Novel pyrimidine nucleoside or salt thereof

FIELD: chemistry.

SUBSTANCE: invention relates to a pyrimidine nucleoside compound of general formula (1) , in which one of X and Y is a cyano group and the other is hydrogen; R1 is hydrogen, (R3)(R4)(R5)Si- or a carbonyl group which includes an alkyl monosubstituted with an amino group; R2 is hydrogen or (R6)(R7)(R8)Si-, provided that at least one of R1 and R2 is not hydrogen; or R1 and R2 together form a 6-member cyclic group -Si(R9)(R10)-, where each of R9 and R10 is a straight or branched alkyl; R3, R4 and R5 denote a straight or branched alkyl optionally substituted alkoxy, or cycloalkyl; R6, R7 and R8 denote a straight or branched alkyl optionally substituted alkoxy, cycloalkyl or phenyl, or to pharmacologically acceptable salts thereof. The invention also relates to a range of specific compounds of formula (1) or to their pharmacologically acceptable salts: 5'-O-triisopropylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-diethylisopropylsilyl-2'-cyano-2,-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-dimethylthexylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-(dimethyl-n-octylsilyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-dimethylthexylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-diethylisopropylsilyl -2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-(tert-butyldimethylsily)-2'-cyano-2'-desoxy-1-β-O-arabinofuranosylcytosine; 3'-O-triisopropylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-dimethylthexylsilyl-5'-O-(L-valyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-(L-valyl)-3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; and 3'-O-cyclopropyl-diisopropylsilyl-2'-cyano-2'-desoxy-1-β-D- arabinofuranosylcytosine.

EFFECT: obtaining formula (1) compounds or their pharmacologically acceptable salts for preparing a medicinal agent for treating tumours.

9 cl, 20 tbl, 1 dwg, 73 ex

 

The technical field to which the invention relates

The present invention relates to 2'-deoxy-2'-cyanopyrimidine nucleoside compound or its salts that exhibit excellent antitumor effect.

The LEVEL of TECHNOLOGY

Currently, cancer is characterized by abnormal proliferation of cells, are still diseases that are most difficult to treat. Therefore there is an urgent need to develop effective tools for the treatment of cancer. Because cell proliferation depends largely on the biosynthesis of nucleic acids, to date, extensive research has focused on drug development-antagonists metabolism of nucleic acids that inhibit the metabolism of nucleic acids.

Among these drugs, resulting in extensive studies have been developed antagonists metabolism of nucleic acid-based derivatives cytidine. For example, were developed cytarabine (non-patent document 1), ancitabine (non-patent document 2), cytarabine ocfosfate (non-patent document 3), gemcitabine (patent document 1) and so on, and now these drugs are used in clinical therapy.

These compounds exhibit anti-tumor effect, established the first on the inhibition of DNA polymerase or ribonucleotide reductase, which leads to inhibition of DNA synthesis. These drugs reach clinical therapeutic results at a certain level. However, cytarabine, ancitabine and cytarabine ocfosfate, as is known, do not show any activity against solid tumors (non-patent document 4). In addition, gemcitabine can be applied to a limited number of types of cancer (non-patent document 4). Thus, these drugs never showed satisfactory antitumor activity.

In order to solve the above problems, has been developed 2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (CNDAC), with the ability to break the DNA chain. Antitumor activity of CNDAC differs from the corresponding activity saidinovich compounds that have been developed (patent document 2 and non-patent documents 5 and 6). In addition, as oral medicines were developed 4-N-Palmitoyl-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (P-CNDAC, Patent document 3 and non-patent documents 7 and 8), and 5'-phosphatidylinositides nucleotide (patent document 4). Found that these CNDAC compounds exhibit interesting antitumor effects (non-patent documents 5 and 8).

However, existing CNDAC compound were not yet on the market. Therefore, there is Stra the need for the development and commercialization of anticancer drugs based on derivatives cytidine, showing an increased antitumor effect and suitable for oral administration.

[Patent document 1] Japanese patent publication (kokoku) No. 6-37394

[Patent document 2] Japanese patent No. 2559917

[Patent document 3] Japanese patent No. 2569251

[Patent document 4] Japanese published patent application (kokai) No. 7-179491

[Non-patent document 1] Evance, J. S. et al. Proc. Soc. Exp. Bio. Med., 106, 350 (1961)

[Non-patent document 2] Hoshi, A. et al. Gann, 67, 725 (1972)

[Non-patent document 3] Kodama, K. et al. Jpn. J. Cancer Res., 80, 679-685 (1989)

[Non-patent document 4] Matsuda, A., et al. Cancer Sci., 95, 105-111 (2004)

[Non-patent document 5] Matsuda, A., et al. J. Med. Chem., 34, 2919-2922 (1991)

[Non-patent document 6] Azuma, A., et al. J. Med. Chem., 36, 4183-4189 (1993)

[Non-patent document 7] Matsuda, Akira and Takuma, Sasaki, Protein, Nucleic Acid and Enzyme, 43, 1981-1989 (1998)

[Non-patent document 8] Katz, M. H. et al. Cancer Res., 64, 1828-1833 (2004)

DISCLOSURE of INVENTIONS

The problems solved by the present invention

The present invention is directed to providing a new pyrimidine nucleoside compound that exhibits an excellent antitumor effect compared to existing pyrimidine nucleoside compounds.

Ways of implementation of the present invention

To solve this problem, the authors of the present invention have conducted extensive studies and found that Perim diNovo nucleoside compound, represented by the following formula (1)or its salt shows excellent bioavailability when administered orally and has excellent antitumor activity in comparison with the existing CNDAC compound. The present invention was developed based on the specified opening.

Accordingly, the present invention provides a new pyrimidine nucleoside compound represented by formula (1):

[F1]

(where one of X and Y represents a cyano, and the other represents a hydrogen atom; one of R1and R2represents a hydrogen atom, carbonyl group, including C1-C6 alkyl group, which monogamist amino group, or a group (R3)(R4)(R5Si-, and the other is a group (R6)(R7)(R8Si-, or R1and R2together form a 6-membered cyclic group,- Si(R9)(R10)-; each R3, R4, R5, R6, R7and R8represents a C1-C10 linear or branched alkyl group which may be substituted, C3-C6 cycloalkyl group which may be substituted, C6-C14 aryl group which may be substituted, or a C1-C6 alkyl group which is substituted by one or two C6-C14 aryl groups and which may be substituted; and each R9and R10represents a C1-C6 linear or branched alkyl group, which may be substituted) or its salt.

The present invention also provides a pharmaceutical composition comprising an effective amount of the compound represented by formula (1)or its salt and a pharmaceutically acceptable carrier.

The present invention also provides an anticancer agent, comprising an effective amount of the compound represented by formula (1)or its salt and a pharmaceutically acceptable carrier.

The present invention also provides the use of compounds represented by formula (1)or salts thereof for the manufacture of a medicinal product.

The present invention also provides a method of treating tumors, comprising introducing an effective amount of the compound represented by formula (1)or its salt.

The technical result of the invention

New pyrimidine nucleoside compounds of the present invention and their salts have excellent antitumor activity and good assorbimento oral introduction and, thus, applicable as an antitumor agent.

Brief description of drawing

The drawing is a graph showing the change in tumor volume when using equitoxic number of connections 19, CNDAC, or P-CNDAC against colon cancer cells human stomachs.

The most preferred method of carrying out the invention

New pyrimidine nucleoside compound of the present invention and salts thereof have a chemical structure represented by the aforementioned formula (1) and which is characterized by the presence of the silyl group in the 3'- and 5'-positions.

Some intermediate compounds for the synthesis of the above CNDAC compounds are known to have silyl group in the 3'- and 5'-positions (for example, patent documents 2 and 3). However, CNDAC compound of the present invention represented by the formula (1), was not disclosed. In addition, the antitumor activity of intermediate compounds for the synthesis of the above CNDAC compounds was not known.

In the formula (1) examples of "C1-C6 alkyl group "is a carbonyl group having a C1-C6 alkyl group, which monogamist amino group"represented by the group R1or R2include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl, and the preferred group is isobutyl.

In the formula (1) examples of "C1-C10 linear or branched alkyl groups"represented by the group R3, R4, R5, R6, R7or R8include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-hexyl, n-octyl and Texel. Preferably " C1-C10 linear or rasvet is certain alkyl group" is a C1-C8 linear or branched alkyl group. More preferably, each of R3, R4and R5and any R6, R7and R8, some of which may be the same or different from each other are C3-C8 linear or branched alkyl group, and other groups which may be the same or different from each other, are C1-C4 linear or branched alkyl groups.

In the formula (1) examples of "C3-C6 cycloalkyl groups represented by the groups R3, R4, R5, R6, R7or R8include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Of them preferred cyclopropyl and cyclohexyl, and the most preferred cyclopropyl.

In the formula (1) examples of "C6-C14 aryl group"represented by the group R3, R4, R5, R6, R7or R8include phenyl and naphthyl.

In the formula (1) "C6-C14 aryl group" of the "C1-C6 alkyl group which is substituted by one or two C6-C14 aryl groups represented by the groups R3, R4, R5, R6, R7or R8represents a group corresponding to the above-mentioned C6-C14 aryl group, and "C1-C6 alkyl group" is a group corresponding to the above C1-C6 alkyl group. Specific examples include benzyl, phenethyl, benzhydryl and naphthylmethyl.

In the formula (1), "Vice"that mo is ut to be associated with R 3, R4, R5, R6, R7, R8, R9or R10may be the same or different from each other (the number of substitutions: one to three). Examples of the substituents include C1-C3 linear or branched alkyl groups such as methyl, ethyl and isopropyl; hydroxyl; C1-C6 of alkoxygroup, such as methoxy, ethoxy, isopropoxy and tert-butoxy; an amino group; halogen atoms such as chlorine and bromine; cyano; and nitro-group.

