Method of producing capecitabine and β-anomer rich trialkylcarbonate compound used therein

FIELD: chemistry.

SUBSTANCE: present invention relates to method of producing capecitabine involving the following steps: 1) hydrolysis of a methylacetonide compound to obtain a triol compound of formula , 2) reaction of the triol compound with haloalkyl formate of the given formula in the presence of a mixture of pyridine and triethylamine to obtain a β-anomer rich trialkylcarbonate compound of formula , 3) glycosylation of the trialkylcarbonate compound using 5-fluorocytosine in the presence of an acid, 4) carbamylation of the obtained compound of formula using n-pentylchloroformate, followed by 5) removal of carbonate hydroxy-protective groups of the furan ring.

EFFECT: efficient method of obtaining capecitabine.

7 cl, 4 ex

 

The technical field

The present invention relates to a method for involving capecitabine, as well as to a method for producing the enriched β-anomer trialkylborane connection.

Prior art

Capecitabine is injected oral anticancer agent, widely used in the treatment of metastatic cancers of the breast and colon. Capecitabine is a nucleoside-based ribofuranose and has a stereochemical structure ribofuranose containing β-oriented 5-fortitudinous fragment at position C-1.

U.S. patent No. 5472949 and 5453497 describe the method of obtaining involving capecitabine by glycosylation tri-O-acetyl-5-deoxy-β-D-ribofuranose of formula I using 5-fertilizin to get cytidine formula II; and carbamylcholine and hydrolysis of the compounds obtained, as shown in the reaction scheme 1

The reaction scheme 1

The compound of formula I, useful as an intermediate in the reaction scheme I, is an isomer having a β-oriented acetyl group at position 1 for the reason that 5-fertilizin is more reactive with respect to the β-isomer of the α-isomer in the reaction of glycosylation due to the occurrence of a substantial part of the next group, which has m the hundred, when the protecting group for the 2-hydroxy-group is acyl.

Accordingly, β-oriented tri-O-acetyl-5-deoxy-β-D-ribofuranose (formula 1) was considered in traditional practice as an indispensable intermediate connection for receiving involving capecitabine. However, this reaction gives a mixture of β - and α-isomers, from which citizen (formula II) shall be allocated by the gas-phase.

Meanwhile, U.S. patent No. 4340729 discloses a method of obtaining involving capecitabine by the method shown in the reaction scheme 2, which includes the hydrolysis of 1-methylacetamide formula III to obtain thiol of formula IV; acetylation of compounds of formula IV using anhydrous acetic anhydride in pyridine to obtain β-/α-anomeric mixture of tri-O-acetyl-5-deoxy-D-ribofuranose of formula V; carrying out vacuum distillation for the purification of β-/α-anomeric mixture and the separation from it of the β-anomer of formula I

The scheme of reactions 2

However, the above method is also complicated by the requirement to stage uneconomical and complicated recrystallization to highlight the β-anomer of a mixture of β-/α-isomers of formula V, which leads to low yield in only about 35-40% (Guangyi Wang et al.,J. Med. Chem., 2000, vol. 43, 2566-2574; Pothukuchii Sairam et al.,Carbohydrate Research, 2003, vol. 338, 303-306;Xiangshu Fei et al.,Nuclear Medicine and Biology, 2004, vol. 31, 1033-1041and Henry M. Kissman et al.,J. Am. Chem. oc., 1957, vol. 79, 5534-5540).

Further, U.S. patent No. 5476932 describes a method of obtaining involving capecitabine by the reaction of 5'-deoxy-5-fortitudine formula VI with intelcorporation to obtain the compounds of formula VII having the amino and 2-,3-hydroxy-group-protected groups5H11CO2and remove hydroxyamine groups of the compounds obtained, as shown in reaction scheme 3

The reaction scheme 3

However, this method involves considerable production costs and also requires several complicated steps for obtaining 5'-deoxy-5-fortitudine formula VI, protection 2-,3-hydroxy groups, its interaction with 5-fertilizing and unprotect 2-,3-hydroxy groups.

