Method of producing abacavir

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing abacavir of formula (I) or pharmaceutically acceptable salt thereof, involving reaction of a compound of formula (II), (I) (II), where R denotes H or (C1-C4)-alkyl radical with an inorganic base such as an alkali metal hydroxide in a mixture of (C1-C6)-alcohol and water; and extraction of abacavir of formula (I) in form of a free base or in form of a pharmaceutically acceptable salt by treating said free base with a corresponding acid.

EFFECT: method ensures high degree of conversion without racemation, enables to minimise formation of impurities and considerably shortens reaction time.

19 cl, 10 ex

 

The invention relates to a method for producing active pharmaceutical ingredient, known as ABC. The method is based on the removal of the protective group of N-2-hazelbaker using certain basic conditions.

The level of technology

Abacavir - international nonproprietary name (INN) {(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl]cyclopent-2-enyl}methanol, CAS # 136470-78-5. Abacavir sulfate is an active selective inhibitor of HIV-1 and HIV-2 and can be used to treat infection with human immunodeficiency virus (HIV).

Structure hemisulfate salt abacavir corresponds to the formula (I):

EP 434450-A reveals some 9-substituted 2-aminopurine, including abacavir and its salts, processes for their preparation and pharmaceutical compositions utilizing these compounds.

In this area there are different ways of receiving abacavir. Some of them get abacavir, on the basis of the appropriate pyrimidine compound, condensing it with chromodoris residue with subsequent cyclization with the formation of the imidazole ring and the completion of entering cyclopropylamino in position 6 of the purine ring.

Pyrimidine compounds, for which it is established that they are suitable as intermediates of the above methods of preparation, including the Ute intermediates N-2-acylated abacavir, such as N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}ndimethylacetamide or N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide. Remove aminosidine group data connections using acidic conditions known in this field. According to example 28 EP 434450-aminosidine group N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide removed by stirring with 1N chloroethanol acid for 2 days at room temperature. The basis of abacavir after adjusting pH to 7.0 and evaporation of the solvent, ultimately, are triturating and chromatographytandem. Then the reaction with the acid being converted into an appropriate salt of abacavir. The main disadvantages of this method are: (i) the use of substantially causing corrosion of mineral acid to remove aminosidine group; (ii) the need for a strong degree of cultivation; (iii) long reaction time required for completion of the reaction; (iv) the need to allocate the free abacavir; and (v) complex chromatographic purification method.

Thus, despite the proposal set forth in the document of the prior art, the exploration of new ways to remove protection N-acylated {(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-p is Rin-9-yl]cyclopent-2-enyl}methanol still represents an important area, since the industrial application of known how difficult that described above. Thus, the present invention describes a new method of removing aminosidine N-acylated {(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl]cyclopent-2-enyl}methanol.

The invention

The inventors have found that removing aminosidine group N-2-acylated {(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl]cyclopent-2-enyl}methanol using a base in a mixture of water and alcohol is very rapid, and the product can be obtained with high yield and with high purity, as there is no significant formation of by-products compared with the method known in this field.

Thus, the present invention relates to the creation of a method of receiving abacavir formula (I) or its pharmaceutically acceptable salt or solvate, which includes the interaction of the compounds of formula (II) with an inorganic base in a mixture (C1-C6)-alcohol and water, where R represents H or (C1-C4)-alkyl radical.

Among providing the greatest advantage of the features of the process of the present invention may be mentioned the following: (i) the hydrolysis is carried out in these basic conditions, the more effect the veins; (ii) it requires less reaction time, because the reaction conditions of the method according to the invention allows to carry out the hydrolysis at higher temperatures; (iii) less the formation of impurities in the reaction conditions of the present invention, the hydrolysis takes place with low by-product formation even at high temperatures, on the contrary, when using acidic conditions, there is rapid decomposition of the product during heating; (iv) the reaction volume is optimized taking into account the fact that the hydrolysis can be conducted at high concentrations; (v) the reaction proceeds without racemization; (vi) abacavir or its salts can easily be distinguished and clear and (vii) receive high outputs.

Detailed description of the invention

As described above, abacavir can be obtained by hydrolysis in basic conditions of the compounds of formula (II) using inorganic bases. In preferred embodiments, the implementation of the compounds of formula (II) are compounds where R represents H, methyl or isopropyl. In a more preferred embodiment, the compound of formula (II) is N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide (compound of formula (II), where R=isopropyl).

Preferably the base is a hydroxide of an alkali metal, such as hydroc the ID of lithium, sodium or potassium. The most preferred alkali metal hydroxide is sodium hydroxide. Preferably the use of a number of inorganic bases in the range from 0.1 to 10 mol of base per mole of starting material of the formula (II). More preferably the amount of base in the range from 1 to 5 mol of base per mole of starting material.

