[2-(azol-1-yl)alkylbenzimidazol-1-yl]alkanoic acids and esters thereof, method of producing said compounds (versions) and growth-regulating composition based on said compounds

FIELD: chemistry.

SUBSTANCE: invention relates to [2-(azol-1-yl)alkylbenzimidazol-1-yl]alkanoic acids and their esters of general formula I, where Z and Y represent a nitrogen atom or a CH-group, or are simultaneously a C-CH=CH-CH=CH-C chain, together consisting of an annelated ring, n and m are equal or different and assume integer values from 1 to 3, R is a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, except [2-(1H-benzimidazol-1-ylmethyl)-1H-benzimidazol-1-yl]acetic acid. The said compounds with general formula I are obtained through alkylation of 2-(azol-1-ylalkyl)benzimidazoles II with esters of ω-halogenalkanoic acids alkylacrylates and γ-butyrolacton in polar aprotonic and protonic solvents in the presence of carbonates of alkali metals, as well as when using interphase transfer catalysts. The invention also relates to a growth-regulating composition based on compounds of general formula I.

EFFECT: use of the derivative in the growth-regulating composition allows for achieving a growth retardant effect.

6 cl, 7 tbl, 9 ex

 

The invention relates to the chemistry of heterocyclic compounds, namely [2-(azole-1-yl)alkylbenzenes-1-yl]alkanoyl acids and their esters of the General formula I:

where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring, n and m are identical or different denote an integer from 1 to 3, R means a hydrogen atom or alkyl group with carbon atoms of 1 to 4, with postregulatory activity. Compounds of General formula I can be used as agricultural products, with postregulatory activity.

The invention relates also to methods of preparing compounds of General formula I, to the use of these compounds in compositions with other auxiliary compounds for regulating plant growth.

The number of known compounds of General formula II [U.S. patent No. 4925853, MKI AC 31/44, Appl. 28.12.1988, publ. 15.05.1990], which has anti-inflammatory effect,

where R1, R2, R3, R4, R5means a hydrogen atom or a lower alkyl group, R6means a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl, R means a hydrogen atom, halogen or lower alkyl group is, which is obtained from 2,3-diaminophenol by heating at 120°C with the appropriate alkhanovym or arylalkylamine acids.

Closest to the claimed structure of the compounds of General formula III [US patent No. 4563455, MKI 07D 401/06, Appl. 9.03.1984, publ. 7.01.1986]having antiulcer activity, where a represents a lower alkyl group, R1means a hydrogen atom, halogen, lower alkyl group or lower alkoxygroup, R2means a hydrogen atom, a lower alkyl group, cycloalkyl, pyridyl or aryl, R3means a nitrogen-containing unsaturated heterocyclic group, Y represents a nitrogen atom or CH group, which is produced by interaction of o-phenylenediamine with the corresponding acids in the presence of various condensing agents, for example N,N'-dicyclohexylcarbodiimide, thionyl chloride, oxochloride phosphorus, ethylchloride and other

It is known that among the representatives of different classes of nitrogen-containing heterocyclic compounds: triazoles, benzimidazole, thiadiazole, indoles and other found highly active drugs that affect photoregulation in very low concentrations. In the practice of agriculture has found a wide application retardants from the group of derivatives of 1,2,4-triazole, such as paclobutrazol (4,4-dimethyl-2-(1,2,4-triazole-1-yl)-1-(4-chlorophenyl)p is ntana-3) [UK patent No. 1595696, MKI307D 233/60, Appl. 18.08.1977, publ. 12.08.1981; F. Kaschani, R. van der Room. Small molecule approaches in plants. // Curr. Opin. Chem. Biol., 2007, Vol.11, No. 1, p. 88-98.].

The main way to obtain 2-substituted benzimidazole is the condensation of o-phenylenediamine with carboxylic acids or their derivatives in the presence of polyphosphoric acid as a solvent, and catalyst [D.W. Hein, R.J. Alheim, J.J. Leavitt. The use of polyphosphoric acid in the synthesis of 2-aryl-and 2-alkyl-substituted benzimidazoles, benzoxazoles and benzothiazoles. // J. Am. Chem. Soc. - 1957. - Vol.79. - P.427-429.]. 2-Pyridylamine the benzimidazole were obtained by the condensation of different pyridineboronic acid with o-phenylenediamine in polyphosphoric acid [E. Alcalde, I. Dinares, L. Perez-Garcia, I. Roca. An Advantageous Synthesis of 2-Substituted Benzimidazoles Using Polyphosphoric Acid. 2-(Pyridil)-lH-benzimidazoles, l-Alkyl-(lH-benzimidazol-2-yl)pyridinium Salts, their Homologues and Vinylogues. // Synthesis - 1992. No. 4. - R-398.]. The use of microwave radiation leads to a reduction of the time of interaction to a few minutes [N. Yu, H. Kawanishi, H. Koshima. Mikrowave-assisted synthesis of aryl and heteroaryl derivatives of benzimidazole. // Heterocycles. - 2003. - Vol.60. No. 6. - P.1457-1460.]. Known method of condensation of o-phenylenediamine with various aldehydes, including heterocyclic, in the presence of zirconium oxychloride [R. Nagawade, D. Shinde. Synthesis of benzimidazole derivatives in the presence of ZrOCl2. // Ukr. org. chemistry. - 2006. - V.42. No. 3. - S-466.], leading to 2-pyridinedimethanol.

The technical problem of the present invention, status of the t increase the effectiveness postregulatory drugs and expand their range.

The technical result of the invention is to provide new compounds of General formula I, methods for their production and increase efficiency postregulatory funds through the use of [2-(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids and their esters of the General formula I and the expansion of the range postregulatory drugs.

According to the present invention [2-(azole-1-yl)alkylbenzenes-1-yl]alcamovia acid of General formula I is obtained by alkylation of 2-(azole-1-illlil)benzimidazole of General formula V, which, in turn, receive cyclocondensation (ω-(azole-1-yl)alkanovykh acids of General formula IV, where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring, n means an integer a number from 1 to 3, with o-phenylenediamine in the presence of polyphosphoric acid (PPA) when heated to 170-180°C.

Next, 2-(azole-1-illlil)a benzimidazole of General formula V is subjected to alkylation of various alkylating agents. To obtain esters [2-(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids of General formula I, where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring, n and m are identical or different denote an integer from 1 to 3, R is a lower alkyl the second group with the number of carbon atoms from 1 to 4, according to the method as alkylating agents use ethers (ω-halogenoalkanes acids, where m denotes an integer from 1 to 3, R is a lower alkyl group with carbon atoms of 1 to 4, Hal means a halogen atom, in an aprotic polar solvents such as acetonitrile, methyl ethyl ketone, DMF, etc. in the presence of carbonates of alkali metals when heated to a temperature of 60-120°C.

