Derivatives of 2-(4-hydroxypiperidine)-1-alkanol and derivatives of 2-(4-hydroxypiperidine)-1-alcanena

 

(57) Abstract:

Usage: in medicine as a drug for the treatment of traumatic brain injury. The inventive products - derivatives of 2-(4-hydroxypiperidine)-1-alkanol f-ly 1, where R2-N or CH3, M, and Q form a divalent radical Z, where Z is chosen from the group comprising f-crystals 2, 3, 4. Reagent 1: compound f-crystals 5, where R2, M and Q above. Reagent 2: sodium borohydride. Reaction conditions: in the environment of the proton solvent at 15-25 degrees.With. The structure of the compounds f-l 1, 2, 3, 4, 5.

connection 1

, ,

connection 2. 2 s and 5 C.p. f-crystals.

The present invention is directed to a neuroprotective (anti-ischemic blocking induced by amino acid receptors) derivatives of 2-(4-hydroxypiperidine)-1-alkanol defined by the following formula 1, and their pharmaceutically acceptable salts, methods of using these compounds for the treatment of stroke, traumatic brain and spine, as well as neuronal degeneration diseases, including (but not limited to) the types of dementia, such as: disease Allgamer, Huntington's disease, and Parkinson's disease in a mammal, especially a human who is described as racemic, the so-called d1-Erythro-compounds with the following relative stereochemical configuration:

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and sold as antihypertensives, as is used along with a number of close analogues. Carron and other U.S. patent 3509164; Drags and other Res. so 21 p. 1992 1999 (1971). Much later it was shown that ifenprodil has anti-ischemic activity and activity blocker induced by amino acid receptors. Gotti and others I. Pharm. Exp. Therap. so 247, pp. 1211-21 (1988); Gale and others, ibid., pp. 1222-32 (1988).

Cm. also French patent 2546166 and EPO publication EP-A1-351282 dated January 17, 1990

The purpose of the present invention in this regard was the discovery of compounds, which has a significant neuroprotective activity, but at the same time characterized by reduced or absence of anti-hypertensive action.

It was reported on the application of certain 1-phenyl-3-(4-aryl-4-alkoxyimino)-1-propanolol as analgesics (U.S. patent 3294804); 1-/4-(amino - and hydroxyalkyl)phenyl/-2-(4-hydroxy-4-callipering)-1-alkanols and alkenone was reported to possess analgesic, antihypertensive, psychotropic or anti-inflammatory activity of the Japan patent Coca 53-02474 (CA 89:u; Derwent Abs. 14858A) and 53-59675 (CA:any funds (EP 398578 and Der 90-350327/47).

The invention is directed to compounds of formula (I),

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in which each of R1, R2and R3selected from the group comprising: hydrogen, alkyl with 1-6 carbon atoms, phenyl and substituted phenyl, the substituents which are selected from the group comprising: a hydroxy-group, alkyl with 1-4 carbon atoms, chlorine, bromine, fluorine, trifluoromethyl, amino group, a nitrogroup and alkoxygroup with 1-4 carbon atoms; or

R1and R2taken together form a methylene, ethylene, propylene or butylene group;

m is 0-2;

n is 1 or 2;

X and Y are each selected from the group comprising: hydrogen, chlorine, bromine, fluorine, trifluoromethyl, alkoxygroup with 1-4 carbon atoms, alkyl with 1-4 carbon atoms, a hydroxy-group, an amino group, a nitrogroup and replaced fenoxaprop, the substituents which are selected from the group comprising: hydrogen, a hydroxy-group, alkyl with 1-4 carbon atoms, chlorine, bromine, fluorine, trifluoromethyl, nitro-group, the amino group and alkoxygroup with 1-4 carbon atoms;

M and Q are each selected from the group comprising: hydrogen, a hydroxy-group, amino group, chlorine, bromine, fluorine, trifluoromethyl, nitro-group, alkyl with 1-4 carbon atoms, alkoxygroup with 1-4 carbon atoms, N,N-dialkylamino with 1-4 atoms PDE R4selected from the group comprising: hydrogen, alkyl with 1-6 carbon atoms, phenyl and substituted phenyl, the substituents which are selected from the group comprising: a hydroxy-group, chlorine, bromine, fluorine, trifluoromethyl, amino group, a nitrogroup, alkyl with 1-4 carbon atoms and alkoxygroup with 1-4 carbon atoms;

and where R5and R6selected from the group comprising: alkyl with 1-6 carbon atoms, phenyl and substituted phenyl, the substituents which are selected from the group comprising: a hydroxy-group, chlorine, bromine, fluorine, trifluoromethyl, amino group, a nitrogroup, alkyl with 1-4 carbon atoms and alkoxygroup with 1-4 carbon atoms;

or M and Q together form a divalent radical Z, where Z is chosen from the group including:

, , ,

, ,

and ;

where R7and R8each is chosen from the group comprising hydrogen and methyl, and their pharmaceutically acceptable salts with acids.

The expression "pharmaceutically acceptable salts with acids" is intended to indicate salts (but without limitation only by them), as the hydrochloride, the hydrobromide, hydroiodide, nitrate, hydrosulfate, dihydrophosphate, mesilate, maleate and succinate. Such salts are conveniently obtained by reaction of compounds of formula (I) in the form of a base with a line which form a precipitate, as a rule, isolated by solvent evaporation and/or by adding a precipitant, followed by filtration.

Featured group of the compounds of the present invention includes those compounds in which M and Q form a radical Z, where Z is , R1and R2the hydrogen and R3methyl, and compounds have 1R, 2S or eritrotsitarnoj configuration in the 1 - and 2-position circuit propanol, i.e., the Second featured a group of compounds of the present invention includes those compounds in which M and Q form a radical Z, where Z is , R1and R2the hydrogen and R3methyl, and compounds have 1S, 2S or threatmodeling configuration in the 1 - and 2 - position circuit propanol, i.e.

