Method for synthesis of fluoroclozapine and derivatives thereof

FIELD: chemistry.

SUBSTANCE: method includes reacting 2,4-difluoro-5-nitro-1-chlorobenzene (2) with a compound of formula (3) to obtain a compound of formula (4) , reducing the compound of formula (4) with sodium dithionite in a suitable solvent to obtain a compound of formula (5) , ring closure of the compound of formula (5) to form a compound of formula (6) , crystallising a compound of formula (7) from the compound of formula (6), reacting said compound of formula (7) with an amino derivative of a compound of formula (9)

EFFECT: high degree of purity.

10 cl, 4 dwg, 4 ex

 

AREA of TECHNOLOGY

The invention relates to pharmacology and medicine and relates to a method of synthesis forclosing and its derivatives, which can be used for the manufacture of drugs for the treatment of mental diseases or mental disorders.

The LEVEL of TECHNOLOGY

Currently mental health is among the most serious problems facing all countries, because in one or another period of life, these problems arise at least every fourth person. Development of new antipsychotic drugs is an extremely important task for modern medicine, because the only drug that effectively eliminates positive and negative symptoms of schizophrenia - clozapine - also has dangerous side effects that limit its use in clinical practice.

Fluorinated analogues of clozapine are effective antipsychotic drugs, which is comparable to clozapine high efficiency combined with the relative safety applications. Getting porpoising clozapine high purity is important because even small amounts of impurities can significantly alter the pharmacological effect and safety profile of the substance.

The prior art discloses ways� synthesis of one of the derivatives forclosing (patent RF №2441867, IPC C07B 403/04, LLC "Valentec", publ. 10.02.2012), the General scheme of which is as follows:

One of the stages of this method is the step of producing the compound of formula (b). For this dissolving 89 g of a compound of formula (a) in 1335 ml of absolute ethanol. To the mixture was added 112,2 ml of concentrated hydrochloric acid, sprinkle 206,5 g of tin chloride and the reaction mass is heated to boiling. The mixture was refluxed for 12 h. the mixture is Then cooled to room temperature, the solvent is evaporated on a rotary film evaporator (EPI). In the distillation residue was added 1 l of water and made basic with aqueous NaOH to pH 9. The resulting suspension was extracted with ethyl acetate three times with 250 ml. the product comes in the form of light yellow or light green powder. The output 64,9 g, 81% of theoretical.

However, obtained by well-known methods the final product is contaminated, and contains not less than 0.15% single impurity, presumably dichloropropanol following formula:

The impurities can be tracked at the stage of recovery of chloride of tin.

Although dichloropropane in its structure close to the target perchloroethane, it is known that the chlorine atom is in its nature more voluminous Deputy, so the receptor profile with�unity may differ significantly. Additionally, the bond C-Cl is more susceptible to hydrolysis compared with the bond C-F, and the formation of reactive metabolite dichloropropanol more likely. Therefore, the presence of impurities dichloropropanol in the final product is highly undesirable.

Disclosure of the INVENTION

The object of the invention is to provide a novel method of synthesis forclosing and its derivatives of high purity where these compounds are collectively represented by the General formula (1):

where to cycle And represents a phenyl, 5 - or 6-membered heteroaryl containing 1 atom of O or 1 O atom and 1 to 2 atom of Ν, or 1 S atom, or 1 S atom and 1-2 atom Ν, or 1-3 of atom Ν, with loop And optionally substituted with 1-3 substituents of R1;

the cycle represents a 5-7 membered saturated or partially unsaturated heterocycle containing 1 atom of O or 1 atom and About 1-2 atoms of N, or 1 S atom, or 1 S atom and 1-2 N atom, or 1 to 3 N atom, wherein the cycle is optionally substituted with 1-3 substituents of R2; where

R1represents hydrogen, C1-3alkyl, optionally substituted by 1-3 R3, O-(C1-3-alkyl optionally substituted by 1-3 R3With1-3-alkyl-O-C1-3-alkyl optionally substituted by 1-3 R3or halogen,

R2represents hydrogen, halogen or C1-3-alkyl optionally substituted by 1-3 R3,

R3pre�represents a halogen or HE.

Under the above-mentioned term "halogen" should be understood fluorine, chlorine, bromine and iodine.

The technical result achieved when using the invention, is to increase the degree of purity forclosing and its derivatives, collectively represented by the above General formula (1), by reducing the content of impurities.