The hydrolysis is carried out in a mixture of water and alcohol, such as ethanol, n-propanol, isopropanol, n-butanol, Isobutanol or tert-butanol. Preferably the solvent system is a mixture of isopropanol and water. Usually the amount of solvent is in the range from 1 to 15 ml/g of starting material. Preferably from 2 to 10 ml/g Similarly, the amount of water is usually in the range of 1-15 ml/g of starting material. Preferably from 1 to 10 ml/year

The reaction is preferably carried out at a temperature in the range from room temperature to the boiling point of the used solvent. In a preferred embodiment, the reaction is carried out at a temperature in the range from 50°C to the boiling point of the mixture. Thus, this provides the advantage, because suddenly the reaction time is greatly reduced at these temperatures and at the same time, there is no significant formation of by-products. In a more preferred options the ante implementation the reaction is carried out at the boiling temperature of the mixture.

Abacavir can be isolated from the reaction medium in the form of a pharmaceutically acceptable salt, preferably hemisulfate salt, separating the aqueous phase and the precipitation of salts of abacavir from the organic phase by adding the appropriate number of corresponding pharmaceutically acceptable salts. Optionally, the second solvent can be added before the separation of the aqueous phase. Examples of suitable solvents include simple aliphatic (C2-C8)-esters, such as ethyl simple ether, isopropyl simple ether, tert-butylmethylamine simple ether, di-n-butyl simple ether or tetrahydrofuran, aromatic (C6-C8)-hydrocarbons, such as toluene or xylene, or chlorinated solvents such as chloroform or methylene chloride. Optionally, the organic phase may be washed with aqueous sodium hydroxide or aqueous solution of the other inorganic bases before adding a pharmaceutically acceptable acid. Higher yields can be obtained when the salt of abacavir are separated from the solvent in an anhydrous environment. For example, water can be removed by azeotropic distillation or by evaporation to dryness and then adding a suitable solvent to precipitate the salt of abacavir.

Hemisulfate salt {(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl]cyclopent-2-enyl}met the Nola is a salt, formed {(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl]cyclopent-2-enyl}methanol and sulfuric acid in a stoichiometric ratio of 2:1.

Alternatively, abacavir can be isolated from the reaction medium in the form of a free base by crystallization. For carrying out the crystallization solvent can be replaced by another. A suitable solvent system for crystallization represents, for example, (C2-C6)-alcohols, such as ethanol, n-propanol, isopropanol, n-butanol, Isobutanol or tert-butanol, (C3-C9)-ketones, such as acetone, methyl isobutyl ketone or methyl ethyl ketone, simple aliphatic (C2-C8)-esters, such as ethyl simple ether, isopropyl simple ether, tert-butylmethylamine simple ether, di-n-butyl simple ether or tetrahydrofuran complex (C2-C10)-esters, such as ethyl acetate, acetonitrile or a mixture called. The preferred system of solvents are acetone, acetonitrile, ethyl acetate, isopropanol or a mixture of isopropanol/tert-butylmethylether simple ether. Optionally, the organic phase may be washed with aqueous sodium hydroxide or aqueous solution of the other inorganic bases before the crystallization of abacavir in the form of free base.

Abacavir can also be isolated from the reaction is Reda in the form of a free base, optional, by adding a solvent selected from simple aliphatic (C2-C8)-ethers and aromatic (C6-C8)-hydrocarbons, the separation of the aqueous phase, optionally, removing the remaining water and crystallization of the ABC formula (I) in the form of the free base in a suitable solvent system. Preferably, the system solvent for crystallization is selected from the systems mentioned above. Optionally, the organic phase may be washed with aqueous sodium hydroxide or aqueous solution of the other inorganic bases before the crystallization of abacavir in the form of free base.

When it is desirable pharmaceutically acceptable salt, it can also be obtained from the base of abacavir treatment of the corresponding acid. The preferred salt is hemisulfate salt of abacavir.

The most suitable conditions for the implementation of this method vary depending on parameters taken into account by the person skilled in the art, such as, for example, the concentration of the reaction mixture, the temperature, the solvent used during the reaction and separating the product, and the like. They can be easily identified by the specified person skilled in the art using the ideas shown in the examples in this description.

In the description of the claims, the word “includes” and variants of this word does not imply the exclusion of other technical features, additives, components or steps. Summary this proposal has been incorporated into it by reference. Additional objectives, advantages and features of the invention will be obvious to experts in this field when reading the description or will be apparent in the implementation in practice of the invention. The following examples are given for illustration and not intended as limitations of the present invention.

Examples

Example 1: getting the ABC of hemisulfate

N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide (6,56 g, is 18.40 mmol) suspended in a mixture of isopropanol (32,8 ml) and 10% NaOH solution (36,1 ml, 92.0 mmol). The mixture was heated at a temperature of phlegmy within 1 h the resulting solution was cooled to 20-25°C and was added tert-butylmethylamine simple ether (32,8 ml). The layers were separated and was added dropwise 96% H2SO4(and 0.61 ml, 11,03 mmol) to the organic layer. This mixture was cooled to 0-5°C and the resulting suspension was filtered. The solid product was dried in vacuum at 40°C. was Obtained ABC of hemisulfate (5,98 g, 97%) as a white powder.

