Derivatives of methotrexate, methods for their preparation and pharmaceutical composition

 

(57) Abstract:

Proposed connection formulas presented in the description, where R1is CH2CH2CH2Ch2o, ch2s, ch2so; R2is a hydrogen atom, a lower alkyl group containing from 1 to 4 carbon atom, or a benzyl group; n is an integer from 1 to 4; R3is COOR4, NHCOR5, CONR6R7, PO3H2, SO3H. This compound has the potential Antirheumatic function, suitable for the treatment of psoriasis and has cancerostatic properties, and also has low toxicity, which makes it suitable use in medicine. 3 s and 5 C.p. f-crystals, 15 ill.

The invention relates to a derivative of methotrexate, more specifically, to novel derivatives of methotrexate suitable as an Antirheumatic agent, agent, healing psoriasis, and cancerostatic agent.

Methotrexate described as a drug, inhibiting growth of cells, malignant neoplasms, psoriatic cells, the growth of actively proliferating tissues, suppressing cellular mitosis (Aghajanian R. N., Therapeutic archive, M.: Medicine, 1987, N1, S. 118-121).

As a derivative of methotrexate, in which an alkyl group that is different from methyl, enter N10are known , for example, the following formula:

,

(J. Med. Chem., 22, R. 862/1979/) or formula:

, (J. Med. Chem. 25, R. 877 /1982/), and the like, but they do not necessarily have sufficient activity.

Summary image

The present invention provides for obtaining a new derivative of methotrexate, represented by the following formula (I):

,

where

R1is a group selected from the group consisting of CH2CH2CH2CH2O, CH2S and CH2SO; R2is a hydrogen atom, lower ALK is 3 is a group represented by the formula: COOR4(where R4is a hydrogen atom or a lower alkyl group containing from 1 to 4 carbon atoms), NHCOR5(where R5is a phenyl group which may have substituents), CONR6R7(where R6is a hydrogen atom or a lower alkyl group containing from 1 to 4 carbon atoms; R7is the group of lower alkyl containing from 1 to 4 carbon atoms, phenyl group or carboxialkilnuyu group, each of which may be substituted, or lower alkylsulfonyl group), PO3H2or SO3H,

The compound of the present invention has excellent anti-rheumatic effect, suitable for the treatment of psoriasis and has cancerostatic action, and is characterized in that it has low toxicity compared with conventional methotrexate.

In Fig. 1-3 presents the number (ratio) 3H-UdR, subject to absorption at the respective concentrations of drugs to be tested; Fig. 4 - the function of inhibiting the growth of keratinocytes in rats; Fig. 5 - the function of inhibiting the growth of keratinocytes in humans. The absorption at the respective concentrations, the hat 100%; in Fig. 6 - the function of inhibiting the growth of cells R; Fig. 7 - the function of inhibiting the growth of the colony 26. The absorption at the respective concentrations of the drugs to be tested are presented in the hope that the absorption in the absence of drugs is 100%; ha Fig. 8 - weight change in rats with injection of methotrexate or compounds of the present invention; Fig. 9 - change in the number of white blood cells (WBC) and red blood cells (RBC), and Fig. 10 - changes in liver function and liver TG.

Description of the preferred options

Compounds of the present invention each are new and still have not been described in any of the references can be obtained, for example, as follows (method a, see Fig. 11-15), where R1, R2, R3and n have the same meaning as above, R' represents a hydrogen atom or a lower alkyl group containing from 1 to 4 carbon atoms, A1and A2each represent a protective group, and X represents a halogen atom.

In method A, the reaction for obtaining compounds of formula (2) from compounds of formula (I) are suspending the compound of formula (I) in acid halogenous agent, such as thionyl chloride, oxalicacid and dimetilformamida and so D. In this formula as a protective group represented by A1you can specify carbobenzoxy, group Totila, a group of acetyl, etc.

The reaction for obtaining compounds of formula (4) from the compounds of formula (2) and the compounds of formula (3) is conducted by adding a solution of the compounds of formula (2) dissolved in a solvent such as dichloromethane, to aqueous solution of compounds of formula (3) under cooling with ice or water, and then stirring the mixture at room temperature with the simultaneous presence of such organic bases as potassium carbonate, sodium hydroxide, sodium bicarbonate, etc.

The reaction for obtaining compounds of formula (5) of the compounds of formula (4) are, by adding the compound of the formula (4) to a solution of anisole or phenol, etc. dissolved in the solution hydrobromides acid, and stirring the resulting mixture at a temperature of 10-60oC, preferably at room temperature. In addition, the reaction for obtaining compounds of formula (5) of the compounds of formula (4) can be carried out by dissolving the compound of the formula (4) in a solvent such as methanol, ethanol, acetic acid, and then stirring the mixture after adding coal in a hydrogen atmosphere at room temperature.

oC, preferably 50-60oC, under stirring. In particular, if R2is a hydrogen atom, 1H. aqueous sodium hydroxide solution is added to a solvent such as methanol, ethanol, etc. and stir the resulting mixture at a temperature of 0-60oC, preferably at 35oC, to obtain the target compound. In this formula as the halogen atom represented by X, you can specify a bromine atom, a chlorine atom, etc.

In method B the reaction for obtaining compounds of formula (9) of the compounds of formula (6) and the compounds of formula (8) is carried out by reaction of the compound of formula (6) and the compounds of formula (8) in a solvent such as dimethylacetamide, dimethylformamide, etc. at a temperature of 0-100oC, preferably 55oC, under stirring.

The reaction for obtaining compounds of formula (7) of the compounds of formula (9) and compounds of formula (3) are, mixing the compound of the formula (9) with the simultaneous presence of cyanide diethylphosphinic acid or dicyclohexylcarbodiimide and 1-hydroxybenzotriazole in a solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, etc. and then adding connected is mesheanii. In particular, if R2is a hydrogen atom, IN an aqueous solution of the hydrochloride of sodium added to the mixture, and stirred the mixture at a temperature of 0-60oC, preferably at room temperature to obtain the target compound.

In method C, the reaction for obtaining compounds of formula (12) of the compounds of formula (10) and the compounds of formula (11) are, dissolving the compound of formula (10) in an aprotic solvent such as chloroform, dichloromethane, tetrahydrofuran, dioxane, etc. by adding the compounds of formula (11), water and, for example, potassium carbonate, triethylamine, sodium bicarbonate, pyridine, etc. to the mixture and stirred the mixture at room temperature. In this formula as a protective group represented by A2you can specify carbobenzoxy, group Totila, a group of acetyl, etc.

The reaction for obtaining compounds of formula (13) of the compounds of formula (12) are in such a solvent as methanol, etc., while stirring at a temperature of -60 to -20oC, preferably at -30oC, and then adding thionyl chloride, by boiling under reflux the mixture.

The reaction for obtaining compounds of formula (14) of the compounds of formula (13) are, dissolving the compound of formula (Menno palladium on coal in an atmosphere of hydrogen at room temperature. The reaction for obtaining compounds of formula (15) from compounds of formula 14 and the compounds of formula (2) lead by dissolving the compound of the formula (2) in dichloromethane etc., by adding the compound of the formula (14) and potassium carbonate or triethylamine and water, and stirring the mixture at room temperature, but the amidation can be conducted using a mixed acid anhydride, active ester or active amide.

The reaction for obtaining compounds of formula (16) of the compounds of formula (15) are adding hydrobromides acid which had previously been dissolved the anisole or phenol, to the compound of formula (15) and stirring the mixture at room temperature.

The reaction for obtaining compounds of formula (17) of the compounds of formula (6) and the compounds of formula (16) is carried out after mixing in an aprotic solvent such as dimethylformamide and dimethylacetamide, at a temperature of 25-100oC, preferably from 50 to 65oC, stirring the mixture in water containing, for example, triethylamine, potassium carbonate or sodium bicarbonate, etc.

The reaction of obtaining compound (1) from compounds of formula (17) are in a solvent such as ethanol, adding an aqueous solution of sodium hydroxide and stirring the mixture at Committee, has Antirheumatic effectiveness, treats psoriasis and has cancerostatic activity. In addition, compared with the methotrexate, it has a lower toxicity. These properties are confirmed in tests in the following experiments.

1. The function of inhibiting the growth of lymphocytes obtained from peripheral blood (Antirheumatic function).

2. The experiment on the growth inhibition of keratinocytes in rats and humans (function treatment of psoriasis).

3. Experiment on inhibition of growth of cancer cells in mice (cancerostatic function).

4. Comparison of the toxicity of methotrexate (MTX), and compounds of the present invention, when continuous intraperitoneal administration to rats.

Experimental example 1. The function of inhibiting the growth of lymphocytes obtained from peripheral blood (Antirheumatic function) (method)

Lymphocytes isolated from human peripheral blood using Ficoll-PaqueRand the medicine appropriately diluted and 105 lymphocytes were cultured with PHA(0.3 ág/ml) in culture plates with 96 cells for 2 days. For 5 h to complete cultivation type3H-UdR (x/cell) and for deoxyuridine). Used medicines listed below.

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In Fig.1-3 depict a relationship based on capture3H-UdR PHA stimulus lymphocytes, and 100% made in the absence of drugs. As clearly seen in Fig.1-3, it was confirmed that the compounds of the present invention beautifully inhibit the growth of lymphocytes (Antirheumatic function) compared with the control compounds.

Experimental example 2. The experiment on the growth inhibition of keratinocytes in rats and humans (treatment of psoriasis).

(1) Experiment on inhibition of keratinocyte growth in rats.

1) were First cultured keratinocytes rats using ZTZ cells of strain Swiss as a feeder layer, which were seeded at a concentration of 4 to 104cells/ml/cell on the plate with 24 cells treated with collagen type IV, using MSD 153 /DMA/10% FCS medium containing growth factors (insulin, hydrocortisone, EGF, cholera toxin), and cultured under 5% CO2and 95% air at 37oC.

2) After 24 h all this washed twice with medium MSDW 153, containing neither thymidine or adenine, and environment change on Wednesday MSDW 153 (1.8 mm Ca), containing growth factors (insulin, hydrocortisone, EGF, cholera toxin) and not sotiriadou is at 37oC for 4 days.

3) of 0.5% MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium] add 100 μl/cell, and left to stand at 37oC for 4 h and then the medium is sucked off. Dye (formazan), formed by living cells, dissolve by adding DMSO (dimethylsulfoxid) 200 μl of the cell. Measure the absorption (A 540) dye, dissolved, and an average of 6 cells is calculated as the relative number of cells.

(2) experiment on the growth inhibition of human keratinocytes.

1) human Keratinocytes obtained from Kurabou K. K., seeded at a concentration of 2 to 104cells/ml/cell in a plate with 24 cells treated with collagen type IV, using MSD 153 medium (0.15 mm Ca), containing growth factors (insulin, hydrocortisone, rhEGF, ethanolamine, phosphoethanolamine) and not containing either thymidine or adenine, and cultured under 5% CO2and 95% air at 37oC.

2) After 24 hours add to this sample, and the mixture was cultured at 5% CO2and 95% air at 37oC for 4 days.

3) of 0.5% MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium] add 100 μl/cell and left to stand at 37oC for 4 hours, DMSO (dimethylsulfoxide) at 200 μl/cell. Absorption (A 550) dissolved dye is measured and the average of the 6 cells is calculated as the relative number of cells.

Used drugs are shown below.

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In Fig. 4 presents the results of an experiment on the growth inhibition of keratinocytes in rats, Fig. 5 - the experimental results for growth inhibition of keratinocytes in humans. Each of the results are presented in the form of relations in the calculation of the absorption equal to 100%; when not added any medication.

As clearly seen in Fig.4 and 5, it was confirmed that the compounds of the present invention have an excellent ability to inhibit the growth of keratinocytes (psoriasis) compared with the control compounds.

Experimental example 3. Experiment on inhibition of growth of cancer cells in mice (cancerostatic function).

Cells P388 lymphoma neoplasm in mice suspended in the medium RPM 11640 (add so that 5% serum, fetal calf, and 10-6M 2-mercaptoethanol), or carcinoma cells colony 26 mice are placed in each well of flat-bottomed microplasmin (available from Corning Co. # 25870) 5 103and the solution medicines prepared with the devices for culturing of carbon dioxide (5% carbon dioxide, 95%, humidity 100%) for 3 days, and then a solution of MGT/3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium dissolved in phosphate buffer saline (pH 7,4; 4,10 mm) with 5 mg/ml) added to each well in an amount of 10 μl, and cultured for another 4 hours. Kultivirovaniya supernatant remove 150 ál of formed dye (formazan) dissolved in DMSO (dimethyl sulfoxide; 150 μl/cell) and absorbance (540 nm) was measured on the spectrophotometer for microplasmin.

Used drugs depicted below.

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In Fig. 6 shows an example of using P388 cells, Fig. 7 is an example of the use of the colony 26. Data are presented in % relative to the cell in which cell growth took place without the addition of drugs, i.e. its absorption is taken as 100%, and was determined by the degree of inhibition of growth by the addition of drugs.

As is clear from Fig. 6 and 7, they confirm that the compounds of the present invention have much higher efficiency for growth inhibition of cancer cells (cancerostatic function), rather than the effectiveness of the control drugs.

Experimental example 4. The comparison that is the lynx.

Eight male rats strain SD intraperitoneally injected with MTX or connection of the present invention once a day with a frequency of 5 days a week for 5 weeks continuously. Input dose of two kinds: 0.25 and 0.5 mg/kg each of MTX and compounds of the present invention. For the control group similarly injected solvent (phosphate buffer, pH 7,4). Each group had five rats.

Observations conducted on the following items:

1) Life or death and the symptoms observed every day.

2) weight Change tel: measured once a week.

3) blood tests: in the last week of drug administration determined the number of white blood cells (WBC) and red blood cells (RBC).

4) Weight of liver and triglycerides (TG) in the liver after injection of drugs was performed an autopsy and determined the weight and content of TG in the liver.

Using the following medications:

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Results.

1) Life or death, symptoms.

Among groups of animals, which were injected MTX, in the group that was administered a dose of 0.25 mg/kg, did not die no rat and abnormal symptoms were observed. However, in the group that was administered a dose of 0.5 mg/kg, was observed anemia, PS other hand, in the group that was administered the compound of the present invention, mice are not killed or in the group, which was administered 0.25 mg/kg, or in the group, which was administered 0.5 mg/kg, and no abnormal symptoms were observed.

2) Changes in body weight.

In Fig. 8 presents the change in weight. Changes in the increment of body weight were lower for the compounds of the present invention than for MTX.

3) blood tests.

In Fig. 9 presents the results of blood examinations. The reduction in the number of WBC and RBC were significantly less in the compounds of the present invention than for MTX.

4) Weight of liver TG content in the liver.

In Fig. 10 presents the weight and liver TG content in the liver. Increment weight and liver TG content in the liver were both lower for the compounds of the present invention than for MTX.

Discussion.

Toxicity of MTX and compounds of the present invention were compared using rats, which was continuously injected intraperitoneally drugs. As a result, all indications on the number of victims, the symptoms, on the change of weight of bodies on the study of blood, the liver weight and the content in liver TG suggests that the toxicity of the compounds of the present scienceline.

To a mixture of water (20 ml) and diethyl ether (20 ml) is added 2.0 g of 5-carboxyaniline and sodium hydroxide (0.6 g), and then, with ice cooling, to the mixture, alternately add carbobenzoxy (2,59) and water (10 ml) containing sodium hydroxide (2.1 g). The resulting mixture was stirred at room temperature for 2 hours, the Reaction mixture was acidified with 2n, hydrochloric acid and precipitated precipitated crystals are collected by filtration. Precipitation was washed with ether and air dried to obtain the title compound (2.8 g).

1H NMR (DMCO-d6) 3,10 (2H, t, J = 8 Hz), a 4.03 (2H, t, J = 8 Hz), 5,23 (2H, s), 7,2 - 8,0 (8H, m).

So melting 194 - 196oC.

Comparative example 2. Getting diethyl-N-(1-carboxybenzene-5-carbonyl) -L-glutamate.

After suspension of the compound (2.5 g) of reference example 1 in thionyl chloride (10 ml) to the resulting mixture is added a catalytic amount of dimethylformamide and the resulting mixture was stirred at room temperature for 30 minutes and Then excess thionyl chloride is removed under reduced pressure and the residue is triturated in n-hexane. the resulting crystals are filtered and dissolved in dichloromethane (20 ml) and the resulting dichloromethane solution was added dropwise to the m After stirring the mixture at room temperature for 2.5 h, the solvent is removed under reduced pressure and to the residue is added a mixed solution of ethyl acetate (200 ml) and dilute hydrochloric acid (200 ml) under cooling with ice. After stirring the mixture for 5 min, the organic layer obtained by separation. The organic layer was washed with 5% aqueous sodium bicarbonate, and then dried over magnesium sulfate. Then remove the ethyl acetate under reduced pressure, and the residue is treated through column chromatography using a solvent mixture chloroform - methanol = 30:1 as eluent to obtain the title compound (3.1 g).