Accordingly, the authors of the present invention tried to develop an effective method of obtaining involving capecitabine and unexpectedly found a new effective way of obtaining high-purity involving capecitabine using trialkylborane intermediate compounds, which does not require uneconomical stages of selection β-anomer.

The invention

Accordingly, the present invention is to develop an improved method for obtaining involving capecitabine, and method of producing enriched β-anomer of trialkylborane that can be is used as an intermediate compound in the specified method.

In accordance with one aspect of the present invention, a method for obtaining involving capecitabine of formula 1, comprising the stages of (1) hydrolysis methylacetamide the compounds of formula 2 to obtain trilogo the compounds of formula 3; (2) interaction of the compounds of formula 3 with halogenacetates formula 4 in the presence of a mixture of pyridine and triethylamine to obtain enriched β-anomer trialkylborane the compounds of formula 5; (3) conduct glycosylation of compounds of formula 5 using 5-fertilizin in the presence of acid to obtain dialkoxybenzene the compounds of formula 6; (4) conduct carbamylcholine the compounds of formula 6 using n-intelcorporation to get carbamoylating the compounds of formula 7; and (5) removal of carbonate groups, protecting the hydroxy-group of compounds of formula (7)

where X represents chlorine, bromine or iodine and R represents methyl or ethyl.

According to another aspect of the present invention, a method for obtaining trialkylborane the compounds of formula 5, is used as intermediate compounds in the specified way

where R has the same meaning as defined above.

Detailed description of the invention

In n the stationary invention trialkylborane compound of formula 5 is a mixture in the ratio from 2:1 to 4:1 β - and α-anomers, which can be used to obtain high-purity involving capecitabine of formula 1 with high yield by the improved method of glycosylation trialkylborane intermediate compounds using 5-fertilizin.

The method of obtaining involving capecitabine according to the invention are summarized in the reaction scheme 4.

The reaction scheme 4

where X and R have the same meanings as defined above.

Next stage of the method according to the invention, shown in the reaction scheme 4, will be described in detail as follows.

Stage 1

In stage 1 triline compound of formula 3 can be obtained by hydrolysis methylacetamide the compounds of formula 2 in a solvent such as aqueous sulfuric acid, according to the conventional method described in U.S. patent No. 4340729. The method according to the present invention may further, optionally, include a process of selection of each anomer obtained trilogo connection.

Stage 2

In stage 2 enriched β-anomer trialkylborane connection can be obtained by providing obtained in stage 1 trialname connection possibilities to react with halogenallylacetic compound of formula 4 in a solvent in the presence of a base, preferably an organic base, such as pyridine, triethylamine and see what camping. The resulting connection is an enriched β-anomer of trialkylborane formula 5, which is the rapid glycosylation at stage 3, because the β-anomer is more reactive than the α-anomer.

When the carbonization trilogo connection is carried out in the presence of pyridine, the resulting compound can be in the form of 1:1-mixture of α - and β-anomers or enriched α-anomer mixture. Further, if the carbonization is carried out in the presence of triethylamine, the resulting connection can be greatly enriched β-anomer mixture having a ratio of β-anomer:α-anomer is high as 6:1, depending on the reaction temperature and its equivalent. However, this carbonization using only triethylamine complicated by the fact that the by - product is the compound of formula 1A can be formed in excess,

where R has the same meaning as defined above.

According to the present invention as a base in this reaction carbonization trilogo compounds can be applied to a mixture of pyridine and triethylamine, which has a specific ratio of components, which makes it possible to obtain enriched β-anomer of the compound of formula 5, the content of which is more than twice with the holding of the α-anomer, at the same time minimizing the formation of impurities, for example, cyclic carbonate compounds of formula 1A. In particular, when the reaction is carried out in the presence of pyridine and triethylamine at low temperature, the content of cyclic carbonate compounds in the reaction product can be reduced to less than 0.2%.

According to the present invention, the pyridine used in the mixture may be applied in amounts of 1 to 2 equivalents, preferably from 1.3 to 1.6 equivalents, per triethylamine. Next, a mixture of pyridine and triethylamine may be used in amounts of 4 to 10 equivalents, preferably from 4 to 6 equivalents, per triline connection.

