-5-(4-methylthiophenyl)pyridine obtained in example 38, and 42 g digidrirovannoe perborate of sodium in 250 ml of acetic acid is heated for 4 hours at 45oC. the Formed crystals are centrifuged under heating, and then washed with water and dried to obtain a 32.6 g of 2-chloro-5-(4-methansulfonate)pyridine is Il-4- (4-methanesulfonyl)-3-butenova acid

Formula (X): A=3-pyridyl, Y1=6-Cl, Y2=H.

Receive according to the method of example 11 of the derivative of example 39.

Solid amorphous substance used in this form in the future.

EXAMPLE 41

3-(6-chloropyridin-3-yl)-2-(2-hydroxyethyl)-3- (4-methanesulfonyl)-2-ethylpropane

Formula (XI): A=3-pyridyl, Y1=6-Cl, Y2=N.

Receive according to the method of example 12 of the derivative of example 40.

Solid amorphous substance used as such in the future.

EXAMPLE 42

(Z)-3-[1-(6-chloropyridin-3-yl)-1-(4-methanesulfonyl)-methylidene]dihydrofuran-2-he

The isomer (Z): Formula (I): A=3-pyridyl, A=phenyl, Y1=6-Cl, X2=Y2=H, X1=4-SO2CH3, R1, R2=0, R3=R4=N.

Receive according to the method of example 13 of the derivative of example 41.

The isomer (Z) receive chromatography with elution of a mixture of dichloromethane/acetone (5/1), and then by means of crystallization in a mixture of acetone/ethyl ether in the form of crystals with a melting point of 172-174oC.

Isomer (E)-3-[1-(6-chloropyridin-3-yl)-1- (4-methanesulfonyl)methylidene] dihydrofuran-2-he get in pure form through crystallization in acetone, Perrier 43

3-etoxycarbonyl-4-(4-forfinal)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=4-F, Y2=H.

Receive according to the method of example 11 from 4-fluoro-4'-methysulfonylmethane obtained in example 2.

The oil used in the same form for the future.

EXAMPLE 44

4-[1-(4-forfinal)-1-(4-methanesulfonyl)methylidene]-dihydrofuran-2-he

Formula (I): a=b=phenyl, X1=4-SO2CH3X2=Y2=H, Y1=4-F, R1, R2=H, R3, R4= 0.

To a solution of 3-etoxycarbonyl-4-(4-forfinal)-4- (4-methanesulfonyl)-3-butenova acid obtained in example 43, in 500 ml ethanol add 13.6 powder anhydrous calcium chloride. The mixture is stirred at room temperature and added drop by drop to 7.5 g of a solution of sodium borohydride in a mixture consisting of 1.5 g of potassium hydroxide, 10 ml of water and 10 ml of ethanol, cooling in an ice bath. After 4 hours at room temperature, the reaction medium is cooled to 0oWith and add drop by drop a solution of 6N-hydrochloric acid. After extraction with dichloromethane the organic phase is dried over magnesium sulfate, evaporated in vacuo and the residue is crystallized in isopropyl ether. The obtained crystals RecA in the form of a mixture (50/50) of the two isomers (E) and (Z), crystals with a melting point 160-164oC.

EXAMPLE 45

3-methyl-4'-methylthioinosine

Formula (III): A=phenyl, Y1=3-CH3, Y2=H.

Receive according to the method of example 1.

Crystals with a melting point 46-47o.

EXAMPLE 46

3-methyl-4'-methysulfonylmethane

Formula (IV): A=phenyl, Y1=3-CH3, Y2=H.

Receive according to the method of example 2.

Crystals with a melting point of 150oC.

EXAMPLE 47

3-etoxycarbonyl-4-(3-were)-4-(4-methanesulfonyl)3-butenova acid

Formula (X): A=phenyl, Y1=3-CH3, Y2=H.

Receive according to the method of example 11 of the derivative of example 46.

The oil used in the same way for the future.

EXAMPLE 48

3-(3-were)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane

Formula (XI): A=phenyl, Y1=3=CH3, Y2=H.

Receive according to the method of example 12 of the derivative of example 47.

Oil is what is, for future reference.

EXAMPLE 49

The isomer (Z)-3-[1-(3-were)-1-(4-methanesulfonyl)methylidene]dihydrofuran-2-he

The isomer (Z): Formula (I)UB>4
=N.

Receive according to the method of example 13 of the derivative of example 48.

Purify by chromatography on silica gel with elution of a mixture of dichloromethane/acetone (99/1), the first suirvey product in the form of crystals with a melting point of 166oC.

EXAMPLE 50

3,4-debtor-4'-methylthioinosine

Formula (III): A=phenyl, Y1=3-F, Y2=4-F.

Receive according to the method of example 1 of the derivative of example 50.

Crystals with a melting point of 96oC.

EXAMPLE 51

3,4-debtor-4'-methysulfonylmethane

Formula (IV): A=phenyl, Y1=3-F, Y2=4-F.

Receive according to the method of example 1 of the derivative of example 50.

Crystals with a melting point of 120oC.

EXAMPLE 52

3-etoxycarbonyl-4-(3,4-differenl)-4-(methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=3-F, Y2=4-F.

Receive according to the method of example 11 of the derivative of example 51.

The oil obtained in the form used in the future.

EXAMPLE 53

3-(3,4-differenl)-3-(4-methanesulfonyl-2-(2-hydroxyethyl)-2-ethylpropane

Formula (XI): A=phenyl, Y1=3-F, Y2=4-F.

Get under/P> EXAMPLE 54

(Z)-3-[1-(3,4-differenl)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-F, Y2=4-F, X2=SO2CH3X2=H, R1, R2=0, R3=R4=H.

Receive according to the method of example 13 of the derivative of example 53.

Purified chromatographically on silica gel with elution of a mixture of dichloromethane/acetone (99/1), the first suirvey product crystals with a melting point of 148oC.

EXAMPLE 55

4-benzylcyanide

A mixture of 37,2 g benzylmercaptan, of 36.3 g of 4-perbenzoate and 42 g of potassium carbonate in 700 ml of 2-butanone refluxed for 7 hours. The solvent is evaporated in vacuum, the residue is treated with water and petroleum ether. Formed crystals are centrifuged, washed with water and petroleum ether to obtain 46 g of 4-benzyldimethylamine in the form of crystals with a melting point of 85oC.

EXAMPLE 56

4 benzylthio-4'-terbinafine

To a suspension of 9.6 g of magnesium turnings in 20 ml of anhydrous ethyl ether is added drop by drop a solution of 44 ml of 4-bromo-1-fervently in 300 ml of anhydrous ethyl ether. After the addition the mixture is stirred for a few minutes in to the anhydrous tetrahydrofuran. Ethyl ether and distil the mixture is refluxed for 3 hours, then cooled with ice. Add one drop of 400 ml of 6N hydrochloric acid and the mixture is refluxed for 6 hours. After the addition of water and dichloromethane the organic phase is decanted and dried over magnesium sulfate, then evaporated in vacuum. The residue is crystallized in isopropyl ether, to obtain 48 g of 4-benzylthio-4'-fermentation in the form of crystals with a melting point of 96oC.

EXAMPLE 57

4-tert-butylaminoethyl-4'-terbinafine

In a solution of 43 g of 4-benzylthio-4'-fermentation obtained in example 56, 300 ml) cooled to 0oWith acetic acid bubbled chlorine before saturation (36 g). The mixture is then stirred for 2 hours at room temperature, poured into ice water and extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and evaporated in vacuum to obtain 47 g of oil which was dissolved in 100 ml of 1,2-dichloroethane. This solution is added drop by drop to a solution of 50 ml of tert-butylamine in 300 ml of 1,2-dichloromethane. The mixture is heated for one hour to 80oC, cooled and washed with water and then with diluted hydrochloric acid. Organicity 25 g of 4-tert - butylaminoethyl-4'-fermentation in the form of crystals with a melting point of 160oC.

EXAMPLE 58

3-etoxycarbonyl-4-(4-tert-butylaminoethyl) -4-(4-forfinal)-3-butenova acid

Formula (XII): A=phenyl, Y1=4-F, Y2=H.

