The pyrimidine-nucleoside, methods for their preparation, pharmaceutical composition

 

(57) Abstract:

Proposed new pyrimidine derivatives represented by the General formulas (1) and (2)

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and salts of these compounds. In the above formulas, R1is a hydroxyl group or amino group which may be substituted acyl group, R2is a hydrogen atom or an alkyl group having 1-4 carbon atoms; R3is a hydrogen atom or a hydroxyl group; and R4and R5- each a hydrogen atom or together they may form a group - R6R7Si-O-Si-R6'R7'- (in which R6, R7, R6'and R7'can be the same or different from each other and each represents C1-C4alkyl). Action: the claimed compounds exhibit excellent antitumor activity or serve as intermediate compounds in the process of obtaining useful anticancer agents. 7 C. and 4 h.p. f-crystals, 4 PL.

The invention relates to new derivatives of pyrimidine nucleoside having excellent antitumor activity.

Up to the present time as a commercially available anticancer agents pyrimidine number representing antagonistic means m, 32, (1967)), UFT (Fujii, S., et al., Gann, 69, 763, (1978)), Carmofur (Hoshi, A., et al., Gann, 67, 725, (1976)), Doxyfluride (Cook, A. F., et al., J. Med. Chem., 22, 1330, (1979)), Cytarabine (Evance, J. S., et al., Proc. Soc. Exp. Bio. Med., 106, 350, (1961)), Ancytabine (Hoshi, A., et al., Gann, 63, 353, (1972)), Enocytabine (Aoshima, M., et al., Cancer Res., 36, 2726 (1976)), and so on

Among mononucleosides pyrimidine with cyano in ribose group known only 3-cyanoimino nuke and 3-cyanoacetyl nucleoside (Untested patent publication Japan N Hei-2-83392, Hei-2-104586 and Hei-2-503002).

The present inventors for a long time conducted long-term studies on the development of new antimetabolites, which would surpass the existing anti-cancer agents, as described above, in order to find those connections that have cyano introduced in the 2-position of the sugar part of the molecule pyrimidine number of nucleosides, which have strong antitumor activity against various tumor systems and which may be intermediate products upon receipt of such compounds, which had a strong anti-tumor activity, and they have completed this invention.

New derivatives of pyrimidine nucleoside with a strong antitumor activity, according to the us is also pharmacologically acceptable non-toxic salts of these compounds of General formulas.

In the above General formulas (1) and (2) R1is a hydroxyl group or amino group which may have a Deputy, selected from the following group A or B; R2is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; R3is a hydrogen atom or a hydroxyl group; and R4and R5each is a hydrogen atom or together can form a group-R6R7Si-O-SiR6'R7'- (in which R6, R7, R6'and R7'can be the same or different from one another and each represents an alkyl group having from 1 to 4 carbon atoms).

(Group A)

Represents an aliphatic acyl having from 1 to 4 carbon atoms, and aromatic acyl having from 7 to 11 carbon atoms, and which may have a substituent in the ring.

(Group B)

Is alkoxycarbonyl group with C1-C4the alkyl, altneratively group with C2-C4alkenyl, aracelikarsaalyna group having from 8 to 12 carbon atoms and which may have a substituent in the ring.

Aliphatic acyl having from 1 to 4 carbon atoms as a substituent R1mentioned above, includes formyl, acetyl, propionyl acyl, having from 7 to 11 carbon atoms, includes benzoyl-naphtol-naphtol, preferably benzoyl. The substituent in the aromatic ring include alkyl having from 1 to 4 carbon atoms, alkoxide having 1-4 carbon atoms, preferably methyl, ethyl, methoxy, ethoxy - and acetyl groups. Alkyl group alkoxycarbonyl group having C1-C4the alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert. -butyl, preferably methyl and tert.- butyl. Alchemilla grouping alkenylcarbazoles group having C2-C4alkenyl, includes vinyl, allyl, Isopropenyl, 1-butenyl and 2-butenyl, preferably allyl. Kalkilya grouping aracelikarsaalyna group having from 8 to 12 carbon atoms include benzyl, phenetyl-naphthylmethyl and-naphthylmethyl, preferably benzyl. The substituent in the aromatic ring include alkyl having from 1 to 4 carbon atoms, alkoxyl having from 1 to 4 carbon atoms and the aliphatic alloctype having from 1 to 4 carbon atoms, preferably methyl, ethyl, methoxy, ethoxy and acetochlor.

R1mentioned above, preferably includes a hydroxyl group, amino group, amino group, gamesplayed, which may have a substituent in the ring, amino group, substituted alkoxycarbonyl group having from 1 to 4 carbon atoms, amino group, substituted alkenylcarbazoles group having C3alkenyl, amino group, substituted aracelikarsaalyna group having 8 carbon atoms, which may have a substituent in the ring, more preferred hydroxyl group, amino group, amino group, substituted aliphatic acyl having 1-2 carbon atoms, amino group, substituted aromatic acyl having 7 carbon atoms, the most preferred amino group and hydroxyl group.

R2an alkyl group having 1-4 carbon atoms, and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert.-butyl, preferably methyl.

R2mentioned above, preferably includes a hydrogen atom and methyl.

R6, R6', R7or R7'is an alkyl group having 1-4 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert.-butyl, preferably isopropyl.

R4and R5mentioned above, each represents a hydrogen atom or together form tetramethyldisiloxane group, tetraethyltin sildesalgslag group, diethylaminopropylamine group, or dibutylaminopropanol group, preferably a hydrogen atom or tetraisopropyldisiloxane group, more preferred hydrogen atom.

Pharmacologically acceptable non-toxic salts of the compounds having the above General formula (1) or (2) of the present invention, can be represented by the salts of mineral acids, such as chlorides, bromides and sulfates, organic sulfonates, such as methanesulfonate, bansilalpet, aliphatic carboxylates, such as acetate, propionate, butyrate and caproate, and aromatic carboxylates such as benzoate.

Among these salts, salts of mineral acids, in particular hydrochloric acid) and aliphatic carboxylates (in particular acetic acid) are preferred.

In compounds (1) and (2) can preferably be mentioned:

1) compounds in which R1represents a hydroxyl group or an amino group which may have a Deputy, selected from the following group A' or B'; R2represents a hydrogen atom or alkyl group having 1-4 carbon atoms; R3represents a hydrogen atom or a hydroxyl gr is safe group.

(Group A') represents an aliphatic acyl having 1-2 carbon atoms and aromatic acyl having 7 carbon atoms, which may have a substituent in the ring.

(Group B') is alkoxycarbonyl group having C1-C4alkyl, altneratively group having C3alkenyl and aracelikarsaalyna group having 8 carbon atoms, which may have a substituent in the ring;

2) compounds in which R1represents a hydroxyl group or an amino group which may have a Deputy, selected from the following group A; R2represents a hydrogen atom or methyl group; R3represents a hydrogen atom or a hydroxyl group; and R4and R5each represents a hydrogen atom.

(Group A') represents an aliphatic acyl having 1-2 carbon atoms and aromatic acyl having 7 carbon atoms, which may have a substituent in the ring;

3) compounds in which R1represents a hydroxyl group, or amino group; R2represents a hydrogen atom or methyl group; R3represents a hydrogen atom or a hydroxyl group; and R4and R5each represents a hydrogen atom.

Table. 1-3 illustrate the compounds of formula A, compounds of formula B and the compounds of formula C. In the table. 1-3 Et, Pr, t.Bu, Al, Bz, BzpMe, BzpOMe, By and ByOAc means ethyl group, through the group, tert.-boutelou group, allyl group, acetyl group, benzoyloxy group, para-methylbenzoyl group, para-methoxybenzoyl group and pair-acetoxymethyl group, respectively.