The task and the required technical result is achieved by a new method of synthesis of compounds of the above formula, which includes:

the interaction of 2,4-Diptera-5-nitro-1-chlorobenzene (2) with a compound of the General formula (3)

in which cycle A and R1defined above, to obtain compounds of the General formula (4)

the recovery of the compounds of the General formula (4) using dithionite sodium in a suitable solvent to produce a compound of the General formula (5)

the cyclization of the compounds of the General formula (5) with the formation of compounds of the General formula (6)

crystallization of the specified compounds of the General formula (6) compounds of the General formula (7)

in a suitable solvent;

the interaction of the compounds of the General formula (7) with an amine derivative compound of the General formula (9)

in which cycle In and R2defined above, to obtain compounds of the General formula (8)

the interaction of a compound of formula (2) with a compound of the formula (3) is carried out in the presence of KF, heating the reaction mixture for 5-6 days at 140-180°C, in the basic conditions in a polar aprotic solvent, where the base used to NaH, KH, t-BuOK, LiOH or CsCO3and in the solvent used is dimethylformamide, N-methylpyrrolidone, DMSO or THF, in addition the interaction of a compound of formula (7) with a compound of formula (9) is carried out in an aprotic solvent, e.g., DMSO or toluene, the stage of the cyclization is carried out in acidic conditions, and at the stage of crystallization in the solvent used diethyl ether, methyl tert-butyl ether, dioxane, and in the recovery stage using THF, 2-methyltetrahydrofuran, cyclopentylmethyl the air.

BRIEF description of the DRAWINGS

Fig. 1 - depicts LC MS product recovery-cyclization (compounds of formula (6') obtained by the proposed method.

Fig. 2 - shows a LC-MS compounds A-1.

Fig. 3 - depicts LC MS of a mixture of intermediate 6' and impurities A-1.

Fig. 4 - depicts a chromatogram of a sample forclosing.

The IMPLEMENTATION of the INVENTION

Below for the purpose of explanation of significant differences the offer�of the invention presents the General scheme of synthesis of compounds of the above formula (1).

The compound of the above formula (4) can be obtained from 2,4-Diptera-5-nitro-1-chlorobenzene 2 and the corresponding nitrile (3) in the presence of KF by heating the reaction mixture for 5-6 days at 140-180°C.

Alternative combination of compounds of the formula (2) and (3) can be conducted under basic conditions in a polar aprotic solvent. Suitable bases include NaH, KH, t-BuOK, LiOH, CsCO3. As solvents may be used dimethylformamide, Ν is methylpyrrolidone, DMSO, THF. 2,4-Diptera-5-nitro-1-chlorobenzene (2) can be obtained from 2,4-Diptera-5-nitro-1-chlorobenzene according to the standard method.

The compound of formula (5) can be obtained from compounds of formula (4) repair using dithionite sodium, for example, THF. Known from the prior art method of obtaining analogues of a compound of formula (5) includes the restoration of the nitro group with tin chloride. However, chloride ions can displace the fluorine atom of the compounds of formula (4) and (5) that leads to the formation of undesirable by - product of a compound of formula (5b), which is very difficult to separate from the target compound of formula (5). When using Na2S2O4as a reducing agent for the formation of a by-product of the formula (5b) is excluded, and the reaction protege� with the formation of a compound of formula (5).

The cyclization of a compound of formula (5) with the formation of a compound of formula (6) is carried out in acidic conditions. The chloride of formula (7) crystallized from the free base of formula (6) in a suitable solvent, for example, destinova the air.

The compound of formula (8) can be obtained from compounds of formula (7) and the corresponding amine derivatives of formula (9). The reaction is conducted in an aprotic solvent, e.g., DMSO or toluene.

Below to illustrate certain aspects of the invention examples of the implementation of the proposed method, namely obtaining forclosing (8') and its derivatives (9'), (10) and (16). The examples below are not meant to in any way limit the scope of the present invention.

Example. 1. The method of synthesis forclosing

1.1. 2,4-Diptera-5-nitro-1-chlorobenzal, the compound of formula (2)

To a cooled to 0°C nitric acid (1.5 l) was added dropwise 0.5 l of a compound of formula (2A). The mixture was stirred for 15 minutes and poured into 25 l of water, cooled to +5°C. the Reaction mass is stirred for 2 minutes and allowed to settle for 1 hour. The product is formed at the bottom in the form of heavy oil. The aqueous phase is decanted, extra�are 1 l of CH 2Cl2. The extract was combined with the product, washed 4 times with water until pH 7. The organic layer was dried with sodium sulfate, the solvent was removed on the EPI. The output of a compound of formula (2) 90-95%.