Receive according to the method of example 11 from derived in example 57 using 2 equivalents of potassium tert-butylate, amorphous powder used in the future.

EXAMPLE 59

3-(4-tert-butylaminoethyl)-3-(4-forfinal)-2-(2-hydroxyethyl)-2-ethylpropane

Receive according to the method of example 12 of the derivative of example 58.

The oil obtained is treated with ethyl ether and the formed crystals are dried to obtain the pure isomer (Z)-3-(4-tert-butylaminoethyl)-3-(4-forfinal)-2- (2-hydroxyethyl)-2-ethylpropane in the form of crystals with a melting point of 152oC. the Filtrate is evaporated in vacuum to obtain an oil residue that corresponds to the isomer (E)-3- (4-tert-butylaminoethyl)-3-(4-forfinal)-2-(2-hydroxyethyl)-2-ethylpropane used further as such.

EXAMPLE 60

(E)-4-[(4-forfinal)-(2-oxopiperidin-3-ilidene)methyl] benzosulfimide

The isomer (S): Formula (I): a=b=phenyl, Y1=4-F, Y2=X2=H, X1=4-SO2NH2, R1, R2=0, RoC.

EXAMPLE 61

(Z)-4-[(4-forfinal)-(2-oxopiperidin-3-ilidene)methyl] -benzosulfimide

The isomer (Z): Formula (I): a=b=phenyl, X1=4-F, X2=Y2=H, Y1=4-SO2NH2, R1, R2=0, R3=R4=N.

Receive according to the method of example 60 from the isomer (Z) obtained in example 59.

Formula (IV): A=phenyl, Y1=4-Cl, Y2=H.

Receive according to the method of example 39 of the derivative of example 5.

Crystals with a melting point of 176oC.

EXAMPLE 63

(Z)-3-etoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=4-Cl, Y2=H.

To a suspension of 20 g of 4-chloro-4'-methysulfonylmethane obtained in example 62, in 100 ml of tert-butanol is added at one time 1.2 g of tert-butyl sodium at room temperature.

The suspension is heated to 40oWith and within 10 minutes, add a solution of 16.9 ml ethylsuccinate in 20 ml of tert-butanol. Within 30 minutes to keep the temperature up to 55oWith, then it is reduced to 35-40oWith; add 140 ml of cold water and the mixture is stirred for 30 minutes. The solution is filtered and the crystals washed with water. The aqueous-alcoholic phase is washed twice with 75 ml of toluene, and then acidified with concentrated hydrochloric acid. The crystals are centrifuged, washed with water and dried in vacuum to obtain 20.2 g (Z)-3-etoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulfonyl)-3-butenova acid, HPLC purity: 81,6%, 12.1% of isomer (E). Recrystallization in 2-propanol allows to obtain 14 g (Z)-3-etoxycarbonyl-4-(4-chlorophenyl) the melting point 183oC.

EXAMPLE 64

(Z)-3-(4-chlorophenyl)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane

Formula (XI): A=phenyl, Y1=4-Cl, Y2=H.

To a solution of 350 g (Z)-3-etoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulfonyl)-3-butenova acid obtained in example 63, in 1.5 l of tetrahydrofuran added drop by drop and under vigorous stirring to 120 ml of the borane complex/metilsulfate. Once added, the solution stirred for 2.5 hours at room temperature. The excess borane hydrolyzing with 100 ml methanol and 100 ml of water. After evaporation in vacuo of the solvent the residue is stirred with water, filtered, washed with water, to obtain (Z)-3-(4-chlorophenyl)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane in the form of wet crystals used as such in the next stage. By drying these crystals and recrystallization in 2-propanol get (Z)-3-(4-chlorophenyl)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane in the form of crystals with a HPLC purity of 98.3% and a melting point of 128oC.

EXAMPLE 65

(Z)-3-[1-(4-chlorophenyl)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

Formula (I): a=b=phenyl, Y1=4-Cl, X2=Y2=H, X1=4-SO2CH3oC.

EXAMPLE 66

3,5-dichloro-4'-metallersensiferum

Formula (III): A=phenyl, Y1=3-Cl, Y2=5-Cl.

Receive according to the method of example 1.

Crystals with a melting point of 108oC.

EXAMPLE 67

3,5-dichloro-4'-methysulfonylmethane

Formula (IV): A=phenyl, Y1=3-Cl, Y2=5-Cl.

Receive according to the method of example 39.

Crystals with a melting point of 200oC.

EXAMPLE 68

(Z)-3-etoxycarbonyl-4-(3,5-dichlorophenyl)-4- (4-methanesulfonyl)-3-butenova acid

The isomer (Z): Formula (X): A=phenyl, Y1=3-Cl, Y2=5-Cl.

Receive according to the method of example 11.

Crystals with a melting point of 180oC.

EXAMPLE 69

(Z)-3-(3,5-dichlorophenyl)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane

The isomer (Z)lo, this what is used in the future.

EXAMPLE 70

(Z)-3-[1-(3,5-dichlorophenyl)-1-(4-methanesulfonyl)-miticide] dihydrofuran-2-he

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-Cl, Y2=5-Cl, X1=4-SO2CH3, X2=N, R1, R2=0, R3=R4=N.

Receive according to the method of example 65.

Crystals with a melting point of 114oC.

EXAMPLE 71

2,4-debtor-4'-methylthioinosine

Formula (III): A=phenyl, Y1=2-F, Y2=4-F.

Receive according to the method of example 1.

Crystals with a melting point 98oC.

EXAMPLE 72

2,4-debtor-4'-methysulfonylmethane

Formula (IV): A=phenyl, Y1=2-F, Y2=4-F.

Receive according to the method of example 39.

Crystals with a melting point of 160oC.

EXAMPLE 73

3-etoxycarbonyl-4-(2,4-differenl)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=2-F, Y2=4-F.

Receive according to the method of example 11.

The oil used as such in the future.

EXAMPLE 74

3-(2,4-differenl)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane

Formula (XI): A=phenyl, Y1st in the future.

EXAMPLE 75

(Z)-3-[1-(2,4-differenl)-1-(4-methanesulfonyl)-methylidene] dihydrofuran-2-he

The isomer (Z): Formula (I): a=b=phenyl, Y1=2-F, Y2=4-F, X1=4-SO2CH3, X2=N, R1, R2=0, R3=R4=N.

Receive according to the method of example 65, cleanse chromatography with elution of a mixture of dichloromethane/acetone (10/0,3).

Crystals with a melting point of 140oC.

EXAMPLE 76

3,5-debtor-4 methylthioinosine

Formula (III): A=phenyl, Y1=3-F, Y2=5-F.

Receive according to the method of example 1.

Crystals with a melting point 90oC.

EXAMPLE 77

3,5-debtor-4'-methysulfonylmethane

Formula (IV): A=phenyl, Y1=3-F, Y2=5-F.

Receive according to the method of example 39.

Crystals with a melting point of 152oC.

EXAMPLE 78

3-etoxycarbonyl-4-(3,5-differenl)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=3-F, Y2=5-F.

Receive according to the method of example 11.

The oil used as such in the future.

EXAMPLE 79

3-(3,5-differenl)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane

Focoltone as such in the future.

EXAMPLE 80

(Z)-3-[1-(3,5-differenl)-3-(4-methanesulfonyl)-methylidene] dihydrofuran-2-he

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-F, Y2=5-F, X1=4-SO2CH3X2=N, R1, R2=0, R3=R4=N.

Receive according to the method of example 65, cleanse chromatography with elution of a mixture of dichloromethane/acetone (10/0,3).

Crystals with a melting point of 162oC.

EXAMPLE 81

4-methyl-4'-methylthioinosine

Formula (III): A=phenyl, Y1=4-CH3, Y2=H.

Receive according to the method of example 1.

Crystals with a melting point of 96oC.

EXAMPLE 82

4-methyl-4'-methysulfonylmethane

Formula (IV): A=phenyl, Y1=4-CH3, Y2=H.

Receive according to the method of example 39.

Crystals with a melting point of 180oC.

EXAMPLE 83

3-etoxycarbonyl-4-(4-were)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=4-CH3, Y2=H.

Receive according to the method of example 11.

The oil used as such in the future.

EXAMPLE 84

3-(4-were)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane
2">

The oil used as such in the future.