Method A.

According to another method ethers [2-(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids of General formula I (method B) is obtained by alkylation of 2-(azole-1-illlil)benzimidazole of General formula V esters (ω-halogenoalkanes acids in aprotic polar solvents, for example acetonitrile, methyl ethyl ketone, DMF, etc. in the presence of carbonates of alkali metals and catalysts phase transfer: crown ethers, Quaternary ammonium bases and the like when heated to a temperature of 60-120°C.

The use of the phase transfer catalyst can improve the yield compounds of General formula I, as well as to reduce the time of interaction.

To obtain esters [2-(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids of General formula I, where m=2, by the method In conducting the alkylation of benzimidazole of General formula V with an excess of alkylacrylate, where R means a lower alkyl group with carbon atoms of 1 is about 4, the ratio from 1:1 to 1:1.5 in the lower aliphatic alcohols in the presence of organic bases such as triethylamine, tetrabutylammonium hydroxide, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), as catalysts.

Method C.

When receiving [2-(azole-1-yl)alkylbenzenes-1-yl]butane acids of General formula I, where m=3, R means a hydrogen atom, by way G 2-(azole-1-illlil)a benzimidazole of General formula V enter into interaction with the alkali metal alcoholate to obtain 2-(azole-1-yl)alkylbenzenesulfonic alkali metals, which alkylate y-butyrolactone when heated to a temperature of 170-180°C.

Way,

The acidification of the estimated number of aqueous solutions of inorganic acids leads to the production of target compounds of General formula I, where m=3, R=H.

All the obtained esters of 2-[(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids of General formula I, where R means a lower alkyl group with carbon atoms of 1 to 4, is subjected to hydrolysis in the presence of an acid as catalyst, followed by neutralization salts to the free compounds by adding a basic reagent.

Hydrolysis of the same esters of the General formula I, where R means a lower alkyl group with the number of atoms in the of Lerida from 1 to 4, carried out in the presence of hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and others, with subsequent acidification of the estimated amount of inorganic acid.

The technical result of the invention is also developing postregulatory compositions consisting of [2-(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids and their esters of the General formula I in a concentration of 0.1-99% and auxiliary substances, which can successfully be applied for the regulation of plant growth.

The successful application of pesticides for the control of various pests to a large extent depends on the preparative form of the drug and the conditions under which the active substance is in contact with pests and pathogens of plant diseases. Depending on the physicochemical properties of the drug, its purpose and method of application selects the most efficient and economical preparative form (composition), it may be, for example, dusty, granules, microencapsulated drugs, wettable powders, concentrates, emulsions, ointments, water dispersible granules, suspension concentrates. Preparative form, in addition to the active substance may include excipients include fillers, solvents, surfactants, water softeners, synergistic additives and other For example, the drug paclobutrazol apply a 25%concentrate suspensions and 50%wettable powder as a system of retardants on fruit and grain crops, as well as for diseases of Apple trees. [Pesticides and plant growth regulators: Ref. ed. / LNB, Kvinnoforum, Sreen. - M.: Chemistry, 1995, p.24, p.124.].

The results postregulatory in vitro tests [2-(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acid compounds 18, 19 help to regulate the growth of plants in the process of ontogenesis. Compound 18 shows pronounced retardant properties in the whole range of concentrations, while the variation of the concentration of the compound 19 gives the possibility to change the properties from retardancy (inhibiting the growth of seedlings) to plant growth.

The invention can be illustrated by the following examples

Example 1.

2-(Benzimidazole-1-ylmethyl)benzimidazole (3)

To the suspension to 3.52 g (at 0.020 mol) benzimidazole-1-luxusni acid in 12,50 g of polyphosphoric acid added 2.16 g (at 0.020 mol) of o-phenylenediamine and heated on an oil bath at a temperature of 170-180°C with vigorous stirring for 5 hours, poured into 75 ml of water and neutralized to a 25%ammonia solution to pH 7-8. The precipitation is filtered off and recrystallized from a mixture of ethanol:water (3:1), pre-lightening races is a thief by boiling with activated carbon. Gain of 2.68 g (54%) of 2-(benzimidazole-1-ylmethyl)benzimidazole (3) with TPL 234-236°C.

Example 2.

2-[3-(Benzimidazole-1-yl)propyl)]benzimidazole (9)

Get a similar 2-(benzimidazole-1-ylmethyl)benzimidazole (3). Allocate dehydrate 2-[3-(benzimidazole-1-yl)propyl]benzimidazole, TPL 87-89°C, which is dried by heating in vacuum over phosphorus pentoxide at a temperature of 110°C. Receive 10,90 g (79%) of 2-[3-(benzimidazole-1-yl)propyl]benzimidazole (9) with TPL 202-204°C.

Similarly receive other 2-(azole-1-yl)alkylbenzenes. (Table 1).

Data on the yield and the melting point of the obtained 2-(azole-1-yl)alkylbenzenes are shown in table 1, the spectral characteristics in table 2.

1H NMR spectra were recorded on the instrument Bruker AC-200" (operating frequency 200 MHz), shifts measured relative to tetramethylsilane, the solvent used d6-DMSO. IR spectra were recorded with prisms NaCl in a thin film in vaseline oil on the device "Specord M80".

Table 1.
Characteristics and output the synthesized 2-(azole-1-yl)alkylbenzenes.
ConnectionYZOutput %MP, °C
1SNSN74195-196
2SNN72188-189
3C-CH=CH-CH=CH-C54234-236
4SNSN66160-161
5SNN56202-204
6C-CH=CH-CH=CH-C67202-204
7SNSN75145-147
8SNN52170-172
9C-CH=CH-CH=CH-C79202-204/td>

Example 3.

Ethyl ester of [2-(imidazol-1-ylmethyl)benzimidazole-1-yl]acetic acid (10)

Method And

A suspension of 2.50 g (0,013 mol) of 2-(imidazol-1-ylmethyl)benzimidazole and 1.85 g (0,013 mol) of finely ground potassium carbonate in 50 ml of absolute acetonitrile is boiled with vigorous stirring for 1 hour, add dropwise a solution of 1.83 ml (2,09 g of 0.017 mol) of ethylchloride in 20 ml of absolute acetonitrile, boil for 2.5 hours, filtered off from the precipitate, the filtrate is evaporated in a water jet vacuum pump, the residue is recrystallized from acetonitrile. Get 1,02 g (27%) of ethyl ester of [2-(imidazol-1-ylmethyl)benzimidazole-1-yl]acetic acid (10) with TPL 181-182°C.

Example 4.