In the formula (1) examples of "(R3)(R4)(R5)Si - (R6)(R7)(R8Si-" presented by the groups R1and R2include tert-butyldimethylsilyl, triisopropylsilyl, triisobutylene, dimethyl-n-octylsilane, dimethylacrylic, trimethylsilyl, triethylsilyl, tri-n-propulsion, tri-n-Boticelli, tri-n-exelsior, n-paperdimension, n-butyldimethylsilyl, isobutyronitrile, n-interdimension, n-existimatio, dimethyl-tert-exelsior, n-delldimension, (3,3-dimethylbutyl)dimethylsilane, 2,3-dimethylpropyleneurea, di-tert-butylmethylether, di-n-butylmethylether, diethylenediamine, n-activisuspicion, n-activitiesall, cyclohexyldimethylamine, dicyclohexylmethyl, isopropylideneglycerol, triphenylsilane, dimethylphenylsilane, tert-butyldiphenylsilyl, methyldiphenylamine, diphenyl(diphenylmethyl)silyl, p-taildaters is l, biphenylmethanol, m-phenoxybenzaldehyde, biphenyldicarboxylic, three(2-biphenyl)silyl, three(o-tolyl)silyl, three(2-methoxyphenyl)silyl, tribenzylamine, benzyldimethylamine, geneticisation, (3-phenylpropyl)dimethylsilane, p-(tert-butyl)geneticisation, penicillinaseproducing, neofundamentalism, bromomethylbiphenyl, chlorotrimethylsilane, 4-chlorobutyronitrile, (dichloromethyl)dimethylsilane, 3-chloropropionitrile, 3,3,3-cryptosporidiosis, 1H,1H,2H,2H-PERFLUORO-n-delldimension, 1H,1H,2H,2H-PERFLUORO-n-octyldodecyl, 3,3,4,4,5,5,6,6,6-nomatter-n-existimatio, bis(chloromethyl)methylsilyl, pentafluorobenzonitrile, pentafluorobenzonitrile, 3,5-bis(trifluoromethyl)phenyldimethylsilane, [3-(chloromethyl)phenylethyl]dimethylsilane, [4-(chloromethyl)phenylethyl]dimethylsilane, acetoxyisobutyryl, 3-acetoxypropionyl, 3-methacryloxypropyltrimethoxysilane, 3-cyanopropionic, [3-(trimethylsiloxy)propyl]dimethylsilane, n-butyldimethylsilyl, aminobutiramida-n-propulsion, aminobutiramida(2,2-dimethylpropyl)silyl, (3-methylbutyl)diisopropylzinc, (2-ethylbutyl)dicyclopropyl, tert-imidiatelly, tert-butyldimethylsilyl, diethyl(3-methylpentan-3-yl)silyl, isobutyleneisoprene, diethyl(2-methylpentan-2-yl)silyl, cyclopropanedicarboxylic, dicyclopentadienyl, diiso Roper(3-methoxypropyl)silyl, (3-ethoxypropan)diisopropylzinc, [3-(tert-Butylochka)propyl]diisopropylzinc, tert-bathilde(3-ethoxypropan)silyl and 3-phenoxypropylamine. Preferably both groups(R3)(R4)(R5)Si - (R6)(R7)(R8Si-" represent tert-butyldimethylsilyl, triisopropylsilyl, diethylenediamine, cyclohexyldimethylamine, triisobutylene, triphenylsilane, tribenzylamine, dimethylaniline, dimethyl-n-octylsilane, dicyclopropyl(2-ethylbutyl)silyl, diethyl(3-methylpentan-3-yl)silyl, tert-butyldimethylsilyl, cyclopropanedicarboxylic or dimethylacrylic, more preferably tert-butyldimethylsilyl, triisopropylsilyl, diethylenediamine, dimethyl-n-octylsilane, cyclopropanedicarboxylic or dimethylacrylic, particularly preferably triisopropylsilyl, cyclopropanedicarboxylic or dimethylacrylic.

In the formula (1) " C1-C6 linear or branched alkyl group"represented by R9or R10includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and n-hexyl.

Preferred pyrimidine nucleoside compound

The compound of the present invention preferably is a compound represented by the formula (1), in which one of X and Y represents a cyano, and the other represents a hydrogen atom; ar is n of R 1and R2is a hydrogen atom, a group (R3)(R4)(R5Si - or carbonyl group, with C1-C6 alkyl group, which monogamist the amino group and the other represents a group (R6)(R7)(R8Si-, or R1and R2together form a 6-membered cyclic group,- Si(R9)(R10)-; R3, R4, R5, R6, R7and R8that may be the same or different from each other and individually represent a C3-C6 cycloalkyl group, phenyl group, benzyl group or a C1-C8 linear or branched alkyl group which may have a C1-C6 alkoxygroup.

The compound of the present invention more preferably is a compound represented by the formula (1), in which one of X and Y represents a cyano, and the other represents a hydrogen atom; R1is a hydrogen atom, valley group or group (R3)(R4)(R5Si-; R2is a hydrogen atom or a group (R6)(R7)(R8)Si (in the case when R1is a hydrogen atom or valley group, R2is not a hydrogen atom); and R3, R4, R5, R6, R7and R8that may be the same or different from each other, are C1-C8 linear or branched alkyl group is whether C3-C6 cycloalkyl group.

The compound of the present invention more preferably is a compound represented by the formula (1), in which one of X and Y represents a cyano, and the other represents a hydrogen atom; R1is a hydrogen atom, L-valley group or group (R3)(R4)(R5Si-; R2represents a hydrogen atom or a group (R6)(R7)(R8)Si (in the case when R1is a hydrogen atom or L-valley group, R2is not a hydrogen atom); and any R3, R4and R5and any R6, R7and R8, some of which can be the same or different from each other, are individually C3-C8 linear or branched alkyl group or cyclopropene group, and other groups which may be the same or different from each other, are C1-C4 linear or branched alkyl groups.

The compound of the present invention most preferably is a compound represented by the formula (1), in which one of X and Y represents a cyano, and the other represents a hydrogen atom; R1is a hydrogen atom, L-valley group, triisopropylsilyl group, diethylethanolamine group, dimethylethoxysilane group or dimethyl-n-octylsilane group, R 2is a hydrogen atom, a tert-butyldimethylsilyloxy group, triisopropylsilyl group, diethylethanolamine group, cyclopropanecarbonitrile group or dimethylethoxysilane group (in the case when R1is a hydrogen atom or L-valley group, R2is not a hydrogen atom).

Preferred examples of pyrimidine nucleoside compounds include the following (a)to(k):

(a) 5'-O-triisopropylsilyl-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;

(b) 5'-O-diethylenediamine-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;

(c) 5'-O-dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;

(d) 5'-O-(dimethyl-n-octylsilane)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;

(e) 3'-O-dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;

(f) 3'-O-diethylenediamine-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;

(g) 3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;

(h) 3'-O-triisopropylsilyl-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;

(i) 3'-O-dimethylacrylic-5'-O-(L-felled)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;

(j) 5'-O-(L-felled)-3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine; and

(k) 3'-O-cyclopropanedicarboxylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranose silicosis.

On Sol pyrimidine nucleoside compounds of the present invention is not restricted by any specific restrictions, if the salt is pharmaceutically acceptable. Examples of salts that can be formed include salts of mineral acids, such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; and organic acid salts such as acetate, propionate, tartrate, fumarate, maleate, malate, citrate, methanesulfonate, p-toluensulfonate and triptorelin. Depending on the type of substituent(s), a pyrimidine nucleoside compound of the present invention can form an optical or geometric isomers. Pyrimidine nucleoside compound of the present invention includes such optical and geometric isomers. These isomers can be separated or used as a mixture. Pyrimidine nucleoside compound of the present invention also encompasses amorphous varieties, polymorphs and a solvate such as a hydrate.

Pyrimidine nucleoside compound of the present invention or its salt can be obtained in accordance with the following reaction scheme, which includes stages 1-11.

[F2]

[F3]

X, Y, R1and R 2listed on stages 1-11, shall have the same meaning as described above. Each of R11and R14represents a protective group for amino group. The protective group is no specific limitation, and can be used with any standard protective group. For example, acceptable protective group include those listed in the document (T.W. Greene, “Protective groups in Organic Synthesis”, A Wiley-Interscience Publication, John Wiley & Sons, New York, 1981, R. 218-287). Specific examples include substituted oxycarbonyl group, such as tert-butoxycarbonyl and benzyloxycarbonyl group. R12is a protective group for hydroxyl group, and examples include triphenylmethyl group, 4-methoxycarbonylmethylene group and 4,4'-dimethoxytrityl group. The group R13-CO2H represents aminobenzamidine carboxylic acid, and examples include amino acids such as glycine, L-alanine, β-alanine, L-valine, L-leucine, L-isoleucine, L-lysine and D-alanine.

(Stage 1)

In stage 1 of pyrimidine nucleoside compound represented by formula (2), or its salt interact with well-known silylium agent such as trialkylsilyl halide, trialkylsilyl or trialkylsilyl represented as (R3)(R4)(R5)Si-Z or (R6)(R7)(R8)Si-Z (where Z before the hat is a halogen atom, tripterocalyx group, acetaminoph etc)with which can be obtained compound represented by the formula (1a). The reaction can be carried out in accordance with any known method. The solvent used in the reaction, there is no particular limitation, as the solvent is inert to the reaction. Examples of the solvent include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N,N-dimethylformamide and dimethylsulfoxide. These solvents may be used separately or in combination. In the reaction, if necessary, can also be used a basis. Examples of bases include organic amines, such as imidazole, 1-Mei, trimethylamine, triethylamine, Tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine and kallidin; and inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate. The solvent may be entirely from the base. In the above reaction (R3)(R4)(R5)Si-Z or (R6)(R7)(R8)Si-Z are used in amounts of about 1-10 mol, preferably about 1-5 mol, and the base is used in the amount of approximately 1-100 mol, preferably adapted the sustained fashion 1-10 mol, relative to 1 mole of the compound represented by formula (2). The values of temperature and the reaction time ranges from -30 to 100°C and from 0.1 to 100 hours, preferably from 0 to 30°C and from 1 to 20 hours. The compound represented by formula (1a) and the resulting reaction can be isolated and purified if necessary. Alternatively, the connection may also be used at a subsequent stage without further purification. Trialkylsilyl halide used in the reaction and is represented as (R3)(R4)(R5)Si-Z or (R6)(R7)(R8)Si-Z, can be obtained using the standard method. For example, trihalomethyl, monoalkylphenols or dialkylaminoalkyl vzaimodejstvuyut with the corresponding alkyllithium or Grignard reagent, resulting in trialkylsilyl represented as (R3)(R4)(R5Si-H or (R6)(R7)(R8Si-H, and then the product interacts with a halogenation agent such as N-chlorosuccinimide, N-bromosuccinimide, N-jodatime, chlorine, bromine, iodine or 1,3-dichloro-5,5-dimethylhydantoin, resulting in trialkylsilyl halide. In the process of obtaining trialkylsilanes represented as (R3)(R4)(R5Si-H can be used additive such as copper bromide. Trialkylsilyl represented as (R3)(R4)(R5)SiH or (R 6)(R7)(R8Si-H, and trialkylsilyl halide represented as (R3)(R4)(R5)Si-Z or (R6)(R7)(R8)Si-Z, can be isolated and purified if necessary. Alternatively, the compounds may also be used in stage 1 in the same form in which received.

(Stage 2)

In stage 2 of the pyrimidine nucleoside compound represented by formula (1a), interacts with the above-mentioned (R3)(R4)(R5)Si-Z or (R6)(R7)(R8)Si-Z in the presence of a base, resulting in a compound represented by the formula (1b). Stage 2 is carried out in the same way as stage 1.

(Stage 3)

At stage 3 of pyrimidine nucleoside compound represented by formula (2), interacts with the above-mentioned (R3)(R4)(R5)Si-Z or (R6)(R7)(R8)Si-Z or with such a connection, as dealkiller dihalogenide or dialkylzinc ditriflate presented as Z-Si(R9)(R10)-Z (where Z has the same meaning as mentioned above), in the presence of a base, as a result, in the same way as in stage 1, can be obtained compound represented by the formula (1b). The values of temperature and the reaction time ranges from -30 to 150°C and from 0.1 to 100 hours, preferably from 0 to 100°C and from 1 to 40 hours. The compound represented by formula (1b) and is received in the reaction, can be isolated and purified if necessary. Alternatively, the connection can also be used on the subsequent stage without further purification.

