Synthesis of esters of 2-chloromethyl-6-methylbenzoic acid

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula , in which R represents H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl. In the alkyl, one or more CH2-groups can be substituted with -O-. The invention also relates to the method of obtaining these compounds. The method involves reacting dimethylbenzoic acid ester with formula where R assumes values given above, with a chlorinating agent in an inert solvent or without a solvent at temperature above 40°C, and then cleaning, if necessary. Formula (I) compounds are essential intermediate products during synthesis of PPAR agonists with formula , in which R represents H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl. In the alkyl, one or more CH2-groups can be substituted with -O-; Y represents -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl; R' represents H, F, Br, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, phenyl; CF3; obtained from reaction of compounds with formula with formula (I) compounds in toluene, N-methylpyrrolidone or other aprotic solvents, in the presence of a suitable base, at temperature lying in the -78°C - +50°C interval, with subsequent extractive processing and, if necessary, crystallisation of the end product.

EFFECT: obtaining new compounds.

8 cl, 5 ex

 

Derivatives of 2-halogenosilanes acid are used as components for the synthesis of biologically active pharmaceutical substances. For various reasons, to use it you need to have a desirable, stable during storage compounds, which can be a simple way to get and clean. These reasons include, for example, ensuring constant quality, avoidance of frequent follow-up examinations substances for reporting product quality, reduce the need for storage in refrigerators and/or use of heatresistant, a gentle introduction to industrial installations, as well as simple cleaning of used tanks.

The esters of 2-methyl bromide-6-methylbenzoic acid (A1 and A2), for example, is known from International application WO-00/64888 (R = isobutyl (A1)) and the International application WO-00/64876 (R = methyl (A2)). These compounds are unstable at room temperature, as they spontaneously cyclists to the lactone (C) and, as you know, free mutagenic were synthesized as a by-product.

Therefore, the use of these thermostabilised substances on an industrial scale is associated with the risk of health difficulties and additional costs.

The esters of 2-methyl bromide-6-methylbenzoic acid of interest, in particular, as the source is x materials for the production of PPAR agonists, as described, for example, in International applications WO-00/64888, WO-00/64876 and WO-03/020269. In this case, in particular, should be called the compounds of formula (C):

where

R is H, (C1-C12)-alkyl, (C3-C8-cycloalkyl, (C6-C12)-aryl, (C1-C4)-alkyl-(C6-C12)-aryl or (C5-C10-heteroaryl, and in the alkyl and cycloalkyl one or more CH2-groups may be replaced by-O - alkyl, cycloalkyl and aryl can be substituted with halogen;

Y represents -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl;

R' denotes H, F, Br, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, phenyl;

R ' denotes H, (C1-C6)-alkyl, (C1-C3-alkylphenyl, (C5-C6-cycloalkyl, phenyl, CF3.

Preferably it should be called the compounds of formula (C), in which the phenyl cycle substituted by the radical R' in m - or p-position.

The objective of the invention is the production of more stable compounds than (A1) and (A2)that does not have the above disadvantages. Additionally, compounds that when you receive them from the original product can also be formed with still insufficient degree of purity, in contrast to the compounds of formulas (A1) and (A2) must be able to receive treatment.

E. the CSO is achieved through the following compounds of formula (I).

The object inventions are the compounds of formula (I):

where

R is H, (C1-C12)-alkyl, (C3-C8-cycloalkyl, (C6-C12)-aryl, (C1-C4)-alkyl-(C6-C12)-aryl or (C5-C10-heteroaryl, and in the alkyl and cycloalkyl one or more CH2-groups may be replaced by-O - alkyl, cycloalkyl and aryl can be substituted with halogen.

Preferred compounds of formula (I), where

R means (C1-C8)-alkyl, (C3-C6-cycloalkyl or (C1-C4)-alkyl-(C6-C12)-aryl which may be substituted with halogen, and one or two CH2-groups may be replaced by-O-.

Especially preferred compounds of formula (I), where

R means (C1-C6)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl which may be substituted with halogen, and one of CH2group can be replaced by-O-.

Highly preferred compounds of formula (I), where

R means methyl, ethyl, propyl, isopropyl, tert-butyl, phenyl, 2-methoxyethyl or benzyl.