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Compounds (1) and (2) of the present invention can be obtained by the use of uracil or 5-lower alkylaryl known compounds (3), (M. Muraoka, A. Tanaka and T. Veda, Chem. Pharm. Bull, 18, 261, (1970)), following reaction stages, depicted in the reaction schemes 1 to 4 (see the end of the description). In schemes 1-4 R1and R2have the meanings above, R4aand R5atogether represent a group of the formula: -R6R7Si-O-SiR6'R7'-, in which R6, R7, R6'and R7'have the meanings given above. R9is alkoxyaryl group having C1-C4alkyl or relaxationenjoy group having C6-C10aryl. Alkyl having 1-4 carbon atoms, and includes methyl, ethyl, propyl, butyl, and so Neal. R10is triarylmethyl group in which the aryl group may be substituted and which includes phenyl, naphthyl and so on, preferably phenyl. Deputy for the aryl group include alkyl group having 1-4 carbon atoms, such as methyl, ethyl, propyl and butyl, alkoxygroup having 1-4 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and acyloxy group having 2-4 carbon atoms, such as acetoxy, propyloxy, butyryloxy, preferably methyl and metaxylene group. X represents a halogen atom, preferably chlorine or bromine. In more detail, the corresponding reaction stages are explained in schemes 1 to 4 (see end of text).

Stage 1.

This stage relates to the production of the compound (4) by rebaseline connection (3).

Rebaseline, normally carried out by methods usually used in this field of chemistry, for example, as follows: (i) mercury salt of compound (3) obtained by adding an alcohol solution of a chloride salt of divalent mercury to a water solution of sodium hydroxide and the compounds (3), run in reaction with a known compound 2,3,5-tri-O-benzoyl-D-reboilered in benzene. The methoxide natrium. Bull, 18, 261, (1970)), and (ii) the compound (3) is treated with trimethylsilylpropyne in benzene in the presence of an organic amine, such as triethylamine, to obtain bis(trimethylsilyl)uracil, which is then treated with 2,3,5-tri-O-benzoyl-D-ribosyl chloride, and then the obtained compound is treated with a solution of sodium methoxide in methanol to obtain compound (4) [T. Nishimura, B. Shimiru and I. Iwai, Chem. Pharm. Bull., 11, 1470, (1963)].

Stage 2.

This stage relates to the production of the compound (5) from the conversion of a carbonyl group at the 4-position of the compound (4) in the amino group. The transformation of the amino group is usually carried out using conventional methods known to experts in this field, for example, as follows:

(i) hexamethyldisilazane and ammonium sulfate are left to interact with the compound (4) by heating in anhydrous formamide order to obtain the compound (5) [Compiled by Townsend and Tipson, Nucleic Acid Chemistry, 227, (1978)].

(ii) a Hydroxyl group in position 2'-, 3' - and 5'-connection (4) protect by acylation or benzoylation. Thionyl chloride and anhydrous dimethylformamide act in chloroform, does not contain alcohol, the compound obtained, and the mixture is then treated with methanol the global groups in positions 2'-, 3'- and 5' of the compound (4) protect by acylation or benzoylation, and then affect the protected derivative with dephosphorylation in pyridine and receive a 4-tizaidine. The obtained compound effect of the lower alkyl iodide, such methyl iodide and ethyl iodide, hydroxide of alkali metal such as sodium hydroxide, to obtain 4-alkylthio compounds as an intermediate product. Next 4 alkylthio connection is treated with liquid ammonia to obtain the compound (5) [J. J. Fox, N. Miller and I. Wenpen, Journal of Medicinal Chemistry, 9, 101 (1966)].

Stage 3.

In this stage, the connection of X-R6R7Si-O-SiR6'R7'the effect on the 3'- and 5'-position of compound (4), which at the same time protected, with the aim of obtaining compound (5). This stage is carried out in accordance with a known method [M. J. Robins, J. S. Wilson, L. Sawyer and M. N. G. James, Can. J. Chem. 61, 1911, (1983)].

Because you are using a solvent, it is preferable to mention the basic solvent such as pyridine.

The reaction is carried out at a temperature of from -10 to 100oC, preferably from 0 to 50oC.

Although the duration of the reaction process varies depending on the temperature at which carry out the reaction, and AI, for example, the solvent is distilled off and the reaction mixture was poured into water, the Resulting mixture is extracted with a solvent that is not miscible with water, such as benzene, simple ether and ethyl acetate, and then the solvent is distilled off and get a connection. Thus obtained compound used in the subsequent stage. If necessary, the compound can be purified by chromatography or by recrystallization.

Stage 3'.

This stage involves the acylation of an amino group at the 4-position of the compound (5) and processing thus acylated compounds X-R6R7Si-O-SiR6'R7'- X with simultaneous protection of 3' and 5' - positions of this acylated compounds with the aim of obtaining compound (6). 3'- and 5' - position can be protected in the same way as in stage (3).

The acylation of the amino group in 4-position carry out the method generally used by experts in this field. For example, in the case of aliphatic acyl or aromatic acyl reactive derivative of the corresponding carboxylic acids, such as halogenisated or acid anhydride is left to interact or corresponding carboxylic acid leave the sludge or orelkinoservisa in reaction run ether of halogenopyrimidines acid, with the appropriate alkoxy, alkenylacyl or aralkylated, or in reaction run dialkyldithiocarbamate, dialkyl dicarbonate or dialkyl dicarbonate with the appropriate alkyl, alkenyl or aralkyl.

As galodamadruga acid can be mentioned, for example, acid chlorides or bromohydrin.

As used condensing means can for example be mentioned N,N'-dicyclohexylcarbodiimide (BCA), 1,1-oxalylamino, 2,2-piperidinomethyl, N, N'-disuccinimidyl carbonate, N,N'-bis(2-oxo-3-oxazolidinyl)-fosinopril, N,N'-carbodiimide, N,N'-disuccinimidyl oxalate (DSO), N,N'-depthlimit oxalate (DFO), N,N'-bis(norbornadiene)oxalate (BNO), 1,1'-bis(benzotriazolyl)oxalate (BBTO), 1,1'-bis(6-chlorobenzotriazole)oxalate (BCTO), 1,1'-bis(6-trifluromethanesulfonate)oxalate (BTBO), etc.

Solvent used is not, in particular restrictions, unless it inhibits the reaction, and includes aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and dimethyl ether of diethylene glycol, alcohols such as methanol, ethanol, n-propanol, from hexanol, and methylcellosolve, ketones, such as acetone, methyl ethyl ketone, methylisobutyl ketone, isophorone, and cyclohexanone, NITRILES such as acetonitrile, isobutyronitrile, amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoramide, sulfoxidov, such as dimethylsulfoxide, sulfolan, and a mixture on the basis of these solvents and water, preferably aromatic hydrocarbons such as benzene, toluene, xylene, ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert. -butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methylcellosolve, ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, and cyclohexanone, NITRILES such as acetonitrile, isobutyronitrile, amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoramide, sulfoxidov, such as dimethyl sulfoxide and sulfolane, and mixed solvents of these organic solvents and water.

The reaction is carried out in the temperature range from 0 to 150oC, preferably from 0 to 100oArticle D., it usually lasts from 1 to 30 h, preferably when the reaction time is from 2 to 5 o'clock

After completion of the reaction, for example, the solvent is distilled off and the reaction mixture was poured into water. The resulting mixture is extracted with water-immiscible solvent, such as benzene, simple ether and ethyl acetate, and the solvent is distilled off from the extract to obtain a connection. Thus obtained compound used in the subsequent stage as such. If necessary, the compound may be isolated and purified using chromatography or by recrystallization.

Stage 4.

This stage is intended to obtain compound (7), is carried out by treating the compound (6) thiocarbanilide reagent in an inert solvent by thiocarbanilide by substitution of the hydroxyl group at the 2'-position of compound (5).

The used solvent is not limited, if it does not inhibit the reaction, and includes amides such as dimethylformamide and dimethylacetamide, sulfoxidov, such as dimethylsulfoxide, and NITRILES, such as acetonitrile, preferably acetonitrile.