(Stage 4)

In stage 4 of the pyrimidine nucleoside compound represented by formula (1b)is treated in acid conditions resulting compound represented by the formula (1c). The acid used in stage 4, there is no specific limitation, until the acid is applicable for removal of the substituent R1. Examples of the acid include mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids, for example triperoxonane acid, acetic acid, propionic acid, formic acid, methanesulfonate acid and p-toluensulfonate acid. These acids may be mixed with water and, if necessary, can also be used a solvent. Examples of the solvent include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N,N-dimethylformamide, dimethylsulfoxide, methanol, ethanol, n-propanol, isopropanol and water. These solvents may be used separately or in combination. The values of temperature and the reaction time ranges from -30 is about 150°C and from 0.1 to 100 hours, preferably from 0 to 100°C and from 1 to 20 hours.

(Stage 5)

On stage 5 of pyrimidine nucleoside compound represented by formula (2), interacts with protecting the amino group of the reagent, resulting in a compound represented by the formula (3). The solvent used in the reaction, there is no specific limitation, as the solvent is inert to the reaction. Examples of the solvent include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N,N-dimethylformamide and dimethylsulfoxide. These solvents may be used separately or in combination. In the reaction, if necessary, can also be used a basis. Examples of the base include organic amines, such as imidazole, 1-Mei, trimethylamine, triethylamine, Tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine and kallidin; and inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate. The solvent may be entirely from the base. Used to protect the amino group of the reagent is no specific limitation until the protective group can be removed under acidic or neutral conditions, and examples include alkoxycarbonylmethyl, such as tert-butoxycarbonylamino; anhydrides alkylphenol acid, such as di-tert-BUTYLCARBAMATE; and Uralelectromed halides, such as benzyloxycarbonylamino. The values of temperature and the reaction time ranges from -30 to 150°C and from 0.1 to 100 hours, preferably from 0 to 100°C and from 1 to 40 hours. The compound represented by formula (3) and the resulting reaction can be isolated and purified if necessary. Alternatively, the connection may also be used at a subsequent stage without further purification.

(Stage 6)

On stage 6 of the pyrimidine nucleoside compound represented by formula (3), interacts with the reagent, hydroxyl protecting group, in the presence of a base, resulting in a compound represented by the formula (4). Examples of the base include organic amines, such as imidazole, 1-Mei, trimethylamine, triethylamine, Tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine and kallidin; and inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate. The solvent may be entirely from the base. The solvent used in the reaction, there is no specific limitation, as the solvent is inert to the reaction. Examples of the solvent include the with dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N,N-dimethylformamide and dimethylsulfoxide. These solvents may be used separately or in combination. On the used reagent, a hydroxyl protecting group, not imposed any specific restrictions until the protective group can be selectively protected 5'-hydroxyl group of the sugar molecule and can be removed under acidic or neutral conditions, and examples include triarylmethyl halides, such as triphenylmethylchloride, 4-methoxycarbonylmethylene and 4,4'-dimethoxymethylsilane. The values of temperature and the reaction time ranges from -30 to 150°C and from 0.1 to 100 hours, preferably from 0 to 100°C and from 1 to 40 hours. The compound represented by formula (4) and the resulting reaction can be isolated and purified if necessary. Alternatively, the connection may also be used at a subsequent stage without further purification.

(Stage 7)

On stage 7 of pyrimidine nucleoside compound represented by formula (4), interacts with the above-mentioned (R3)(R4)(R5)Si-Z or (R6)(R7)(R8)Si-Z in the presence of a base, resulting in a compound represented by the formula (5). Examples of the base include organic amines, such as imidazole, 1-IU is elimidate, trimethylamine, triethylamine, Tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine and kallidin; and inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate. The solvent may be entirely from the base. The solvent used in the reaction, there is no specific limitation, as the solvent is inert to the reaction. Examples of the solvent include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N,N-dimethylformamide and dimethylsulfoxide. These solvents may be used separately or in combination. The compound represented by formula (5) and the resulting reaction can be isolated and purified if necessary. Alternatively, the connection may also be used at a subsequent stage without further purification.

(Stage 8)

On stage 8 of pyrimidine nucleoside compound represented by formula (5), interacts with the reagent for removing the protective groups, resulting in a compound represented by the formula (6). In that case, when the protective group for 5'-hydroxyl groups in the sugar molecule is triarylmethyl group, examples of the solvent include dichloromethane, chlorof the Republic of Moldova, the ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, acetone, N,N-dimethylformamide, dimethylsulfoxide, methanol, ethanol, n-propanol, isopropanol and water. These solvents may be used separately or in combination. On the used reagent for removing the protective groups, and there is no specific limitation, and can be used with standard reagents. For example, when the protecting group for the 5'-hydroxyl groups in the sugar molecule is triarylmethyl group, examples of the reagent for removing the protective groups include mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids, for example triperoxonane acid, acetic acid, propionic acid, formic acid, methanesulfonate acid and p-toluensulfonate acid. The values of temperature and the reaction time ranges from -30 to 150°C and from 0.1 to 100 hours, preferably from 0 to 100°C and from 1 to 40 hours. The compound represented by formula (6) and the resulting reaction can be isolated and purified if necessary. Alternatively, the connection may also be used at a subsequent stage without further purification.

(Stage 9)

On stage 9 of pyrimidine nucleoside link is, represented by formula (6), interacts with the reagent for removing the protective groups, resulting in a compound represented by the formula (1c). In that case, when the protective group for the 4-amino group is tert-butoxycarbonyl group, examples of the solvent include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, acetone, N,N-dimethylformamide, dimethylsulfoxide, methanol, ethanol, n-propanol, isopropanol and water. These solvents may be used separately or in combination. On the used reagent for removing the protective groups, and there is no specific limitation, and can be used with standard reagents. For example, in the case where the protective group for the 4-amino group is tert-butoxycarbonyl group, examples of the reagent for removing the protective groups include mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids, for example triperoxonane acid, acetic acid, propionic acid, formic acid, methanesulfonate acid and p-toluensulfonate acid. The values of temperature and the reaction time ranges from -30 to 150°C and from 0.1 to 100 hours, preferably from 0 to 100°C and from 1 to 40 cha is impressive. It should be noted that the stages 8 and 9 can be held in one stage instead of two separate stages.

(Stage 10)

On stage 10 pyrimidine nucleoside compound represented by formula (6), condensed with the appropriate carboxylic acid with a protected amino group, resulting in the formation of the ether carboxylic acid represented by the formula (7). The type of the condensation reaction, and there is no specific limitation until condensation takes place between a conventional carboxylic acid and alcohol in such a way that the result is broadcast. For example, there may be used a mixed anhydride, condensing agent, etc. When using a mixed anhydride, examples of the base include organic amines such as trimethylamine, triethylamine, Tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine and kallidin; and inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate. Examples of the reagent used for the formation of a mixed acid anhydride with an amino acid with a protected amino group include isobutylparaben and pivaloyloxy. Examples of the condensing agent include carbodiimide compounds such as dicyclohexylcarbodiimide, the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbody the foreign Ministry and N,N'-carbonyldiimidazole. Examples of the condensing auxiliary substances include 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboximide and 4-dimethylaminopyridine. The solvent used in the reaction, there is no specific limitation, as the solvent is inert to the reaction. Examples of the solvent include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N,N-dimethylformamide and dimethylsulfoxide. These solvents may be used separately or in combination. The compound represented by the formula (7) and the resulting reaction can be isolated and purified if necessary. Alternatively, the connection may also be used at a subsequent stage without further purification.

(Stage 11)

On stage 11 of pyrimidine nucleoside compound represented by formula (7), interacts with the reagent for removing the protective groups, resulting in a compound represented by the formula (1d). In the case where each of the protective groups for the 5'-amino - and 4-amino group is tert-butoxycarbonyl group, examples of the solvent include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, acetone, N,N-dimethylformamide, dimiti the sulfoxide, methanol, ethanol, n-propanol, isopropanol and water. These solvents may be used separately or in combination. On the used reagent for removing the protective groups, and there is no specific limitation, and can be used with standard reagents. For example, in the case where each of the protective groups for the specified amino group is tert-butoxycarbonyl group, examples of the reagent for removing the protective groups include mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids, for example triperoxonane acid, acetic acid, propionic acid, formic acid, methanesulfonate acid and p-toluensulfonate acid. The values of temperature and the reaction time ranges from -30 to 150°C and from 0.1 to 100 hours, preferably from 0 to 100°C and from 1 to 40 hours.

Thus obtained compound of the present invention and other compounds can be converted into the corresponding salts, preferably pharmaceutically acceptable salts, using well-known methods.

The compound of the present invention, its salt and other compounds and their salts can be isolated and purified using standard methods of separation/purification such as concentration, extraction RA is the founders, filtration, recrystallization or any chromatographic method.

When using the compounds of the present invention as a drug compound is mixed with a pharmaceutical carrier, and in accordance with the preventive and therapeutic purposes can be selected several dosage forms. Can be used in any dosage form, and examples include oral forms, injections, suppositories, ointments and plasters. Of these dosage forms are preferably used oral forms. These dosage forms may be obtained with the help of any pharmaceutical methods known in the art.

Used in the pharmaceutical carrier can be any of organic and inorganic substances-carriers which are generally used as materials for the preparation of drugs. In the solid drug carrier included in the form of foundations, lubricants, binders, powder or similar additives. In liquid medicines carrier included as a solvent, dissolving excipient, suspending agent, isotonic agent, buffer, soothing agent or similar additives. If necessary, may also include other additives such as a preservative, anti sident, dye and sweetener.

In the preparation of solid oral drug compound of the present invention is mixed with the base and additional additives such as binder, baking powder, grease, dye, sweetener and flavoring, after which the mixture is formed into tablets, coated tablets, granules, powder, capsules, etc. by using the conventional method. These supplements can be an additive commonly used in the prior art, and examples include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid (base); water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone (binder); dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride of stearic acid and lactose (leavening agents); purified talc, salts of stearic acid, sodium tetraborate and polyethylene glycol (lubricants); titanium oxide and iron oxide (dyes); and sucrose, orange peel, citric acid and in which nnuu acid (sweeteners and flavorings).

In the preparation of oral liquid medicines connection of the present invention is mixed with additives, such as sweeteners, buffers, stabilizers and flavorings, after which the mixture is formed into a liquid oral medicine, syrup, elixir, etc. using a conventional method. In this case, sweetener and flavoring may be the same as described above. Examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth gum, gum Arabic and gelatin.

Preparation of solution for injection, the compound of the present invention is mixed with additives such as a pH Adjuster, buffer, stabilizer, isotonic agent and local anesthetic, after which the mixture is formed in the form of subcutaneous, intramuscular and intravenous fluids for injection using a conventional method. In this case, examples of the pH regulator and buffer include sodium citrate, sodium acetate and sodium phosphate, and examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid and timelocal acid. Examples of local anesthetic include procaine hydrochloride and lidocaine hydrochloride. Examples of the isotonic agent include sodium chloride and glucose.