EXAMPLE 85

[E)-3-[1-(4-were)-3-(4-methanesulfonyl)methylidene]dihydrofuran-2-he

The isomer (S): Formula (I): a=b=phenyl, Y1=4-CH3, Y2=H, X1=4-SO2CH3X2=H, R1, R2=0, R3=R4=N.

Receive according to the method of example 65, cleanse chromatography with elution of a mixture of dichloromethane/acetone (10/0,3).

Crystals with a melting point of 222oC.

EXAMPLE 86

3-bromo-4'-methylthioinosine

Formula (III): A=phenyl, Y1=3-Br, Y2=N.

Receive according to the method of example 1.

Crystals with a melting point 90oC.

EXAMPLE 87

3-bromo-4'-methysulfonylmethane

Formula (IV): A=phenyl, Y1=3-Br, Y2=H.

Receive according to the method of example 39.

Crystals with a melting point of 170oC.

EXAMPLE 88

3-etoxycarbonyl-4-(3-bromophenyl)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=3-Br, Y2=H.

Receive according to the method of example 11.

The oil used as such in the future.

EXAMPLE 89

3-(3-bromophenyl)-3-(4-methysulfonylmethane method of example 12.

The oil used as such in the future.

EXAMPLE 90

(Z)-3-[1-(3-bromophenyl)-3-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-Br, Y2=H, X1=4-SO2CH3, X2=N, R1, R2=0, R3=R4=N.

Receive according to the method of example 65, purify by chromatography with elution of a mixture of dichloromethane/acetone (10/0,3).

Crystals with a melting point of 162oC.

EXAMPLE 91

3-chloro-4-fluoro-4'-methylthioinosine

Formula (III): A=phenyl, Y1=3-Cl, Y2=4-F.

Receive according to the method of example 1.

Crystals with a melting point of 116oC.

EXAMPLE 92

3-chloro-4-fluoro-4'-methysulfonylmethane

Formula (IV): A=phenyl, H1=3-Cl, Y2=4-F.

Receive according to the method of example 39.

Crystals with a melting point of 146oC.

EXAMPLE 93

3-etoxycarbonyl-4-(3-chloro-4-forfinal)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=3-Cl, Y2=4-F.

Receive according to the method of example 11.

The oil used as such in the future.

EXAMPLE 94

3-(3-chloro-4-forfinal)-3-(4-tx2">

Receive according to the method of example 12.

The oil used as such in the future.

EXAMPLE 95

(Z)-3-[1-(3-chloro-4-forfinal)-1-(4-methanesulfonyl)methylidene]dihydrofuran-2-he

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-Cl, Y2=4-F, X1=4-SO2CH3, X2=N, R1, R2=0, R3=R4=N.

Receive according to the method of example 65, purify by chromatography with elution of a mixture of dichloromethane/acetone (10/0,3).

Crystals with a melting point of 123oC.

EXAMPLE 96

4-bromo-4'-methylthioinosine

Formula (III): A=phenyl, Y1=4-Br, Y2=H.

Receive according to the method of example 1.

Crystals with a melting point of 148oC.

EXAMPLE 97

4-bromo-4'-methysulfonylmethane

Formula (IV): A=phenyl, Y1=4-Br, Y2=H.

Receive according to the method of example 39.

Crystals with a melting point of 188oC.

EXAMPLE 98

3-etoxycarbonyl-4-(4-bromophenyl)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=4-Br, Y2=H.

Receive according to the method of example 11.

The oil used as such in the future.

WHEN THE UB>1
=4-Br, Y2=H.

Receive according to the method of example 12.

The oil used as such in the future.

EXAMPLE 100

(Z)-3-[1-(4-bromophenyl)-1- (4-methanesulfonanilide] dihydrofuran-2-he

The isomer (Z): Formula (I): a=b=phenyl, Y1=4-Br, Y2=N, X2=4-SO2CH3, X2=N, R1, R2=0, R3=R4=H.

Receive according to the method of example 65, purify by chromatography with elution of a mixture of dichloromethane/acetone (10/0,3).

Crystals with a melting point of 204oC.

EXAMPLE 101

2-(4-methylthiophenyl)furan

Formula (III): A=2-furyl, Y1=Y2=H.

Receive according to the method of example 1.

Crystals with a melting point of 86oC.

EXAMPLE 102

2-(4-methansulfonate)furan

Formula (IV): A=2-furyl, Y1=Y2=H.

Receive according to the method of example 39.

Crystals with a melting point of 112oC.

EXAMPLE 103

3-etoxycarbonyl-4-(furan-2-yl)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X):=2-furyl, Y1=Y2=H.

Receive according to the method of example 11.

The oil used as such in the future.

Receive according to the method of example 12.

The oil used as such in the future.

EXAMPLE 105

(Z)-3-[1-(furan-2-yl)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

The isomer (Z): Formula (I): A=2-furyl, B=phenyl, Y1=Y2=H, X1=4-SO2CH3X2=H, R1, R2=0, R3=R4=N.

Receive according to the method of example 65, purify by chromatography with elution of a mixture of dichloromethane/acetone (10/0,3).

Crystals with a melting point of 170oC.

EXAMPLE 106

(4-methylthiophenyl)cyclohexane

Formula (III): A=cyclohexyl, Y1=Y2=H.

Receive according to the method of example 1.

Crystals with a melting point of 110oC.

EXAMPLE 107

(4-methansulfonate)cyclohexane

Formula (IV): A=cyclohexyl, Y1=Y2=H.

Receive according to the method of example 39.

Crystals with a melting point of 116oC.

EXAMPLE 108

3-etoxycarbonyl-4-cyclohexyl-4-(4-methanesulfonyl)3-butenova acid

Formula (X): A=cyclohexyl, Y1=Y2=H.

Receive according to the method of example 11.

The oil used Ethylpropane

Formula (XI): A=cyclohexyl, Y1=Y2=H.

Receive according to the method of example 12.

The oil used as such in the future.

EXAMPLE 110

(Z)-3-[1-cyclohexyl-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

The isomer (Z): Formula (I): A=cyclohexyl, B=phenyl, Y1=Y2=H, X1=4-SO2CH3X2=H, R1, R2=0, R3=R4=N.

Receive according to the method of example 65.

Crystals with a melting point of 148oC.

EXAMPLE 111

3-fluoro-4-methyl-4'-methylthioinosine

Formula (III): A=phenyl, Y1=3-F, Y2=4-CH3.

To a suspension of 6.4 g of magnesium shavings in 5 ml of anhydrous ethyl ether is added drop by drop a solution of 50 g of 4-bromo-2-Tortolla in 150 ml of anhydrous ethyl ether. After the addition the mixture is stirred for 30 minutes, then add a solution of 4-methylthioamphetamine in 200 ml of anhydrous tetrahydrofuran. Ethyl ether and distil the mixture is heated under reflux for 4 hours. After returning to room temperature, add one drop of 300 ml of 6N hydrochloric acid. The mixture is then heated under reflux for 6 hours, cooled at room temp is dry. The residue is crystallized in ethyl ether, to obtain 25 g of 3-fluoro-4-methyl-4'-methyldibenzothiophene in the form of crystals with a melting point of 94oC.

EXAMPLE 112

3-fluoro-4-methyl-4'-methysulfonylmethane

Formula (IV): A=phenyl, Y1=3-F, Y2=4-CH3.

Receive according to the method of example 39.

Crystals with a melting point of 170oC.

EXAMPLE 113

(Z)-3-etoxycarbonyl-4-(3-fluoro-4-were)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=3-F, Y2=4-CH3.

Receive according to the method of example 11, cleanse, processing the crude mixture of two isomers (E) and (Z) with 1 equivalent of D-(+) - methylbenzylamine in 5 volumes of ethyl acetate. Formed crystals are removed (Sol-isomer (E)) and the filtrate acidified with diluted hydrochloric acid, decanted and evaporated in vacuum to obtain an oil corresponding to the isomer (Z), containing less than 5% of the isomer (E).

EXAMPLE 114

(Z)-3-(3-fluoro-4-were)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane

Formula (XI): A=phenyl, Y1=3-F, Y2=4-CH3.

Receive according to the method of example 12.