The solvent may be dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetonitrile, dimethylformamide or a mixture thereof, preferably dichloromethane.

Halogenoalkane compound of formula 4 can be applied in a quantity of 3 to 10 equivalents, preferably from 5 to 7 equivalents per triline connection.

Preferably, the above reaction is carried out at a temperature of from -50 to -30°C., preferably from -35 to 30°C, as in the case of carrying out the reaction at temperatures above -30°C may form a cyclic carbonate compound in an excessive amount.

Stage 3

At stage 3 dialkoxybenzene compound (formula 6) can be obtained by glycosylation of compound obtained in stage 2, using 5-fertilizin in a solvent in the presence of acid.

In the above reaction, in order to suppress the competing reaction of the amino groups in 1-anomeric position, is preferably used instead of 5-fertilizin Siciliano derived 5-fertilizin, obtained by the reaction of 5-fertilizin with silylium agent such as hexamethyldisilazane, according to the conventional method. 5-Fertilizin or Siciliano derived can be applied in amounts of 1 to 2 equivalents, preferably one equivalent per trialkylborane compound of formula 5.

Acid is used to accelerate glycosylation, and representative examples of acids may include ethylaminoethanol, methylaluminoxane, SnCl4, trimethylsilyltrifluoromethane acid and triftormetilfullerenov acid, preferably trimethylphenylsulfonyl acid. Further, the acid may be used in quantities of 0.5 to 3 equivalents, preferably one equivalent per trialkylborane compound of formula 5.

According to the present invention the solvent is used in the above reaction, may be ethyl acetate, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetonitrile or dimethylformamide, preferably acetonitrile, and the reaction may be conducted at temperatures from 0 to 50°C, preferably from 20 to 35°C.

According to the present invention, the connection of dialkylacrylamide formula 6 can be obtained from the enriched β-anomer trialkylborane the compounds of formula 5 with an increased more than 10% of the output relative to the conventional method using tri-O-acetyl-5-deoxy-β-D-ribofuranose (formula I), for example, with a high yield of more than 90% by glycosylation. In particular, the compound of formula 6 obtained by the method according to the invention has a high purity of more than 98.5 per cent. Further, with the use of high-purity compounds with a high output at the subsequent stages of the method according to the invention it is possible to obtain a final product, capecitabine, with high purity of 99.5%.

Stage 4

In stage 4 carbamylcholine compound of formula 7 can be obtained by implementing carbamylcholine dialkoxybenzene compound obtained in stage 3, with ispolzovaniem n-intelcorporation in a solvent in accordance with a customary method.

In this reaction n-interharmonic can be applied in amounts of 1 to 3 equivalents, before occhialino from 1.1 to 1.5 equivalent per dialkoxybenzene compound of formula 6.

The solvent may be an organic solvent, such as chloroform, dichloromethane, dichloroethane, tetrahydrofuran, and acetonitrile, preferably dichloromethane.

Meanwhile, during carbamylcholine organic base such as triethylamine and pyridine, can be added to the reaction mixture to neutralize the hydrochloric acid formed during the reaction, and the organic base may be used in amounts of 1 to 5 equivalents, preferably from 1.3 to 2.5 equivalents per dialkoxybenzene compound of formula 6.

The above reaction can be conducted at temperatures from -10 to 10°C., preferably from -5 to 5°C.

Carbamylcholine can be carried out quantitatively, and it is preferable that its product was used at a subsequent stage, without the process of selection.

Stage 5

Stage 5 capecitabine of formula 1 can be obtained by removal of carbonate groups protecting the hydroxyl group of carbamoylating compound obtained in stage 4, according to the usual method.

In accordance with the conventional method described in the book Theodora W. Green,Green's Protective Groups in Organic Synthesis, 4th Ed.,2007, pp. 280, 998 and 1022, Wiley-Interscience, in the case of coexistence in connection carbonate groups, protecting hydroxy, urethane protect time groups carbonaceous protective group can be selectively removed by controlling the reaction temperature and the concentration used here Foundation. This selective removal of protection based on the difference between the reactivity of carbonate and urethane protective groups, carbonate groups can be removed even at pH 10 at room temperature, while removing urethane groups requires a high pH values above 12, and high temperature more than 100°C.