1.2. 2-(2-nitro-5-fluorescent-4-chlorobenzylamino)

the benzonitrile, a compound of the General formula (4)

In a 500 ml flask equipped with a sand bath, thermocouple, and magnetic stirrer was 115 g of a compound of formula (2), 34.5 g of KF and 84,2 g of a compound of formula (3'). The reaction mass is heated with stirring at 150-160°C for 5-6 days, monitoring the reaction by NMR. The reaction is considered complete when the contents of the source compounds of the formula (2) is not more than 15% in relation to the product.

The reaction mixture was cooled to 60°C and add, while stirring, 500 ml of ethyl alcohol. The mixture is cooled with stirring to 20°C, filter, wring out. The substance is washed on the filter with three portions of ethanol (150 ml) and two portions of 200 ml. of water Yield 87 g, 50% of theoretical.

1.3. 2-(2-amino-5-fluorescent-4-chlorobenzylamino)

the benzonitrile, a compound of the General formula (5)

48.5 g of a compound of formula (4') are dissolved in 670 ml of tetrahydrofuran. Then add a solution of 144.7 g of dithionite sodium in 560 ml of water and 45 ml of methanol. The reaction �Assou incubated with stirring for 1 hour. After a full course of reaction in the reaction mixture add a solution of 70,5 g of sodium bicarbonate in 750 ml of water. Stirred for 15 minutes. The product comes in the form of a light gray powder. The yield was 60 g, 65% of theoretical.

1.4. 11-amino-7-fluorescent-8-chloro-5H-dibenzo[b,e][1,4] diazepin, the compound of the General formula (6)

105 g of a compound of formula (5') is dissolved in 1 liter of ethyl alcohol. To the mixture was added 68 ml of concentrated aqueous HCl. The reaction mass is heated to boiling with stirring and continue boiling for 4-5 hours. The mixture is then cooled to room temperature and the solvent is removed on the EPI. In the distillation residue was added 800 ml of acetonitrile. The mixture was stirred for 15 min. the crystals Formed are filtered off, drained and washed on the filter with 200 ml of acetonitrile. A yield of 85 g, 81% of theoretical.

1.5. 11-amino-7-fluorescent-8-chloro-5H-dibenzo[b,e][1,4]diazepine hydrochloride, the compound of the General formula (7)

To the suspension is 64.9 g of a compound of formula (6') in 45S ml of diethyl ether was added 124 ml of 3M HCl in dioxane. The reaction mass is stirred for 30 min. the crystals Formed are filtered off, drained and washed on the filter with two portions of 150 ml of diethyl ether. The yield was 73 g, 98% t�auraticheskogo.

1.6. 11-(4-methylpiperazin-1-yl)-7-fluorescent-8-chloro-5H-dibenzo[b,e][1,4]diazepin, the compound of the General formula (8)

In a 2 l flat-bottomed flask equipped with a magnetic stirrer and reflux condenser, dissolve 98 g of a compound of formula (7') in a mixture of toluene:DMSO=490:490 ml, add 291,7 ml of methylpiperazine. The instrument was purged with argon, remove the inert gas from the cylinder (leaving the balloon is filled with argon and refluxed for 36 h. the reaction mixture was Poured into water and extracted three times with ethyl acetate in portions of 150 ml). the combined organic layer was washed with three portions of water (150 ml. Dried over sodium sulfate and the solvent is distilled off on the EPI.

In the distillation residue are added 500 ml of chloroform, stirred for IPA 10 min. the Precipitated crystals filtered off, press on the filter and washed with 100 ml of methanol on the filter. The product of formula (8') is cleaned by recrystallization from methanol with activated charcoal, calculating the volume of solvent per 1 g of product in 15 ml of methanol and 10 mass% of a compound of formula (8') of activated charcoal. Exit 59 g of 61%.

Example 2. Synthesis of 11-(piperazine-1-yl)-7-fluorescent-8-chloro-5H-dibenzo[b,e][1,4]diazepine

In a 2 l flat-bottomed flask equipped with a magnetic stirrer and reflux condenser, dissolve 63 � of a compound of formula (7') in a mixture of toluene:DMSO=315:315 ml add to 145.6 g of piperazine. The instrument was purged with argon, remove the inert gas from the cylinder (leaving the balloon is filled with argon) and the reaction mass is refluxed for 36 h. TLC control (dichloro methane:methanol =20:1).

The mixture is cooled to room temperature, and poured into 2 liters of water. Extracted with three portions of 200 ml of ethyl acetate. The combined organic layers were washed with three portions of 100 ml. of water and Then the organic layer was dried over sodium sulfate.