The oil used as such in Dan-2-he

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-F, Y2=4-CH3X1=4-SO2CH3, X2=N, R1, R2=0, R3=R4=N.

Receive according to the method of example 65.

Crystals with a melting point of 169-170oC.

EXAMPLE 116

4-trifluoromethyl-4'-methylthioinosine

Formula (III): A=phenyl, Y1=4-CF, Y2=H.

Receive according to the method of example 1.

Crystals with a melting point of 139oC.

EXAMPLE 117

4-trifluoromethyl-4'-methysulfonylmethane

Formula (IV): A=phenyl, Y1=4-CF3, Y2=H.

Receive according to the method of example 39.

Crystals with a melting point of 138oC.

EXAMPLE 118

3-etoxycarbonyl-4-(4-triptoreline)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=4-CF3, Y2=H.

Receive according to the method of example 11.

The oil used as such in the future.

EXAMPLE 119

3-(4-triptoreline)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane

Formula (XI):=penid, Y1=4-CF3, Y2=H.

Receive according to the method of example 12.

The oil used as drofuran-2-he

The isomer (S): Formula (I): A=B=phenyl, Y1=4-CF3, Y2=H, X2=4-SO2CH3, X2=N, R1, R2=0, R3=R4=H.

Receive according to the method of example 65, purify by chromatography with elution of a mixture of dichloromethane/acetone (10/0,3).

Crystals with a melting point of 188-189oC.

EXAMPLE 121

4 benzylthio-4'-chlorobenzophenone

Receive according to example 56 4-bromchlorenone and 4-benzyldimethylamine obtained in example 55.

Crystals with a melting point of 134oC.

EXAMPLE 122

4-tert-butylaminoethyl-4'-chlorobenzophenone

Receive according to example 57.

Crystals with a melting point of 163oC.

EXAMPLE 123

3-etoxycarbonyl-4-(4-tert-butylaminoethyl )-4-(4-chlorophenyl)-3-butenova acid

Formula (XII): A=phenyl, Y1=4-Cl, Y2=H.

Receive according to the method of example 58.

The oil used as such in the future.

EXAMPLE 124

(Z)-3-(4-tert-butylaminoethyl)-3-(4-chlorophenyl)-2-(2-hydroxyethyl)-2-ethylpropane

Receive according to the method of example 12. The oil obtained is treated with ethyl ether and the formed crystals are centrifuged to obtain the isomer (Z) in the form of crystals with a melting point of 120oC.

EXAMPLE 125

(Z)-4-[(4-chlorophenyl)-(2-oxopiperidin-3-ilidene)methyl] benzosulfimide

Formula (I): a=b=phenyl, Y1=4-Cl, Y2=H, X1=4-SO2NH2X2=H, R1, R2=0, R3= R4=H.

A solution of 10 g of (Z)-3-(4-tert-butylaminoethyl)-3-(4-chlorophenyl)-2-(2-hydroxyethyl)-2-ethylpropane obtained in example 124, 80 ml triperoxonane acid is heated under reflux for 15 hours. After evaporation of the solvent in vacuo the residue is treated with dichloromethane. The organic phase, washed with water, then dried over magnesium sulfate and evaporated in vacuum to obtain an oil, which crystallized in a mixture of acetone/isopropyl ether, and the gain of 3.9 g (Z)-4-[(4-chlorophenyl)-(2-oxopiperidin-3-ilidene)methyl] benzosulfimide in the form of crystals with a melting point 187-189oC.

EXAMPLE 126

4 benzylthio-3'-fluoro-4'-methylbenzophenone

Receive according to example 56 4-bromo-2-vtortola.

Crystals with a melting point of 122oC.

EXAMPLE 127

4-tert-butyl aminosulfonyl-3-fluoro-4'-methylbenzophenone

Receive according to example 57.

Crystals with a melting point of 132oC.

EXAMPLE 1281
=3-F, Y2=4-CH3.

Receive according to the method of example 58. The oil obtained is treated with tert-butylation ether and the formed crystals are centrifuged to obtain the isomer (E) with a melting point of 96oC. the Filtrate was concentrated in vacuo to obtain the isomer (Z) in the form of an oil used as such in the future.

EXAMPLE 129

(Z)-3-(4-tert-butylaminoethyl)-3-(3-fluoro-4-were)-2-(2-hydroxyethyl)-2-ethylpropane

Receive according to example 12 of the isomer (Z) of the acid of example 128.

The oil used as such in the future.

EXAMPLE 130

(Z)-4-[(3-fluoro-4-were)-2-(2-oxopiperidin-3-ilidene)methyl] benzosulfimide

Formula (I): a=b=phenyl, Y1=3-F, Y2=4-CH3X1=4-SO2NH2, X2=H, R1, R2=0, R3=R4=H.

Receive according to example 125.

Crystals with a melting point of 170-172oC.

EXAMPLE 131

3 benzylthio-4'-fluoro-3'-methylbenzophenone

Receive according to example 56 5-bromo-2-Tortolla.

Crystals with a melting point of 123oC.

EXAMPLE 132

4-tert-butylaminoethyl-4'-fluoro-3'-methylbenzophenone

Get under p is(4-tert-butylaminoethyl)-4-(4-fluoro-3-were)-3-butenova acid

Formula (XII): A=phenyl, Y1=3-CH3, Y2=4-F.

Receive according to the method of example 58, with the resulting oil is treated with tert-butylation ether and the formed crystals are removed (the isomer (E)). The filtrate is evaporated in vacuum to obtain the isomer (Z) in the form of an oil used as such in the future.

EXAMPLE 134

(Z)-3-(4-tert-butylaminoethyl)-3-(4-fluoro-3-were)-2-(2-hydroxyethyl)-2-ethylpropane

Receive according to example 12.

Crystals with a melting point of 128oC.

EXAMPLE 135

(Z)-4-[(4-fluoro-4-were)-(2-oxopiperidin-3-ilidene)methyl] benzosulfimide

Formula (I): a=b=phenyl, Y1=3-CH3, Y2=4-F, X1=4-SO2NH2X2=H, R1, R2=0, R3=R4=N.

Receive according to example 125.

Crystals with a melting point 228-229oC.

EXAMPLE 136

(E)-3-(4-tert-butylaminoethyl)-3-(3-fluoro-4-were)-2-(2-hydroxyethyl)-2-ethylpropane

Receive according to example 12 of the isomer (E) of the acid of example 128.

The oil used as such in the future.

EXAMPLE 137

(E)-3-(4-tert-butylaminoethyl)-3-(3-fluoro-4-were)-2-(2-Gil)-2-(2-hydroxyethyl)-2-ethylpropane, obtained in example 136, in 50 ml of ethanol containing 3 g of sodium hydroxide and 5 ml of water, heated under reflux for 2 hours. The mixture was concentrated in vacuo, treated with water, washed with ethyl ether, then acidified with diluted hydrochloric acid and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, then evaporated to dryness in vacuo to obtain a residue, which crystallized in isopropyl ether, and obtain 7.6 g (E)-3-(4-tert-butylaminoethyl)-3-(3-fluoro-4-were)-2-(2-hydroxyethyl)-3-propanolol acid in the form of crystals with a melting point of 160oC.

EXAMPLE 138

(E)-2-[1-(4-tert-butylaminoethyl)-1-(3-fluoro-4-were)methylidene]butane-1,4-diol

To a solution of 7.8 g (E)-3-(4-tert-butylaminoethyl)-3-(3-fluoro-4-were)-2-(2-hydroxyethyl)-3-propanolol acid obtained in example 137, in 50 ml of anhydrous tetrahydrofuran, add one drop of 5 ml of the borane complex/metilsulfate. The mixture is stirred for 6 hours at room temperature, then add one drop of 10 ml of methanol. The mixture was concentrated in vacuo, treated with an aqueous potassium carbonate solution and extracted with ethyl alcohol. The organic phase is dried over magnesium sulfate and n] butane-1,4-diol in the form of crystals with a melting point of 106oC.

EXAMPLE 139

(E)-4-[(3-fluoro-4-were)-(tetrahydrofuran-3-ilidene)methyl] benzosulfimide

Formula (I): a=b=phenyl, X1=3-F, X2=4-CH3, Y1=4-SO2NH2, Y2=H, R1=R2=R3= R4=H.