In the present invention the selective removal of protection can be carried out in an organic solvent such as a mixture of methanol and water (2:1 vol./about.) in the presence of a base comprising sodium hydroxide and sodium carbonate, at temperatures from -10 to 0°C., preferably from -5 to 0°C.

Accordingly, according to the method of the present invention, using as intermediate compounds enriched β-anomer trialkylborane compounds containing β-anomer is more than two times higher than the α-anomer, you can get capecitabine with high purity, > 99%, avoiding uneconomic allocation process β-anomer. Further, the method according to the invention provides a high total yield of 90% in stage 4 and stage 5.

The following examples are intended to further explain the invention without limiting its scope.

Example 1.Obtaining 1,2,3-tri-O-methoxycarbonyl-5-deoxy-D-ribofuranose (compound of formula 5)

20 g of methyl 2,3-O-isopropylidene-5-deoxy-D-ribf ranose was dissolved in 100 ml of 2 mol%. aqueous sulfuric acid, and the mixture was stirred at 80-85°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove about one third to one half of the solvent. To the resulting concentrate was added 100 ml of 2 mol%. aqueous sulfuric acid, the resulting mixture was stirred at 80-85°C for 1 hour, cooled to room temperature and added to it the acid carbonate of sodium up until the pH of the mixture does not become equal to 3.0 to 3.5. The resulting solution was concentrated under reduced pressure, mixed with 100 ml of acetonitrile and 20 g of anhydrous sodium sulfate, followed by stirring for 30 min, filtered and the filtrate was concentrated under reduced pressure to obtain 5-deoxy-D-ribofuranose.

14.3 g (0,107 mole) of 5-deoxy-D-ribofuranose was added to 200 ml of dichloromethane was added thereto to 30.1 ml (0,372 mol) of pyridine and 37 ml (0,266 mol) of triethylamine and the mixture was cooled to -30°C. 49,1 ml (0,638 mol) of methylcarbamate was added thereto dropwise at -30°C. for 30 minutes, the reaction mixture was heated to 10°C, was added thereto 100 ml of water and the resulting mixture was stirred for 30 minutes. The organic layer was separated and washed successively with 200 ml of 1N HCl, aqueous sodium bicarbonate and aqueous NaCl. The resulting organic layer was dried over b is wodnym sodium sulfate, was filtered and removed from him the solvent, getting to 27.7 g specified in the connection header.

β-anomer:α-anomer = 2,7:1

NMR characterization of the β-anomer:1H NMR (300 MHz, CDCl3): δ 1,42 (d, 3H), 3,82 (with, 9H), 4,34-to 4.41 (m, 1H), 5,00 (DD, 1H), 5,28 (DD, 1H), 6,07 (d, 1H)

NMR characterization of the α-anomer:1H NMR (300 MHz, CDCl3): δ 1,37 (d, 3H), 3,81 (with, 9H), 4,40-4,48 (m, 1H), 4,90 (DD, 1H), 5,17 (DD, 1H), 6,29 (d, 1H)

Example 2.Obtain 2',3'-di-O-methoxycarbonyl-5'-deoxy-5-fortitudine (compound of formula 6)

Mixed 11.6 g (0,090 mol) 5-fortitudine, 19 ml hexamethyldisilazane and 24 ml of acetonitrile and 0.2 g of ammonium sulfate was added to the mixture, which was heated under reflux for 1 h After cooling the reaction mixture to room temperature, thereto was added 72 ml of acetonitrile, and then subjected the resulting mixture to distillation to remove approximately 60 ml of the solvent. The resulting solution was cooled to room temperature, mixed with 27.7 g (0,090 mol) of the compound obtained in example 1, and 72 ml of acetonitrile, and the resulting mixture was cooled to 20°C. After adding thereto dropwise at 25°C. of 16.3 ml (0,090 mol) trimethylsilyltrifluoromethane the reaction mixture was stirred at room temperature overnight, cooled to 10°C, was mixed with of 45.4 g cyclohexanone sodium and was stirred for 30 minutes To it was added dropwise to 9.8 g of water and 72 ml of dichloromethane, and the resulting solution was stirred for 2 h, filtered, and the solid is washed with 72 ml of dichloromethane. The filtrate was washed with 120 ml of 4% sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, obtaining a 35.8 g specified in the connection header.