Ethyl ester of [2-(imidazol-1-ylmethyl)benzimidazole-1-yl]acetic acid (10)

Method B

Suspension 5,94 g (0,030 mol) of 2-(imidazol-1-ylmethyl)benzimidazole, 4,27 g (0,031 mol) of finely ground potassium carbonate and 0.54 g (1,498 mmol), dibenzo-18-crown-6 in 70 ml absolute acetonitrile is boiled with vigorous stirring for 1 hour, add dropwise a solution of 3,90 ml (4,43 g, being 0.036 mol) of ethylchloride in 20 ml of absolute acetonitrile, and then boil with vigorous stirring for 30 minutes. The resulting reaction mass is then cooled, filtrowa. The precipitate is boiled with 100 ml of methanol, cooled and filtered. The filtrates are combined evaporated in a water-jet pump vacuum to dryness, the residue is boiled with 50 ml of methanol, filtered off. From the filtrate the solvent is distilled off, the residue is recrystallized from a mixture of ethanol:isopropanol (1:1). Get 6,28 g (74%) of ethyl ester of [2-(imidazol-1-ylmethyl)benzimidazole-1-yl]acetic acid (10) with TPL 184-185°C.

Example 5.

Ethyl ester of 3-[2-(benzimidazole-1-ylmethyl)benzimidazole-1-yl]propionic acid (15)

Method C.

To a solution of 4.00 g (to 0.016 mol) of 2-(benzimidazole-1-ylmethyl)benzimidazole and 0.05 ml (0.51 g, 0,322 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 15 ml absolute ethanol was added 2.10 ml (1.64 g, 0.019 mol) acrylate and boil with vigorous stirring for 20 hours. The solvent is distilled to dryness in a water jet vacuum pump, the residue is recrystallized twice from isopropyl alcohol. Gain of 1.93 g (35%) of ethyl ester of 3-[2-(benzimidazole-1-ylmethyl)benzimidazole-1-yl]propionic acid (15) with TPL 144-146°C.

Data on the yield and the melting point of the obtained ethyl esters [2-(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids are shown in table 3, the spectral characteristics in table 4.

Table 3.
Characteristics and output sintezirovannyh ethyl esters [2-(azole(1-Il)alkylbenzenes-1-yl]alkanovykh acids.
ConnectionnmYZMethodOutput %TPL, °C
12345678
1011CHCHAnd27184-185
B74
1111CHNAnd62164-165
B69

123 45678
1211C-CH=CH-CH=CH-CAnd72217-219
B68
1321SNSNAnd50176-177
1421SNNAnd67112-114
1512C-CH=CH-CH=CH-CIn35144-146

Example 6.

4-[2-(Benzimidazole-1-ylmethyl)benzimidazole-1-yl]butane acid (16)

Way,

To methylate solution n is sodium, obtained by dissolving 0.39 g (of 0.017 mol) of sodium in 25 ml of methanol, add to 3.36 g (of 0.017 mol) of 2-(1,2,4-triazole-1-ylmethyl)benzimidazole, boiled for 1 hour, the solvent is distilled off in a water jet vacuum pump. To the residue add 1.3 ml (1.45 g, is 0.017 mol) of γ-butyrolactone and heated at a temperature of 170-180°C for 1 hour, cooled and acidified by adding 8.5 ml of 2n hydrochloric acid, the precipitate is filtered off, dried over R2About5and get 2,78 g (58%) of 4-[2-(benzimidazole-1-ylmethyl)benzimidazole-1-yl]butane acid (16) with TPL 182-184°C.

Example 7.

[2-(Imidazol-1-ylmethyl)benzimidazole-1-yl]acetic acid (17)

A mixture of 0.50 g (1,761 mmol) ethyl ester [2-(imidazol-1-ylmethyl)benzimidazole-1-yl]acetic acid (10) and 3.30 ml (14,538 mmol) of a 15% solution of hydrochloric acid, boil for 2 hours, evaporated to dryness in a water-jet vacuum pump. Obtain 0.55 g (95%) of the dihydrochloride [2-(imidazol-1-ylmethyl)benzimidazole-1-yl]acetic acid, with TPL 268-269°C.

Stage of free acid: 0,30 g (0,912 mmol) of the dihydrochloride [2-(imidazol-1-ylmethyl)benzimidazole-1-yl]acetic acid are dissolved in 2.5 ml of water and with vigorous stirring, 0.25 g (1,824 mmol) of three-hydrate sodium acetate, precipitated precipitate is filtered off and dried. Obtain 0.12 g (51%) of [2-(imidazol-1-ylmethyl)benzimidazole-1-yl]acetic acid (17) with TPL 288-289°C.

EN the logical receive other [2-(azole-1-yl)alkylbenzenes-1-yl]alcamovia acid. (Table 5).

Data on the yield and the melting point of the obtained [2-(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids are shown in table 5, the spectral characteristics in table 6.

Table. 5.
Characteristics and output synthesized [2-azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids.
ConnectionnmYZOutput %TPL, °C
1613C-CH=CH-CH=CH-C58182-184
1711SNSN51288-289
1811SNN77264-265
1911 C-CH=CH-CH=CH-C66323-324
2021SNSN81185-187
2121SNN51189-191
2212C-CH=CH-CH=CH-C65258-260

Example 8.

The composition of the emulsion concentrate

Active substance [2-(azole-1-yl)alkylbenzenes-1-yl]albanova acid 100 g

Alkylbenzenesulfonate calcium salt (ABS) 50 g

Ethoxylated op (OP-7) 50 g

Cyclohexanone 300 g

A mixture of xylenes 500 g

Example 9. Compounds 18 and 19 were tested for postregulatory activity. The object of the study were the seeds of cucumber (variety "Electron"). It was used the shorthand method [Hava. Methodological guidelines for laboratory screening of synthetic growth regulators races of the clusters. // Cherkassy: Niitekhim, 1985, 29 S.], which consisted in the cultivation of seeds of cucumber in vitro for 8 days. The seeds were cultured on agar nutrient medium Murashige and Skoog [T. Murashige, F. Skoog. A revised medium for rapid grouth and bioassays with tobacco tissue cultures. // Phisiol. Plant. - 1962. - Vol.15. No. 5. - P.473-497.], does not contain substances of hormonal nature, in culture vessels with a volume of 200 ml Preparations were subjected to cold sterilization (missed solutions through bacterial filters) and then add them in in advance paavolainen nutrient medium MS, which was subsequently poured into culture vessels. Cucumber seeds surface sterilized with 0.1% solution of mercuric chloride for 10 minutes, after which they were washed three times with sterile distilled water and placed on a nutrient medium MS. Culture vessels with plant material was transferred into a light room, where he supported the temperature is 22°C, constant lighting fluorescent lamps, the intensity of the 3 tisk., humidity 70%.