1H-NMR (CDCl3, ) : to 1.19 (3H, t, J = 7 Hz), 1,25 (3H, t, J = 7 Hz); from 2.1 to 2.6 (4H, m), 3,06 (2H, t, J = 8 Hz), 3,8 - 4,3 (6H, m), and 4.75 (1H, m), 5,20 (2H, s), 6,79 (1H, d, J = 7 Hz), of 7.2 to 7.7 (8H, m).

So melting 120 - 121oC.

Comparative example 3. Getting diethyl-N-(indolin-5-carbonyl)-L-glutamate.

Compound (1.8 g) of comparative example 2 are dissolved in 80 ml of tetrahydrofuran and after adding 10% palladium on coal (0.4 g) and the resulting mixture is stirred in hydrogen atmosphere for 5 hours. Palladium on coal removed by filtration using celite to obtain specified in saggs), 3,59 (2H, t, J = 8 Hz), 4,07 (2H, sq J = 7 Hz), 4,19 (2H, sq J = 7 Hz), and 4.75 (1H, m), 6,47 (1H, d, J = 9 Hz), of 6.68 (1H, d, J = 7 Hz), was 7.45 (1H, d, J = 9 Hz), 7,49 (1H, s).

So melting 96 - 97oC.

Example 1. Getting diethyl-N-[1-(2,4-diamino-6-pteridinyl)-methyl-indolin-5-carbonyl]-L-glutamate.

In dimethylacetamide ( 3 ml) suspended the compound (214 mg) of comparative example 3 and the adduct of 6-methyl bromide-2,4-diamino-pteridinediamine isopropanol (250 mg) and the resulting mixture was stirred at 50 - 55oC for 4 h, After cooling, to the reaction mixture are added water (15 ml) containing 124 mg of triethylamine, and then the resulting mixture was extracted with chloroform (350 ml), separated into four times. After that, the organic layer is dried over magnesium sulfate, the solvent is removed under reduced pressure, and the residue is treated through column chromatography with silica gel using a mixed solvent of chloroform-methanol = 10:1 as eluent to obtain the title compound (200 mg).

1H NMR (DMCO-d6, ) : 1,22 (3H, t, J = 7 Hz), of 1.30 (3H, t, J = 7 Hz), 2.0 to 2.5 (4H, m), of 3.07 (2H, t, J = 8 Hz), of 3.57 (2H, t, 8 Hz), 4,10 (2H, sq J = g Hz) to 4.23 (2H, sq J = 7 Hz), 4,79 (1H, m), of 5.24 (2H, s), 6,51 (1H, d, J = 9 Hz), 6,76 (1H, d, J = 7 Hz), EUR 7.57 (1H, s), to 7.59 (1H, d, J = 9 Hz), 8,82 (1H, s). T. melting point 168-170oC.

I).

The compound (170 mg) of example 1 are dissolved in 33 ml of ethanol and to this solution add 1 N. aqueous sodium hydroxide solution (0,84 ml) at 35oC, and the resulting mixture was stirred at the same temperature for 4.5 hours. After continuous stirring at 25oC for 20 hours the reaction mixture are added water (2 ml). The reaction mixture is evaporated to dryness under reduced pressure. The residue is dissolved in water (15 ml), the pH of the resulting solution set 3,7 1H. hydrochloric acid while cooling with ice and left to stand in a cold place over night. The precipitate is collected by filtration to obtain the title compound (130 mg).

1H-NMR (DMCO-d6, ): (2H, m), 2,32 (2H, m), 2,98 (2H, so J=8 Hz), of 3.56 (2H, t, J=8 Hz), 4,29 (IH, m), a 4.53 (2H, s) of 6.71 (IH, d, J=9 Hz), EUR 7.57 (IH, s), to 7.59 (IH, d, J=9 Hz), 8,72 (IH, s). T. melting 201-204oC (decomposition).

Comparative example 4. Getting dimethyl-N-(1-carbobenzoxy-5-carbonyl)-L-aminoadipate.

After suspension of 1-carbobenzoxy-5-carboxylic acid (3.1 g) in 10 ml of thionyl chloride to this suspension is added a catalytic amount of dimethylformamide and the mixture was stirred at room temperature for 2 hours Then seatlle filtered and dissolved in 30 ml of dichloromethane, the resulting dichloromethane solution was added dropwise to aqueous solution (30 ml) containing dimethyl-L-aminodimethylaniline (2.7 g) under cooling with ice water. Next, to the reaction solution was added potassium carbonate (5.6 g). After stirring the mixture at room temperature overnight, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform. Chloroformate layer was washed with 1 N. hydrochloric acid and dried over anhydrous sodium sulfate and then the solvent is removed under reduced pressure. Then the obtained residue is treated through column chromatography with silica gel using a mixed solvent of chloroform-methanol = 100:1 as eluent to obtain the title compound (3.1 g).

1H-NMR (CDCl3, ): 1,6-2,1 (4H, m), a 2.36 (2H, t, J=6.8 Hz), of 3.13 (2H, m), 3,66 (3H, s), 4.09 to (2H, m), 4,78 (IH, d, J=7.8 Hz), 7,2-7,5 (6H, m), 7,63 (2H, m).

Comparative example 5. Getting dimethyl-N-(indolin-5-carbonyl)-L-L--aminoadipate.

To 30% solution of hydrogen bromide in acetic acid (15 ml) containing 1.5 g of anisole, add the compound (1.5 g) of comparative example 4, and the resulting mixture was stirred at room temperature for 4 hours. Then, when re is the product. Almost all the ether layer was removed and the oily suspended in chloroform. The resulting suspension is then washed with saturated aqueous sodium bicarbonate solution, and the chloroform layer is collected by separation. The chloroform layer is dried over sodium sulfate, and the solvent is removed under reduced pressure to obtain the title compound (960 mg).

1H-NMR (CDCl3, ): 1,6 - 2,1 (4H, m), 2,36 (2Y, t, J=6.8 Hz), of 3.07 (2H, m), 3,66 (3H, s), 3,66 (2H , m), of 3.77 (2H, c), 4,78 (IH, m), 6,62 (2H, m), 7,54 (2H. m).

Example 3. Getting dimethyl-N-[-((2,4-diamino-6-pteridinyl) methyl)-indolin-5-carbonyl]-L-aminoadipate.

In 20 ml of dimethylacetamide suspended the compound (960 mg) of comparative example 5, the adduct of 6-methyl bromide-2,4 - diaminotrinitrobenzene isopropanol (1140 mg), the resulting suspension is stirred at 50-60oC for 6 hours After cooling, the mixture was poured into saturated aqueous sodium bicarbonate solution, the desired product is extracted with chloroform, divided into three portions. The organic layer is dried over sodium sulfate, the solvent is removed under reduced pressure. The resulting residue is placed in a column with silica gel, using high quality solvent is a mixed solvent of chloroform-methanol = 100:10 to receive (2 H, m), of 3.57 (2H, m) to 3.67 (3H, s), of 3.78 (3H, s), a 4.53 (2H, s), 4,74 (IH, m), 6,52 (IH, d, J=8,33 Hz), 7,01 (IH, d, J=7.8 Hz), EUR 7.57 (2H, m), 8,77 (IH, s).

Example 4. Obtain N-[-((2,4-diamino-6-pteridinyl) methyl)indolin-5-carbonyl]-L-aminoadipic acid.

The compound (400 mg) 3 dissolved in ethanol (22 ml) 1H. an aqueous solution of sodium hydroxide (3.1 ml) are added to the solution at 35oC, and the resulting mixture was stirred at the same temperature for 4 hours After continued stirring at 25oC for further 20 h to the reaction mixture add 3 ml of water, and the reaction mixture is evaporated under reduced pressure to dryness. During the drying process the external temperature is controlled so that it does not exceed 30oC. a Yellowish solid material obtained was dissolved in water (10 ml) and the resulting solution was adjusted to a pH of 3.7 1H. hydrochloric acid and left to stand in the refrigerator for 2 hours the precipitate is collected by filtration to obtain the title compound (320 mg).

1H-NMR (CDCl3, ): 1,4 - 1,9 (4H, m), of 2.23 (2H, t, J=6.8 Hz), 3,01 (2H, m) to 3.58 (2H, m), 4,32 (IH, m), 4,55 (2H, s), 6,69 (IH, d, J=8,3 Hz), 7,63 (2H, m), 8,10 (IH, q, j=8,3 Hz), 8,72 (IH, s).

Comparative example 6. Obtaining N-(1-carbobenzoxy - 5-carbonyl) N-benzoyl-L-ornithology methyl ester ( 150 mg) and 750 mg of potassium carbonate, and 4 ml of water, and the mixture was intensively stirred at room temperature for 12 hours Then the reaction mixture was poured into water, extracted with chloroform, and the chloroform layer is washed with a solution of 1H. hydrochloric acid and dried over sodium sulfate. The solvent is removed under reduced pressure and the resulting residue is applied to silica gel and chromatographic, using as eluent a mixture of chloroform-methanol = 100:3, to obtain the title compound (140 kg).

1H-NMR (CDCl3, ): 1,6 - 2,2 (4H, m) and 3.15 (2H, t, J=8,8 HZ), of 3.56 (2 H, m), of 3.78 (3H, s), 4,10 (2H, t, J=8,8 Hz), 4,82 (IH, m), 5,27 (2H, s) 6,70 (IH, m), 6.89 in (IH, m), 6.89 in (IH, d, J was 8.8 Hz), 7, (8H, m), 7,80 (2H. m).

Comparative example 7. Obtaining N(indolin-5-carbonyl)- N-benzoyl-L-ornitologia methyl ester.

Compound (140 mg) of comparative example 6 is added to 30% solution of bromi the th temperature for 4 h Then, when a large quantity of ether is added to the reaction solution, the precipitate appears reddish-brown product. Almost all the ether layer was removed and the oily product is suspended in chloroform. The resulting suspension was washed with saturated aqueous sodium bicarbonate, and extracted with chloroform. The chloroform layer is dried over sodium sulfate, and the solvent is removed under reduced pressure to obtain the title compound (50 mg).

1H-NMR (CDCl3, ): 1,6 - 2,1 (4H, m), to 3.02 (2H, t, H=8,8 Hz) to 3.56 (2H, m), 3,62 (2H, t, H=8,8 Hz in), 3.75 (3H, s), 4,79 (IH, m), 6,55 (IH, d, J=7.8 Hz), 6,86 (2H, m), (2H, m), of 6.99 (IH, m) and 7.1 and 7.6 (5H, m), of 7.82 (1H, m).

Example 5. Obtaining N-[-((2,4-diamino-6-peridinin)methyl] indolin-5-carbonyl]- N-benzoyl-L-ornitologia methyl ester.

In 1 ml of diethylacetamide suspended connection (50 kg) of comparative example 7, the adduct of 6-methyl bromide-2,4-diaminopyrimidine isopropanol (44 mg) and the resulting mixture is stirred at a temperature of 50-55oC for 4 h, After cooling, to the reaction mixture add 3 ml of water containing triethylamine (22 mg), and the resulting mixture extracted with chloroform. After chloroformate layer is dried over sulfate hydroxide is but using as elution solvent a mixed solvent of chloroform-methanol = 10: 1. to obtain the compound (34 mg).

1H-NMR (CDCl3, ): 1,6 - 2,2 (4H, m), of 3.07 (2H, t, J=8,8 Hz), 3,50 (2H. m) to 3.56 (2H, t, J=8,8 Hz), with 3.79 (3H, s), a 4.53 (2H, s), 4,76 (IH, s), 6,52 (IH, d, J=8,3 Hz), 7,19 (IH, d, J=7,6 Hz), was 7.45 (3H, m), a 7.62 (2H, m), 7,80 (2H, m), 8,76 (IH, s).

Example 6. Obtaining N-[1-[(2,4-diamino-6-pteridinyl)methyl) indolin-5-carbonyl]- N-benzoyl-L-ornithine.

In 5 ml of ethanol was dissolved the compound (34 mg) of example 5, to this solution was added 1N. an aqueous solution of sodium hydroxide (0.1 ml) and the resulting mixture was stirred at 35oC for 4.5 hours After stirring for 20 h at 25oC to the reaction mixture was added 1 ml of water, and the reaction mixture is evaporated to dryness under reduced pressure. During this procedure, external temperature regulating so that it does not exceed 30oC. Get a yellowish solid product was dissolved in 5 ml of water, and the pH of the solution was adjusted to 3.7 by adding 1N. hydrochloric acid and leaving to stand in the refrigerator for 2 hours the precipitation is collected by filtration to obtain the title compound (26 mg).

1H-NMR (DMCO-d6, ): of 1.64 (2H, m) and 1.83 (2H, m), 2,98 (2H, t, J = 8,3 Hz), of 3.57 (2H, t, J = 8,3 Hz), 4,36 (2H, m), a 4.53 (2H, s), only 6.64 (2H, m), 7,45 (3H, m), to 7.59 (2H, m), 7,82 (2H, Mar 8. Obtaining N-phthaloyl - N-carbobenzoxy methyl ester.

of 2.45 g of phthalic anhydride is added to 70 ml of dichloromethane to a solution of N-carbobenzoxy-L-ornithine (2.0 g), and then to this mixture, add 70 ml of water and 1.12 g of potassium carbonate, and the mixture was stirred at room temperature for 15 hours. The resulting mixture was condensed to 60 ml under reduced pressure and the pH set 3 using 1N. of hydrochloric acid. The amount of precipitation collected by filtration and dried in vacuum. The obtained white crystals dissolved in methanol with a low content of water (80 ml) and the resulting solution is cooled to -30oC and stirred for 10 minutes. Then slowly added dropwise 2 ml of thionyl chloride at the same temperature. The reaction mixture is allowed to slowly warm to room temperature and refluxed for 2 hours the Solvent is removed under reduced pressure and the resulting residue is treated chromatography on silica gel, using as eluent a mixture of chloroform-methanol = 100:1 to obtain the title compound (2.16 g).

1H-NMR (CDCl3, ): 1,6 - 2,0 (4H, m), of 3.69 (5H, m), 4,20 (1H, m) 5,096 (2H, s) 5,70 (1H, m), 7,29 (5H, m), 7,66 (the Ira.

After adding 500 mg of 10% palladium on coal to methanol solution (100 ml) of the compound (2.16 g) of comparative example 8, the mixture is stirred in hydrogen atmosphere at room temperature for 20 hours Palladium on coal removed by filtration using celite, and the solvent is removed under reduced pressure. The resulting residue is treated through column chromatography with silica gel, using as eluent a mixture of chloroform-methanol = 100: 3, to obtain the title compound (223 mg).

1H-NMR (CDCl3, ): a 1.7 - 2.1 (4H, m in), 3.75 (2H, m), 3,83 (3H, s), 7,76 (2H, m), to 7.84 (2H, m).

Comparative example 10. Obtaining N-/1-carbobenzoxy - 5-carbonyl/- N-phthaloylglycine methyl ether complex.

Adding 2.5 ml of thionyl chloride for 1-carbobenzoxy-5-carboxylic acid (297 mg) to obtain a suspension and a catalytic amount of dimethylformamide to the resulting suspension, the resulting mixture was stirred for 2 h at room temperature. Then the mixture is evaporated to dryness under reduced pressure. The obtained solid material was dissolved in dichloromethane (7 ml) and to this solution was added the compound (250 mg) compared amerivault at room temperature for 12 hours Then the reaction mixture was poured into water, extracted with chloroform, and CHLOROFORMATES layer was washed with 1 N. hydrochloric acid and dried over sodium sulfate. The solvent is removed under reduced pressure. The residue is treated through column chromatography with silica gel, using as eluent a mixture of chloroform - methanol = 100:3, to obtain the title compound (330 mg).

1H-NMR (CDCl3, ): 1,6 - 2,1 (4H, m), of 3.12 (2H, t, J = 8,8 Hz), and 3.72 (2H, m), 3,76 (3H, s) 4,08 (2H, t, J = 8,8 Hz), 4,84 (1H, m), 5,27 (2H, s), to 6.80 (1H, d, J = 7.8 Hz), 7,1 - 7,5 (6H, m), 7,5 - 7,9 (6H, m).

