2,6-dinitro-containing substituted purine derivatives, methods for production thereof and use

FIELD: chemistry.

SUBSTANCE: invention relates to anti-tumour purine derivatives of formula (A) and salts thereof, as well as pharmaceutical compositions based thereon, a method for production thereof where W is an alkyl-substituted amine, a pyrrolidine, piperidine, morpholine or piperazine residue, optionally substituted with C1-C6 alkyl or hydroxy; Y is H or a saccharide residue, Z is H; Q is an optionally substituted quinoline residue. The disclosed method involves reacting a corresponding purine protected at the 9th position with corresponding precursors of groups W and Q.

EFFECT: novel compounds with low toxicity, a wide anticancer range, high anticancer activity, high stability, suitable for producing anti-tumour drugs.

12 cl, 3 tbl, 31 ex

 

THE TECHNICAL FIELD. The INVENTION RELATES to

The present invention relates to pharmaceutical chemistry, in particular, to 2, 6-dinitrogenase substituted purine derivative, method for their production and their use.

BACKGROUND of INVENTION

Malignant tumors (cancers) are one of the most common diseases, providing now a detrimental effect on human health and threaten human life. Worldwide each year, cancer kills more than 5 million people. Although currently developed and applied certain therapeutic agents and methods, such as surgery, radiotherapy, chemotherapy and so on, the indicator of the effectiveness of treatment in General is not high. Currently, the method of chemotherapy mainly characterized by several disadvantages, such as low selectivity, severe side effects, etc. Thus, organizations dealing with developments in the field of pharmaceutical industry in various countries around the world, focusing on the creation of anticancer drugs, which would have more low toxicity, mild side effect, high anticancer activity, high stability, etc.

According to available information, the number of derivatives of purine characterized on the certain antiviral and antitumor activity. Cm. relevant documents: EP 0353955, WO 9201968, JP 10120682, KR 9100441 etc.

In the known technical solutions in this area reveals a number of poison substituted purine derivatives, for example, Unsubstituted purine derivatives used for the treatment of allergic diseases, are disclosed in US patent 4853386; derivatives of N6-cyclopropylamino-N-purine, which has antiviral activity, are disclosed in patents JP 2003-55377 A and JP 2003-119197 A. Glycolytically purine derivatives having anti-inflammatory effect are disclosed in J. Org. Chem. (str~3215. volume 69, 2004). Derivatives of N2-butylphenyl-2-methoxypurine with the activity of DNA polymerase and eukaryotic cells, are disclosed in J. Med. Chem. (str-181, vol. 27, 1984). 2,6,9-triple-substituted purine derivatives disclosed in Tetraheron Letters (1827~1830, vol. 39, 1998). In addition, a number of compounds with antitumor effect, disclosed in the patent CN 200510026846. The specialists in this field of technology need to develop N2N6-disubstituted purine derivatives, characterized by a higher antitumor activity, while conducting further research to enhance the antitumor activity of N2N6-disubstituted compounds of purine.

A BRIEF STATEMENT of the substance of the INVENTION

The technical problem of the present invention of zakluchaetsa research on the development of N 2N6-disubstituted purine derivatives having lower toxicity, greater anticancer range, higher anticancer activity and high stability. The present invention provides for the creation of compounds 2, 6-dinitrogenase substituted purine by the formula (A) or their salts or solvate or solvate of salt:

Where W denotes selectively monosubstituted C1~C6alkylamino straight or branched chain, optionally monosubstituted With3~C6alkyl, or alkenyl or alkynylamino straight or branched chain, optionally disubstituted by C1~C6alkylamino straight or branched chain, optionally disubstituted With3~C6alkyl, or alkenyl or alkynylamino straight or branched chain, W can also represent amino, substituted With two different1~C6alkanes with a straight or branched chain, or indicate amino, substituted With two different3~C6the olefins with a straight or branched chain, or amino, one end of which is substituted With1~C6alkanol, and the other end replaced With3~C6the olefin or selectively substituted hemerocallidaceae secondary nitrogen, such as pyrrolidine, piperidine, morphine or piperazinyl; zamestitelnitsa C 1~C6alkyl or halogen, or hydroxyl with a straight or branched chain;

Y denotes H or a pharmaceutically acceptable saccharide, in which the saccharide preferably denotes any of the following formulas:

,,,

Z represents H or any of the following formulas:

,,

Q represents H or any of the following formulas:

,,,

,,,

,,,

,,,

,,,

,,

in which b, E, G, R, T, M each independently represents N or C1~C6alkyl or haloalkyl straight or branched chain, With3~C6cycloalkyl, halogen, CN, NH2methoxyl, ethoxyl or nitro.

W preferably the seat is no amino, cyclopropylamino, cyclobutylamine, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamine, allylamino, methylethylamine, ethylethylene, propylethylene, diallylamine, ethanolamine or any of the following formulas:

,,,,,

,,

W preferably represents cyclopropylamino, dimethylamino, diethylamino, methylethylamine, allylamino, diallylamine or any of the following formulas:

,,,,,

,

Q preferably represents any of the following formulas:

,,,,

,,,,

,,,

in which Y is N.

The aim of the present invention is to provide the following connections:

Another objective of the present invention is to provide a method of producing the above compounds according to formula (A) or their salts or solvate or solvate of salt, and the method illustrated by the below formula:

The method of obtaining compounds includes the following steps:

1) at the first stage, the compound (a) reacts with 2,3-dihydropyran in the presence of such catalysts as paratoluenesulfonyl acid, pyridinium salt paratoluenesulfonyl acid or resin acid or other catalyst for the protection of the 9th nitrogen atom of the purine; however, in the course of the reaction the molar ratio of compounds (a) to 2,3-dihydropyrano is approximately 1:1~5; then in the presence of atravesado solvent, such as triethylamine, sodium carbonate, potassium carbonate or sodium bicarbonate is condensation with W and get a connection (b); however, the molar ratio of the compound (a) to W is approximately 1:1~5, the reaction temperature of the condensation W of approximately 20~100°C, preferably about 40~60°C.

2) then proceeds catalytic reaction mix and the reaction of removing the protective groups and the salt formation between the compound (b) and Q-NH2, resulting in a receive connection (d); however, the molar ratio of the compound (b) to the Q-NH2approximately 1:0.5 to~2.

In a catalytic reaction of a combination of ligand includes tri-o-tolylphosphino, three-tert-butylphosphine, 2,2'-diphenylphosphino -1,1'-binaphthalene, 1,1'-diphenylphosphine-ferrocene, a simple ether bis(2-diphenylphosphinite is), 9,9-dimethyl-4,5-diphenylphosphine Xanten, or the ligand is a compound according to the formula 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; the catalyst is a catalyst based on transition metal is palladium or Nickel, for instance, PdCl2Pd(OAc)2Pd2(dba)3, Ni(OAc)2or Ni/C; base is tert-piperonyl sodium tert-piperonyl potassium, potassium carbonate, cesium carbonate or tripotassium phosphate. The solvent is aprotic solvent, such as tetrahydrofuran, simple isopropyl ether, simple etilenglikolevye ether, dioxane, pyridine, 1-methyl-2-pyrrolidone (NMP), 1,3-dimethyltrimethylene (DMPU), toluene or xylene, or a mixture of solvents containing one or more solvents selected from the above.

During the course of the catalytic reaction combination reaction temperature is about 15~150°C, preferably about 55~120°C, or the reaction proceeds when exposed to microwave heating. The reaction of removing the protective group and the salt formation at stage 2 would take place in an acidic medium such as hydrochloric acid, sulfuric acid, Hydrobromic acid, methanesulfonate acid, benzolsulfonat acid, paratoluenesulfonyl acid, Malinova acid, fumaric acid, lactic acid or citric acid, etc., When this molar ratio is their connection (s) to hydrochloric acid, sulfuric acid, Hydrobromic acid, methanesulfonic acid, benzosulfimide acid, paratoluenesulfonyl acid, maleinovoi acid, fumaric acid, lactic acid or citric acid can be 1:1~10, respectively.

3) Neutralization of the compound (d) sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide to obtain a compound (e).