In the experiment each connection was studied in 5 concentrations: 0,001, 0,01, 0,1, 1,0, 10,0 mg/l of Compounds of General formula I was administered on Wednesday MS in the form of the composition, representing 1%solution of I in DMSO, with a total concentration of DMSO in the medium of 0.1%. A control variant, not containing nutrient medium hormones and investigational drugs. At the end of the 8th day is Uchali linear and weight of seedlings of cucumber: the length of the root system (cm), the length of the aerial parts of seedlings (cm), dry and fresh weight of seedlings (g). Data to test the influence of these compounds on the germination of seeds of cucumber variety "Electron" are shown in table 7.

Table 7.
The influence of compounds 18, 19 on the germination of seeds of cucumber variety "Electron" (on day 8).
ConnectionConcentration, mg/mlThe aboveground partThe root systemWet weightDry weight
Cmcmgg
123456
0,001
0,01
180,1
1
10

123456
0,001
0,01
190,1
1
10
Control-3,18,54,87000,3406

The use of compounds of General formula I can expand the range postregulatory preparations by using the lowest concentration of the active substance, and in the case of the use of compound 18 in the concentration range from 0.01 to 10 mg/l to achieve a stable retardante effect.

1. [2-(azole-1-yl)alkylbenzenes-1-yl]alcamovia acids and their esters of the General formula I

where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring, n and m are identical or different denote an integer from 1 to 3, R means a hydrogen atom or alkyl group with carbon atoms of 1 to 4, with the exception of [2-(1H-benzimidazole-1-ylmethyl)-1H-benzimidazole-1-yl]acetic acid.

2. The way to obtain [2-(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids and their esters of the General formula I,

where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring, n and m are identical or different denote an integer from 1 to 3, R means a hydrogen atom Il the alkyl group with the number of carbon atoms from 1 to 4
namely, that 2-(azole-1-illlil)a benzimidazole of General formula II, where Z, Y and n have the same meanings as in formula I, alkylate esters of ω-halogenoalkanes acids of General formula III, where m denotes an integer from 1 to 3, R has the same meaning as in formula I, Hal means a halogen atom,

in aprotic polar solvents in the presence of carbonates of alkali metals when heated to a temperature of from 60 to 120°C.

3. The way to obtain [2-(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids and their esters of the General formula I

where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring, n and m are identical or different denote an integer from 1 to 3, R means a hydrogen atom or alkyl group with carbon atoms of 1 to 4,
namely, that 2-(azole-1-illlil)a benzimidazole of General formula II, where Z, Y and n have the same meanings as in formula I, alkylate esters of ω-halogenoalkanes acids of General formula III, where m denotes an integer from 1 to 3, R has the same meaning as in formula I, Hal means a halogen atom,

in aprotic polar solvents in the presence of carbonates of alkali metals in nahrawan and to a temperature of from 60 to 120°C in the presence of phase transfer catalysts.

4. The way to obtain [2-(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids and their esters of the General formula I,

where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring, n means an integer from 1 to 3, m=2, R means a hydrogen atom or alkyl group with carbon atoms of 1 to 4, namely, that 2-(azole-1-illlil)a benzimidazole of General formula II, where Z, Y and n have the same meanings as in formula I, the alkylate alkylacrylate the General formula IV, where R has the same meaning as in formula I,

in the lower aliphatic alcohols in the presence of organic bases as catalysts.

5. The way to obtain [2-(azole-1-yl)alkylbenzenes-1-yl]alkanovykh acids of General formula I,

where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring, n means an integer from 1 to 3, m=3, R means a hydrogen atom, namely, that 2-(azole-1-illlil)a benzimidazole of General formula II, where Z, Y and n have the same meanings as in formula I,
enter into interaction with the alkali metal alcoholate to obtain 2-(azole-1-yl)alkylbenzenesulfonic alkali metals, which is s alkylate γ-butyrolactone V when heated to a temperature of 170-180°C

6. Postregulatory composition comprising a plant growth regulator in a concentration of 0.1-99% and excipients, characterized in that as a plant growth regulator use [2-(azole-1-yl)alkylbenzenes-1-yl]alcamovia acids and their esters of the General formula I

where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring, n and m are identical or different denote an integer from 1 to 3, R means a hydrogen atom or alkyl group with carbon atoms of 1 to 4.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of common formula (I) , in which: A, if available, means (C1-C6)-alkyl; R1 means group NR6R7, (C4-C7)-azacycloalkyl, (C5-C9)-azabicycloalkyl, besides, these groups, unnecessarily, are substituted with one or more substituents, selected from (C1-C5)-alkyl or halogen; A-R1 is such that nitrogen of radical R1 and nitrogen in position 1 of pyrazole are necessarily separated at least by two atoms of carbon; R3 means radical H, OH, NH2, ORc, NHC(O)Ra or NHSO2Ra; R4 means phenyl or heteroaryl, unnecessarily, substituted with one or more substituents, selected from halogen, CN, NH2, OH, ORc, C(O)NH2, phenyl, polyfluoroalkyl, linear or ramified (C1-C6)-alkyl, besides these substituents, unnecessarily, are substituted with halogen, and moreover, heteroaryl radicals are 3-10-member, containing one or more heteroatoms, selected from sulphur or nitrogen; R5 means radical H, linear or ramified (C1-C6)-alkyl; Ra means linear or ramified (C1-C6)-alkyl; Rc means linear or ramified (C1-C6)-alkyl, (poly)fluoroalkyl or phenyl; R6 and R7, independently from each other, means hydrogen, (C1-C6)-alkyl; R6 and R7 may create 5-, 6- or 7-member saturated or non-saturated cycle, which includes one heteroatom, such as N, and which, unnecessarily, substituted with one or more atoms of halogen; to its racemates, enantiomers, diastereoisomers and their mixtures, to their tautomers and their pharmaceutically acceptable salts, excluding 3-(3-pyridinyl)-1H-pyrazole-1- butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine. Invention is also related to methods for production of compounds of formula (I) and to pharmaceutical composition intended for treatment of diseases that appear as a result of disfunction of nicotine receptors α7 or favorably responding to their modulation, on the basis of these compounds.

EFFECT: production of new compounds and pharmaceutically acceptable composition on their basis, which may find application in medicine for treatment, prophylaxis, diagnostics and observance over development of psychiatric or neurological disorders or diseases of central nervous system, when cognitive functions deteriorate or quality of sensor information processing drops.