If the reagent used for the implementation of the reaction, before and includes a lower alkoxycarbonylmethyl, such as methoxytyramine, and toxicomanilor and aristoteleion, such as phenoxythiocarbonyl and neftekhimicheskoi.

The reaction is carried out at temperatures from -20 to 50oC, preferably from -10 to 10oC.

Although the duration of the reaction depends on the connection, the temperature of the reaction and so on, it is usually from 1 to 30 h, preferably from 2 to 5 o'clock

For the more effective carrying out of the reaction can be used organic amines, such as 4,4-dimethylaminopyridine and triethylamine.

After completion of the reaction, the desired compound may be isolated by standard methods. For example, the reaction mixture was poured into water, the resulting mixture is extracted with water-immiscible solvent, such as benzene, simple ether and ethyl acetate, and then the solvent is distilled off to obtain a desired compound. Thus obtained compound is usually used as such without further processing in the subsequent stage. If necessary, the connection can be cleared and allocated to different chromatographic methods or by recrystallization.

Stage 5.

the 4 and R5together form a group of the formula-R6R7Si-O-SiR6R7-; and R3represents a hydrogen atom, and is the treatment of the compound (7) obtained in stage 4, regenerating means and the reagent to introduce a nitrile group, in an inert solvent.

Solvent used, in particular, is not limited in choice, if it did not inhibit the reaction, and includes aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, aromatic hydrocarbons such as benzene, toluene and xylene, simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol, the preferred aromatic hydrocarbons such as benzene and toluene.

As a reagent used to introduce a nitrile group, use preferably alkalinity, such as tert.-isobutyronitrile, and the reducing reagent preferably includes a hydride triamcinolone having an alkyl group of 1-4 carbon atoms, for example, anti-hydride.

The reaction is usually carried out at a temperature of from 50 to 250oC, preferably from 80 to 150oC. Although the duration reacts the preferred cases, it varies from 1 h to 5 h

For more effectively carrying out the reaction as a catalyst can be used radical initiator, such as azobisisobutyronitrile.

The compound (1a) obtained immediately after completion of the reaction of this stage is a mixture of compounds in which the coordination of the nitrile group is-coordination-coordination, respectively. Such compounds can be processed by the method of absorption or ion-exchange chromatography, using a variety of media, such as activated carbon and silica gel, gel filtration using a column with Sephadex, or recrystallization using an organic solvent, such as a simple ether, ethyl acetate and chloroform, for separating a mixture of such compounds, depending on the desired goals.

Stage 6.

This stage is intended to obtain compound (8) and is carried out by oxidation of the hydroxyl group in 2-position of compounds (6) and can be performed using known methods (F. Hansske et al., Tetrahedron 40, 125, (1984)).

Solvent used, in particular not limited to, until it does not inhibit the reaction and can races is olwal and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform; ethers, such as tetrahydrofuran, dioxane and dimethoxyethane; amides, such as dimethylformamide, dimethylacetamide and hexamethylphosphoramide; sulfoxidov, such as dimethyl sulfoxide, ketones such as acetone and methyl ethyl ketone; and NITRILES, such as acetonitrile; preferred halogenated hydrocarbon such as methylene chloride or chloroform.

The reaction is carried out at room temperature from 0 to 100oC, preferably from 10 to 40oC.

Although the duration of the reaction depends on the connection, the temperature of the reaction and so on, it usually ranges from 10 min to 12 h, preferably from 30 minutes to 3 hours

Incidentally, the oxidation of which were discussed above, can be accelerated by adding moving between layers of catalyst, such as triethylmethylammonium and tributylammonium.

The reaction is usually carried out at temperatures from 0 to 100oC, preferably from 10 to 40oC.

Although the reaction time varies depending on the compound, the reaction temperature and so on, it usually ranges from 10 min to 12 h, preferably from 30 minutes to 3 hours

Soy is shaped methods. For example, the reaction mixture was poured into water, the resulting reaction mixture is extracted with water-immiscible solvent, such as benzene, simple ether and ethyl acetate, and then the solvent is distilled off from the extract to obtain compound (8). If necessary, the connection may be further treated, for example, using the methods of absorption or ion-exchange chromatography using a variety of media, such as activated carbon and silica gel, gel filtration using a column with Sephadex, or recrystallization using an organic solvent, such as a simple ether, ethyl acetate and chloroform.

Stage 7.

This stage is used to obtain the desired compound (1B) and is carried out by treatment with cyanide compounds (8) in an inert solvent in the presence of a base.

Solvent used, in particular not restricted until until inhibits the reaction, and includes the mixed solvent based aliphatic hydrocarbon such as hexane, heptane, ligroin and petroleum ether, and water; a mixed solvent based on aromatic hydrocarbons, such as Isopropylamine ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol and water; the preferred mixed solvent on the basis of simple ether and water.

The base used in this reaction, particularly not limited, and there may be mentioned organic bases and inorganic bases include hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, and carbonates of alkali metals such as sodium carbonate and potassium carbonate, the preferred bicarbonate of an alkali metal.

Cyanide, which is used in the reaction, in particular not limited to, until he is soluble in water with formation of the cyanide ion, and preferably includes cyanides of alkali metals such as sodium cyanide and potassium cyanide.

The reaction is usually carried out at temperatures from 0 to 100oC, preferably in the temperature range 10-40oC.

Although the duration of the reaction varies depending on the connection, the temperature of the reaction and so on, usually it is carried out for from 30 minutes to 96 hours, preferably from 5 to 24 h

The compound (1B) obtained in this stage, may be collected, isolated and purified by combined aushima with water solvent, such as benzene, simple ether and ethyl acetate, and then the solvent is distilled off from the extract to obtain the desired connection. If necessary, the thus obtained compound may be further processed by absorption or ion-exchange chromatography, using such media as activated carbon and silica gel filtration using a column of Sephadex, or recrystallization using an organic solvent, such as a simple ether, ethyl acetate and chloroform.

The compound (1B) allocated directly after completion of the reaction, a mixture of compounds in which the coordination of the nitrile group is to coordinate and coordinate accordingly. Such compounds can be subjected to further separation by the method of adsorption or ion-exchange chromatography using such media as activated carbon and silica gel, gel filtration using a column of Sephadex or recrystallization using such an organic solvent as a simple ether, ethyl acetate and chloroform for the extraction of a mixture of the corresponding compounds depending on the desired goals.

Stage 9.

This stage is used to obtain the compounds (1A) the method of reductive elimination of thiocarbanilide in the 2'-position of compound (9).

Solvent used, in particular not limited to, until it does not inhibit the reaction, and includes alifaticheskie hydrocarbons, such as hexane, heptane, ligroin and petrolane ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol, and aromatic hydrocarbons such as benzene and toluene; the preferred aromatic hydrocarbons such as benzene and toluene.

Used reagent preferably includes hydrides trialkyl tin, such as tributylamine hydride.

The reaction is usually carried out at a temperature of from 50 to 250oC, preferably at the boiling point of the used solvent.

The duration of reaction is generally from 30 min to 10 h, preferably from 30 minutes to 3 hours

In order to more effective is butyronitrile.

Thus obtained the required connection can be collected, isolated and purified by a combination of various suitable methods. For example, the reaction mixture was poured into water, the resulting mixture is extracted with water-immiscible solvent, such as benzene, simple ether and ethyl acetate, and then the solvent is distilled off from the extract to obtain the desired compound. If necessary, the thus obtained compound may be further subjected to, for example, adsorption or ion-exchange chromatography using a variety of media, such as activated carbon and silica gel, gel filtration using a column of Sephadex or recrystallization using a solvent such as ether, ethyl acetate and chloroform.