Comparative example 11. Obtaining N(indolin-5-carbonyl)- N-phthaloylglycine methyl ether complex.

To 30% solution of hydrogen bromide - acetic acid (8 ml) containing 300 ml of the phenol type compound (330 mg) of comparative example 10, the resulting mixture was stirred at room temperature for 4 h Then the reaction mixture is added a large amount of ether, get in the Deposit of reddish-brown oily product. Almost all of the ethyl layer was removed and the oily product is suspended in chloroform. The resulting suspension was washed with saturated aqueous sodium bicarbonate and extracted CHL is Holocene specified in the title compound (147 mg).

1H-NMR (CDCl3, ): 1,6 - 2,1 (4H, m), totaling 3.04 (2H, t, J = 8,3 Hz), 3,62 (2H, t, J = 8,3 Hz), and 3.72 (2H, m in), 3.75 (3H, s), a 4.86 (1H, m), 6,5 - 6,7 (2H, m), 7,52 (2H, m), 7,68 (2H, m), 7,82 (2H, m).

Example 7. Obtaining N-[1-(2,4-diamino-6-pteridinyl)methyl) indolin-5-carbonyl]- N-phthaloylglycine methyl ester.

146 mg of the compound of comparative example 11 and 115 g of the adduct of 6-methyl bromide-2,4-diaminopyrimidine isopropanol suspended in 1.0 ml of dimethylacetamide, and the resulting suspension stirred at 50-55oC for 4 h, After cooling, to the resulting mixture add 4 ml of water containing 30 mg of triethylamine, and the mixture was stirred, and then extracted with chloroform. Chloroformate layer is dried over sodium sulfate, the solvent is removed under reduced pressure. The resulting residue is treated through column chromatography using a mixed solvent of chloroform-methanol = 10:1 as eluent to obtain the title compound (140 mg).

1H-NMR (CDCl3, ): 1.7 to 2.2 (4H, m), 3,06 (2H, t, J = 8,3 Hz), of 3.56 (2H, t, J = 8,3 Hz), and 3.72 (2H, m), 3,76 (3H, s), a 4.53 (2H, s), 4,88 (2H, m), 6,45 - 6,62 (2H, m), 7,56 (2H, m), 7,71 (2H, m), to 7.84 (2H, m), 8,82 (1H, s).

Example 8. Obtaining N-[1-(2,4-diamino-6-pteridinyl)methyl) indolin-5-comfort 2 N. aqueous sodium hydroxide (10 ml), the mixture was stirred at 30oC for 12 hours the mixture is evaporated to dryness under reduced pressure, and the resulting yellowish solid material dissolved in water (5 ml). the pH of this solution set 3,7 1 N. hydrochloric acid and left to stand in the refrigerator for 2 hours the precipitation is collected by filtration. The obtained yellow solid product is treated through column chromatography with silica gel using a mixed solvent of chloroform - methanol - 28% aqueous ammonia = 5:4:1 as eluent to obtain the title compound (20 mg).

1H-NMR (DMCO-d6: ): of 1.5 - 2.1 (4H, m), 3,14 (2H, t, J = 8,3), to 3.58 (2H, t, J = 8,3), to 4.38 (1H, m), of 4.54 (2H, s) of 6.71 (1H, m), and 7.3 and 7.6 (4H, m), of 7.6 to 7.8 (3H, m), 8,08 (1H, m), 8,71 (1H, s).

T. melting 195-199oC (decomposition).

Comparative example 12. Obtaining N-(3-methoxycarbonylbenzyl)-N-carbobenzoxy methyl ester.

To a dichloromethane solution (40 ml) N-carbobenzoxy-L-ornithine (2.4 g) is added 2.1 g of methylisophthalic, and then 40 ml of water and 2.4 g of potassium carbonate, the resulting mixture was stirred at room temperature for 15 hours Received Siberut by filtration and dried in vacuum. The obtained white solid material was dissolved in 10 ml of methanol with low water content, the resulting solution is cooled to 30oC and stirred for 10 minutes and Then 3 ml of thionyl chloride are slowly added dropwise at the same temperature. The reaction solution slowly return to room temperature, and then refluxed for 2 hours the Solvent is removed under reduced pressure and the resulting residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol = 100:1 to obtain the title compound (600 mg).

1H-NMR (CDCl3, ): 1,6 - 2,0 (4H, m), of 3.46 (2H, m), 3,70 (3H, s) to 3.89 (3H, s), 4,34 (1H, m), to 5.08 (2H, s), 5,88 (1H, d, J = 7.8 Hz), 7,31 (5H, s), 7,45 (1H, m), with 8.05 (2H, m), to 8.41 (1H, s).

Comparative example 13. Obtaining N-(3-methoxycarbonylbenzyl)ornitologia methyl ester.

After adding 10% palladium on coal (100 mg) to a solution of methanol (100 ml) of the compound (600 mg) of comparative example 12, the resulting mixture is stirred in hydrogen atmosphere at room temperature for 20 hours Palladium on coal removed by filtration using celite, and the solvent is removed under reduced pressure. This residue is treated on chromatogra the data in the title compound (360 mg).

1H-NMR (CDCl3, ): 1,6 - 2,0 (4H, m), 3,50 (3H, m), and 3.72 (3H, s) to 3.92 (3H, s). 7,49 (1H, t, J = 7.8 Hz), 7,63 (1H, m), 8,0 - 8,2 (2H, m), 8,43 (1H, s).

Comparative example 14. Obtaining N-(1-carbobenzoxy-5-carbonyl)- N- (3-methoxycarbonylbenzyl)ornitologia methyl ester.

Adding thionyl chloride (5 ml) to 1-carbobenzoxy-5-carboxylic acid (350 mg) to obtain a suspension, and then a catalytic amount of dimethylformamide, the mixture is stirred at room temperature for 2 hours Then the mixture is evaporated to dryness under reduced pressure. The obtained solid material was dissolved in dichloromethane (7 ml) and to this solution was added the compound (360 mg) of comparative example 13 and 650 mg of potassium carbonate. Then add 7 ml of water, the mixture was intensively stirred at room temperature for 12 hours Then the reaction mixture was poured into water and extracted with chloroform, and CHLOROFORMATES layer was washed with 1 N. hydrochloric acid, and then dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is treated through column chromatography with silica gel, elwira a mixture of chloroform-methanol = 100:3, to obtain specified in zaglav (2H, t, J = 3 Hz), 4,78 (1H, m), of 5.26 (2H, Shir.C.), 7,16 (1H, d, J = 7,3 Hz), 7,2 - 7,6 (7H, m), the 7.65 (2H, m), of 7.9 to 8.1 (2H, m), 8,43 (1H, s).

Comparative example 15. Obtaining N(indolin-5-carbonyl)- N-(3-methoxycarbonylbenzyl)ornitologia methyl ester.

To 30% solution bromatological acid (6 ml) containing anisole (0.5 g), add the compound (390 mg) of comparative example 14, the resulting mixture was stirred at room temperature for 4 h Then the reaction mixture is added a large amount of air, get a reddish-brown oily residue. Almost all the ether layer was removed and the oily product is suspended in chloroform. This suspension was washed with saturated aqueous sodium bicarbonate and extracted with chloroform. Chloroformate layer is dried over sodium sulfate, the solvent is removed under reduced pressure. The obtained white solid is recrystallized from a mixture of n-hexane-chloroform-methanol to obtain the title compound (192 mg).

1H-NMR (CDCl3, ): a 1.7 - 2.1 (4H, m), 3,05 (2H, t, J = 8,3 Hz), 3,53 (2H, m) to 3.67 (2H, t, J = 8,3 Hz in), 3.75 (3H, s) to 3.89 (3H, s), and 4.75 (1H, m), of 6.73 (1H, d, J = 7.8 Hz), 7,16 (1H, d, J = 7.8 Hz), 7,47 (1H, m), 7,55 (2H, m), of 8.09 (2H, m), to 8.45 (1H, s).

Example 9. Paleontol)ornitologia methyl ether complex.

In dimethylacetamide (2.5 ml) suspended the compound (192 mg) of comparative example 15, 6-methyl bromide-2,4-diaminopyrimidine (142 mg) and the resulting suspension stirred at 50-55oC for 4 h, After cooling, to this mixture, add water (5 ml) containing triethylamine (43 mg) and the resulting mixture is stirred, and then extracted with chloroform. Chloroformate layer is dried over sodium sulfate, the solvent is removed under reduced pressure. The resulting residue is treated through column chromatography with silica gel, using as eluent a mixture of chloroform-methanol = 10:1 to obtain the title compound (110 mg).

1H-NMR (CDCl3, ): a 1.7 - 2.1 (4H, m), 3,06 (2H, t, J = 8,3 Hz), 3,55 (4H, m), of 3.78 (3H, s), 3,93 (3H, s) to 4.52 (2H, s), 4,79 (1H, m), 6,51 (1H, d, J = 7.8 Hz), 7,05 (1H, d, J = 7.8 Hz), between 7.4 and 7.7 (3H, m), 8,0 - 8,2 (2H, m), to 8.45 (1H, m), 8,77 (1H, s).

Example 10. Obtaining N-[1-[(2,4-diamino-6-peridinin)methyl) indolin-5-carbonyl]- N-isophthalonitrile.

110 mg of the compound of example 9 is dissolved in 14 ml of ethanol and then the solution is added to 0.48 ml of 1 N. aqueous solution of sodium hydroxide, the mixture was stirred at 35oC for 4.5 h Then the mixture was stirred at 25oC for 20 h, the reaction to shift the external temperature is controlled so not to exceed 30oC. Receives a yellow solid, which was dissolved in 5 ml of water and the solution brought to a pH of 3.7 with a solution of 1 N. hydrochloric acid and transfer to the refrigerator for 2 hours. The precipitation is collected by filtration to obtain 78 mg specified in the title compound.

1H-NMR (DMCO-d6, ): of 1.5-2.0 (4H, m), and 3.0 (2H, t, J = 8,8 Hz), 3,32 (2H, m) and 3.59 (2H, t, J = 8,81 Hz), and 4.40 (1H, m), 4,56 (2H, s), 6,69 (1H, d, J = 8,3 Hz), 7,56 (1H, m), 7,63 (2H, m), 8,0 - 8,2 (2H, m), 8,44 (1H, s), 8,65 (1H, m), 8,73 (1H, s).

Comparative example 16. Obtain methyl ester of N-(4-methoxycarbonylbenzyl)- N-carbobenzoxy.

To 60 ml (2 g) N-carbobenzoxy-L-ornithine in dichloromethane added 3.0 g of methyltriethoxysilane and then added to the mixture of 60 ml of water and 4.8 g of potassium carbonate, the mixture is stirred at room temperature for 15 hours, the Mixture is condensed under reduced pressure to 50 ml and adjusted to pH 3 with a solution of 1 N. hydrochloric acid, the precipitated precipitate is collected by filtration and dried in vacuum. Get a white solid, was dissolved in 100 ml of methanol with low water content, the solution is cooled to -30oC and stirred for 10 minutes Then gradually added dropwise 3 ml of thionyl chloride with the toy under reflux for 2 hours The solvent is removed under reduced pressure and the resulting residue is subjected to chromatographic treatment on silica gel using as eluent a mixture of chloroform-methanol = 100:1 to obtain 710 mg specified in the title compound.

1H-NMR (CDCl3, ): 1,6 - 2,1 (4H, m), 3,51 (2H, m), 3,74 (3H, s), of 3.94 (3H, s), 4,43 (1H, m), 5,11 (2H, s), of 5.53 (1H, m), 6,63 (1H, BS), 7,34 (5H, s), 7,83 (2H, d, J = 8,8 Hz), 8,08 (2H, d, J = 8,8 Hz).

Comparative example 17. Obtain methyl ester of N-(4-methoxycarbonylbenzyl)ornithine.

After adding 10% (100 mg), palladium carbon black to a solution of 710 mg of the compound of comparative example 16 in 100 ml of methanol, the mixture is stirred at room temperature in a hydrogen atmosphere for 20 hours. Palladium soot is removed by filtration using celite, and the solvent is removed under reduced pressure. The resulting residue is subjected to chromatographic treatment on silica gel using as eluent a mixture of chloroform-methanol = 100:3 to obtain 410 mg specified in the title compound.

1H-NMR (CDCl3, ): 1,6 - 2,1 (4H, m), 3,49 (3H, m), of 3.73 (3H, s), of 3.94 (3H, s), 7,20 (1H, m), to 7.84 (2H, d, J = 8,3 Hz), of 8.09 (2H, d, J = 8,8 Hz).

Comparative example 18. Obtain methyl ester of N

1H-NMR (CDCl3, ): 1.7 to 2.2 (4H, m), and 3.16 (2H, t, J=8,3 Hz), 3,61 (1H, m), with 3.79 (3H, s), of 3.94 (3H, s), of 3.94 (3H, s), 4,11 (2H, t, J=8,3 Hz), a 4.83 (1H, m), from 5.29 (2H, s), 6.89 in (1H, d, J=7,3 Hz), 7,02 (1H, m), yield of 7.40 (5H, m), 7,66 (2H, d, J=7,3 Hz), of 7.90 (2H, d, J=8,8 Hz), 8,08 (2H, d, J=8,8 Hz).

Comparative example 19. Obtain methyl ester of N(indolin-5-carbonyl)- N-(4-methoxycarbonylbenzyl)ornithine.

To a 10 ml solution of 1 g of phenol in 30% hydrobromides acid to h Then, after adding to the reaction mixture of a large number of ether, the precipitated red-brown oily product. Almost all of the ether layer is removed and the oily product is suspended in chloroform. The suspension was washed with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The chloroform layer is dried over sodium sulfate and the solvent is removed under reduced pressure. The obtained white solid is recrystallized from a mixture of n-hexane-chloroform-methanol to obtain the title compound (145 mg).

1H-NMR (CDCl3, ): 1,6 - 2,1 (4H, m), 3,05 (2H, t, J=8,3 Hz), 3,48 (2H, m), 3,62 (2H, t, J=8,3 Hz), 3,76 (3H, s), of 3.94 (3H, s), and 4.75 (1H, m), to 6.57 (1H, d, J=7.8 Hz), 7,19 (1H, d, J=7.8 Hz), 7,55 (2H, m), 7,89 (2H, d, J=8,3 Hz), 8,07 (2H, d, J=8,3 Hz).

Example 11. Obtain methyl ester of N-[1-((2,4-diamino-6-pteridinyl)methyl)indolin-5-carbonyl]- N-(4 - methoxycarbonylbenzyl)ornithine.

In 2 ml of dimethylacetamide suspended 140 mg of the compound of comparative example 19 and 105 mg of 6-methyl bromide-2,4-diaminopyrimidine and the suspension is stirred at 50-55oC for 4 h, After cooling, to the mixture add 4 ml of water containing 27 mg of triethylamine, the mixture is stirred and then extrahieren the residue is subjected to chromatographic treatment on silica gel using as eluent a mixture of chloroform-methanol = 10:1 to obtain the title compound (180 mg).

1H-NMR (CDCl3, ): 1,6 - 2,1 (4H, m), is 3.08 (2H, t, J=8,8 Hz), grows 3.4 - 3.7 (4H, m), with 3.79 (3H, s), of 3.94 (3H, s), of 4.54 (2H, s), a 4.83 (1H, m), of 6.52 (1H, d, J=8,3 Hz), 6,79 (1H, d, J=6.8 Hz), 7,17 (1H, m), to 7.59 (2H, M), a 7.92 (2H, d, J=8,3 Hz), of 8.09 (2H, d, J=8,3 Hz), 8,81 (1H, s).

Example 12. Obtaining N-[1-(2,4-diamino-6-pteridinyl)methyl) indolin-5-carbonyl]- N-telesotalania.

150 mg of the compound of example 11 is dissolved in 11 ml of ethanol and then the solution was added 0.8 ml of 1 N. aqueous sodium hydroxide solution, and the mixture was stirred at 35oC for 4.5 h Then the mixture was stirred at 25oC for 20 h, add 1 ml of water to the reaction mixture and evaporated to dryness under reduced pressure. During this procedure, the external temperature is maintained so as not to exceed the 30oC. the Obtained yellow solid was dissolved in 5 ml of water and the solution brought to a pH of 3.7 with a solution of 1 N. hydrochloric acid and stored in the refrigerator for 2 hours the precipitation is collected by filtration to obtain the title compound (109 mg).