A solution of 6.3 g (E)-2-[1-(4-tert-butylaminoethyl)-1-(3-fluoro-4-were)methylidene] butane-1,4-diol obtained in example 138, 75 ml triperoxonane acid is heated under reflux for 10 hours. The solvent was concentrated in vacuo and the residue treated with dilute sodium hydroxide solution, washed with dichloromethane and then acidified with diluted hydrochloric acid and extracted with dichloromethane. The organic phases are combined and dried over magnesium sulfate, then evaporated in vacuum. The residue was diluted with tert-butylmethyl ether to obtain 4 g of (E)-4-[(3-fluoro-4-were)tetrahydrofuran-3-ilidene)methyl] benzosulfimide in the form of crystals with a melting point of 174-176oC.

EXAMPLE 140

4 benzylthio-3'-chloro-4'-terbinafine

Receive according to example 56 4-bromo-2-chloroperbenzoic.

Crystals with a melting point of 102oC.

EXAMPLE 141

4-tert-butyl aminosulfonyl-3'-hdor-4'-terbinafine

3-etoxycarbonyl-4-(4-tert-butylaminoethyl)-4-(3-chloro-4-forfinal)-3-butenova acid

Formula (XII): A=phenyl, Y1=3-Cl, Y2=4-F.

Receive according to the method of example 58.

The oil used as such in the future.

EXAMPLE 143

(Z)-4-[(3-chloro-4-forfinal)-(2-oxopiperidin-3-ilidene)methyl]benzosulfimide

Formula (I): a= b=phenyl, Y1=3-Cl, Y2=4-F, X1=4-SO2NH2, X2=N, R1, R2=0, R3=R4=N.

To a solution of 17 g of 3-etoxycarbonyl-4- (4-tert-butylaminoethyl)-4-(3-chloro-4-forfinal)-3-butenova acid obtained in example 142, 150 ml of tetrahydrofuran, add a drop of 7 ml of borane complex/metilsulfate. The mixture is stirred for 6 hours at room temperature, then add one drop of 30 ml of ethanol. After adding an aqueous solution of potassium carbonate, the mixture is extracted with dichloromethane. The organic phase is dried and evaporated in vacuum. The residue (13.8 g) is treated with 30 ml of ethanol solution containing 3 g of sodium hydroxide in 10 ml of water, and the mixture is heated to 70oC for 3 hours. The solvent was concentrated in vacuo, and the residue is treated with water; the aqueous phase is washed with ethyl ether, acidified with hydrochloric is t with ethyl ether and the resulting crystals are centrifuged, to obtain 3 g of (E)-3-(4-tert-butylaminoethyl)-3-(3-fluoro-4-chlorophenyl)-2-(2-hydroxyethyl)-3-propanolol acid (melting point 180oC). The filtrate was concentrated in vacuo, and the residue is treated with 60 ml triperoxonane acid. The mixture is heated under reflux for 17 hours, then concentrated in vacuo. The residue is treated with dilute sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, then evaporated in vacuo to obtain 2 g (Z)-4-[(3-chloro-4-forfinal)-(2-oxopiperidin-3-ilidene)methyl]benzene sulfonamida in the form of crystals with a melting point 244-246oC.

EXAMPLE 144

4 benzylthio-3'-fluoro-4'-methoxybenzophenone

Receive according to example 56 4-bromo-2-fernicola.

Crystals with a melting point of 125oC.

EXAMPLE 145

4-tert-butylaminoethyl-3'-fluoro-4'-methoxybenzophenone

Receive according to example 57.

Crystals with a melting point of 136oC.

EXAMPLE 146

(Z)-3-etoxycarbonyl-4-(4-tert-butylaminoethyl)-4-(3-fluoro-4-methoxyphenyl)-3-butenova acid

Formula (XII): A=phenyl, Y1=3-F, Y2=4-OMe.

Receive according to the method of example 58, the floor is used as such in the future.

EXAMPLE 147

(Z)-3-(4-tert-butylaminoethyl)-3-(3-fluoro-4-methoxyphenyl)-2-(2-hydroxyethyl)-2-ethylpropane

Receive according to example 12.

The oil used as such in the future.

EXAMPLE 148

(Z)-4-[(3-fluoro-4-methoxyphenyl)-(2-oxopiperidin-3-ilidene)methyl] benzosulfimide

Formula (I): a=b=phenyl, Y1=3-F, Y2=4-OMe, X1=4-SO2NH2, X2=N, R1, R2=0, R3=R4=N.

Receive according to example 125.

Crystals with a melting point of 149-150oC.

EXAMPLE 149

3-(4-perbenzoic)pyridine

To a suspension of 140 g of the hydrochloride of nicotinic acid chloride in 500 ml of fervently cooled to 0oTo add portions 280 g of aluminium chloride. The mixture is refluxed for 6 hours, then cooled and poured on ice. After adding sodium hydroxide to pH 8 and the mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, then evaporated in vacuum. The residue is crystallized in a mixture of pentane/isopropyl ether, to get to 108.5 g of 3-(4-perbenzoic)pyridine in the form of crystals with a melting point of 91oC.

EXAMPLE 150

3-(4-benzyldimethyl)pyridine

To a solution of 43 g bivaet 20 minutes at room temperature and add 70 g of 3-(4-perbenzoic)pyridine, obtained in example 149. The mixture is heated for 8 hours to 80oWith, then concentrated in vacuo, and the residue is treated with water. Formed crystals are centrifuged, dissolved in dichloromethane, the solution is dried over magnesium sulfate and concentrated in vacuo. The residue is crystallized in a mixture of pentane/isopropyl ether and obtain 81 g of 3-(4-benzyldimethyl)pyridine in the form of crystals with a melting point of 102oC.

EXAMPLE 151

3-(4-tert-buylamisilonline)pyridine

Receive according to example 57.

Crystals with a melting point of 179oC.

EXAMPLE 152

(Z)-3-etoxycarbonyl-4-(4-tert-butylaminoethyl)-4-(3-pyridyl)-3-butenova acid

Formula (XII): A=3-pyridyl, Y1=Y2=H.

Receive according to the method of example 58, with the resulting oil is treated with warm ethyl acetate and the formed crystals are centrifuged (isomer (E) with a melting point of 209oC). The filtrate is evaporated, and the residue treated with pentane, crystallized to obtain the isomer (Z) in the form of crystals with a melting point of 209oC.

EXAMPLE 153

(Z)-3-(4-tert-butylaminoethyl)-3-(3-pyridyl)-2-(2-hydroxyethyl)-2-ethylpropane

Receive according to what Z)-[(3-pyridyl)-(2-oxopiperidin-3-ilidene)methyl]benzosulfimide

Formula (I): A=3-pyridyl, A=phenyl, X1=4-SO2NH2X2=H, Y1=Y2=H, R1, R2=0, R3=R4=N.

Receive according to example 125.

Crystals with a melting point 219-220oC.

EXAMPLE 155

3-chloro-4-methoxy-4'-methylthioinosine

Formula (III); A=phenyl, Y1=3-Cl, Y2=4-OMe.

Receive according to the method of example 1.

Crystals with a melting point of 110oC.

EXAMPLE 156

3-chloro-4-methoxy-4'-methysulfonylmethane

Formula (IV): A=phenyl, Y1=3-Cl, Y2=4-OMe.

Receive according to the method of example 39.

Crystals with a melting point of 164oC.

EXAMPLE 157

(Z)-3-etoxycarbonyl-4-(3-chloro-4-methoxyphenyl)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X): A=phenyl, Y1=3-Cl, Y2=4-OMe.

Receive according to the method of example 11, and the oil obtained is treated with ether and the formed crystals are centrifuged to obtain the isomer (Z) in the form of crystals with a melting point of 179oC.

EXAMPLE 158

(Z)-3-(3-chloro-4-methoxyphenyl)-3-(4-methanesulfonyl)-2-hydroxyethyl)-2-ethylpropane

Formula (XI): A=phenyl, Y1=3-Cl, Y2=4-OMe.<">

EXAMPLE 159

[Z)-3-[1-(3-chloro-4-methoxyphenyl] -1-(4-methanesulfonyl)-methylidene] dihydrofuran-2-he

Formula (I): a=b=phenyl, Y1=3-Cl, Y2=4-OMe. X1=4-SO2CH3X2=H, R1, R2=0, R3=R4=H.