An additional objective of the present invention is to provide a pharmaceutical composition, in which the pharmaceutical composition is comprised of compounds according to formula (A) or their salts or solvate, or solvate of their salts and pharmaceutically acceptable excipients. Salt is a salt of the accession acid, obtained by using organic or inorganic acid, the acid is preferably hydrochloric acid, sulfuric acid, bromatological, methanesulfonic acid, benzosulfimide acid, paratoluenesulfonyl acid, maleinovoi acid, fumaric acid, lactic acid, citric acid or salt is a salt of the attaching base, obtained by using organic or inorganic bases. The pharmaceutical composition is made in the form of tablets, capsules, pills, liquid preparation for oral administration, granules, powder, injection, implant or of the preparation for external use.

Testing of antitumor activity in vitro and in vivo show that the compounds in accordance with the present invention have antitumor activity. Compounds have an inhibitory effect on the growth of cancer cells (Colon 26) and sarcoma S180 in mice. Compound, or salt or solvate, or a solvate their salts could be used for the manufacture of a medicine for treatment or prevention of neoplastic diseases. Neoplastic diseases include lung cancer, liver cancer, leukemia, osteosarcoma, pancreatic cancer, skin cancer, melanoma, microcarcinoma, oophoroma, rectal carcinoma, gastric carcinoma, colon carcinoma, breast carcinoma, carcinoma of the uterus, endometrial carcinoma, cervical carcinoma, carcinoma of the vagina, carcinoma of the vulva, carcinoma of the esophagus is, carcinoma of the small intestine, carcinoma of endocranium, carcinoma of soft tissue, cancer of the urethra, prostate cancer, lymphocytoma, bladder cancer, kidney cancer or cancer of the urethra, cancer of the spine, neuroglial tumors of the brain and pituitary adenoma.

DETAILED DESCRIPTION of the PRESENT INVENTION AND ITS PREFERRED embodiments

Below, in particular, describes the present invention with reference to examples. These examples are given to illustrate the technical solutions of the present invention and should not be construed as limiting the present invention.

Examples 1-3 Obtaining compounds of formula I, II, III

Example 1 Obtaining compound I

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml), and then in a mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added triethylamine (8 ml) at delegirovano, for 15 minutes were added allylamine (7 ml), and then in a mixture flowed reaction for 0.5 hours the Completion of the reaction was checked by the method of subtly is lainey chromatography and then the mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no separation of a large number of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (12 g). The yield was approximately 77.3 per cent.

2. In a 250 ml triggerlevel flask were successively added solid purine (10.4 g)obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate white (11.5g). The yield was approximately 82.6% of per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10.0 g, obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). All solids were completely dissolved and obtained clear solution is orange. Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (11.5g).

1H-NMR (DMSO-d6+D2O, ppm) δ: the 4.29 (2H, s), a total of 5.21 (1H, dd, J=2.0 a, 10,4 Hz), 5,32 (1H, dd, J=2.0 a, and 17.2 Hz), 6,10 (1H, t), 7,98 (1H, dd, J=5,2, 8,4 Hz), to 8.20 (1H, d, J=9,2 Hz), 8.34 per (blocked), 8,84 (2H, overlapped), of 8.92 (1H, d, J=8,4 Hz), the remaining 9.08 (1H, dd, J=5,2, 1,2 Hz).

13C-NMF (DMSO-d6, ppm) δ: 43,0, 106,0, 113,2, 116,4, 121,6, 122,4, 128,7, 129,8, 134,2, 134,4, 138,9, 141,1,142,5, 144,5, 149,3, 151,5, 155,4.

4. In a 100 ml flask was stirred methanesulfonate (10 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid light yellow color. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and got the connection I (5,4 g).

(+)-ESI MS m/z: 318 [M+H]+.

Example 2 Obtaining the compound (II)

Compound I (2.5 g) and bis (trimethylsilyl) ndimethylacetamide (3.5 ml) were mixed in anhydrous acetonitrile (10 ml). The above mixture was stirred at room temperature for 1 hour. Next, to the mixture was added a solution tetraacetyl ribofuranose (3.5 g)dissolved in acetonitrile (8 ml), and dimethylterephthalate (0.6 ml) and heated at delegirovano for 5 hours. To the mixture was added bovine serum albumin (0.7 ml) and then was stirred for 24 hours. Completion of reaction was checked by the method of thin-film chromatography. The solvent was concentrated under reduced pressure, and the residue was dissolved in methanol (15 ml). Through the above mixture was passed ammonia gas for 1.5 hours. The solvent was removed under reduced pressure, the residue was purified by the method of columnar chromatography on silica gel and got connection II (2.6 g).

(+)-ESI MS m/z: 450 [M+H]+.

Example 3 to Obtain compound III

1. 60% NaH (0.4 g) and anhydrous acetonitrile (50 ml) was mixed with compound I (2.5 g). The above mixture was stirred in a protective atmosphere of nitrogen for 30 minutes. To the mixture for 10 minutes was added in portions 3,5-di-para-toluensulfonyl-2-deoxy-β-D-ribofuranose-1-chloride (3 g). After reaction at room temperature for 2 hours and subsequent filtration, the filtrate conc is listed until dry and got an oil substance. Next, the oily substance was purified by the method of columnar chromatography and obtained solid (2.5 g).

2. The above solid, 50% sodium methoxide (0.6 g) and methanol (100 ml) were mixed, and between them ran the reaction at room temperature for 5 hours with constant stirring. The pH of the above mixture was adjusted to neutral values using acetic acid. The solvent is kept off, the residue was purified by the method of columnar chromatography and obtained the compound III (1.3 g).

(+)-ESI MS m/z: 434 [M+H]+.

Example 4-6 Obtaining compounds of formula IV, V, VI

Example 4 to Obtain compound IV

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added triethylamine (7.9 ml), then for 15 minutes were added pyrrolidine (7.8 ml) at this temperature, and then in a mixture of reaction proceeded at this temperature for 0.5 h the Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtered what I precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (12.3 g). The output amounted to approximately 75.6%of the.

2. In a 250 ml triggerlevel flask were successively added purine (11,0 g)obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (11.9 g). The output amounted to approximately 82.6% of per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added met Sultonova acid (5 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (12.0 g).

1H-NMR (DMSO-d6, ppm) δ: to 2.06 (4H, s), is 2.41 (6H, s), 3,93(4H, brs), 7,95 (1H, dd,J=5,2 Hz, J=8,4 Hz), 8,17(1H, d, J=9,2 Hz), 8,31(1H, dd, J=2,4 Hz, J=a 9.4 Hz), to 8.45(1H, s), cent to 8.85(1H, d, J=2,0 Hz), of 8.90 (1H, d, J=8.4 and Hz), 9,04 (1H, d, J=4 Hz), there is a 10.03 (replacement 1H, s, D2O disappeared).

4. In a 100 ml flask was stirred salt methanesulfonic acid (10 g)obtained in the previous step, and water (60 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound IV (5,4 g).

Example 5 Obtaining connection V

Compound IV (2.5 g) and bis (trimethylsilyl) ndimethylacetamide (3.5 ml) were mixed in anhydrous acetonitrile (10 ml). The above mixture was stirred at room temperature for 1 hour. Next, to the mixture was added a solution tetraacetyl ribofuranose (3.5 g)dissolved in acetonitrile (8 ml), and dimethylterephthalate (0.6 ml) and heated at delegirovano is within 5 hours. To the mixture was added bovine serum albumin (0.7 ml) and then was stirred for 24 hours. Completion of reaction was checked by the method of thin-film chromatography. The solvent was concentrated under reduced pressure, and the residue was dissolved in methanol (15 ml). Through the above mixture was passed ammonia gas for 1.5 hours. The solvent was removed under reduced pressure, the residue was purified by the method of columnar chromatography on silica gel and got the connection V (2.3 g).

(+)-ESI MS m/z: 464 [M+H]+.

Example 6 to Obtain compound VI

1. 60% NaH (0.4 g) and anhydrous acetonitrile (50 ml) was mixed with compound IV (2.5 g). The above mixture was stirred in a protective atmosphere of nitrogen for 30 minutes. To the mixture for 10 minutes was added in portions 3,5-di-para-toluensulfonyl-2-deoxy-β-D-ribofuranose-1-chloride (2.9 g). In the mixture, there was the addition reaction for 2 hours. After filtration, the filtrate was concentrated until dry and got an oil substance. Next, the oily substance was purified by the method of columnar chromatography and obtained solid (2.5 g).