Example 2: obtain the ABC of hemisulfate

N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide (6,56 g, is 18.40 mmol) suspended in a mixture of isopropanol (32,8 ml) and 10% NaOH solution (36,1 ml, 92.0 mmol). The mixture was heated at the rate which the atur of phlegmy within 1 hour The resulting solution was cooled to 20-25°C and was added toluene (32,8 ml). The layers were separated and was added dropwise 96% H2SO4(and 0.61 ml, 11,03 mmol) to the organic layer. This mixture was cooled to 0-5°C and the resulting suspension was filtered. The solid product was dried in vacuum at 40°C. was Obtained ABC of hemisulfate (5,42 g, 88%) as a white powder.

Example 3: obtaining the ABC of hemisulfate

To a solution of N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide (1.0 g, 2,80 mmol) in isopropanol (10 ml) was added 10% NaOH solution (5.5 ml, 14,03 mmol). The mixture was heated at a temperature of phlegmy within 1 h the resulting solution was cooled to 20-25°C and the aqueous layer was separated. To the organic layer was added dropwise 96% H2SO4(0,07 ml, 1,22 mmol). The mixture was concentrated to half volume and the salt was filtered. To the resulting solution was added dropwise 96% H2SO4(0,07 ml, 1,22 mmol) and cooled to 0-5°C. the Solid product was filtered and dried in vacuum at 40°C. was Obtained ABC of hemisulfate (0.56 g, 60%) as a white powder.

Example 4: get abacavir of hemisulfate

N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide (5.0 g, 14,03 mmol) suspended in a mixture of isopropanol (25 ml) and 10% NaOH solution (27.5 ml, 70,1 mmol). The mixture was heated at a temperature of phlegm is within 1 hour The resulting solution was cooled to 20-25°C and the aqueous solution was discarded. The organic layer was concentrated to dryness. Added isopropanol (10 ml), and additionally double-evaporated (concentrated) to dryness. To this residue was added isopropanol (25 ml) and the salt was filtered. To the resulting solution was added dropwise 96% H2SO4(of 0.39 ml, 7.0 mmol). This mixture was cooled to 0-5°C and the resulting suspension was filtered. The solid product was dried in vacuum at 40°C. was Obtained ABC of hemisulfate (3.7 g, 79%) as a white powder.

Example 5: Receiving abacavir of hemisulfate

A mixture of N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide (10 g, 28 mmol), isopropanol (100 ml) and 10% NaOH solution (to 16.8 ml, 42 mmol) was heated at a temperature of phlegmy within 1 h the resulting solution was cooled to 20-25°C and washed several times with 25% NaOH solution (10 ml). Wet organic layer was neutralized to pH 7,0-7,5 to 17% chloroethanol acid and concentrated to dryness in vacuo. The residue was dissolved in isopropanol (100 ml) and the salt was filtered. To the filtrate was added dropwise 96% H2SO4(0,78 ml, 14.0 mmol). This mixture was cooled to 0-5°C and the precipitate was filtered and dried under vacuum at 40°C, receiving 15.0 g (80%) of the ABC of hemisulfate in the form of a white powder.

Example 6: get abacavir

N-{6-cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide (1.0 g, 2,80 mmol) suspended in a mixture of isopropanol (2 ml) and 10% NaOH solution (1.1 ml, 2,80 mmol). The mixture was heated at a temperature of phlegmy within 1 h the resulting solution was cooled to 20-25°C and was added tert-butylmethylamine simple ether (2 ml). The aqueous layer was discarded, the organic phase was cooled to 0-5°C and the resulting suspension was filtered. The solid product was dried in vacuum at 40°C. Abacavir (0,62 g, 77%) was obtained as a white powder.

Example 7: get abacavir

N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide (1,25 g, 3,51 mmol) suspended in a mixture of isopropanol (2.5 ml) and 10% NaOH solution (to 1.37 ml, 3,51 mmol). The mixture was heated at a temperature of phlegmy for 1 h and concentrated to dryness. The residue was led from acetone. Abacavir (0,47 g, 47%) was obtained as a white powder.

Example 8: get abacavir

N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide (1,25 g, 3,51 mmol) suspended in a mixture of isopropanol (2.5 ml) and 10% NaOH solution (to 1.37 ml, 3,51 mmol). The mixture was heated at a temperature of phlegmy for 1 h and concentrated to dryness. The residue was led from acetonitrile. Abacavir (0,43 g, 43%) was obtained as a white powder.

Example 9: Getting abacavir

A mixture of N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}from butyramide (10 g, 28 mmol), isopropanol (100 ml) and 10% NaOH solution (to 16.8 ml, 42 mmol) was heated at a temperature of phlegmy within 1 h the resulting solution was cooled to 20-25°C and repeatedly washed with 25% NaOH solution (10 ml). Wet organic layer was neutralized to pH 7,0-7,5 to 17% chloroethanol acid and concentrated in vacuum to dryness. The residue was led from ethyl acetate (150 ml), receiving abacavir (7.2 g, 90%).

Example 10: Getting abacavir

A mixture of N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide (10 g, 28 mmol), isopropanol (100 ml) and 10% NaOH solution (to 16.8 ml, 42 mmol) was heated at a temperature of phlegmy within 1 h the resulting solution was cooled to 20-25°C and repeatedly washed with 25% NaOH solution (10 ml). Wet organic layer was neutralized to pH 7,0-7,5 to 17% chloroethanol acid and concentrated in vacuum to dryness. The residue was led from acetone (300 ml), receiving abacavir (7.0 g, 88%).