1H-NMR (CDCl3, ): of 1.5 - 2.0 (4H, m) of 3.00 (2H, t, J=8,8 Hz), 3,30 (2h, m) to 3.58 (2H, t, J=8,8 Hz), 4,36 (1H, m), of 4.54 (2H, s), of 6.68 (1H, d, J=8,8 Hz), a 7.62 (2H, m), to $ 7.91 (2H, d, J=8,3 Hz), to 7.99 (2H, d, J=8,3 Hz), 8,10 (1H, d, J=7.8 Hz), 8,61 (1H, m), 8,71 (1H, s).

So melting 2-L-glutamate.

To 8 ml of a solution of 2.2 g-benzyl-N-t-butoxycarbonyl-L - glutamate and 0.92 ml of triethylamine in tetrahydrofuran is added 2 ml of a solution of 0.8 ml of isobutylparaben in tetrahydrofuran at -20oC in nitrogen atmosphere and the mixture is stirred for 30 minutes. Then to the mixture is added 0.5 ml of aniline and the mixture is stirred for 1 h, the Mixture is left to gradually warm to room temperature and stirred further for 20 hours the Solvent is removed under reduced pressure and the resulting residue is dissolved in chloroform. The chloroform layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and then condensed under reduced pressure. The resulting residue is subjected to chromatographic treatment on silica gel using as eluent a mixture of chloroform-methanol = 99:1 to obtain the title compound (1.7 g).

1H-NMR (CDCl3, ): the 1.44 (9H, s), 1,79 - of 1.97 (1H, m), 2,27 - 2,4- (2H, m), 4,32 - of 4.44 (1H, m), 5,16 (2H, s), 5,22 is 5.38 (1H, m), was 7.08 (1H, t, J= 7,3 Hz), 7,26 - 7,33 (7H, m), 7,55 (2H, d, J=7.8 Hz), 8,42 (1H, s).

Comparative example 21. Getting-benzyl-anilino-L - glutamate.

1.7 g of the compound of comparative example 20 is dissolved in 8 ml triperoxonane acid under ice cooling, and is orapharma. The chloroform layer was washed with saturated aqueous sodium bicarbonate and then dried over sodium sulfate. The solvent is removed under reduced pressure to obtain the title compound (1.3 g).

1H-NMR (CDCl3, ): 1,86 - 2,0 (1H, m), 2,17 - of 2.38 (1H, m), 2,42 of $ 2.53 (2H, m), 3,53 - of 3.60 (1H, m), of 5.15 (2H, s), 7,07 (1H, t, J=7,3 Hz), 7,29 - to 7.35 (7H, m), of 7.48 (2H, d, J=7.8 Hz), of 8.27 (1H, BS).

Comparative example 22. Getting-benzyl-N-(1 - carbobenzoxy-5-carbonyl)- -anilino-L-glutamate.

2 ml of thionyl chloride are added to 419 mg of 1-carbobenzoxy - 5-carboxylic acid and the mixture is stirred at room temperature for 2 hours the mixture is Then evaporated to dryness under reduced pressure. The obtained solid product is dissolved in 2 ml of dichloromethane and to the solution add a solution containing 400 mg of the compound of comparative example 21, in 2 ml of dichloromethane and 0.21 ml of triethylamine under ice cooling in a nitrogen atmosphere, and the mixture is stirred over night. The reaction mixture was sequentially washed with a solution of 1 N. hydrochloric acid, saturated aqueous sodium bicarbonate and water, dried over sodium sulfate and then remove the solvent under reduced pressure. The resulting residue is subjected to chromatographic is alavie compound (317 mg).

1H-NMR (CDCl3, ): 2,10 - of 2.20 (1H, m), 2,29 is 2.51 (3H, m), 3,05 (2H, t, J=8,8 Hz) 4,06 (2H, t, J=8,8 Hz), 4,76 - 4,88 (1H, m), is 5.18 (2H,s), 5,28 (2H, BS), 7,05 (1H, t, J=7,3 Hz), 7,18 (1H, d, J=7.8 Hz), 7.23 percent - 7,30 (2H, m), 7,33 (5H, s), 7,39 (5H,s), 7,43 - 7,66 (4H, m), 7,80 - to 7.84 (4H, m), to 8.57 (1H, BS).

Comparative example 23. Obtaining N-(1-carbobenzoxy - 5-carbonyl)- -anilino-L-glutamato acid.

580 mg of the compound of comparative example 22 was dissolved in 30 ml of a mixed solvent of chloroform-methanol = 1:2 and to the solution is added to 0.98 ml of aqueous 1N. of sodium hydroxide, and the mixture is stirred at room temperature overnight. The temperature of the water bath is maintained up to 30oC or below, the solvent is removed under reduced pressure. The resulting residue is dissolved in water, then the solution is acidified with 1N. hydrochloric acid and the mixture extracted with chloroform. Then the chloroform layer is dried over sodium sulfate, the solvent is removed under reduced pressure to obtain the title compound (413 mg).

1H-NMR (CDCl3, ): 2,17 - to 2.29 (2H, m), 2,52 - of 2.56 (2H, m), and 2.79 (2H, t, J= 7.8 Hz), 3,81 (2H, t, J=7.8 Hz), 4,51 - br4.61 (1H, m) to 5.17 (2H, s) 6,94 (1H, t, J=7,3 Hz), 7,13 (2H, t, J=7.8 Hz), 7,34 (5H, s), 7,43 - the 7.65 (5H, m), 8,03 (1H, BS), of 9.02 (1H, s).

Comparative example 24. Getting-methyl-N-(1-carbobenzoxy 20 ml of dry methanol, add 2 ml trimethylsilyldiazomethane to the solution and the mixture is stirred for 10 hours Then add 3 ml trimethylsilyldiazomethane and the mixture is stirred for 20 hours After removal of the solvent under reduced pressure the resulting residue is subjected to chromatographic treatment on silica gel using as eluent chloroform and then a mixture of chloroform methanol = 199:1 to obtain the title compound (252 mg).

1H-NMR (CDCl3, ): 2.06 to of 2.21 (1H, m), 2,31 - of 2.56 (3H,m), is 3.08 (2H, t, J= 8,8 Hz), of 3.77 (3H,s) 4,08(2H, t, J=8,8 Hz), 4,77 - to 4.87 (1H, m), 5,28 (2H, s), 7,07 (1H, t, J=7,3 Hz), to 7.15 (1H, d,J=7.8 Hz), 7,28 (2H, t, J=7.8 Hz), 7,37 - the 7.43 (5H, m), 7,58 (2H, d, J=7.8 Hz), 7,62-to 7.68 (2H, m), 7,86 (1H, BS), 8,67 (1H, BS).

Comparative example 25. Getting-methyl-N-(indolin-5-carbonyl)- -anilino-L-glutamate.

After adding 10% (50 mg), palladium carbon black to 10 ml of a solution of 250 mg of the compound of comparative example 25 in methanol the mixture is stirred in hydrogen atmosphere at room temperature for 15 hours of Palladium carbon is removed by filtration using celite and the solvent is removed under reduced pressure. The resulting residue is subjected to chromatographic treatment with silica gel, using as eluent a mixture of chloroform-methane is H-NMR (CDCl3, ): 1,99-to 2.13 (1H, m), a 2.36-to 2.55 (3H, m), 3,03 (2H, t, J= 8,8 Hz) to 3.64 (2H, t, J=8,8 Hz), of 3.77 (3H,s) 4,08 (1H, BS), 4,79-4,88 (1H, m), 6,55 (1H, d, J=8,3 Hz), 6,92 (1H, d, J=7,3 Hz), was 7.08 (1H, t, J=7,3 Hz), 7,30 (2H, t, J=7.8 Hz), 7,53-the 7.65 (4H, m), 9,01 (1H, BS).

Example 13. Getting - methyl-N-[1-(2,4-diamino-6-pteridinyl)methyl)-indolin-5-carbonyl]-): 2,01-of 2.09 (1H, m), 2,39-2,48 (3H, m), totaling 3.04 (2H,t, J= 8,8 Hz) to 3.58 (2H, t, J=8,8 Hz), of 3.78 (3H, c), a 4.53 (2H, s), 4,79-4,89 (1H, m), 6.48 in (1H, d, J=7.8 Hz), 6.87 in (1H, d, J=7.8 Hz), was 7.08 (1H, t, J=7.8 Hz), 7,26-to 7.32 (2H, m), to 7.59-to 7.64 (4H, m), 8,81(1H, s).

Example 14.

Obtaining N-[1-((2,4-diamino-6-pteridinyl)methyl)indolin-5-carbonyl] - -anilino-L-glutamato acid.

82 mg of the compound of example 13 is dissolved in a mixed solvent (15 ml) ethanol - water = 2:1 and then add 0.15 ml of aqueous 1 n sodium hydroxide solution, and the mixture is stirred at room temperature for 60 hours, the Temperature of the water bath and supports up to 30oC or below, the solvent is removed under reduced pressure. The resulting residue is dissolved in a saturated aqueous solution of sodium bicarbonate and the pH of the solution was adjusted to 3.7 1H. the hydrochloric acid. Loose orange precipitate is collected by filtration to obtain the title compound (61 mg).

1H-NMR (DMCO-d6, ): 1,99-2,23 92H, m), 2,42 is 2.51 (2H, m), 2,98 (2H, t, J= 7,8 Hz) and 3.59 (2H, t, J=8,3 Hz), 4,, = 7,3 Hz), the rate of 8.75 (1H, c), to 9.93 (1H, s).

Comparative example 26. Getting - benzyl-N-t-butoxycarbonyl- -(2 methoxycarbonylamino)-L-glutamate.

262 mg of N, N'-carbonyldiimidazole added to 5 ml of a solution-benzyl-N-t-butoxycarbonyl-L-glutamate in tetrahydrofuran in a nitrogen atmosphere under ice cooling and the mixture is stirred for 1 hour Then add 2 ml to 0.19 ml of methyl o-aminobenzoate in tetrahydrofuran and the mixture is stirred for 5 hours. Then, the mixture is left to gradually warm to room temperature and further stirred for 48 hours the Solvent is removed under reduced pressure and the resulting residue is subjected to chromatographic treatment using silica gel as the eluent to obtain the title compound (273 mg).

1H-NMR (CDCl3, ): of 1.41 (9H, s), 2,04-to 2.18 (1H, m), 2,20 of-2.32 (1H, m), 2,48-to 2.57 (2H, m) to 3.92 (3H, s), 4,34 - 4,47 (1H, m), is 5.18 (2H, s), 5,19 at 5.27 (1H, m), was 7.08 (1H, t, J=7.8 Hz), 7,34 (5H, s), 7,53 (1H, t, J=7,3 Hz), 8,02 (1H, d, J=7.8 Hz), 8,68 (1H, d, J=7.8 Hz), 11,06 (1H, s).

Comparative example 27. Getting-benzyl -(2-methoxycarbonylamino)-L-glutamate.

632 mg of the compound of comparative example 26 is dissolved in 4.5 ml triperoxonane acid under ice cooling and the mixture is stirred techou washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate and remove the solvent under reduced pressure. The resulting residue is subjected to chromatographic treatment using silica gel and chloroform as eluent and then a mixture of chloroform-methanol = 97:3 to obtain the title compound (413 mg),

1H-NMR (CDCl3, ): 1,91-2,02 (1H, m), 2,20-of 2.30 (1H, m), 2,55-of 2.64 (2H, m), 3,56 -3, 62 (1H, m) to 3.92 (3H, s) to 5.17 (2H, s), 7,07 (1H, t, J=8,3 Hz), 7,35 (5H, s), 7,53 (1H, t, J=8 Hz), 8,02 (1H, d, J=8,3 Hz), 8,69 (1H, d,J= 8,8 Hz), 11,08(1H, BS).

Comparative example 28. Obtaining 1 -[(2,4-diamino-6-pteridinyl)methyl] indoline-5-carboxylic acid.

87 mg of 1-carbobenzoxy-5-carboxylic acid and 136 mg of the adduct of 6-methyl bromide-2,4-diaminopyridine hydrobromide and 1/2 isopropanol suspended in 2 ml of dimethylacetamide and the suspension is stirred at 55oC for 4 h To the reaction mixture are added 20 ml of water and the mixture is left in the refrigerator over night. Precipitated solid is collected by filtration, dissolved in a small amount of 1 N. aqueous solution of sodium hydroxide and the solution is brought to pH 6.5 1H. the hydrochloric acid. Loose brown precipitate is collected by filtration to obtain specified in the title compound (56 mg).

1H-NMR (DMCO-d6, ): a 3.01 (2H, t, J=8,8 Hz) to 3.64 (1H, t, J=8,8 Hz), 4,60 (2H, s), of 6.68 (1H, d, J=8,3 Hz), 7,16 (2H, c), 7,58 (1H, c), the 7.65 (1H, d, J=8,3 Hz), of 8.09 (1H, BS), 8,2 - 2 methoxycarbonylamino)-L-glutamate.

To 5 ml of the suspension 134 mg of the compound of comparative example 28 and 108 mg of 1-hydroxybenzotriazole and dimethylformamide add 1.5 ml of a solution of 123 mg of dicyclohexylcarbodiimide in dimethylformamide under ice cooling in a nitrogen atmosphere and the mixture is stirred for 30 minutes and Then 1.5 ml of a solution of the compound of comparative example 27 in dimethylformamide is added to the mixture, the mixture is left to warm gradually to room temperature and stirred for 24 h, the Reaction mixture was subjected to chromatographic treatment using silica gel and ethyl acetate as eluent, and then a mixture of chloroform-methanol = 19:1 to obtain a connection, specified in the title (29 mg).

1H-NMR (CDCl3, ): 2,32 is 2.46 (2H, m), 2,46 - 2,70 (2H, m), 2,96 (2H, t, J= 8,8 Hz), 3,49 (2H, t, J=8,3 Hz) to 3.89 (3H, s), to 4.46 (2H, s), a 4.83-of 4.90 (1H, m), 5,20 (2H, s) 6,40 (1H, d, J=8,3 Hz), 7,05(1H, t, J=8,3 Hz), 7,14 (1H, d, J= 7.8 Hz), 7,34 (5H, c), 7,41 - to 7.59 (3H, m), of 7.96 (1H, d, J=8,3 Hz) 8,64 (1H, d, J=8,3 Hz), 8,77 (1H, s).

Example 16. Obtaining N-[1-[2,4-diamino-6-pteridinyl)methyl)indolin-5-carbonyl]-): 1,95-of 2.25 (2H,m), 2,39-of 2.58 (2H,m), 2,98 (2H, t, J= 8,3 Hz) and 3.59 (2H, t, J=8,3 Hz), to 4.38 ñ 4.50 (1H, m), of 4.57 (2H, s), 6,69 (1H, d, J = 8,3 Hz), 7,12 (1H, t, J = 7.8 Hz), 7.24 to to 7.35 (2H, m), 7,51 - to 7.64 (3H, m), of 7.96 (1H, d, J = 7.8 Hz), 8,04 - 8,39 (4H, m), of 8.47 (1H, d, J = 7.8 Hz), 8,78 (1H, s), >/P>In 75 ml-benzyl-N-t-butoxycarbonyl-L-glutamate in dimethylformamide are suspended 2.5 g of sodium bicarbonate and then to the suspension add 75 ml 10,52 g under the conditions in dimethylformamide, and the mixture is stirred at room temperature for 24 h Then the reaction mixture is condensed under reduced pressure, add 70 ml of water to the residue and the mixture is extracted with a solution of ethyl acetate - n-hexane = 1:1. The organic layer is washed with water and dried over sodium sulfate, the solvent is removed under reduced pressure. The resulting residue is subjected to chromatographic treatment using silica gel and as eluent a mixture of ethyl acetate - n-hexane = 1:2 to obtain the title compound (5.2 g).

1H-NMR (CDCl3, ) : USD 1.43 (9H, s), 1,92 is 2.01 (1H, m), 2,11 - is 2.37 (1H, m) 2,42 is 2.51 (2H, m) of 3.73 (3H, s) to 4.23 - and 4.40 (1H, m), 5,12 (2H, s), to 7.35 (5H, s).

Comparative example 30. Getting-methyl-N-t-butoxycarbonyl-L-glutamate.

After adding 10% (1.1 g) palladium carbon black to a 30 ml solution of 5.2 g of compound of comparative example 29 in methanol the mixture is stirred in hydrogen atmosphere at room temperature for 15 hours of Palladium carbon is removed by filtration using celite, and the solvent delete the Oia and the solution washed with chloroform. After separation of the aqueous layer was adjusted pH to 4 with 5% citric acid and then extracted with chloroform. Chloroformate layer is dried over sodium sulfate and remove the solvent under reduced pressure to obtain the title compound (3.9 g).