In the preparation of suppositories compound of the present invention is mixed with novtel the m for drugs, known in the prior art, such as polyethylene glycol, lanolin, cocoa butter and triglyceride fatty acid, and an optional surfactant, such as Tween (registered trademark), after which the mixture is formed into candles using a conventional method.

In the preparation of ointments compound of the present invention is mixed, if necessary, with commonly used additives, such as base, stabilizer, humectant, preservative, etc., after which the mixture is mixed and formed into dosage form using a conventional method. Examples of bases for ointments include liquid paraffin, white petrolatum, white wax, octyldodecanol alcohol and paraffin. Examples of the preservative include p-oxymethylene, p-acetylbenzoic and p-oxypropylated.

In the process of making plaster above-mentioned ointment, cream, gel, paste or similar material is applied on a standard substrate using a conventional method. Examples of suitable substrates include woven and non-woven cotton fabric, staple fiber or chemical fiber; and film and foam plates, made of soft vinyl chloride, polyethylene or polyurethane.

The standard dose of a compound of the present invention, which should be included in any of the above medicines varies dependent on the STI from the patient, want to enter the compound of the invention, dosage forms, or other factors. Usually a standard dose is preferably from about 0.05 to 1000 mg for oral medicines, about 0.01 to 500 mg injection, and approximately 1-1000 mg for suppositories. A daily dose of a medicinal product, includes any of the above dosage forms, which varies depending on the condition, body weight, age, sex, etc. of the patient, cannot be determined accurately. However, usually, the daily dose for an adult is approximately 0.05 to 5000 mg, preferably 0.1 to 1000 mg Standard dose is preferably administered once a day or split method two to four times.

Examples of diseases (in the case of malignant tumors), which can be cured by injection of a medicinal product containing the compound of the present invention include head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder/biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, cancer of uterus, kidney cancer, bladder cancer, prostate cancer, testicular tumor, osteosarcoma and soft tissue sarcoma, leukemia, malignant lymphoma, plasmacytoma myeloma, skin cancer and a tumor the brain.

The present invention will be further described in detail with reference to reference examples, comparative examples, examples (working examples), examples of pharmacological tests and sample compositions. However, none of them shall not be construed as limiting the invention.

Example 1

5'-O-(tert-Butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (1)

2'-Cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (hereinafter referred to as CNDAC) (1,02 g, 4.04 mmol) suspended in pyridine (40 ml). To the resulting suspension was added tert-butyldimethylsilyl (790 mg, the 5.25 mmol). The mixture was stirred at room temperature for 24 hours under nitrogen atmosphere. After removal of solvent the residue is twice boiled with toluene and purified by column chromatography on silica gel (5% methanol/chloroform), resulting in compound 1 was obtained as a white solid (1.19 g, 80%).

1H-NMR (DMSO-d6) δ to 7.67 (1H, d, J=7,6 Hz), 7,18 (2H, userd), 6,18 (1H, d, J=5,9 Hz), 6,12 (1H, d, J=7,6 Hz), the 5.65 (1H, d, J=7,6 Hz), the 4.29 (1H, DD, J=a 13.9 Hz, J=8.1 Hz), 3,84 at 3.69 (4H, m), 0,81 (9H, s), 0,00-0,01 (each 3H, each s); FAB-LRMS m/z 367 (MH+). Analysis. Calculated for C16H26N4O4Si: C, 52,44; H, 7,15; N, 15,29. Found: C, 52,01; H, 7,10; N, 15,02; etc. 185°C (decomp.).

Example 2

5'-O-Triisopropylsilyl-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (2)

The General procedure of example 1 was repeated using CNDAC (1.01 g, 4.00 mmol) and triisopropylsilane (1,68 ml of 8.00 mmol), resulting in compound 2 was obtained as a white solid (720 mg, 44%).

1H-NMR (DMSO-d6) δ 7,76 (1H, d, J=7,3 Hz), 7,26 (2H, users), 6,28 (1H, d, J=5,9 Hz), to 6.22 (1H, d, J=7,6 Hz), 5,72 (1H, d, J=7,6 Hz), of 4.44 (1H, DDD, J=a 13.9 Hz, J=8,1 Hz, J=5,9 Hz), 4,01-of 3.77 (4H, m), 1,16-1,04 (21H, m); FAB-LRMS m/z 409 (MH+). Analysis. Calculated for C19H32N4O4Si: C, 55,86; H, 7,89; N, 13,71. Found: C, 55,83; H, of 7.48; N, 14,10; etc. 177°C (decomp.).

Example 3

5'-O-Diethylenediamine-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (3)

The General procedure of example 1 was repeated using CNDAC (1.01 g, 4.00 mmol) and diethylazodicarboxylate (800 μl, 4,36 mmol), resulting in compound 3 was obtained as a white solid (762 mg, 50%).

1H-NMR (DMSO-d6) δ 7,79 (1H, d, J=7,3 Hz), 7,26 (2H, users), 6,27 (1H, d, J=5.6 Hz), 6,21 (1H, d, J=7,3 Hz), 5,74 (1H, d, J=7,6 Hz), and 4.40 (1H, DD, J=a 13.9 Hz, J=7.9 Hz), 3.96 points is 3.76 (4H, m), 0,97-0,92 (13H, m), 0.67 and-0,58 (4H, m); FAB-LRMS m/z 381 (MH+). Analysis. Calculated for C17H28N4O4Si: C, 53,66; H, 7,42; N, 14,72. Found: C, 55,69; H, 7,16; N, 14,89; etc. 175°C (decomp.).

Example 4

5'-O-Cyclohexyldimethylamine-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (4)

The General procedure of example 1 was repeated using CNDAC (1,00 g of 3.96 mmol) and cyclohexyldimethylamine is a (808 ál, 4,36 mmol), resulting in compound 4 was obtained as a white solid (1,03 g, 66%).

1H-NMR (DMSO-d6) δ 7,71 (1H, d, J=7,6 Hz), 7,21 (2H, userd), to 6.19 (1H, d, J=5.3 Hz), x 6.15 (1H, d, J=7,3 Hz), of 5.68 (1H, d, J=7,6 Hz), 4,30 (1H, DD, J=a 13.9 Hz, J=7.9 Hz), 3,83-3,66 (4H, m)of 1.62 (5H, m), 1,14-1,01 (5H, m), 0,65 (1H, m)0,00 (6H, s); FAB-LRMS m/z 393 (MH+). Analysis. Calculated for C18H28N4O4Si: C, 55,08; H, 7,19; N, 14,27. Found: C, 54,96; H,? 7.04 baby mortality; N, 14,49; etc. 152-153°C.

Example 5

5'-O-(tert-Butyldiphenylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (5)

The General procedure of example 1 was repeated using CNDAC (1,00 g of 3.96 mmol) and tert-butyldiphenylsilyl (1,42 ml, 5,54 mmol), resulting in compound 5 was obtained as a white solid (1.68 g, of 3.42 mmol, 86%).

1H-NMR (DMSO-d6) δ of 7.70 (1H, d, J=7,6 Hz), to 7.64 (4H, m), 7,50-7,40 (6H, m), 7,27 (2H, d, J=7,6 Hz), 6,34 (1H, d, J=5.6 Hz), and 6.25 (1H, d, J=7,6 Hz), 5,59 (1H, d, J=7,6 Hz), 4,55 (1H, DD, J=of 13.7 Hz, J=7,6 Hz), 3,97-a-3.84 (4H, m)of 1.02 (9H, s); FAB-LRMS m/z 491 (MH+). Analysis. Calculated for C26H30N4O4Si: C, 63,65; H, 6,16; N, 11,42. Found: C, 63,38; H, 6,18; N, 11,60; etc. 187°C.

Example 6

5'-O-Dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (6)

The General procedure of example 1 was repeated using CNDAC (1,00 g of 3.96 mmol) and dimethylacrylamide (1,01 ml of 5.15 mmol), resulting in compound 6 was obtained as a white solid (905 mg, 58).

1H-NMR (DMSO-d6) δ of 7.60 (1H, d, J=7,3 Hz), to 7.15 (2H, userd), 6,14 (1H, d, J=5,9 Hz), between 6.08 (1H, d, J=7,3 Hz), 5,63 (1H, d, J=7,6 Hz), 4,24 (1H, DD, J=a 13.9 Hz, J=7,3 Hz), 3,79-of 3.64 (4H, m), for 1.49 (1H, m), 0.76 to 0,73 (12H, m), 0,07 that 0,00 (acwc. 6H, s); FAB-LRMS m/z 395 (MH+). Analysis. Calculated for C18H30N4O4Si: C, 54,80; H, 7,66; N, 14,20. Found: C, 54,54; H, 7,71; N, 14,12; etc. 188°C (decomp.).

Example 7

5'-O-Triisobutylene-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (7)

The General procedure of example 1 was repeated using CNDAC (1,00 g of 3.96 mmol) and triisobutylaluminum (1,28 ml of 4.75 mmol), resulting in compound 7 was obtained as a white solid (1.68 g, 94%).

1H-NMR (DMSO-d6) δ 7,73 (1H, d, J=7,6 Hz), 7,28 (2H, userd), to 6.22 (1H, d, J=5,9 Hz), to 6.19 (1H, d, J=7,3 Hz), 5,74 (1H, d, J=7,6 Hz), 4,37 (1H, DD, J=of 13.7 Hz, J=7,1 Hz), 3,89 is 3.76 (4H, m), of 1.80 (3H, m)0,93 (18H, m)to 0.63 (6H, m); FAB-LRMS m/z 451 (MH+). Analysis. Calculated for C22H38N4O4Si: C, 58,64; H, 8,50; N, 12,43. Found: C, 58,49; H, 8,59; N, 12,20; etc. 152°C.

Example 8

5'-O-Triphenylene-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (8)

The General procedure of example 1 was repeated using CNDAC (1,00 g of 3.96 mmol) and triphenylmethylchloride (1.40 g, of 4.75 mmol), resulting in compound 8 was obtained as a white solid (1,14 g, 56%).

1H-NMR (DMSO-d6) δ 7,62-7,42 (16H, m), 7.23 percent (2H, userd), 6,30 (1H, d, J=5.6 Hz), to 6.22 (1H, d, J=7,6 Hz), of 5.39 (1H, d, J=6.9 Hz), a 4.53 (1H, DD, J=a 13.9 Hz, J=7,6 Hz, 4,10-of 3.95 (2H, m), a-3.84 (2H, m); FAB-LRMS m/z 511 (MH+). Analysis. Calculated for C28H26N4O4Si: C, 65,86; H, 5,13; N, 10,97. Found: C, 65,26; H, 5,20; N, 10,89; etc. 203°C (decomp.).

Example 9

5'-O-Transiciel-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (9)

The General procedure of example 1 was repeated using CNDAC (1,00 g of 3.96 mmol) and tributyltinchloride (1,60 g of 4.75 mmol), resulting in compound 9 was obtained as a white solid (1.64 g, 75%).

