N2-quinolyl- or isoquinolyl-substituted purine derivatives, methods for preparing and using thereof

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

 

The present invention relates to pharmaceutical chemistry and particularly to the N2-chinolin or ethanolic-substituted purine derivative, processes for their preparation, pharmaceutical compounds comprising these derivatives, and methods of using these derivatives in the treatment of cancer.

Cancer remains a major threat to human health. The majority of cancers in humans caused by environmental factors, and millions of people die every year from cancer worldwide. Although many methods of treatment, such as surgery, radiation therapy, chemotherapy, etc. are available, their therapeutic effect is generally quite low. Therefore, the use of pharmaceutical drugs remains one of the most effective ways to prevent and treat cancer.

Derivatives of purine or pyridine are known to possess antiviral or antitumor activity. See, for example, patent documents EP 173624, EP 253412, EP 353955, WO 9201698, EP 481214, etc.

In natural or synthetic derivatives of pyridine nucleotides or purine or another heterocyclic group is in position 1 Zaharenko rings (corresponding to position 2 hydroxylamine derivatives of furan). These compounds was reported to have antitumor or antiviral activity.

Another group PR is svodnik, About6-alkyl derivatives of purine, known for their ability to inhibit the activity Of6-alkylguanine-DNA alkyltransferase (AGT), thereby improving the effectiveness of alkylating agents as drugs cancer chemotherapy.

Although it is not yet clear what the mechanism of destruction of the cancer cell On6-methylguanine in cells with a deficit Atasi (adenylyltransferase), in General it is understood that the mechanism of action Of6-chloroethylamine due to the presence of collateraldamage intermediate, which forms the cross-linkage of DNA strands. Such crosslinking can be eliminated or prevented by Dichlorotoluene with the participation of Atasi, for example, using AGT. Methods of blocking On6-alkylguanine-DNA alkyltransferase (AGT) in tumor cells is described, for example, in U.S. patent No. 5091430 and in the international application WO 9113898.

N-Substituted derivatives of purine known. For example, N6-disubstituted purine derivatives that can be used for treating allergies, described, for example, in U.S. patent 4853386. Derivatives of 6-cyclopropylamino-N-purine, has antiviral properties, described in the Japan patent JP 2003-55377 a and JP 2003-119197 A. glycosylated Derivatives of purine, which has anti-inflammatory properties, described in the journal of Org. Chem. (2004, 69:3212-3215). Derivatives of N2-butylphenyl-2'-detox the purine which have the properties of inhibition of eukaryotic DNA polymerase α, described in the journal of Med. Chem. (1984, 27:175-181). 2,6,9-Substituted purine derivatives described in the journal Tetrahedron Letters (1998, 39:1827-1830).

However, any one of the aforementioned compounds was not known to have antitumor activity or had the ability to inhibit abnormal cell growth. Accordingly, there is a need to anticancer drugs, which could be used as antitumor agents with low toxicity, broad spectrum anti-carcinogenic action and high stability.

DISCLOSURE of INVENTIONS

The present invention relates to highly stable N2-substituted purine derivative with low toxicity and high antitumor activity.

The invention relates to compounds having the following formula (A):

where W represents hydrogen, optionally substituted linear or branched C1-6alkyl, optionally substituted C3-6cycloalkyl or optionally substituted C1-6haloalkyl;

Y represents hydrogen or a pharmaceutically acceptable saccharide any of the following formulas:

,,,;

Z represents hydrogen or a Deputy, having any of the following formulas:

,,;

Q represents a Deputy, having any of the following formulas:

,,,
,,,
,,,
,,,
,

and b, E, G, R, T and M each independently represents hydrogen, linear or branched C1-6alkyl or haloalkyl,3-6cycloalkyl, halogen, cyano or amino.

Preferably in the compound according to the invention having the formula (A), W represents hydrogen or a Deputy, having any of the following formulas:

,,,,

,,,,

,

More preferably, W represents one of:

,,,

Most preferably, W represents:

or

In one of the preferred implementations of the compounds according to the invention having the formula (A), Q represents:

, ,,
,

More preferably Q represents the following group:

.

In one of the preferred implementations of the compounds according to the invention having the formula (A), Deputy b, E, G, R, T, or M each independently represents hydrogen, fluorine, methyl, trifluoromethyl, cyano or amino, mainly hydrogen.

In one of the preferred implementations of the compounds according to the invention having the formula (A), Y represents hydrogen.

Most preferred are the following compounds:

The compound (I)

p>

it is especially preferred.

Other implementation of the present invention is a library of compounds, which includes any of the above described compound, or its salt or its hydrate.

The present invention discloses also a method of obtaining the above-described compounds. In one implementation of the compounds according to the invention can be obtained in accordance with the following schema.

1) the Reaction is carried out with the participation of the compounds of formula (a) and Q-NH2

with the obtained compounds of formula (b)

The above reaction is carried out in an organic solvent with the participation of the compounds of formula (a) and Q-NH2when a molar ratio of 0.8 to 1.5; the mixture is heated at a temperature of 50-150°C and the reaction continued for 1-72 hours. Then to the reaction mixture, water is added and the reaction mixture is allowed to cool at room temperature. X represents bromine.

2) Preparation of the compounds of formula (C)

The reaction is carried out in an organic solvent with the participation of the compounds of formula (b) and halogenation agent; the mixture is heated at 50 to 150°C and the reaction continued for 1-72 hours, after which the reaction mixture, the cooling gap is up. Then add water and with acid adjusted pH of the mixture to a value of 2-5, after which the mixture is allowed to cool at room temperature. X' represents chlorine.

(3) Preparation of the compounds of formula (f)

The reaction is carried out in an organic solvent with the participation of the compounds of formula (C) and W-NH2when a molar ratio of 0.8-1.5 in the presence of an acid acceptor, the mixture is heated at 50 to 150°C., and the reaction continues for 1-72 hours. Then the solvent is removed by distillation.

According to another embodiment of the present invention also provides a method of obtaining the corresponding salts of the aforementioned compounds.

Compounds according to the invention can be prepared in accordance with the following schema.

1) the Reaction is carried out with the participation of the compounds of formula (k) and W-NH2

with the obtained compounds of formula (e)

The reaction is carried out in an organic solvent with the participation of the compounds of formula (k) and W-NH2when a molar ratio of 0.8-1.5 in the presence of an acid acceptor; the mixture is heated at a temperature of 30-120°C., and the reaction continues for 1-72 hours. Then the solvent is removed by distillation. X is bromo, X' is chlorine, and W as above.

2) Received the E. the compounds of formula (f) by reaction of compounds of formula (e) Q-NH 2

The reaction is carried out in an organic solvent with the participation of the compounds of formula (e) and W-QH2when a molar ratio of 0.8-1.5 in the presence of an acid acceptor. The mixture is heated at a temperature of 70-170°C., and the reaction continues for 1-72 hours. Then the solvent is removed by distillation. Salt of the compounds of formula (a) may be any pharmaceutically acceptable salt, known to specialists in this field. Additive salts of the compounds may be synthesized with the participation of organic or inorganic acids, preferably such as hydrochloride, hydrobromide, hydroiodide, p-toluensulfonate, phosphate, sulfate, perchloric, acetate, triptorelin, propionate, salt, citric acid, malonate, succinate, lactate, oxalate, tartrate, benzoate. Salt can also be formed by reactions involving basis as inorganic and organic salts of alkaline earth metals such as magnesium salts, calcium salts, organic amines, such as morpholine, piperidine, dimethylamine, diethylamine etc.

In the preferred embodiment of the compounds according to the invention can be obtained in accordance with the following paths a and B.