2. The above solid, 50% sodium methoxide (0.7 g) and methanol (100 ml) were mixed, and between them ran the reaction at room temperature for 5 hours with constant stirring. The pH of the above mixture was adjusted to neutral the nogo values using acetic acid. The solvent is kept off, the residue was purified by the method of columnar chromatography and obtained compound VI (1.4 g).

(+)-ESI MS m/z: 448 [M+H]+.

Example 7-9 Obtaining compounds of formulas VII, VIII, IX

Example 7 Obtaining compounds VII

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added methylaminopropane (4.6 g), then for 30 minutes were added triethylamine (21 ml) at this temperature, and then in a mixture of reaction proceeded at this temperature for 1 hour. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (11,0 g). The output amounted to approximately 7.7 percent.

2. In a 250 ml triggerlevel flask were successively added purine (10.0 g)obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (10.7 g). The output amounted to approximately 82.2% in the calculation of aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got to means honat (11.3 g).

1H-NMR (DMSO-d6, ppm) δ: 2,44 (6N, s)and 3.15 (3H, s), 7,95 (1H, dd, J=5,2 Hz, J=8,0 Hz), 8,18 (1H, d, J=8,8 Hz), with 8.33 (1H, dd, J=2,4 Hz, J=a 9.4 Hz), to 8.70 (1H, s), 8,86 (1H, d, J=2,0 Hz), 8,91 (1H, d, J=8,4 Hz), 9,05 (1H, dd, J=1,2 Hz, J=5,2 Hz), 10,14 (replacement 1H, s, D2O has disappeared).

4. In a 100 ml flask was stirred methanesulfonate (10 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound VII (5,2 g).

Example 8 connection VIII

The free base of compound VII (2.5 g) and bis (trimethylsilyl) ndimethylacetamide (3,7 ml) were mixed in anhydrous acetonitrile (10 ml). The above mixture was stirred at room temperature for 1 hour. Next, to the mixture was added a solution tetraacetyl ribofuranose (3.5 g)dissolved in acetonitrile (8 ml), and dimethylterephthalate (0.6 ml) and heated at delegirovano for 5 hours. To the mixture was added bovine serum albumin (0.7 ml) and then was stirred for 24 hours. Completion of reaction was checked by the method of thin-film chromatography. The solvent was concentrated under reduced pressure, and the residue was dissolved in methanol (15 ml). Through the above mixture missed gazoo the different ammonia for 1.5 hours. The solvent was removed under reduced pressure, the residue was purified by the method of columnar chromatography on silica gel and the obtained compound VIII (2.7 g).

(+)-ESI MS m/z: 424 [M+H]+.

Example 9 the connection IX

1. 60% NaH (0,42 g) and anhydrous acetonitrile (50 ml) was mixed with compound VII (2.5 g). The above mixture was stirred in a protective atmosphere of nitrogen for 30 minutes. To the mixture for 10 minutes was added in portions 3,5-di-para-toluensulfonyl-2-deoxy-β-D-ribofuranose-1-chloride (3.5 g). In the mixture of reaction proceeded for 2 hours. After filtration, the filtrate was concentrated until dry and got an oil substance. Next, the oily substance was purified by the method of columnar chromatography and obtained solid (2.3 g).

2. The above solid, 50% sodium methoxide (0.75 g) and methanol (100 ml) were mixed, and between them ran the reaction at room temperature for 5 hours with constant stirring. The pH of the above mixture was adjusted to neutral values using acetic acid. The solvent is kept off, the residue was purified by the method of columnar chromatography and received the connection IX (1.2 g).

(+)-ESI MS m/z: 408 [M+H]+.

Example 10 to Obtain compound X

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). In sukasana the mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added triethylamine (7.9 g), and further thereto was added DL-aminopropanol (7.0 ml) at this temperature. Later in the mixture of reaction proceeded at this temperature for 1 hour. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (11.6 g). The output amounted to approximately 70,4%.

2. In a 250 ml triggerlevel flask were successively added purine (11.6 g)obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. actionnow the mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (11.5g). The output amounted to approximately 79,0% per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). All solids were dissolved to obtain a clear solution. Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (12.3 g).

1H-NMR (DMSO-d6, ppm) δ: of 1.32 (3H, d, J=6,4 Hz), 2,44 (6H, s), 3,63 (2H, m), 4,43 (1H, brs), of 7.96 (1H, dd, J=5,2 Hz, J=8,4 Hz), 8,00 (1H, brs), 8,19 (1H, d, J=9,2 Hz), 8,29 (1H, dd, J=2,4 Hz, J=a 9.4 Hz), 8,82 (1H, s), cent to 8.85 (1H, d, J=2,0 Hz), of 8.90 (1H, d, J=8,4 Hz), 9,05 (1H, dd, J=1,2 Hz, J=5,2 Hz), 10,18 (1H, s).

4. In a 100 ml flask was stirred methanesulfonate (12 g)obtained in the previous step, and water (60 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, pH d who was wireway to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound X (6.5 g).

(+)-ESI MS m/z: 335 [M+H]+.

Example 11 the connection XI

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added triethylamine (7.9 g), and further thereto was added L-aminopropanol (7,0 ml). Later in the mixture of reaction proceeded at this temperature for 1 hour. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (12.2 g). The output amounted to approximately 74,0%.

2. In a 250 ml triggerlevel flask, poach the Reden added purine (11.6 g), obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (12.1 g). The output amounted to approximately 83.2% of per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (11.9 g).

1H-NMR (DMSO-d6, ppm) δ: of 1.32 (3H, d, J=6,8 Hz), 2,44 (6H, s), 3,63 (2H, m), 4,43 (1H, brs), of 7.96 (1H, dd, J=5,2 Hz, J=8,4 Hz), 8,01 (1H, brs), 8,19 (1H, d, J=9,2 Hz), 8,29 (1H, dd, J=2,4 Hz, J=a 9.4 Hz), 8,82 (1H, s), cent to 8.85 (1H, d, J=2,4 Hz), of 8.90 (1H, d, J=8,8 Hz), 9,05 (1H, d, J=1,2 Hz, J=5,2 Hz), 10,19 (1H, s).

4. In a 100 ml flask was stirred methanesulfonate (11 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XI (5.8 g).

Example 12 Obtaining compounds XII

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added methylpiperazin (9.0 g) and triethylamine (8 ml). Later in the mixture of reaction proceeded at this temperature for 1 hour. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and races is lavali. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (12.0 g). The output amounted to approximately 67.4 per cent.

2. In a 250 ml triggerlevel flask were successively added purine (11,8 g)obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (12.0 g). The output amounted to approximately 77.8% in the calculation of aminoquinoline.

3. 250 ml of odnogolosy flask were mixed compound (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). Later in videocase the Noah mixture reaction proceeded for 1 hour at delegirovano, and there was natural cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (11.5g).

4. In a 100 ml flask was stirred methanesulfonate (11 g)obtained in the previous step, and water (60 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid light yellow color. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XII (5.9 g).

(+)-ESI MS m/z: 361 [M+H]+.

Example 13 Obtaining compounds XIII

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added triethylamine (8 ml) and to it was added diallylamine (11,4 ml) at this temperature for 20 minutes, then in a mixture of reaction proceeded at this temperature for 0.5 hours. Conclusion re the work was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (12.9 g). The output amounted to approximately 73.1 per cent.

2. In a 250 ml triggerlevel flask were successively added purine (12.0 g)obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (12.2 g). The output amounted to approximately 79.7 per cent per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10.0 g)obtained at the output of the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). All solids were dissolved to obtain a clear solution. Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (10.8 g).

1H-NMR (DMSO-d6, ppm) δ: 2,44 (6H, s), br4.61 (4H, s), 5,19 at 5.27 (4H, m), 6,01 (2H, m), 7,98 (1H, dd, J=5,6 Hz, J=8,6 Hz), 8,14-8,18 (2H, m), 8,32 (1H, dd, J=2,4 Hz, J=9,2 Hz), 8,82 (1H, d, J=2,0 Hz), 8,86 (1H, d, J=8,8 Hz), 9,04 (1H, dd, J=1,6 Hz, J=5,4 Hz), to 9.91 (replacement 1H, s, D2O disappeared).