1. How to obtain abacavir formula (I) or its pharmaceutically acceptable salts, including (a) the interaction of the compounds of formula (II),

where R represents H or (C1-C4)-alkyl radical with an inorganic base such as alkali metal hydroxide in the mixture (C1-C6)-alcohol and water; and (b) the allocation of abacavir formula (I) VI is e free base or as pharmaceutically acceptable salts by means of: processing the specified free base corresponding acid or processing allocated in the form of the free base corresponding abacavir the acid.

2. The method according to claim 1, where R in the compound of formula (II) represents isopropyl.

3. The method according to claim 2, where the alkali metal hydroxide is a hydroxide of sodium.

4. The method according to claim 3, where (C1-C6)alcohol is a isopropanol.

5. The method according to claim 1, where the reaction is carried out at a temperature that is included in the range from 50°C to the boiling point of the mixture.

6. The method according to claim 1, where the ABC (I) is isolated in the form of a salt, and the allocation method (b) includes: (i) adding a solvent selected from the group consisting of aliphatic simple (C2-C8)-ethers, aromatic (C6-C8)-hydrocarbons and chlorinated solvents such as chloroform or methylene chloride; (ii) separating the aqueous phase; (iii) conducting at least one washing with an aqueous solution of an inorganic base such as alkali metal hydroxide; (iv) removing the remaining water; and (v) deposition pharmaceutically acceptable salt from the organic phase by adding the corresponding pharmaceutically acceptable acid.

7. The method according to claim 6, where the specified salt of abacavir (I) represents hemisulfate salt.

8. The method according to claim 1, where the ABC formula (I) is isolated in the form of free base, and the allocation method (b) involves the crystallization of abacavir (I) in the form of a free base of suitable systems of the solvent, selected from the group comprising (C2-C6)-alcohols, (C3-C9)-ketones, simple aliphatic (C2-C8)-esters, complex (C2-C10)-ethers, acetonitrile or mixtures thereof; and, if necessary, processing the received connection pharmaceutically acceptable acid with formation of the corresponding salt.

9. The method of claim 8, where the ABC formula (I) is isolated in the form of free base, and the allocation method (b) involves the crystallization of abacavir (I) in the form of a free base of a suitable solvent system selected from the group comprising tert-butylmethylamine simple ether, acetone, acetonitrile and ethyl acetate; and, if necessary, processing the received connection pharmaceutically acceptable acid with formation of the corresponding salt.

10. The method according to claim 1, where the ABC (I) is isolated in the form of free base, and the allocation method (b) includes: (i) adding a solvent selected from the group consisting of aliphatic simple (C2-C8)-ethers and aromatic (C6-C8)-hydrocarbons; (ii) separating the aqueous phase; (iii) conducting at least one washing with an aqueous solution of an inorganic base; (iv) removing the remaining water; and (v) the crystallization of abacavir (I) in the form of a free base of a suitable solvent system selected from the group comprising(C 2-C6)-alcohols, (C3-C9)-ketones, simple aliphatic (C2-C8)-esters, complex (C2-C10)-ethers, acetonitrile or mixtures thereof; and, if necessary, processing obtained at stage (v) compounds pharmaceutically acceptable acid with formation of the corresponding salt.

11. The method of claim 8, where the system solvent for crystallization of the free base of abacavir selected from the group consisting of acetone, acetonitrile, ethyl acetate, isopropanol and mixtures of isopropanol/tert-butylmethylether simple ether.

12. The method according to claim 1, where the base is a sodium hydroxide, a R in the compound of formula (II) represents isopropyl.

13. The method according to item 12, abacavir where (I) is isolated in the form of a salt, and (b) the selection includes: (i) adding a solvent selected from the group consisting of aliphatic simple (C2-C8)-ethers, aromatic (C6-C8)-hydrocarbons and chlorinated solvents selected from the group comprising chloroform and methylene chloride; (ii) separating the aqueous phase; (iii) conducting at least one washing with an aqueous solution of an inorganic base; (iv) removing the remaining water; and (v) deposition pharmaceutically acceptable salt from the organic phase by adding the corresponding pharmaceutically acceptable acid.

14. Spasibo para.12, where abacavir formula (I) is isolated in the form of free base, and the allocation method (b) involves the crystallization of abacavir (I) in the form of a free base of a suitable solvent system selected from the group comprising (C2-C6)-alcohols, (C3-C9)-ketones, simple aliphatic (C2-C8)-esters, complex (C2-C10)-ethers, acetonitrile or mixtures thereof; and, if necessary, processing the received connection pharmaceutically acceptable acid with formation of the corresponding salt.