1H NMR (CDCl3): δ 1,47 (d, 3H), 3,79 (with, 3H), 3,81 (with, 3H), 4,22~4,30 (m, 1H), 4,94 (DD, 1H), 5,39 (DD, 1H), 5,76 (d, 1H), 6,00 (users,1H), 7,37 (d, 1H), 8,78 (users,1H)

Example 3.Obtain 2',3'-di-O-methoxycarbonyl-5'-deoxy-5-fluoro-N4(pentyloxybenzoyl)cytidine (compound of formula 7)

35,8 g (0,099 mol) of the compound obtained in example 2 was mixed with 163 ml dichloromethane and 11 ml (0,136 mol) of pyridine and stirred. After cooling the resulting mixture to a temperature of -5 to 0°C. thereto was added dropwise a 15.7 ml (0,109 mol) of n-intelcorporation, maintaining at the same time, the temperature of the reaction mixture below 0°C, followed by adding thereto, after the mixture was heated to room temperature and was stirred for 2 hours, 1N HCl. The organic layer was separated, sequentially washed 163 ml saturated sodium bicarbonate and 163 ml of water, dried over anhydrous sodium sulfate and concentrated when s is low pressure, getting 42,9 g specified in the connection header.

1H NMR (CDCl3): δ 0,91 (t,3H), 1,33~1,40 (m, 4H), 1,48 (d, 3H), 1,69~1,74 (m, 2H), 3,82 (with, 6H), 4,16 (t, 2H), 4,27~4,32 (m, 1H), 4,93 (DD, 1H), 5,32 (DD, 1H), of 5.83 (d, 1H), 7,40 (with, 1H), 12,2 (users, 1H)

Example 4.Obtaining 5'-deoxy-5-fluoro-N4(pentyloxybenzoyl)cytidine (compound of formula 1)

42.9 g of the compound obtained in example 3 was added to 215 ml of methanol, and the mixture was stirred and cooled to a temperature of -5 to 0°C. 10.8 g of NaOH was dissolved in 107 ml of water, and NaOH solution was added, maintaining the temperature of the reaction mixture below 0°C. the resulting mixture was stirred for 30 min and added to it dropwise 48 ml of 6N HCl until the pH of the reaction mixture does not become equal to 5.3. The resulting mixture is then washed twice 215 ml of dichloromethane and once with 108 ml of dichloromethane, and the combined organic layer was washed 215 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. After adding thereto 129 ml of ethyl acetate, the residue was mixed with 97 ml of ethyl acetate by stirring for crystallization. Thereto was added dropwise 97 ml of hexane to give crystals to grow, and the resulting mixture was stirred for 1 h, cooled to 0°C and the mixture was stirred for 1 h Obtained the resulting solid was filtered, washed 86 ml of a mixture of ethyl acetate and hexane (1:1 vol./vol.), was cooled to 0°C and dried at 35°C in a vacuum drying Cabinet during the night, receiving 28.6 g of the connection specified in the header.

1H NMR (CD3OD): δ 0,91 (t, 3H), 1,36~1,40 (m, 4H), 1,41 (d, 3H), 1,68~1,73 (m, 2H), 3.72 pointsDD, 1H), 4,08 (DD, 3H), 4,13~4,21 (m, 3H), 5,70 (with, 1H), of 7.96 (d, 1H)

Although the invention has been described with reference to the above specific embodiments, various modifications of the invention, which can be done by specialists, also fall within the scope of the invention as defined in the attached claims.