4. In a 100 ml flask was stirred methanesulfonate (10 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XIII (5.6 g).

Example 14 the connection XIV

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture paramesh the Wali and was heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added triethylamine (8 ml) and to it was added piperidine (9,2 ml) at this temperature for 20 minutes, then in a mixture of reaction proceeded at this temperature for 0.5 hours. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (12.8 g). The output amounted to approximately 75.2 per cent.

2. In a 250 ml triggerlevel flask were successively added purine (11.5g)obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin-layer method chromatog is the her. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (11.3 g). The output amounted to approximately 75.9% in the calculation of aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (11,7 g).

1H-NMR (DMSO-d6, ppm) δ: 1.70 to (6N, m)2,44 (6H, s), 4,19 (4H, s), to 7.99 (1H, dd, J=5,2 Hz, J=8,2 Hz), 8,19 (2H, m), 8,32(1H, dd, J=2,0 Hz, J=a 9.4 Hz), 8,79(1H, d, J=2,0 Hz), 8,91(1H,d,J=8,0 Hz), 9,05 (1H, dd, J=1,2 Hz, J=5,2 Hz), 9,95 (replacement 1H, s, D2O has disappeared).

4. In a 100 ml flask was stirred methanesulfonate (11 g)obtained in the previous step, and water (60 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, who then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XIV (6.0 g).

Example 15 Obtaining compounds XV

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added triethylamine (8 ml) and to it was added N-ethylpiperazine (10.3 g) at this temperature for 20 minutes, then in a mixture of reaction proceeded at this temperature for 0.5 hours. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (13,0 g). The output amounted to approximately 70.0%of them.

2. In a 250 ml triggerlevel flask were successively added purine (12.2 g), p is obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (13,2 g). The output amounted to approximately 83.0 per cent per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (10,9 g).

1H-NMR (DMSO-d6, ppm) δ: of 1.30 (3H, d, J=7,4 Hz), 2,43 (6H, s),3,21 (4H, m)and 3.59 (2H, m), 3,70 (2H, m), the 5.45 (2H, m), to 7.99 (1H, d, J=5,2 Hz, J=8,4 Hz), 8,08 (1H, brs), to 8.20 (1H, d, J=9,2 Hz), a 8.34 (1H, dd, J=2,0 Hz, J=a 9.4 Hz), 8,82 (1H, d, J=2,4 Hz), 8,98 (1H, d, J=8,4 Hz), 9,05 (1H, dd, J=1,2 Hz, J=5,6 Hz), 9,77 (1H, brs), to 9.93 (1H, s,).

4. In a 100 ml flask was stirred methanesulfonate (10 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XV (5.8 g).

Example 16 Obtaining compounds XVI

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added triethylamine (7.9 ml) and to it was added morpholine (7.9 ml) at this temperature. Later in the mixture of reaction proceeded at this temperature for 1 hour. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (11.2 g). The output amounted to approximately 65,4%.

2. In a 250 ml triggerlevel flask were successively added purine (11.6 g)obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (11.5g). The output amounted to approximately 76.8% of per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed compound (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). All solid washes the VA was dissolved to obtain a clear solution. Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (11,7 g).

1H-NMR (DMSO-d6, ppm) δ: 2,42 (6N, s), of 3.78 (4H, m), 4,22 (4H, s), 7,98 (1H, dd, J=5,2 Hz, J=8,4 Hz), 8,10 (1H, s), 8,17 (1H, d, J=9,2 Hz), 8,32 (1H, dd, J=2,0 Hz, J=a 9.4 Hz), 8,80 (1H, d, J=1,6 Hz), to 8.94 (1H, d, J=8,8 Hz), 9,04 (1H, d, J=5,2 Hz), of 9.89 (1H, s).

4. In a 100 ml flask was stirred methanesulfonate (10 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XVI (5,4 g).

Example 17 Obtaining compounds XVII

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography In the flask was added triethylamine (8 ml) and to it was added Isopropylamine (7.7 ml) at delegirovano within 15 minutes. Later in the mixture of reaction proceeded at this temperature for 0.5 hours. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (10.8 g). The output amounted to approximately 70.0%of them.

2. In a 250 ml triggerlevel flask were successively added purine (11,0 g)obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and received con the gat (11,7 g). The output amounted to approximately 83.6 percent per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed compound (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). All solids were dissolved to obtain a clear solution. Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (9.7 g).

1H-NMR (DMSO-d6, ppm) δ: of 1.35 (6H, d, J=6,4 Hz), 2,47 (6H, s), 4,35 (1H, brs), of 7.97 (1H, dd, J=5,2 Hz, J=8,6 Hz), of 8.09 (1H, brs), to 8.20 (1H, d, J=9,2 Hz), 8,31(1H, dd, J=2,0 Hz, J=a 9.4 Hz), 8,83(2H, superimposed), 8,89 (1H, d, J=8,4Hz), 9,06 (1H, dd, J=1,2 Hz, J=5,2 Hz), and 10.20 (1H, s).

(+)-ESI MS m/z: 320 [M+H]+.

4. In a 100 ml flask was stirred methanesulfonate (9 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid light yellow color. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XVII (4.8 g).

Example 8 connection XVIII

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added triethylamine (8 ml) and to it was added diethylamine (9.6 ml) at this temperature for 20 minutes, then in a mixture of reaction proceeded at this temperature for 0.5 hours. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (12.3 g). The output amounted to approximately 75,1%.

2. In a 250 ml triggerlevel flask were successively added purine (11,0 g)obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 m is). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (11.9 g). The output amounted to approximately 82.2% in the calculation of aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (11.3 g).

1H-NMR (DMSO-d6, ppm) δ: 1.30 on (6N, t, J=7,0 Hz), 2,44 (6H, s), of 3.97 (4H, brs), 8,02 (1H, dd, J=5,6 Hz, J=8,4 Hz), 8,21 (1H, d, J=9,2 Hz), 8,31-8,35 (2H, m), cent to 8.85 (1H, d, J=2,0 Hz), to 8.94 (1H, d, J=8,4 Hz), a 9.09 (1H, d, J=5,2 Hz).

4. In a 100 ml flask was stirred methanesulfonate (10 g)obtained in the previous this is e, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XVIII (5.5 g).

(+)-ESI MS m/z: 334 [M+H]+.

Example 19 the connection XIX

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added triethylamine (8 ml) and to it was added methylethylamine (7.7 ml) at delegirovano for 20 minutes, then in a mixture of reaction proceeded at this temperature for 0.5 hours. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After the filter is of the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got solid (10.3 g). The output amounted to approximately 65.9%of.

2. In a 250 ml triggerlevel flask were successively added 6-aminoquinoline (5.0 g), 2-chloro-N-methyl-N-ethyl-9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine (10.3 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (10.5 g). The output amounted to approximately 75.0% of per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed compound (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then Visu ivali in vacuum at 40°C for 6 hours and got methanesulfonate (11.2 g).

4. In a 100 ml flask was stirred methanesulfonate (10 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XIX (5,4 g).

Compound XIX: (+)-ESI MS m/z: 320 [M+H]+.

Example 20 the connection XX

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added dimethylamine hydrochloride (7.3 ml) and to it was added triethylamine (22 ml) at this temperature for 30 minutes, then in a mixture of reaction proceeded at this temperature for 0.5 hours. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer to the centered as long while there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (8,9 g). The output was about to 59.8%.

2. In a 250 ml triggerlevel flask were successively added purine (8,9 g)obtained in the previous step, 6-aminoquinoline (4.5 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (10.5 g). The output amounted to approximately 86.4% in the calculation of aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). All solids were dissolved to obtain a clear solution is Further in the above mixture reaction proceeded for 1 hour at delegirovano, and there was natural cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (9,8 g).

4. In a 100 ml flask was stirred methanesulfonate (9 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XX (4.9 g).

(+)-ESI MS m/z: 306 [M+H]+.