The path And

Path B

Pharmaceutical dial on offer is emomo the invention it is possible to enter mammals (including humans) internally (for example, oral or rectal), topically or parenterally, or by inhalation injection, for example, in the oral cavity, injection, implant, or applied externally. Suitable forms for oral administration include tablets (such as regular tablets, buccal tablets, sublingual tablets, oromucosal tablets (tablets for use in the oral cavity), chewable tablets, dispersible tablets, soluble tablets, effervescent tablets, vaginal tablets, vaginal effervescent tablets, slow release tablets, tablets with kontroliruemym-release tablets with intersolubility coating, buccal tablets fast release), capsules (hard capsules, soft capsules, capsule slow-release capsules controlled release capsules with intersolubility coating and so on), pills (microvilli, sweetened pills, pills), liquid dosage forms for oral administration (syrups, oral solutions, suspensions, emulsions, etc.), granules (granules for suspension, effervescent granules, granules with intersolubility coating granules of slow-release pellets with controlled-release and so on), powders; injectable dosage forms, including solutions for injection, sterile powders for injection or sterile solid cha is based (including drugs, obtained using technologies crystallization of the solvent, spray drying or freeze drying (lyophilization), and so on), concentrated solutions for injection, implants, and dosage forms for external use, such as candles, aerosols, aerosol powders, sprays, films, gels, plasters, etc.

The pharmaceutical preparation according to the invention can be prepared by any known in the pharmaceutical field by the method of preparation of dosage forms. It can be used for the treatment of cancer and related diseases, both independently and in combination with another or with other anticancer drugs. The number of active component that is added to the filler to prepare a dosage form may differ depending on the object of treatment and method of administration.

Compounds according to the invention can be used for the prevention or inhibition of abnormal cell proliferation, especially in tumors or cancers, including lung cancer, liver cancer, leukemia, osteosarcoma, pancreatic cancer, skin cancer, melanoma, microcarcinoma, oophoroma, rectal carcinoma, gastric carcinoma, colon cancer, breast cancer, salpingectomy, carcinoma membrane of the uterus, karzi the WMD cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, carcinoma of the small intestine, endocrine carcinoma, sarcoma of soft tissue, cancer of the urethra, prostate cancer, lymphocytoma skin, bladder cancer, cancer of the kidney or ureter, cancer of the spine, tumors of the brain and pituitary adenoma.

Studies of the compounds according to the invention, in experiments on the inhibition of growth of tumor cells in vitro, it was found that these compounds show a remarkable inhibitory effect on cell growth of lung cancer in men, liver cancer and leukemia, incubated in vitro, as well as the dependence of the inhibitory effect is dose-dependent. For the best compound of the formula I, the value of the IC50=11,22 mg/ml for cancer cells human liver, IC50=12,8 mg/ml for cell leukemia (blood cancer) human and IC50=10,24 mg/ml cell lung cancer person. When the pharmaceutical compound according to the invention was administered to mice by intraperitoneal injection, the value of LD50for mice was 160 mg/kg

In the experiment on inhibition of tumor N22liver cancer mice a dose of 80 mg/kg inhibitory effect of these drugs was 69%.

The compounds may find use in the treatment of tumors in combination with chemotherapy, radiotherapy and biological therapy to improve treatment efficiency and smart the sewing pharmaceutical side effects.

PHARMACOLOGICAL EXPERIMENTS

Antitumor activity of the compounds was determined on the example compounds I.

The connection I

1. The definition of the IC50(Lewis lung cancer).

(a) cells of Lewis lung cancer grown in an environment of DMEM containing 15% calf serum, were made in 96-well plate with 1×104cells/well and the plate was placed at 37°C in 5% CO2- incubator. The compound was diluted to the appropriate concentration with DMEM containing 15% calf serum. Was added to the diluted solution in each well of 96-hole tablet, 3 wells for each concentration and 6 holes for net control. After 72 hours of incubation solution was added MTT and incubated for 1 hour, then was added DMSO to enhance color and was determined by the absorbance value on the analyzer using the enzyme label. To calculate the lethal dose of each concentration was estimated IC50graphical method.

Lung cancer Lewis: IC50=10,24 mg/ml

(b) Defined IC50=11,22 mg/ml of compound I for cancer cells human liver by the same above-mentioned testing method.

(c) Defined IC50=12,8 mg/ml of compound I to cell leukemia (blood cancer) person with the same above-mentioned testing method. Thus it is shown that this link is has the ability to inhibit tumor cell growth.

2. Remarkable antitumor activity.

(a) Divided arbitrarily 30 mice (Kunming line), male and females equally, with the weight on 21-22 g, 3 groups, each of which consisted of 10 mice. Vaccinated cells H22liver cancer in 0.2 ml each mouse subcutaneously in the right side of the abdomen. The next day continuously for 7 days was administered intraperitoneally injected once a day 80 mg/kg and 40 mg/kg of compound I mice, respectively, each of the two groups separately. The control group mice were injected intraperitoneally DMSO + saline. The next day after stopping the introduction of the mice killed, identified the body weight and tumor weight of each mouse, and calculated the degree of inhibition of tumor growth. The compound had an obvious antitumor activity against H22with the degree of inhibition of tumor growth 69% and 40% at the dosage of 80 mg/kg and 40 mg/kg, respectively.

The degree of inhibition of compound I for liver cancer
DoseBody weight (g)Weight of tumor (g)The degree of inhibition (%)
To After
80 mg/kg20,621,40,5269
40 mg/kgof 21.925,80,9940
Control21,329,71,62

(b) Inhibition of growth of cancer cells in vitro

Treated cell lung cancer man (Lewis) and leukemia cells doses of compound I to 8 mg/ml and 16 mg/ml, the observed growth of cells within 4 days. The difference between groups, which were treated and control group during the first two days were insignificant, but starting from the third day, the number of cells in the groups exposed to treatment dramatically decreased, and the cancer cells in the control group were growing logarithmically. This difference between groups increased over time.

The above pharmacological experiments show that the above compound according to the invention has the obvious effect of inhibiting the growth of liver cancer cells, leukemia cells (solid plots the ol and soft tumor) and the corresponding dose-response.

Examples of carrying out the invention

The invention is illustrated below by examples of implementation that are used only in order to disclose the technical nature of the invention but do not limit the invention.

Examples 1-3

The formation of compounds I, II and III.

The path And

Example 1. The connection I

1) 200 ml of water, 20 g (93 mmol) of 2-poslednego gipoksantina, 13 g (90 mmol) of 6-aminoquinoline mixed with 60 ml of monoethylene ether of ethylene glycol and the mixture is boiled under reflux for 48 hours, the completion of reaction was checked by thin-layer chromatography (TLC). Then the reaction mixture was poured into ice water, the separated solid phase by filtration, washed with 200 ml of concentrated ammonia water and 3×50 ml of methanol and dried. The resulting crude product was purified column chromatography on silica gel to obtain the result of 14.2 g of compound 2 (yield 57%).

2) 12 g (43 mmol) of compound 2, 150 ml of phosphorus oxychloride and 15 ml of N,N-xylidine was mixed, and the mixture is boiled under reflux for 30 minutes. Then the reaction mixture is poured into 2000 ml of ice water. After 2 hours the pH value of the mixture was adjusted with acetic acid to pH=3. The solid phase was separated by filtration. The resulting crude product was purified column chromatography is and silica gel to obtain the result 11.5g chloride 3 (yield 90%).

3) Were mixed 10 g (34 mmol) of the chloride of 3, 10 ml (145 mmol) of cyclopropylamine, 28 ml (200 mmol) of triethylamine and 100 ml of DMF (dimethylformamide). The mixture was stirred at 100°C to maintain the reaction for 3 hours. Completion of reaction was checked by thin-layer chromatography (TLC). Then the solvent was removed by distillation, and the residue was dissolved in dimethyl ether of ethylene glycol. The mixture was filtered, the solvent of the filtrate was removed by distillation, and the obtained residue was purified column chromatography on silica gel with results in 7 g (22 mmol) of compound I (TPL>250°C), (yield 65%).

Compound I: 1H NMR (DMSO-d6, δ): 0,640-0,642 (2H, s), 0,845-0,860 (2H, m), 3,045 (1H, s), 7,0411-7,432 (1H, m), 7,632 (1H, s, the peak disappeared after the addition of heavy water), 7,865-7,888 (2H, m), 7,997-8,018 (1H, m), 8,116-8,136 (1H, m), 8,623-8,682 (2H, m), 9,242 (1H, s, the peak disappeared after the addition of heavy water), 12,400 (1H, s, the peak disappeared after the addition of heavy water). MS (ESI): 318 (M+N+), 340 (M+Na+).