16 cl, 106 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of common formula IC1: , where A represents cyano; B represents hydrogen; R1, R2, R3 and R4 independently represent hydrogen; alkyl; halogen or nitro; R5 and R6 independently represent hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heteroarylalkyl; alkenyl; carboxyalkyl; cyanoalkyl; diphenylalkyl; aryl, arylalkoxyaryl, arylalkyl, arylalkylaryl, arylcarbonylaryl or aryloxyaryl, or R5 and R6, together with atom of nitrogen, to which they are connected, create heterocyclic ring system; or to salts of such compound; at the same time "heteroaryl" used separately or in combination, is related to mono-, bi- or tricyclic aromatic ring system, which contains up to 14 atoms included in ring, in which at least one ring contains at least one heteroatom, independently chosen from nitrogen, oxygen or sulfur, besides specified heteroaryl group may be unsubstituted or substituted with one to three substituents, independently selected from alkyl and alkoxy; "diphenylalkyl" is related to alkyl group, where each of two atoms of hydrogen is substituted with unsubstituted phenyl group; "aryl" is related to carbocyclic group, selected from group, which consists of phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, antryl, phenantryl, fluorenyl, indanyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl group, besides specified aryl group may be unnecessarily substituted with functional groups in number from one to three, which are separately and independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, cyano, halogen, halogenlkoxy, halogenalkyl and nitro groups, where in certain specific cases, if aryl group represents condensed system from several rings, in which not all the rings are aromatic, one of carbon atoms of which is not included into aromatic ring may be in oxidised condition, and according fragment of ring -CH2- will be substituted by fragment-C(O); "arylalkoxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkoxygroup, where aryl group is unsubstituted; "arylalkyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkyl group, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "aryloxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via oxygen bridge, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "arylcarbonyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via carbonyl group, where aryl group is unsubstituted; "heterocyclic ring system", used separately or in combination, is related to monocyclic, bicyclic or polycyclic ring system, which contains up to 15 atoms included into ring, at least one of which represents heteroatom, independently selected from nitrogen, oxygen or sulfur, besides specified ring system may be saturated, partially unsaturated, unsaturated or aromatic, where specified heterocyclic fragment may be unnecessarily substituted with one or more substituents, every of which separately and independently is selected from group made of halogen and halogenalkyl, excluding the following compounds: {3-[(E)-2-cyano-2-(4-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-m-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(3-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-phenylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-benzylcarbamoyl-2-cyanovinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-o-tolylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-t-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(4-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-ethylphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2~cyano-2-(4- ethoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-isopropylcarbamoylvinyl)indole-1-yl]acetic acid; {3-[(E)-2-cyano-2-(3-etoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-[[2-(1H-indole-3-yl)ethyl]amino]-3-oxo-1-propenyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-chlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-(4-methyl-piperidine-1-yl)-3-oxopropenyl]indole-1-yl}acetic acid; {3-[(E)-2-(3-chloro-4-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(3-phenylpropylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2,3-dichlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-(5-chloro-2-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxybenzylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; and {3-[(E)-2-cyano-3-oxo-3-(4-phenyl-piperazine-1-yl)propenyl]indole-1-yl}acetic acid. Invention is also related to pharmaceutical composition, and also to application of compounds of clause 1.

EFFECT: production of biologically active compounds, which have activity of antagonist coupled with G-protein of chemoattractant receptor of molecules homologue released by Th2-cells.

11 cl, 156 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to a tetrazole compound with general formula I , where X3 and X4 are independently N and C, where one of X3 and X4 is certainly C; P is phenyl; m equals 1 or 2, where if m equals 1, R1 is bonded to P through a carbon atom on ring P in the meta-position of ring P relative the point at which P is bonded to X3, and if m equals 2, R1 is bonded to P through a carbon atom on ring P in positions 2 and 5 of ring P; R1 is halogen, C1-6alkyl, OC1-6alkyl or cyano group; X1 is C2-3alkyl, C2-3alkenyl, NR3, O, S, CR3R4, SO, SO2; X2 is a bond, CR3R4, O, S, NR3, SO, SO2; R3 and R4 are independently chosen from a group which consists of hydrogen, hydroxy, C1-6alkyl; Q is triazolyl, piperazinyl, or triazole or imidazole ring, condensed with a 6- or 7-member heterocyclic ring with one or two N atoms as heteroatoms; R is C1-6alkyl, C3-6cycloalkyl, pyridinyl, which can be substituted with a nitro, cyano, halogen or OC1-4alkyl group; phenyl, which can be substituted with a halogen, C1-4alkyl, OC1-4alkyl group; (CO)OC1-4alkyl; pyrimidinyl, which can be substituted with a OC1-4alkyl group; p equals 0, 1 or 2, or pharmaceutically acceptable salt or hydrate thereof.

EFFECT: invention also relates to method of inhibiting activity of mGluR5 receptors.

11 cl, 44 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new benzimidazole derivatives with general formula (I), where A represents -CH2-, -C(O), -C(O)-C(Ra)(Rb)-, X represents a -CH- radical; Ra and Rb independently represent a hydrogen atom or (C1-C6)alkyl radical; R1 represents a hydrogen atom or (C1-C8)alkyl radical; R2 represents a (C1-C8)alkyl radical; R3 represents -(CH2)P-Z3, -C(O)-Z'3 or -C(O)-NH-Z"3; Z3 represents (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl-N(RN)carbonyl, (C3-C7)cycloalkyl, aryl, arylthio or heteroaryl radical, Z3 is bonded to the -(CH2)P- through a carbon atom, heteroaryl radical, which is a 5-10- member heteroaryl, which contains 1-2 identical or different heteroatoms, chosen from sulphur, nitrogen or oxygen, and optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group or -(CH2)P'-V30-Y3; aryl radical, chosen from phenyl or naphthyl, optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group, cyano group, (C2-C6)alkenyl, pyrrolidinyl, phenyl, phenyloxy, phenylalkyloxy, 5-7- member heteroaryl, containing 1-3 nitrogen atoms and -(CH2)p'-V31-Y3; V30 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; V31 represents -O-, -S-, -SO2-, -C(O)-, -C(O)-O-, -N(RN)-, -NH-C(O)- or a covalent bond; Y3 represents a hydrogen atom or (C1-C6)alkyl radical, optionally substituted with one or more identical or different halogen radicals; RN represents a hydrogen atom or (C1-C6)alkyl radical; Z3 represents a radical with a given formula (see below); Z'3 represents a phenyl radical, optionally substituted with one ore more identical or different substitutes, chosen from -(CH2)P"-V'3-Y'3; V'3 represents -O-; Y'3 represents a hydrogen atom or (C1-C6)alkyl radical; Z"3 represents a hydrogen atom or -(CH2)q-A"3 radical; A"3 represents (C1-C6)alkyl, phenyl or thienyl radical; alkyl or phenyl radical can be optionally substituted with one or more identical or different substitutes, chosen from halogen and -V"3-Y"3; V"3 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; Y"3 represents a hydrogen atom or (C1-C6)alkyl radical; p is an integer from 0 to 6; p' and p" independently represent an integer from 0 to 1; q is an integer from 0 to 2; R4 represents a radical with formula -(CH2)S-R'4; R'4 represents a 5-7- member heterocycloalkyl, containing at least one nitrogen atom and optionally substituted with (C1-C6)alkyl; or a radical with formula -NW4W'4; W4 represents a hydrogen atom; W'4 represents a hydrogen atom; s is an integer from 0 to 6; in racemic or enantiomeric form or any combination of the said forms, or its pharmaceutically acceptable salt. The invention also relates to a method of obtaining a compound in paragraph 1, a pharmaceutical composition based on the said compound and its use in making a medicinal agent.