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The present invention also is directed to pharmaceutical preparations containing compounds of the invention of formula I, and methods of treatment of disorders of the Central nervous system in mammals, in particular humans, which consists in the introduction to the mammal a neuroprotective effective amount of the compounds of formula (1). Such medicines and methods are particularly valuable for the treatment of traumatic injuries of the brain and spinal cord, stroke, disease Allgamer, Parkinson's disease, Bo is purposed on the intermediate compounds of the formula:

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where R2and R3each is chosen from the group comprising: hydrogen, alkyl with 1-6 carbon atoms, phenyl and substituted phenyl, the substituents which are selected from the group comprising: a hydroxy-group, alkyl with 1-4 carbon atoms, chlorine, bromine, fluorine, trifluoromethyl, amino group, a nitrogroup, and alkoxygroup with 1-4 carbon atoms;

m is 0-2;

n is 1 or 2;

X and Y are each selected from the group comprising: hydrogen, chlorine, bromine, fluorine, trifluoromethyl, alkoxygroup with 1-4 carbon atoms, alkyl with 1-4 carbon atoms, a hydroxy-group, an amino group, a nitrogroup and replaced fenoxaprop, the substituents which are selected from the group comprising: hydrogen, a hydroxy-group, alkyl with 1-4 carbon atoms, chlorine, bromine, fluorine, trifluoromethyl, nitro-group, the amino group and alkoxygroup with 1-4 carbon atoms;

M and Q are each selected from the group comprising: hydrogen, a hydroxy-group, amino group, chlorine, bromine, fluorine, trifluoromethyl, nitro-group, alkyl with 1-4 carbon atoms, alkoxygroup with 1-4 carbon atoms, N,N-dialkylamino with 1-4 carbon atoms in each alkyl, N-alkylamino with 1-4 carbon atoms, NHCOR4, NHCOOR5and NHSO2R6; where R4selected from the group comprising: hydrogen, alkyl with 1-4 carbon atoms, fluorine, trifluoromethyl, amino, nitrogroup, alkyl with 1-4 carbon atoms and alkoxygroup with 1-4 carbon atoms;

R5and R6each is chosen from the group comprising: alkyl with 1-6 carbon atoms, phenyl and substituted phenyl, the substituents each selected from a group including: a hydroxy-group, chlorine, bromine, fluorine, trifluoromethyl, amino group, a nitrogroup, alkyl with 1-4 carbon atoms and alkoxygroup with 1-4 carbon atoms;

or M and Q together form a divalent radical Z, where Z is chosen from the group including:

, , ,

, ,

and

where R7and R8each is chosen from the group comprising: hydrogen and methyl.

Depending on the specific values of R1, R2and R3the compounds of formula (I) can have one or two asymmetric center, therefore, we can exist in various isomeric forms. All such isomers are encompassed by the scope of the present invention. The individual isomers can be isolated by classical methods, well known to the specialist.

Compounds of the present invention the above formula (I) can easily get a General way by the reaction of chlorinated formula (II) with a piperidine of formula (III) with subsequent vosstanovlenie get with the Deputy-HE-NH2in protected form, i.e. in groups-OA1or-NHA2in the compounds of the formula (IV). Define A1and A2are given below. Such protected ketones are usually obtained by the reaction of appropriately substituted 2-halo-1-Alcanena formula (II) with an appropriately substituted piperidinophenyl formula (III), for example:

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The reaction of the compound of formula (II) with the compound of the formula (III) is generally carried out under conditions typical for reactions of nucleophilic substitution. If both reagents approximately equal to its availability, they can be used in a molar equivalents, though, when one of the reagents more affordable, it is usually recommended to be used in excess in order to facilitate the flow of this bimolecular reaction in a shorter period of time. The reaction is usually carried out in the presence of at least 1 molar equivalent of a base, which can serve as itself a derivative of piperidine in case of its availability, but more commonly the use of a tertiary amine, at least partially comparable in its power with the nucleophilic piperidine. The reaction is carried out in an inert under the reaction conditions solvent, for example ethanol. If desired, the reaction catalyze debacle not crucial, but usually somewhat increased in order to promote the reaction in a shorter period of time, but not so high as to lead to unnecessary degradation. Satisfactory results usually produces a temperature in the range of 50-120oC. it is Convenient to conduct the reaction at the boiling temperature of the reaction mixture.

As used in the preceding paragraph and the next is the expression "inert under the reaction conditions solvent" refers to any solvent not interfering with the parent compounds, reagents, intermediate compounds or reaction product with a decrease in the result of the interaction of the yield of the target compound.

If desired, the intermediate ketones of formula (IV), in which the substituents OH and NH2located in a protected form (OA1or NHA2), at this stage, conventional methods can be released.

For example, if A1is triisopropylsilyl or tert-butyldimethylsilyl, the protective group can be easily removed by the action of tetrabutylammonium (usually in the amount of 2 molar equivalents) in an inert under the reaction conditions solvent, such as tetrahydrofuran. If A1benzyl or A2benzyloxycarbonyl inert under the reaction conditions solvent, for example, the use as the catalyst 10% Pd/C, preferably at low pressures (e.g., 1-10 atmospheres) and temperatures (for example, 20-75o(C) in an inert under the reaction conditions solvent, such as methanol.

Typically, the intermediate ketones of formula (IV), it is convenient to transform into the corresponding alcohols in one of two common methods of recovery with selective receipt or tree-derived or Erythro-derivative of formula (I).

As used in the previous paragraph and throughout the description of the meaning of the term "tree or 1S, 2S refers to the following relative configuration at the 1 - and 2-position circuit propanol:

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and the term "Erythro-or 1R, 2S refers to the following relative configuration at the 1 - and 2-position circuit propanol:

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To obtain the target Erythro-derivative of formula (I) corresponding to an intermediate ketone of formula (IV) usually recover the potassium borohydride, usually used in excess (for example, more than 5 molar equivalents) in the presence of glacial acetic acid in proton solvent such as ethanol in the temperature range of 15-25oC.

To obtain the target tree-derivative of formula (I) corresponding intermediate the molar equivalents) in proton solvent, for example, ethanol, usually in the temperature range of 15-25oC. the Resulting reaction mixture chromatographic on a column of silica gel with obtaining the specified tree-derivative of formula (I).

Any protective groups still remaining after recovery of the ketone, then remove the use of the above standard methods.