Receive according to the method of example 65.

Crystals with a melting point 177oC.

EXAMPLE 160

2-(4-methylthiophenyl)thiophene

Formula (III): A=2-thienyl, Y1=Y2=H.

Receive according to the method of example 1.

Crystals with a melting point of 60oC.

EXAMPLE 161

2-(4-methansulfonate)thiophene

Formula (IV): A=2-thienyl, Y1=Y2=H.

Receive according to the method of example 39.

Crystals with a melting point of 140oC.

EXAMPLE 162

(E)-3-etoxycarbonyl-4-(4-methanesulfonyl)-4-(2-thienyl)3-butenova acid

Formula (X):=2-thienyl, Y1=Y2=H.

Receive according to the method of example 11.

Crystals with a melting point of 120oC.

EXAMPLE 163

(E)-3-(4-methanesulfonyl)-3-(2-thienyl)-2-(2-hydroxyethyl)-2-ethylpropane

Formula (XI):=2-thienyl, Y1=Y2=H.

Receive according to the method of example 12.

Creden]dihydrofuran-2-he

Formula (I): A=2-thienyl,-phenyl, Y1=Y2=H. X1=4-SO2CH3X2=H, R1, R2=0; R3=R4=H.

Receive according to the method of example 65.

Crystals with a melting point of 246oC.

EXAMPLE 165

4-(2-naphtol)methyldibenzo

Formula (III): A=2-naphthyl, Y1=Y2=H.

Receive according to the method of example 1.

Crystals with a melting point 98oC.

EXAMPLE 166

4-(2-naphtol)methansulfonate

Formula (IV): A=2-naphthyl, Y1=Y2=H.

Receive according to the method of example 39.

Crystals with a melting point of 150oC.

EXAMPLE 167

3-etoxycarbonyl-4-(2-naphthyl)-4-(4-methanesulfonyl)-3-butenova acid

Formula (X):=2-naphthyl, Y1=Y2=H.

Receive according to the method of example 11.

The oil used as such in the future.

EXAMPLE 168

3-(2-naphthyl)-3-(4-methanesulfonyl)-2-(2-hydroxyethyl)-2-ethylpropane

Formula (XI):=naphthyl, Y1=Y2=H.

Receive according to the method of example 12.

The oil used as such in the future.

EXAMPLE 169

(Z)-3-[1-(2-naphthyl)-1-(4-metasolv the CH3X2=H, R1, R2=0, R3=R4=H.

Receive according to the method of example 65, clear chromatographia when the elution of a mixture of dichloromethane/acetone (10/0,3).

Crystals with a melting point of 244oC.

EXAMPLE 170

3, 5-dichloro-4'-terbinafine

A mixture of 50 g of the chloride of 3,5-dichlorobenzoyl and 150 ml of fervently cooled to 0oWith and add portions 65 g trichloride aluminum. The mixture is stirred at room temperature for 2 hours, then in 4 hours refluxed. After cooling, the mixture was poured onto a mixture of ice/dilute hydrochloric acid and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated to dryness to obtain 59 g of 3,5-dichloro-4'-fermentation in the form of crystals with a melting point of 65oC.

EXAMPLE 171

3,5-dichloro-4'-benzylcyanide

Receive according to the method of example 150 3 -, 5-dichloro-4'-fermentation obtained in example 170.

Crystals with a melting point of 80oC.

EXAMPLE 172

4-tert-butylaminoethyl-3',5'-dichlorobenzophenone

Receive according to example 57 from 3,5-dichloro-4'- benzylthiazolidine obtained in example 171.

Kristall)-4-(3,5-dichlorophenyl)-3-butenova acid

Formula (XII): A=phenyl, Y1=3-Cl, Y2=5-C1.

Receive according to the method of example 58.

The oil used as such in the future.

EXAMPLE 174

3-(4-tert-butylaminoethyl)-3-(3,5-dichlorophenyl)-2-(2-hydroxyethyl)-2-ethylpropane

Receive according to the method of example 12.

The oil used as such in the future.

EXAMPLE 175

(Z)-4-[(3,5-dichlorophenyl)-2-(2-oxopiperidin-3-ilidene)methyl] benzosulfimide

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-Cl, Y2=5-Cl, X1=4-SO2NH2X2=H, R1, R2=0, R3=R4=H.

Receive according to the method of example 65. The obtained crystals chromatographic on silica gel with elution of a mixture of dichloromethane/acetone (9/1), after recrystallization in acetic acid to obtain (Z)-4-[(3,5-dichlorophenyl)-(2-oxopiperidin-3-ilidene) methyl] benzosulfimide in the form of crystals with a melting point of 217oC.

EXAMPLE 176

3-chloro-4'-terbinafine

Receive according to the method of example 170.

Crystals with a melting point of 76oC.

EXAMPLE 177

3-chloro-4'-benzylcyanide

Receive according to the method of example 150 3-chloro-4'-torbe

4-tert-butylaminoethyl-3'-chlorobenzophenone

Receive according to example 57 from 3'-chloro-4'- benzylthiazolidine obtained in example 177.

Crystals with a melting point of 128oC.

EXAMPLE 179

3-etoxycarbonyl-4-(4-tert-butylaminoethyl)-4'(3-chlorophenyl)-3-butenova acid

Formula (XII): A=phenyl, Y1=3-Cl, Y2=H.

Receive according to the method of example 58.

The oil used as such in the future.

EXAMPLE 180

3-(4-tert-butylaminoethyl)-3-(3-chlorophenyl)-2-(2-hydroxyethyl)-2-ethylpropane

Receive according to the method of example 12.

The oil used as such in the future.

EXAMPLE 181

(Z)-4-[(3-chlorophenyl)-(2-oxopiperidin-3-ilidene)methyl] benzosulfimide

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-Cl, Y2=H, X1=4-SO2NH2X2=H, R1, R2=0, R3=R4=H.

Receive according to the method of example 65, purified chromatographically on silica gel with elution of a mixture of dichloromethane/acetone (10/1).

Crystals with a melting point 178oC.

EXAMPLE 182

4-fluoro-3'-methylbenzophenone

Receive according to the method of example 170.

the Ute according to the method of example 150 4-fluoro-3'- methylbenzophenone, obtained in example 182.

Crystals with a melting point 98oC.

EXAMPLE 184

4-tert-butylaminoethyl-3'-methylbenzophenone

Receive according to example 57 4-benzylthio-3'- methylbenzophenone obtained in example 183.

Crystals with a melting point of 116oC.

EXAMPLE 185

3-etoxycarbonyl-4-(4-tert-butylaminoethyl)-4-(3-were)-3-butenova acid

Formula (XII): A=phenyl, Y1=3-CH3, Y2=H.

Receive according to the method of example 58.

The oil used as such in the future.

EXAMPLE 186

3-(4-tert-butylaminoethyl)-3-(3-were)-2-(2-hydroxyethyl)-2-ethylpropane

Receive according to the method of example 12.

The oil used as such in the future.

EXAMPLE 187

(Z)-4-[(3-were)-(2-oxopiperidin-3-Ideen)methyl]benzosulfimide

The isomer (Z): Formula (I): a=b=phenyl, Y1=3-CH3, Y2=H, X1=4-SO2NH2X2=H, R1, R2=0, R3=R4=H.

Receive according to the method of example 65. The oil obtained chromatographic on silica gel with elution of a mixture of dichloromethane/acetone (10/1), to obtain (Z)-4-[(3-LASS="ptx2">

EXAMPLE 188

3-chloro-4-methoxy-4'-benzylcyanide

Receive according to the method of example 56 from 2-chloro-4-bromoanisole.

Crystals with a melting point of 115oC.

EXAMPLE 189

4-tert-butylaminoethyl-3'-chloro-4'-methoxybenzophenone

Receive according to example 57 3-chloro-4-methoxy-4'-benzylcyanide.

Crystals with a melting point of 120oC.