The alkyl may be branched or unbranched. Halogen means Cl, Br, I, preferably Cl. Under heteroaryl understand 5-10-membered aromatic cycles, which contain from one to che is ireh identical or different heteroatoms from the series N, O, S, as, for example, pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazol, thiazole, isothiazol, triazole, tetrazole, triazine, tetrazine; preferred are pyrrole, imidazole, oxazole, thiazole and pyridine.

The object of the invention, then, is a method of obtaining compounds of formula (I):

where

R is H, (C1-C12)-alkyl, (C3-C8-cycloalkyl, (C6-C12)-aryl, (C1-C4)-alkyl-(C6-C12)-aryl or (C5-C10-heteroaryl, and in the alkyl and cycloalkyl one or more CH2-groups may be replaced by-O - alkyl, cycloalkyl and aryl can be substituted with halogen,

characterized in that the esters of dimethylbenzoic acid of formula (II):

where R has the above significance, enter into interaction with gloriouse reagent, such as, for example, sulfurylchloride, N-chlorosuccinimide (NCS), 1,3-dichloro-5,5-dimethylhydantoin (NDDH) or trichloroisocyanurate acid [Org. Process Research and Development,6, 384-393 (2002)], in an inert solvent, such as, for example, CCl4, chlorobenzene, or without solvent, at temperatures above 40°and, if necessary, and then subjected to purification.

The reaction is preferably carried out at a temperature of 60 to 90°C. At lower t is mperature, 40°With, see the chlorination in the aromatic part. Cleaning is preferably carried out by distillation or by filtering through silica gel.

Chlorinated compounds of formula (I) is not available or only very inaccessible due to chlorination with opening cycle of the lactones (B), as lackenby skeleton is very stable. Further, derivatives of 2-chloromethylbenzene acid unexpectedly can be subjected to distillation, can be selected from a chemical point of view, the degree of purity and during storage they do not react spontaneously with the formation of lactones.

Transformation of chlorinated compounds of formula (I) in a more reactive bromine - or iododerma compounds may also be useful to increase the reactivity of this structural element molecules in the further synthesis (for example, to get agonists of PPAR (C)). These compounds, however, then have the mentioned in the introduction of "technical" shortcomings. The transformation of chlorinated compounds in the bromine - or idatabase connection is carried out using alkali metal halides in inert solvents, preferably using a bromide or sodium iodide in acetone at boiling temperature under reflux. Alternatively, perhalogenated and further synthesis can be performed also in the ideal one-stage method with the use of catalytic or stoichiometric amounts of alkylhalogenide, in terms of used chlorinated connection.

The object of the present invention, then, is a method of obtaining compounds of formula (C):

where

R is H, (C1-C12)-alkyl, (C3-C8-cycloalkyl, (C6-C12)-aryl, (C1-C4)-alkyl-(C6-C12)-aryl or (C5-C10-heteroaryl, and in the alkyl and cycloalkyl one or more CH2-groups may be replaced by-O - alkyl, cycloalkyl and aryl can be substituted with halogen;

Y represents -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl;

R' denotes H, F, Br, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, phenyl;

R ' denotes H, (C1-C6)-alkyl, (C1-C3-alkylphenyl, (C5-C6-cycloalkyl, phenyl, CF3;

characterized in that compounds of the formula (C1):

where Y, R' and R" have the above significance, enter into an interaction with compounds of formula (I):

where R has the above significance, in toluene, N-organic or other aprotic solvents, in the presence of a suitable base, preferably with the use of potassium tert-butylate, at temperatures from -78°to +50°C, preferably at temperatures between -30� C to +20°C, and then subjected to extractive processing and, if necessary, the resulting product is crystallized.

The compounds of formula (I) are distinguished by high stability in comparison with the corresponding bromodomain connections. If you compare the stability of the methyl ester of 2-methyl bromide-6-methylbenzoic acids with stability of similar chlorine-containing compounds, find the following result: methyl ester of 2-chloromethyl-6-methylbenzoic acid can perekanatisya without decomposition at temperatures between 66°to 77°at a pressure of 0.1 mbar, only the temperature of the bottom of the column above 120°leads to a significant formation of lactone. At room temperature they can remain stable for several months. The storage stability of the methyl ester of 2-methyl bromide-6-methylbenzoic acid clearly different. At room temperature the number prosteradlo connection decreases rapidly within a few days, during the week from 92,6% to 81,0%, within 2 weeks to 67.8% and within 2 months to 7.8%. At the same time increases the amount of lactone from 1.9% to more of 13.9% after 2 weeks and to 89.5% for 2 months.