The compound (1A) obtained after the reaction in this stage, is a mixture of compounds in which the coordination of the nitrile group - is-coordination-coordination, respectively. Such compounds can be subjected, for example, adsorption or ion-exchange chromatography using a variety of media, such as activated carbon and silica gel, gel filtration using a column tracecut and chloroform, to separate the mixture of compounds to the corresponding separate connections depending on the goal.

Stages 10 and 12.

These stages are designed to produce the desired compounds (1C) and (1D) and implemented by the impact of eliminating funds for R4aand R5athe compound (1B) and (1A) in an inert solvent in order to remove the Deputy at the amino group, if necessary.

Although the solvent used in the reaction elimination R4aand R5ain particular, it is not limited to, until it inhibits the reaction, it should be mentioned that the preferred ethers, such as tetrahydrofuran and dioxane. Used reagent, in particular not limited to, until it is typically used for elimination of the silyl group, and here we can mention one reagent, which forms the anion fluoride, such as tetrabutylammonium fluoride.

The reaction is usually carried out at temperatures from 0 to 40oC, preferably at room temperature.

Although the duration of the reaction varies depending on the compound, the temperature at which the reaction is carried out, it is from 10 min to 24 h, predpochtitelen various suitable methods. For example, the reaction mixture was poured into water, extracted the resulting mixture of water-immiscible solvent, such as benzene, simple ether and ethyl acetate, and then the solvent is distilled off from the extract to obtain compound (8). If necessary, the thus obtained compound can be subjected to further processing, for example, adsorption or ion-exchange chromatography using a variety of media, such as activated carbon and silica gel, gel filtration using a column of Sephadex or recrystallization using an organic solvent, such as a simple ether, ethyl acetate and chloroform.

Incidentally, in the case when R2is substituted by an amino group, it can sometimes eliminirovat at the same time.

Stage 11 and 13.

These stages are intended to obtain compound (1C) and (1D) of the present invention, carried out under the influence of the eliminated funds for the protective group cleavage substituent at R2in an inert solvent, and this stage is selected, if it is needed.

Although the elimination of the protective groups varies salicylaldoxime method:

a) in the case where the protective group is an aliphatic acyl group, aromatic acyl or allyloxycarbonyl, these protective groups can be removed by treatment with acid in the presence or absence of solvent. As used acids there may be mentioned hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid and Hydrobromic acid, preferably acetic acid.

As the solvent used here may be mentioned alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert.-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran and dioxane; and a mixed solvent of organic solvent and water.

The reaction is carried out at a temperature from 0 to 40oC, preferably at room temperature.

Although the duration of the reaction varies depending on the reaction temperature, it ranges from 10 min to 24 h, preferably from 1 to 5 o'clock

Thus obtained the required connection can be Aut, and the residue is subjected to, for example, adsorption or ion-exchange chromatography using a variety of media, such as activated carbon and silica gel, gel filtration using a column of Sephadex or recrystallization using solvents such as simple ether, ethyl acetate and chloroform;

b) if the protective group represented by orelkinoservisa, such a protective group can be eliminated by catalytic reduction using a catalyst.

As the solvent used here should be mentioned alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol, saturated hydrocarbons such as hexane and cyclohexane, ethers such as tetrahydrofuran and dioxane, and lower fatty acids, such as acetic acid and propionic acid, preferably methanol, ethanol, acetic acid and propionic acid.

As used catalyst, there can preferably be mentioned platinum and palladium on carbon.

The reaction is carried out at a temperature of 0 - 40oC, preferably conducting at room temperature.

Although prolonged from 1 h to 5 h

Thus obtained the required connection can be collected, separated and purified by using various suitable methods. Usually the reaction mixture is distilled, and the residue is subjected to, for example, adsorption or ion-exchange chromatography using a variety of media, such as activated carbon and silica gel, gel filtration using a column of Sephadex, or recrystallization using an organic solvent, such as a simple ether, ethyl acetate and chloroform.

Stage 14.

This stage is intended to obtain compound (10) and is carried out by the protective action of the reagent to the compound (1D) in an inert solvent.

As the solvent used here may be mentioned a basic solvent such as pyridine and a neutral solvent, such as benzene, toluene and simple ether.

Although the protective reagent used in this reaction, particularly not limited, so long as he can specifically protect only one hydroxyl group in the 5'-position, it is convenient to use for these purposes triphenylmethane, monomethoxypolyethylene, dimethoxyethane, etc. S="ptx2">

The duration of reaction is generally from 30 min to 10 h, preferably from 1 h to 5 h

When using a neutral solvent as a solvent for the more effective carrying out of the reaction can be used an organic amine, such as triethylamine.

Thus obtained compound can be collected, separated and purified by a combination of various suitable methods. For example, the reaction mixture was poured into water, the resulting mixture is extracted with water-immiscible solvent, such as benzene, simple ether and ethyl acetate, and then the solvent is distilled off from the extract to obtain a desired compound. If necessary, the thus obtained compounds can be subjected, for example, adsorption or ion-exchange chromatography using a variety of media, such as activated carbon and silica gel, gel filtration using a column of Sephadex or recrystallization using an organic solvent, such as a simple ether, ethyl acetate and chloroform.

Stage 15.

This stage is intended to obtain compound (11) and is under the action of the reagent,isoimage solvent can be mentioned, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroliana ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and dimethyl ether of diethylene glycol; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; NITRILES such as acetonitrile and isobutyronitrile; amides, such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoramide, and sulfoxidov, such as dimethyl sulfoxide and sulfolane; preferred aromatic hydrocarbons such as benzene, toluene and xylene.

As used reagent may be mentioned a compound having a thiocarbonyl group, such as thiocarbonyldiimidazole, phenoxythiocarbonyl.

The reaction is carried out at a temperature of -10 to 50oC, preferably at room temperature.

The duration of reaction is usually from 1 h to 24 h, preferably from 3 to 10 PM

Thus obtained the desired connection can be collected, separated and purified by combin irout water-immiscible solvent, such as benzene, simple ether and ethyl acetate, and then the solvent is distilled off from the extract to obtain a desired compound. If necessary, the thus obtained compound can be subjected to adsorption or ionoobmennoi chromatography using a variety of media, such as activated carbon and silica gel, gel filtration using a column of Sephadex or recrystallization using an organic solvent, such as a simple ether, ethyl acetate and chloroform.

Thus obtained the required connection can be collected, separated and purified by a combination of various suitable methods. For example, the reaction mixture was poured into water, the resulting mixture is extracted with water-immiscible solvent, such as benzene, simple ether and ethyl acetate, and then the solvent is distilled off from the extract to obtain the desired compound. If necessary, the thus obtained compound can be subjected, for example, adsorption or ion-exchange chromatography using a variety of media, such as activated carbon and silica gel, gel filtration using a column with Seade the t and chloroform.

Stage 16.

This stage is used to obtain the desired compound (2a) of the present invention and is carried out by the action of the tool, removing the protection of the hydroxyl group of compound (11) in an inert solvent.

Although the elimination of the protective groups varies depending on the nature of the protective group, it is usually carried out according to the method, which is known to specialists in this area, in that case, when the protective group is triarylmethyl, which is the preferred protective group, its elimination carried out as follows.

Although the solvent used, in particular, is not limited in this reaction, it preferably include alcohols, such as methanol, ethanol; ethers, such as tetrahydrofuran and dioxane; and a mixed solvent of organic solvent and water.

As the reagent is usually used acid. Acid, in particular not limited to, until the used acid is represented by the acid Branstad, and preferably includes an inorganic acid such as hydrochloric acid and sulfuric acid, and organic acid such as acetic acid is used.

The reaction is usually carried out at temperatures from 0 to 50oC, preferably at room temperature.