The organic phase was filtered through a layer of silica gel (10 mm) and washed on the filter with 2 liters of ethyl acetate. The mother liquor was extracted with 4 M solution of hydrochloric acid in water. Thereafter, the aqueous phase was washed with three portions of ethyl acetate in 150 ml. Then, upon cooling, the aqueous phase was made basic with pre-cooled 4 Μ NaOH to pH 10. The precipitated crystals filtered off, drained and washed on the filter with three portions of 150 ml of water.

The resulting product of formula (8") was recrystallized from toluene (ethanol, methyl ethyl ketone), calculating the volume of solvent per 1 g of product, 3 ml of solvent. The yield is 45 g, 50% of theoretical.

Example 3. Synthesis 11-(4-(2-(2-hydroxyethoxy)ethyl) piperazine-1-yl)-7-fluorescent-8-chloro-5H-dibenzo[b,e][1,4]diazepine

In a 2 l flat-bottomed flask, equipped with magnetic metalcase reflux, dissolve 75 g of a compound of formula (7') in a mixture of toluene:DMSO=375:375 ml, add 413 ml of 1-[2-(2-hydroxyethoxy) ethyl]piperazine. The instrument was purged with argon, remove the inert gas from the cylinder (leaving the balloon is filled with argon and refluxed for 36 h. the Yield of 48 g of 61%.

Example 4. 2-methyl-4-(4-methylpiperazin-1-yl)-8-fluorescent-7-chloro-10H-benzo[b]thieno[2,3-e][1,4]diazepin, the compound of formula (16)

4.1. 2-amino-5-methylthiophene-3-carbonitrile, the compound of formula (11)

Sulfur (S8, 0.9 g), propionic aldehyde (2 ml) and dimethylformamide (6 ml) are transferred into the three-neck round bottom flask equipped with addition funnel and a refrigerator. The mixture is cooled to 0°C and dropwise added triethylamine (2.3 ml). The resulting dark solution was heated to room temperature within 1 hour. A solution of malononitrile (1,71 ml) in DMF (3.2 ml) is transferred into the funnel and is added dropwise. The resulting brown liquid was stirred overnight at room temperature.

The reaction mass was poured into 80 ml of water and ice, the resulting orange precipitate was filtered, washed with cold water and dried in vacuo. The yield of 78%.

4.2. 5-methyl-2-(2-nitro-5-fluorescent-4-chlorophenyl-amino)thiophene-3-carbonitrile, the compound of formula (12)

To 0.26 g of NaH (obtained from a 55% suspension in oil by washing in hexane) was added 1 ml anhydrous THF. 0.5 g of a compound of formula (11) and 0.7 g of a compound of formula (2) are dissolved in 1.5 ml anhydrous THF and added to a suspension of NaH dropwise, maintaining the temperature below 30°C. the Reaction mixture was stirred overnight in a nitrogen atmosphere.

The mixture was poured into 11 ml of a mixture of ice water, neutralized with concentrated HCl, and extracted with 36 ml of dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue is purified chromatographically on silica gel (eluent ethyl acetate:hexane 1:9). The yield of 0.68 g, 60%.

4.3. 2-(2-amino-5-fluorescent-4-chlorobenzylamino)-5-methylthiophene-3-carbonitrile, the compound of formula (13)

0.52 g of the compound of formula (12) was dissolved in 6.7 ml of tetrahydrofuran. Then add a solution of 1.45 g of dithionite sodium 5.6 ml of water and 0.4 5 ml of methanol. The reaction mixture is incubated with stirring for 1 hour. After a full course of reaction in the reaction mixture is added a solution of 0.70 g of sodium bicarbonate in 7.5 ml of water. Stirred for 15 minutes. The product comes in the form of a light gray powder. Yield 0.25 g, 53% of theoretical.

4.4. 4-amino-2-methyl-8-fluorescent-7-chloro-10H-benzo[b]thieno[2,3-e][1,4]diazepin, the compound of formula (14)

1.13 g of the compound of formula (13) was dissolved in 10 ml 96% ethanol. To the mixture was added to 0.68 ml of concentrated aqueous HCl. The reaction mass is heated to boiling with stirring and continue boiling for 4-5 hours. The mixture is then cooled to room temperature and the solvent is removed on the EPI. In the distillation residue was added 8 ml of acetonitrile. The mixture was stirred for 15 min. the crystals Formed are filtered off, drained and washed on the filter with 2 ml of acetonitrile. Output 1 g, 89% of theoretical.

4.5. 4-amino-2-methyl-8-fluorescent-7-chloro-10H-benzo[b]thieno[2,3-e][1,4]diazepine hydrochloride, the compound of formula (15)

To a suspension of 0.7 g of compound 14 in 4.5 ml destravado ether was added to 1.24 ml of 3M HCl in dioxane. The reaction mass is stirred for 30 min. the crystals Formed are filtered off, drained and washed on the filter with two portions in 1.5 ml of diethyl ether. The yield 0.78 g, 98% of theoretical.