15. The method according to item 12, abacavir where (I) is isolated in the form of free base, and the allocation method (b) includes: (i) adding a solvent selected from the group consisting of aliphatic simple (C2-C8)-ethers, aromatic (C6-C8)-hydrocarbons; (ii) separating the aqueous phase; (iii) conducting at least one washing with an aqueous solution of an inorganic base; (iv) removing the remaining water; and (v) the crystallization of abacavir (I) in the form of a free base of a suitable solvent system selected from the group comprising (C2-C6)-alcohols, (C3-C9)-ketones, simple aliphatic (C2-C8)-esters, complex (C2-C10)-ethers, acetonitrile or mixtures thereof; and, if necessary, processing the compounds obtained in stage (v) pharmaceutically acceptable the second acid with formation of the corresponding salt.

16. The method according to claim 10, where the system solvent for crystallization of the free base of abacavir selected from the group consisting of acetone, acetonitrile, ethyl acetate, isopropanol and mixtures of isopropanol/tert-butylmethylether simple ether.

17. The method according to claim 1, where the base is a hydroxide of sodium, R in the compound of formula (II) represents isopropyl, and (C1-C6-alcohol is a isopropanol.

18. The method according to claim 1, where the ABC (I) is isolated in the form of a salt, and (b) the selection includes: (i) adding a solvent selected from the group consisting of aliphatic simple (C2-C8)-ethers, aromatic (C6-C8)-hydrocarbons and chlorinated solvents selected from the group comprising chloroform or methylene chloride; (ii) separating the aqueous phase; and (iii) deposition pharmaceutically acceptable salt from the organic phase by adding the corresponding pharmaceutically acceptable acid.

19. The method according to item 12, abacavir where (I) is isolated in the form of a salt, and (b) the selection includes: (i) adding a solvent selected from the group consisting of aliphatic simple (C2-C8)-ethers, aromatic (C6-C8)-hydrocarbons and chlorinated solvents selected from the group comprising chloroform or methylene chloride; (ii) the Department of water f is s; and (iii) deposition pharmaceutically acceptable salt from the organic phase by adding the corresponding pharmaceutically acceptable acid.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I in free form or in form of pharmaceutically acceptable salt, which possess properties of adenosine receptor A2A agonists. In formula I , R1 represents (C1-C8)alkylcarbonyl, (C3-C8)cycloalkylcarbonyl, -SO2(C1-C8)alkyl, phenyl(C1-C4)alkylcarbonyl or -(C=O)-C(=O)-NH(C1-C8)alkyl, optionally substituted with R4; R2 represents H or (C1-C8)alkyl, optionally substituted with (C6-C10)aryl; R3 represents halogen or(C2-C8)alkinyl, or R3 stands for aminogroup, optionally substituted with (C3-C8)cycloalkyl, optionally substituted with amino, or R3 represents (C1-C8)alkylaminogroup, optionally substituted with hydroxy, phenyl or R5, or R3 stands for R6, optionally substituted with amino or -NH-C(=O)-NH-R7, or R3 stands for -NH-R6, optionally substituted with -NH-C(=O)-NH-R7, or R3 stands for (C1-C8)alkylaminocarbonyl, optionally substituted with. -NH-C(=O)-NH-R8; R4, R5 and R6 represent independently 5- or 6-member heterocyclic ring, which contains one-two N ring heteroatoms, optionally substituted with amino or (C1-C8)alkyl; and R7 and R8 represent independently 5- or 6-member heterocyclic ring, which contains one-two ring heteroatoms selected from N and S, and is optionally substitutedf with halogen, (C1-C8)alkylsulfonyl or 5- or 6-member aromatic heterocyclic ring, which contains one N ring heteroatom. Invention also relates to pharmaceutical composition and to application of said compounds for treatment of states, mediated by activation of adenosine receptor A2A.

EFFECT: obtaining composition, which possesses properties of adenosine receptor A2A agonists.

10 cl, 3 tbl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel purine derivatives of general formula I in free form or in form of a pharmaceutically acceptable salt which have A2A agonist properties. In formula I , R1 denotes a N-bonded 5-6-member heterocyclic group containing 1-4 nitrogen atoms in the ring, which can be optionally substituted with oxo, phenyl or C1-8-alkyl, optionally substituted with hydroxy; R2 is hydrogen or C1-C8-alkyl, optionally substituted with hydroxy or 1-2 phenyls possibly substituted with hydroxy or C1-C8-alkoxy; R3 is C2-C8-alkynyl or C1-C8-alkoxycarbonyl, or R3 is amino substituted with C3-C8-cycloalkyl, optionally substituted with amino, hydroxy, benzyloxy or NH-C(=O)-NH-R6, or R3 is amino substituted with R4, -R4-benzyl or C5-C10-mono- or bicarbocyclic group, optionally substituted with hydroxy or C1-C8-alkoxycarbonyl, or R3 is aminocarbonyl optionally substituted with R5, or R3 is C1-C8-alkylamino optionally substituted with hydroxy, R5, NH-C(=O)-C1-C8-alkyl, -MH-SO2-C1-C8-alkyl, -NH-C(=O)-NH-R6 or phenyl, optionally substituted with phenyloxy, or R3 is a N-bonded 5-member heterocyclic group containing 1 nitrogen atom in the ring which may optionally be substituted with amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino and other groups.

EFFECT: compounds can be useful in treating conditions mediated by activation of the adenosine A2A receptor, especially inflammatory or obstructive respiratory tract diseases.