The initial compounds and the reagents required for the synthesis of compounds of formula (I) of the present invention, are readily available and can be obtained on an industrial scale according to the literature methods or by methods described in the preparative examples.

The compounds of formula (I) of the present invention have selective neuroprotective activity, based on their anti-ischemic activity and the ability to block induced by amino acid receptors, characterized in that the reduced or lack of a significant hypotensive activity. Anti-ischemic activity of the compounds of the present invention determines one or more of the methods described previously in the works Gotti and others and Carter and others, cited above, or similar methods.

The ability of compounds nastojasih the cold rat neurons in culture, subjected to the action excitotoxic amino acid glutamate. The following are typical methods.

Part 1 Selection of cells

Rats on the 17th day of pregnancy remove the embryos and placed in a solution of Tired. Then remove the brain and placed in a fresh solution of Tired. Using a scalpel to remove iris diamond brain and talus. Forebrain then divided into two hemispheres. Then, gently remove the meninges. Hippocam appears in a darkish folded area inside the boundaries of the cortical layer. Hippocam carefully separated from the rest of the fabric and placed in a separate corner of the Cup. After fully opening the fabric hippocam stored in the corner of the Cup, cut into pieces the size of 1 mm, the resulting pieces are selected by a Pasteur pipette and placed in a sterile tube. Gently suck the solution Tirade and add not containing calcium and magnesium solution Tirade. Fabric washed three times not containing calcium and magnesium solution Tirade. The final leaching solution is incubated for 15 minutes at 37oC. the Buffer is again removed and replaced with 1 l of fresh, not containing calcium and magnesium solution Tirade. Then add trypsin at a concentration of 01, (100 MK is inkubirovanija with trypsin fabric washed containing serum environment, aiming to stop the action of trypsin. The fabric is again suspended in 1 ml of fresh medium and triturated with having a small bore Pasteur pipette. Then use hemocytometer count the number of cells. After that, cells are placed in 96-minute honeycomb tablets to tissue cultures of the firm Falcon Primaria in the amount of 75,000 cells per cell in the full environment. Full environment consists of a minimum essentional environment (MES) with salts Earl, 10% fetal calf serum (Hanlon), 10% horse serum, 1-glutamine (2 mm), penicillin-streptomycin (100 u per ml) and glucose (bringing the final concentration of 21 mm from the prepared General X100 solution containing 27.8 g per 100 ml). On day 3 in the tablets make a fresh environment. On the 6th day of culture with fresh medium was added at a concentration of 10 μm cytosine arabinoside. Two days later, cytosine arabinoside removed and replaced with a stabilizing environment, representing complete medium minus fetal calf serum. After that, twice a week in tablets serving fresh environment. Three weeks after opening the tablets used in the experiments for the determination of glutamate toxicity to ensure the necessary development in neuronal culture.

Part 2 Processing glutamate and postpet is riedy wash does not contain chlorides control saline (KCP-C1). KCP-C1 contains 69 mm Na2SO4, 2,67 mm K2SO4, 0.33 mm NaHPO4, 0.44 mm KH2PO4, 1 mm NaNCO3, 1 mm MgSO4, 10 mm HEPES (N-2-hydroxyethylpiperazine-N1-econsultancy acid), 22.2 mm glucose and 71 mm sucrose, pH 7.4. After washing, add a glutamate at a concentration of 1-3 mm in KCP-C1 buffer, and the corresponding control cells contain buffer without glutamate. Tablets incubated for 15-20 minutes at 37oC. After incubation with glutamate tablets twice washed with serum-free medium. Subjects medicines are prepared in appropriate concentrations in serum-free medium and added to the appropriate wells of microtiter tablet (100 µl per cell). In the cells of the negative control contribute serum-free medium without drugs. Several processed glutamate cells, which also contribute serum-free medium without drugs, serve as a positive control. Tablets is incubated for about days at 37oAnd the next day to determine the survival rate using analyses with the use of lactate-dehydrogenase (LDH) and methylthiotetrazole (MMT).

Part 3. The definition of survival

Each tablet remove 100 ál of medium and transferring the l cell. The MTT solution is prepared by adding 100 ál of MTT solution 5 mg /ml in phosphate buffer saline (PBS)) for every 100 ál of serum-free medium. Tablets incubated for 4-6 hours at 37oC. Then, in each cell make 100 μl of an alcohol solution of acid (0,08 N. HCl in isopropanol/ and the contents of the cells strongly stirred to dissolve the purple crystals. Control cells must contain the medium with MTT and the alcoholic solution of the acid, but in the absence of cells. Then tablets take readings on a microplate reader using settings on two wavelengths: the test filter at 570 nm and a reference filter at 630 nm. Plates should be read within 1 hour.

The remote environment is then analyzed for LDH. Equal volumes of remote samples added to the LDH reaction mixture. In this case, the content of the corresponding cells unite with getting samples of 500 µl. For each sample, prepare the reaction mixture, which is mixed 480 μl of 0.1 M sodium phosphate buffer (pH 7.5), 10 μl of nutriiveda (66 mm) and 10 µl of the recovered OVER (each flask containing 5 mg of recovered OVER triggers in 440 μl of 0.1 G. of NaOH and the sample using 10 µl of the mixture). The sample is rapidly DOB DU-8.

Unwanted hypotensive activity is also determined by the known methods, for example, by the method of the Canon, and others have also cited above.

Such selective neuroprotective anti-ischemic activity and activity by blocking induced by amino acid receptors makes the compounds of the present invention is suitable for the treatment of traumatic injuries of the brain and spine, congenital disorders of the Central nervous system (CNS), for example: stroke, disease Allgamer, Parkinson's disease and Huntington's disease without significant simultaneous unnecessary fall in blood pressure. Systemic treatment of these diseases in humans neuroprotective amount of compounds of formula (I) dosage will usually be in the range of 0.02-10 mg/kg/day (1-500 mg/day for the average person weighing 50 kg) as a single or divided doses, regardless of the route of administration. Of course, depending on the specific compound and the specific nature of a particular disease your doctor may be prescribed dosage and not covered by the specified interval. As a rule, it is recommended that the oral route of administration. However, if the patient is unable to swallow, or oral absorption kaki">

Compounds of the present invention is usually administered in the form of pharmaceutical preparations containing at least one compound of formula (I) in a mixture of c pharmaceutically acceptable carrier or diluent in a ratio of 1:20-20: 1, respectively. Such drugs are usually prepared by standard methods using solid or liquid carriers or diluents, depending on the intended route of administration: for oral administration in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders, etc. for parenteral administration in the form of injectively solutions or suspensions, etc. and for administration topically in the form of solutions, lotions, ointments, creams, etc.