EFFECT: new benzimidazole derivatives have good affinity to certain subtypes of melanocortin receptors.

26 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I) compounds and to their use in treating diseases related to lipid storage disorders, such as atherosclerosis and diabetes. In R1 represents hydrogen, alkyl, halogen, formyl, hydroxyalkyl or trifluoromethyl, R2 represents hydrogen, alkyl or halogen, R3 represents hydrogen or alkyl, R4 represents hydrogen, alkyl, hydroxy or alkoxy, R5 and R6 are chosen from hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxycarbonyl and phenyl, A represents aryl or heterocyclyl, m equals 0-3, n equals 0-1, p equals 0-3, sum of m, n and p equals 1-4, the bond between carbon atoms Ca and Cb is a single or double carbon-carbon bond.

EFFECT: obtaining new biologically active compounds.

27 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with formula (I): (I) A is absent or represents (CH2)2; L is CH or N; M is NR1, O, S, S(O) or S(O)2; R1 is C1-6alkyl, substituted with phenyl {which itself is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, CF3}; phenyl {which is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, CF3, C1-4alkylthio}, S(O)2R, S(O)2NR6R7, C(O)R8; R2 is phenyl (which is possibly substituted with halogen, CN or C1-4halogenalkyl), thienyl or halogenthienyl; R3 is hydrogen or methyl; Rb is hydrogen or C1-3alkyl; R4 is a five- or six-member heterocycle, containing at least one carbon atom, one to four nitrogen atoms and, possibly, one oxygen or sulphur atom, where the carbon atom in the said heterocycle R4 is possibly substituted with oxo, C1-6alkyl [which is possibly substituted with halogen, OH, C1-4alkoxy, S(C1-4alkyl) group or piperidinyl {which it self is possibly substituted with benzene [which is possibly substituted with a S(O)2(C1-4alkyl) group], C(O)(C1-4alkoxy) group, C(O)NH2, C(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)2 or S(O)2(C1-4alkyl) [where alkyl is possibly substituted with fluoro]}], C3-6cycloalkyl, CN, C(O)NH2, C(O)NH(phenylC1-2alkyl) group, phenyl [which is possibly substituted with a S(O)2(C1-4alkyl) group] or benzyl [which is possibly substituted with a S(O)2(C1-4alkyl) group]; if possible, the nitrogen atom in the said heterocycle R4 is substituted with C1-6alkyl [which is possibly substituted with C1-4alkoxy, S(O)(C1-4alkyl) group, S(O)2(C1-4alkyl), C(O)(C1-4alkoxy), CONH2, CONH(C1-4alkyl), CON(C1-4alkyl)2, phenyl{which is possibly substituted with C1-4alkyl, C1-4alkoxy, S(O)(C1-4alkyl) group or S(O)2(C1-4alkyl)}, piperidinyl {which is possibly substituted with a S(O)(C1-4alkyl) group or S(O)2(C1-4alkyl)}], C3-6cycloalkyl, CO(C1-4alkyl) group [which is possibly substituted with a halogen], S(O)2(C1-4alkyl) group [which is possibly substituted with fluorine], COO(C1-6alkyl) group, phenyl [which is possibly substituted with a S(O)(C1-4alkyl) or S(O)2(C1-4alkyl) group]; - under the condition that the nitrogen atom in the said heterocycle R4 is substituted with an alky group, the said alkyl does not have C1-4alkoxy, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl) substitute on the carbon atom, bonded to the nitrogen atom in the said heterocycle R4; - five- or six-member heterocyle R4 is possibly condensed with cyclohexane, piperadine, benzole, pyridine, pyridazine, pyrimidine or pyrazine ring; ring carbon atoms in the said condensed cyclohexane, piperadine, benzole, pyridine, pyridazine, pyrimidine or pyrazine ring are possibly substituted with a halogen, C1-4alkyl, C1-4alkoxy, CF3, S(C1-4alkyl), S(O)(C1-4alkyl) or S(O)2(C1-4alkyl) group; and the nitrogen atom of the condensed piperidine ring is possibly substituted with C1-4alkyl [which is possibly substituted with oxo, halogen, OH, C1-4alkoxy, C(O)(C1-4alkoxy), C(O)NH2, C(O)NH(C1-4alkyl) group, C(O)N(C1-4alkyl)2 group, C(O)(C1-4alkyl)group [where alkyl is possibly substituted with C1-4alkoxy or halogen], benzene [which is possibly substituted with S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)], C(O)(C1-4alkoxy), C(O)NH2, C(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)2 or S(O)2(C1-4alkyl) group [where alkyl is possibly substituted with fluoro]; R5 is C1-6alkyl [which is possibly substituted with a halogen (for example fluoro), C1-4alkoxy, phenyl {which itself is possibly substituted with a halogen, C1-4alkyl, C1-4alkoxy}], C3-7cycloalkyl (which is possibly substituted with a halogen or C1-6alkyl), piranyl, phenyl {which is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy}, or a 5- or 6-member saturated nitrogen-containing heterocyclic ring {which is possibly substituted with a S(O)2(C1-4alkyl) or C(O)(C1-4alkyl) group}; R8 is hydrogen, C1-4alkyl [which is possibly substituted with halogen (for example fluro), C1-4alkoxy, phenyl{which itself is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy}], C3-7cycloalkyl (which is possibly substituted with halogen or C1-4alkyl), piranyl, phenyl {which is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy}, or a 5- or 6-member saturated nitrogen-containing heterocyclic ring {which is possibly substituted with S(O)2(C1-4alkyl) or C(O)(C1-4alkyl) group}; R6 and R7 are bonded, forming a 5- or 6-member ring which is possibly substituted with C1-4alkyl; R9 and R10 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts. The invention also relates to a method of obtaining compounds in paragraph 1, to a method of modulating activity of CCR5 receptor, as well as to a pharmaceutical composition.