Although the duration of the reaction depends on the source materials of the type of acid used in the reaction, and so on, it usually runs from 10 minutes to 18 hours, preferably when the reaction time is from 30 minutes to 5 hours

Thus obtained the required connection can be collected, separated and purified with a combination of various suitable methods. For example, the reaction mixture was poured into water, the resulting mixture is extracted with water-immiscible organic solvent, such as benzene, ether and ethyl acetate, and then the solvent is distilled off from the extract to obtain the desired compound. If necessary, the thus obtained compound is subjected to adsorption or ion-exchange chromatography, using various media, such as activated carbon and silica gel, gel filtration using a column of Sephadex or recrystallization using such an organic solvent as a simple ether, ethyl acetate and chloroform.

The present invention is further illustrated by the examples, comparative examples, and examples of piano-3',5'-O-(1,1,3,3 - tetraisopropyldisiloxane-1,3-diyl)--D-ribofuranosyl]thymine.

In 15 ml of a mixture of ether-water (2 : 1) was dissolved 997 mg of 1-(3,5-0-TIPDS-a-D-Erythro-menthofuran-2-Brazil)thymine, to the resulting solution was added 196 mg of sodium cyanide and 336 mg of sodium bicarbonate, the resulting mixture was stirred at room temperature for 36 hours After completion of the reaction, to the reaction mixture were added ethyl acetate and the mixture washed three times with water. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate, and the solvent is removed in the process of evaporation. The residue was purified by the method of column chromatography, using a column of silica gel (diameter 2.4 cm x 9.5 cm). As eluent used a mixture of ethyl acetate and hexane (1 : 2). After elution received of 1.03 g (97.5% of output) connection, the name of which is given in the header. The compound was obtained as white foam.

1H NMR (CDCl3) memorial plaques: 9.20 and 8.52 (1H, ush.C.); 7.43 and 7.36 (1H, d, J= 6.8 Hz); 6.22 and 6.00 (1H, s); 5.08 (1H, ush.C.); 4.32-3.94 (4H, m); 1.92 (3H, d, J=1.7 Hz); 1.12-1.07 (28H, m).

Example 2. 1-(2'-Cyano-2'-deoxy-3',5'-O-TIPDS-a-D-arabinofuranosyl)-thymine.

In 2 ml of anhydrous acetonitrile was dissolved 100 mg of the compound of example 1 and 10 mg of 4,4-dimethylaminopyridine (denoted hereafter by the abbreviation DMAR). To the resulting solution was added 39 mm fenoxycarb the completion of the reaction was added ethyl acetate to the reaction mixture and the mixture is washed three times with water. The mixture was dried over sodium sulfate and the solvent was distilled. The residue was purified by the method of column chromatography, using a column of silica gel (diameter of the column of 1.6 and height 10 cm). As eluent used a mixture of methanol and chloroform (1:99), after elution received 71 mg (73,7%) connection, the name of which is given in the header.

1H NMR (CDCl3) memorial plaques: 7.36 (1H, d, J=1.2 Hz); 6.28 (1H, d, J=7.3 Hz); 4.67 (1H, DD, J=8.3, 9.3 Hz); 4.17 (1H, DD, J=2.2 Hz, 13.2 Hz); 4.04 (1H, DD, J=2.9, 13.2 Hz); 3.78 (1H, DD, J=2.2, 2.9 Hz); 3.58 (1H, DD, J=7.3, 9.3 Hz); 1.94 (1H, DD, J=1.2 Hz); 1.15-1.04 (28H, m).

Example 3. 1-(2'-Cyano-2'-deoxy--D-arabinofuranosyl)thymine.

At 0oC in a stream of nitrogen in 3 ml of anhydrous tetrahydrofuran (THF) was dissolved 178 mg of the compound of example 2, the resulting solution was dropwise added 20 ml of acetic acid and 0.70 ml of a solution of tetrabutylammonium 1 M-THF, the mixture is then stirred for 1.5 hours After completion of the reaction, the reaction mixture was concentrated, purified by the method of column chromatography, using a column of silica gel (diameter of the column 1.8 and height 8 cm). As eluent used a mixture of ethanol and chloroform (8-10 : 92-90) and was led from the ether and ethanol, the result was 27 mg of the compound, the name of the cat> memorial plaques: 11.49 (1H, s); 7.85 (1H, d, J=1.1 Hz); 6.25 (1H, d, J=0.6 Hz); 6.20 (1H, d, J=7.1 Hz); 5.30 (1H, t, J=4.9 Hz); 4.47 (1H, DDD, J= 6.0, 8.2, 8.8 Hz); 3.89 (1H, DD, J=7.1, 8.8 Hz); 3.47 (1H, DDD, J=2.2, 3.3, 8.2 Hz); 3.62 (1H, DDD, J=3.3, 4.9, 11.1 Hz); 1.78 (3H, d, J=1.1 Hz).

Example 4. 1-(2'-Cyano-2'-deoxy-3',5'-O-TIPDS-a-D-arabinofuranosyl)-N4-benzoylacetone.

Repeating the procedure of example 1, using 294 mg of N4-benzoyl-1-(3,5-TIPDS-a-D-retropectoral-2-Brazil)cytosine. Next were repeated procedure of example 2 using crude product, the result was 174 mg (49.1 per cent) of the connection, the name of which is given in the header. The compound was obtained as solid product is yellowish-white in color.

1H-NMR (CDCl3) memorial plaques 8.89 (1H, ush.C); 8.11 (1H, d, J = 7.7 Hz); 7.93-7.45 (5H, m); 7.67 (1H, d, J=7.7 Hz); 6.36 (1H, d, J=6.6 Hz); 4.67 (1H, t, J=8.1 Hz); 4.18 (1H, DD, J=2.9, 13.2 Hz); 3.91 (1H, DD, J=2.9, 2.9, 8.1 Hz); 3.75 (1H, DD, J=6.6, 8.1 Hz); 1.15-1.04 (28H, m).

Example 5. 1-(2'-Cyano-2'-deoxy--D-arabinofuranosyl)-N4-benzoylacetone.

Repeating the procedure of example 3, using 100 mg of the compound of example 4, and crystallization was carried out from methanol, the result received 25 mg of the titled compound as white crystals.

1H-NMR (DMCO-d6) memorial plaques: 11.34 (1H, ush.s); 8.4 (1H, d, J=7.7 Hz); 8.00 (2H, m), 7.66-7.49 (3H, m), 7.42 (1H, d, J=7.7 Hz); 6.2, the sh.d, J=12.5 Hz); 3.65 (1H, ush.d, J=12.5 Hz).

Example 6.1-(2'-Cyano-2'-deoxy-3', 5'-O-TIPDS-a-D-arabinofuranosyl)-N4-acetylcytosine.

Were repeated procedure of example 4 using 2 g of N4-acetyl-1-(3,50-0-TIPDS-a-D-retropectoral-2-Brazil)cytosine; the crystals obtained after evaporation of the solvent, were collected by filtering a mixture of ether/hexane, and after cleaning them received 703 mg compound, the name of which is given in the header. The compound obtained in the form of white crystals.

1H-NMR (CDCl3) memorial plaques: 9.92 (1H, ush.s); 8.07 (1H, d, J=7.7 Hz); 7.55 (1H, d, J=7.7 Hz); 6.34 (H, d, J=7.0 Hz); 4.63 (1H, t, J=8.8 Hz); 4.18 (1H, DD, J= 2.4 Hz, 13.4 Hz); 4.06 (1H, DD, J=2.7 Hz, 13.4 Hz); 3.89 (1H, DD, J= 2.4, 2.7, 8.8 Hz); 3.72 (1H, DD, J=7.0, 8.8 Hz); 2.30 (3H, s), 1.13-1.03 (28H, m).

Example 7. 1-(2'-Cyano-2'-deoxy--D-arabinofuranosyl)-N4-acetylcytosine.

The procedures of example 3 were repeated using 1.07 g of the compound of example 6. After cleaning the crystals obtained by evaporation of the solvent and collected by filtering the mixture of ether and hexane, obtained 480 mg of the compound, the name of which is given in the header. The compound obtained in the form of white crystals.