1H-NMR (CDCl3, ) : the 1.44 (9H, s), 1,89 - 2,04 (1H, m), 2,09 - of 2.27 (1H, m in), 3.75 (3H, s), 4,34 (1H, m), 5,17 - to 5.21 (1H, m), 9,38 (1H, BS).

Comparative example 31. Getting-methyl-N-t-butoxycarbonyl- -(3-ethoxycarbonylphenyl)-L-glutamate.

To 10 ml of a suspension of 1.6 g of compound of comparative example 30 and 0.8 g of 1-hydroxybenzotriazole in dichloromethane add 5 ml of a solution of 1.5 g of dicyclohexylcarbodiimide in dichloromethane under ice cooling in a nitrogen atmosphere and the mixture is stirred for 30 minutes Then add 1.5 g of ethyl m-aminobenzoate and the mixture is left to gradually warm to room temperature and stirred for 20 hours the Solvent is removed under reduced pressure, the obtained residue is added ethyl acetate and filtered off the insoluble white matter. The filtrate is condensed under reduced pressure and the resulting residue is subjected to chromatographic treatment using silica gel and chloroform as eluent, and then to shift the UB>, ) : of 1.33 (3H, t, J = 7,1 Hz) of 1.47 (9H, s), 1,82 - 2,04 (1H, m), 2,20 - 2,39 (1H, m), 2,45 is 2.51 (2H, m), 3,74 (3H, s), 4,32 - 4,43 (1H, m), 4,37 (2H, d, J = 7,1 Hz), lower than the 5.37 (1H, d, J = 7,3 Hz), 7,40 (1H, t, J = 7.8 Hz), for 7.78 (1H, d, J = 7.8 Hz), of 7.96 (1H, d, J = 9.3 Hz), 8,13 (1H, s), 8,83 (1H, BS).

Comparative example 32. Getting-methyl -(3 - ethoxycarbonylphenyl)-L-glutamate.

2.5 g of the compound of comparative example 31 was dissolved in 15 ml triperoxonane acid under ice cooling and the solution stirred for 1 h the Solvent is removed under reduced pressure and the residue is dissolved in chloroform. Chloroformate layer was washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate and remove the solvent under reduced pressure. The resulting residue is subjected to chromatographic treatment using silica gel and as eluent a mixture of chloroform-methanol = 19:1 to obtain the title compound (1.6 g).

1H-NMR (CDCl3, ) : of 1.39 (3H, t, J = 7,1 Hz), 1,74 (2H, s), 1,82 of 1.99 (1H, s), 2,15 of - 2.32 (1H, m), 2,52 - 2,62 (2H, m), 3,54 - of 3.60 (1H, m), 3,74 (3H, s), 4,37 (2H, q, J = 7,1 Hz), 7,39 (1H, t, J = 7?3 Hz), to 7.77 (1H, d, J= 7,3 Hz), 7,94 (1H, d, J = 7,8 Hz), to 7.99 (1H, s), 8,63 (1H, BS).

Comparative example 33. Getting-methyl-N-(1-carbobenzoxy-5-carbonyl)- - -(3-ethoxycarbonylphenyl)-L-glutamate.

4 ml of t is temperature for 2 hours The mixture is then evaporated to dryness under reduced pressure. The obtained solid substance was dissolved in 4 ml of dichloromethane and add 4 ml of a solution containing 529 mg of the compound of comparative example 32 and 0.36 ml of triethylamine in dichloromethane under ice cooling in a nitrogen atmosphere, and the mixture is stirred over night. The reaction mixture was sequentially washed with a solution of 2 N. hydrochloric acid and saturated aqueous sodium bicarbonate and water and dried over sodium sulfate, and then remove the solvent under reduced pressure. The resulting residue is subjected to chromatographic treatment using silica gel and chloroform as eluent, and then a mixture of chloroform-methanol = 99:1 to obtain the title compound (870 mg).

1H-NMR (CDCl3, ) : to 1.37 (3H, t, J = 7,1 Hz), 2,08 - 2,22 (1H, m), a 2.36 - to 2.57 (3H, m), 3,06 (2H, t, J = 8,8 Hz), of 3.77 (3H, s) 4,07 (2H, t, J = 8,8 Hz), 4,30 - and 4.40 (2H, d, J = 7,1 Hz), 4,78 - to 4.87 (1H, m), 5,28 (2H, BS), 7,13 (1H, d, J = 7.8 Hz), 7,30 - the 7.43 (6H, m), 7,60 - to 7.67 (2H, m), 7,74 (1H, d, J = 7.8 Hz), 7,89 (1H, d, J = 7,8 Hz) to 8.12 (1H, BS), 8,96 (1H, BS).

Comparative example 34. Getting-methyl-N-(indolin-5-carbonyl)- -(3-ethoxycarbonylphenyl)-L - glutamate.

After adding 10% (0.17 g) and palladium carbon black to 11 ml 842 mg connection sravnitelnaia soot is removed by filtration using celite and remove the solvent under reduced pressure. The resulting residue is subjected to chromatographic treatment using silica gel and chloroform as eluent, and then a mixture of chloroform-methanol = 99:1 to obtain the title compound (448 mg).

1H-NMR (CDCl3, ) : of 1.36 (3H, t, J = 7,1 Hz), a 2.0 to 2.25 (1H, m), (2,25 - 2,48 (1H, m), 2,48 at 2.59 (2H, m), with 2.93 (2H, t, J = 8,8 Hz), of 3.57 (2H, t, J = 8,8 Hz), 3,71 (3H, s), 4,18 (1H, BS), 4,34 (2H, t, J = 7,1 Hz), 4,73 -4,48 (1H, m), 6,46 (1H, d, J = 8,8 Hz), 7,16 (1H, d, J - 7.8 Hz), 7,32 (1H, t, J = 7.8 Hz), 7,50 - 7,53 (2H, m), 7,73 (1H, d, J = 7,8 Hz) 7,87 (1H, d, J = 7,3 Hz), 8,19 (1H, s), 9,39 (1H, BS).

Example 17. Getting-methyl-N-[1-[(2,4-diamino-6-pteridinyl)methyl)indolin-5-carbonyl]- -(3-ethoxycarbonylphenyl)-L-glutamate.

In 5 ml of dimethylacetamide suspended 448 mg of the compound of comparative example 34 and 587 mg of the adduct of 6-bromo-2,4-diaminopyridine hydrobromide and isopropanol and the suspension is stirred at room temperature for 36 h, the Reaction mixture was subjected to chromatographic treatment using silica gel and ethyl acetate as eluent, and then a mixture of chloroform-methanol = 9:1 to obtain the title compound (653 mg).

1H-NMR (DMCO-d6, ) : of 1.34 (3H, t, J = 6.8 Hz), 1,96 of - 2.32 (2H, m), 2,32 at 2.59 (2H, m) of 3.00 (2H, t, J = 7,3 Hz), 3,56 - 3,66 (5H, s), 4,32 (2H, q, J = 6.5 Hz), 4,40 - 4,56 (3H, m), 6,66 - of 6.71 (3H, BS), 7,39 of N-[1-[(2,4-diamino-6-pteridinyl)methyl)indolin-5-carbonyl]- -(3-carboxanilide)-L-glutamato acid.

303 mg of the compound of example 17 is dissolved in 10 ml of methanol, add the 1.06 ml of 1 N. aqueous solution of sodium hydroxide and the mixture is stirred at room temperature for 12 hours Add 1 ml of water and the mixture is then further stirred for 2 hours At the same time supporting the temperature of the water bath 30oC or below, remove the solvent under reduced pressure. The resulting residue is dissolved in a saturated aqueous solution of sodium bicarbonate and the solution brought to a pH of 3.7 1 N. hydrochloric acid. Loose orange precipitate is collected by filtration to obtain the title compound (157 mg).

1H-NMR (DCO-d6, ) : 1,97 - of 2.25 (2H, m), 2,42 - of 2.58 (2H, m), 2,99 (1H, t, J = 8,8 Hz) and 3.59 (2H, t, J = 8,8 Hz), 4,33 is 4.45 (1H, m), 4,59 (2H, s) of 6.71 (1H, d, J = 8,3 Hz), 6,93 (2H, BS), 7,39 (1H, t, J = 7.8 Hz), EUR 7.57 - of 7.82 (5H, m), 7,88 - of 8.04 (1H, m), 8,06 - to 8.12 (1H, m), 8,15 compared to 8.26 (2H, m), is 8.75 (1H, s), 10,12 (1H, s).

Comparative example 35. Getting-benzyl-N-carbobenzoxy-N',N'-dimethyl-L-glutaminate.

0,14 ml atilglukuronida added to 2 ml of tertrahydrofuran ring solution containing 508 mg-benzyl-N-carbobenzoxy-L-glutamate and to 0.19 ml of triethylamine at -20oC in nitrogen atmosphere and the mixture is stirred for 30 minutes Then add 3 ml of dichloromethane solution of 112 mg DIMET Atisa to room temperature, and the resulting residue is dissolved in chloroform. Chloroformate layer is washed successively with a saturated aqueous solution of sodium bicarbonate and 1 N. hydrochloric acid and dried over sodium sulfate, and then remove the solvent under reduced pressure. The resulting residue is subjected to chromatographic treatment using silica gel and as eluent a mixture of chloroform - methanol = 49:1 to obtain the title compound (453 mg).

1H-NMR (CDCl3, ) : 1,97 - is 2.37 (4H, m), of 2.86 (3H, c), 2,90 (3H, c), 4,39 - to 4.41 (1H, m), 5,10 (2H, c) to 5.17 (2H, c), 5,86 - of 5.89 (1H, m), 7,34 (10H, c).

Comparative example 36. Obtaining N-carbobenzoxy-N',N'-dimethyl-L-glutamine.

To 5 ml of a solution of 450 mg of the compound of comparative example 35 in methanol was added 1 N. aqueous solution of sodium hydroxide and the mixture is stirred at room temperature overnight. At the same time supporting the temperature of the water bath 30oC or below, the solvent is removed under reduced pressure. The resulting residue is dissolved in water and then the solution is acidified with 1 N. hydrochloric acid, the mixture is extracted using chloroform. Then chloroformate layer is dried over sodium sulfate, the solvent is removed under reduced pressure to PM), 2,42 - of 2.56 (1H, m), was 2.76 - 2,84 (1H, m), 2,98 (3H, c) of 3.00 (3H, c), 4,19 - 4,27 (1H, m), 5,09 (2H, c), 6,04 - the 6.06 (1H, m), 7,37 (10H, c).

Comparative example 37. Getting-methyl-N-carbobenzoxy-N',N'-dimethyl-L-glutaminate.

In 4 ml of dry methanol was dissolved 3530 mg of the compound of comparative example 36, add 5 ml trimethylsilyldiazomethane and the mixture is stirred for 5 hours the Solvent is removed under reduced pressure to obtain the title compound (338 mg).

1H-NMR (CDCl3, ) : 1,96 is 2.43 (4H, m), of 2.92 (3H, c), 2,95 (3H, c), 3,74 (3H, c), 4,28 - and 4.40 (1H, m), 5,10 (2H, c), 5,80 (1H, m), 7,35 (5H, c).

Comparative example 38. Getting-methyl-N',N'-dimethyl-L-glutaminate.

After adding 10% (70 mg), palladium carbon black to 10 ml of a methanol solution of 580 mg of the compound of comparative example 37 the mixture is stirred in hydrogen atmosphere at room temperature for 15 hours of Palladium carbon is removed by filtration using celite and the solvent is removed under reduced pressure. The resulting residue is subjected to chromatographic treatment using silica gel and as eluent a mixture of chloroform-methanol = 19:1 to obtain the title compound (160 mg).

1H-NMR (CDCl3, ) : 1,74 - of 1.92 (1H, m), 2.06 to of 2.23 (1H, m), 2.4 benzoquinoline-5-carbonyl)-N',N'-dimethyl - L-glutaminate.

2 ml of thionyl chloride are added to 295 mg of 1-carbobenzoxy-5-carboxylic acid and the mixture is stirred at room temperature for 2 CV. Then evaporated to dryness under reduced pressure. The obtained solid is dissolved in 2 ml of dichloromethane and to the solution was added 2.5 ml of dichloromethane solution containing 160 mg of the compound of comparative example 38 and 0.18 ml of triethylamine under ice cooling in a nitrogen atmosphere, and the mixture is stirred over night. The reaction mixture was sequentially washed with a solution of 1 N. hydrochloric acid, saturated aqueous sodium bicarbonate and water, dried over sodium sulfate and then remove the solvent under reduced pressure. The resulting residue is subjected to chromatographic treatment using silica gel and chloroform as eluent, and then a mixture of chloroform=methanol = 99:1 to obtain the title compound (359 mg).

1H-NMR (CDCl3, ) : 2,22 of - 2.32 (2H, m), 2,43 is 2.55 (2H, m) to 2.94 (3H, c), 2,98 (3H, c) and 3.15 (2H, t, J = 8,8 Hz), 3,76 (3H, c), 4,10 (2H, t, J = 8,8 Hz), 4,58 - and 4.68 (1H, m), 5,28 (2H, c), of 7.36 - 7,41 (6H, m), 7,71 (1H, c), of 7.90 (1H, d, J = 5,9 Hz).

Comparative example 40. Getting-methyl-N-(indolin-5-carbonyl)-N', N'-dimethyl-L-glutaminate.

After adding 10% (70 mg) allshare hydrogen at room temperature for 15 hours Palladium soot is removed by filtration using celite and the solvent is removed under reduced pressure. The resulting residue is subjected to chromatographic treatment using silica gel and as eluent a mixture of chloroform-methanol = 99:1 to obtain the title compound (131 mg).

1H-NMR(CDCl3, ) : 2,19 - of 2.30 (2H, m); 2,44 of $ 2.53 (2H, m), with 2.93 (3H, c), totaling 3.04 (2H, t, J = 8,3 Hz), 3,62 (2H, t, J = 8,3 Hz in), 3.75 (3H, c), 4,14 (1H, BS), 4,60 - 4,70 (1H, m), 6,56 (1H, d, J = 7.8 Hz), 7,51 to 7.62 (3H, m).

Example 19. Getting-methyl-N-[1-((2,4-diamino-6-pteridinyl)methyl)-indolin-5-carbonyl] -N',N'-dimethyl-L-glutaminate.

In 4 ml of dimethylacetamide suspended 131 mg of the compound of comparative example 40 and 233 mg of the adduct of 6-methyl bromide-2,4-diaminopyrimidine and isopropanol and the suspension is stirred at room temperature for 24 h, the Reaction mixture was subjected to chromatographic treatment using silica gel as an eluent of ethyl acetate and then a mixture of chloroform-methanol = 9:1 to obtain the compound indicated in the title (95 mg).

1H-NMR (CDCl3, ) : 1,98 - 2,17 (2H, m), 2,42 (2H, t, J = 6.8 Hz), 2,84 (3H, c) to 2.94 (3H, c) of 3.00 (2H, t, J = 8,3 Hz) and 3.59 (2H, t, J = 8,3 Hz) to 3.64 (3H, c), 4,30 was 4.42 (1H, m), 4,55 (2H, c), of 6.68 (1H, d, J = 7,3 Hz), 7,60 - to 7.64 (2H, m), a 8.34 (1H, d, J = 7,3 Gutemine.

70 mg of the compound of example 19 is dissolved in 5 ml of methanol and to the solution was added 0.15 ml of 1 N. aqueous solution of sodium hydroxide, and the mixture is stirred at room temperature for 12 hours Then the solution add 2 ml of water and the mixture is further stirred for 5 hours the Temperature of the water bath at the same time supporting up to 30oC or below, remove the solvent under reduced pressure. The resulting residue is dissolved in a saturated aqueous solution of sodium bicarbonate and the solution brought to a pH of 3.7 1H. the hydrochloric acid. Loose orange precipitate is collected by filtration to obtain the compound indicated in the title (16 mg).

1H-NMR (CDCl3, ) : 1,96 - of 2.08 (2H, m), is 2.41 (2H, t, J = 7,1 Hz), 2,82 (3H, c), of 2.92 (3H, c), a 3.01 (2H, t, J = 7.8 Hz), 3,62 (2H, t, J = 7.8 Hz), 4,27 - 4,37 (1H, m), to 4.62 (2H, c), 6,72 (1H, d, J = 8,8 Hz), b - to 7.64 (2H, m), 8,24 (1H, d, J = 6.8 Hz), 8,87 (1H, c), 12,46 (1H, BS).