Example 2. Obtaining the compound (II)

Mixed 10 ml of anhydrous acetonitrile, was 4.76 g (15 mmol) of compound I, obtained according to example 1, and 6.3 ml (25 mmol) of N,O-bis(trimethylsilyl)ndimethylacetamide. The mixture was stirred at room temperature for 1 hour. Dissolved 1.27 g (4 mmol) tetraarylborates in 10 ml of acetonitrile, then added to a mixture of 1.10 ml (16 mmol) of trimethylsilyltriflate (TSTF) and boiled with reverse holo is rinicom for 5 hours. To the mixture was added 1.25 ml (5 mmol) N,O-bis(trimethylsilyl)ndimethylacetamide and then was stirred for 24 hours. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 20 ml of methanol. The reaction mixture was treated with gaseous ammonia for 2 hours. The solvent was removed by distillation under reduced pressure. The obtained residue was purified column chromatography on silica gel, which results in the 4.65 g of compound (II) (yield 72%).

Compound II: MS (ESI): 450 (M+N+), 472 (M+Na+).

Example 3. Obtain compound III

Mixed 10 g (to 31.5 mmol) of 2-(6-aminoquinolyl)-6-cyclopropylamino, i.e. compounds I, obtained according to example 1, 1.5 g (37.8 mmol) of 60% NaH and 150 ml of anhydrous acetonitrile. The mixture was stirred for 30 minutes in nitrogen atmosphere. Then within 20 minutes to the mixture in portions added 12 g (to 31.5 mmol) of 3,5-di-para-toluenesulfonyl-2-deoxy-β-D-ribofuranosyl-1-chloride. The mixture was stirred at room temperature for 2 hours. The mixture was filtered, the solvent of the filtrate was removed by distillation. The residue was purified column chromatography on silica gel, to obtain the result of 9.8 g of 2-(6-aminoquinolyl)-6-cyclopropylamino-9-(3,5-di-para-toluenesulfonyl-2-deoxy-β-D-ribofuranosyl)purine (yield 47%).

The above product was added to 25 mmol of sodium methoxide and 400 ml of methanol. A mixture of AC is stirred at room temperature for 5 hours. Then the pH value of the mixture was adjusted with acetic acid to pH=7. The solvent was removed by distillation and the obtained residue was purified column chromatography on silica gel with results in 5 g of 2-(6-aminocell)-6-cyclopropylamino-9-(2-deoxy-β-D-ribofuranosyl)purine, that is, the compound III (yield 80%). Compound III: MS (ESI): 434 (M+H+), 456 (M+Na+).

Example 4. The connection I

Receiving compound I as described in example 1 under the following path:

1) of 3.78 g (20 mmol) of dichloropurine 4 was dissolved in 50 ml of DMF, was added to 1.4 ml (20 mmol) of cyclopropylamine and is 3.08 ml (22 mmol) of triethylamine. The reaction mixture was carried out at a temperature of 80°C for 5 hours. Completion of reaction was checked by thin-layer chromatography (TLC). Then the solvent was removed by distillation under reduced pressure, and the obtained residue was purified column chromatography on silica gel to obtain the result 3,34 g of compound 5 (yield 80%).

2) 2,99 g (of 14.3 mmol) of compound 5 was mixed with 5.1 g (36,1 mmol) 6-aminoquinoline, 50 ml of DMF and 2.4 ml (17,1 mmol) of triethylamine. The mixture was heated at 140°C under reflux for 72 hours. The TLC analysis confirmed that the reaction was essentially complete. The solvent was removed by distillation under reduced pressure. The obtained residue was purified column chromatography n is silica gel, to get of 3.54 g of compound I (yield 78%).

Examples 5-7 illustrate the formation of compounds IV, V, and VI.

Example 5. Obtaining compounds IV

1) was Mixed with 200 ml of water, 20 g (93 mmol) of 2-bromopyrimidine, 13 g (90 mmol) of 5-aminoquinoline and 60 ml nanometrology ether of ethylene glycol. The mixture was boiled under reflux for 48 hours. Completion of reaction was checked by thin-layer chromatography (TLC). The reaction mixture was cooled to room temperature and poured into ice water, the precipitate was separated by filtration, washed with 200 ml of concentrated ammonia water and three times with 50 ml of methanol, and then dried. The obtained residue was purified column chromatography on silica gel to obtain 8 g of the product 6 (yield 32%).

2) Mixed 12 g (43 mmol) of the product 6, 150 ml of phosphorus oxychloride and 15 ml of N,N-xylidine. The mixture was boiled under reflux for 30 minutes. The mixture was cooled to room temperature and then 2 hours poured into 2000 ml of ice water, the pH was brought to 3 with acetic acid. The yellow precipitate was isolated by filtration. The obtained residue was purified column chromatography on silica gel, to obtain 12.0 g of chloride 7 (yield 94%).

3) Mixed 10 g (34 mmol) of the chloride 7, 10 ml (145 mmol) of cyclopropylamine, 28 ml (200 mmol) of triethylamine and 100 ml of DMF. The mixture was heated at 100°C for 3 hours the century Completion of reaction was checked by thin-layer chromatography (TLC). The solvent was removed by distillation, after which the residue was dissolved in diethyl ether of ethylene glycol. The mixture was filtered, the solvent of the filtrate person to distil, and the resulting residue was purified column chromatography on silica gel to obtain 9 g of compound IV (yield 84%).

Part IV: MS (ESI): 318 (M+H+), 340 (M+Na+).

Example 6. Getting connection V

Mixed 10 ml of anhydrous acetonitrile, was 4.76 g (15 mmol) of compound IV obtained according to example 5, and 6.3 ml (25 mmol) of N,O-bis(trimethylsilyl)ndimethylacetamide. The mixture was stirred at room temperature for 1 hour. Dissolved 1.27 g (4 mmol) tetraarylborates in 10 ml of acetonitrile, then added to a mixture of 1.10 ml (16 mmol) TSTF and the mixture is boiled under reflux for 5 hours. Then added to a mixture of 1.25 ml (5 mmol) N,O-bis(trimethylsilyl)ndimethylacetamide and then was stirred for 24 hours. Completion of reaction was checked by thin-layer chromatography (TLC). The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 20 ml of methanol. The reaction mixture was treated with gaseous ammonia for 2 hours under reduced pressure. The solvent was removed by distillation. The obtained residue was purified column chromatography on silica gel to p in order to obtain 4,07 g of compound V (yield 63%).

Part V: MS (ESI): (M+H+), 472 (M+Na+).

Example 7. Obtaining compounds VI

Mixed 10 g (to 31.5 mmol) of compound IV, 2-(5-aminoquinolyl)-6-cyclopropylamino obtained in example 5, 1.5 g (37.8 mmol) of 60%NaH and 150 ml of anhydrous acetonitrile. The mixture was stirred for 30 minutes in nitrogen atmosphere. Then within 20 minutes added in portions to a mixture of 12 g (to 31.5 mmol) of 3,5-di-para-toluensulfonyl-2-deoxy-β-D-ribofuranosyl-1-chloride. The mixture was stirred at room temperature for 2 hours. Then the mixture was filtered and the solvent of filtrate was removed by distillation. The residue was purified column chromatography on silica gel, obtained 8.0 g of 2-(5-aminoquinolyl)-6-cyclopropylamino-9-(3,5-di-para-toluenesulfonyl-2-deoxy-β-D-ribofuranosyl)purine (yield 38%).

The above product was added to 25 mmol of sodium methoxide and 400 ml of methanol. The mixture was stirred at room temperature for 5 hours. The pH value of the mixture was brought to 7 with acetic acid. The solvent was removed by distillation and the obtained residue was purified column chromatography on silica gel to obtain 5.75 g of 2-(5-aminoquinolyl)-6-cyclopropylamino-9-(2-deoxy-β-D-ribofuranosyl)purine, i.e. compounds VI (yield 92%).

Compound VI: MS (ESI): 434 (M+H+), 456 (M+Na+).

Example 8. Obtaining compounds IV, an alternative example 5

The process of obtaining the soedineniya IV were as follows:

Mixed 2,99 g (of 14.3 mmol) of compound 5, 5,1 g (36,1 mmol) 5-aminoquinoline, 50 ml of DMF and 2.4 ml (17,1 mmol) of triethylamine. The mixture was heated at 140°C under reflux for 72 hours. Completion of reaction was checked by thin-layer chromatography (TLC). The solvent was removed by distillation under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain 2,88 g of compound IV (yield 63%).