The present invention is illustrated by the following examples, but without limiting its parts.

All nonaqueous reactions carried out in an atmosphere of dry oxygen-free nitrogen, which simplifies and maximizes output. All solvents/thinners dried by standard published methods or get them in a pre-dried state. All of the reaction mixture is stirred with a magnetic or mechanical stirrer. NMR spectrum recorded at 300 MHz and the data are given in ppm in descending surface micrometers, as a rule, only strong signals.

Example 1.

()-3,4-Dihydro-6-(1-hydroxy-2-(1-(4-hydroxy-4 - phenoxymethyl) piperidine) ethyl) quinoline-2-(1H)-he

A mixture of 300 mg (1,23 mmol) 4-hydroxy-4-(phenoxymethyl)-piperidine hydrochloride, 409 mg (of 1.84 mmole) 6-(2-chloroacetyl)-3,4-dihydroquinoline-2 (1H)-she 0,514 ml (0,373 g, 3.7 mmol) of triethylamine in 25 ml of acetonitrile is heated to about day 60oC. the Solvent is then removed under vacuum, the residue is distributed between water and ethyl acetate and the organic layer is again washed with water and brine. An ethyl acetate layer is dried with brine and magnesium sulfate and after evaporation of the solvent obtained as brown solid 3,4-dihydro-6-(1-oxo-2-(1-(4-hydroxy-4-phenoxymethyl) piperidine) ethyl) quinoline-2 (1H)-he used at the subsequent stage of recovery without additional purification.

The resulting ketone is dissolved in 25 ml of absolute ethanol and to the solution in portions over 20 minutes are added 500 mg (of 13.1 mmol) NaBH4. The reaction mixture is stirred 4 hours at room temperature, then the solvent is removed and the residue partitioned between water and ethylacetate. After drying, removal of the ethyl acetate in vacuo and chromatography of the OST, ,83 (2H, s), 6,82-7,38 (8H, m).

Example 2.

()-5-(1-Hydroxy-2-(1-(4-hydroxy-4-phenoxy) piperidine) ethyl) benzimidazole-2-it.

The title compound is obtained according to the method of example 1 of the hydrochloride of 4-hydroxy-4-(phenoxymethyl) piperidine (1,23 mmole), 5-(2-chloroacetyl)-2-hydroxybenzimidazole (of 1.84 mmole) and triethylamine (3.7 mmol) in 25 ml of acetonitrile. The resulting ketone is stirred with sodium borohydride (of 13.1 mmol) in absolute ethanol, and after chromatography on silica gel get the target connection. Exit 35% so pl. 232-235oC. Analysis. The calc. for C21H25N3O4H2O: C 62,81, H 6,77, N 10,46. Found: C 62,98, H Is 6.54, N 10,32.

Example 3

()-5-(1-Hydroxy-2-(1-hydroxy-4-phenoxymethyl)- piperidinyl) ethyl)-2-oxoindole

The title compound is obtained according to the method of example 1 of the hydrochloride of 4-hydroxy-4-(phenoxymethyl) piperidine (1,23 mmol), 5-(2-chloroacetyl) oxindole (of 1.84 mmol) and triethylamine (3.7 mmol) in 25 ml of acetonitrile. The resulting ketone is stirred with sodium borohydride in absolute ethanol, and after chromatography on silica gel with a yield of 40% receive the title compound, so pl. 171-174oC.

Example 4

()-Erythro-5-(1-hydroxy-2-(1-(4-hydroxy-4-phenoxymethyl) piperidinyl) propyl) benim the Il) piperidinyl) propane-1-it in 10 ml of glacial acetic acid and 50 ml of absolute ethanol was added in portions during 15 - 20oWith 944 mg (17,48 mmol) of potassium borohydride and the resulting solution stirred for about a day at room temperature. Then the reaction mixture is evaporated to dryness and the residue is transferred in a minimum amount of water. Adding to the obtained solution solid NaHCO3set pH 7-8 with formation of a precipitate. The resulting product is insoluble in chloroform and is relatively insoluble in ethyl acetate. Together, evaporated to dryness and crystallizing the residue is transferred into ethanol and filtered to remove salts. The ethanol is evaporated, the residue is transferred in isopropanol and treated with gaseous HCl in ether with the deposition of non-crystalline salt, which is filtered off and dried in a current of dry nitrogen. The obtained product is dissolved in ethyl acetate in a mixture of methanol and lighten decolorizing activated carbon, after which the methanol is distilled off. Cooled obtain 410 mg (40%) of colorless crystalline product, so pl. 25-255oC. IR (KBr) 5,90 microns; NMR (CD3OD) d: 1,22 (3H, d, I 7), 1,95-of 2.09 (2H, m), 2,15-2,3 (2H, m), 3,42 is 3.76 (4H, m), 3,91 (2N, c), vs. 5.47 (1H, s), 6,92-to 7.35 (8H, m).

Example 5

()-Threo-5-(1-hydroxy-2-(1-(4-hydroxy-4-phenoxymethyl) -piperidinyl) propyl) benzimidazole-2-it.