Listed below are the following examples, not limiting the scope of protection of the invention:

Example 1

Synthesis of methyl ester of 2-chloromethyl-6-methylbenzoyl to the slots

11.9 g of Methyl ester of 2,6-dimethylbenzoic acid in 50 ml of chlorobenzene at room temperature mix from 8.2 g of sulfurylchloride and 40 mg azobisisobutyronitrile. Stirred for 2 hours at a temperature of 60-90°C. Then mixed with 80 ml of a saturated solution of NaHCO3. After phase separation the organic phase is washed with 100 ml of 10%aqueous solution of Na2SO3, the organic phase is dried over magnesium sulfate and the chlorobenzene is distilled off in vacuum. Obtain 15.5 g of colorless liquid. The product is distilled in a high vacuum (0.1 mbar; 66-77°). Yield: 10.2 g (71% of theory; purity 95.2 per cent according to liquid chromatography (LC)).

Example 2

Synthesis of isopropyl ester of 2-chloromethyl-6-methylbenzoic acid

19.2 g of Isopropyl ether 2,6-dimethylbenzoic acid in 100 ml of carbon tetrachloride at room temperature is mixed with 13.3 g of N-chlorosuccinimide and 200 mg azobisisobutyronitrile. Refluxed for 3 hours. After cooling, is filtered off under vacuum and succinimide washed with 20 ml of carbon tetrachloride. The filtrates are combined and the carbon tetrachloride is distilled off in vacuum. Obtain 21.8 g of colorless liquid. The product is distilled in a high vacuum of 0.05 mbar; 94-97°). Output: a 13.9 g (61% of theory; purity 93,6% according to LC).

Example 3

Synthesis of 2-methoxyethyl the th ether 2-chloromethyl-6-methylbenzoic acid

10.4 g of 2-Methoxyethanol ether 2,6-dimethylbenzoic acid at room temperature is mixed with a 5.4 g sulfurylchloride and 40 mg azobisisobutyronitrile. Stirred for 1-2 hours at a temperature of 60-90°C. Then mixed with 20 ml of water, the phases are separated and the organic phase is dried over magnesium sulfate. The product is distilled in a high vacuum (0.02 mbar; 95-103°). Yield: 6.4 g (66% of theory; purity of 91.8% according to LC).

Example 4

Synthesis of benzyl ether of 2-chloromethyl-6-methylbenzoic acid

12.0 g of Benzyl ester of 2,6-dimethylbenzoic acid in 50 ml of carbon tetrachloride at room temperature is mixed with a 5.4 g sulfurylchloride and 40 mg azobisisobutyronitrile. Stirred for 4-5 hours at boiling temperature under reflux. Then mixed with 40 ml of a saturated solution of NaHCO3. After phase separation the organic phase is washed with 50 ml of 10%aqueous solution of sodium sulfite and the organic phase is dried over magnesium sulfate. Containing product solution is filtered through silica gel and optionally washed with 20 ml of carbon tetrachloride. After removal of the solvent in vacuum to give the product as a pale yellow oil. Yield: 8.0 g (73% of theory; purity 88,4% according to LC).