EFFECT: obtaining new biologically active compounds with modulating effect towards CCR5 receptor.

15 cl, 29 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of general formula (II) , whereat values R1, R2, X, R11, R12, R18, R19, m, n are displayed in claim 1 of the formula.

EFFECT: compounds display agonistic and antagonistic activity which allows to propose their usage in pharmaceutical compositions for treatment of diseases and distresses connected with histamine H3 receptor.

38 cl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) or pharmaceutically acceptable salts thereof, where R1 is chosen from a group containing optionally substituted C1-C6alkyl, lower alkoxy group, (lower)alkoxy(lower)alkyl, cycloalkyoxy(lower)alkyl, lower thioalkyl, (lower)alkylthio(lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R2 is chosen from a group containing optionally substituted (lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R3 is chosen from a group containing halogen, cyano group, optionally substituted (lower alkyl, lower thioalkyl, aryl, aryl(lower)alkyl, lower alkenyl, lower alkynyl); R4 is chosen from a group containing hydrogen, halogen, cyano group, hydroxyl group, optionally substituted (lower alkyl, lower alkoxy group, aryl, pyridyl, aryl(lower)alkyl, heteroaryl, which is an aromatic mono- or bicyclic hydrocarbon, containing from 5 to 9 ring atoms, from which one or more is a heteroatom, chosen from O, N or S, and an amino group) and a group, with formula R8-Z-(CH2)n-; where Z is a single bond or chosen from a group consisting of O, NH, CH2, CO, SO, SO2 or S; where R8 is chosen from a group containing optionally substituted (aryl, pyridyl); and where n=0, 1 or 2; R5 represents hydrogen; R6 is chosen from a group containing halogen, optionally substituted lower alkoxy group; R7 is one or more substitutes, independently chosen from a group containing hydrogen, optionally substituted lower alkoxy group; where the optional substitute or substitutes when R1-R8 are independently chosen from a group containing halogen, hydroxyl group, lower alkyl, mono- or di(lower)alkylamino group, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di(lower)alkylaminocarbonyl, amino group, carboxyl group, lower alkoxy group, C3-C12cycloalkyl, (lower)alkylcarbonyl, (lower)alkoxycarbonyl, nitrile, aryl; all of which, except halogen, are independently optionally substituted with one or more substitutes, chosen from a group containing halogen, hydroxyl group, lower alkyl, sulfinyl, sulfonyl, sulfanyl, amino group, carboxyl group, lower alkoxy group, carbamoyl. Invention also relates to formula (I'), to a pharmaceutical composition, as well as use of formula (I) compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds, for preventing or treating bone diseases, associated with very low or resorption of calcium.

6 cl, 151 ex

FIELD: organic chemistry, medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to S-enantiomers of compound of the formula (I): wherein n means a number 1 or 2. S-enantiomers of compound of the formula (I) are chosen from (2S)-3-(4-{2-[benzyl(hexyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropionic acid and (2S)-2-ethoxy-3-(4-{2-[hexyl-(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propionic acid and their pharmaceutically acceptable salts and solvates. Also, invention relates to a pharmaceutical preparation possessing agonistic activity with respect to PPARα (human alpha-receptors activated by peroxisome proliferator) and comprising compound of the formula (I) in mixture with pharmaceutically acceptable adjuvants, excipients and/or carriers. S-enantiomer of the formula (I) is used in producing a medicinal agent used in treatment of lipid disorders (dyslipidemia) associated with or not associated with resistance to insulin. Also, this compound is used in treatment or prophylaxis of lipid disorders (dyslipidemia) associated or not associated with resistance to insulin and diabetes mellitus type 2. Invention provides using derivatives of phenylpropionic acid as agonists of human alpha-receptors activated by peroxisome proliferator (PPARα).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

12 cl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing phenylene-bis-benzimidazole-tetrasulfonic acid. Method involves interaction of o-phenylenediamine with terephthalic and chlorosulfonic acid in the presence of strong acids for 10-15 h. Phenylene-bis-benzimidazole-tetrasulfonic acid prepared at the first stage after reaction is dissolved in water and treated with activated carbon followed by removing the latter. Then phenylene-bis-benzimidazole-tetrasulfonic acid disodium salt is precipitated by addition of sodium chloride. At the second stage it is dissolved in water again, treated with activated carbon again followed by removing the latter and pure phenylene-bis-benzimidazole-tetrasulfonic acid disodium salt is precipitated from filtrate by its acidification. If necessary, the prepared salt can be purified additionally. Phenylene-bis-benzimidazole-tetrasulfonic acid disodium salt can be used in cosmetic agents as ultraviolet filter A. Invention provides preparing phenylene-bis-benzimidazole-tetrasulfonic acid disodium salt without impurities.

EFFECT: improved preparing method.

7 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula I , its pharmaceutically acceptable salt or stereoisomer, where X is -CH- or -N-; n equals 0, 1, 2 or 3; m equals 0, 1 or 2; R1 and R4 are each independently selected from hydrogen, halogen, cyano, perfluoroC1-6alkyl, C1-10alkyl, C2-10alkenyl, C3-8cycloalkylC0-10alkyl, R5 is hydrogen; R2 and R3 are each independently selected from hydrogen, hydroxyC0-10alkyl, perfluoroC3-6alkyl, C1-10alkyl, C3-8cycloalkylC0-10alkyl, (C0-10alkyl)1-2aminocarbonyloxyC0-10alkyl, C3-8heterocyclylcarbonyloxyC0-10alkyl, to their use in making a medicinal agent with activity which his mediated with androgen receptor modulation (SARM), as well as to a pharmaceutical composition and preparation method thereof.

EFFECT: novel compounds which can be used as androgen receptor modulators (SARM) are obtained and described.

15 cl, 5 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents phenyl group, containing 1-3 substitutes, selected from halogen and cyano group; R2 represents pyridyl group, which has 1-3 substitutes, selected from monocyclic or polycyclic heterocyclic group, which can have 1-3 substitutes, selected from halogen atoms, cyanogroup, as well as other values of R2 radical, given in formula of invention, R3 represents phenyl group or pyridyl group, which has 1-2 substitutes, selected from halogen and trihalogenmethyl group; R4 represents hydrogen atom; and X represents -SO2-; its salt or its solvate. As well as to medication and pharmaceutical composition, inhibiting production or secretion of β-amyloid protein, and containing compound of formula (I), and to application of compound of pt.1 in order to obtain medication.

EFFECT: obtaining novel compounds, inhibiting production or secretion of β-amyloid protein.