To a suspension of 325 mg (0.82 mmol) ()-1-(5-(2-hydroxyl ablaut a total of 700 mg (18.4 mmol) of bergerat sodium and the reaction mixture is stirred for about a day at room temperature. The solvent is then evaporated, the residual foam is distributed between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. United an ethyl acetate extracts are dried, evaporated and chromatography of the residual foam on silica gel with elution with a mixture of ethanol-ethyl acetate (1:1) get in the form of a white solid of the title compound, so pl. > 250oC. NMR (acetone-d6d: of 0.79 (3H, d, I 7), 1,71-of 1.88 (2H, m), 11,9-of 2.08 (2H, m), 2,48-is 2.88 (4H, m), 3,01 (1H, t, I 7), 3,88 (2H, s), 4.26 deaths (1H, d, I 7), 6,86-to 7.32 (8H, m). Analysis. The calc. for C22H27N3O41,5 H2O: C 62,24, H 7,12, N 8,89. Found: 61,72, H 6.73 X, N 9,03.

Example 6

()-Erythro-3,4-dihydro-6-(1-hydroxy-2-(1-(4-hydroxy-4-phenoxymethyl) piperidinyl) propyl) quinoline-2 (1H)-he.

To a solution 7,13 g (17.5 mmol) ()-1-(6-(1,2,3,4-tetrahydro-2-oxopyrrolidin))-2-(1- (4-hydroxy-4-hydroxy-4-phenoxymethyl)-piperidinyl) propane-1-she's in 135 ml of absolute ethanol and 70 ml of glacial acetic acid portions at 15-20oTo add to 6.22 g (115 mmol) KBH4, after which the mixture is left for 30 minutes to warm to room temperature. The reaction mixture is evaporated to dryness, the residue is transferred into the cold water with ice and alkalinized solid NaHCO3. The formed precipitate is filtered off, washed with water and p is Airout with ethyl acetate, the combined extracts are dried with brine and MgSO4and after evaporation receive an additional 786 mg of product (total yield 62%). A sample of the product (510 mg) was dissolved in ethyl acetate and treated with a solution of gaseous HCl in ether to obtain 475 mg of the crystalline hydrochloride, T. pl. 214-216oC (decomp.). IR (KBr): mcm: NMR (CD3OD) d: to 1.15 (3H, d, I 7), 1,86-2,04 (2H, m), 3,52-3,66 (2H, m), 3,69 to 3.8 (1H, m), 3,86 (2H, s), of 5.34 (1H, s), for 6.81-of 6.96 (4H, m), 7,17-7,28 (4H, m).

Example 7

()-Threo-3,4-dihydro-6-(1-hydroxy-2-(1-(4-hydroxy-4-phenoxymethyl) piperidinyl) propyl) quinoline-2 (1H)-he.

To a suspension of 700 mg (1,71 mmole) ()-1-(5-(2-hydroxybenzimidazole))-2-(1-(1-(4-hydroxy-4-phenoxymethyl) piperidinyl) propane-1-she's in 20 ml of absolute ethanol are added in several portions a total of 1.5 g (39,5 mmol) NaBH4and the reaction mixture is stirred for about a day at room temperature. The solvent is then evaporated, the residual foam is distributed between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined extracts are dried, evaporated and chromatography of the residual foam on silica gel with elution with a mixture of ethanol-ethyl acetate (1:1) to obtain white solid with so pl. 192-196oC. When restoring a small number of Erythro-from what to 3.02 (1H, t, I 7), a-3.84 (2H, s), 4,28 (1H, d, I 7), 6,8-7,34 (8H, m). Analysis. The calc. for C22H27N3O41,5 H2O: C 65,88, H 7,6, N OF 6.4. Found: C 65,74, H 7,09, N Of 6.31.

Example 8

()-Erythro-5-(1-hydroxy-2-(1-(4-hydroxy-4-phenoxymethyl) piperidinyl)propyl)oxindol

A mixture of 0.5 g (2.05 mmole) of the hydrochloride of 4-hydroxy-4-(phenoxymethyl)piperidine, 0.5 g (2.25 mmol) of 5-(2-chloropropionyl)oxindole and 1 ml (0,725 g, 7,18 mmol) of triethylamine in 20 ml of acetonitrile is boiled for 24 hours. The solvent is then removed in vacuo and the residue distributed between ethyl acetate and water. An ethyl acetate layer washed with water, then brine and dried over MgSO4. After concentrating receive in the form of foam tan 537 mg (66% ) of the ketone, which is used in subsequent reactions without further purification.

A solution of 500 mg (of 1.26 mmol) of the ketone in 20 ml of ethanol is treated by adding portions 1 g (26,3 mmol) NaBH4and the resulting mixture is stirred for 24 hours at room temperature. The solvent is removed in vacuo and the residue distributed between ethyl acetate and water. An ethyl acetate layer was washed with brine and dried over MgSO4, then evaporated to dryness. The remainder chromatographic on silica gel with elution by ethyl acetate with a gradual increase in the concentration of this is, is), the 2.4 to 2.65 (4H, m), of 2.86 (1H, m), 3,32-3,4 (2H, m), with 3.79 (2H, s), 4.2V (1H, d, I 7), 6,7-to 7.35 (8H, m), 10,34 (1H, s).

Example 9

()-1-(6-1,2,3,4-Tetrahydro-2-oxopyrrolidin))-2-(1- (4-hydroxy-4-phenoxymethyl)piperidinyl)propane-1-he

A suspension of 8.3 g (to 34.06 mmol) of the hydrochloride of 4-hydroxy-4-phenoxymethylpenicillin and of 8.09 g (to 34.06 mmol) 6-(2-chloro-1-propionyl)-1,2,3,4-tetrahydroquinolin-2(1H)-she's in 100 ml of acetonitrile is treated 16,61 ml (12,04 g, 0.12 mmole) of triethylamine, boiled for 3 hours and then stirred for about a day at room temperature.

The reaction mixture is transferred into water and extracted 3 times with ethyl acetate. The combined extracts washed with brine, dried over magnesium sulfate and evaporation are foam. The foam is dissolved in a hot mixture of methanol with ethyl acetate and, after cooling, get the precipitated tan, which, as found, is the source chloroethanol and which discarded. The filtrate is evaporated, the residue is dissolved in ethyl acetate, where to accelerate crystallization add ether. Filtration of the product and washing with ether get 8,84 g (63,6% ) of the title compound cream color, so pl. 137oC. the Analytical sample is crystallized from ethyl acetate NMR (CD3OD) d: of 1.28 (3H, d, I 7), 1,6-of 1.92 (4H, m), 2,52-2,84 (6N, m) of 3.00 (2H, t, I 7 in), 3.75 (2H, s), 4,22 (1H) - Rev.: C 70,16, H IS 6.78, N 6,76.