9 cl, 5 tbl, 161 ex

FIELD: organic chemistry, heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new compounds - purine derivatives of the general formula (I): in free form or salt wherein X means oxygen or sulfur atom or group NR5; R1 means alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group that can be substituted optionally with hydroxy-, carboxy-group or alkoxycarbonyl; or if X means NR5 then R1 can mean alternatively heterocyclic group taken among benzylpiperidyl or the formula: ; or group of the formula (II): ; R2 means hydrogen atom, alkyl or alkoxy-group; R3 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, alkoxycarbonyl, -N(R9)R10, (C1-C4)-alkylene-SO2N(R11)R12 or -CON(R13)R14; or if two substitutes R2 and R3 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-10 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen and sulfur atom; R4 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, -SO2N(R11)R12, -N(R9)R10 or -CON(R13)R14; or if two substitutes R3 and R4 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen or sulfur atom; R5 means hydrogen atom or alkyl; R6, R7 and R8 mean hydrogen atom, or one of these radicals means -SO2NH2, -N(CH3)COCH3, -CONH2 and two others mean hydrogen atom; R9 means hydrogen atom or alkyl; R10 means hydrogen atom, -COR15 wherein R15 means alkyl, alkoxy-group; or R9 and R10 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R11 means hydrogen atom or alkyl; R12 means hydrogen atom, alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl; or R11 and R12 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R13 and R14 each and independently of one another means hydrogen atom or alkyl with exception of 2-(para-n-butylanilino)-6-methoxypurine, 2-(para-n-butylanilino)-6-(methylthio)purine, 2,6-di-(phenylamino)-purine, 2,6-di-(para-tolylamino)-purine and 2-(para-tolylamino)-6-(phenylamino)-purine.

EFFECT: valuable biochemical properties of compounds.

11 cl, 4 tbl, 221 ex

The invention relates to novel 2,6,9-triple-substituted purine derivative of General formula I, having the effect of selective inhibitors of kinases of the cell cycle, which can be used, for example, for the treatment of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes type I, multiple sclerosis, and for the treatment of cancer, cardiovascular diseases such as restenosis, etc

The invention relates to new compounds of General formula I

< / BR>
where R is chosen from the group comprising R2, R2NH - or R3R4N-R5-, where R2selected from the group including9-C12-alkyl,

< / BR>
and

< / BR>
where each R6independently selected from the group including hydrogen, C3-C8-cycloalkyl,1-C4-alkyl and (CH2)m-phenyl, where m = integer 0-8; x = 1-8 integer; n = 0-8 integer; z is chosen from the group comprising phenyl, heterocycle, cycloalkyl and naphthalene, and M is chosen from the group comprising hydrogen, C1-C4-alkyl,

< / BR>
and

< / BR>
where each R6' are independently selected from the group including hydrogen, C3-C8-cycloalkyl,1-C4-alkyl and (CH2)m-phenyl, where m' = integer 0-8; n' = integer 0-8; x' = 1-8 integer; Q is hydrogen or C1-C4-alkyl, and Z' is chosen from the group comprising phenyl, heterozygote selected from the group including D, E,

< / BR>
and

< / BR>
where each D is independently selected from the group comprising trifluoromethyl, triptoreline and C1-C4-alkoxy; each E is independently selected from the group including Hal, HE and1-C8-alkyl; Z is chosen from the group comprising phenyl, cycloalkyl and naphthalene; each R6"is hydrogen, n = integer 0-8; x" = 1-8 integer, and M' is hydrogen, Z' may be optionally substituted by groups D', E', each D' is independently selected from the group comprising trifluoromethyl, triptoreline and C1-C4-alkoxy; each E' is independently selected from the group including Hal, HE and1-C8-alkyl; R3and R4selected from the group including hydrogen, C1-C4-alkyl and (CH2)y-phenyl, where y = 0-8 integer, provided that R3and R4both denote hydrogen; R5- C1-C8-alkylene and R1selected from the group including cyclopentyl, cyclopentenyl and isopropyl, and their pharmaceutically acceptable salts, optical isomers and hydrates, provided that when R2refers to a group

< / BR>
< / BR>
< / BR>
and

< / BR>
where D, b, R6", x", n", M' and Z" accept above values

the method of treatment of a patient with proliferative disorders by assigning the compounds I, the method of preventing apoptosis of nerve cells, ways of protecting nerve cells from apoptosis and destruction caused by antitumor agents, and pharmaceutical composition

The invention relates to new derivatives of purine of formula I, II, III and IV, pharmaceutical compositions and method of treatment of a pathological state characterized by thrombotic activity

The invention relates to new compounds of General formula I, in which R is selected from the group consisting of R2, R2NH or H2N-R3 where R2 is selected from the group consisting of C1-C8the alkyl and formula (II), where Z is selected from the group consisting of phenyl, heterocycle and cycloalkyl, each R4 independently represents hydrogen or C1-C4alkyl, and n is an integer equal to 1 to 8; where each1-C8alkyl, and Z optionally substituted by 1-3 substituents, which may be the same or different, selected from the group consisting of Hal, HE and1-C4of alkyl; R3 represents C1-C8alkylene; and R1 is selected from the group consisting of cyclopentyl and isopropyl, and their pharmaceutically acceptable salts, optical isomers and hydrates