Example 21 the connection XXI

1. 100 ml of triggerlevel flask were mixed 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt paratoluenesulfonyl acid (0.2 g). The above mixture was stirred and heated to a temperature of 35°C, within 5 minutes it was added 2,3-dihydropyran (12 ml). Later in the mixture of reaction proceeded at 50~60°C for 3 hours Completion of the reaction was checked by thin layer chromatography. To the flask was added triethylamine (8 ml) and piperazine (7.3 ml) for 20 minutes, then in a mixture of reaction proceeded at this temperature for 1 hour. Completion of reaction was checked by thin layer chromatography. The reaction is mesh was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid purine (12.4 g). The output amounted to approximately 72,7%.

2. In a 250 ml triggerlevel flask were successively added purine (12.0 g)obtained in the previous step, 6-aminoquinoline (5.0 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5,4 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (12.7 g). The output amounted to approximately 85,0% per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). Viseu azanuy the mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). All solids were dissolved to obtain a clear solution. Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (12.1 g).

1H-NMR (DMSO-d6, ppm) δ: 2,43 (9H, s), up 3.22 (2H, m),3,54-3,66 (4H, m), 5,41 (2H, m), 8,01 (1H, dd, J=5,2 Hz, J=8,6 Hz)to 8.12 (1H, s), 8,21 (1H, d, J=a 9.6 Hz), a 8.34 (1H, dd, J=2,0 Hz, J=9,0 Hz), 8,83 (1H, d,, J=2,0 Hz), 8,99 (1H, d, J=8,8 Hz), 9,06 (1H, d, J=4,2 Hz), 9,98 (replacement 2H, brs, D2O has disappeared).

4. In a 100 ml flask was stirred methanesulfonate (11 g)obtained in the previous step, and water (60 ml). To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XXI (5.3g).

Example 22 to Obtain compounds XXII

1. In 3000 ml of triggerlevel flask were mixed 2,6-dichloropurine (300 g), ethyl acetate (1500 ml) and pyridinium salt paratoluenesulfonyl acid (3 g). The above mixture was stirred and heated to a temperature of 35°C, within 30 minutes it was added 2,3-dihydropyran (360 ml). Later in the mixture of reaction proceeded at 50~60°C for 5 hours Completion of the reaction conducted by the Yali by thin layer chromatography. To the flask was added triethylamine (240 ml) and to it was added cyclopropylamine (204 ml) delegirovano within 30 minutes. Later in the mixture of reaction proceeded at this temperature for 0.5 hours. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed with ethyl acetate, and the filtrate was washed with water 3 times and was stratified. The organic layer was concentrated until until there was no release of a large amount of solid particles. After filtration the precipitate was washed with ethyl acetate 3 times and then dried under vacuum at 50°C for 5 hours and got a solid connection of 2-chloro-N-cyclopropyl-9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine (364 g).

2. In a 250 ml triggerlevel flask were successively added 6-amino-8-methylinosine (5.0 g), 2-chloro-N-cyclopropyl-9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine (10.2 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed about the th etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (11.2 g). The output amounted to approximately 85,3% per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (11.3 g).

1H-NMR (DMSO-d6, ppm) δ: 0.75 in (2H, s), of 0.95 (2H, m), 2,41 (6N, s), was 2.76 (3H, s), 3,12 (1H, brs), to 7.84 (1H, dd, J=4,8 Hz, J=8,2 Hz), to 8.12 (1H, s), and 8.50 (replacement 1H, brs, D2O disappeared), 8,71 (3H, m), 8,93 (1H, d, J=4,0 Hz), of 10.05 (replacement 1H, s, D2O has disappeared).

4. In a 100 ml flask was stirred methanesulfonate (10 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and the floor is Ali compound XXII (5.3g).

Example 23 the connection XXIII

1. In a 250 ml triggerlevel flask were successively added 6-amino-8-methoxyethanol (5.0 g), 2-chloro-N-cyclopropyl-9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine (9.3 g), catalyst Pd(OAc)2(0.25 g), ligand 7 (0.25 g), tert-piperonyl sodium (4.5 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (11,0 g). The output amounted to approximately 88.8% of the per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed compound (10.0 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 RA is a, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (11.8 g).

1H-NMR (DMSO-d6, ppm) δ: 0,73 (2H, s), of 0.93 (2H, m),2,37 (6N, s), 3,14 (1H, brs), 4,13 (3H, s), of 7.96 (2H, m), 8,30 (replacement 1H, s, D2O disappeared), 8,64 (2H, brs), 8,86 (2H, m), 10,01 (replacement 1H, s, D2O has disappeared).

3. In a 100 ml flask was stirred methanesulfonate (11 g)obtained in the previous step, and water (60 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XXIII (6,1 g).

Example 24 the connection XXIV

1. In a 250 ml triggerlevel flask were successively added 6-amino-8-trifloromethyl (5.0 g), 2-chloro-N-cyclopropyl-9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine (7.6 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (4.0 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 is Aza, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (8.5 g). The output amounted to approximately 76.8% of per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (8 g)obtained in the previous step, acetone (50 ml) and water (40 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (3.8 ml). All solids were dissolved to obtain a clear solution. Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (8.7 g).

1H-NMR (DMSO-d6, ppm) δ: 0,69 (2H, s), 0,76 (2H, brs), is 2.40 (6H, s), 2,97 (1H, brs), to 7.77 (1H, dd, J=4,0 Hz, J=8,2 Hz), 8,46 (3H, m), 8,53 (1H, d, J=8,4 Hz), 8,86 (replacement 1H, brs, D2O disappeared), 9,10 (1H, d, J=4,0 Hz), 9,46 (replacement 1H, brs, D2O has disappeared).

3. In a 100 ml flask was stirred methanesulfonate (8 g)obtained in the previous step, and water (40 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtration is ovali, the precipitate was washed with acetone, dried under vacuum and obtained compound XXIV (4.5 g).

Example 25 the connection XXV

1. In a 250 ml triggerlevel flask were successively added 2-methyl-4-aminoquinoline (5.0 g), 2-chloro-N-cyclopropyl-9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine (10.2 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5.0 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (11.8 g). The output amounted to approximately 89.9 percent per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (10 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after the head of the cope rearrangement. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got solid methanesulfonate (10,9 g).

1H-NMR (DMSO-d6, ppm) δ: 0.75 in (2H, m), 0,87 (2H, m), is 2.37 (6H, s), and 2.79 (3H, s), 3,10 (1H, brs), 7,78 (1H, m), 8,02 (2H, m), 8,35 (replacement 1H, brs, D2O disappeared), at 8.60 (1H, m), 8,91 (2H, m), is 10.68 (replacement 1H, s, D2O has disappeared).

3. In a 100 ml flask was stirred methanesulfonate (10 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XXV (5,2 g).

Example 26 to Obtain compounds XXVI

1. In a 250 ml triggerlevel flask were successively added 8-chloro-6-aminoquinoline (5.0 g), 2-chloro-N-cyclopropyl-9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine (9.0 g), catalyst Pd(OAc)2(0.25 g), ligand 7 (0.25 g), tert-piperonyl sodium (4.5 g) and simple etilenglikolevye ether (100 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration of sludge is completely washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (4.6 g). The output amounted to approximately 37.7 per cent per aminoquinoline.

3. 250 ml of odnogolosy flask were mixed conjugate (4.5 g)obtained in the previous step, acetone (30 ml) and water (30 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (2 ml). All solids were dissolved to obtain a clear solution. Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got solid methanesulfonate (4.5 g).

1H-NMR (DMSO-d6, ppm) δ: 0,74 (2H, m), and 0.98 (2H, m), 2,42 (6H, s), of 3.07 (1H, s), 7,63 (1H, m), 8,32 (1H, d, J=8,4 Hz), of 8.47-8,54 (2H, m), a total of 8.74-8,87 (2H, m), 10,04 (replacement 1H, brs, D2O has disappeared).

3. In a 100 ml flask was stirred methanesulfonate (4 g)obtained in the previous step, and water (25 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, vesus the Wali in vacuum and the obtained compound XXVI (2.3 g).

Example 27 to Obtain compound XXVII

1. In a 250 ml triggerlevel flask were successively added 3-aminopyridine (5.0 g), 2-chloro-N-cyclopropyl-9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine (16.0 g), catalyst Pd(OAc)2(0.4 g), ligand 7 (0.4 g), tert-piperonyl sodium (7.5 g) and simple etilenglikolevye ether (130 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (12.9 g). The output amounted to approximately 69,1% per aminopyridine.

