Method of producing abacavir

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

 

The technical FIELD TO WHICH the INVENTION RELATES

The present invention relates to a method for producing active pharmaceutical ingredient, known as ABC. The method is based on the formation of the purine ring in the specific conditions.

The LEVEL of TECHNOLOGY

Abacavir is an International non-proprietary Name {(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl]cyclopent-2-enyl}methanol and has a CAS number 136470-78-5. The abacavir sulfate is a potent selective inhibitor of HIV-1 and HIV-2 and can be used in treating infected with human immunodeficiency virus (HIV).

Structure of salt hemisulfate abacavir represented by formula (I):

Patent document EP 434450-A reveals some 9-substituted-2-aminopurine, including abacavir and its salts, methods of its production and pharmaceutical compositions utilizing these compounds.

In the prior art there are known various methods of receiving abacavir. Some of them get abacavir, on the basis of the corresponding pyrimidine compounds through a process involving the interaction of the compounds or derived therefrom intermediate the connection with the remainder of similar sugar, cyclization for the formation of the imidazole ring and put the e cyclopropylamino 6 position of the purine ring.

The prior art describes several ways of carrying out the cyclization of the intermediate compounds of abacavir. According to patent document EP 434450-A cyclization of some intermediate compounds of abacavir, including the following intermediate compounds, where R is cyclopropylamine or chloride,

is carried out using formic acid or a reactive derivative of formic acid, optionally in the presence of co-solvent and a strong anhydrous acid, such as econsultancy acid. There is no specific example in which the cyclization is carried out in the presence of anhydrous acid. Example 27 illustrates the cyclization of (+)-(1R,4S)-CIS-N-[4-chloro-5-formamide-6-{[4-(hydroxymethyl)-2-cyclopenten-1-yl]amino}-2-pyrimidinyl]isobutyramide using triethylorthoformate and concentrated aqueous hydrochloric acid, thus the amino group in the 5 position of the pyrimidine hydrolyzed and the connection cyclists. The main disadvantage is the formation of several by-products that affect the yield and purity of the compounds.

Patent document EP 741710-A describes the cyclization of N-{2-amino-4-chloro-6-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enylamine]pyrimidine-5-yl}formamide with the following formula:

with COI is whether the same conditions, cyclization, as in the previous patent application, i.e. triethylorthoformate and concentrated hydrochloric acid.

The same authors of both patent applications claim in a later publication (cf. S.M. Daluge with co-workers,Nucleosides, Nucleotides &nucleic acids2000, vol.19, pp. 297-327)that cyclization of N-{2-amino-4-chloro-6-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enylamine]pyrimidine-5-yl}formamide proceeds smoothly in triethylorthoformate and concentrated aqueous hydrochloric acid, but it is not cyclized in utilitiarian with anhydrous acid, for example econsultancy acid, concentrated sulfuric acid or anhydrous chloroethanol acid. According to this document the rapid formation of cyclic compounds when using concentrated aqueous hydrochloric acid suggests that the conformation of the source material may be unfavorable for cyclization and that the addition of water destroys internal hydrogen bonds and facilitates the cyclization.

Patent document WO 2005/023811 describes the cyclization of [(1S,4R)-4-(2,5-diamino-6-chloropyrimidine-4-ylamino)cyclopent-2-enyl]methanol following formula

using triethylorthoformate and a catalytic amount of anhydrous or concentrated chloroethanol acid, carrying out the cyclization is preferably in aprotic non-polar will dissolve the Le. Unlike the source material of the above-mentioned patent applications, in this case, the amino group in the 2 and 5 positions unprotected.

Despite the disclosure of these documents prior art, develop new ways of cyclization of the intermediate compounds of abacavir, in particular, the intermediate compounds having protected acyl group of an amino group in the 2 and 5 positions of the pyrimidine is a still developing field, as known methods have low yields and purity, as noted above. Thus, it is desirable to create a new way cyclization of these intermediate compounds of abacavir to obtain purine structure.

The INVENTION

The authors of the present invention found that the cyclization of pyrimidine intermediate compounds of abacavir, N-{4-chloro-5-formamido-6-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enylamine]pyrimidine-2-yl}isobutyramide, proceeds with high yield and essentially without the formation of by-products, using a solution of anhydrous chloroethanol acid in isopropanol and triethylorthoformate in the absence of water. The method includes removing the formyl group at the 5-amino group of the pyrimidine by solvolysis in the absence of water and the cyclization of the compounds obtained using cyclisme agent, such as three is tritovores. It was unexpectedly found that in contrast to the limit for the prior art, the cyclization proceeds effectively using anhydrous acid. The presence of alcohol allows the unprotect/cyclization, avoiding the disadvantages of the known methods of forming purine ring with high yield and high purity.