The invention relates to a method for producing analogues of nucleosides dimethoxyaniline

FIELD: organic chemistry, heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new compounds - purine derivatives of the general formula (I): in free form or salt wherein X means oxygen or sulfur atom or group NR5; R1 means alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group that can be substituted optionally with hydroxy-, carboxy-group or alkoxycarbonyl; or if X means NR5 then R1 can mean alternatively heterocyclic group taken among benzylpiperidyl or the formula: ; or group of the formula (II): ; R2 means hydrogen atom, alkyl or alkoxy-group; R3 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, alkoxycarbonyl, -N(R9)R10, (C1-C4)-alkylene-SO2N(R11)R12 or -CON(R13)R14; or if two substitutes R2 and R3 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-10 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen and sulfur atom; R4 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, -SO2N(R11)R12, -N(R9)R10 or -CON(R13)R14; or if two substitutes R3 and R4 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen or sulfur atom; R5 means hydrogen atom or alkyl; R6, R7 and R8 mean hydrogen atom, or one of these radicals means -SO2NH2, -N(CH3)COCH3, -CONH2 and two others mean hydrogen atom; R9 means hydrogen atom or alkyl; R10 means hydrogen atom, -COR15 wherein R15 means alkyl, alkoxy-group; or R9 and R10 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R11 means hydrogen atom or alkyl; R12 means hydrogen atom, alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl; or R11 and R12 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R13 and R14 each and independently of one another means hydrogen atom or alkyl with exception of 2-(para-n-butylanilino)-6-methoxypurine, 2-(para-n-butylanilino)-6-(methylthio)purine, 2,6-di-(phenylamino)-purine, 2,6-di-(para-tolylamino)-purine and 2-(para-tolylamino)-6-(phenylamino)-purine.

EFFECT: valuable biochemical properties of compounds.

11 cl, 4 tbl, 221 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel purine derivatives of general formula I in free form or in form of a pharmaceutically acceptable salt which have A2A agonist properties. In formula I , R1 denotes a N-bonded 5-6-member heterocyclic group containing 1-4 nitrogen atoms in the ring, which can be optionally substituted with oxo, phenyl or C1-8-alkyl, optionally substituted with hydroxy; R2 is hydrogen or C1-C8-alkyl, optionally substituted with hydroxy or 1-2 phenyls possibly substituted with hydroxy or C1-C8-alkoxy; R3 is C2-C8-alkynyl or C1-C8-alkoxycarbonyl, or R3 is amino substituted with C3-C8-cycloalkyl, optionally substituted with amino, hydroxy, benzyloxy or NH-C(=O)-NH-R6, or R3 is amino substituted with R4, -R4-benzyl or C5-C10-mono- or bicarbocyclic group, optionally substituted with hydroxy or C1-C8-alkoxycarbonyl, or R3 is aminocarbonyl optionally substituted with R5, or R3 is C1-C8-alkylamino optionally substituted with hydroxy, R5, NH-C(=O)-C1-C8-alkyl, -MH-SO2-C1-C8-alkyl, -NH-C(=O)-NH-R6 or phenyl, optionally substituted with phenyloxy, or R3 is a N-bonded 5-member heterocyclic group containing 1 nitrogen atom in the ring which may optionally be substituted with amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino and other groups.

EFFECT: compounds can be useful in treating conditions mediated by activation of the adenosine A2A receptor, especially inflammatory or obstructive respiratory tract diseases.

9 cl, 5 tbl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I in free form or in form of pharmaceutically acceptable salt, which possess properties of adenosine receptor A2A agonists. In formula I , R1 represents (C1-C8)alkylcarbonyl, (C3-C8)cycloalkylcarbonyl, -SO2(C1-C8)alkyl, phenyl(C1-C4)alkylcarbonyl or -(C=O)-C(=O)-NH(C1-C8)alkyl, optionally substituted with R4; R2 represents H or (C1-C8)alkyl, optionally substituted with (C6-C10)aryl; R3 represents halogen or(C2-C8)alkinyl, or R3 stands for aminogroup, optionally substituted with (C3-C8)cycloalkyl, optionally substituted with amino, or R3 represents (C1-C8)alkylaminogroup, optionally substituted with hydroxy, phenyl or R5, or R3 stands for R6, optionally substituted with amino or -NH-C(=O)-NH-R7, or R3 stands for -NH-R6, optionally substituted with -NH-C(=O)-NH-R7, or R3 stands for (C1-C8)alkylaminocarbonyl, optionally substituted with. -NH-C(=O)-NH-R8; R4, R5 and R6 represent independently 5- or 6-member heterocyclic ring, which contains one-two N ring heteroatoms, optionally substituted with amino or (C1-C8)alkyl; and R7 and R8 represent independently 5- or 6-member heterocyclic ring, which contains one-two ring heteroatoms selected from N and S, and is optionally substitutedf with halogen, (C1-C8)alkylsulfonyl or 5- or 6-member aromatic heterocyclic ring, which contains one N ring heteroatom. Invention also relates to pharmaceutical composition and to application of said compounds for treatment of states, mediated by activation of adenosine receptor A2A.