1H-NMR (DMCO-d6) memorial plaques: 10.97 (1H, ush.C); 8.36 (1H, d, J=7.7 Hz); 7.26 (1H, d, J=7.7 Hz); 6.27 (1 Hz); 3.63 (1H, ush.d, J=12.1 Hz), 2.11 (3H, s).

Example 8. 1-(2'-Cyano-2'-deoxy--D-arabinofuranosyl)cytosine.

In 55 ml of methanol was dissolved 100 mg of the compound of example 7, the resulting solution was added 2.5 ml of acetic acid, and then boiled under reflux on an oil bath for 5 days. After completion of the reaction the solvent was evaporated and the residue purified, having passed through a column of silica gel ( 1.8 x 7 cm). As eluent used a mixture of methanol and chloroform (12-15 : 88-85) and further purification was performed by HPLC (D-ODS-5,5% methanol-water), and then was led from a mixture of ethanol-ether. The result was 29 mg of the compound, the name of which is given in the header. The compound was obtained as white crystals.

1H-NMR (DMCO-d6) memorial plaques: 7.83 (1H, d, J=7.1 Hz); 7.27 (2H, ush.C); 6.17 (1H, d, J=6.6 Hz); 6.15 (1H, d, J=7.1 Hz); 5.79 (1H, d, J=7.6 Hz); 5.14 (1H, t, J=4.9 Hz); 4.40 (1H, DD, J=6.6 Hz, 7.1, 7.7 Hz); 3.77 (1H, t, J=7.1 Hz); 3.74 (1H, DDD, J= 2.8, 4.5, 7.7 Hz); 3.73 (1H, DDD, J=2.8, 4.9, 12.6 Hz); 3.60 (1H, DDD, J=2.8, 4.9, 12.6 Hz).

Example 9. 1-(2'-Cyano-2'-deoxy--D-arabinofuranosyl)cytosine monohydrochloride.

In 5 ml of 3% mixture of hydrochloric acid-methanol was dissolved 40 mg of the compound of example 8, and then the mixture was stirred for 50 min at room temperature. Pinene, the name of which is given in the header. The compound obtained in the form of white crystals.

1H-NMR (DMCO-d6) memorial plaques: 8.5 (1H, s); 8.30 (1H, d, J=7.7 Hz); 6.21 (1H, d, J=7.2 Hz); 6.12 (1H, d, J=7.7 Hz); 4.43 (1H, DD, J=7.1 Hz, 7.7 Hz); 3.97 (1H, t, J=7.1 Hz); 3.83 (1H, DDD, J=2.8, 3.3, 7.7 Hz); 3.76 (1H, DD, J=2.8, 12.6 Hz); 3.62 (1H, DD, J=3.8 Hz, 12.6 Hz).

Example 10. 1-(2'-Cyano-2'-deoxy-3',5'-O-TIPDS-a-D-ribofuranosyl)thymine.

In 4 ml of anhydrous toluene suspended 400 mg of 3',5'-0-TIPDS-2'-0-phenoxythiocarbonyl and to the resulting suspension was added 1.8 ml of tert.-utilitaria, followed by heating on an oil bath at 100oC in a current of argon gas. To the mixture dropwise added 4 ml of azobisisobutyronitrile (50 mg) and tributylamine hydride (0.25 ml) in toluene, the addition was carried out for one hour using a syringe pump. Three hours after completion of the addition to the mixture was added 0.25 ml of tributylamine hydride and the resulting mixture was stirred for 19 h, then drove the solvent(s). The residue was purified by the method of column chromatography using a column of silica gel ( 2,2 x 8 cm). As eluent used chloroform. The result obtained 70 mg of the compound, the name of which is given in the header. The compound was obtained as yellow foam is J=2.6 Hz, 4.8 Hz); 1.90 (3H, d, J=1.1 Hz); 1.10-1.01 (28H, m).

Example 11. 1-(2'-Cyano-2'-deoxy--D-ribofuranosyl)thymine.

The procedures of example 3 were repeated using the compound of example 10 (70 mg) and after purification of the solid product obtained by evaporation of the solvent, collected by filtration with ether, received 17 mg of the compound, the name of which is given in the header. The compound was obtained as solid product is yellowish-white in color.

1H-Yarm (DMCO-d6) memorial plaques: 11.49 (1H, ush.C.); 7.64 (1H, d, J=1.1 Hz); 6.32 (1H, d, J=5.5 Hz); 6.27 (1H, d, J=8.2 Hz); 5.22 (1H, ush.C.); 4.37 (1H, DDD, J= 2.8, 5.5, 5.5 Hz); 3.93 (1H, m); 3.75 (1H, DD, J=5.5, 8.2 Hz); 3.66-3.51 (2H, m); of 1.78 (3H, d, J=1.1 Hz).

Example 12. 1-(2'-Cyano-2', 3'-deoxy-2', 3'-didehydro--D-ribofuranosyl/thymine.

In 3 ml of acetic acid was dissolved in 112 ml of the compound of comparative example 3 and the resulting solution was stirred at room temperature for 1 h After completion of the reaction the solvent was evaporated and the residue was purified over silica gel column with a diameter of 1.6 and a height of 8.5 see as eluent used a mixture of ethanol and chloroform (8:92). The solvent was evaporated, and the precipitated crystals were collected by filtration using a mixture of ether and hexane. The result was 22 mg compounds, razvanm.d: 11.53 (1H, ush.C.); 7.81 (1H, d, J=1.1 Hz); 7.63 (1H, d, J= 1.1 Hz); 7.02 (1H, DD, J=1.7, 3.9 Hz); 5.33 (1H, t, J=4.9 Hz); 5.05 (1H, DDD, J= 2.8, 2.8, 3.9 Hz); 3.74 (1H, DDD, J=2.8, 4.9, 12.6 Hz); 3.67 (1H, DDD, J=2.8, 4.9, 12.6 Hz); 1.75 (3H, d, J=1.1 Hz).

Example 13. 1-(2'-Cyano-2',3'-dideoxy-2',3'-didehydro--D-arabinofuranosyl)-N4-acetylcytosine.

The procedures of example 12 were repeated using 70 mg of the compound of comparative example 4. After purification by passing through a column of silica gel (diameter of the column 1.8 and height 7 cm) as eluent used a mixture of ethanol and chloroform to 10:90) gave a crystallization from a mixture of ethanol and ethyl acetate, the result was 14 mg compound, the name of which is given in the header. The compound obtained in the form of crystals.

1H-Yarm (DMCO-d6) memorial plaques: 11.02 (1H, c); 8.33 (1H, d, J=7.1 Hz); 7.65 (1H, t, J= 7.1 Hz); 7.24 (1H, d, J=7.1 Hz); 7.12 (1H, DD, J=1.7, 3.3 Hz); 5.30 (1H, t, J=4.9 Hz); 5.12 (1H, m); 3.74 (1H, DD, J=3.3, 12.6 Hz); 3.67 (1H, DD, J=3.3, 12.6 Hz); 2.12 (3H, s).

Example 14. N4-benzyloxycarbonylation.

In pyridine, to the extent possible, melted a 4.86 g cytidine, and the resulting solution was subjected twice to azeotropic distillation to remove the contained moisture. To the residue was added 100 ml of pyridine and the resulting mixture was added of 12.6 ml of trimethylchlorosilane when ohla is sexylolita (30-35% solution in toluene). After stirring the mixture at room temperature, the mixture was left to stand overnight. Then to the mixture was added 40 ml of water and the resulting mixture was stirred for 1.5 hours After adding methylene chloride and separated the organic layer and washed with a saturated solution of sodium chloride. Then the organic layer was dried over anhydrous magnesium sulfate and drove the solvent. The residue was subjected to azeotropic distillation three times with toluene and ethanol. The result was 6,13 g connection, the name of which is given in the header. The compound is obtained as a crystalline residue.