3. 250 ml of odnogolosy flask were mixed compound (10 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (6 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then h is stirred under vacuum at 40°C for 6 hours and got methanesulfonate (12 g).

1H-NMR (DMSO-d6, ppm) δ: of 0.68 (2H, m), of 0.93 (2H, m), of 2.38 (6H, s), 3,01 (1H, brs), of 7.97 (1H, dd, J=5,6 Hz, J=8,8 Hz), 8,24 (replacement of 1H, brs, D2O disappeared), 8,46 (1H, d, J=5,2 Hz), 8,54 (1H, brs), 8,69 (1H, d, J=8,4 Hz), to 9.66 (1H, s), of 10.25 (replacement 1H, brs, D2O has disappeared).

3. In a 100 ml flask was stirred methanesulfonate (11 g)obtained in the previous step, and water (60 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XXVII (5.3g).

Example 28 to Obtain compounds XXVIII

1. In a 250 ml triggerlevel flask were successively added 2-aminopyridine (5.0 g), 2-chloro-N-cyclopropyl-9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine (16.0 g), catalyst Pd(OAc)2(0.4 g), ligand 7 (0.4 g), tert-piperonyl sodium (7.5 g) and simple etilenglikolevye ether (130 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue PTS is attended by the method of columnar chromatography on silica gel and got conjugate (10.5 g). The output amounted to approximately 56,0% per aminopyridine.

3. 250 ml of odnogolosy flask were mixed conjugate (10 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (6 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (11,7 g).

1H-NMR (DMSO-d6, ppm) δ: 0,78 (2H, m), and 0.98 (2H, m), 2,39 (6H, s), 3,06 (1H, brs), 7,30 (1H, m), 7,47 (1H, d, J=8,8 Hz), 8,14 (1H, m), 8,30 (1H, s), of 8.47 (1H, s), 9,17 (replacement 1H, brs, D2O disappeared), 11,71 (replacement 1H, brs, D2O has disappeared).

3. In a 100 ml flask was stirred methanesulfonate (11 g)obtained in the previous step, and water (60 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XXVIII (5.0 g).

Example 29 to Obtain compound XXIX

1. In a 250 ml triggerlevel flask were successively added 4-aminopyridine (5.0 g), 2-chloro-N-cyclepro the Il-9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine (16.0 g), the catalyst Pd(OAc)2(0.4 g), ligand 7 (0.4 g), tert-piperonyl sodium (7.5 g) and simple etilenglikolevye ether (130 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (13,7 g). The output amounted to approximately 73.4% per aminopyridine.

3. 250 ml of odnogolosy flask were mixed conjugate (10 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (6 ml). All solids were dissolved to obtain a clear solution. Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (10,9 g).

1H-NMR (DMSO-d6, ppm) δ: 0,71 (2H, m)to 0.92(2H, m), 2,42 (6H, s), 3,05 (1H, brs), scored 8.38 (2H, brs), 8,54 (2H, m), is 8.75 (1H, s), 11,03 (replacement 1H, brs, D2O has disappeared).

3. In a 100 ml flask was stirred methanesulfonate (10 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XXIX (5.0 g).

Example 30 the connection XXX

1. In a 250 ml triggerlevel flask were successively added paranitroaniline (5.0 g), 2-chloro-N-cyclopropyl-9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine (10,9 g), catalyst Pd(OAc)2(0.3 g), ligand 7 (0.3 g), tert-piperonyl sodium (5.8 g) and simple etilenglikolevye ether (130 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (12.5 g). The output amounted to approximately 8.6 percent per aminopyridine.

3. 250 ml of odnogolosy flask were mixed conjugate (10 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (5 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (10.3 g).

1H-NMR (DMSO-d6, ppm) δ: 0,70 (2H, m), of 0.95 (2H, m), 2,48 (6H, s), 3,06 (1H, brs), 8,13 (2H, m), 8,19 (2H, m), 8,49 (1H, brs), 8,99 (1H, s), 10,26 (1H, s).

3. In a 100 ml flask was stirred methanesulfonate (10 g)obtained in the previous step, and water (50 ml) and was heated with constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and got the connection XXX (5,1 g).

Example 31 the connection XXXI

1. In a 250 ml triggerlevel flask were successively added para-toluidine (5.0 g), 2-chloro-N-cyclopropyl-9-(tetrahydro-2H-Piran-2-yl)-N-purine-6-amine (13,7 g), catalyst Pd(OAc)2(0.4 g), ligand 7 (0.4 g), tert-piperonyl sodium (7.5 g) and simple etilogy ltimately ether (130 ml). The above mixture was stirred and heated to deregulirovania, and the reaction mixture proceeded for 2.5 hours while delegirovano. Completion of reaction was checked by thin layer chromatography. The reaction mixture was cooled to room temperature. After filtration the precipitate was fully washed simple etilenglikolevye ether 2 times, and the filtrate was concentrated until dry, the residue was purified by the method of columnar chromatography on silica gel and got conjugate (12.3 g). The output amounted to approximately 72.3% in the calculation aminopyridine.

3. 250 ml of odnogolosy flask were mixed conjugate (10 g)obtained in the previous step, acetone (60 ml) and water (60 ml). The above mixture was stirred and was heated and then added methanesulfonyl acid (6 ml). Further, in the above mixture reaction proceeded for 1 hour at delegirovano, and occur naturally cooling the mixture to room temperature after mixing. After filtration the precipitate was washed with acetone 3 times, then dried under vacuum at 40°C for 6 hours and got methanesulfonate (10.8 g).

1H-NMR (DMSO-d6, ppm) δ: 0,79 (2H, m), 0,97 (2H, m), of 2.34 (3H, s), is 2.44 (6H, s), 7,21 (2H, d, J=8,4 Hz), of 3.07 (1H, brs), to 7.67 (2H, d, J=8,4 Hz), 8,49 (1H, s), of 9.56 (1H, brs).

3. In a 100 ml flask was stirred methanesulfonate (10 g)obtained in the previous step, and water (50 ml) and was heated at p is constant stirring until it dissolves. To the mixture was added 10% potassium carbonate solution, the pH value was regulated to about 10, and then stood solid. The above mixture was cooled and filtered, the precipitate washed with acetone, dried under vacuum and obtained compound XXXI (5.0 g).

Tests were carried out on the antitumor activity in vitro and in vivo using the compounds obtained in the above examples. When used in vitro method of analysis sulforhodamine and method of the MTT assay, and the duration was approximately 72 hours. Specific data on the activity are shown in table 1. Data on the inhibitory effect of compounds on the growth of cancer Conlon26 in mice are shown in table 2, and the inhibitory effect of compounds on the growth of sarcoma S180 in mice are shown in table 3.

Table 1.
Determination of anticancer activity of compounds in vitro IC50(µm)
RoomThe sequence number of connectionsNon-small cell lung cancerColon cancer HT-29Cancer human liver Bel-7402Cancer of the lymph nodes Ramos
1 ADR0,050,380,020,19
2I3,618,611,585,78
3IV2,280,380,670,67
4VII6,654,010,231,27
5X12,4924,151,784,96
6XI17,2318,294,585,95
7XIII1,711,94of 3.463,01
8XIV1,33 2,22to 4.622,93
9XV3,364,275,462,87
10XXI6,272,742,332,33
11XXIIIof 13.185,725,912,63
12XXIVof 11.69>100>100>100
13XXV13,82,255,285,28
14XXVI3,113,131,291,29
15XXVIII61,4181,4180,1 51,91
16XXIXat 7.5516,774,894,14
17XXX11,09>100>100>100
Note: ADR is a control drug, i.e. by adriamycin.

Table 2.
Inhibitory effect of compounds on the growth of cancer Conlon26 in mice
GroupConnectionDose (mg/kg)The route of administration of medicationInitial body weight (g)Final body weight (g)Weight of tumor (g)The weight of the body after removal of the tumor (g)Ingabire-
of (%)
XC-4AI150oral21,10 17,960,4317,26of 76.52
XC-4AI100oral19,4718,150,6917,4662,25
CS-4BXX150oral19,9018,680,3818,3179,47
CS-4BXX100oral19,6418,740,5118,2372,31
XC-4CXII150oral19,1618,280,9117,3650,16
XC-4CXII 100oral19,0619,161,1917,9835,18
XC-4DIV150oral20,1018,410,8317,5754,45
XC-4DIV100oral20,0919,321,2218,1033,31
CTX30Intraperi-
Topolino
20,0320,330,4019.93 pera 78.14
Negative control19,7820,441,8318,61

The explanation is of: oral means a drug via the oral probe; IPR means the introduction of the drug by abdominal injection. MMS means cyclophosphamide for injection.