Examples 9-11 illustrate the formation of compounds VII, VIII and IX.

Example 9. Obtaining compounds VII

1) In 200 ml of water was mixed with 20 g (93 mmol) of 2-pageposition, 13 g (90 mmol) of 8-aminoquinoline and 60 ml nanometrology ether of ethylene glycol, after which the mixture was boiled under reflux for 48 hours. Completion of reaction was checked by thin-layer chromatography (TLC). Then the reaction mixture was poured into ice water, the separated precipitate is filtered, washed it in 200 ml of ammonia water and CH ml of methanol and dried. The obtained residue was purified column chromatography on silica gel to obtain 11.4 g of product 8 (yield 46%).

2) Mixed 12 g (43 mmol) of compound 8, 150 ml of phosphorus oxychloride and 15 ml of N,N-xylidine and the mixture is boiled under reflux for 30 minutes. Then cooled the mixture to room temperature within 2 h the owls, then poured into 2000 ml of ice water. The pH value of the mixture was brought to 3 with acetic acid. The yellow precipitate was separated by filtration. The obtained residue was purified column chromatography on silica gel, obtained 10.3 g of chloride 9 (yield 81%).

3) Mixed 10 g (34 mmol) of the chloride 9 with 10 ml (145 mmol) of cyclopropylamine, 28 ml (200 mmol) of triethylamine and 100 ml of DMF. The mixture was stirred at 100°C for 3 hours. The solvent was removed by distillation, and the residue was dissolved in dimethyl ether of ethylene glycol. The mixture was filtered, the solvent of the filtrate was removed by distillation and the obtained residue was purified column chromatography on silica gel, received 6 g of compound VII (yield 56%).

Compound VII: VII: MS (ESI):318 (M+H+), 340 (M+Na+).

Example 10. Obtaining compounds VIII

10 ml of anhydrous acetonitrile was mixed with a value of 4.76 g (15 mmol) of compound VII and 6.3 ml (25 mmol) of N,O-bis(trimethylsilyl)ndimethylacetamide. The mixture was stirred at room temperature for 1 hour. Dissolved 1.27 g (4 mmol) tetraacetyl-ribofuranose in 10 ml of acetonitrile and then added to a mixture of 1.10 ml (16 mmol) TSTF. The mixture was boiled under reflux for 5 hours. Added to a mixture of 1.25 ml (5 mmol) N,O-bis(trimethylsilyl)ndimethylacetamide and then was stirred for 24 hours. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 20 ml of methanol. The reaction is th mixture was placed in an atmosphere of ammonia gas for 2 hours. The solvent was removed by distillation under reduced pressure. The obtained residue was purified column chromatography on silica gel to get 4.2 g of compound VIII (yield 65%).

Compound VIII: MS (ESI): 450 (M+H+), 472 (M+Na+).

Example 11. Getting connection IX

10 g (to 31.5 mmol) of compound VII, that is, 2-(8-aminoquinolyl)-6-cyclopropylamino, mixed with 1.5 g (37.8 mmol) of 60%NaH and 150 ml of anhydrous acetonitrile. The mixture was stirred for 30 minutes in nitrogen atmosphere. Then within 20 minutes to the mixture in portions was added 12 g (to 31.5 mmol) of 3,5-di-para-toluensulfonyl-2-deoxy-β-D-ribofuranosyl-1-chloride. The mixture was stirred at room temperature for 2 hours. Then the mixture was filtered, and the solvent of filtrate was removed by distillation. The oily residue was purified column chromatography on silica gel, received of 7.4 g of 2-(8-aminoquinolyl)-6-cyclopropylamino-9-(3,5-di-para-toluensulfonyl-2-deoxy-β-D-ribofuranosyl)purine (yield 35%).

The above product was added to 25 mmol of sodium methoxide and 400 ml of methanol. The mixture was stirred at room temperature for 5 hours. The pH value of the mixture was brought to 7 with acetic acid. The solvent was removed by distillation and the obtained residue was purified column chromatography column on silica gel, was obtained 3.2 g of compound IX (51%yield).

Connection IX: MS (ESI): 434 (M+N+), 456 (M+Na+).

Example 12. Obtaining compounds VII, alternative example 9

The process for obtaining compounds was carried out as follows:

2,99 g (of 14.3 mmol) of compound 5 was mixed with 5.1 g (36,1 mmol) 8-aminoquinoline, 50 ml of DMF and 2.4 ml (17,1 mmol) of triethylamine. The mixture was heated at a temperature of 140°C under reflux for 72 hours. Completion of reaction was checked by TLC. The solvent was removed by distillation under reduced pressure. The obtained residue was purified column chromatography column on silica gel, received 4,10 g of compound VII (yield 90%).

Examples 13-15 illustrate the formation of compounds X, XI and XII.

Example 13. Getting connection X

1) In 200 ml of water was mixed with 20 g (93 mmol) of 2-pageposition, 13 g (90 mmol) of 3-aminoquinoline and 60 ml nanometrology ether of ethylene glycol and the mixture is boiled under reflux for 48 hours. Completion of reaction was checked by TLC. Then the reaction mixture was poured into ice water, the solid precipitate was separated by filtration, washed with ammonia water (200 ml) and three times with methanol (3×50 ml) and dried. The obtained residue was purified column chromatography on silica gel, obtained from 15.0 g of compound 10 (yield 60%).

2) Mixed 12 g (43 mmol) of compound (10, 150 ml of phosphorus oxychloride and 15 ml of N,N-xylidine and the mixture is boiled the under reflux for 30 minutes. Then the mixture was cooled at room temperature for 2 hours. Then the reaction mixture is slowly poured into 2000 ml of ice water, the pH value of the mixture was brought to 3 with acetic acid. The yellow precipitate was isolated by filtration. The obtained residue was purified column chromatography on silica gel, received 10,9 g chloride 11 (yield 85%).

3) Mixed 10 g (34 mmol) of the chloride 11 with 10 ml (145 mmol) of cyclopropylamine, 28 ml (200 mmol) of triethylamine and 100 ml of DMF. The mixture was stirred at 100°C for 3 hours, the completion of reaction was checked by TLC. The solvent was removed by distillation, and the residue was dissolved dimethyl ether of ethylene glycol. The mixture was filtered, the solvent of the filtrate was removed by distillation and the obtained residue was purified column chromatography on silica gel, received the 10.1 g of compound X (yield 94%).

Connection X: MS (ESI): 318 (M+H+), 340 (M+Na+).

Example 14. Obtaining compounds XI

Mixed 10 ml of anhydrous acetonitrile, was 4.76 g (15 mmol) of compound X and 6.3 ml (25 mmol) of N,O-bis(trimethylsilyl)ndimethylacetamide. The mixture was stirred at room temperature for 1 hour. Then 1.27 g (4 mmol) tetraacetyl-ribofuranose, dissolved in 10 ml of acetonitrile, and 1,10 ml (16 mmol) TSTF added to the mixture and boiled under reflux for 5 hours. Then to the mixture was added 1.25 ml (5 mmol) N,O-bis(triethylsilyl)ndimethylacetamide, then eremetical within 24 hours and the completion of reaction was checked by TLC. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 20 ml of methanol. The reaction mixture was stirred in an atmosphere of ammonia gas for 2 hours. The solvent was removed by distillation under reduced pressure. The obtained residue was purified column chromatography on silica gel, received equal to 4.97 g of compound XI (yield 77%).

Compound XI: MS (ESI): 450 (M+H+), 472 (M+Na+).

Example 15. Obtaining compounds XII

Mixed 10 g (to 31.5 mmol) of compound X, 1.5 g (37.8 mmol) of 60%NaH and 150 ml of anhydrous acetonitrile. The mixture was stirred for 30 minutes in nitrogen atmosphere. Then within 20 minutes to the mixture was added in portions 12 g (to 31.5 mmol) of 3,5-di-para-toluensulfonyl-2-deoxy-β-D-ribofuranosyl-1-chloride. The mixture was stirred at room temperature for 2 hours. Then the mixture was filtered and the solvent of filtrate was removed by distillation. The oily residue was purified column chromatography on silica gel, obtained 8.8 g of 2-(3-aminoquinolyl)-6-cyclopropylamino-9-(3,5-di-para-toluensulfonyl-2-deoxy-β-D-ribofuranosyl)purine (yield 42%).