Thus, the present invention relates to a method for the ABC formula (I) or its pharmaceutically acceptable salt, or their solvate,

includes stage circuit loop in the compound of formula (IV) by reaction of the compounds of the formula (IV) with a solution of anhydrous chloroethanol acid (C1-C6)-alcohol, and then with three(C1-C4)-alkalineforming in anhydrous conditions to obtain compounds of formula (III), where R1 represents a (C1-C4)-alkyl radical.

Among the remarkable primary features of the present invention can include the following: (i) cyclization carried out in these anhydrous conditions, a more efficient; (ii) reduced the formation of impurities in the reaction conditions of the present invention is the solvolysis with low formation of by-products; (iii) the absence of racemization; (iv) fewer ciclismo agent; and (v) is required of men is more time for reaction.

DETAILED description of the INVENTION

In a specific embodiment, the present invention is a method of obtaining abacavir (I) or its pharmaceutically acceptable salt, or their solvate includes a circuit loop in the compound of formula (IV), where R1=isopropyl, N-{4-chloro-5-formamido-6-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enylamine]pyrimidine-2-yl}isobutyramide with the formula (IVa).

In a preferred embodiment, the circuit loop in the compound of formula (IV) is accomplished by first interaction of the compounds of the formula (IV) with a solution of anhydrous chloroethanol acid in isopropanol to remove the formyl group at the amino group in the 5 position of the pyrimidine, and then triethylorthoformate.

Usually the solvolysis reaction for removing the protective group at the 5-amino group is carried out with excess chloroethanol acid. As a rule, use from 1 to 25 mol solution chloroethanol acid in alcohol to 1 mol of the starting material. In a preferred embodiment, the molar ratio is 6:1. Preferably the reaction of the solvolysis is carried out in the temperature range from room temperature (approximately 20-25C) to boiling point with a fridge. More preferably, the reaction is carried out at a temperature in the range of approximately 30-50C.

Usually the reaction to three(C1-C4)-alkalineforming carried out in the temperature range of approximately 0C-30C. More preferably, at a temperature of 5-10C. In a preferred embodiment, use cyclisme agent in the amount of 2-5 mol ciclismo agent to 1 mol of the starting material.

Despite the fact that the solution chloroethanol acid (C1-C6)-alcohol and three(C1-C4)-alkylaromatic can be added at the same time, the best results are obtained with the sequential addition of a solution chloroethanol acid (C1-C6)-alcohol and three(C1-C4)-alkalineforming. Thus, in a particular embodiment, after addition of a solution chloroethanol acid in isopropanol, the reaction mixture is stirred for at least 10 minutes before adding triethylorthoformate. Preferably the mixture is stirred for approximately 2 hours before adding triethylorthoformate.

As shown in the examples, when carrying out the cyclization in anhydrous conditions dramatically increases the yield and chemical purity of the compounds. In addition, significantly reduces the required number ciclismo agent.

The compound of formula (IVa) can be obtained according to the described Example 23 in European patent application EP 921121-A. the compounds of formula (IV) can be obtained similarly.

In a preferred embodiment of the present invention the above-mentioned method of receiving abacavir or agopermalink acceptable salts, or their solvate, further includes the following stages:

(i) reaction of compounds of formula (III) with cyclopropylamine with obtaining the compounds of formula (II), where R1 represents a (C1-C4)-alkyl radical;

(ii) hydrolysis of the amide of formula (II) receiving abacavir (I) or its salt; and, if required, conversion of abacavir (I) in free form, in salt, or conversion obtained according to this method, the salt of abacavir (I) in free form ABC (I) or into another salt.

Thus, obtained above in stage cyclization of the compound of formula (III) may be, for example, turned into abacavir via interaction with cyclopropylamino, usually in the presence of base and a suitable solvent, followed by hydrolysis of the compounds to obtain abacavir or its salts. The hydrolysis can be carried out in acidic conditions, as described, for example, in Example 28 European patent application EP 434450-A.

Abacavir can be isolated from the reaction medium in the form of a pharmaceutically acceptable salt, preferably hemisulfate salt. Hemisulfate salt {(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl]cyclopent-2-enyl}methanol I denotes a salt formed between {(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl]cyclopent-2-enyl}methanol and sulfuric acid in a stoichiometric ratio of 21. Alternatively, the compound of formula (I) can be isolated from the reaction medium in the form of free base. When you want pharmaceutically acceptable salt, it can also be obtained from the basic form of abacavir by treatment of the corresponding acid. The preferred salt is hemisulfate salt abacavir obtained by processing the main form of abacavir with sulfuric acid in a stoichiometric ratio of 2:1. Alternatively, the salt of abacavir (I)obtained according to the present method, can be converted into another salt.