Example 5

2-Methyl-6-[3-(2-phenyloxazol-4-ylethoxy)propoxymethyl]-benzoic acid

<> 4.8 g of Methyl ester of 2-chloromethyl-6-methoxybenzoic acid at room temperature is dissolved in 250 ml of acetone and mixed with 35 g of sodium iodide. The mixture is refluxed for 6 hours. Then the solvent is removed in vacuum at a temperature of 0°C. the Residue is analyzed by liquid chromatography with mass spectrometry (purity methyl ester 2-iodomethyl-6-methylbenzoic acid 87,7% according to the analysis) and dissolved in 20 ml of toluene. The solution for 10 minutes at -20°With added dropwise to a mixture of 5.0 g of 3-(2-phenyloxazol-4-ylethoxy)propan-1-ol, 4.8 g of potassium tert-butylate and 30 ml of toluene. Then stirred for 6 hours at a temperature of 20°C, diluted with 100 ml water and the aqueous phase is separated. The organic phase is mixed with 40 ml of N-methylpyrrolidone and 10 ml of 32%sodium hydroxide solution and within 8 hours refluxed when using the water separator. After this is mixed with 100 ml of water and extracted with twice 25 ml of methyl tert-butyl ether. The aqueous phase is acidified with 5 ml of acetic acid and extracted twice with 50 ml ethyl acetate. After phase separation the organic phase is dried over magnesium sulfate and the solvent is removed in vacuum. After crystallization from diisopropyl ether gain of 4.2 g of 2-methyl-6-[3-(2-phenyloxazol-4-ylethoxy)propoxymethyl]what antinoi acid (50% of theory; the purity of 99.2% according to HPLC).

1. The compounds of formula (I):

where R is H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl, and alkyl, one or more CH2-groups may be replaced by-O-.

2. The compounds of formula (I) according to claim 1, where R means (C1-C8)-alkyl, or (C1-C4)-alkyl-(C6-C12)-aryl, and one or two CH2-groups may be replaced by-O-.

3. The compounds of formula (I) according to claim 1 or 2, where R means (C1-C6)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl, and one of CH2group can be replaced by-O-.

4. The compounds of formula (I) according to claim 1 or 2, where R is methyl, ethyl, propyl, isopropyl, tert-butyl, 2-methoxyethyl or benzyl.

5. The method of obtaining compounds of formula (I) according to claims 1 to 4, characterized in that the ester dimethylbenzoic acid of formula (II)

where R has the above significance, enter into interaction with gloriouse reagent in an inert solvent or without solvent, at temperatures above 40°and then, if necessary, purified.

6. The method of obtaining compounds of formula (C)

where R oz is achet N, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl, and alkyl, one or more CH2-groups may be replaced by-O-;

Y represents -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl;

R′ means H, F, Br, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, phenyl;

R′′ means N, (C1-C6)-alkyl, (C1-C3-alkylphenyl, (C5-C6-cycloalkyl, phenyl, CF3;

characterized in that compounds of the formula (C1)

where Y, R′ and R′′ have the above significance, enter into an interaction with compounds of formula (I)

where R has the above significance, in toluene, N-organic or other aprotic solvents, in the presence of a suitable base at a temperature of from -78 to 50°and then subjected to extractive processing and, if necessary, the final product is crystallized.

7. The method of obtaining compounds of formula (C) according to claim 6, where the phenyl cycle is substituted by a residue R′ m - or p-position.

8. The use of compounds of formula (I) according to claims 1 to 4 to obtain the PPAR agonists of the General formula (C).



 

Same patents:

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a compound of the formula (I) where A ring is (C3-C8)-cycloalkyl or (C3-C8)-cycloalkenyl where two carbon atoms in the cycloalkyl ring can be substituted by oxygen atoms; R1, R2 are H, F, Cl, Br, OH, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl independently from each other; R3 is H or (C1-C6)-alkyl; R4, R5 are H, (C1-C6)-alkyl independently from each other; X is (C1-C6)-alkyl where one carbon atom in the alkyl group can be substituted by oxygen atom; Y is (C1-C6)-alkyl where one carbon atom in the alkyl group can be substituted by oxygen atom; and its pharmaceutically acceptable salts. The invention also concerns such compounds as (+)-cis-2-(3-(2-(4-fluorphenyl)oxazole-4-ylmethoxy)cyclohexyloxymethyl)-6-methylbenzoic acid of the formula 6b , 2-{3-[2-(3-methoxyphenyl)-5-methyloxazole-4-ylmethoxy]cyclohexyl-oxymethyl}-6-methylbenzoic acid of the formula 53 and 2-methyl-6-[3-(5-methyl-2-n-tolyloxazole-4-ylmethoxy)cyclohexylomethyl]benzoic acid of the formula 70 , or their enantiomers. The invention also concerns pharmaceutical composition exhibiting PPARα agonist effect, including one or more compounds of the formula (I) as an active component together with a pharmaceutically acceptable carrier. The pharmaceutical composition is obtained by mixing of active compound of the formula (I) with a pharmaceutically acceptable carrier and rendering it a form viable for introduction.