Comparative example 41. Obtain [1-(2,4-diamino-6-pteridinyl)methyl] -1,2,3,4-tetrahydro-6-quinoline-carboxylic acid.

In 3 ml dimethylacetamide suspended 178 ml adduct 6-bromomethyl,4-diaminophenylmethane and isopropanol and 55 mg of 1,2,3,4-tetrahydro-6-quinoline-carboxylic acid and the suspension is stirred at 60-65oC during the night. After cooling, add 10 ml of water to the reactions the bottom. The precipitation is collected by filtration to obtain the title compound (70 ml).

1H-NMR (DMCO-d6, ): 2,08 (2H, t, J = 8 Hz), is 2.88 (2H, t, J = 8 Hz), 3,68 (2H, t, J = 8 Hz), 4.72 in (2H, s), 6,62 (1H, d, J = 9 Hz), of 7.48 (2H, m), 8,51 (1H, s).

Example 21. Getting diethyl-N-[1-((2,4-diamino-6-pteridinyl) -methyl)-1,2,3,4,-tetrahydro-6-hinolincarbonova]-L-glutamate.

In 6 ml of anhydrous dimethylformamide are suspended 60 mg of triethylamine and 98 mg of diethylphosphoramidite and further to the suspension is added 60 mg of the compound of comparative example 41, and the mixture is stirred. After dissolution, the mixture is stirred at 80oC for 3 min and cooled to room temperature, followed by stirring for 10 minutes Then added to the mixture of 20 mg of triethylamine and 40 mg diacylglyceride and the mixture was stirred at 80oC within 2 hours After completion of the reaction the solvent is removed under reduced pressure, to the residue is added chloroform and CHLOROFORMATES layer was washed with saturated aqueous sodium bicarbonate. After drying chloroformate layer over magnesium sulfate the solvent is removed under reduced pressure and the resulting residue is subjected to chromatographic treatment using silica gel and as aamr (DMCO-d6, ) : 1.1 to 1.4 (6H, m), 1.8 - 2.4m (4H, m), 2.40 a (2H, t, J = 8 Hz), 2,82 (2H, t, J = 8 Hz), 3,51 (2H, t, J = 8 Hz), 4,0 - 4,3 (4H, m), with 4.64 (1H, m), and 4.75 (2H, s), of 6.65 (1H, d, J = 9 Hz), 7,47 (2H, m), 8, 65 (1H, s).

Example 22. Obtaining N-[1-((2,4-diamino-6-pteridinyl)methyl)- -1,2,3,4, -tetrahydro-6-hinolincarbonova]-L-glutamato acid.

In 10 ml of ethanol was dissolved 50 mg of the compound of example 21 and to the solution is added to 0.24 ml of 1N. an aqueous solution of sodium hydroxide at 35oC, and the mixture is stirred at the same temperature for 4.5 hours Stirring is then continued at 25oC for 20 h and the reaction mixture was added 1 ml of water. While cooling with ice water, the reaction mixture was adjusted to a pH of 3.7 1H. hydrochloric acid and leave overnight in a cool place. The precipitation is collected by filtration to obtain the compound indicated in the title (27 mg).

1H-NMR (DMCO-d6, ): 1,8 - 2,2 (4H, t, J = 8 Hz), a 2.75 (2H, t, J = 8 Hz), of 3.60 (2H, t, J = 8 Hz), 4,36 (1H, m), 4,70 (2H, s), 6,62 (1H, d, J = 9 Hz), 7,51 (2H, m), to 8.62 (1H, s).

So melting 204-208oC (decomposes).

Comparative example 42. Obtaining methyl-4-[(2,4-diamino-6-pteridinyl)methyl)-3,4-dihydro-2H-1,4-benzoxazin-7-carboxylate.

In 10 ml of dimethylacetamide suspended 410 mg of the adduct of 6-methyl bromide-2,4-diaminopyrimidine and isopropanol is SUP>C for 4 h and at a temperature of 90oC for 19 hours After cooling dimethylacetamide condense under reduced pressure and add chloroform and an aqueous solution of sodium bicarbonate to the condensate. Then the precipitate, is filtered off, the organic layer washed with water and dried over magnesium sulfate and remove the solvent under reduced pressure. The residue is subjected to chromatographic treatment using silica gel and as eluent a mixture of chloroform-methanol = 97: 3 to obtain the title compound (100 mg).

1H-NMR (CDCl3:CD3OD=9:1, ) : 3,63 (2H, Shir.t) of 3.84 (3H, s), 4,32 (2H, BRT), 4,72 (2H, s), of 6.68 (1H, d, J = 9.0 Hz), 7,47 (1H, s) to 7.50 (1H, d, J = 9.0 Hz), 8,71 (1H, c).

Comparative example 43. Getting 4-[(2,4-diamino-6-pteridinyl)methyl] -3,4-dihydro-2H-1,4-benzoxazin-7-carboxylic acid.

60 mg of the compound of comparative example 42 are suspended in a mixed solvent of 20 ml of 1N. an aqueous solution of sodium hydroxide and 20 ml of methanol and the suspension is refluxed under heating for 2.5 hours, After cooling the solvent is removed, water is added and the mixture is brought to pH 5 (suspended) solution of 1H. of hydrochloric acid. The mixture is left in a cold place, the precipitation is collected Phi is, : 3,63 (2H, m), 4,22 (2H, m), 4,71 (2H, s), 7,21 (1H, s), 8,29 (1H, s).

Example 23. Getting diethyl-N-[4-((2,4-diamino-6-pteridinyl) methyl)-3,4-dihydro-2H-1,4-benzoxazin-7-carbonyl]-L-glutamate.

To a solution of 64 μl of diethylphosphoramidite, 60 μl of triethylamine and 5 ml of anhydrous dimethylformamide are added 50 ml of the compound of comparative example 43 and the mixture is stirred under nitrogen atmosphere at 80oC for 5 min After cooling to room temperature, add 20 μl of triethylamine and 34 mg diethylphthalate and the mixture is again heated to 80oC under stirring for 2.5 hours, After cooling, the reaction mixture is extracted with chloroform and CHLOROFORMATES layer successively washed with saturated aqueous sodium bicarbonate and saline. After drying, chloroformed layer over magnesium sulfate the solvent is removed under reduced pressure. The resulting residue is subjected to chromatographic treatment using silica gel and as eluent a mixture of chloroform-methanol = 19:1 to obtain the title compound (10 ml).

1H-NMR (CDCl3: CD3OD = 9:1, ): of 1.23 (3H, t, J = 6,8 Hz) of 1.29 (3H, t, J = 6.8 Hz), 3,60 (2H, m), 4,11 (2H, q, J = 6.8 Hz), 4,22 (2H, q, J = 6.8 Hz), 4,32 (2H, m), 4,71 (2H, s), 6,69 (1H, d, J = 10 Hz), 7,29 (1H, d, J = 10.0 Hz)that is arbonyl]-L-glutamato acid.

In 3 ml of ethanol dissolving 9 mg of the compound of example 23 and to the solution was added 1N. an aqueous solution of sodium hydroxide, the mixture is stirred at room temperature for 4 days. The solvent is removed and the residue is subjected to chromatographic treatment using silica gel and a mixed solvent of chloroform-methanol-aqueous ammonia = 5:4:1. The fractions containing specified in the title compound, collect and remove the solvent. The residue is dissolved by the addition of saturated aqueous sodium hydrogen carbonate solution (200 μl) and a solution of water until a pH of about 4 (suspended) by adding dropwise 1N. hydrochloric acid solution and leave overnight in a cool place. The precipitation is collected by filtration to obtain the title compound (2.8 mg).

1H-NMR (DMCO-d6, ): 1,86 - of 1.95 (1H, m), 1,95 - 2,03 (1H, m), 2,24 - of 2.38 (2H, m) to 3.67 (2H, t, J = 3.8 Hz), 4,25 (2H, t, J = 3.8 Hz), 4,30 (1H, m), 4,70 (2H, s), 6,83 (1H, d, J = 8.6 Hz), 7,26 (1H, s), 7,30 (1H, d, J = 8.6 Hz), of 8.09 (1H, m), to 8.70 (1H, s).

IR (KBr)max3464, 1642 and 1512 cm-1.

Example 25. Obtaining methyl-N-[1-((2,4-diamino-6-pteridinyl) methyl)-indanyl-5-carbonyl]-DL-2-amino-4-phosphonobutyric.

In 30 ml of aqueous dimethylformamide are suspended 272 mg of triethylamine and 440 mg diethylthiophosphate the offer was stirred at room temperature overnight (solution A). On the other hand, in 5 ml of aqueous methanol is dissolved DL-2-amino-4-phosphonobutyric acid at 0oC and then gradually to the solution add 1 ml of thionyl chloride at the same temperature. Then, the mixture is left to warm to room temperature and stirred over night and remove the solvent under reduced pressure. The resulting residue is dissolved in aqueous dimethylformamide (solution B). Then solutions a and B are mixed. To the mixed solution is then added 505 mg of triethylamine and the mixture is stirred at room temperature for 3 days. Then remove the solvent under reduced pressure to obtain 700 mg of the residue. From the obtained residue selected 100 mg and spend fractionation using high-performance liquid chromatography (column UMC - A323) and as eluent a mixture of water-acetonitrile-triperoxonane acid = 87,5: 12,5:1 to obtain the title compound (2 mg).

1H-NMR (D2O ) : 1.7 to 2.3 (4H, m), 3,06 (2H, t, J = 7 Hz), to 3.58 (2H, t, J = 8 Hz), of 3.84 (3H, s), 4,36 (1H, m), 4,70 (2H, s), 6,63 (1H, d, J = 8.6 Hz), 7,60 (2H, m), 8,78 (1H, s).

Comparative example 44. Obtaining methyl-4-amino-3-hydroxybenzoate.

40 mg of methanol is suspended 4-amino-3-hydroxybenzoic acid and through the suspension pass 6 o'clock The precipitation is collected by filtration, washed three times with ether and then dried in vacuo to obtain the title compound (4.15 g).

1H-NMR (CDCl3, ) : a 3.83 (3H, s), of 6.68 (1H, d, J = 8 Hz), 7,41 (2H, m).

Comparative example 45. Getting 4-methoxycarbonyl-2-hydrochlorathiazide.

In 30 ml of dichloromethane was dissolved 1.0 g of the compound of comparative example 44 and 4.0 ml of triethylamine and the solution is cooled to 0oC. To the solution are added dropwise 5 ml of a dichloromethane solution of 1.0 ml of chloroacetanilide in nitrogen atmosphere for 8 min, and the mixture is stirred at the same temperature for 1 h Then the reaction mixture is added saturated aqueous solution of ammonium chloride, and the precipitated precipitate is collected by filtration. Using a mixture of chloroformate, conduct recrystallization to obtain compound indicated in the title (0,83 g).

1H-NMR (CDCl3, ): 3,90 (3H, s), 4,25 (2H, s), 7,52 (2H, m), of 8.37 (1H, d, J = 8 Hz).

Comparative example 46. Obtaining methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-carboxylate.

In 300 ml of ethanol is suspended 6.0 g of the compound of comparative example 45 and to the suspension is added 5.0 g of potassium acetate, and the mixture is boiled with a reflux who shat in a vacuum to obtain specified in the title compound (5.2 g).

1H-NMR (DMCO-d6, ) : of 3.80 (3H, s), 4,63 (2H, s), to 6.95 (1H, m), the 7.43 (1H, m), 7,56 (1H, m).

Comparative example 47. Obtaining methyl-3,4-dihydro-2H-1,4-benzoxazin-7-carboxylate.

In a nitrogen atmosphere to 30 ml of tetrahydrofuran, add a set of tetrahydrofurane (1 M solution, 10 ml) and 440 mg of the compound of comparative example 46 at 0oC, and the mixture is stirred at room temperature for 15 min and then refluxed for 4 hours, the Reaction mixture was cooled to room temperature and add 2.5 ml of solution 6 N. hydrochloric acid. The reaction mixture is condensed under reduced pressure, poured into water and alkalinized 2 N. aqueous solution of sodium hydroxide. Then specified in the title compound is extracted with ethyl acetate and the resulting organic layer was washed with saline and dried over magnesium sulfate. After removal of the solvent under reduced pressure the resulting residue is subjected to chromatographic treatment using silikagelevye column. The remainder of the show and elute mixed solvent of hexane-ethyl acetate = 3:2 to obtain the title compound (310 mg).

1H-NMR (CDCl3, ) : of 3.46 (2H, m), of 3.84 (3H, s), 4,22 (2H, t, J = 4,4 is benzoxa-3,4-dihydro-2H-1,4-benzoxazin-7-carboxylate.

In 50 ml of tetrahydrofuran was dissolved 1.4 g of the compound of comparative example 47 and to the solution is gradually added 700 mg of sodium, and the mixture is stirred at room temperature for 30 minutes Then add 3 ml of carbobenzoxy and the mixture is stirred over night. After adding to the reaction mixture a few drops of water, the reaction mixture was poured into cold water and indicated in the title compound is extracted with ethyl acetate. The obtained organic layer is dried over sodium sulfate and remove the solvent under reduced pressure. The residue is recrystallized from a mixture of hexane-ethyl acetate to obtain the title compound (1,79 g).

1H-NMR (CDCl3, ) : of 3.85 (3H, s), 3,91 (2H, m), 4,25 (2H, m), of 5.34 (2H, s), 7,35 (5H, m), 7,53 (2H, m), to 7.99 (1H, m).

Comparative example 49. Obtaining N-carbobenzoxy-3,4-dihydro-2H-1,4-benzoxazin-7-carboxylic acid.

In 50 ml of ethanol is suspended 1,79 g of compound of comparative example 48 and to the suspension is added to 8.2 ml of 1 N. aqueous solution of sodium hydroxide, and the mixture is stirred over night. The solvent is removed under reduced pressure, the obtained residue is dissolved in 20 ml of water. Then the solution is gradually added a solution of 1 N. hydrochloric acid is AI compound (1.39 g).

1H-NMR (CDCl3, ) : 3,82 (2H, m), 4,14 (2H, m) to 5.13 (2H, s), of 7.2 to 7.7 (7H, m), 7,95 (1H, m).

Comparative example 50. Getting dimethyl-N-(3,4-dihydro-2H-4,4-benzoxazin-7-carbonyl-L- -aminoadipate.

In 5 ml of thionyl chloride are suspended 800 mg of the compound of comparative example 49, to the mixture is added a catalytic amount of dimethylformamide, and the mixture is stirred at room temperature for 2 hours and Then the excess thionyl chloride is removed under reduced pressure and the residue triturated with hexane. After you collect the resulting crystals by filtration, the crystals are dissolved in 20 ml of dichloromethane to dichloromethane solution was added dropwise an aqueous solution containing 1.0 hydrochloride dimethyl-L--aminoadipic acid and 1.0 g of triethylamine while cooling with ice water. The mixture is stirred at room temperature over night and remove the solvent under reduced pressure. To the residue add mixed solution of ethyl acetate and diluted hydrochloric acid while cooling with ice water. After stirring for 5 min to separate the organic layer and then the organic layer was washed with saturated aqueous sodium bicarbonate. After drying over magnesium sulfate the solvent is removed when p is the mixture is stirred in hydrogen atmosphere at room temperature overnight. Palladium soot is removed by filtration using celite, and the solvent is removed under reduced pressure. The resulting residue is subjected to chromatographic treatment using silikagelevye column and as eluent a mixture of chloroform-methanol = 100:1 to obtain the title compound (230 mg).

1H-NMR (CDCl3, ) : 1,6 - 2,1 (4H, m), of 2.38 (2H, t, J = 6.8 Hz), of 3.46 (2H, m), 3,68 (3H, s), of 3.77 (3H, s), 4,24 (2H, m), 4.72 in (1H, m), 6,59 (1H, d, J = 8,3 Hz), 7,33 (2H, m).

Example 26. Getting dimethyl-N-[I-((2,4-diamino)-6-pteridinyl)methyl]-3,4-dihydro-2H-1,4-benzoxazin-7-carbonyl]-L-aminoadipate.

In 3 ml of dimethylacetamide are suspended in 20 ml of the compound of comparative example 50 and adduct (226 mg), 6-methyl bromide-2,4-diaminopyrimidine and isopropanol, and the suspension is stirred at 60oC for 6 hours After cooling, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer is dried over magnesium sulfate and remove the solvent under reduced pressure. The resulting residue is subjected to chromatographic treatment using silikagelevye column and as elution solvent a mixed solvent of chloroform-methanol = 10:1 to obtain soede (3H, C) 3,76 (3H, s), 4,39 (2H, m), of 4.67 (2H, BS), to 4.73 (1H, m), of 6.66 (1H, d, J = 8,3 Hz), 6.99 (1H, t, J = 7,3 Hz), 7,29 (2H, m), to 8.70 (1H, s).