Table 3.
Inhibitory effect of compounds on the growth of sarcoma S180 in mice
GroupConnectionDose (mg/kg)The route of administration of medicationInitial body weight (g)Final body weight (g)Weight of tumor (g)The weight of the body after removal of the tumor (g)Ingabire-
of (%)
XC-4AI200oral18,9716,040,6815,3670,21
XC-4AI100oralto 19.7418,320,7117,6168,3
CS-4BXX200oral19,58Ls 16.800,6116,2073,38
CS-4BXX100oral19,9616,530,6315,9072,19
XC-4CXII200oral19,4621,351,2120,1446,96
XC-4CXII100oral19, 22 the22,581,6320,9428,19
XC-4DIV200oral19,491,0218,1055,37
XC-4DIV100oral18,9920,771,5519, 22 the31,95
CTX30intraperi-
Neale
19,6520,310,4619,8579,82
Negative control18,7723,042,2820,77

Explanation: oral means a drug via the oral probe; IPR means the introduction of the drug by abdominal injection. MMS means cyclophosphamide for injection.

Data about activity in vitro in table 1 show that most of the compounds have a certain antitumor activity, while compounds I, VII, XIII, XIV, XV, XXI, and XXVI are the higher antitumor activity against four different cancer cells, in particular, the potency of the compound IV is maximum. In accordance with the certain result of activity in vivo at a dose of 100 mg/kg compound I has a stronger inhibitory effect on cancer and Colon26 sarcoma S180 in mice. Compared with the connection I connection XX has a stronger antitumor effect. At a dose of 100 mg/kg% inhibition of compound XX in relation to cancer Colon26 in mice reaches 72,31%, and the percentage of inhibition of sarcoma S180 in mice - 72,19%.

1. The compounds of formula (A) or their salts:

in which:
W represents monosubstituted With3-C6alkenylamine straight or branched chain, disubstituted With1-C6alkylamino straight or branched chain, disubstituted With3-C6alkenylamine straight or branched chain or residue of pyrrolidine, piperidine, research or piperazine, which selectively may have substituents selected from C1-C6the alkyl or hydroxy;
Y denotes H or a pharmaceutically acceptable saccharide, in which the saccharide means any of the following formulas:
,,,;
Z represents H,
Q denotes any of the below formula:
,,,
,,,

in the above formulas, b, E, G, R, T, M each independently represents N or C1-C6alkyl or haloalkyl straight or branched chain, halogen, methoxy or ethoxyl, with the exception of the compounds: N6-t-butyl-N2-(2-methyl-quinoline-6-yl)-N-purine-2,6-diamine, N6-t-butyl-N2-quinoline-6-yl-N-purine-2,6-diamine, N6-(1,1-dimethyl-propyl)-N2-quinoline-6-yl-N-purine-2,6-diamine.

2. The compounds of formula (A) or their salts according to claim 1, in which W denotes a dimethylamino, diethylamino, methylethylamine, allylamino, methylethylamine, ethylethylene, propylethylene, diallylamine, ethanolamine or any of the following formulas:
,,,,,
,,.

3. The compounds of formula (A) or their salts according to claim 1, in which Y represents H; W represents dimethylamino, diethylamino, methylethylamine, allylamino, diallylamine or any of the following formulas:
,,, ,,
,.

4. The compounds of formula (A) or their salts according to claim 1, in which Q denotes any of the below formula:
,

5. The compounds of formula (A) or their salts according to claim 1, in which the compound of formula (A) means any of the following connections:









6. Pharmaceutical composition for treatment of tumor diseases comprising compounds of formula (A)or their salts according to any one of claims 1 to 5 and a pharmaceutically acceptable excipient.

7. The pharmaceutical composition according to claim 6, in which the salt is a salt in which soedineniya acid, obtained by using organic or inorganic acid or salt is a salt of joining the Foundation, obtained by using organic or inorganic bases; acid is hydrochloric acid, sulfuric acid, Hydrobromic acid, methanesulfonic acid, benzosulfimide acid, paratoluenesulfonyl acid, maleic acid, fumaric acid, lactic acid or citric acid.

8. The pharmaceutical composition according to claim 6 or 7, in which the pharmaceutical composition is made in the form of tablets, capsules, pills, liquid preparation for oral administration, granules, powder, injection, implant or of the preparation for external use.

9. The method of obtaining the above compounds according to formula (A)or their salts according to any one of claims 1 to 5, comprising the following steps:
1) at the first stage at 50-60°C. the compound (a) reacts with 2,3-dihydropyran in the presence of such catalysts as paratoluenesulfonyl acid, pyridinium salt paratoluenesulfonyl acid to protect the 9th nitrogen atom of the purine, then in the presence of triethylamine fragment W described in claim 1, is made by the condensation of a corresponding amine, pyrrolidine, piperidine, research or piperazine with the product obtained in the reaction of the compound (a) with 2,3-dihydropyrano, obtaining the soedineniya (b), during the reaction the molar ratio of compounds (a) to 2,3-dihydropyrano is approximately 1:1-5; and the ratio of compounds (a) to the reagent in step 2) is approximately 1:1-5;

TNR means the residue of the ether tetrahydropyranyl with four hydrogen atoms,
2) in the presence of catalysts, bases and proton solvent flows through catalytic reaction mix and the reaction of removing the protective groups and the salt formation between the compound (b) and Q-NH2when delegirovano order to obtain the compound (d); however, the molar ratio of the compound (b) to the Q-NH2approximately 1:0.5 to 2;


in the catalytic reaction of the combination of the ligand comprises a compound of formula 7;
;
the catalyst is a catalyst based on transition metal is palladium, such as PdCl2Pd(OAc)2Pd2(dba)3;
the reason is tert-piperonyl sodium tert-piperonyl potassium, potassium carbonate, cesium carbonate or tripotassium phosphate;
the reaction of removing the protective group and the salt formation could take place in an acidic medium such as hydrochloric acid, sulfuric acid, Hydrobromic acid, methanesulfonate acid, benzolsulfonat acid, paratoluenesulfonyl Isleta, maleic acid, fumaric acid, lactic acid or citric acid, with the molar ratio of the compound (C) to hydrochloric acid, sulfuric acid, Hydrobromic acid, methanesulfonic acid, benzosulfimide acid, paratoluenesulfonyl acid, maleic acid, fumaric acid, lactic acid or citric acid is about 1:1-10;
3) neutralization of the compound (d) sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide to obtain a compound (e),
.

10. The method of obtaining the above compounds of formula (A) or their salts according to claim 9, in which the reaction proceeds when exposed to microwave heating; the aprotic solvent is a tetrahydrofuran, a simple isopropyl ether, simple etilenglikolevye ether, dioxane, pyridine, 1-methyl-2-pyrrolidone (NMP), 1,3-dimethyltrimethylene (DMPU), toluene or xylene, or a mixture of solvents containing one or more solvents selected from the above.

11. The use of compounds of the formula (A)or their salts according to any one of claims 1 to 5 in the manufacture of a medicine for treatment or prevention of neoplastic diseases.

12. The use of compounds of the formula (A)or their salts according to claim 11, in which the tumor Soboleva what I include lung cancer, liver cancer, leukemia, osteosarcoma, pancreatic cancer, skin cancer, melanoma, microcarcinoma, oophoroma, rectal carcinoma, gastric carcinoma, colon carcinoma, breast carcinoma, carcinoma of the uterus, endometrial carcinoma, cervical carcinoma, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, carcinoma of the small intestine, carcinoma of endocranium, carcinoma of soft tissue, cancer of the urethra, prostate cancer, lymphocytoma, bladder cancer, kidney cancer or cancer of the urethra, cancer of the spine, neuroglial tumors of the brain and pituitary adenoma.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a monohydrate of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide through contact of a compound of formula

with aqueous methylamine at temperature equal to approximately 2.5-7.5°C. The invention also relates to a method of producing an intermediate compound of formula (4): involving reaction of a compound of formula (1) with 14.3-16.7-fold molar excess hydrazine hydrate at temperature equal to approximately 60-65°C to obtain the corresponding hydrazine of formula (2), followed by contact between the compound of formula (2) and excess ethyl-2-formyl-3-oxopropionate, optionally in the presence of an acid.