1. The method of obtaining involving capecitabine of formula 1, comprising the stage of:
(1) hydrolysis methylacetamide the compounds of formula 2 to obtain trilogo the compounds of formula 3;
(2) the interaction of the compounds of formula 3 with halogenacetates formula 4 in the presence of a mixture of pyridine and triethylamine to obtain enriched β-anomer trialkylborane the compounds of formula 5;
(3) glycosylation of compounds of formula 5 using 5-fertilizin in the presence of acid to obtain dialkoxybenzene the compounds of formula 6;
(4) carbamylcholine the compounds of formula 6 using n - intelcorporation to get carbamoylating the compounds of formula 7; and
(5) the Alenia carbonate hydroxyamine groups in compounds of formula (7):







where X represents chlorine, bromine or iodine, and R represents methyl or ethyl.

2. The method according to claim 1, wherein pyridine is used in amounts of 1 to 2 equivalents per triethylamine.

3. The method according to claim 1, wherein a mixture of pyridine and triethylamine are used in quantities of 4 to 10 equivalents based on the compound of formula 3.

4. The method according to claim 1, wherein the reaction in stage (2) is conducted at a temperature of from -50°C. to -30°C.

5. The method according to claim 1, wherein the acid used in stage (3) is ethylaminoethanol, methylaluminoxane, SnCl4, trimethylsilyltrifluoromethane acid or triftormetilfullerenov acid.

6. The method according to claim 5, in which the acid is used in amount of 0.5 to 3 equivalents based on the compound of formula 5.

7. The method of obtaining trialkylborane the compounds of formula 5, which includes stages:
(1) hydrolysis methylacetamide the compounds of formula 2 to obtain trilogo the compounds of formula 3; and
(2) the interaction of the compounds of formula 3 with halogenacetates formula 4 in the presence of a mixture of pyridine and triethyl is mine for the production of enriched β-anomer of trialkylborane formula 5:




where X and R have the meanings given in claim 1.



 

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25 cl, 9 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of phenylglycine of the formula (I) , to their hydrates or solvates, and/or to physiologically acceptable salts and/or physiologically acceptable esters possessing inhibitory effect on amidolytic activity of the complex factor VIIa/tissue factor that can be used for therapeutic and/or prophylactic treatment of diseases, for example, thrombosis. In the formula (I) R1 means (C1-C6)-alkyl; R2 means hydrogen atom, hydroxy-(C1-C6)-alkoxy-, (C1-C6)-alkoxycarbonyloxy-, (C1-C6)-alkoxy-group or halogen-(C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy-group; R3 means hydrogen atom, (C1-C6)-alkoxy- or heterocycloalkyloxy-group wherein heterocycloalkyl group means 5-6-membered ring comprising a heteroatom taken among nitrogen and oxygen atom; R4 means hydrogen atom or ester residue that is cleaved off under physiological conditions. R5 means hydrogen atom, hydroxy-group, (C1-C6)-alkoxycarbonyl, halogen-(C1-C6)-alkoxycarbonyl, (C6)-aryloxycarbonyl,(C6)-arylalkoxycarbonyl, (C1-C6)-alkoxy-(C1-C6)-alkoxy(C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkyloxycarbonyl, (C2-C6)-alkynyloxycarbonyl, 5-methyl-2-oxo[1,3]dioxol-4-yl-methoxycarbonyl, (C6)-arylcarbonyloxy-, (C1-C6)-alkylaminocarbonyloxy-group, (C1-C6)-alkylcarbonyl, arylcarbonyl, arylaminocarbonyl or heteroarylcarbonyl wherein heteroaryl represents 5-6-membered ring comprising nitrogen atom the cycle; X means atom F, Cl or Br. Also, invention relates to a method for preparing compounds, intermediates substances and pharmaceutical composition and a method for treatment.

EFFECT: improved preparing method, valuable medicinal properties of agents and composition.

29 cl, 5 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new aromatic diketone derivatives of formula I

(R4, R5, R6, and R7 are independently H, OH, X-alkyl, wherein X represents oxygen; K is group of formula II

or III

;

L is group of formula IV

;

or K and L together form group of formula VI ,

wherein R1 and R3 are independently H or alkyl; R2 is H or alkyl; X1-X7 are independently O, NH; and ring "cyclus" together with carbon atom labeled with letters c and d represents anthraquinone, hydroquinone or phenyl, optionally substituted with one or more hydroxyl, alkoxyl, or alkyl groups), as well as pharmaceutically accepts salts thereof, ethers, esters, tautomers, stereomers and mixtures in any ratio. Derivatives of present invention are glucose-6-phosphatetranslocase inhibitors. Also disclosed are method for production of derivatives, pharmaceutical composition containing the same, and uses thereof as drugs, in particular for treatment of diabetes mellitus.