The most suitable conditions for the realization of this method vary depending on the parameters considered by the expert in this prior art, such as, for example, the concentration of the reaction mixture, the temperature used in the reaction solvent and isolation of the product, and the like. They can be easily identified referred to a specialist in this prior art using the examples in this Description.

Everywhere in the Description and the claims, the word "comprises" and variations of this word are not intended to exclude other technical features, additives, components or steps. Summary of the present patent application is fully incorporated in this document by reference. Additional objects, advantages the and and features of the present invention will be apparent to the skilled in this art upon consideration of the Description or developed through practical use of the invention.

EXAMPLES

Comparative Example 1. Obtaining (-)-N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide using aqueous HCl

In nitrogen atmosphere N-{4-chloro-5-formamido-6-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enylamine]pyrimidine-2-yl}isobutyramide (2.0 g, 5,65 mmol) was dissolved in isopropanol (14 ml) and 35% HCl (3 ml, 33,92 mmol). The mixture was heated for 2 hours at 40-42C. the resulting solution was cooled to 8-10C, then added triethylorthoformate (2.8 ml, 16,95 mmol) and stirred the reaction mixture at this temperature for 2 hours. HPLC analysis showed the absence of chemical reaction, then added triethylorthoformate (to 21.6 ml, 130 mmol) and stirred at 8-10C for more than 2 hours. Then slowly added NaHCO3 (2.9 g, 33,92 mmol), stirred 30 minutes and filtered salt. To the resulting clear solution was added NaHCO3 (475 mg, the 5.65 mmol) and cyclopropylamine (2 ml, 28.3 mmol), the mixture was boiled under reflux for 1 hour and then filtered salt. The filtrate was evaporated, added to the residue isopropanol (10 ml) and concentrated twice to dryness. The syrup was dissolved in hot isopropanol (15 ml). This mixture was cooled to 0-2C. and filtered the resulting suspension. The solid residue was dried in vacuum at 30C. Was obtained 0,428 g (21%) of (-)-N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent--enyl]-9H-purine-2-yl}isobutyramide in the form of a pink powder. HPLC analysis: 87,7%+5.1% Abacavir.

Example 1. Obtaining (-)-N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide using HCl solution in isopropanol

In nitrogen atmosphere N-{4-chloro-5-formamido-6-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enylamine]pyrimidine-2-yl}isobutyramide (20,0 g, 56,53 mmol) was dissolved in anhydrous 2M HCl solution in isopropanol (170 ml, 339,17 mmol). The mixture was heated for 2 hours at 40-42C. the resulting solution was cooled to 8-10C, then added triethylorthoformate (28,2 ml, 169,59 mmol) and stirred the reaction mixture at this temperature for 2 hours. Then slowly added NaHCO3 (28,50 g, 339,17 mmol), stirred 30 minutes and filtered salt. To the resulting clear solution was added NaHCO3 (4,75 g, 56,53 mmol) and cyclopropylamine (19.6 ml, 282,65 mmol), the mixture was boiled under reflux for 1 hour and then filtered salt. The solution was evaporated and dissolved syrup in hot isopropanol (200 ml). This mixture was cooled to 0-2C. and filtered the resulting suspension. The solid residue was dried in vacuum at 30C. Was obtained 14,42 g (72%) of (-)-N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide in the form of a white powder. HPLC analysis: 94,4% + 4,0% of Abacavir.

Example 2. Obtaining (-)-N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobut Ramada

In nitrogen atmosphere N-{4-chloro-5-formamido-6-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enylamine]pyrimidine-2-yl}isobutyramide (15 g, 42,4 mmol) was dissolved in anhydrous 1N HCl solution in isopropanol (254 ml, 254,4 mmol) and was heated for 2 hours at 40-42C. the resulting solution was cooled to 5-10C. and added triethylorthoformate (21 ml, 127,2 mmol). The resulting mixture was stirred at 5-10C for 2 hours. Then slowly added NaHCO3 (21,37 g, 254,4 mmol), stirred 30 minutes and filtered salt. To the resulting clear solution was added NaHCO3 (of 3.56 g, 42,43 mmol) and cyclopropylamine (14.7 ml, 212 mmol), the mixture was boiled under reflux for 1 hour and then filtered salt. The solution was evaporated and dissolved syrup in hot isopropanol (120 ml). This mixture was cooled to 0-2C. and filtered the resulting suspension. The solid residue was dried in vacuum at 30C. Was obtained 10,97 g (73%) of (-)-N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purine-2-yl}isobutyramide in the form of a white powder. HPLC analysis: 95,0%+3.8% Abacavir.