1H-NMR (DMSO-d6) δ 7,40 (1H, d, J=7,6 Hz), 7.24 to 6,97 (17H, m), 6,24 (1H, d, J=5.8 Hz), 6,21 (1H, d, J=7,6 Hz), of 5.53 (1H, d, J=7,6 Hz), to 4.38 (1H, DD, J=13.5 Hz, J=7,6 Hz), 3,93 (1H, DD, J=11.7 Hz, J=2.1 Hz), 3,85-to 3.73 (3H, m), and 2.14 (6H, s). FAB-LRMS (negative) m/z 551 (M-H)-. Analysis. Calculated for C31H32N4O4Si: C, 67,37; H, Of 5.84; N, 10,14. Found: C, 67,12; H, 5,64; N, 10,54; etc. 188°C (decomp.).

Example 10

5'-O-(Dimethyl-n-octylsilane)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (10)

CNDAC (1,00 g of 3.96 mmol) was dissolved in N,N-dimethylformamide (hereinafter DMF) (40 ml), and then to the solution was added imidazole (593 mg, 8,72 mmol) and dimethyl-n-artilharia (1,04 ml, 4,36 mmol). The resulting mixture was stirred at room temperature for 3 hours in nitrogen atmosphere. The reaction mixture was distributed between ethyl acetate and water, the formed organic layer was washed with saturated saline solution, and then washed so the organization is practical layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on neutral silica gel (5-12% methanol/chloroform), resulting in compound 10 was obtained as a white solid (940 mg, 56%).

1H-NMR (DMSO-d6) δ 7,87 (1H, d, J=7,6 Hz), 7,34 (2H, userd), of 6.31 (2H, m), of 5.82 (1H, d, J=7,4 Hz), of 4.44 (1H, DD, J=a 13.4 Hz, J=7,7 Hz), 3,97-3,81 (4H, m)of 1.34 (12H, m)of 0.93 (3H, m)of 0.68 (2H, m)to 0.19 (6H, s); FAB-LRMS m/z 423 (MH+). Analysis. Calculated for C20H34N4O4Si·0,2H2O: C, 56,36; H, 8,14; N, 13,15. Found: C, 56,36; H, a 7.92; N, 13,67; etc. 142°C.

Example 11

5'-O-Dimethylphenylsilane-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (11)

The General procedure of example 10 was repeated using CNDAC (1,00 g of 3.96 mmol) and dimethylphenylsilane (723 μl, 4,36 mmol), resulting in compound 11 was obtained as a white solid (624 mg, 40%).

1H-NMR (DMSO-d6) δ 7,72 (1H, d, J=7,6 Hz), EUR 7.57 (2H, m), 7,41 (3H, m), 7,25 (2H, userd), 6,24 (1H, d, J=5.6 Hz), of 6.20 (1H, d, J=7,3 Hz), 5,64 (1H, d, J=7,6 Hz), to 4.38 (1H, m), 3,92-of 3.77 (4H, m), and 0.37 (6H, s); FAB-LRMS m/z 387 (MH+). Analysis. Calculated for C18H22N4O4Si·0,5H2O: C, 54,67; H, 5,86; N, 14,17. Found: C, 54,77; H, 7,80; N, 14,01; etc. 139-140°C.

Example 12

5'-O-Dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-ribofuranosylthiazole (12)

2'-Cyano-2'-deoxy-1-β-D-ribofuranosylthiazole triptorelin (55 mg, 0,150 mmol) was dissolved in DMF (0.5 ml), after which it is aStore was added imidazole (41 mg, 0,602 mmol) and dimethylethoxysilane (29,4 μl, 0.15 mmol). The resulting mixture was stirred at room temperature for 5 hours in nitrogen atmosphere. The reaction mixture was distributed between ethyl acetate and water, the formed organic layer was washed with saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on silica gel (7-10% methanol/chloroform), resulting in compound 12 was obtained as a white foam (59 mg, 100%).

1H-NMR (DMSO-d6) δ to 7.61 (1H, d, J=7,6 Hz), 7,32 (2H, users), of 6.29 (1H, d, J=5.6 Hz), 6,28 (1H, d, J=7,3 Hz), 5,74 (1H, d, J=7,6 Hz), 4.26 deaths-4,32 (1H, m), 3,91-of 3.95 (1H, m), 3,76 (1H, DD, J=3,6 Hz, J=11.5 Hz), 3,71 (1H, DD, J=3.6 Hz, J=11.5 Hz), 3,56-of 3.60 (1H, m), 1,53-to 1.63 (1H, m), 0,81 is 0.86 (12H, m)0,00 (6H, s); FAB-LRS m/z 395 (MN+). Analysis. Calculated for C18H30N4O4Si: C, 54,80; H, 7,66; N, 14,20. Found: C, 54,62; H, to 7.59; N, 14,47; etc. 187-187,5°C.

Example 13

5'-O-Dimethylacrylic-3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (13)

Compound 6 (79 mg, 0,200 mmol) was dissolved in DMF (2 ml), and then to the solution was added imidazole (54 mg, 0,793 mmol) and tert-butyldimethylsilyl (60 mg, 0.40 mmol), after which the mixture was stirred at room temperature for 24 hours under nitrogen atmosphere. The reaction mixture of distributed and between ethyl acetate and water, formed organic layer was washed with saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on silica gel (2% methanol/chloroform), resulting in compound 13 was obtained as a white foam (74 mg, 73%).

1H-NMR (DMSO-d6) δ a 7.62 (1H, d, J=7,6 Hz), 7,30 (2H, users), 6,23 (1H, d, J=7,6 Hz), 5,77 (1H, d, J=7,6 Hz), a 4.53 (1H, t, J=7,6 Hz)to 3.92 (2H, m), of 3.77 (2H, m)to 1.61 (2H, m)0,86 (21H, m)0,12 (12H, m); FAB-LRMS m/z 509 (MH+).

Example 14

3',5'-bis-O-dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (14)

CNDAC hydrochloride (3,40 g of 11.8 mmol) was dissolved in DMF (100 ml), then to the solution was added imidazole (5,42 g, 94,4 mmol) and dimethylethoxysilane (9,27 ml, to 47.2 mmol). The resulting mixture was stirred at 50°C for 20 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was distributed between ethyl acetate and water. Formed organic layer was washed with saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on silica gel (0-10% methanol/chloroform), resulting in compound 14 was obtained as a white foam (4,80 g, 76%).

1H-NMR (DMSO-d6) δ a 7.62 (1H, d, J=7,6 Hz), 7,29 (2H, users), 6,23 (1H, d, J=7,6 Hz), 5,77 (1H, d, J=7,6 Hz), a 4.53 (1H, DD, J=7,6 Hz, J=7,3 Hz), 3,91 (2H, m), 3,83-3,71 (2H, m)to 1.60 (2H, m), 0,85 (24H, m)0,14 (12H, m).

Example 15

3',5'-Bis-O-diethylenediamine-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (15)

The General procedure of example 13 was repeated using CNDAC (1,00 g of 3.96 mmol) and diethylazodicarboxylate (1,83 ml, 10.0 mmol), resulting in compound 15 was obtained as a white foam (1,96 g, 97%).

1H-NMR (DMSO-d6) δ 7,76 (1H, d, J=7,4 Hz), 7,34 (2H, users), 6,30 (1H, d, J=7,6 Hz), of 5.82 (1H, d, J=7,4 Hz), and 4.68 (1H, DD, J=7.7 Hz, J=7,4 Hz), a 4.03 (2H, m), a 3.87 (2H, m), 1,01 (26H, m)0,71 (8H, m); FAB-LRMS m/z 509 (MH+).

Example 16

3',5'-Bis-O-triisobutylene-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (16)

The General procedure of example 14 was repeated using CNDAC (1,00 g of 3.96 mmol) and triisobutylaluminum (3,22 ml of 12.0 mmol), resulting in compound 16 was obtained as a white foam (2,48 g, 96%).

1H-NMR (DMSO-d6) δ the 7.65 (1H, d, J=7,4 Hz), 7,30 (2H, userd), to 6.19 (1H, d, J=7,3 Hz), USD 5.76 (1H, d, J=7,4 Hz), 4,58 (1H, DD, J=6,9 Hz, J=6,8 Hz), a 3.87 (3H, m in), 3.75 (1H, DD, J=3.1 Hz, J=11.5 Hz), 1,88-1,72 (6H, m), 0,94 (36H, m), 0,75-0,59 (12H, m); FAB-LRMS m/z 649 (MH+).

Example 17

3',5'-Bis-O-(dimethyl-n-octylsilane)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (17)

The General procedure of example 14 was repeated using CNDAC (1,00 g of 3.96 mmol) and dimethyl-n-octyltin is chloride (2.38 ml, 10.0 mmol), resulting in compound 17 was obtained as a colourless oil (970 mg, 41%).

1H-NMR (DMSO-d6) δ 7,71 (1H, d, J=7,4 Hz), 7,26 (2H, user,d), to 6.19 (1H, d, J=7,4 Hz), 5,74 (1H, d, J=7,6 Hz)to 4.52 (1H, DD, J=7,6 Hz, J=7,7 Hz)to 3.92 (1H, DD, J=7.9 Hz, J=7,6 Hz), 3,86-to 3.67 (3H, m), 1,25 (24H, m)of 0.82 (6H, m)0,60 (4H, m), 0,10 (12H, m).

Example 18

3',5'-O-(Di-tert-butylsilane)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (18)

CNDAC (504 mg, a 2.01 mmol) and silver nitrate (747 mg, was 4.42 mmol) was dissolved in DMF (20 ml), and then to the solution was added di-tert-butylsilane(triftorbyenzola) (712 μl, 2.21 mmol) under cooling with ice. The reaction mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere, and then to the mixture was added triethylamine (612 μl, was 4.42 mmol)and the reaction mixture was stirred again for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was distributed between ethyl acetate and water. Formed organic layer was washed with water and saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was added chloroform, and the resulting solution was filtered through celite to remove insoluble substances. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel (2-5% of the methane is l/chloroform) followed by recrystallization from hexane, resulting compound 18 was obtained as a white solid (712 mg, 91%).

1H-NMR (DMSO-d6) δ 7,72 (1H, d, J=6.9 Hz), 7,33 (2H, userd), 6,44 (1H, users), 5,79 (1H, d, J=7,3 Hz)to 4.33 (2H, m)4,06 (2H, m), 3,81 (1H, m), 1,04, 0,97 (each 9H, each s); FAB-LRMS m/z 393 (MH+). Analysis. Calculated for C18H28N4O4Si·1,3H2O: C, 51,98; H, 7,42; N, 13,47. Found: C, 52,00; H, 6,98; N, 12,94; etc. 139-140°C.

Example 19

3'-O-Dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (19)

Compound 14 (5,11 g, 9,52 mmol) was dissolved in tetrahydrofuran (hereinafter THF) (50 ml). To the solution was added 80%aqueous solution triperoxonane acid (50 ml). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was thrice boiled with ethanol, and then to the solution was added chloroform. White solid deposited precipitate was obtained by filtration. The solid was dissolved in a solvent mixture of 10% methanol-chloroform, and the resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate. Formed organic layer was washed with water and saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was recrystallized from hexane, and thus the floor is Ali compound 19 as a white solid (3.04 from g, 81%).