Example 27. Obtaining N-[1-((2,4-diamino)-6-pteridinyl)methyl] -3,4-dihydro-2H-1,4-benzoxazin-7-carbonyl]-L-aminoadipic acid.

260 mg of the compound of example 26 is dissolved in 12 ml of ethanol, to the solution was added to 0.45 ml of 1 N. aqueous solution of sodium hydroxide at 35oC, and the mixture is stirred at the same temperature for 4 hours Then continue stirring at 25oC for 20 hours, add 0,5 ml of water to the reaction mixture and removing the ethanol under reduced pressure. The resulting residue is dissolved in 6 ml of water, adjusted to a pH of 3.7 1H. solution of hydrochloric acid while cooling with ice water and leave in a cool place overnight. The precipitation is collected by filtration to obtain the title compound (176 mg).

1H-NMR (DMCO-d6, ) : of 1.5 - 2.0 (4H, m), and 2.14 (2H, t, J = 6.8 Hz), 3,68 (2H, m), 4,28 (3H, m), 4,71 (2H, BS), to 6.80 (1H, t, J = 8,3 Hz), 7,31 (2H, m), 8,13 (1H, d, J = 7,3 Hz), 8,71 (1H, s).

Comparative example 51. Getting-methyl - benzyl-N-t-butoxycarbonyl-L-glutamate.

In 75 ml dimethylformamide solution of 5.0 g-benzyl-N-t-butoxycarbonyl-L-glutamate is suspended 2.5 g of sodium bicarbonate and suspension add 7 24 PM Then the reaction mixture is condensed under reduced pressure, the residue is poured into 70 ml of water and extracted with a mixed solution of ethyl acetate-n-hexane = 1:1. The organic layer is washed with water and dried over sodium sulfate, the solvent is removed under reduced pressure. The resulting residue is subjected to chromatographic treatment using silikagelevye column and as eluent a mixture of ethyl acetate-n-hexane = 1:2 to obtain the connection specified in the title (5,2 g).

1H-NMR (CDCl3, ) : USD 1.43 (9H, s), 1,92 is 2.01 (1H, m), 2,11 - is 2.37 (1H, m), 2,42 is 2.51 (2H, m), of 3.73 (3H, s), 4,23 - and 4.40 (1H, m), 5,12 (2H, s), to 7.35 (5H, s).

Comparative example 52. Getting-methyl-N-t - butoxycarbonyl-L-glutamate.

After adding 10% (1.1 g) palladium soot to 30 ml of methanol containing 5.2 connection of comparative example 51, the mixture is stirred in hydrogen atmosphere at room temperature for 15 hours of Palladium carbon is removed by filtration using celite and remove the solvent under reduced pressure. The resulting residue is dissolved in a saturated aqueous solution of sodium bicarbonate and the solution was washed with chloroform. After separation of the aqueous layer was adjusted its pH to 4 to 5% citric acid and extracted with chloro the treatment specified in the title compound (3.9 g).

1H-NMR (CDCl3, ): the 1.44 (9H, s), 1,89 - 2,04 (1H, m), 2,09 - of 2.27 (1H, m), 2,33 at 2.59 (2H, m in), 3.75 (3H, s), 4,24 - of 4.44 (1H, m), 5,17 - to 5.21 (1H, m), 9,38 (1H, BS).

Comparative example 53. Getting hydrochloride methyl-4-amino-n-butyrate.

In 20 ml of methanol solution of 1.0 g of 4-amino-n-butterboy acids miss gaseous hydrogen chloride for 10 minutes and the mixture is stirred at room temperature for 5 hours the Solvent is removed under reduced pressure to obtain the title compound (1.5 g).

1H-NMR (DMCO-d6, ): 1,83 - of 2.24 (2H, m), 2,32 - 2,60 (2H, m), was 2.76 - 3,26 (2H, m), 3,61 (3H, s), compared to 8.26 (2H, Shir.C).

Comparative example 54. Getting-methyl-N-t - butoxycarbonyl-N'-/3-methoxycarbonylpropionyl/-L-glutaminate.

To 5 ml of tertrahydrofuran ring solution of 518 mg of the compound of comparative example 52 add 0.33 ml of triethylamine and 1 ml of tertrahydrofuran ring solution, 0,31 ml isobutylparaben at -20oC in nitrogen atmosphere, and the mixture is stirred for 30 minutes Then added to a mixture of 5 ml tetrahydropyranol suspension 366 mg of the compound of comparative example 53 and 0.33 ml of triethylamine, the mixture is stirred for 1 hour. The mixture is left to gradually warm to room temperature and then AC. dilatatory layer is washed successively with 5% aqueous citric acid solution, saturated aqueous citric acid, saturated aqueous sodium bicarbonate and water and dried over sodium sulfate. The solvent is removed under reduced pressure, the obtained residue is subjected to chromatographic treatment using silikagelevye column and as eluent a mixture of chloroform:methanol = 99:1 to obtain the title compound (575 mg).

1H-NMR (CDCl3, ): the 1.44 (9H, s), 1,78 of 1.99 (3H, m), 2,16 - 2,19 (1H, m), 2,22 - 2,31 (2H, m), 2,39 (2H, t, J = 7,1 Hz), 2,70 (2H, q, J = 6.5 Hz), 3,68 (3H, s), 3,74 (3H, s), 4,14 - or 4.31 (1H, m), to 5.35 (1H, BS), to 6.43 (1H, BS).

Comparative example 55. Getting-methyl-N'-(3-methoxycarbonylpropionyl)-L-glutaminsintetaza.

726 mg of the compound of comparative example 54 was dissolved in 2 ml triperoxonane acid under ice cooling, and the mixture is stirred for 1 h the Solvent is removed under reduced pressure to obtain the title compound (754 mg).

1H-NMR (CDCl3: CCD3OD = 20:1, ): 0,92 (2H, q, J = 6.3 Hz), 2,04 - to 2.42 (4H, m) of 2.50 (2H, t, J = 6.3 Hz), 3,17 - 3,24 (2H, m) to 3.67 (3H, s), 3,81 (3H, s), 4.09 to to 4.15 (1H, m), 7,44 (1H, t, J = 6.0 Hz).

Comparative example 56. Getting-methyl-N-billaut to 599 mg of 1-carbobenzoxy-5-carboxylic acid, and the mixture is stirred at room temperature for 2 hours the mixture is Then evaporated to dryness under reduced pressure. The obtained solid substance was dissolved in 7 ml of methylene chloride, to the solution was added 3 ml of an aqueous solution 754 mg of the compound of comparative example 55 and 534 mg of sodium bicarbonate at room temperature and the mixture is stirred for 15 hours To the mixture add sodium bicarbonate until then, until the pH is 8, and the insoluble portion removed by filtration using celite and separate methylenchloride layer. Methylenchloride layer is washed successively 1 N. hydrochloric acid and water, dried over sodium sulfate. The solvent is removed under reduced pressure and the resulting residue is subjected to chromatographic treatment using silikagelevye column and as eluent a mixture of chloroform-methanol = 99:1 to obtain the title compound (474 mg).

1H-NMR (CDCl3, ): is 1.81 (2H, q, J = 7.0 Hz), 2,09 - of 2.27 (4H, m); of 2.34 (2H, t, J = 7,3 Hz) and 3.15 (2H, t, J = 9.0 Hz), with 3.27 (2H, t, J = 5.4 Hz), the 3.65 (3H, s), of 3.77 (3H, s), 4,10 (2H, t, J = 8,8 Hz), 4,65 - of 4.75 (1H, m), 5,28 (2H, C), 6,38 - of 6.45 (1H, m), of 7.36 - 7,46 (6H, m), 7,66 - to 7.68 (2H, m).

Comparative example 57. Getting-methyl-N-(indolin-5 - carbonyl)-N'-(3-methoxycarbonylpropionyl comparative example 56 the mixture is stirred in hydrogen atmosphere at room temperature for 15 hours After removal of the palladium soot filtration using celite remove the solvent under reduced pressure to obtain the title compound (350 mg).

1H-NMR(CDCl3, ): 1,66 - 2,48 (8H, m), 2,81 - 3,30 (4H, m), 3,50 (2H, t, J = 6.0 Hz), to 3.64 (3H, s), of 3.73 (3H, s), 4,49 - to 4.81 (1H, m), 6,51 (2H, d, J = 9.0 Hz), 6,62 - 6,84 (1H, m), 7,21 - 7,33 (1H, m), 7,42 - EUR 7.57 (2H, m).

Example 28. Getting-methyl-N-[1-[(2,4-diamino-6-pteridinyl)- indolin-5-carbonyl]-N'-(3-methoxycarbonylpropionyl)-L-glutaminate.

In 7 ml of dimethylacetamide suspended 350 mg of the compound of comparative example 57 and 414 mg of the adduct of 6-methyl bromide-2,4-diaminopyrimidine and isopropanol and the suspension is stirred at room temperature for 24 hours To the mixture of 0.29 ml of triethylamine, and the mixture is stirred for 10 min, and then subjected to chromatographic treatment using silikagelevye column and as an eluent of ethyl acetate and then a mixture of chloroform-methanol = 9:1 to obtain the compound indicated in the title (263 mg).

1H-NMR (DMCO-d6: CDCl3= 7:3, ): 1,67 (2H, q, J = 6.9 Hz), 1,91 with 2.14 (2H, m), 2,19 is 2.33 (4H, m), 2,97 - 3,13 (4H, m), 3,56 - 3,59 (5H, m), the 3.65 (3H, s), 4,34 - of 4.44 (1H, m), 4,55 (2H, s), to 6.67 (1H, d, J = 8,3 Hz), 7,32 (4H, BS), a 7.62 - 7,66 (2H, m), to 7.84 (1H, t, J = 8,3 Hz), with 8.33 (1H, d, J = 7,3 Hz), 8,71 (1H, s).

To 5 ml of 250 mg of the compound of example 28 in methanol added to 0.95 ml of 1 N. aqueous solution of sodium hydroxide and the mixture is stirred at room temperature for 20 hours the Temperature of the water bath at the same time supporting up to 30oC or below, and remove the solvent under reduced pressure. The resulting residue is subjected to chromatographic treatment using silikagelevye column and as eluent a mixture of chloroform-methanol-28% aqueous ammonia = 5:4:1 to obtain a brown solid. The obtained solid is dissolved in water, filtered off the insoluble part and bring the solution to pH of 3.7 with a solution of 1 N. hydrochloric acid. Loose brownish precipitate is collected by filtration to obtain the title compound (144 mg).

1H-NMR (DMCO-d6: CDCl3= 9:1, ): to 1.61 (2H, q, J=7.0 Hz), 1,89-of 2.09 (2H, m), 2,13-of 2.30 (4H, m), 2.95 and-3,10 (4H, m) to 3.58 (2H, t, J=8.0 Hz), 4,25-to 4.38 (1H, m), 4,55 (2H, c), 6,70 (1H, d, J=8,3 Hz), to 7.61-the 7.65 (1H, m), a 7.85 (1H, t, J=5.8 Hz), 8,21 (1H, d, J=7,3 Hz), 8,73 (1H, c).

Example 30. Obtaining N-[1[[2,4-diamino-6-pteridinyl)methyl)nicolin-5-carbonyl]homocysteine ammonium.

To 6 ml of a suspension of 330 ml hydrobromide homocysteinemia acid in benzene add 870 μl of triethylamine and 630 μl of chlorotrimethylsilane byvaut, the filtrate is condensed to obtain milirovannie homocysteinemia acid (450 mg). In nitrogen atmosphere in 18 ml of dimethylformamide is dissolved 213 μl dimethylthiophosphate and 172 μl of triethylamine and small portions add 170 mg of 1-(2,4-diamino(-6-pteridinyl)methyl)indolin-5-carboxylic acid at room temperature and the mixture is stirred at the same temperature for 3 hours To the solution add 2 ml dimethylformamide solution of 450 mg milirovannie homocysteinemia acid and the mixture is stirred at room temperature for 2 days. Then to the reaction mixture was added 1 ml of water and remove the solvent under reduced pressure. To the residue add 3% aqueous solution of ammonium bicarbonate and after removing insoluble by filtration, the filtrate was processed using a column with DEAE-cellulose, washed with water and elute 3% aqueous solution of ammonium bicarbonate to obtain the title compound (18 mg).

1H-NMR (D2O ) : 2,0-2,4 (2H, m), 3,15 (4H, m), 3,49 (2H, m), 4,34 (1H, m), of 4.49 (2H, s), 6,66 (1H, m), 7,55 (2H, m), 8,69 (1H, s).

Comparative example 58. Obtaining methyl-3,4-dihydro-2H-1,4-benzodiazepinovaja.

A mixture of 15 g of 2-aminobenzothiazole-6-carboxylic acid, 22 g getrootnode temperature and add to it 20 ml of water, 40 ml of 1,2-dibromethane and 3 g of hexadecyltrimethylammonium, and the mixture is refluxed for 6 hours the Mixture is cooled to room temperature, added to a mixture of water and chloroform, and the insoluble portion is removed by decantation. The aqueous layer was adjusted to pH 3 with hydrochloric acid and collected chloroformate layer. Received chloroformate layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue is dissolved in methanol. Through a solution of miss gaseous hydrogen chloride for 10 min and the mixture is stirred at room temperature overnight. To the residue obtained by removing the solvent under reduced pressure, add water and ethyl acetate, the aqueous layer was adjusted to pH 5 1H. aqueous solution of sodium hydroxide and then extracted with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue is subjected to chromatographic treatment using a silica column and as eluent a mixture of ethyl acetate-hexane=1:4 to obtain the title compound (721 mg).

1

313 mg of the compound of comparative example 58 was dissolved in 10 ml of tetrahydrofuran and the solution is gradually added 180 mg of sodium hydride, and the mixture is stirred at room temperature for 20 minutes Then added to the mixture of 1.3 ml of carbobenzoxy, and the mixture is stirred over night. After adding water, the mixture extracted with ethyl acetate. The resulting organic layer is dried over anhydrous sodium sulfate and then remove the solvent under reduced pressure. The residue is subjected to chromatographic treatment on a column of silica gel, using as eluent a mixture of ethyl acetate hexane= 1: 10, receive methyl-N-carbobenzoxy-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylate and suspended in 15 ml of ethanol. To the suspension is added to 1.9 ml of 1 N. aqueous solution of sodium hydroxide and the mixture is stirred over night. The solvent is removed under reduced pressure and the obtained residue was dissolved in 20 ml of water. Then slowly add a solution of 1 N. hydrochloric acid to pH 3 and the mixture is extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained is removed the silica gel and as eluent a mixture of chloroform-methanol=95:5 to obtain the title compound (208 mg).

1H-NMR (CDCl3: CD3OD)=9:1, ): 3,0-2,3 (2H, m), of 3.8-4.1 (2H, m), a 5.25 (2H, s), 7,3-7,9 (8H, m).

Comparative example 60. Getting diethyl-N-(3,4-dihydro-2H-1,4-benzothiazin-7-carbonyl)-glutamate.

To 5 ml dimethylformamide solution containing 208 mg of the compound of comparative example 59, 151 mg of diethyl-L-glutamatergic, 90 mg of 1-hydroxybenzotriazole and 70 μl of N-methylmorpholine add 145 mg dicyclohexylcarbodiimide under ice cooling, and the mixture is stirred at the same temperature for 1 h and then at room temperature overnight. To the mixture is added ethyl acetate, the precipitate is filtered off and the filtrate is washed successively with an aqueous solution of sodium bicarbonate and saturated saline and dried over anhydrous sodium sulfate. The residue obtained by removal of solvent under reduced pressure, subjected to chromatographic treatment using a column with silica gel and as eluent a mixture of ethyl acetate-hexane= 1:2, receive diethyl-N-(N'-carbobenzoxy-3,4-dihydro-2H-1,4-benzothiazin-7-carbonyl)-L - glutamate and dissolved in 20 ml of ethanol. After adding 10% (700 mg), palladium carbon black to the solution, the solution is stirred in hydrogen atmosphere at room temperature overnight the situation. The resulting residue is subjected to chromatographic treatment using a column with silica gel and as eluent a mixture of ethyl acetate-hexane=2:3 to obtain the title compound (83 mg).