4.6. 2-methyl-4-(4-methylpiperazin-1-yl)-8-fluorescent-7-chloro-10H-benzo[b]thieno[2,3-e][1,4]diazepin, the compound of formula (16)

1.2 compound 15 was dissolved in a mixture of toluene:DMSO=4,9:4,9 ml, was added to 2.9 ml of methylpiperazine. The mixture was heated in an inert gas atmosphere for 36 h. the reaction mixture was Poured into water and extracted three times with ethyl acetate portions of 1.5 ml. The combined organic layer was washed with three portions of water, 1.5 ml. Dried over sodium sulfate and the solvent is distilled off on the EPI. Output 1.1 g, 77% of theoretical.

Below is evidence of increasing purity of the product obtained by the proposed method.

The FC sample No. 1 was synthesized by the standard method using SnCl2. Analysis of sample No. 1 showed that the content of individual impurities does not exceed 0,332%, and the total content of impurities -1.248%. The study of intermediates showed that the formation of impurities occurs during the recovery phase SnCl2.

Fig. 1 shows LC MS product recovery-cyclization (compounds of formula (6')), obtained by the proposed method. It has been suggested that the major impurity formed during recovery is a derivative dichlorobenzothiazole A-1.

The hypothesis was confirmed by comparison of LC MS spectrum of product recovery and dichlorobenzothiazole. Fig. 2 shows LC-MS compounds A-1. Fig. 3 shows LC MS of a mixture of intermediate 6' and impurities A-1.

Sample forclosing FC 2 was synthesized according to the proposed method, in which the recovery Prov�Ried out using dithionite sodium. Fig. 4 shows a chromatogram of the compounds. The peak area in Fig. 4 corresponds to the number of impurities. It is seen that the content of the basic substance (peak No. 8)>99,85%, the total content of impurities in a new sample of 0.15%, the maximum content of individual impurities 0,047% (peak No. 6). Thus, comparing the data for the FC sample No. 1 obtained according to the prototype, and the data for the FC sample No. 2 obtained according to the invention, it is seen that the degree of purity forclosing FC No. 2, obtained by the method according to the invention, above, which confirms the achievement of the technical result.

The proposed invention is not limited to that described above variants of implementation, but rather covers various modifications and variations within the essence and scope of the proposed claims.

1.The method of obtaining compounds of formula (1):

where to cycle And represents a phenyl, 5 - or 6-membered heteroaryl containing 1 atom of O or 1 O atom, and 1-2 N atom, or 1 S atom, or 1 S atom and 1-2 N atom, or 1 to 3 N atom, wherein the cycle And optionally substituted with 1-3 substituents of R1;
the cycle represents a 5 to 7 membered saturated or partially unsaturated heterocycle containing 1 atom of O or 1 atom and About 1-2 atoms of N, or 1 S atom, or 1 S atom and 1-2 N atom, or 1 to 3 N atom, wherein the cycle is optionally substituted 1-3 Deputy�and R 2; where
R1represents hydrogen, C1-3alkyl, optionally substituted by 1-3 R3And O1-3-alkyl optionally substituted by 1-3 R3With1-3-alkyl-O-C1-3-alkyl optionally substituted by 1-3 R3or halogen,
R2represents hydrogen, halogen or C1-3-alkyl optionally substituted by 1-3 R3
R3represents a halogen or HE,
which includes:
the interaction of 2,4-Diptera-5-nitro-1-chlorobenzene (2) with a compound of the formula (3)

in which cycle A and R1defined above, to produce a compound of formula (4)

the recovery of the compounds of formula (4) using dithionite sodium in a suitable solvent to produce a compound of formula (5)

the cyclization of the compounds of the formula (5) with the formation of a compound of formula (6)

crystallization from a specific compound of formula (6) compounds of the formula (7)

in a suitable solvent;
the interaction of the compounds of formula (7) with an amine derivative compound of the formula (9)

in which cycle In and R2defined above, to produce a compound of formula (8)

2. A method according to claim 1, in to�Thor the interaction of a compound of formula (2) with a compound of the formula (3) is carried out in the presence of KF, heating the reaction mixture for 5-6 days at 140-180°C.

3. A method according to claim 1, wherein the interaction of a compound of formula (2) with a compound of the formula (3) is carried out in basic conditions in a polar aprotic solvent.

4. A method according to claim 3, wherein the quality base used to NaH, KH, t-BuOK, LiOH or CsCO3.

5. A method according to claim 3, wherein the solvent used is dimethylformamide, Ν is methylpyrrolidone, DMSO or THF.

6. A method according to claim 1, wherein the interaction of a compound of formula (7) with a compound of the formula (9) is carried out in an aprotic solvent.