1H-NMR (DMSO-d6) δ 7,79 (1H, d, J=7,6 Hz), 7,26 (2H, userd), to 6.19 (1H, d, J=7,6 Hz), 5,77 (1H, d, J=7,6 Hz), 5,19 (1H, DD, J=5.3 Hz, J=4.9 Hz), of 4.57 (1H, DD, J=6,9 Hz, J=7,3 Hz), 3,85 (1H, DD, J=7,6 Hz, J=7,3 Hz), 3,74 (2H, m)to 3.56 (1H, m)to 1.59 (1H, m), 0,84 (12H, m), 0,18, 0,15 (each 3H, each s); FAB-LRMS m/z 395 (MH+). Analysis. Calculated for C18H30N4O4Si: C, 54,80; H, 7,66; N, 14,20. Found: C, 54,54; H, of 7.70; N, 13,82; etc. 159-161°C.

Example 20

3'-O-Dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine methanesulfonate (20)

Compound 14 (3.00 g, 5,11 mmol), synthesized in a manner similar to example 14, except that the purification was not performed, was dissolved in ethanol (10 ml). To the solution was added methanesulfonyl acid (800 μl). The mixture was stirred at room temperature for 2.5 hours. Then to the reaction mixture were added ethyl acetate (10 ml), and white solid deposited precipitates were isolated by filtration, resulting in the received connection 20 in the form of a white solid (1.42 g, 57%).

1H-NMR (DMSO-d6) δ 9,58 (1H, users), 8,64 (1H, users), 8,23 (1H, d, J=7.9 Hz), 6,23 (1H, d, J=7,3 Hz), 6,17 (1H, d, J=7.9 Hz), 4,60 (1H, DD, J=7,6 Hz, J=7.9 Hz), 4,08 (1H, DD, J=7,6 Hz, J=7.9 Hz), 3,80 (2H, m)to 3.58 (1H, DD, J=3.6 Hz, J=12,5 Hz), is 2.37 (3H, c)to 1.59 (1H, m)of 0.85 (12H, m), 0,18, 0,16 (each 3H, each s); FAB-LRMS (negative) m/z 489 (M-H)-; The analysis. Calculated for C19H34N4O7SSi: C, 46,51; H, 6,98; N, 11,42. Found: C, 46,46; H, 7,02; N, 1,42; so 203-204°C.

Example 21

3'-O-Diethylenediamine-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (21)

To compound 15 (400 mg, 0.786 mmol) was added 80% aqueous solution of acetic acid (20 ml)and the mixture was stirred at room temperature for 5 hours. The reaction mixture was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. Formed organic layer is then washed with water and saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on neutral silica gel (2-15% methanol/chloroform)followed by recrystallization from hexane, the resulting compound 21 was obtained as a white solid (116 mg, 39%).

1H-NMR (DMSO-d6) δ 7,79 (1H, d, J=7,6 Hz), 7,25 (2H, userd), 6,17 (1H, d, J=7,3 Hz), 5,77 (1H, d, J=7,4 Hz), 5,20 (1H, t, J=5.3 Hz), 4,60 (1H, DD, J=6,9 Hz, J=6,8 Hz), 3,86 (1H, DD, J=6,9 Hz, J=7,3 Hz in), 3.75 (2H, m), 3,57 (1H, m), 0,97 (13H, m)0,66 (4H, m); FAB-LRMS m/z 381 (MH+). Analysis. Calculated for C17H28N4O4Si·0,7H2O: C, 51,94; H, RATE OF 7.54; N, 14,25. Found: C, 52,06; H, 7,33; N, 13,87; etc. 161-163°C.

Example 22

3'-O-Triisobutylene-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (22)

Compound 16 (1,30 g, 2.00 mmol) was dissolved in THF (16 ml). To a solution of obavljale 80%aqueous solution triperoxonane acid (4 ml), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. Formed organic layer is then washed with water and saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on silica gel (5-10% methanol/chloroform)followed by recrystallization from hexane, the resulting compound 22 was obtained as a white solid (270 mg, 30%).

1H-NMR (DMSO-d6) δ 7,80 (1H, d, J=7,6 Hz), 7,27 (2H, userd), 6,16 (1H, d, J=7,3 Hz), 5,78 (1H, d, J=7,4 Hz), to 5.21 (1H, DD, J=5.3 Hz, J=4.9 Hz), 4,63 (1H, DD, J=6,6 Hz, J=6.4 Hz), 3,85-3,71 (3H, m)to 3.58 (1H, m), is 1.81 (3H, m), of 0.95 (18H, m), is 0.69 (6H, m); FAB-LRMS m/z 451 (MH+). Analysis. Calculated for C22H38N4O4Si·0,7H2O: C, 57,04; H, TO 8.57; N, 12,09. Found: C, 56,98; H, 8,35; N, 11,96; etc. 101-102°C.

Example 23

3'-O-(Dimethyl-n-octylsilane)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (23)

Compound 17 (573 mg, 0,966 mmol) was dissolved in THF (5 ml). To the solution was added 50%aqueous solution of acetic acid (5 ml)and the resulting mixture was stirred for 20 minutes under ice cooling. The reaction mixture was dissolved in ethyl acetate and washed with saturated aq is m solution of sodium bicarbonate. Formed organic layer is then washed with water and saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on neutral silica gel (2-10% methanol/chloroform), resulting in compound 23 was obtained as a white solid (111 mg, 27%).

1H-NMR (DMSO-d6) δ 7,79 (1H, d, J=7,3 Hz), 7,26 (2H, userd), 6,18 (1H, d, J=7,3 Hz), 5,77 (1H, d, J=7,6 Hz)to 5.17 (1H, DD, J=5.3 Hz, J=4.9 Hz), 4,55 (1H, t, J=7,3 Hz), 3,86 (1H, DD, J=7,6 Hz, J=7,3 Hz), and 3.72 (2H, m), 3,56 (1H, m), 1,25 (12H, m), is 0.84 (3H, m)0,60 (2H, m)of 0.14 (6H, s); FAB-LRMS m/z 423 (MH+). Analysis. Calculated for C20H34N4O4Si: C, 56,84; H, 8,11; N, 13,26. Found: C, 56,83; H, 8,16; N, 13,12; etc. 153-154°C.

Example 24

4-N-(tert-Butoxycarbonyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (24a)

CNDAC (10.0 g, to 39.6 mmol) was dissolved in DMF (250 ml). To the solution was added di-tert-BUTYLCARBAMATE (26,0 g, 119 mmol)and the resulting mixture was stirred in an atmosphere of nitrogen for 28 hours at 50°C. the Reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5-10% methanol/chloroform), resulting in compound 24a was obtained as a white solid (8,30 g, 59%).

1H-NMR (DMSO-d6) δ of 10.47 (1H, s), 8,31 (1H, d, J=,6 Hz), 7,07 (1H, d, J=7.8 Hz), of 6.26 (1H, d, J=5.6 Hz), of 6.20 (1H, d, J=7,1 Hz), 5,24 (1H, m), 4,43 (1H, m), 3,90 (1H, m), 3,83 (1H, m), 3,76 (1H, m)to 3.64 (1H, m)of 1.47 (9H, s); FAB-LRMS m/z 353 (MH+). Analysis. Calculated for C15H20N4O6·1,3H2O: C, 47,95; H, THE 6.06; N, 14,91. Found: C, 48,04; H, 5,95; N, of 14.46; etc. 120-122°C (decomp.).

4-N-(tert-Butoxycarbonyl)-5'-O-dimethoxytrityl-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (24b)

Compound 24a (of 4.00 g of 11.4 mmol) was dissolved in pyridine (70 ml). To the resulting solution was added dimethoxyethane (4,65 g, 13.7 mmol)and the resulting mixture was stirred in nitrogen atmosphere at room temperature for 22 hours. The reaction was suppressed methanol, after which the solvent was removed under reduced pressure. The remainder of the double-boiled with toluene, after which the obtained product was dissolved in chloroform, followed by washing with water and then saturated saline solution. Then washed thus the organic layer was dried over anhydrous sodium sulfate and solvent was removed. The residue was purified by column chromatography on silica gel (0-2,5% methanol/chloroform), resulting in compound 24b was obtained as a yellow foam (6,64 g, 89%).

1H-NMR (DMSO-d6) δ 10,48 (1H, s), of 8.27 (1H, d, J=7.8 Hz), 7,35 (4H, m), 7,26 (5H, m), 6.90 to (5H, m), 6,40 (1H, d, J=5,9 Hz), 6,27 (1H, d, J=7,3 Hz), 4,60 (1H, DD, J=14.4 Hz, J=8.1 Hz), of 3.96 (1H, m in), 3.75 (6H, s), 3.46 in-3,36 (2H, m)of 1.46 (9H, s); FAB-LRMS (negative) m/z 653 (M-H)-.

Compound 24b (6,58 g, 10.1 mmol) was dissolved in DMF (60 ml). To the resulting solution were added imidazole (2,73 g of 40.3 mmol) and tert-butyldimethylsilyl (3.03 g, 20,1 mmol)and the resulting mixture was stirred in nitrogen atmosphere at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and then the residue was distributed between ethyl acetate and water. The organic layer was washed with saturated saline solution, followed by drying over anhydrous sodium sulfate. After removal of solvent the residue was added 80% aqueous solution of acetic acid, and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was thrice boiled with ethanol. The resulting mixture was distributed between ethyl acetate and water. Formed organic layer is then washed with water and saturated salt solution. Then washed thus the organic layer was dried over anhydrous sodium sulfate and solvent was removed. The residue was purified by column chromatography on silica gel (0-2% methanol/chloroform), resulting in compound 24c received in the form of a pale yellow foam (4.11 g, 88%).

1H-NMR (CDCl3) δ 8,03 (1H, d, J=7.9 Hz), 7,42 (1H, users), 7,31 (1H, d, J=7,6 Hz), and 6.25 (1H, d, J=6.6 Hz), 4,71 (1H, m)to 4.01 (2H, m), 3,85 (1H, m), 3,68 (1H, m), and 2.26 (1H, is IRS), is 1.51 (9H, s)of 0.91 (9H, s)of 0.18, and 0.15 (each 3H, each s); FAB-LRMS m/z 467 (MH+).

3'-O-(tert-Butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine triptorelin (24)

Compound 24c (620 mg, of 1.33 mmol) was dissolved in dichloromethane (10 ml). To the resulting solution was added triperoxonane acid (10 ml) under ice cooling, and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was dissolved in ethanol and concentrated under reduced pressure. The residue was thrice boiled with ethanol, followed by the addition of chloroform. White solid deposited precipitates were isolated by filtration, resulting in compound 24 was obtained as a white solid (560 mg, 88%).

1H-NMR (DMSO-d6) δ 8,91 (1H, users), to 8.25 (1H, users), 8,10 (1H, d, J=7.9 Hz), 6,21 (1H, d, J=7,3 Hz), 6,04 (1H, d, J=7.9 Hz), 4,59 (1H, DD, J=7.7 Hz, J=7,6 Hz), a 4.03 (1H, DD, J=7.9 Hz, J=7,4 Hz), 3,83-3,55 (4H, m)of 0.87 (9H, ), 0,14, 0,13 (each 3H, each s); FAB-LRMS (negative) m/z 479 (M-H)-. Analysis. Calculated for C18H27F3N4O6Si: C, 44,99; H, To 5.66; N, 11,66. Found: C, 44,89; H, to 5.58; N, of 11.61; etc. 163-165°C.