EFFECT: obtaining of diarylcycloalkyl derivatives applicable as PPAR-activators.

9 cl, 2 tbl, 67 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new displaced heterocyclic derivatives that can be used in treatment of diabetes and to reduce the content of cholesterol. In formula m is 1; n is 1; Q is C; A is -(CH2)x2-0-(CH2)x3-, where x2 varies from 1 to 3 and x3 is 0; B is a bond or it is (CH2)x4, where x4 varies from 1 to 2; X represents CH or N; X2, X3, X4, X5, X6 represent C, N, O; provided that one from X2 X3 X4 X5 and X6 represents N; and at least one of X2, X3, X4, X5, and X6 represents C; R1 represents H or C1-C6alkyl; R2 is H; R2a, R2b and R2c can be equal or different and selected from H, C1-C6alkyl, C1-C6alkoxy, halogen or thyano; R3 is selected from phenyloxycarbonile, C1-C6alkyloxycarbonile, phenylcarbinol, phenyl, alkoxy; Y represents CO2R4 (where R4 represents H or C1-C6alkyl); (CH2)m can be not necessarily displaced by 1 substitute.

EFFECT: produced are pharmaceutical composition for treatment of diabetes and to reduce the content of cholesterol.

13 cl, 2 tbl, 22 dwg, 88 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts. Proposed compounds possess properties of agonists of receptors activated by peroxisome proliferators (PPAR agonists) and can be used in treatment of such diseases as diabetes mellitus, hypertension, atherosclerotic diseases and others. In the general formula (I) R1 means lower alkyl, monocyclic (C3-C6)-cycloalkyl; R2 means hydrogen atom, halogen atom, lower alkyl, lower alkoxy-group wherein at least one of three radicals R3, R4, R5 or R6 is not hydrogen atom; or R3 and R4 are bound together to form a ring with carbon atoms to which they are bound, and R3 and R4 mean in common -CH=CH-S-, -S-CH=CH-, -CH=CH-CH=CH-, and R5 and R6 are given above; R7 means lower alkyl, lower alkenyl; R8 means hydrogen atom or lower alkyl; n = 1, 2 or 3. Also, invention relates to a pharmaceutical composition based on the invention compounds and to using compounds of the invention in preparing medicinal agents used in treatment and/or prophylaxis of diseases mediated by agonists PPARα and/or PPARγ.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 13 sch, 71 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters. Proposed compounds possess properties of agonists of receptors activated by peroxisome proliferators (PPAR agonists) and can be used in treatment of such diseases as diabetes mellitus, hypertension, atherosclerotic diseases and others. In the general formula (I) R1 represents phenyl, optionally mono-, di- or tri-substituted with halogen atom, lower alkyl, fluorine-lower alkyl, lower alkoxy-group; R2 represents hydrogen atom or lower alkyl; R3 and R4 represents independently of one another hydrogen atom, hydroxy-group, halogen atom, lower alkyl, fluorine-(lower alkyl), lower alkoxy-group wherein at least one of radicals R3 and R4 doesn't represent hydrogen atom; R5 represents lower alkoxy-group; R6 represents hydrogen atom or lower alkyl; n = 1. Also, invention relates to a pharmaceutical composition based on compounds of the invention.

EFFECT: valuable medicinal properties of compounds.

19 cl, 1 tbl, 7 sch, 56 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds of the general formula (I): wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents hydrogen atom, -CO-R3 wherein R3 represents (C2-C6)-alkyl substituted optionally with halogen atom, -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom or (C1-C4)-alkyl; R5 represents (C1-C8)-alkyl, (C2-C8)-alkenyl and others; Y represents compound of the formula: wherein R7 represents hydrogen atom or (C1-C4)-alkyl; R8 represents (C5-C8)-alkyl, (C4-C8)-cycloalkyl and others; X represents oxygen atom or sulfur atom and others. Also, invention relates to pharmaceutically acceptable salts of these compounds. Compounds of the formula (I) possess hypoglycemic and/or hypolipidemic activity and can be used in medicine in treatment of diabetes mellitus, hyperlipidemia, hyperglycemia, diseases caused by resistance to insulin and other diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 3 tbl, 131 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