EFFECT: obtaining composition, which possesses properties of adenosine receptor A2A agonists.

10 cl, 3 tbl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing abacavir of formula (I) or pharmaceutically acceptable salt thereof, involving reaction of a compound of formula (II), (I) (II), where R denotes H or (C1-C4)-alkyl radical with an inorganic base such as an alkali metal hydroxide in a mixture of (C1-C6)-alcohol and water; and extraction of abacavir of formula (I) in form of a free base or in form of a pharmaceutically acceptable salt by treating said free base with a corresponding acid.

EFFECT: method ensures high degree of conversion without racemation, enables to minimise formation of impurities and considerably shortens reaction time.

19 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: nucleic base (e.g. uracil, cytosine, adenine, guanine, hypoxanthine, xanthine or similar) reacts with perfluoroalkyl halide in the presence of sulphoxide, peroxide and an iron compound to obtain a perfluoroalkyl-substituted nucleic base.

EFFECT: high cost effectiveness as an intermediate compound for producing medicinal agents.

15 cl, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing abacavir of formula (I) or salts or solvates thereof. Abacavir has strong HIV-1 and HIV-2 selective inhibitor activity and can be used in treating patients infected with HIV. The method involves i) closing the ring in a compound of formula (IV) by first reacting said compound (IV) with an anhydrous hydrochloric acid solution in (C1-C6)-alcohol, preferably isopropanol, and then with tri(C1-C4)-alkylorthoformate in anhydrous conditions to obtain a compound of formula (III), ii) reaction of the compound of formula (III) with cyclopropylamine to obtain a compound of formula (II) and iii) hydrolysis of the compound of formula (II) to obtain abacavir (I) or salt thereof. R1 denotes a (C1-C4)-alkyl radical, preferably isopropyl.

EFFECT: obtaining an end product with higher output and higher quality.

12 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new purine derivatives of formula (I) and to their pharmaceutically acceptable salts exhibiting the properties of adenosine receptor A2A agonists. The compounds can find application for preparing a drug for treating an inflammatory or obstructive respiratory disease. In formula

,

R1, R2 and R3 are those as specified in the patent claim.

EFFECT: preparing new purine derivatives of formula (I) or their pharmaceutically acceptable salts showing the properties of adenosine receptor A2A agonists.

8 cl, 2 tbl, 264 ex

Compounds // 2461559

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new purine derivatives possessing the properties of an inhibitor of the enzyme CDK specified in CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9. In formula (I): R1 and R2 each independently represents H, C1-6alkyl or C1-6halogenalkyl; R3 and R4 each independently represents H, C1-6-alkyl or C1-6-halogenalkyl; R5 represents C1-6-alkyl or C3-12-cycloalkyl, or C3-12-cycloalkyl-C1-6-alkyl each of which may be optionally substituted by one or more OH groups; R6 represents wherein Y represents N, X and Z represents CR9; R7, R8 and R9 optionally represent H, alkyl or C1-6-halogenalkyl; wherein at least one of R7 , R8 and R9 is other than H. The invention also refers to a pharmaceutical composition containing said compounds, using the compounds for treating alopecia, stroke, a proliferative disease, such as cancer, leukaemia, glomerulonephritis, rheumatoid arthritis, psoriasis, viral diseases, such as a disease caused by human cytomegalovirus, type 1 herpex simplex virus, type 1 human immunodeficiency virus, a neurodegenerative disease, a CNS disease, such as Alzheimer's disease.

EFFECT: preparing new purine derivatives possessing the properties of the inhibitor of the enzyme CDK.

30 cl, 8 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel purinyl derivatives of formula or , a stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, where n equals 0, 1, 2 or 3; X is O, S or NR', where R' is hydrogen or methyl; Y is cycloalkyl, phenyl, benzo[1,3]dioxolyl or pyridyl, where the cycloalkyl, phenyl, benzo[1,3]dioxolyl and pyridyl are possibly substituted with one substitute selected from a group consisting of halogen, trifluoromethyl, cyano, nitro and amine; R1 is hydrogen, alkyl or alkoxy-alkyl; and Het is a pyrazolyl group which is substituted twice or more with substitutes selected from a group consisting of alkyl, hydroxy-alkyl, halogen, trifluoromethyl, alkoxy-carbonyl and phenyl. The invention also relates to pharmaceutical compositions which are useful for treating or relieving symptoms of diseases and disorders associated with activity of potassium channels.

EFFECT: novel compounds which can be used as potassium channel modulators are obtained and described.

12 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(5-isopropoxy-1H-pyarazol-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine or pharmaceutically acceptable salt thereof, having inhibiting activity with respect to Trk (tropomyosin-related kinase). The compounds can be used as a medicinal agent for treating cancer. The invention also relates to use of said compound of pharmaceutically acceptable salt thereof to produce a medicinal agent for treating cancer in a warm-blooded animal and a pharmaceutical composition containing said compound or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, a solvent or an inert filler.

EFFECT: high efficiency of using the compound.

4 cl, 26 ex

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