Example 10

()-1-(5-(2-Hydroxybenzimidazole))-2-(1-(4-hydroxy-4-phenoxymethyl)piperidinyl)propane-1-he

Suspension 2,43 g (10 mmol) of the hydrochloride of 4-hydroxy-4-phenoxymethylpenicillin and 2.25 g (10 mmol) 5-(2-chloro-1-PROPYNYL)-2-hydroxybenzimidazole in 40 ml of acetonitrile is treated 4,88 ml (3,53 g, 35 mmol) of triethylamine, the reaction mixture is boiled for 90 minutes and then leave for two days at room temperature.

Then the reaction mixture was transferred into a mixture of water with ethyl acetate, suspended layer is filtered off, and, as was found, the precipitate is pure product (1,15 g after drying). The filtrate set pH 7 and extracted several times with ethyl acetate to obtain after washing with brine and drying over MgSO4colorless solid, recrystallization of which from a hot mixture of ethyl acetate-methanol receive an additional 560 mg of product (total yield 43% ), so pl. 230-235oC (decomp.). NMR (CD3OD/DMCO-d6d: 1,29 (2H, d, I 7), 1,6-of 1.92 (4H, m), 2,54-2,84 (4H, m), of 3.77 (2H, s), 4.26 deaths (1N, K, I, 7), 6,86-7,1 (6N, m), 7,75-a 7.92 (2H, m).

Example 11

()-1-(5-Oxindoles))-2-(1-(4-hydroxy-4 - phenoxymethyl)-piperidinyl)propane-1-he

The title compound is obtained according to the method of example 10 of the hydrochloride of 4-hydroxy-4-the Rila mountains. The title compound selected crystallization from a hot mixture of ethyl acetate-methanol in the form of an amorphous foam. Output 66,4% NMR (CDCl3d: of 1.28 (3H, d, I 7), 1,58-of 1.78 (4H, m), 2,4-2,84 (4H, m), of 3.54 (2H, s), 3,76 (2H, s), 4.09 to (1N, K, I, 7), 6,78-of 6.96 (3H, m), 7,14-7,26 (2H, m), 7,84-with 8.05 (3H, m) 9,52 (1H, broad s), for 9.64 (1H, broad s).

Preparative example 1

3,4-Dihydroquinoline-2-(1H)-he

To a suspension of 50 g (0,259 mol) o-nitrocatechol acid in 500 ml of ethanol, add 5 teaspoons of Ni-Raney and hydronaut about the day in a rocking chair Parra at an initial pressure of 50 psi (3.5 kg/cm2). The next morning the pressure to increase to 50 psi (3.5 kg/cm2) and the reaction continued for another 5 hours. Removal of the catalyst the reaction mixture was filtered and then washed in the layer of silica gel with a mixture of ethyl acetate with ethanol to remove traces of salts of Nickel. Evaporation of the filtrate to yield 57% receive the title compound. NMR (DMCO-d6d: of 2.45 (2H, t, I 7), 2,87 (2H, t, I 7), 6.87 in (2N, IR.d, I 7 and 7), 7,12 (for 7.12 (2H, DV. d, I 7 and 10), 10,08 (1H, s). So pl. 165-166oC.

Preparative example 2

6-(2-Chloropropionyl)-3,4-dihydroquinoline-2(1H)-he

To a stirred suspension of 72.5 g (0,544 mol) AlCl3800 ml CS2in the atmosphere of dry N2add a 14.1 ml (20 g, 0,177 mole) of 2-chloropropionitrile followed pribivaetsya separation of phases. The reaction is terminated by pouring the reaction mixture with vigorous stirring on ice. The resulting pale yellow precipitate is filtered off, washed with water and after drying for about a day at the P2O5get to 27.7 g (91%) of target compound, so pl. 236,5-238oC.

Preparative example 3

5-(2-Chloropropionyl)-2-hydroxybenzimidazole

The title compound obtained by the method of preparative example 2 from 2-hydroxybenzimidazole (0,136 mol), aluminum chloride (0,544 mol) and 2-chloropropionitrile (0,177 mol) in 800 ml CS2. The title compound with a yield of 92% allocate filtering, so pl. 245oC (decomp.). Analysis. The calc. for C10H9ClN2O2: C 53.47 USD, H OF 4.04, N 12,47. Found: C 54,41, H 4,07, N 13,25.

Preparative example 4

5-(2-Chloropropionyl)oxindol

The title compound obtained by the method of preparative example 2 from oxindole (0,136 mol), aluminum chloride (0,544 mol) and 2-chloropropionitrile (0,177 mol) in 800 ml CS2. The title compound with a yield of 91% isolated by filtration, so pl. +57-158oC.

Preparative example 5

6-(2-Chloroacetyl)-3,4-dihydroquinoline-2(1H)-he

The title compound obtained by the method of preparative example 2 3,4-dihydrogen connection with the release of 50% of the allocated filtering, so pl. 215-216oC.

Preparative example 6

5-(2-Chloroacetyl)-2-hydroxybenzimidazole

The title compound obtained by the method of preparative example 2 from 2-hydroxybenzimidazole (0,136 mol), aluminum chloride (0,544 mol) and 2-chloroacetanilide (0,177 mol) in 800 ml CS2. The title compound with a quantitative yield of the selected filtering, so pl. 273-275oC (decomp.).

Preparative example 7

5-(2-Chloroacetyl)oxindol

The title compound obtained by the method of preparative example 2 from oxindole (0,136 mol), aluminum chloride (0,544 mol) and 2-chloroacetanilide (0,177 mol) in 800 ml CS2. The title compound with a yield of 90% isolated by filtration, so pl. 236,5-239oC.