14 cl, 1 tbl, 296 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to alkylated (1H-benzimidazol-5-yl)-(-4-substituted phenyl)-amine derivatives, in particular compound of formula and pharmaceutically acceptable salts or solvates thereof, wherein R1, R2, and R9, are independently hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluorimethoxy, azido, etc.; R7 is optionally substituted C1-C10-alkyl, C3-C10-cycloalkyl, etc.; A is-OR3 or NR4R3; R8 is hydrogen, -Cl, -Br, -F, cyano, nitro, etc.; and meanings of the rest substituents are as defined in specification. Also disclosed is composition for MEK inhibition and uses of benzinidazole compounds.

EFFECT: new compounds with value biological properties.

32 cl, 56 ex

FIELD: organic chemistry of heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new ortho-substituted and N-substituted indoles of the formula (α): or (β): or their pharmaceutically acceptable salts wherein Z1 represents -CR4 or nitrogen atom (N); R4 means hydrogen atom (H), (C1-C6)-alkyl comprising optionally oxygen atom (O) or nitrogen atom (N) possibly substituted with halogen atom, keto-group, 5-6-membered cycloaliphatic radical possibly comprising 1-2 oxygen atoms (O) or nitrogen atom (N); Z2 represents -CH or -CR wherein R means (C1-C6)-alkyl; R1 means compound of the formula: wherein X1 means -CO or its isostere; m = 0, 1; Y represents alkyl that can be substituted; or two Y form in common (C2-C3)-alkylene; n = 0, 1 or 2; Z3 represents -CH; X2 represents -CH, -CH2 or their isostere; Ar represents one or two phenyl groups bound with X2 wherein phenyl can be substituted; R2 represents hydrogen atom (H), (C1-C6)-alkyl or aryl wherein each aryl comprises, possibly, oxygen atom (O) or nitrogen atom (N) and can be substituted. Proposed compounds are selective inhibitors of p38α kinase.

EFFECT: valuable biochemical properties of compounds.

34 cl, 5 tbl, 23 ex

FIELD: pharmaceutical technology.

SUBSTANCE: method involves extraction of the above-ground part of yellow poppy (Glaucium flavum Crantz.) with an organic solvent, the following filtration, alkalization of an aqueous-acid solution, extraction of alkaloids with an organic solvent, removing an organic solvent under vacuum, treatment of prepared glaucine base with hydrochloric acid and purifying the product. Extraction of vegetable raw is carried out with 60% aqueous alcohol solution in the presence or tribasic mineral acid, for example, phosphoric acid. Organic solvent is removed under vacuum, an aqueous vat residue is neutralized with mixture of calcium carbonate and calcium chloride, or calcium carbonate and aluminum chloride followed by filtration. Filtrate is alkalinized to obtain alkaloid bases that are extracted from an aqueous phase with an organic solvent, preferably, with aromatic solvent, for example, with benzene or toluene. Organic phase is evaporated under vacuum, residue is treated with hydrochloric acid and product is subjected for purification, or after filtration alkaloid hydrochlorides formed are extracted with chloroform. Organic phase is evaporated under vacuum and product is subjected for purification. Invention provides simplifying the process.

EFFECT: improved preparing method.

2 cl, 5 ex

The invention relates to new guanidinium heterocyclic compounds of the formula (I), where R1denotes H, alkyl or is absent when R1missing link (a) is a double bond, D represents CR2, R2selected from H, alkyl, halogen, or, when is a CR3D can be N, denotes NR9, CR3=CR8, CR3, S, where R9denotes H, alkyl, alkenyl or quinil and where R3and R8selected from H, alkyl, alkenyl, quinil or cyano, R4, R5, R6each independently selected from H, alkyl, alkenyl, quinil, cyano, halogen or NH-C(= NR10)OTHER11(guanidine), R10and R11selected from H, methyl and ethyl, and where only one of R1, R5and R6is guanidines, R7selected from H, alkyl, alkenyl, quinil and halogen

The invention relates to novel benzimidazole compounds represented by the General formula I

< / BR>
where denotes the number 0, 1, 2 or 3; R1represents an alkyl group, phenyl group or a monocyclic heterocyclic group containing as the heteroatom N or O, and these groups may be substituted once or more than once, by substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cyano, amino and nitro; or R1represents cyano or a group of formula-alkyl-CO2R2alkenyl-CO2R2, -CO-R2, -CO2(CH2)mR2or-C(R3)=N-OR2where m denotes the number 0, 1, 2 or 3; R2represents hydrogen, alkyl, phenyl, benzyl, 5 - or 6-membered heterocyclic group, which 5 - or 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R2may represent a group of the formula -(CH2)q-NR4R5, -(CH2)q-CON(R4R5), -(CH2)q-CO2R4or-alkyl-CO2R4where R4and R5independently представляюUP> represents a group of General formula-CO2-R9where R9represents an alkyl or R9can represent a 6-membered heterocyclic group, and this 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R9represents a group of General formula-alkyl-N(R10R12), where R10and R12independently represent hydrogen or alkyl; or R11represents a group of General formula II

< / BR>
where n denotes the number 0, 1, 2 or 3; R' and R" together with the N atom to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member, one oxygen atom and/or one additional nitrogen atom; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed by R' and R", may be substituted once or more than once by a group of the formula -(CH2)px, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, hydroxyl, alkyl or alkenyl, and these alkyl and alkenyl can be possibly substituted by one or more the>R6or-CON-R6R7where R6and R7independently represent hydrogen or alkyl; or R11may represent a group of General formula III

< / BR>
where n denotes the number 1; R' represents hydrogen or alkyl; R'" and R" 'together with the atoms to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member one chain-CH=CH-; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed R'" and R"", may be substituted once or more than once by a group of the formula -(CH2)pX, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, alkyl; or its pharmaceutically acceptable salt; provided that if R11is morpholinyl, R1may not represent tert-butyl; pharmaceutical compositions having the properties of the modulator of the GABAANDreceptors and the treatment of disorders and diseases of the living organism, and it is a disorder or disease responsive to modulation of GABAAND-receptor complex of the Central nervous

The invention relates to new derivatives of benzimidazole of formula 1, where R1represents hydrogen or hydrocarbon group with a short chain, R2- CH2HE, COOH, СООR34,4-dimethyl-2-oxazoline

The invention relates to new halogensubstituted the benzimidazole of the formula I, in which R1, R2, R3and R4mean hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, a group of the formula Z - R5where R5means unsubstituted phenyl, pyridinyl which can be substituted by trifluoromethyl, and Z denotes oxygen, sulfur; R2and R3together signify unsubstituted or substituted alkylenes chain with 3 or 4 links, in which two (non-adjacent) carbon atoms may be replaced by oxygen atom; A denotes a group of the formula: - SO2- R6or

,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt
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