The above product was added to 25 mmol of sodium methoxide and 400 ml of methanol. The mixture was stirred at room temperature for 5 hours. The pH value of the mixture was brought to 7 with acetic acid. The solvent was removed by distillation and the obtained residue was purified of colonos the second chromatography on silica gel, received of 5.06 g of compound XII (yield 81%).

Compound XII: MS (ESI): 434 (M+N+), 456 (M+Na+).

Example 16. The connection is X, an alternative Example 9

The process of obtaining the connection is as follows:

Mixed 2,99 g (of 14.3 mmol) of compound 5 with 5.1 g (36,1 mmol) 3-aminoquinoline, 50 ml of DMF and 2.4 ml (17,1 mmol) of triethylamine. The mixture was heated under reflux at a temperature of 140°C for 72 hours. Completion of reaction was checked by TLC. The solvent was removed by distillation. The obtained residue was purified column chromatography on silica gel, received of 3.54 g of compound X (yield 78%).

Examples 17-19 illustrate the formation of compounds XIII, XIV and XV.

Example 17. Obtaining compounds XIII

1) In 200 ml of water was mixed with 20 g (93 mmol) of 2-pageposition, 13 g (90 mmol) of 1-aminoquinoline and 60 ml nanometrology ether of ethylene glycol and the mixture is boiled under reflux for 48 hours. Completion of reaction was checked by TLC. Then the reaction mixture was poured into ice water, the solid precipitate was separated by filtration, washed with ammonia water (200 ml) and three times with methanol (3×50 ml) and dried. The obtained residue was purified column chromatography on silica gel, obtained 14.2 g of compound 12 (yield 57%).

2) Mixed 12 g (43 mmol) of compound 12, 150 ml oxychloro is and phosphorus and 15 ml of N,N-xylidine and the mixture is boiled under reflux for 30 minutes. Then the mixture was cooled at room temperature for 2 hours. Then the reaction mixture is poured into 2000 ml of ice water, the pH was brought to 3 with acetic acid. The yellow precipitate was isolated by filtration. The obtained residue was purified column chromatography on silica gel, received 11.5g chloride 13 (yield 90%).

3) Mixed 10 g (34 mmol) of the chloride 13 with 10 ml (145 mmol) of cyclopropylamine, 28 ml (200 mmol) of triethylamine and 100 ml of DMF. The mixture was stirred at 100°C for 3 hours. Completion of reaction was checked by TLC. The solvent was removed by distillation, and the residue was dissolved dimethyl ether of ethylene glycol. The mixture was filtered, the solvent of the filtrate was removed by distillation and the obtained residue was purified column chromatography on silica gel quartz, got 4,2 g of compound XIII (yield 39%).

Compound XIII: MS (ESI): 318 (M+H+), 340 (M+Na+).

Example 18. Getting connection XIV

Mixed 10 ml of anhydrous acetonitrile, was 4.76 g (15 mmol) of compound XIII and 6.3 ml (25 mmol) of N,O-bis(trimethylsilyl)ndimethylacetamide. The mixture was stirred at room temperature for 1 hour. Then 1.27 g (4 mmol) tetraacetyl-ribofuranose, dissolved in 10 ml of acetonitrile, and 1,10 ml (16 mmol) TSTF added to the mixture and boiled under reflux for 5 hours. Then to the mixture was added 1.25 ml (5 mmol) N,O-bis(triethylsilyl)ndimethylacetamide, then re is shivali within 24 hours and completion of reaction was checked by TLC. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 20 ml of methanol. The reaction mixture was stirred in an atmosphere of ammonia gas for 2 hours. The solvent was removed by distillation under reduced pressure. The obtained residue was purified column chromatography on silica gel, received of 4.2 g of compound XIV (yield 64%).

Compound XIV: MS (ESI): 450 (M+H+), 472 (M+Na+).

Example 19. Obtaining compounds XV

Mixed 10 g (to 31.5 mmol) of compound XIII, 1.5 g (37.8 mmol) of 60%NaH and 150 ml of anhydrous acetonitrile. The mixture was stirred for 30 minutes in nitrogen atmosphere. Then within 20 minutes added in portions to a mixture of 12 g (to 31.5 mmol) of 3,5-di-para-toluensulfonyl-2-deoxy-β-D-ribofuranosyl-1-chloride. The mixture was stirred at room temperature for 2 hours. Then the mixture was filtered and the solvent of filtrate was removed by distillation. The oily residue was purified column chromatography on silica gel, got to 7.09 g of 2-(1-aminoquinolyl)-6-cyclopropylamino-9-(3,5-di-para-toluenesulfonyl-2-deoxy-β-D-ribofuranosyl)purine (yield 34%).

The above product was added to 25 mmol of sodium methoxide and 400 ml of methanol. The mixture was stirred at room temperature for 5 hours. The pH value of the mixture was brought to 7 with acetic acid. The solvent was removed, disti is the transmission, and the obtained residue was purified column chromatography on silica gel, obtained 3.8 g of compound XV (yield of 60.8%).

Compound XV: MS (ESI): 434 (M+H+), 456 (M+Na+).

Example 20. Obtaining compounds XIII, alternative example 17

The process of obtaining the connection is as follows:

Mixed 2,99 g (of 14.3 mmol) of compound 5 with 5.1 g (36,1 mmol) 3-aminoquinoline, 50 ml of DMF and 2.4 ml (17,1 mmol) of triethylamine. The mixture was heated under reflux at a temperature of 140°C for 72 hours. Completion of reaction was checked by TLC. The solvent was removed by distillation. The obtained residue was purified column chromatography on silica gel, received 4,16 g of compound XIII (yield 92%).

Examples 21-22 illustrate the formation of compounds XVI, XVII and XVIII.

Example 21. Obtaining compounds XVI

10 g (34 mmol) of compound 3 was mixed with 10.3 g (145 mmol) of cyclobutylamine, 28 ml (200 mmol) of triethylamine and 100 ml of DMF. The mixture was stirred at 100°C for 3 hours. Completion of reaction was checked by TLC method. The solvent was removed by distillation and the residue was dissolved with dimethyl ether of ethylene glycol. The mixture was filtered and the solvent of filtrate was removed by distillation and the obtained residue was purified column chromatography on silica gel, obtained 6.8 g of compound XVI (yield 60%).

<> Compound XVI: MS (ESI): 332 (M+H+), 354 (M+Na+).

Example 22. Obtaining compounds XVII

Mixed 10 ml of anhydrous acetonitrile, equal to 4.97 g (15 mmol) of the compound XVI and 6.3 ml (25 mmol) of N,O-bis(trimethylsilyl)ndimethylacetamide. The mixture was stirred at room temperature for 1 hour. Then 1.27 g (4 mmol) tetraacetyl-ribofuranose, dissolved in 10 ml of acetonitrile, and 1,10 ml (16 mmol) TSTF added to the mixture and boiled under reflux for 5 hours. Then to the mixture was added 1.25 ml (5 mmol) N,O-bis(triethylsilyl)ndimethylacetamide, then was stirred for 24 hours. Completion of reaction was checked by TLC. The solvent was removed by distillation under reduced pressure, and the residue was dissolved with 20 ml of methanol. The reaction mixture was stirred in an atmosphere of ammonia gas for 2 hours. The solvent was removed by distillation under reduced pressure. The obtained residue was purified column chromatography on silica gel, received 4.71 g of compound XVII (71%yield).

Compound XVII: MS (ESI): 464 (M+H+), 486 (M+Na+).

Example 23. Obtaining compounds XVIII

Mixed 10 g (to 31.5 mmol) of compound XVI, i.e. the 2-(6-aminoquinolyl)-6-cyclobutylamine, 1.5 g (37.8 mmol) of 60%NaH and 150 ml of anhydrous acetonitrile. The mixture was stirred for 30 minutes in nitrogen atmosphere. Then within 20 minutes added in portions to a mixture of 12 g (to 31.5 mmol) of 3,5-di-para-tawassul the Nile-2-deoxy-β-D-ribofuranosyl-1-chloride. The mixture was stirred at room temperature for 2 hours. Then the mixture was filtered and the solvent of filtrate was removed by distillation. The oily residue was purified column chromatography on silica gel, was obtained 2-(6-aminoquinolyl)-6-cyclobutylamine-9-(3,5-di-para-toluenesulfonyl-2-deoxy-β-D-ribofuranosyl)purine.