EFFECT: method enables to obtain, in a single step, a crystalline compound in form of a monohydrate and also exclude undesirable impurities of the compound of formula 2 in the end product owing to use of intermediate product 4.

15 cl, 7 ex, 5 dwg

FIELD: medicine, pharmacology, bioorganic chemistry, pharmacy.

SUBSTANCE: invention relates to the effective using amount of β-L-2'-deoxynucleoside of the formula (I) or (II) used in manufacturing a medicinal agent used in treatment of hepatitis B, pharmaceutical compositions containing thereof, and methods for treatment of hepatitis B. Proposed agent shows the enhanced effectiveness in treatment of hepatitis B.

EFFECT: enhanced and valuable medicinal properties of agent.

83 cl, 6 tbl, 11 ex

The invention relates to certain oxipurinol the nucleosides, compounds related data oxipurinol the nucleosides, acyl derivatives and compositions that contain at least one of these compounds

The invention relates to novel acyl derivatives of guanosine formula I, inosine formula II, xanthosine formula III, deoxyinosine formula IV, deoxyguanosine formula V, inosine - 2',3'-(acyclic)dialcohol formula VI or pharmaceutically acceptable salts

The invention relates to O6substituted derivatives of guanine, method of their production and to their use for the treatment of tumor cells

The invention relates to a method for obtaining enriched beta-anomer nucleoside of the formula I, where T is fluorine and R is the corresponding nucleoside described in paragraph 1 of the formula

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula or to pharmaceutically acceptable salts thereof for treating the Flaviviridae infection, as well as to a pharmaceutical composition thereof, and to the use thereof in preparing a drug. In the compound of formula (IVa), the base* represents a purine or pyrimidine base; R1 and R2 together form a cyclic 3',5'-phosphate ester; R7 represents halogen, particularly F or Cl; Y3 independently represents H, F, Cl, Br or I.

EFFECT: preparing the compounds for treating the Flaviviridae infection.

22 cl, 32 ex, 4 dwg

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

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for large-scale production of a A2A_adenosine receptor agonist, particularly a monohydrate of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide: . The invention also discloses methods of producing intermediate products used to produce said monohydrate, and directly the monohydrate of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide.

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15 cl, 6 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a monohydrate of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide through contact of a compound of formula

with aqueous methylamine at temperature equal to approximately 2.5-7.5°C. The invention also relates to a method of producing an intermediate compound of formula (4): involving reaction of a compound of formula (1) with 14.3-16.7-fold molar excess hydrazine hydrate at temperature equal to approximately 60-65°C to obtain the corresponding hydrazine of formula (2), followed by contact between the compound of formula (2) and excess ethyl-2-formyl-3-oxopropionate, optionally in the presence of an acid.

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15 cl, 7 ex, 5 dwg

FIELD: chemistry.

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EFFECT: application of the compound in production of a drug for treatment of the disease connected with A2A receptors.

12 cl, 1 tbl, 57 ex

FIELD: pharmacology.

SUBSTANCE: invention refers to the compounds with formula (I) And to its pharmaceutically applicable salts, as well as to the use of these compounds as medical products, in particular for treatment of pain or inflammation, and to pharmaceutical compositions on the base of the compounds. In the given formula when X=Y=Z=OH, R1 is OCH2CF2CF3; phenoxygroup (substituted with 3-(4-trifluormethylphenyl), 3,4-dichlorine, (3-trifluormethyl, 4-fluorine), (3-trifluormethyl, 4-chlorine), (3-chlorine, 4-cyanogroup) or 3,5-bis (trifluormethyl)), 1-piperazinyl-(4-(3,4-dichlorphenyl)); phenyl group substituted with 3,4-dichlorine, 3,5-difluorine, or 3,5-bis(trifluormethyl) or 3,4,5-trifluorine); or 2-benzofuranil fragment; or when X=Y=OH and Z=OMe, R1 is OCH3, COH2CHF2, OCH2 cyclopentyl, O-(2,5-difluorphenyl) or (S)-sec-butyl aminogroup; or when X=H and Y=Z=OH, R1 is n-hexylamino- or cyclopentylaminogroup; or when X=Z=OH and Y=H, R1 is cyclopentylaminogroup.

EFFECT: enhanced treatment of pain or inflammation.

25 cl, 23 ex, 21 dwg

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.

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15 cl, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula or to its pharmaceutically acceptable salts, where W is cycloalkyl; Y is hydrogen or pharmaceutically acceptable saccharide of formula, or Z is hydrogen; Q is a substitute chosen from a group consisting from and each B, E, G, R, T and M is hydrogen.

EFFECT: invention refers to methods for preparing the compounds (A) and their salts, to the based pharmaceutical composition for treatment of cancers and the associated diseases, as well as to application of said compounds and their salts in making pharmaceutical preparations for prevention and treatment of cancers.

15 cl, 1 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to phosphoramidite derivatives of general formula where Bx denotes adenine, guanine, cytosine, thymine or uracil, where the amine group of adenine, guanine and cytosine can be optionally protected by a protective group selected from acetyl and phenoxyacetyl; R1 is a substitute of general formula in which R11, R12 and R13 are identical or different, and each denotes hydrogen or alkoxy; R2a and R2b are identical or different, and each denotes alkyl; and WG1, WG2 denote a cyano group. The invention also pertains to a multistep method of producing the said compounds. The invention also relates to intermediate compounds of the said method, namely: an intermediate ether compound of general formula where L is a halogen or a C1-C5alkylthio group; WG1 is a cyano group; an intermediate compound of general formula where Bx denotes adenine, guanine, cytosine, thymine or uracil, where the amine group of adesine, guanine and cytosine can be optionally protected by a protective group selected from an acetyl group and a phenoxyacetyl group; and WG1 denotes a cyano group; an intermediate compound of general formula where Bx is as described above; R1 is a substitute of general formula (2); an intermediate compound of general formula where Bx is as described above; A is a silicon-containing substitute of general formula or where R6 denotes alkyl and WG1 denotes a cyano group. The invention also relates to a method of producing an oligonucleotide of general formula where each B independently denotes adenine, guanine, cytosine, uracil or thymine; each R independently denotes H or hydroxyl and at least one of R denotes hydroxyl; Z denotes H or a phosphate group; and n is an integer between 1 and 100, involving steps A-G, characterised by use of said phosphoramidite derivatives as a monomer compound of nucleic acid at step B.

EFFECT: high yield.

7 cl, 1 dwg, 21 ex

FIELD: chemistry.

SUBSTANCE: in compound of formula (I): , R1 represents C1-4-alkoxy C3-6cycloalkyl optionally substituted with atom of halogen, hydroxyl, trifluoromethyl, optionally substituted with halogen atom 5-6-member heterocyclyl, in which heteroatoms are selected from oxygen, optionally substituted with halogen atoms phenyl or optionally substituted with halogen atoms 5-6-member heteroaryl, in which heteroatoms are selected from nitrogen and/or sulfur; R2 represents hydrogen or trifluoromethyl; R3 represents hydrogen, optionally substituted with atom of halogen, C3-6cycloalkyl, optionally substituted with atom of halogen, trifluoromethyl, C1-4-alkyl phenyl, optionally substituted with atom of halogen, trifluoromethyl, C1-4-alkoxy heterocyclyl, which has in ring 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, or optionally substituted with C1-4-alkyl 5-6-member heterocyclyl, which has in ring 1-2 heteroatoms, selected from nitrogen or oxygen, R4 and R5 independently represent hydrogen; X represents covalent bond or lower alkylene; X1 represents covalent bond or lower alkylene, Y represents covalent bond or lower alkylene, optionally substituted with hydroxy or cycloalkyl; and Z represents -C=C-, -R6C=CR7- or -CHR6CHR7-, where R6 and R7 in each position represent hydrogen or lower alkyl.

EFFECT: antilipolytic effect of compounds.

30 cl, 7 dwg, 31 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

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

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

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