7. A method according to claim 6, wherein the solvent used DMSO or toluene.

8. A method according to claim 1, wherein the cyclization is carried out in acidic conditions.

9. A method according to claim 1, wherein in the crystallization step as the solvent used diethyl ether, methyl tert-butyl ether, dioxane.

10. A method according to claim 1, wherein the solvent in the recovery stage using THF, 2-methyltetrahydrofuran, cyclopentylmethyl ether.



 

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20 cl, 7 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula IV, VIII-A and X, and to their pharmaceutical acceptable salts possessing the inhibitory activity on PI3-kinase (phosphoinositide-3-kinase). In compounds of formula IV and IX and Wd is specified in a group consisting of, , , and each of which can be substituted. In formula VIII-A, the group Wd represents the group or , wherein Ra is hydrogen, R11 is amino; in compound IV, Wa2 represents CR5; Wa3 represents CR6; Wa4 represents N or CR7; in compound IX, Wa1 and Wa2 independently represent CR5, N or NR4, and Wa4 independently represents CR7 or S, wherein no more than two neighbouring atoms in a ring represent atom or sulphur; Wb5 represents N; B represents a grouping of formula II, as well as in case of compound IV, B means C1-C10alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl having one to six ring heteroatoms specified in N, O and S; in case of compound IX, B also means C1-C10alkyl, C3-C10cycloalkyl or 6-merous heterocycloalkyl having nitrogen atom; Wc represents C6-C10aryl or 5-18-merous heteroaryl having one or more ring heteroatoms specified in N, O and S, or phenyl or 6-merous heteroaryl respectively is equal to an integer of 0, 1, 2, 3 or 4; X is absent or represents -(CH(R9))z-, respectively; z is equal to 1; Y is absent. The other radical values are specified in the patent claim.

EFFECT: compounds can be used for treating such diseases, as cancer, bone disorders, an inflammatory or immune disease, diseases of the nervous system, metabolic disorders, respiratory diseases, thrombosis or cardiac diseases mediated by PI3-kinase.

68 cl, 11 dwg, 7 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula wherein each of R1 and R2 is independently selected from a group consisting of a hydrogen atom, nitro and NR6R7; R3 is C1-C8alkyl; each of R4 and R5 is independently selected from a group consisting of C1-C8alkoxy, phenoxy and phenyl(C1-C8alkylene)oxy; each of R6 and R7 is independently selected from a group consisting of a hydrogen atom, C1-C8alkyl, C(O)R8 and SO2R8;R8 is selected from a group consisting of a hydrogen atom, C1-C8alkyl, halogen-substituted C1-C8-alkyl, C1-C8-alkyl, substituted (C1-C8-alkylsubstituted amino), C1-C8-alkyl, substituted with piperidine and C1-C8-alkyl, substituted with morpholine.

EFFECT: reduced PDE4 enzyme activity and treating PDE4 enzyme mediated diseases or conditions.

21 cl, 2 tbl, 32 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a compound of formula and to its pharmaceutically acceptable salt and its enantiomers, wherein D means pyridyl, which is substituted by 1-2 independently specified groups R38; M means , wherein * means an attachment position to D; and † means an attachment position to Z; Z means -O-; Ar means phenyl, which is optionally substituted by 0-4 groups R2; and G means ; wherein each R38 means -C0-C6-alkyl-(substituted by one group containing heterocyclyl, which means a monocyclic structure, and contains 5 to 7 atoms, wherein 1 or 2 atoms are independently specified in a group containing N, O and S optionally substituted by one or more oxo groups); in each specific case R2 is independently specified in -H and halogen; each R13 means -H; Q means cyclopropyl. The invention also refers to a pharmaceutical composition based on the composition of formula (I), a method for inhibiting the activity of protein kinase of the growth factor receptors and a method of treating choroidal neovascularisation.

EFFECT: there are prepared new compounds possessing the activity on protein kinase inhibitors.