Example 25

4-N-(tert-Butoxycarbonyl)-5'-O-dimethoxytrityl-3'-O-dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (25a)

Compound 24b (1.20 g, to 1.83 mmol) was dissolved in DMF (15 ml). To the resulting solution were added imidazole (1.50 g, 29.4 mmol and dimethylethoxysilane (2,87 ml, 14.7 mmol)and the resulting mixture was stirred in nitrogen atmosphere for 40 hours at 50°C. the Reaction mixture was concentrated under reduced pressure, and the residue was distributed between ethyl acetate and water. Formed organic layer was washed with saturated saline solution, followed by drying over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate= 3:1 - 1:1), resulting compound 25a was obtained as a white foam (1.25 g, 86%).

1H-NMR (CDCl3) δ of 8.15 (1H, d, J=7,6 Hz), 7,43-7,22 (9H, m), 7,13 (1H, d, J=7,6 Hz)6,86 (4H, m), 6,33 (1H, d, J=6.3 Hz), of 4.67 (1H, t, J=5.6 Hz), 3,99 (1H, m), 3,81 (6H, s), 3,63 (2H, m)to 3.35 (1H, m)and 1.51 (9H, s), 0,77 (12H, m), 0,15, -0,07 (each 3H, each s); FAB-LRMS (negative) m/z 795 (M-H)-.

3'-O-Dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine triptorelin (25)

Compound 25a (1,23 g, 1.54 mmol) was dissolved in dichloromethane (10 ml). To the resulting solution was added triperoxonane acid (10 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was dissolved in ethanol and concentrated under reduced pressure. The residue was thrice boiled with ethanol, followed by the addition of chloroform. White solid deposited precipitates were isolated by filtration, resulting in CEG the compound 25 was obtained as a white solid (613 mg, 78%).

1H-NMR (DMSO-d6) δ 8,11 (1H, m), from 6.22 (1H, d, J=7,6 Hz), equal to 6.05 (1H, m), 4,59 (1H, t, J=7,6 Hz)to 4.01 (1H, t, J=7,6 Hz), of 3.78 (2H, m)to 1.59 (1H, m)of 0.85 (12H, m), 0,18, 0,16 (each 3H, each s); FAB-LRMS (negative) m/z 507 (M-H)-. Analysis. Calculated for C20H31F3N4O6Si·0,2H2O: C, 46,90; H, 6,18; N, 10,94. Found: C, 46,76; H, 6,10; N, 10,67; etc. 151-154°C.

Example 26

3'-O-Dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine hydrochloride (26)

Compound 25 (720 mg, of 1.42 mmol) was dissolved in 10% of a solvent mixture of methanol/chloroform (100 ml), followed by washing with a saturated aqueous solution of sodium bicarbonate (70 ml). Formed organic layer is then washed with water and saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was dissolved in chloroform (30 ml), and then to the solution was added dropwise 4 N. hydrochloric acid/dioxane (354 μl, of 1.42 mmol). Formed white precipitate was isolated by filtration, followed by washing with chloroform and drying, resulting in compound 26 was obtained as a white solid (552 mg, 91%).

1H-NMR(DMSO-d6) δ a 9.60 (1H, users), 8,59 (1H, users), 8,19 (1H, d, J=7,6 Hz), to 6.19 (1H, d, J=7,6 Hz), 6,16 (1H, d, J=7.9 Hz), of 4.57 (1H, t, J=7,6 Hz), Android 4.04 (1H, DD, J=7,6 Hz, J=7.9 Hz), of 3.77 (2H, m), 3,55 (1H, m)of 1.55 (1H, m,), 0,81 (12H, m), 0,15, 0,13 (each 3H, it is Edy C); FAB-LRMS (negative) m/z 429 (M-H)-. Analysis. Calculated for C18H31ClN4O4Si: C, 50,16; H, 7,25; N, 13,00. Found: C, 49,82; H, 7,31; N, 12,98; etc. 206°C (decomp.).

Example 27

4-N-(tert-Butoxycarbonyl)-5'-O-dimethoxytrityl-3'-O-triisopropylsilyl-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (27a)

Procedure for the synthesis of compound 25a was repeated, except that used the compound 24b (1.20 g, to 1.83 mmol) and triisopropylsilane (3,11 ml, 14.7 mmol), resulting in compound 27a was obtained as a white foam (1.07 g, 72%).

1H-NMR (CDCl3) δ of 8.27 (1H, d, J=7,6 Hz), 7,44-6,83 (15H, m), 6,32 (1H, d, J=6.3 Hz), 4,78 (1H, DD, J=4,6 Hz, J=4.3 Hz), 3,80 (6H, s)to 3.67 (2H, m), 3,37 (1H, m)and 1.51 (9H, s)0,97 (21H, m); FAB-LRMS (negative) m/z 809 (M-H)-.

3'-O-Triisopropylsilyl-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (27)

Compound 27a (1,05 g, 1,29 mmol) was dissolved in dichloromethane (10 ml). To the resulting solution was added triperoxonane acid (10 ml) under cooling with ice. The temperature of the reaction mixture was raised to room, after which the mixture was stirred for 90 minutes. The reaction mixture was dissolved in ethanol and concentrated under reduced pressure. The residue was thrice boiled with ethanol, and then the obtained residue was purified by column chromatography on silica gel (10% methanol/chloroform), resulting in the obtained white solid. P the obtained solid substance was dissolved in 10% solvent mixture methanol/chloroform, with subsequent washing with a saturated aqueous solution of sodium bicarbonate. Formed organic layer is then washed with water and saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate, followed by removal of solvent, the resulting compound 27 was obtained as a white foam (390 mg, 75%).

1H-NMR (DMSO-d6) δ 7,80 (1H, d, J=7,6 Hz), 7,26 (2H, userd), x 6.15 (1H, d, J=6.9 Hz), 5,77 (1H, d, J=7,6 Hz), 5,23 (1H, m), to 4.73 (1H, t, J=5,9 Hz), a-3.84 (1H, m), a-3.84 (2H, m in), 3.75 (1H, m), of 3.60 (1H, m), 1,60 (21H, m); FAB-LRMS m/z 409 (MH+). Analysis. Calculated for C19H32N4O4Si·0,8H2O: C, 53,95; H, 8,01; N, 13,25. Found: C, 53,85; H, 7,81; N, 13,01; etc. 162-163°C.

Example 28

3',5'-bis-O-dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-ribofuranosylthiazole (28)

2'-Cyano-2'-deoxy-1-β-D-ribofuranosylthiazole triptorelin (183 mg, 0,500 mmol) was dissolved in DMF (2 ml). To the resulting solution was added imidazole (204 mg, 3.00 mmol) and dimethylethoxysilane (295 μl, 1.50 mmol)and the resulting mixture was stirred in nitrogen atmosphere at 60°C for 13 hours. The reaction mixture was distributed between ethyl acetate and water, and the formed organic layer was washed with saturated saline solution, followed by drying over anhydrous sodium sulfate. The solvent was removed and the residue was purified using a column of chromatogr is the philosophy on silica gel (0-5% methanol/chloroform), resulting compound 28 was obtained as a white foam (248 mg, 92%).

1H-NMR (DMSO-d6) δ 7,58 (1H, d, J=7,3 Hz), 7,32 (2H, users), and 6.25 (1H, d, J=6.9 Hz), of 5.75 (1H, d, J=7,6 Hz), 4,46 (1H, DD, J=3,6 Hz, J=5.6 Hz), 3,91 (1H, DD, J=3,6 Hz, J=5.6 Hz), with 3.79 (2H, m)to 3.67 (1H, m), 1,60 (1H, m), 0,85 (24H, m), 0,18, 0,15 (each 3H, each s)of 0.11 (6H, s); FAB-LRMS m/z 537 (MH+)

Example 29

3'-O-Dimethylacrylic-2'-cyano-2'-deoxy-1-β-D - ribofuranosylthiazole (29)

Compound 28 (200 mg, 0,372 mmol) was dissolved in ethanol (1 ml). To the resulting solution was added water (100 ml) and methanesulfonyl acid (58 μl, 0.89 mmol)and the resulting mixture was stirred at 40°C for 3 hours. The reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. Formed organic layer is then washed with water and saturated saline solution, followed by drying over anhydrous sodium sulfate. After removal of solvent the residue was recrystallized from methanol-diisopropyl ether, resulting in compound 29 was obtained as a white solid (95 mg, 65%).

1H-NMR (DMSO-d6) δ of 7.70 (1H, d, J=7,4 Hz), 7,32 (2H, userd), of 6.29 (1H, d, J=7.9 Hz), 5,77 (1H, d, J=7,6 Hz), 5,19 (1H, t, J=5.3 Hz), of 4.54 (1H, DD, J=2.5 Hz, J=5.6 Hz), with 3.89 (1H, m), 3,74 (1H, DD, J=5.4 Hz, J=7.9 Hz), 3,54 (2H, m)to 1.61 (1H, m)of 0.87 (12H, m), 0,18, 0,15 (each 3H, each s); FAB-LRMS m/z 395 (MH+); so 179-182°C.

Example 30

3'-O-Demethylase silyl-2'-cyano-2'-deoxy-1-β-D-ribofuranosylthiazole methanesulfonate (30)

Compound 29 (52 mg, 0,131 mmol) was dissolved in methanol (150 ml). To the resulting solution was added methanesulfonyl acid (8,5 μl, 0.13 mmol)and the resulting mixture was stirred at 50°C for 5 minutes. Then to the reaction mixture was added butyl acetate (1.5 ml), followed by ice cooling. White solid deposited precipitates were isolated by filtration, resulting in compound 30 was obtained as a white solid (56 mg, 88%).

1H-NMR (DMSO-d6) δ at 9.53 (1H, users), 8,56 (1H, users), 8,10 (1H, d, J=7.8 Hz), 6,17 (1H, d, J=6,1 Hz), 6,13 (1H, d, J=7.8 Hz), of 4.57 (1H, DD, J=3,9 Hz, J=5.7 Hz), 3,99 (1H, DD, J=3.1 Hz, J=6.6 Hz), 3,88 (1H, t, J=5,9 Hz), 3,68 (1H, DD, J=3.1 Hz, J=12,4 Hz), of 3.56 (1H, DD, J=3.0 Hz, J=12,4 Hz), was 2.34 (3H, s)to 1.60 (1H, m)of 0.85 (12H, m), 0,18, 0,15 (each 3H, each s); FAB-LRMS (negative) m/z 489 (M-H)-; etc. 211-212°C.

Example 31

4-N-(tert-Butoxycarbonyl)-3'-O-dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (31a)

Procedure for the synthesis of compound 24c was repeated, except that used the compound 24b (3.00 g, 4,58 mmol) and dimethylethoxysilane (5,38 ml, a 27.4 mmol), resulting in compound 31a was obtained as a white foam (1.78 g, 79%).