EFFECT: new compounds and pharmaceutical composition for treatment of diabetes mellitus.

20 cl, 4 tbl, 6 ex

The invention relates to a new therapeutic drug for diabetes and includes the compound of the formula I: R1-C(O)-C(R2')(R2)-X-C(O)-R3where X represents a group of formula-C(R4)(R5)-, -N(R6)-, -O-; where R4is a hydrogen atom, a C1-C5alkyl, carboxy, phenyl, C2-C5acyl, C2-C5alkoxycarbonyl, R5is a hydrogen atom, a C1-C5alkyl; R6is hydrogen; R1is phenyl, optionally substituted C1-C5by alkyl, hydroxy, hydroxyalkyl, C2-C6alkenyl, acyl, carboxy, teinila, C3-C7cycloalkyl; biphenyl, optionally substituted C1-C5the alkyl or hydroxy; naphthyl; terphenyl; C3-C7cycloalkyl, optionally substituted C1-C5the alkyl or phenyl; optionally substituted C1-C5alkyl; pyridyl; sensational; substituted; indanyl; fluorenyl or group; R2is hydrogen, C1-C5alkyl, optionally substituted by carboxy; R2'is hydrogen; R3- C1-C5alkyl, optionally substituted by phenyl or C1-C4alkoxy, C1-C4alkoxy; hydroxy; phenyl; C3-C72)2-; R2and R5taken together, form a simple bond or-CH2-, - (CH2)3-, -(CH2)4-; R2, R2', R4and R5taken together form =CH-CH=CH-CH=; R2' and R3taken together form a-CH(R8)-OH, -CH(R8)-CH(R9)-, -CH(R8)NH; R8and R9is hydrogen, and pharmaceutically acceptable salts

The invention relates to a new means of plant protection

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the following compounds: N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trofluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-methyl-1-hydroxy-ethyl)-1-ethyl-1H-imidazole-4-yl}-benzyl}-3-hydroxy-propyl)-3-chloro-4-(,2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidazole-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trifluoro-1-methyl-ethoxy)-benzamide, 3-chloro-N-[2-[(N,N-dimethylglicyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-(1-(2-(dimethylamino)acetamido)-3-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide, 3-chloro-N-(2-[(2-methylalanyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-[(3-hydroxy)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide, as well as to their pharmaceutically acceptable salts.

EFFECT: obtained compounds and salts can be used for treatment cell proliferative diseases and disorders by modulating activity of mitotic kinesin CENP-E.

26 cl, 102 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing N-(β-hydroxyethyl)-4,6-dimethyldihydropyrimidone-2, known in medicine as Xymedon, involving recrystallisation of hydrochloride, N-(β-hydroxyethyl)-4,6-dimethyldihydropyrimidone-2 from ethanol and then treated with a sodium hydroxide solution in ethanol. The sodium chloride formed is removed by filtering. Crude N-(β-hydroxyethyl)-4,6-dimethyldihydropyrimidone-2 is separated by evaporating ethanol and purified by double recrystallisation from chemically pure isopropyl alcohol in the presence of aluminium oxide and activated carbon.

EFFECT: method enables to obtain a highly pure product.

3 ex

FIELD: medicine.

SUBSTANCE: invention refers to cosmetology, specifically to an agent for dyeing keratin-containing fibres, first of all, human hairs, containing at least one compound of formula (I) and/or its enamic form, with R meaning allylic group, hydroxyalkyl group with 2-6 carbon atoms, or if required, substituted benzyl group, X- meaning a physiologically acceptable anion, and at least one aldehyde.

EFFECT: invention allows producing dyeing with shine, improved washability and light resistance.

18 cl, 3 ex, 3 tbl

The invention relates to a new compound - derived 4-oxo-1,4-dihydropyrimidin formula I, having antihypoxic, cerebroprotective and immunotropic activity, and may find application in medicine
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