The above product was added to 25 mmol of sodium methoxide and 400 ml of methanol. The mixture was stirred at room temperature for 5 hours. The pH was brought to 7 with acetic acid. The solvent was removed by distillation and the obtained residue was purified column chromatography on silica gel, obtained 7 g of compound XVIII, i.e. the 2-(6-aminoquinolyl)-6-cyclobutylamine-9-(2-deoxy-β-D-ribofuranosyl)purine (output 51,8%).

Compound XVIII: MS (ESI): 448 (M+H+), 470 (M+Na+).

Example 24. Obtaining compounds XVI

The process of obtaining the connection is as follows:

1) of 3.78 g (20 mmol) of dichloropurine 4, dissolved in 50 ml of DMF, mixed with 1.4 ml (20 mmol) of cyclobutylamine and is 3.08 ml (22 mmol) of triethylamine. The mixture was stirred at a temperature of 80°C for 5 hours. Completion of reaction was checked by TLC. The solvent was removed by distillation under reduced pressure and the obtained residue was purified column chromatography on silica gel, obtained 4.1 g of compound 14 (o is d 92%).

2) Mixed 2,99 g (of 14.3 mmol) of compound 14 with 5.1 g (36,1 mmol) 3-aminoquinoline, 50 ml of DMF and 2.4 ml (17,1 mmol) of triethylamine. The mixture was heated under reflux at a temperature of 140°C for 72 hours. Completion of reaction was checked by TLC. The solvent was removed by distillation under reduced pressure. The obtained residue was purified column chromatography on silica gel, received 3,82 g of compound XVI (yield 81%).

Example 25. Getting hydrochloride and lactate connection I

Obtain hydrochloride of compound I.

Mixed 10 g (31,54 mmol) of compound I, 210 ml of ethanol and 25 ml of water. The mixture was heated to dissolve the compound I. Then to the mixture was added drip 0.7 ml (37,85 mmol) of an aqueous solution of HCl (2 mol/l). The mixture was boiled under reflux for 0.5 hours. Then the mixture was left to slowly cool to room temperature, and then cooled the mixture to a temperature below 5°C for 5 hours. A pale yellow precipitate was separated by filtration. Pale yellow residue after drying weighed 10 g (yield 90%). The melting temperature of the pale yellow residue was higher than 270°C.

Obtaining lactate compounds I.

Mixed 5 g of compound I, 105 ml (15,77 mmol) of 95% ethanol and 12.5 ml of water. The mixture was heated to dissolve the compound I. Then to the mixture was added drip 10% solution of lactic acid in ethanol. The mixture was heated with reverse hall is dildocam for 1 hour. Then the mixture was left to slowly cool to room temperature, and then cooled the mixture to a temperature below 5°C for 5 hours. A pale yellow precipitate was separated by filtration. Pale yellow residue after drying weighed 5.6 g (yield 87%). The melting temperature of the pale yellow residue was 239-248°C.

Example 26. Preparation of dosage forms

Preparation of coated tablets

The composition of core tablets:

The connection I50 g
Microcrystalline cellulose150 g
Lactose50 g
Natrocarbonatite starch25 g
The sodium carboxymethyl cellulose15 g
Microporosity silica gel1.5 g
On1000 tablets

The technological process. Mix accurately by weight of compound I and lactose, then add to the mixture the silica gel in order to improve fluidity. Add and mix other pharmaceutical adjuvants, and then perform direct tabla is the key.

The composition shell: coating Opadry 25 g in the amount of 80% ethanol.

Cooking injection

The composition of the injection:

Connection 150 g
Polysorbate 80 (Tween-80)20 g
Ethyl medical30 g
Water for injection is addedup to 10,000 ml
On1000 ampoules

The technological process. Mix accurately by weight of compound I and Tween-80 and pounded into powder, then add to the mixture of 0.3% ethyl alcohol to dissolve the compound I and Tween-80 with heat. The liquid is filtered to 0.22 µm membrane filter under sterile conditions, then poured into ampoules of 10 ml and sterilized in an autoclave at a temperature of 100°C.

1. The compound having the following formula (A):

or its pharmaceutically acceptable salt,
where W represents C3-6cycloalkyl;
Y represents hydrogen or a pharmaceutically acceptable saccharide, having a formula selected from the group consisting of:

Z represents hydrogen
Q represents a Deputy selected from the group consisting of:


E, G, R, T and M each represents hydrogen.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where W is a Deputy selected from the group consisting of:

3. The compound according to claim 1 or its pharmaceutically acceptable salt, where Y is hydrogen.

4. The compound according to claim 1 or its pharmaceutically acceptable salt, where W is a Deputy selected from the group consisting of:

and, E, G, R, T and M each represents hydrogen.

5. The compound according to claim 1 or 3, or its pharmaceutically acceptable salt, where W is selected from the group consisting of:
or
a Q is a Deputy selected from the group consisting of:

6. The compound according to claim 1 is whether its pharmaceutically acceptable salt, where Q is a

7. The compound according to claim 1, characterized in that its salts are pharmaceutically acceptable salts, which can be additive salts formed with inorganic or organic acids, preferably hydrochloric salt, Hydrobromic salt, itestosterone salt, p-toluensulfonate salt, phosphate salt, sulfate salt, chlorocichla salts, acetic acid salts, triperoxonane acid, propionate, citrates, malonate salt, succinate, salt, lactic acid, oxalate, tartrate salt and salt benzoate and salts that can be formed with bases, including inorganic or organic bases.

8. The compound according to claim 5, characterized in that it has a formula selected from the group consisting of the following formulae (I-XVIII):








9. The compound according to claim 5, characterized in that it has the formula I

10. Pharmaceutical composition for treatment of cancer and related diseases containing a compound according to any one of claims 1 to 9 or its salt in an effective amount, is selected depending on the object of treatment and the method of administration, and pharmaceutically acceptable filler.

11. The pharmaceutical composition of claim 10, characterized in that it has the form of tablets, capsules, pills, liquid preparation for oral administration, granules, powder, injection, implant or of the preparation for external use.

12. The method of obtaining the compounds of formula (A) according to any one of claims 1 to 9 and its salts, comprising the following operations:
(1) conducting the reaction of compounds of formula (a) Q-NH2when molar ratio of 0.8 to 1.5 in an organic solvent at a temperature of approximately from 50 to 150°C. for 1-72 h with getting through the first reaction mixture, adding water to the first reaction mixture and cooling the first reaction mixture at room temperature to obtain the compound of formula (b)

(2) conducting the reaction of compounds of formula (b) with a halogenation agent in an organic solvent at a temperature of from about 0 to 150°C. for 1-72 h to obtain the second reaction mixture, adding water to the second reaction mixture and regulating the pH of the second reaction mixture to approximately 2-5 using acid, and cooling the second reaction mixture at room temperature to obtain the compound of formula (C)

and
(3) conducting the reaction of the compound (C) W-NH2when molar ratio of 0.8 to 1.5 in an organic solvent in the presence of an acid acceptor at a temperature of approximately from 50 to 150°C. for 1-72 h followed by removal of the solvent by distillation, to obtain the compound of formula (f)

where X represents bromo, X' represents a chlorine, a W and Q are as defined in claim 1.

13. The method of obtaining the compounds of formula (A) according to any one of claims 1 to 9 and its salts, comprising the following operations:
(1) conducting the reaction of compounds of formula (k) with W-NH2when molar ratio of 0.8 to 1.5 in an organic solvent in the presence of an acid acceptor at a temperature of from about 30 to 120°C. for 1-72 h followed by removal of the solvent by distillation, to obtain the compound of formula (e)
and
(2) conducting the reaction of compounds of formula (e) Q-NH2when molar ratio of 0.8 to 1.5 in an organic solvent in the presence of the acceptor to the slots at a temperature of from about 70 to 170°C. for 1-72 h followed by removal of the solvent by distillation, to obtain the compound of formula (f)

where X represents chlorine, X' represents a chlorine, a W and Q are as defined in claim 1.