1H-NMR (CDCl3: CD3OD=9:1, ): 1,24 (6H, m), 2,0-2,7 (4H, m), 2,9-3,1 (2H, m), 3,6-3,8 (2H, m), 3,9-4,4 (5H, m), of 6.45 (1H, d, J=8.0 Hz), 7,2-7,6 (2H, m).

Example 31. Getting diethyl-N - [1-[(2,4-diamine)-6-pteridinyl)methyl] -3,4-dihydro-2H-1,4 - benzothiazin-7-carbonyl]-L-glutamate.

In 3 ml of dimethylacetamide suspended 83 mg of the compound of comparative example 60 and 85 mg of the adduct of 6-methyl bromide-2,4-diaminopyridine hydrobromide and isopropanol, and the suspension is stirred at 60oC for 3 h and then at 100oC for 30 minutes After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted three times with chloroform. The organic layer is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The resulting residue is subjected to chromatographic treatment using a column with silica gel and as eluent a mixture of chloroform-methanol=93:7 to obtain the title compound (21 mg).

1H-NMR (CDCl3: CD3OD=9:1, ): of 1.26 (6H, MSS="ptx2">

Example 32. Obtaining N-[1-[(2,4-diamino)-6-pteridinyl] methyl]-3,4-dihydro-2H - 1,4-benzothiazin-7-carbonyl]-L-glutamato acid.

20 mg of the compound of example 31 was dissolved in 2 ml of ethanol and to the solution add 170 ál of 1 N. aqueous solution of sodium hydroxide at 35oC, and the mixture is stirred at the same temperature for 4 hours Then continue stirring at 25oC for 20 hours, is added to the reaction mixture 0.5 ml of water and removing the ethanol under reduced pressure. The resulting residue is dissolved in 6 ml of water, adjusted to pH 3.7 to 1 N. hydrochloric acid while cooling with ice water and leave in a cool place overnight. The precipitation is collected by filtration to obtain the compound indicated in the title (18 mg).

1H-NMR (DMCO-d6, ): 1,8-2,2 (2H, m), is 2.30 (2H, m), 3,18 (2H, m), of 3.95 (2H, m), 4,37 (1H, m), was 4.76 (2H, s), 6,79 (1H, d, J=8,8 Hz), 7,42 (1H, m), to 7.59 (1H, d, J=2.0 Hz), by 8.22 (1H, d, J=7,3 Hz), 8,67 (1H, s).

Example 33. Obtaining N-[1[(2,4-diamino-6-pteridinyl)methyl)-1-oxo-3,4-dihydro-2H-1,4 - benzothiazin-7-carbonyl]-L-glutamato acid.

10 mg of the compound of example 32 is suspended in 1 ml of water and to the solution add 1 N. aqueous solution of sodium hydroxide to dissolve the mixture. To the solution while cooling with ice add 50 ál of 0.5 M metaperiodate Chille precipitate is collected by filtration to obtain compound, specified in the title (4 mg).

1H-NMR (DMCO-d6, ): 1,8-2,2 (2H, m), 2,33 (2H, m), 2,9-3,3 (2H, m), 3,8-4,0 (1H, m), 4,2-4,5 (2H, m), a 4.83 (1H, d, J=17,1 Hz), 5,19 (1H, d, J= 17,1 Hz), 7,07 (1H, d, J=9,2 Hz), 7,7 - 7,9 9 (1H, m), of 8.1 to 8.2 (1H, m), 8,42 (1H, m), 8,72 (1H, s).

IR (KBr)max2800-3600, 1644, 1608, 1552, 1504 and 1008 cm-1.

The field Mass spectrometry MS 515 (M+1)+< / BR>
Comparative example 61. Getting benzyl-N-t-butoxycarbonyl-N'-methanesulfonylaminoethyl.

In 268 ml of tetrahydrofuran is dissolved to 13.6 g of N,N'-carbonyldiimidazole and 25 g-benzyl-N-(t-butoxycarbonyl)glutamate and the mixture is stirred under ice cooling for 1 h Then the solution is added dropwise to 132 ml tertrahydrofuran ring solution containing 20.5 g methanesulfonamide and 32.9 g of 1,8-diazabicyclo-(5,4,0)-7-undecene while cooling with ice. After adding the solution dropwise, the mixture is left to warm to room temperature and stirred for 4 days. After adding to the mixture of 500 ml of 1 N. hydrochloric acid, the mixture is extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure to obtain the compound indicated in the title (30 mg).

1H-NMR (CDCl3, ): of 1.42 (9H, c), 1,8-2,8 (4H, m) of 3.25 (3H, s), 4,32 (1H, m), 5,14 (2H, s), 7,40 (5H>/P>the 4.65 g of compound of comparative example 61 was dissolved in 60 ml triperoxonane acid and the solution was stirred at room temperature for one hour. Then the reaction mixture is condensed under 30oC and dissolve by adding ether to obtain the compound indicated in the title (4.5 g).

1H-NMR(CDCl3, ): 1,8 - 2,8 (4H, m), 3,20 (3H, s), 4,50 (1H, m), 5,28 (2H, s), 7,42 (5H, s).

Example 34. Getting benzyl-N-[1-[(2,4-diamino-6 - pteridinyl)methyl]indolin-5-carbonyl]-N'-methanesulfonylaminoethyl.

In 18 ml of dimethylformamide is dissolved 213 μl dicalciumphosphate and 172 μl of triethylamine in a nitrogen atmosphere and the solution was added 160 mg of 1-[(2,4-diamino-6-pteridinyl)methyl]indoline-5-carboxylic acid in small portions, and the mixture is stirred at the same temperature for 3 hours To a mixture of 3 ml dimethylformamide solution containing 450 mg of the compound of comparative example 62 and 180 μl of triethylamine, and the mixture is stirred at room temperature for 3 days. Then to the reaction mixture was added 1 ml of water and remove the solvent under reduced pressure. The residue is subjected to chromatographic treatment using a column with silica gel and as eluent a mixed solvent x

1H-NMR (DMCO-d6, ): 1,9 - 2,1 (2H, m), 2,3 - 2,5 )2H, m), 2,98 (2H, t, J=8.6 Hz), or 3.28 (3H, s), 3,55 (2H, t, J=8.6 Hz), is 4.21 (1H, m), a 4.53 (2H, s), 5,04 (2H, s) of 6.71 (1H, d, J=8.6 Hz), 7,34 (5H, s), 7,55 (2H, m), 8,72 (1H, s).

Example 35. Obtaining N-[1-[(2,4-diamino-6-pteridinyl)methyl]indolin-5 - carbonyl]-N'-methysulfonylmethane.

25 mg of the compound of example 34 is suspended in 15 ml of ethanol and the suspension add 200 ál of 1 N. aqueous solution of sodium hydroxide, and the mixture is stirred at room temperature overnight. Then to the mixture is added 0.5 ml of water and removing the ethanol under reduced pressure. The resulting residue is dissolved in 6 ml of water and the solution brought to a pH of 3.7 1 N. hydrochloric acid while cooling with ice water and leave in a cool place overnight. The precipitation is collected by filtration to obtain the compound indicated in the title (20 mg).

1H-NMR (DMCO-d6, ): 1,9 - 2,1 (2H, m), 2,2 - 2,4 (2H, m) of 3.00 (2H, t, J=8.6 Hz), 3,19 (3H, s), of 3.60 (2H, t, J=8.6 Hz), 4,35 (1H, m), 4,56 (2H, s) 6,70 (1, d, J=8.6 Hz), 7,63 (2H, m), is 8.75 (1H, s).

Example 36. Synthesis of dimethyl ether N-(4-carbobenzoxy-3,4-dihydro-2H-1,4-benzothiazin-7-carbonyl)-L- -aminoadipic acid.

Thionyl chloride (10 ml) was added to 4-carbobenzoxy-3,4-dihydro-2H-1,4-benzothiazin-7-carboxylic acid (2.0 g), followed by permeableness dry. The resulting solid material was dissolved in dichloromethane (25 ml) and the resulting solution was added sequentially aqueous solution (25 ml) of dimethyl-L- -aminoadipate hydrochloride (1.4 g) and then potassium carbonate (3.4 g), followed by stirring overnight. The reaction solution was poured into saturated aqueous sodium bicarbonate solution and was extracted with organic matter chloroform. Next, the chloroform layer was washed for 1H. hydrochlorite acid, dried over sodium sulfate, and the solvent drove away under reduced pressure. The resulting residue was subjected to chromatography in a column of silica gel using as eluting solution of chloroform-methanol = 100:1, and receiving the above-mentioned compound (2.35 g).

1H-NMR (CDCl3, value ): 1,6-2,1 (4H, m), is 2.37 (2H, t, J=7,1 Hz), 3,20 (2H, m) to 3.67 (3H, s), of 3.78 (3H, s), 3,98 (2H, m), of 4.77 (1H, m), 5,23 (2H, s), 6.75 in (H, d, J=7,3 Hz), was 7.36 (5H, m), of 7.48 (2H, m), 7,63 (1H, d, J= 1.5 Hz).

Synthesis of dimethyl ether N-(3,4-dihydro-2H-1,4-benzothiazin-7-carbonyl)- L- -aminoadipic acid.

The result of the above dimethyl ether N-(4-carbobenzoxy-3,4-dihydro-2H-1,4 - benzothiazin-7-carbonyl)-L- -aminoadipic acid (14.8 g) was added to a 30% increase solution (200 ml), anisole (15 g) in hydrogen bromide and acetic acid is ranged a large number of ether, due to the precipitate which formed a red-brown oily substance. The greater part of the ether layer was removed, and the oily substance is suspended in chloroform. The resulting suspension was washed with saturated aqueous sodium bicarbonate solution and was extracted with chloroform. The chloroform layer was dried over sodium sulfate, and the solvent is kept under reduced pressure, obtaining the above-mentioned compound (7.6 g).

1H-NMR (CDCl3CD3OD, values ): 1,6-2,0 (4H, m), 2.40 a (2H, t, J=6.8 Hz), 3,01 (2H, m), 3,68 (5H, m), of 3.78 (3H, s), 4,5 (1H, m), 6,50 (H, d, J= 8,8 Hz), 7,41 (2H, m), 7,51 (1H, d, J=2.0 Hz).

Synthesis of dimethyl ether N-(1-((2,4-diamino-6-pteridinyl)methyl)-3,4 - dihydro-2H-1,4-benzothiazin-7-carbonyl)-L- -aminoadipic acid.

The result of the above dimethyl ether N-(3,4-dihydro-2H-1,4-benzothiazin-7-carbonyl)-L- -aminoadipic acid (7.6 g) and adduct (8,2 g), Hydrobromic salt 6-bromomethyl-2,4-diaminopyridine with isopropanol was suspensively in dimethylacetamide (120 ml) followed by stirring at 60oC for 13 h After cooling, the reaction solution was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with a mixed solution of chloroform and methanol in a ratio of 10:1. The organization of the I residue was subjected to chromatography in a column of silica gel, using as an eluting solution of chloroform-methanol = 10:1, and receiving the above-mentioned compound (5.8 g).

1H-NMR (CDCl3CD3OD, values ): 1,6-2,0 (4H, m), 2,39 (2H, t, J=7,1 Hz), 3,17 (2H, m), 3,68 (3H, s), 3,76 (3H, s), of 3.94 (2H, m), of 4.66 (1H, m), 4,79 (2H, s) 6,70 (1H, d, J=8,8 Hz), 7,42 (2H, m), a 7.62 (1H, d, J=2.4 Hz), 8,67 (1H, s).

Synthesis of N-(1-((2,4-diamino-6-pteridinyl)methyl)-3,4-dihydro-2H-1,4-benzothiazin-7-carbonyl)-L- -aminoadipic acid.

The result of the above dimethyl ether N-(1-((2,4-diamino-6-pteridinyl)methyl)-3,4-dihydro-2H-1,4-benzothiazin-7-carbonyl)-L-): of 1.5-1.9 (4H, m), of 2.21 (2H, t, J=7,1 Hz) and 3.15 (2H, m), of 3.96 (2H, m), of 3.96 (2H, m), 4,30 (1H, m), was 4.76 (2H, s), is 6.78 (1H, d, J=8,8 Hz), 7,44 (1H, m), 7,60 (1H, s), 8,17 (1H, d, J=7.8 Hz), 8,65 (1H, s).

Example 37. The formulation of tablets.

The composition of the used fillers, %:

Crystalline lactose (100 M) - 75,5

Crystalline cellulose PH101 - 20,00

Corn starch - 4,0

Magnesium stearate and 0.5

N-(1-((2,4-diamino-6-pteridinyl)methyl)-3,4-dihydro-2H-1,4-benzothiazin-7 - carbonyl)-L- -aminoadipic acid (0.3 g) was mixed with the above fillers (2.7 g) for the preparation of the composition. Thus obtained mixture of the composition (100 mg) was pressed at a static pressure of 1 t/tab using a punch and die (6.5 mm in diameter, 0 mg) of the same composition, as used above, and received capsules.

1. Derivatives of methotrexate General formula I

< / BR>
where R1selected from the group consisting of-CH2-, -CH2CH2- CH2O, CH2S - or-CH2SO;

R2is hydrogen, C1-C4-alkyl or benzyl;

R3- COOR4(where R4is hydrogen or C1-C4-alkyl), NHCOR5(where R5is phenyl which may be substituted alkoxycarbonyl or a carboxyl group), CONR6R7(where R6is hydrogen or C1-C4-alkyl, R7- C1-C4-alkyl, phenyl or carboxialkilnuyu group, each of which may be substituted alkoxycarbonyl, carboxyl or alkyl group, or R7lowest alkylsulfonyl group), PO3H2or SO3H;

n=1 to 4, an integer.

2. Connection on p. 1, wherein R3- COOR4(where R4has the specified values), PO3H2or SO3H.

3. Connection on p. 1, wherein R3- NHCOR5where R5has the specified values.

4. Connection on p. 1, wherein R3- CONR6R7where R6and R7have ukazannoy cells, containing the active principle together with a pharmaceutically acceptable carrier or diluent, wherein the active beginning it contains an effective amount of the compounds under item 1.

6. The method of obtaining compounds of General formula I

< / BR>
where R1- R3and n are specified in paragraph 1, the values

characterized in that the compound of General formula I - 1

< / BR>
where R1has the specified values;

A1is a protective group,

subjected to interaction with the compound of the formula I - 2

< / BR>
where R2, R3and n have the specified values,

in accordance with the usual methods for the synthesis of amide acid, the resulting amide of General formula I - 3

< / BR>
where R1- R3n and A1have the specified values,

remove protection and subjected to interaction with the compound of the formula I - 4

< / BR>
where X is halogen.

7. The method of obtaining compounds of formula I on p. 1, characterized in that the compound of formula I - 4

< / BR>
where X is halogen,

subjected to interaction with the compound of the formula I - 5

< / BR>
where R1has the specified values;

R' is hydrogen or lower alkyl,

the compound obtained of General formula I - 6

a compound of formula I-2;

< / BR>
where R2, R3and n have the specified values.

8. The method of obtaining the compounds of formula I'

< / BR>
where R1, R2, n and R' have the above values,

characterized in that the compound of formula I - 7

< / BR>
where R2and n have the above meanings;

A2- protective group,

subjected to interaction with the compound of the formula I - 8

< / BR>
the resulting compounds of formula I - 9

< / BR>
where R2n and A2have the specified values,

remove protection and subjected to interaction with the compound of the formula I - 1

< / BR>
where A1and R1have the specified values,

in accordance with conventional methods of synthesis of amide acid and the resulting amide of formula I - 10

< / BR>
where R1, R2n and A1have the specified values,

subjected to interaction with the compound of the formula I - 4

< / BR>
where X is halogen,

with the subsequent reaction of the disclosure ring of the obtained compound to obtain the target compound.

Priority signs and claims:

14.08.90 when R1- CH2CH2CH2; R2is hydrogen, C1-C4-alkyl; R3- COOR4; R4is hydrogen, C1-C4-alkyl; n = 1 - 4, bonalnoy or a carboxyl group.

19.04.91 when R1- CH2O, CH2S, CH2SO.

12.06.91 when R2- benzyl; R3- CONR6R7; R6is hydrogen, C1-C4-alkyl; R7- C1-C4-alkyl, phenyl or carboxyl group, each of which may be substituted alkoxycarbonyl, carboxyl or alkyl group, or R7lowest alkylsulfonyl group.

03.07.91 when R3- PO3H2, SO3H.

30.07.91 on p. 5.

 

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< / BR>
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