1H-Yarm (270 MHz DMCO-d6) memorial plaques: 8.40 (1H, d, J=7.3 Hz); 7.31-7.55 (5H, m); 7.02 (1H, d, J= 7.3 Hz); 5.77 (1H, d, J=2.4 Hz); 5.19 (2H, c); 3.88-3.99 (3H, m).

Example 15. 3',5'-0-TIPDS-N4-benzyloxycarbonylation.

The pyridine was dissolved 6.0 g of the compound of example 14 and the resulting solution was subjected twice to azeotropic distillation to remove moisture contained in the connection. The residue was dissolved in 200 ml of pyridine and then there was added 5,09 ml of 1,3-sodium dichloro-1,1,3,3-tetraisopropyldisiloxane, after which the mixture was stirred at room temperature. After the mixture stood for two days, the solvent was distilled. The residue was dissolved in methylene chloride and PAA sodium and saturated aqueous sodium chloride. The residue was dried over anhydrous sodium sulfate, the solvent was evaporated and the obtained 10,23 g connection, the name of which is given in the header.

1H-Yarm (270 MHz DMCO-d6) memorial plaques: 10.83 (1H, ush. C.); 8.12 (1H, d, J= 7.8 Hz); 7.32-7.43 (5H, m); 7.03 (1H, d, J=7.3 Hz); 5.59 (1H, s); 5.19 (1H, s); 3.91-4.24 (5H, m), 0.80-1.14 (28H, m).

Example 16. N4-benzyloxycarbonyl-1-(3,5-0-TIPDS-a-D-retropectoral-2-Brazil)cytosine.

To 70 ml of methylene chloride was added 13,16 g pyridine dichromate, and 3.31 ml of acetic anhydride, were 0.94 ml of pyridine and 2.5 g of celite, the resulting mixture was stirred for 40 minutes Separately dissolved of 7.23 g of compound of example 15 in 30 ml of methylene chloride and the resulting solution was added to the solution obtained above. After stirring the thus obtained mixture at room temperature for 5 h to it was added ethyl acetate and drove methylene chloride. The residue was dissolved in ethyl acetate, and the insoluble part was filtered. After washing the filtrate of 1 M hydrochloric acid, saturated aqueous sodium chloride, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, the filtrate was dried over anhydrous magnesium sulfate. The solvent was distilled and the residue is purified method is Tate got 2,84 g connection the name of which is given in the header.

1H-NMR (270 MHz DMCO-d6) memorial plaques: 10.98 (1H, ush.C.); 8.15 (1H, d, J=7.3 Hz); 7.32-7.44 (5H, m); 7.09 (1H, d, J=7.3 Hz); 5.49 (1H, s); 5.20 (2H, s); 5.07 (1H, d, J=8.3 Hz); 3.95-4.04 (3H, m), 0.92-1.12 (28H, m).

Example 17. N4-benzyloxycarbonyl-2'-cyano-3',5'-O-TIPDS - M. D.: 11.0 (1H, ush.C.); 8.05 (1H, d, J=7.3 Hz); 7.83 (1H, ush.C.); 7.33-7.44 (5H, m); 7.13 (1H, d, J=7.8 Hz); 5.93 (1H, s); 5.21 (2H, s); 3.93-4.33 (4H, m), 0.96-1.07 (28H, m)

Example 18. N4-benzyloxycarbonyl-2'-cyano-deoxy-3',5'-O-TIPDS-,'-azobisisobutyronitrile and 0.20 ml tributylamine hydride in the specified sequence and in a current of nitrogen gas, and then was stirred at 100oC for 2 h the Solvent was distilled and the residue was purified over silica gel (eluent used a mixture of methylene chloride and methanol 99:1), resulted in 202 mg of the compound, the name of which is given in the header.

1H-NMR (270 MHZ DMCO-d6) memorial plaques : 10.96 (1H, ush.C.); 8.02 (1H. d, J= 7.3 Hz); 7.32-7.44 (5H, m); 7.12 (1H, d, J=7.8 Hz); 6.20 (1H, d, J=7.8 Hz); 5.20 (2H, s); 3.91-4.72 (5H, m); 0.95-1.23 (28H, m).

Example 19. N4-benzyloxycarbonyl-2'-cyano-2'-deoxy--D-arabinofuranosylcytosine.

In 5 ml of tetrahydrofuran was dissolved 192 mg of the compound of example 18, and after the resulting solution was chilled on ice in a current of nitrogen gas, it added rest massively on ice for 2 hours The solvent was distilled and the residue was purified by chromatography on silica gel (eluent used a mixture of methylene chloride and methanol 95: 5), the result was 94 mg of the compound, the name of which is given in the header.

1H-NMR (270 MHz DMCO-d6) memorial plaques : 10.92 (1H, ush.C.); 8.36 (1H, d, J= 7.3 Hz); 7.34-7.44 (5H, m); 7.11 (1H, d, J=7.8 Hz); 6.25 (1H, d, J=5.4 Hz); 5.20 (2H, s); 5.24 (1H, d, J=4.4 Hz); 4.43 (1H, sq J=7.3 Hz, 12.7 Hz); 3.61-3.93 (4H, m)

Example 20. 2'-Cyano-2',3 dideoxy-2',3'-didehydro--D-ribofuranosylthiazole.

Were repeated procedure of synthesis of the compound of example 12 using 300 mg of the compound of example 8, the received 60 mg of the compound, the name of which is given in the header.

1H-NMR (270 MHz DMCO-d6) memorial plaques : 7.79 (1H, d, J=7.3 Hz); 7.55-7.56 (1H, m); 7.36 (2H, d, J=7.3 Hz); 7.07 (1H, DD, J=1.96, 3.90 Hz); 5.78 (1H, d, J=7.3 Hz); 5-18-5.21 (1H, m); 5.01-5.03 (1H, m); 3.65-3.70 (2H, m).

Comparative example 1. 1-[2'-Cyano-2'-deoxy-5'-O-(4,4'-dimethoxytrityl)- M. D. : 8.40 (1H, ush.C.); 7.50 (1H, d, J=1.2 Hz); 4.77-7.26 (9H, m); 6.90-6.80 (4H, m), 6.27 (1H, d, J=6.8 Hz); 4.74 (1H, d, J=6.8 Hz); 3.93 (1H, m); 3.79 (6H, s); 3.61 (1H, m); 3.30 (2H, m); 1.67 (1H, d, J=1.2 Hz).

Comparative example 2. 1-[2'-Cyano-2'-deoxy-5'-O-(4,4-dimethoxytrityl)- M. D. : 8.80 (1H, ush.C.); 8.19 (1H, d, J=7.6 Hz); 7.41-7.14 and 6.89-6.76 (14H, m); 6.30 (1H, d, J=6.1 Hz); 4.79 (2H, m); 4.08 (2H, m); 3.79 (6H, phenylmethyl)- 2 x 6.5 cm). As eluent used a mixture of ethyl acetate with hexane from 1:1 to 2: 1). The result was 162 mg of the compound, the name of which is given in the header. The compound was obtained in the form of caramel white.

1H-NMR (CDCl3) memorial plaques: 8.40 (1H, ush.C.); 7.45 (1H, d, J=1.1 Hz); 7.10 (1H, d, J= 1.8 Hz); 7.06 (1H, d, J=1.8 Hz, 4.0 Hz); 5.10 (1H, DDD, J=2.6, 3.3, 4.0 Hz); 4.12 (3H, s); 3.61 (1H, DD, J=2.6, 11.0 Hz); 3.45 (1H, DD, J= 3.3, 11.0 Hz); 1.90 (3H, d, J=1.1 Hz).