EXAMPLE 190

3-etoxycarbonyl-4-(4-tert-butylaminoethyl)-4-(3-chloro-4-methoxyphenyl)-3-butenova acid

Formula (XII): A=phenyl, Y1=3-Cl, Y2=OMe.

Receive according to the method of example 58.

The oil used as such in the future.

EXAMPLE 191

3-(4-tert-butylaminoethyl)-3-(3-chloro-4-methoxyphenyl)-2-(2-hydroxyethyl)-2-ethylpropane

Receive according to the method of example 12.

The oil used as such in the future.

EXAMPLE 192

(Z)-4-[3-chloro-4-methoxyphenyl)-(2-oxopiperidin-3 - ilidene)methyl] benzosulfimide and (E)-4-[(3-chloro-4-methoxyphenyl)-(2-oxopiperidin-3-ilidene)methyl]benzosulfimide

Formula (I): a=b=phenyl, Y1=3-Cl, Y2=4-OMe, X1=4-SO2NH2, X2=N, R1, R2=0, R3=R4=H.

Pharmacology

Anti-inflammatory effect of the compounds of the examples were determined on the model Karaganov edema and analgesic activity of kaolin model of arthritis.

METHODS

Anti-inflammatory

Anti-inflammatory effects were determined in rats in the text on carriedby swelling. The product is administered orally at the rate 2.5 ml/100 g (n=6 animals per dose) after 2 hours and 30 minutes after oral fluid overload by (2.5 ml/100 g), one hour after the introduction of the product was caused by swelling of the plantar subcutaneous injection of 2% aqueous solution of Cartagena. The results are expressed in table 1 in the form of DI50dose in mg/kg, resulting in 50% increase decrease swelling, calculated by linear regression taking into account the maximum amount of swelling for each tested product.

Analgesic effect

Analgesic effect was determined in rats in the test on kaolin arthritis. 30 minutes after intramuscular injection of 10% aqueous suspension of kaolin product is administered orally at a rate of 1 ml/100 g (n=10 animal is', obtained in the control, calculated by using linear regression.

Inhibition of the enzymatic activity of cyclooxygenase-1 and cyclooxygenase-2.

The studied molecule is pre-incubated for 10 minutes at 25oWith 2 units of cyclooxygenase-1 (purified enzyme seminal vesicle RAM) or with 1 u of cyclooxygenase-2 (purified enzyme the sheep placenta). Arachidonic acid (6 μm for Cox-1 and 4 μm for Cox-2) was added to the reaction medium and incubated for 5 minutes at 25oC. At the end of the incubation time of the enzymatic reaction was stopped by adding 1N HC1 and received PGE2 they dosaged with EIA.

The results are expressed in table 2 in the form CI50the concentration in nm corresponds to 50% increase maximum inhibition of the enzymatic activity on cyclooxygenase-1 and cyclooxygenase-2 (n=1-4) definitions.

Tolerance

Gastric tolerance

Gastrointestinal tolerance was studied in rats Charles river strain CD weight 110-150, the Animals were housed on a water diet 24 hours before the introduction of the product or only one filler by mouth at the rate of 1 ml/100 g (n= 6 animals per dose). Six hours pontificating hemorrhagic spots and scars on the stomach allows you to set the index of ulcer formation (0:no lesion, 1:1-2 lesions, 2: 3-4 lesions, 3:5-8 lesions, 4:9-16 lesions, 5: 17 lesions) and to calculate the 50% svoebraznuju dose (see table 3, where DU50=dose expressed in mg/kg, causing 4-5 lesions).

Toxicology

First performed toxicity tests show that the products of examples have no harmful effect when the dose up to 300 mg/kg dose was administered to rats orally).

1. Diarylethylene derivatives, characterized in that they meet the General formula (I)

< / BR>
in which cycles a and b denote independently phenyl, naphthyl, heterocycle derived from 5-6 links, including one heteroatom, a derivative of a saturated hydrocarbon cycle with 3-7 carbon atoms; at least one of the substituents1X2, Y1or Y2necessarily mean the group-S(O)nR, in which n is an integer 0, 1 or 2, R is lower alkyl with 1-6 carbon atoms, a group-SO2NH2and is in the para-position; the other means independently a hydrogen atom, halogen atom, lower alkyl with 1-6 carbon atoms, trifluoromethyl, lower O-alkyl with 1-6 carbon atoms or X1and X2or Y1and Y2necessarily mean the group of methylendioxy; R1kind, lowest halogenated with 1-6 carbon atoms, an aromatic radical selected from the group comprising phenyl, naphthyl, thienyl, furyl or pyridyl, or R1, R2or R3, R4mean oxygen atom.

2. Derivatives of formula (I) under item 1, characterized in that the loops a and b independently denote phenyl, naphthyl, pyridyl, furyl, thienyl, cyclohexyl; at least one of the substituents X1X2, Y1or Y2necessarily mean the group-S3, -SO2CH3or-SO2NH2; other means independently a hydrogen atom, halogen atom, lower alkyl with 1-6 carbon atoms, trifluoromethyl, lower alkyl with 1-6 carbon atoms; R1, R2mean oxygen atom; R3, R4denote independently a hydrogen atom or a lower alkyl with 1-6 carbon atoms.

3. Derivatives under item 1 or 2, characterized in that the cycle means phenyl.

4. Derivatives under item 1 or 2, characterized in that cycle And means phenyl or pyridyl.

5. Derivatives in one of the paragraphs. 1-4, characterized in that the1means group 4-SO2CH3or group 4-SO2NH2and X2means a hydrogen atom.

6. Derivatives in one of the paragraphs. 1-5, otlichuy the Torah or chlorine atom.

7. Derivatives in one of the paragraphs. 1-6, characterized in that the1, R2mean oxygen atom, and R3and R4indicate each a hydrogen atom.

8. Derivatives under item 1, characterized in that they are chosen from compounds of the formula

(E)-3-[1-(4-forfinal)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

< / BR>
(Z)-3-[1-(4-chlorophenyl)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

< / BR>
(Z)-3-[1-(3,4-dichlorophenyl)-1-(4-methanesulfonyl)methylidene] dihydrofuran-2-he

< / BR>
(Z)-3-[1-(6-chloropyridin-3-yl)-1-(4-methanesulfonyl)-methylidene] dihydrofuran-2-he

< / BR>
(Z)-4-[4-chlorophenyl)-(2-oxopiperidin-3-ilidene)methyl] benzosulfimide

< / BR>
(Z)-4-[(3-fluoro-4-were)-(2-oxopiperidin-3-ilidene)methyl] benzosulfimide

< / BR>
9. The method of obtaining compounds of formula (I) according to one of paragraphs. 1-8, characterized in that it comprises the reaction of interaction of the ketone of the formula

< / BR>
in which a, b, X1X2, Y1and Y2have the values listed in paragraph 1, with alkylacrylate formula

< / BR>
in which R' is lower alkyl with 1-6 carbon atoms, preferably ethyl, according to the conditions of the condensation reaction Stobbe, in the presence of an alcoholate, in particular, tert-butyl sodium, or calories solvent, such as toluene, and the choice of a condensing agent and solvent allow to focus the response to a certain type of isomer,

to obtain the derivatives of esters containing acid group of the formula

< / BR>
in which a, b, X1X2, Y1and Y2have the values listed in paragraph 1;

selective reduction of the acid group of the above-mentioned derivatives of esters containing an acid group, for example, by exposure of borane in tetrahydrofuran, to obtain the esters containing an alcohol group of the formula

< / BR>
in which a, b, X1, X2, Y1and Y2have the values listed in paragraph 1;

then the cyclization of these esters containing an alcohol group by heating, for example in toluene, in the presence of paratoluenesulfonyl acid.

10. Pharmaceutical composition with anti-inflammatory and analgesic effect, characterized in that it contains a pharmaceutically effective amount of the compounds of formula (1) PP. 1-8, if necessary, put in a pharmaceutically acceptable excipient, binder or carrier.

11. The pharmaceutical composition according to p. 10, characterized in that it nachtergaele dose of 0.1 500 mg.

Priority signs:

04.04.1996 - cycles a and b simultaneously represent phenyl;

26.06.1996 - cycles a and b simultaneously denote a derivative of the heterocycle with 6 units and 1 heteroatom.