7 cl, 8 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of obtaining compounds of formula . The compounds of formula 6 are intermediate products for obtaining dihydrothieno[3,2-d]pyrimidines, which produce an impact on the cardiovascular system, possess sedative action, or can be applied in treatment of inflammatory diseases of joints, skin, eyes or diseases of the peripheral or central nervous system, respiratory or gastrointestinal disorders. The method includes the following stages: a) interaction of reagents of formulas HS-CH2-CO2Ra and CHR5=CR4-CO2Ra with obtaining an intermediate product of formula ; and b) cyclisation of the intermediate product of formula 7 in a solvent in the presence of TiCl2(O-iPr)2, TiCl(O-iPr)3, TiCl3(O-iPr) and in the presence of a base-amine, with obtaining a product of formula 6. Ra stands for alkyl, R4 and R5 are independently selected from a group, including H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C6-C10-aryl, C6-C10-aryl-C1-C6-alkylene, C5-C10-heteroaryl-C1-C6-alkylene, C3-C10-heterocycle and C5-C10-heteroaryl, -O-C1-C6-alkyl, -O-C6-C10-aryl, -O-C3-C10-heterocycle and -O-C5-C10-heteroaryl, -NR'R", fluorine, C1-C6-fluoroalkyl and C1-C6-fluoroalkoxygroup, where R' and R" are independently selected from a group, including H and C1-C6-alkyl, and where in each case the group can be optionally substituted with one or more groups, selected from a group, including OH, oxogroup, halogen, C1-C6-alkyl and O-C1-C6-alkyl. The method makes it possible to obtain the intermediate products 6, which do not require carrying out distillation and chromatographic purification between stages in realisation of processes suitable for wide-scale synthesis of dihydrothieno[3,2-d]pyrimidines.

EFFECT: invention results in higher total output of the final products as compared to that in realisation of methods of preceding level of technology.

6 cl

FIELD: chemistry.

SUBSTANCE: invention relates to compound with structural formula (I) or to its pharmaceutically acceptable salt, where R represents cyanogroup. Invention also relates to method of obtaining said compound and to pharmaceutical composition against platelet aggregation based on the compound.

EFFECT: obtained is novel compound and based on its pharmaceutical composition, which can be applied in medicine for production of medication for prevention or treatment of diseases of cardiac and cerebral vessels, such as coronary syndromes, myocardial infarction and myocardial ischemia, caused by aggregation of platelets.

13 cl, 3 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound, represented by the following formula

,

or its pharmaceutically acceptable salt. In claimed formula each symbol has values, determined in formula of invention. Versions of formula [I] compound and particular compounds are also objects of invention. In addition, invention relates to pharmaceutical composition, ITK inhibitor and means for treatment or prevention of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection and other diseases and methods of treating said diseases.

EFFECT: claimed compounds inhibit induced T-cellular kinase (ITK).

32 cl, 86 tbl, 387 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a novel compound of formula

(I)

or its pharmaceutically acceptable salt, possessing properties of the IKKβ and TNFα inhibitor. The compound can be used with an additional therapeutic agent, selected from vincristine, camptothecin hydrochloride (CPT-11), lefunomid, dexamethasone and TNFα. Preferable are compounds of formula (I), corresponding to 2-{5-chloro-2-[(1R,2R)-2-hydroxycyclopentylamino]pyrimidin-4-yl}-N-cyclopropyl-1H-indole-4-carboxamide and 2-{5-chloro-2-[(1R,2S)-2-hydroxycyclopentylamino]pyrimidin-4-yl}-N-cyclopropyl-1H-indole-4-carboxamide.

EFFECT: compound can be applied in the treatment of inflammatory diseases such as rheumatoid arthritis, chronic obstructive lung disease, bronchial asthma, multiple sclerosis and intestinal inflammatory diseases, or cancer diseases, such as multiple myeloma, colon cancer, pancreas cancer and ovary cancer, by IKKβ inhibition.