Preparative example 8

Hydrochloride 4-hydroxy-4-phenoxymethylpenicillin

To dry dimethylsulfoxide (250 ml) under nitrogen atmosphere not containing added oil sodium hydride (2.16 g, and 0.09 M) and the mixture is heated at 60-65oWith until a homogeneous black solution (about 1 hour). Then add 19,83 g (0,09 M) trimethylsulfoxonium (little heat) and the mixture is stirred until the brown color of the solution (about 30 minutes). Then add a solution of 13.4 g (67,3 mm) N-tacciono the mixture is transferred into 1 l of cold water and extracted 4 times with 100 ml of hexane. The combined hexane extracts are washed with water, brine and dried over magnesium sulfate. After filtration and evaporation receive 11,75 g (yield 78%) of 6-tert-butyloxycarbonyl-1-oxa-6-azaspiro-(2,5)octane as a white crystalline substance.

Additional extraction of the aqueous layers with hexane (3x 50 ml) get another 650 mg of product, which in total gives the output 82.5%

So pl. of 57.5-59,5oC; IR (KBr): 5,9 microns; NMR d: 1,32 -1,48 (2H, m), 1,42 (N, C), 1,74-1,8 (2H, m), 2,65 (2H, s), 3,31-of 3.43 (2H, m), 3,61-and 3.72 (2H, m); analysis calc. for C11H19NO3: C 61,94, H 8,98, N 6,57. Found: C 62,05 H A 9.09, N 6,58.

To a solution of 10,37 g (0,11 M) phenol in 100 ml of dimethyl sulfoxide are added in several portions not containing oil sodium hydride (1,99 g of 82.8 mmol), maintaining the temperature within 20 -25o(Bath with cold water). Followed by stirring the reaction mixture for 45 minutes at room temperature to obtain a suspension of gray. Added dropwise 11,75 g (55.2 mmol) of 6-tert-butyloxycarbonyl-1-oxa-6-azaspiro(2,5)octane in 65 ml of dimethyl sulfoxide, after which the reaction mixture is heated for 7 hours at 55-60oC and then stirred for about a day at room temperature.

Then the reaction mixture was transferred into 1 l of cold water and axnd magnesium sulfate receive in the form of oil 17,01 g (100% ) of the target N-tert-butyloxycarbonyl-4-hydroxy-4-phenoxymethylpenicillin.

IR (film): 5,91, 2,95 microns; NMR (CDCl3d: 1,46 (N, C), 1,53-1,8 (4H, m), 3,13-3,3 (2H, m), 3,8 (2H, s), 3,8-3,98 (2H, m), 6,84-6,99 (2H, m), 7,22-7,44 (3H, m). Analysis. The calc. for C17H25NO4: C 66,42, H 8,2, N 4,56. Found: C 65,72, H 8,21, N 4,77.

A solution of N-tert-butyloxycarbonyl-4-hydroxy-4-phenoxymethylpenicillin in 150 ml of methanol saturated with gaseous HCl. After cooling, the mixture is again treated with gaseous HCl and this operation is repeated again. After the formation of the crystals, the reaction mixture is treated with 500 ml of anhydrous ether and stirred for about a day at room temperature.

The product is filtered, washed with dry ether and after drying in a stream of dry nitrogen receive 10,85 g (80,6%) of crystalline product, so pl. 202-204oC. IR (KBr): 3,06, 3,14, 3,44, 3,57, 6,33, 8,06 microns; NMR (D2O) d: 2 (4H, broad s) to 3.34 (4H, broad s), 4 (2H, s), 6,98-to 7.09 (3H, m), 7.3 to the 7.43 (2H, m). Analysis. The calc. for C12H17NO2HCl C $ 59.13 USD, H 7,44, N 5,75. Found: C 5 58,98, H 7,11, N 5,65.

1. Derivatives of 2-(4-hydroxypiperidine)-1-alkanol General formula

< / BR>
where R2selected from the group comprising hydrogen or methyl;

M and Q together form a divalent radical Z, where Z is chosen from the group including

< / BR>
or

< / BR>
or their pharmaceutically acceptable salts. is achene.

3. Connection on p. 1, characterized in that it corresponds to the formula

< / BR>
where M and Q have the specified values.

4. Connection on p. 3, wherein Z is a radical of the formula

< / BR>
5. Connection on p. 2, wherein Z is a radical of the formula

< / BR>
6. Connection on p. 2, wherein Z is a radical of the formula

< / BR>
7. Derivatives of 2-(4-hydroxypiperidine)-1-Alcanena General formula

< / BR>
where R2represents hydrogen or methyl;

M and Q together form a divalent radical Z, where Z is chosen from the group including

< / BR>
or

.

 

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FIELD: organic chemistry, medicine, pharmacy.

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(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing compounds of the formula (I): wherein R means halogen atom; R1 means hydrogen atom (H); R2 means cyano-group (CN); X means oxygen atom (O) or H, H; n = 2, 3, 4, and their acid-additive salts. If X means oxygen atom (O) then the method involves interaction of compound of the formula (II): with compound of the formula (III): R-(CH2)n-CO-L (III) wherein L means halogen atom or others in the process of Friedel-Crafts acylation reaction in the presence of Lewis metalhalides of type R'-Al(Cl)2 as a catalyst wherein R' means (C1-C6)-alkyl. Prepared compound of the formula (I) is isolated as a base or its acid-additive salts followed by reduction by using complex hydrides and activation with Lewis metalhalides of type R'-Al(Cl)2. Method provides preparing compounds with the yield 87-89%.

EFFECT: improved preparing method.

3 cl, 4 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of novel compounds of formulas (Ia-g): wherein: (a) R means -OCH3; R1 means phenyl (Ph); (b) R means -OCH3; R1 means 4-bromophenyl (4-Br-Ph); (c) R means -OCH3; R1 means CH3; (d) R means -OCH3; R1 means 4-CH3-Ph; (e) R means -OCH3; R1 means C2H5; (f) R means -OCH3; R1 means hydrogen atom (H); (g) R means -O-CH2-CH2-O-; R1 means CH3. Method involves interaction of benzhydrol of formulas (IIa-g): wherein values R and R1 are given above with N-furan-2-yl-methyl-4-methylbenzenesulfonamide of the formula: in acetic acid medium in boiling for 0.2-20 h in the presence of phosphoric acid as a catalyst wherein 3 ml of phosphoric acid are added per 0.01 mole of benzhydrol of formulas (IIa-g). Compounds of formulas (Ia-g) can be used in synthesis of novel analogs of anti-tumor preparations.