The invention relates to compounds of the formula

< / BR>
in which R1and R2each independently represents CNS group containing 1 to 4 carbon atoms, R3- H or acylcarnitine group containing 2 to 5 carbon atoms, R4- CNS group containing 1 to 4 carbon atoms, in free form and also, if such exist, in the form of salt

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula I R1 represents phenyl, possibly substituted with phenyl or heterocyclic group, or heterocyclic group, possibly substituted with phenyl, where said heterocyclic group represents mono- or bicyclic ring, containing 4-12 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, each phenyl or heterocyclic group possibly being substituted with one or more than one of the following groups: C1-6alkyl group; phenylC1-6alkyl, alkyl, phenyl or alkylphenyl group is possibly substituted with one or more than one from Rb; halogen; -ORa; -OSO2Rd; -SO2Rd; -SORd; -SO2ORa; where Ra represents H, C1-6alkyl group, phenyl or phenylC1-6alkyl group; where R represents halogeno, -OH, -OC1-4alkyl, Ophenyl, -OC1-4alkylphenyl, and Rd represents C1-4alkyl; group -(CH2)m-T-(CH2)n-U-(CH2)p- is bound either in third, or in fourth position in phenyl ring, as shown with figures in formula I, and represents group selected from one or more than one of the following: O(CH2)2, O(CH2)3, NC(O)NR4(CH2)2, CH2S(O2)NR5(CH2)2, CH2N(R6)C(O)CH2, (CH2)2N(R6)C(O)(CH2)2, C(O)NR7CH2, C(O)NR7(CH2)2 and CH2N(R6)C(O)CH2O; V represents O, NR8 or single bond; q represents 1, 2 or 3; W represents O, S or single bond; R2 represents halogeno or C1-4alkoxyl group; r represents 0, 1, 2 or 3; s represents 0; and R6 independently represent H or C1-10alkyl group; R4, R5, R7 and R8 represent hydrogen atom; and to their pharmaceutically acceptable salts.

EFFECT: increase of composition efficiency.

12 cl, 31 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing dimethyl-1,5-naphthalene dicarboxylate that is used in preparing polymers based on thereof and articles made of these polymers. The economic and effective method involves the following stages: (1) dehydrogenation of 1,5-dimethyltetraline to yield 1,5-dimethylnaphthalene; (2) oxidation of 1,5-dimethylnaphthalene prepared at dehydrogenation stage to yield 1,5-naphthalene dicarboxylic acid being without accompanying isomerization stage, and (3) esterification of 1,5-naphthalene dicarboxylic acid prepared at oxidation stage in the presence of methanol to yield the final dimethyl-1,5-naphthalene dicarboxylate.

EFFECT: improved preparing method.

9 cl, 3 dwg, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing acylated 1,3-dicarbonylic compounds used as agrochemicals or intermediate products in manufacturing agrochemicals. Also, invention describes a method for preparing tautomeric forms of acylated 1,3-dicarbonylic compounds. Method involves the arrangement reaction of the corresponding enol ester and this rearrangement reaction is carried out in the presence of alkaline metal azide. Method provides eliminating the requirement in expensive isolating process of catalyst/reagent in systems for waste treatment.

EFFECT: improved preparing method.

7 cl, 3 ex

The invention relates to the field of organic chemistry

The invention relates to new PROPYNYL-diaromatics compounds having the link propenyl General formula (I)

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in which Ar represents a radical chosen among the radicals of the following formula:

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where R1-H, -CH3CH2OR6, -OR6or-COR7; R6X is a radical of the formula

< / BR>
or

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R2and R3-H, lower alkyl straight or branched chain or6or together R2and R3form a 5 or 6-membered cycle; R4-H or lower alkyl or-OR6, R5= R4, R6-H or lower alkyl or-OR9, R7-H, lower alkyl or or8orwhere R' and R"are H or lower alkyl, R8Is H or alkyl, R9is lower alkyl; R10-H, lower alkyl or the radical OR6; R11- radical-OR6while the radicals R10and R11taken together, may form oxoprop (C = O), as well as their salts with alkali or sensenich for use in human or veterinary medicine or in cosmetic compositions
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