14. The use of compounds according to any one of claims 1 to 9 and their salts upon receipt of pharmaceutical preparations for the prevention and treatment of neoplastic diseases.

15. The application 14, characterized in that the said neoplastic disease is selected from the group comprising lung cancer, liver cancer, leukemia, osteosarcoma, pancreatic cancer, skin cancer, melanoma, microcarcinoma, oophoroma, rectal carcinoma, gastric carcinoma, colon cancer, breast cancer, salpingectomy, carcinoma membrane of the uterus, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, carcinoma of the small intestine, endocrine carcinoma, sarcoma of soft tissue, cancer of the urethra, prostate cancer, lymphocytoma skin, bladder cancer, cancer of the kidney or ureter, tumors of the spine, tumors of the brain and pituitary adenoma.



 

Same patents:

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 pertains to the method of obtaining 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine and can be used in organic chemistry and pharmaceutical industry. The method lies in that, 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine and sodium azide interact in the presence of the above mentioned tetrametylammonium chloride boiled for 4 hours in absolute acetonitrile. The obtained compound is cleaned by elution of benzol. The residue is dissolved in chloroform and the desired product is separated during precipitation using hexane.

EFFECT: high degree of purity with high output.

1 ex

FIELD: chemistry.

SUBSTANCE: method implies that suspension 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranozile)purine in 60% anhydrous hydrogen fluoride solution of pyridine is diazotizied with tert-butylnitrite during 1 hour at (-18) - (-22)°C. Reaction mixture is decomposed with cut ice. Reaction product is purified by, flash-chromatography on aluminum oxide. Then produced 2-fluorine-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranozile)purine is hydrogenated at air pressure in 10% acetic acid solution of absolute ethyl acetate with 10% palladium on carbon solution occurrence during 18 hours. Reaction product is purified in acetonitrile solution by flash-chromatography on aluminum oxide at 50-55°C and crystallized from alcohol.

EFFECT: production of compound of high purity with high output.

2 ex

FIELD: chemistry.

SUBSTANCE: invention applied for relates to process of obtaining 2,6- dichlor-9-(2,3,5-tru-O-acetyl-β-D-ribofuranozyl) purine and may be used in organic chemistry and pharmaceutical industry. The process involves conduction of 2,6- dichlor-9-(2,3,5-tru-O-acetyl-β-D-ribofuranozyl) purine with tret-butyl nitrite in the methylene chloride medium at (-18)-(-22)°C during 2 hours in presence of pyridine hydrochloride and phosphorus oxychloride followed by decomposing the reaction mixture with chipped ice, and cleansing of the target product in methylene chloride with flash-chromatography on silica gel.

EFFECT: obtaining of substance with high grade of purity and high output by simplified technology.

1 ex

FIELD: chemistry.

SUBSTANCE: this invention covers method of production of 2-chloroadenosine and may be used in organic chemistry and pharmaceutical industry. The method includes ammonolysis of 2.6-di-chloro-9-(2,3,5-tri-O-acetyl-(β-O-ribofuranozyl)purine in absolute ethyl acetate saturated with ammonia at 0°C during 3 days with further hydrolysis of obtained 5'-0-acetyl-2-chloro-adenosine with 20% ammonia solution in methanol at 20°C during 6 hours, isolation of desired product from the reaction mixture by boiling in mixture of chloroform and methanol, their volumetric ratio 3:1, and purification by crystallization from water.

EFFECT: production of substance with high purity.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds that are partial and complete agonists of adenosine A1 receptors of the formula (1): wherein R1 means cyclopentyl, cyclohexyl or tetrahydrofuranyl optionally substituted with hydroxy-group or -CO2CH2CH3; R2 means hydrogen atom; R3 means phenyl, isoxazole, thiophenyl or thiazolyl substituted optionally with one or more substitutes chosen from group comprising methyl, methoxy- group, fluorine atom and chlorine atom; R4 and R5 mean hydrogen atom; T means a covalent bond or methylene group; X means covalent bond; Y means -O-, -NH- or covalent bond; Z means alkylene group comprising of 1-3 carbon atoms. Proposed compounds can be used in treatment of different morbid states, in particular, tachycardia and atrium tremor, stenocardia, myocardium infarction and hyperlipidemia, and to a pharmaceutical composition based on these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

22 cl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): , wherein R1 represents lower alkyl or lower alkyl substituted with phenyl; X represents a covalent bond; R2 represents compound of the formula: R4-Z-Y-C≡C-, pyrazolyl substituted with phenyl, or pyrazolyl substituted with heteroaryl wherein Y represents alkylene; Z represents oxygen atom; R4 represents phenyl substituted with halogen atom or (lower)-alkoxy-group comprising 1-3 carbon atoms; R3 represents hydroxymethyl group. Also, invention relates to a method for synthesis of compounds of the formula (I) and to a pharmaceutical composition possessing effect of agonist of adenosine A3-receptors. Invention provides synthesis of novel biologically active compounds and pharmaceutical compositions based on thereof possessing effect of agonist of adenosine A3-receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

24 cl, 3 tbl, 18 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to oligomer comprising at least one nucleoside analogue of L-ribo-CNA of the general formula (Ia) wherein X represents -O-; B represents nitrogen base; P means radical position in an internucleoside linkage followed by monomer or 5'-terminal hydroxy-group; P* means an internucleoside linkage with precede monomer or 3'-terminal hydroxy-group; R2* and R4* mean in common biradical -(CH2)0-1-O-(CH2)1-3-(CH2)0-1-S-(CH2)1-3- or -(CH2)0-1-NR-(CH2)1-3- wherein R means hydrogen atom, alkyl or acyl; R1*, R2, R3*, R5 and R5* mean hydrogen atom. Also, invention proposes nucleoside analogues used in preparing oligomers. Proposed oligomers elicit the enhanced affinity to complementary nucleic acids and can be used as a tool in molecular-biological investigations and as antisense, antigen agents of agents activating genes.

EFFECT: valuable properties of analogues.

15 cl, 3 tbl, 4 dwg, 17 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I) wherein each among R represents independently hydrogen atom, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, phenyl or phenyl-(C1-C3)-alkyl; X and X' represent -CH2OH, -CO2R2, -OC(O)R2, -CH2OC(O)R2 or C(O)NR3R4 wherein R2, R3 and R4 represent independently hydrogen atom (H), (C1-C6)-alkyl substituted optionally with one-three (C1-C6)-alkoxy-groups, (C1-C6)-alkylthio-groups, halogen atoms, hydroxy-, amino-, mono-(C1-C6)-alkyl)-amino-, di-(C1-C6)-alkyl)-amino-group; Z and Z' represent independently (C1-C6)-alkyl broken optionally with one-three sulfur atoms (S) or non-peroxide oxygen atom (O), or they absent; n = 1-3; or to its pharmaceutically acceptable salt. Compounds are agonists of adenosine A2A-receptors and can be used for inhibition of inflammatory response or inflammation treatment.

EFFECT: valuable medicinal properties of compounds.

56 cl, 1 tbl, 21 dwg, 37 ex

FIELD: chemistry.

SUBSTANCE: in formula I Rf is an alkyl group containing 1-2 carbon atoms, in which 1-5 hydrogen atoms are substituted with 1-5 fluorine atoms, and R is an amine group or an amine group substituted with an amino acid residue of general formula NH(COCHR'NH)-H, where R' is hydrogen, a side chain of natural amino acid which is C1-C4alkyl, possibly substituted with a hydroxy group, a hydroxyl group, disodium or an ammonium phosphate group. The invention also relates to versions of the method of producing compounds of formula I, involving the following steps: fluoroalkylation of 4-hydroxy-3-methoxybenzaldehyde or 4-hydroxybenzaldehyde in the presence of an interphase transfer catalyst, to obtain 4-fluoroalkoxy-3-methoxybenzaldehyde (V) or 4-fluoroalkoxybenzaldehyde (VII), respectively, subsequent selective demethylation (V) with lithium diphenylphosphine and a protection of a hydroxy group or nitration (VII) in the 3rd position. The obtained compounds undergo Wittig reacton using a ylide of 3,4,5-trimethoxybenzyltriphenylphosphonium and the desired product is extracted.