EFFECT: improved method of synthesis, valuable medicinal property of preparations.

2 tbl, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to methods (variants) for synthesis of stable form of indole-3-carbonol hydrate. Indole-3-carbonol hydrate is a known compound and used in pharmaceutical industry. Method for synthesis of indole-3-carbinol hydrate involves the reduction reaction of indole-3-carboxaldehyde with sodium boron hydride in (C1-C3)-alkyl alcohol medium, Water is added to a prepared reaction mass and kept at decreased temperature up to its complete precipitation followed by drying at environment temperature. Alternative method involves isolation of the reaction product after reaction mass obtained after carrying out the reduction reaction and crystallization from water or aqueous (C1-C3)-alkyl alcohol at weak heating, the following cooling and keeping the prepared solution at temperature about zero and its drying at environment temperature. If necessary, synthesized indole-3-carbinol hydrate is re-crystallized additionally from water or aqueous (C1-C3)-alkyl alcohol and keeping the prepared solution at temperature from +3°C to -18°C and its drying at environment temperature. Proposed methods provide preparing product showing enhanced stability and without undesirable impurities of by-side conversion substances and solvents used in re-crystallization.

EFFECT: improved method of synthesis.

3 cl, 7 dwg, 7 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to novel compounds of indoline of the formula (I): , wherein R1 and R3 are similar or different and each means hydrogen atom (H), lower alkyl group or lower alkoxy-group; R2 means -NO2, -NHSO2R6 [wherein R means (C1-C20)-alkyl group, aryl group or -NHR7 (wherein R7 means H, -COR13 (wherein R13 means H, lower alkyl group) or lower alkoxycarbonyl group)], -NHCONH2 or lower alkyl group substituted with -NHSO2R6 [wherein R6 means (C1-C20)-alkyl group, aryl group or -NHR7 (wherein R7 means H, -COR13 (wherein R13 means H, lower alkyl group) or lower alkoxycarbonyl group)]; R4 means H, (C1-C20)-alkyl group optionally substituted with hydroxy-group, -COR13 (wherein R13 means H, lower alkyl group), lower alkenyl group, lower alkoxy-lower alkyl group, lower alkylthio-lower alkyl group, (C3-C8)-cycloalkyl group or (C3-C8)-cycloalkyl-(C1-C3)-alkyl group; R5 means (C1-C20)-alkyl group, (C3-C8)-cycloalkyl group or aryl group; R12 means H, lower alkyl group, lower alkoxy-lower alkyl group or lower alkylthio-lower alkyl group wherein aryl represents phenyl or naphthyl, or its pharmaceutically acceptable salt. Compounds possesses the strong inhibitory effect on activity of acyl-coenzyme A:cholesterol acyltransferase and the strong inhibitory effect on lipid peroxidation processes that allows its using as a component of pharmaceutical compositions.

EFFECT: valuable medicinal and biochemical properties of compound and pharmaceutical compositions.

31 cl, 5 tbl, 68 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel indole derivatives with the common formula I: or its pharmaceutically acceptable salt, where R1 is (a) -X-aryl-Y-Z and (b) -X-heteroaryl-Y-Z, where aryl and heteroaryl are unsubstituted or substituted with 1-3 groups, chosen independently from A; aryl means phenyl or naphthyl; heteroaryl means the monocyclic or condensed bicyclic aromatic ring structure containing one heteroatom chosen independently from N or O, where the monocyclic ring or each ring of the bicyclic ring structure means the penta- or hexamerous ring; X means the bond CH2, CH(CH3) and C(CH3)2; Y means -CH=CH-, -CH(OH)CH(OH)-, -OCR7R8-, -SCR7R8- and -CH2CR5R6-; Z means -CO2H, tetrazole; A means C1-4alkyl, -OC1-4alkyl and halogen, where alkyl, and -Oalkyl, each not necessarily substituted with 1-5 halogens; R5, R6, R7 and R8 , each independently means H, C1-C5alkyl, -OC1-C5alkyl, C3-6cycloalkyl and phenyl, where C1-C5alkyl, -OC1-C5alkyl, C3-6cycloalkyl and phenyl are not necessarily substituted with 1-5 halogens; and C3-6cycloalkyl and phenyl are additionally not necessarily substituted with 1-3 groups, independently chosen from C1-C3alkyl and -OC1-C3alkyl, at that, the said C1-C3alkyl and -OC1-C3alkyl are not necessarily substituted with 1-3 halogens; or alternatively, R7 and R8 together can form the C3-C6cycloalkyl group; or alternatively, when R1 means -X-phenyl-Y-Z, Y means -OCR7R8 and R7 are chosen from group containing H, C1-C5alkyl, -OC1-C5alkyl, then R8 can, not necessarily , mean the 1-2-hydrocarbon bridge, bound to the phenylic ring by the orthoposition relative to Y, and generating in this way the 5- or 6-membered heterocyclic ring, condensated with the phenylic ring; R2 means C1-C4alkyl, which is not necessarily substituted with 1-5 halogens; R3 means (a) bensoxazolil, (d) aryl, (e) -C(=O)aryl, (f) -C(=O)heteroaryl, (g) -Oaryl, (i) -S(O)naryl and where R3 is not necessarily substituted with 1-3 substituting groups, independently chosen from halogen, C1-3alkyl, -OC1-3alkyl and -SC1-3alkyl, where C1-3alkyl, -OC1-3alkyl and -SC1-3alkyl are not necessarily substituted with 1-5 halogens; each R4 means from H, halogen, C1-C5alkyl and -OC1-C5alkyl, where C1-C5alkyl and -OC1-C5alkyl are not necessarily substituted with 1-5 halogens; n is the even number 0-2 and p is the even number 1-3.

EFFECT: composition I reveals agonistic activity considering PPAR, that allows to use them in pharmaceutical composition, in means to fix PPAR and production of medication to fix PPAR.

33 cl, 8 tbl, 32 ex

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