 

Same patents:

The invention relates to trehzameshchenny phenyl derivative of the General formula (1) in which Y represents a group or SIG1where R1represents a C1-C6alkyl group, optionally substituted by up to three halogen atoms; R2represents a C1-C6alkyl or C3-C8cycloalkyl provided that Y and-OR2are not both methoxypropane; R3represents a hydrogen atom or a hydroxy-group; R4and R5that may be the same or different, represent a group -(CH2)nAr, where n = 0 or 1 and Ar is a phenyl or heteroaryl group containing one or two 5 - and/or 6-membered ring containing up to three heteroatoms selected from oxygen, sulfur and nitrogen, where Ar is optionally substituted with halogen, C1-C6the alkyl, C1-C6hydroxyalkyl,1-C6alkoxy, C1-C6alkoxy-C1-C6the alkyl, C1-C6halogenation, amino,

di-(C1-C6)alkylamino-C1-C6by alkyl, hydroxyl, formyl, carboxyla,1-C6alkoxycarbonyl,1-C6alkanoyloxy, thiol, carboxamido,1-C6alkanolamine,

The invention relates to new piperidine derivative of the formula I, where R1means sensational, benzofuranyl, naphthyl which may be substituted with halogen, C1-C6-alkyl, C1-C6-alkoxygroup, substituted thienyl or substituted furanyl, which is substituted by halogen, C1-C6-alkyl, C3-C6-cycloalkyl or1-C6-alkenyl, R2means halogen and R3means1-C6-alkyl or C3-C6-cycloalkenyl, or their pharmaceutically acceptable salt, or solvate

The invention relates to new derivatives benzoylpyridine General formula (I), where R1means alkyl with 1-8 carbon atoms, a represents a group represented by the formula of the invention, means (-CH2-)aor (-CO-)band means an integer of 0 to 8, preferably 1, 2, 3 or 4, b means of 0,1 or 2, preferably 1, R2means unsubstituted or substituted alkyl with 1-8 carbon atoms, unsubstituted phenyl, NR3R4or preferably the five-membered heterocycle represented in the claims, in which U, V, W, X and Z can mean CH, NH, O or S, R3and R4denote alkyl with 1-8 carbon atoms

The invention relates to new Bermatingen compounds, the United propylenebis communication, General formula I where Ar represents a radical of formula (a) or (b), R1is-OR6or-COR7, R2represents a polyether radical, comprising 1 to 6 carbon atoms and 1 to 3 atoms of oxygen or sulfur, and if in the latter case, R4represents a linear or branched C1-C20alkyl, he is in ortho - or meta-position relative to X-Ar connection, R3represents lower alkyl, or R2or R3taken together form a 6-membered ring, optionally substituted by at least one of the stands and/or optional split the atom of oxygen or sulfur, R4represents H, linear or branched C1-C20alkyl or aryl, R5represents H or-OR8, R6represents H, R7represents H, -OR10or-N(r)r (r) r are H, lower alkyl or taken together with the nitrogen atom form a ring of morpholino, R8represents H or lower alkyl, R10represents H, linear or branched C1-C20alkyl, X represents a divalent radical, which is from right to left or Vice versa has the formula (d), R11Fri carboxylic acid and the optical and geometrical isomers of the above compounds of formula (I)

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

The invention relates to new derivatives of chloropyridinyl formula I where Het is a group of formula a, b, C, d or e, R1is hydrogen, unsubstituted or substituted C1- C6alkyl, and the substituents selected from the group comprising halogen, phenyl, cyano, C1- C4alkoxy, C1- C4alkylthio,1- C4alkylsulphonyl; C2- C4alkenyl, unsubstituted or substituted C1- C4alkoxygroup; phenyl or unsubstituted or substituted 1 or 21- C4alkoxygroup, n = 1 or 2, and their acid additive salts

The invention relates to new N-substituted azaheterocyclic carboxylic acids f-crystals (I) or their salts, in which R1and R2independently represent a hydrogen atom, halogen atom, trifluoromethyl, C1-C6-alkyl or C1-C6-alkoxy: Y is the grouporin which only the underlined atom participates in the cyclic system; X is a group-O-, -S-, -CR7R8, -CH2-CH2-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2CH2CH2-, -CH=CH-, -NR9-(C= O)-, -O-CH2-, -(C= O)- or -(S=O)-, where R7, R8and R9independently represent a hydrogen atom or a C1-C6-alkyl; z = 1, 2, or 3; m = 1 or 2, n = 1 when m = 1 and n = 0 when m = 2; R4and R5each represents a hydrogen atom or, when m = 2, can both work together to develop a bond; R6is hydroxyl or C1-C8-alkoxygroup, or its pharmaceutically acceptable salt, provided that is not included compound 10-(3-(3-carbomethoxy-1-piperidyl) propyl) phenothiazines and 10-(3-(3-carborexics-1-piperidyl) propyl) phenothiazines

The invention relates to new derivatives of 1-[2-(substituted vinyl)]-5H-2,3-benzodiazepine, method of production thereof, pharmaceutical composition, method thereof and method of treating diseases of the Central nervous system

The invention relates to the derivatives of pyrazole and herbicides containing them

The invention relates to new N-substituted azaheterocyclic carboxylic acids f-crystals (I) or their salts, in which R1and R2independently represent a hydrogen atom, halogen atom, trifluoromethyl, C1-C6-alkyl or C1-C6-alkoxy: Y is the grouporin which only the underlined atom participates in the cyclic system; X is a group-O-, -S-, -CR7R8, -CH2-CH2-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2CH2CH2-, -CH=CH-, -NR9-(C= O)-, -O-CH2-, -(C= O)- or -(S=O)-, where R7, R8and R9independently represent a hydrogen atom or a C1-C6-alkyl; z = 1, 2, or 3; m = 1 or 2, n = 1 when m = 1 and n = 0 when m = 2; R4and R5each represents a hydrogen atom or, when m = 2, can both work together to develop a bond; R6is hydroxyl or C1-C8-alkoxygroup, or its pharmaceutically acceptable salt, provided that is not included compound 10-(3-(3-carbomethoxy-1-piperidyl) propyl) phenothiazines and 10-(3-(3-carborexics-1-piperidyl) propyl) phenothiazines

The invention relates to new benzofuranyl derivatives and to the method of obtaining these derivatives

The invention relates to a new use of derivatives of imidazole, to new derivatives of imidazole, the way they are received, to the new obtained intermediate products and to pharmaceutical compositions based on derivatives of imidazole

The invention relates to new derivatives of 4-hydroxypiperidine formula I

< / BR>
where X represents-O-, -NH-, -CH2-, -CH=, -SNON - or-CO-; R1-R4independently from each other denote hydrogen, a hydroxy-group, (lower) alkylsulfonyl or acetaminoph; R5-R8independently from each other denote hydrogen, a hydroxy-group, (lower)alkyl, halogen, (lower)alkoxygroup, trifluoromethyl or cryptometrics; a and b may denote a double bond, provided that when a represents a double bond, b is unable to designate a double bond; n = 0-2; m = 1-3; p = 0 or 1, and their pharmaceutically acceptable additive salts

The invention relates to new piperidine derivative of the formula I, where R1means sensational, benzofuranyl, naphthyl which may be substituted with halogen, C1-C6-alkyl, C1-C6-alkoxygroup, substituted thienyl or substituted furanyl, which is substituted by halogen, C1-C6-alkyl, C3-C6-cycloalkyl or1-C6-alkenyl, R2means halogen and R3means1-C6-alkyl or C3-C6-cycloalkenyl, or their pharmaceutically acceptable salt, or solvate

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is an integer, R

The invention relates to new derivatives benzoylpyridine General formula (I), where R1means alkyl with 1-8 carbon atoms, a represents a group represented by the formula of the invention, means (-CH2-)aor (-CO-)band means an integer of 0 to 8, preferably 1, 2, 3 or 4, b means of 0,1 or 2, preferably 1, R2means unsubstituted or substituted alkyl with 1-8 carbon atoms, unsubstituted phenyl, NR3R4or preferably the five-membered heterocycle represented in the claims, in which U, V, W, X and Z can mean CH, NH, O or S, R3and R4denote alkyl with 1-8 carbon atoms
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