Comparative example 4. 1-[2'-Cyano-2',3'-dideoxy-2',3'-didehydro-5'-O-(4,4-dimethoxytrityl)- M. D.: which 9.22 (1H, c); is 8.16 (1H, d, J = 7,3); 7,35 - 7,22 (9H, m); to 6.95 (1H, DD, J = 1,8, 4.0 Hz); 6.90 to-6,84 (5H, m); of 6.68 (1H, dt, J = 1.8 Hz); to 5.08 (1H, DDD, J = 2.6, 2.9, 4.0 Hz); 3.82 (6H, s); 3,71 (1H, DD, J=2,9, 11.7 Hz); 3.59 (1H, DD. J =2.6 Hz); 2.24 (3H, s).

Comparative example 5. N4-benzyloxycarbonyl-2'-cyano-2'-phenoxythiocarbonyl-3',5'-O-TIPDS - M. D.: 11.02 (1H, ush.C.); 8.00 (1H, d, J = 7.8 Hz); 7.31 -7.98 (1OH, m); 7.11 (1H, d, J =7.8 Hz); 6.29 (1H, s); 5.75 (1H, ush.s); 5.20 (2H, s); 3.98-4.17 (3H, m); 1.00 - 1.12 (28H, m).

Preparative example 1. Hard capsules.

Each standard hard gelatin capsule type cap - capacity was loaded with 100 mg of powdered complex of example 1, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate. Thus prepared capsules were washed and dried to ensure tverdokopchenyh shivali 100 mg of the complex of example 1 0.2 g of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98,8 mg of lactose. The resulting mixture alloy preformed. If necessary, the tablets can be coated.

Preparative example 3. The injection.

10% by volume propylene glycol was mixed with 1.5% by weight of the complex of example 1. The mixture is then brought to a predetermined volume by adding distilled water for injection, then performed the sterilization.

Preparative example 4. Suspension.

To 5 ml was added with stirring 100 mg of finely ground complex of example 1, 100 mg of carboxymethylcellulose sodium, 5 mg of sodium benzoate, 1.0 g of a solution of sorbitol (Pharmacopoeia of Japan) and 0.25 ml of vanillin, then spent homogenization order to obtain a suspension.

The activity of the compounds. Description of the testing procedures.

1. Evaluation of antitumor activity in vitro.

Antitumor activity in vitro was evaluated using the strain cancerous human cells. As a culture medium for cancer cells solution was used RPMD 640 containing 10% immobilized bovine serum and 50 g/ml kanamycin. Cancer cells (1104cells/ml) were verovali in the incubator in an atmosphere of carbon dioxide at 37oC for 72 h, the Viability of cancer cells was determined by MTT method, according to which to determine the number of living cells in the culture fluids containing sample compounds, and therefore containing no sample tested compounds (blind experience), measuring the intensity of visible light (absorption in the visible region of the spectrum), using for these purposes, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide, which gives staining, the intensity of which increases proportionally to the number of living cells. The degree of antitumor activity was evaluated by IR50(concentration g/ml) required to inhibit cell proliferation by 50%. Value IR50determined from the graphical dependences % proliferation of cancer cells in the sample containing the compound of the present invention (% relative to the blind experience) concentration (in logarithmic coordinates) compounds in the sample. The results are summarized in table. 4.

Compounds (1) and (2) of the present invention show strong antitumor activity against L cells transplanted mice, as well as in relation to various forms of human cancer. They can be easily absorbed by the body when the pen is useful for the treatment or prevention of diseases, generating tumors, as a new type of anticancer agents based on a pyrimidine nucleoside. In addition, compounds (1) and (2) of the present invention is very useful as an intermediate in the production of excellent anticancer agents. Derivatives of pyrimidine nucleoside of the present invention can be warm-blooded animals, including humans. Dosage forms include drugs for intravenous injection, subcutaneous injection, intramuscular injection and suppositories for parenteral administration, as well as pills, capsules, powders and granules for oral administration.

Although the dose for an adult organism varies depending on the disease to be treated, method of administration, number of doses and period of treatment, the drug is administered in an amount of from 0.01 to 5 g per day at one time or spend the fractional dose.

In addition, the present compound may be used in combination with other protivoopuholevymi means, such as drugs based on nitrosoanatabine, for example, 5 Fu, AraC, ACNU and BCNU, cisplatin, daunomycin, adriamycin, mitomycin C or etoposide. In addition, these derivatives of pyrimidine nucleoside can be obtained in nainie drugs and formulations containing pharmaceutically acceptable derivative of pyrimidine nucleoside.

The composition for injection is produced in the form of disposable ampoules for injection or in vials containing dose for reusable injection. The compositions can contain additives, such as suspendresume tools, stabilizers and dispersing agents, and, as a rule, the composition is a powder, which is again dissolved before use in an appropriate solvent such as sterilized water - water that does not contain pyrogenic substances. Such a composition can be obtained, for example, by dissolving the derivative of pyrimidine nucleoside in acetone, spill on ampoules and freeze-drying after adding water. Further, the compositions for oral administration may be issued in the form of tablets, capsules, powders, granules and syrups containing the appropriate number of derivatives of pyrimidine nucleoside to receive.

1. The pyrimidine-nucleoside of the General formula I

< / BR>
or their pharmacologically acceptable salts,

where R1- OH, amino group, possibly substituted aliphatic C1- C5-acyl, benzoyl;

R2- H, C1- C4-alkyl;

R3- H, OH;

R4- H;

R5P>, R6', R7' are the same or different, C1- C4-alkyl.

2. Compounds of General formula I on p. 1, wherein R1- OH or amino group, possibly substituted aliphatic C1- C4-acyl or benzene; R4and R5together represent tetraisopropyldisiloxane group.

3. Compounds of General formula I on p. 1, wherein R2- H or methyl, R4- H, R5- H.

4. Compounds of General formula I on p. 1, wherein R1- OH or amino group.

5. Compounds of General formula I on p. 1, selected from

1-(2'-cyano-D-2'-deoxy-arabinofuranosyl)cytosine,

1-(2'-cyano-D-2'-deoxy-arabinofuranosyl)thymine,

1-(2'-cyano-D-2'-deoxy-ribofuranosyl)cytosine,

1-(2'-cyano-D-2'-deoxy-arabinofuranosyl)thymine,

1-(2'-cyano-D-2'-deoxy-ribofuranosyl)thymine,

or their pharmacologically acceptable salts.

6. The pharmaceutical composition exhibiting anti-tumor activity that contains a derived pyrimidine-nucleoside as an active ingredient and a pharmaceutically acceptable carrier, characterized in that as the derived pyrimidine-nucleoside is used as a compound of General formula I on p. 1 and R2defined in paragraph 1, R4Aand R5atogether form a group - R6R7-Si-O-Si-R6'R7'where R6, R7, R6', R7' is defined in paragraph 1, characterized in that conduct the interaction of compounds of General formula

< / BR>
R1, R2, R4a, R5ahave the specified values, and R9- alkoxy, C1- C4-thiocarbonyl group with restoring and tianyoude agent.

8. The method of obtaining compounds of General formula 1B

< / BR>
where R1and R2defined in paragraph 1, R4Aand R5adefined in paragraph 7,

characterized in that conduct the interaction of compounds of General formula

< / BR>
where R1, R2, R4aand R5ahave the above values with tianyoude agent.

9. The method of obtaining compounds of General formula 1c

< / BR>
where R1and R2defined in paragraph 1,

characterized in that conduct the interaction of compounds of General formula 1B

< / BR>
where R1and R2defined above, and R4Aand R5adefined in paragraph (7 debateroom agent.

10. The method of obtaining compounds of General formula 1a

< / BR>
where R1and R2defined in paragraph 1, R4Aand R5adefined the>R4a, R5adefined above, R9-alkoxysilanes,

containing C1- C4-alkyl, with a reducing agent.

11. The method of obtaining compounds of General formula

< / BR>
where R1and R2defined in paragraph 1, and R3, R5together form a carbon-carbon bond,

characterized in that conduct the interaction of compounds of General formula

< / BR>
where R1, R2, R3, R5have the specified values, and R10- protective group with debateroom agent.

 

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