EFFECT: obtaining novel combretastin derivatives of formula (I), having angiogenesis inhibiting activity, which can be used as anticancer and/or antiangiogenic agents.

6 cl, 17 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: method of preparing photosensitiser involves treatment of a suspension of lyophilically dried spirulina, for example, in methanol or a absolute alcohol until alkyl pheophorbide is obtained and with reaction of the latter with ethylenediamine for example, preferably in an organic solvent, extraction of the corresponding ether of a monoamide of chlorine e 6, its dissolution in alcohol and adding, for example, adipic acid in molar ratio 2:1. Apyrogenic water is added to the photosensitiser of structural formula (1), such that content of chlorine salts is equal to 30-40 mg per 10 ml of the alcohol-water mixture (1:1).

EFFECT: replacing the negative charge on the periphery of the chlorine macrocycle with a positive charge by introducing into the peripheral substitute amine groups to obtain cation-charged chlorines in order to change distribution of the photosensitiser in the body in order to increase affinity to tumours, possibility of controlling distribution owing to combination of different alkyls and different organic acids with different basicity in the structural formula through a novel drug formulation, having good therapeutic properties for treating cancer and other diseases through photodynamic therapy methods for cancer and other neoplastic diseases of different origins compared to existing medicinal agents containing chlorine e 6.

5 cl, 6 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to (3-trifluromethylphenyl)amide 6-(6-hydroxymethylpyrimidin-4-yloxy)naphthalene-1-carboxylic acid or tautomer or salt thereof. The invention also relates to a pharmaceutical composition which has protein kinase inhibiting activity, based on the said compound and use of the said compound to prepare pharmaceutical compositions for use in treating protein kinase dependent diseases, preferably proliferative diseases, particularly tumorous diseases.

EFFECT: improved properties of compounds.

6 cl, 115 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1, compounds of formula 5 and pharmaceutically acceptable salts thereof. In formulae 1 5 Y denotes -C(O)-, X denotes -N(R11)-, R1 denotes a residue of formula 1a or 1b - for formula 1 or residue of formulae 5a or 5b - for formula 5 1a 1b 5a 5b, R2 and R7 independently denote H, hydroxyl or (C1-C6)alkyl; R3 and R6 each independently denotes H, hydroxyl or (C1-C6)alkyl; R4 and R5 each independently denotes H or (C1-C6)alkyl; the rest of the radicals are described in the formula of invention. The invention also relates to separate compounds given in the formula of invention, a pharmaceutical composition having Bcl bound protein inhibiting properties, which contains a therapeutically effective amount of the disclosed compound, a method of treating a bc1 mediated disorder, involving introduction of a therapeutically effective amount of the disclosed compound and a method of treating a bc1 mediated disorder involving administration to a patient in need of treatment of an effective amount of camptothecin and therapeutically effective amount of the disclosed compound.

EFFECT: high efficiency of the composition.

84 cl, 12 tbl, 1 dwg, 217 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, where R1 -OH, R2- CONAA', SO2NAA', SO2NA-benzyl, SO2NHAr, SO2NAHet, SO2NHA or S(O)mHet, R3, R5, R6 - H, R4 - H, Hal or A, Y - OH, A, A' denotes a straight or branched C1-C10 alkyl, in which one CH2 group can be substituted with NR8, where R8 denotes a straight or branched C1-C6 alkyl or cycloalkyl, Ar denotes phenyl, Het denotes a saturated C5-C6-heterocyclic ring containing 1-2 nitrogen atoms, which can be substituted with A, m equals 1 or 2, and pharmaceutically suitable salts or tautomers thereof. The invention also relates to a method of producing said compounds and pharmaceutically suitable salts or tautomers thereof. The invention also relates to use of said compounds, salts or tautomers to prepare a medicinal agent for treating and/or preventing diseases affected by HSPS90 inhibition, as well as a medicinal agent based on said active ingredients, having HSP90 inhibiting activity. The invention also relates to an intermediate compound of formula I-1, where Z denotes A, Y - OH, R1 - OCH3, R2 - SO2Het, SO2NHAr or SO2NAA', R3 - H, R4 - Hal or A, R5, R6 - H, Ar - phenyl, Het - saturated C5-C6-heterocyclic ring, containing 1-2 nitrogen atoms which can be substituted with A, A, A' - straight or branched C1-C10 alkyl.

EFFECT: high efficiency of the composition.

6 cl, 1 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole derivatives of the formula I: , where R1 and R2 independently denote Ph; mono- or disubstituted in different positions of the ring Ph, where substitute denotes -OCH3; C5-heteroaryl with one heteroatom selected from O or S; R2 denotes H, NO2, NH2, C(O)NH2; R4 denotes H, a straight or branched C1-C6-alkyl; n equals the number of methylene groups and is between 1 and 8 inclusively; X denotes O, S, NH; Y NH, -CH2-; Z denotes O, S; W denotes -OH, hydroxylamine, hydrazine, alkylhydrazine.

EFFECT: compounds can inhibit histone deacetylase, which enables their use in cancer treatment.

10 cl, 9 dwg, 18 ex

FIELD: chemistry.

SUBSTANCE: present invention describes novel compounds of formula (I), where substitutes R1, R2, R3, Ar and A are described in the formula of invention, having histone deacetylase inhibiting activity, use thereof and methods for synthesis of said compounds.

EFFECT: improved composition properties.

15 cl, 72 ex, 9 tbl, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry. The developed versions of the method for producing the agent showing anticancer activity enables basidiomycete cultivation shorter from 2-3 weeks to 7 days and higher mycelium yield due to developing a composition of a nutrient medium, cultivation environment, sowing mycelium preparation, as well as higher efficacy of the agent. The method for producing the agent provides preparing the sowing basidiomycetes mycelium, preparing a processing medium, sowing the processing nutrient medium containing carbon and nitrogen sources, mineral salts with the prepared sowing mycelium, culturing basidiomycete to produce a submerged culture and recovering the agent showing anticancer activity. The sowing basidiomycetes mycelium is prepared in two stages, first of which is executed on a dense nutrient medium containing a corn extract, wheat water and agar, while the second one - on a fluid medium containing glucose, soya flour, potassium dihydrophosphate, magnesium sulphate and arachidonic acid. The prepared processing medium contains vegetable oil and soya flour in amounts 10-27 g/l and 16-27 g/l of water respectively, as well as potassium dihydrophosphate and magnesium sulphate in amounts 2.0-3.5 g/l and 0.2-0.4 g/l respectively. The basidiomycetes used are Ganoderma lucidum (Curt.:Fr.) P.Karst or Hypsizygus ulmarius (Bull.) Redhead, or Trametes versicolor (L.:Fr.) Pilat. The agent showing anticancer activity is recovered from the submerged culture prepared by cultivation or of the basidiomycete mycelium. The efficacy of the anticancer agent expressed by tumour growth inhibition in experiments in vivo makes 43-83%.

EFFECT: creation of the agent showing anticancer activity refers to the method for producing said agent by basidiomycetes cultivation in the submerged culture.

24 cl, 1 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine and deals with anti-sense oligonucleotides for treatment and/or prevention of, at least, one of the following diseases: asthma, hypereosinophilia. Essence of the invention includes oligonucleotides aimed against sequences of nucleic acids, coding receptor, selected from group, which consists of receptor CCR3 and common subunit of receptors IL-3, IL-5 and GM-CSF with sequences SEQ ID NO:1 and SEQ ID NO:14.

EFFECT: reduction of toxicity in comparison with hormonal medications.

39 cl, 8 ex, 11 tbl, 21 dwg

FIELD: medicine.

SUBSTANCE: claimed is medication for treatment of blood loss, consisting of complex representing combination of insulin 14 U, glucose solution 10% - 400 ml, sodium adenosine triphosphate 1% - 1 ml, panangin 10 ml, strophanthin acetate 0.05% - 0.25 ml, ascorbic acid 5% - 2 ml, riboxin 10ml, analgin 25% - 1 ml, polyglucinum 6% -400 ml.

EFFECT: medication in express-mode simultaneously produces rehabilitating action on all factors of blood loss etiopathogenesis, including elimination of acidosis, stress and pain syndrome.

1 ex

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