30 cl, 4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) such as below, or to their pharmaceutically acceptable salts, wherein R1 means H, C1-8alkyl morpholinyl, haloC1-8alkylamino, C1-8alkyloxadiazolyl, hydroxyl, halopyrrolidinyl, azetidinyl, C1-8alkylamino, amino, cyano C1-8alkylamino, halophenylC1-8alkylamino or cyanoC3-8cycloalkylamino; R2, R3, R4, R5 and R6 independently mean H, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkyloxy, halogen, hydroxyl, cyanopyrazinyloxy, halogen, hydroxyl, cyanopyrazinyloxy, pyrazolyl, C1-8alkylpyrazolyl, imidazolyl, benzimidazolyl, 6-oxo-6H-piridazinyl, C1-8alkyl-6-oxo-6H-pyridazinyl, piperazinyl, N-C1-8alkylpiperazinyl, piperidinyl, difluoropyrrolidinyl, phenylimidazolyl, oxo-pyrrolidinyl, oxo-oxazolidinyl, morpholinyl, oxo-morpholinyl, oxo-pyridinyl, 2-oxo-2H-pyrazinyl, difluoropiperidinyl, haloC1-8alkylpiperidinyl, piperidinylC1-8alkoxy, oxetanyloxy, C1-8alkylpyrazolyl, halopyridinyl, C1-8alkylpyridinyl, C3-8cycloalkyl, C3-8 cycloalkylC1-8alkyl, halophanyl, C1-8alkylcarbonylamino-C3-8-cycloalkyl-C1-8alkyl, haloC1-8alkylpiperazinyl, C1-8alkylamino, C1-8alkoxy-C1-8alkylpiperazinyl, C3-8cycloalkylpiperazinyl, hexahydropyrrolo[1,2-a]pyrazinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, C1-8alkylimidazolyl, azetidinyl, C3-8cycloalkylpiperazinyl, C1-8alkylimidazolyl, C1-8alkoxy C1-8alkoxy, imidazo[4,5-c]pyridinyl, C1-8alkylpiperazinyl, hexahydro-pyrrolo[1,2-a]pyrazinyl, haloazetidinyl, pyrimidinyl and C2-8alkenyloxy; A1 means -CH2-, carbonyl, -C(O)O- or is absence; A2 means N, CR7; A3 means N, CR8; A4 means N, CR9; R7 means H, C1-8alkyl, haloC1-8alkyl, halogen, hydroxyl, haloC1-8alkylaminocarbonyl; halophenylC1-8alkylaminocarbonyl, phenyl-C3-8-cycloalkylaminocarbonyl, haloC1-8alkylphenylC1-8alkylaminocarbonyl, halophenylC3-8 cycloalkylaminocarbonyl, halophenylC3-8cycloalkylC1-8alkylaminocarbonyl; R8 means H, C1-8alkyl, haloC1-8alkyl, halogen or hydroxyl; or R7 and R8 together with a carbon atom they are attached to, form C3-8cycloalkyl or substituted pyrrolidine, wherein substituted pyrrolidine represents pyrrolidine, N-substituted haloC1-8alkyl or formyl; R9 means H, C1-8alkyl, haloC1-8alkyl, halogen or nitro; or R8 and R9 together with a carbon atom they are attached to, form C3-8cycloalkyl; or its pharmaceutically acceptable salt

EFFECT: compounds inhibit the enzyme catepsin that enables using them in pharmaceutical compositions.

27 cl, 8 dwg, 1 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a chemical compound of formula wherein R=benzyl and to an antituberculous therapeutic agent representing a composition of imidazo[1,2-b][1,2,4,5]tetrazine derivative of formula I, wherein R=benzyl, isopropyl or phenyl and the known antituberculous preparation pyrazinamide with the ingredients in mole ratio 1:1.

EFFECT: there are prepared new antituberculous therapeutic agents.

2 cl, 2 tbl, 6 ex

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A represents CRaRb or -CH2-CH2-; R1 represents hydrogen or alkyl; R2 represents hydrogen or alkyl; R3 represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, 1H-pyrazolyl or substituted 1H-pyrazolyl, wherein substituted aryl represents aryl substituted by 1-3 substitutes independently specified in alkyl, halogen and halogenalkyl, and wherein substituted 1H-pyrazolyl represents 1H-pyrazolyl substituted by 1-3 substitutes independently specified in alkyl and aryl; Ra represents hydrogen or methyl; Rb represents hydrogen or methyl; or Ra and Rb together with a carbon atom, to which they are attached, form cyclopropyl, cyclobutyl or cyclopentyl; provided Ra and Rb both represent hydrogen, or both represent methyl simultaneously, R3 represents (1-methylcyclopropyl)methyl, which possess the inhibitory action on 11b-HSD1.

EFFECT: preparing the compounds, which possess the inhibitory action on 11b-HSD1.

15 cl, 1 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to application of 2-R1-4-R2-6-polynitromethyl-1,3,5-triazines of general formula: , where n=0, X=NO2, Cl, Br, R1=R2=OR3, OAr (R3=CH3, C2H5, CH2(CH2)6CH3, CH2CH2Cl, Ar=metha-C6H4CH3), R1=OR3, OAr, R2=N(C2H5)2; n=1, X=Cl, R1=OR3, R2=NH(CH2)2NH2, N(CH2CH2)2NCH3 as compounds, which possess antibacterial activity.

EFFECT: identification of compounds based on 1,3,5-triazine derivatives, which possess high antibacterial activity.

3 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to mixture of E- and Z-isomers of (4-bromophenyl)ethylidene hydrazide of 2-[6-methyl-1-(thiethan-3-yl)uracyl-3-yl]acetic acid in molar ratio 3.5:1 of general formula: .

EFFECT: obtained is novel mixture of isomers, demonstrating hypotensive activity.

2 cl, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I):

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

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