Example 3. Getting hemisulfate abacavir

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 boiled under reflux for 1 hour. The resulting solution ohla the or to 20-25C and added tert-butyl methyl ether (32,8 ml). The layers were separated and added dropwise 96% H2SO4 (0,61 ml, 11,03 mmol) to the organic layer. This mixture was cooled to 0-5C. and filtered the resulting suspension. The solid residue was dried in vacuum at 40C. Hemisulfate ABC (5,98 g, 97%) was obtained as a white powder.

Example 4. Getting hemisulfate abacavir

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 boiled under reflux for 1 hour. The resulting solution was cooled to 20-25C. and added toluene (32,8 ml). The layers were separated and added dropwise 96% H2SO4 (0,61 ml, 11,03 mmol) to the organic layer. This mixture was cooled to 0-5C. and filtered the resulting suspension. The solid residue was dried in vacuum at 40C. Hemisulfate ABC (5,42 g, 88%) was obtained as a white powder.

Example 5. Receiving 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 boiled under reflux for 1 hour. The resulting solution was cooled to 20-25C. and added tert-butyl methyl ether (2 ml). Removed the water layer, the organic phase was cooled to 0-5C. and filtered the resulting suspension. TV is RDY the residue was dried in vacuum at 40C. Abacavir (0,62 g, 77%) was obtained as a white powder.

1. How to obtain abacavir formula (I)or its pharmaceutically acceptable salt, or MES,

including : (i) stage circuit loop in the compound of formula (IV) via a first interaction of the compounds (IV) with a solution of anhydrous chloroethanol acid (C1-C6)-alcohol and then with three(C1-C4-alkalineforming in anhydrous conditions to obtain compounds of formula (III)

where R1is a (C1-C4)-alkyl radical,
ii) the interaction of the compounds of formula (III) with cyclopropylamine with obtaining the compounds of formula (II)

where R1is a (C1-C4)-alkyl radical; and
iii) hydrolysis of compounds of formula (II) receiving abacavir (I) or its salt; and, if required, conversion of abacavir (I) in free form, in salt or conversion obtained according to this method, the salt of abacavir (I) in free form ABC (I) or into another salt.

2. The method of receiving according to claim 1, where R1represents isopropyl.

3. The method of receiving according to claim 1 where (C1-C6-alcohol is a isopropanol.

4. The method of receiving according to claim 1, where three(C1-C4)alkylaromatic is triethylorthoformate.

5. The method of receiving according to claim 1, where the reaction with a solution of anhydrous chloroethanol acid (C1-C6)-alcohol is carried out in the temperature range from room temperature up to the boiling temperature under reflux, followed by reaction with three(C1-C4-alkalineforming in the temperature range 0-30C.

6. The method of receiving according to claim 2, where (C1-C6-alcohol is a isopropanol.

7. The method of receiving according to claim 2, where three(C1-C4-alkylaromatic is triethylorthoformate.

8. The method of receiving according to claim 6, where three(C1-C4-alkylaromatic is triethylorthoformate.

9. The method of obtaining of claim 8, where the reaction with a solution of anhydrous chloroethanol acid (C1-C6)-alcohol is carried out in the temperature range from room temperature up to the boiling temperature under reflux, followed by reaction with tri(C1-C4-alkalineforming in the temperature range 0-30C.

10. The method of receiving according to claim 2, additionally comprising the following stages:
(i) reaction of compounds of formula (III) with cyclopropylamine with obtaining the compounds of formula (II)

where R1represents isopropyl;
(ii) hydrolysis of compounds of formula (II) receiving abacavir (I) or its salt; and, if required, conversion of abacavir (I) in free form to a salt reconversion obtained according to this method, the salt of abacavir (I) in free form ABC (I) or into another salt.

11. The method of obtaining of claim 8, additionally comprising the following stages:
(i) reaction of compounds of formula (III) with cyclopropylamine with obtaining the compounds of formula (II)

where R1represents isopropyl;
(ii) hydrolysis of compounds of formula (II) receiving abacavir (I) or its salt; and, if required, conversion of abacavir (I) in free form, in salt or conversion obtained according to this method, the salt of abacavir (I) in free form ABC (I) or into another salt.

12. The method of receiving according to claim 9, additionally comprising the following stages:
(i) reaction of compounds of formula (III) with cyclopropylamine with obtaining the compounds of formula (II)

where R1represents isopropyl;
(ii) hydrolysis of compounds of formula (II) receiving abacavir (I) or its salt; and, if required, conversion of abacavir (I) in free form, in salt or conversion obtained according to this method, the salt of abacavir (I) in free form ABC (I) or into another salt.



 

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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.

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

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

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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

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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