1H-NMR (CDCl3) δ of 8.04 (1H, d, J=7,6 Hz), 7,45 (1H, users), 7,31 (1H, d, J=7,6 Hz), 6,28 (1H, d, J=6.3 Hz), to 4.73 (1H, t, J=5.0 Hz), Android 4.04 (2H, m), 3,91 (1H, m), 3,71 (1H, DD, J=4,6 Hz, J=6.3 Hz), of 2.16 (1H, m), and 1.54 (9H, ), of 0.90 (12H, s)of 0.26 and 0.22 (each 3H, each s).

4-N-(tert-Butoxycarbonyl who yl)-3'-O-dimethylacrylic-5'-O-[N-(tert-butoxycarbonyl)-L-valil]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (31b)

Compound 31a (742 mg, 1.50 mmol) was dissolved in dichloromethane (20 ml), after which the resulting solution was added Boc-L-Val-OH (652 mg, 3.00 mmol), EDC (575 mg, 3.00 mmol) and DMAP (9 mg, 0.08 mmol), and then the resulting mixture was stirred in nitrogen atmosphere at 0°C for 4 hours. The reaction mixture was distributed between ethyl acetate and water, and the formed organic layer was sequentially washed with water and saturated saline solution, followed by drying over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on silica gel (0-2% methanol/chloroform), resulting in compound 31b was obtained as a white foam (1.04 g, Quant.).

1H-NMR (CDCl3) δ of 7.97 (1H, d, J=7,6 Hz), 7,37 (2H, m), from 6.22 (1H, d, J=5,9 Hz), free 5.01 (1H, d, J=8,2 Hz), 4,56 (2H, m), the 4.29 (2H, m), 4,17 (1H, m), and 3.72 (1H, DD, J=5,9 Hz, J=3.0 Hz), to 2.15 (1H, m)and 1.51, 1,46 (each 9H, each s), 1,01 is 0.86 (18H, m), 0,21, 0,17 (each 3H, each s); FAB-LRMS m/z 694 (MH+).

3'-O-Dimethylacrylic-5'-O-(L-felled)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine-bis(triptorelin) (31)

Compound 31b (1,00 g, 1.44 mmol) was dissolved in dichloromethane (10 ml). Under ice cooling, to the resulting solution were added triperoxonane acid (10 ml) and the resulting mixture was stirred for 3 hours. The reaction mixture was dissolved in ethanol and concentrated under reduced pressure. The residue is repeatedly boiled with this is Nole, followed by purification using column chromatography on silica gel (5-15% methanol/chloroform), resulting in compound 31 was obtained as a white solid (812 mg, 78%).

1H-NMR (CDCl3) δ to 8.41 (2H, users), to 7.93 (1H, users), of 7.75 (1H, users), of 7.69 (1H, d, J=7,6 Hz), to 6.19 (1H, d, J=7.9 Hz), 5,88 (1H, d, J=7,6 Hz), and 4.75 (1H, t, J=7,6 Hz), of 4.54 (1H, m), to 4.38 (1H, m), 3,99 (3H, m), 2,17 (1H, m), 1,59 (1H, m)of 0.95 (6H, m)of 0.85 (12H, m), 0,21, 0,18 (each 3H, each s); FAB-LRMS m/z 494 (MH-2TFA)+. Analysis. Calculated for C27H41F6N5O9Si: C, 44,93; H, 5,73; N, 9,70. Found: C, 44,90; H, 6,18; N, 9,99; etc. 118-120°C.

Example 32

4-N-(tert-Butoxycarbonyl)-5'-O-[N-(tert-butoxycarbonyl)-L-valil]-3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (32a)

Compound 24c (700 mg, 1.50 mmol) was dissolved in dichloromethane (20 ml), after which the resulting solution was added Boc-L-Val-OH (652 mg, 3.00 mmol), EDC (575 mg, 3.00 mmol) and DMAP (9 mg, 0.08 mmol), and then the resulting mixture was stirred in nitrogen atmosphere at 0°C for 3 hours. The reaction mixture was distributed between ethyl acetate and water, and the formed organic layer was sequentially washed with water and saturated saline solution, followed by drying over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on silica gel (0-2% methanol/chloroform), resulting in the connection 32a which was lucali in the form of a white foam (1,02 g, the Quant.).

1H-NMR (CDCl3) δ 7,98 (1H, d, J=7.9 Hz), 7,38 (2H, m), 6,23 (1H, d, J=5,9 Hz), free 5.01 (1H, d, J=8,4 Hz), 4,56 (2H, m), 4,34-to 4.14 (3H, m), of 3.73 (1H, DD, J=5,9 Hz, J=2,8 Hz), to 2.15 (1H, m), 1,52, 1,46 (each 9H, each s), 1,01-0,91 (15H, m), 0,18, 0,14 (each 3H, each s); FAB-LRMS m/z 666 (MH+).

5'-O-(L-Felled)-3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine-bis(triptorelin) (32)

Compound 32a (960 mg, 1.44 mmol) was dissolved in dichloromethane (10 ml). Under ice cooling, to the resulting solution were added triperoxonane acid (10 ml)and the resulting mixture was stirred for 90 minutes. The reaction mixture was dissolved in ethanol and concentrated under reduced pressure. The residue is repeatedly boiled with ethanol, followed by purification using column chromatography on silica gel (5-15% methanol/chloroform), resulting in compound 32 was obtained as a white solid (682 mg, 68%).

1H-NMR (DMSO) δ 8,43 (2H, users), 7,79 (1H, users), to 7.67 (2H, m), 6,18 (1H, d, J=8,2 Hz), 5,86 (1H, d, J=7,6 Hz), and 4.75 (1H, m), a 4.53 (1H, m), to 4.38 (1H, DD, J=6,6 Hz, J=and 12.2 Hz), 3,99 (3H, m), 2,17 (1H, m)of 0.95 (6H, t, J=7,3 Hz)to 0.88 (9H, s), 0,17, 0,15 (each 3H, each s); FAB-LRMS m/z 466 (MH-2TFA)+; The analysis. Calculated for C25H37F6N5O9Si·0,3H2O: C, 42,95; H, 5,42; N, 10,02. Found: C, 42,86; H, of 5.89; N, 10,14; etc. 118-120°C.

Example 33

5'-O-(Di-tert-butylmethylether)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (33)

Di-Tr is t-butylmethylether (2.00 g, 12.6 mmol) was dissolved in dichloromethane (25 ml), and to the resulting solution at 0°C was added N-bromosuccinimide (2.14 g, 12,0 mmol), after which the resulting mixture was stirred at room temperature for an hour and a half. The solvent was removed under reduced pressure, and the residue was dissolved in DMF (6.3 ml). To the resulting solution was added CNDAC hydrochloride (1.45 g, 5,04 mmol) and imidazole (of 2.06 g, 30.2 mmol)and the resulting mixture was allowed to mix at room temperature overnight. The reaction mixture was distributed between ethyl acetate and water, and the formed organic layer was washed with saturated saline solution, followed by drying over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on neutral silica gel (0 to 9% methanol/chloroform)followed by recrystallization from methanol, the resulting compound 34 was obtained as a white solid (350 mg, 17%).

1H-NMR (DMSO-d6) δ 7,72 (1H, d, J=7,3 Hz), 7,38 (2H, userd), 6,28 (1H, d, J=5,9 Hz), 6,21 (1H, d, J=7,3 Hz), 5,74 (1H, d, J=7,3 Hz), of 4.44 (1H, DD, J=a 13.4 Hz, J=7.8 Hz), 3,98 (1H, m) 3,89-3,81 (3H, m), and 0.98 (18H, s), 0,11 (3H, C); FAB-LRMS m/z 409 (MH+); The analysis. Calculated for C19H32N4O4Si: C, 55,86; H, 7,89; N, 13,71. Found: C, 55,85; H, To $ 7.91; N, 14,11.

Example 34, 35

tert-Imidiatelly (34a)

Magnesium (2,43 g, 100 mmol) and iodine (catalytic amount) was added to the THF (20 ml), to the resulting solution under nitrogen atmosphere for 20 minutes was added dropwise tert-amiloride (12.3 ml, 100 mmol), after which the mixture was stirred at room temperature for 1 hour. After completion of the exothermic reaction the mixture was stirred at 50°C for 5 hours, resulting in a solution of tert-nilmanifold in THF.

Trichlorosilane (9,70 ml, for 96.1 mmol) was dissolved in THF (100 ml), and to the resulting solution at 0°C under nitrogen atmosphere was added dropwise a solution of ethylmagnesium in THF (0,93M, 200 ml, 186 mmol), then stirred at room temperature for 1 hour. To the mixture was added copper bromide (I) (286 mg, 2.00 mmol)and then dropwise within 30 minutes was added a previously prepared solution of tert-nilmanifold in THF (100 ml)and the resulting mixture was stirred at 70°C for 8 hours. The reaction mixture was cooled, and then to the resulting solution was added a saturated aqueous solution of ammonium chloride and n-pentane. Formed organic layer is washed three times with water and once with saturated saline solution, followed by drying over anhydrous sodium sulfate. The solvent was removed, followed by purification by distillation under reduced pressure, the resulting compound 34a was obtained as a colourless liquid (boiling point; 30 mm Hg, 95°C fraction, a 4.53 g, 30%).

1H-NMR (CDCl3) δ 3,47 (1H, m), 1,32 (2H, m), 1.04 million-of 0.93 (6H, m)of 0.91 (6H, s)0,86 (3H, t, J=7,6 Hz), and 0.61 (4H, m).

5'-O-(tert-Imidiatelly)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (34)

3',5'-Bis-O-(tert-imidiatelly)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (35)

Compound 34a (2.00 g, 12.6 mmol) was dissolved in dichloromethane (25 ml), and to the resulting solution at 0°C was added N-bromosuccinimide (2,90 g, 12.3 mmol)and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in DMF (5 ml). To the resulting solution was added CNDAC hydrochloride (1,11 g, a 3.87 mmol) and imidazole (1,72 g of 32.0 mmol)and the resulting mixture was allowed to mix at room temperature overnight. The reaction mixture was distributed between ethyl acetate and water, and the formed organic layer was washed with saturated saline solution, followed by drying over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on neutral silica gel (0 to 9% methanol/chloroform), in which the connection 34 (494 mg, 31%), and compound 35 (600 mg, 27%) was obtained as a white foam.

The connection 34

1H-NMR (DMSO-d6) δ 7,74 (1H, d, J=7,6 Hz), 7,27 (2H, userd), of 6.26 (1H, m), of 6.20 (1H, d, J=7,6 Hz), 5,73 (1H, d, J=7,3 Hz), 4,34 (1H, m), of 3.95 (1H, m), 3,86-of 3.78 (3H, m)of 1.34 (2H, q, J=7.8 Hz), 1.06 a is-0.97 (6H, m), 089 (6H, C), or 0.83 (3H, t, J=7.8 Hz), 0,69 (4H, q, J=7,8 Hz); FAB-LRMS (negative) m/z 407 (M-H)-.

The connection 35

1H-NMR (DMSO-d6) δ 7,63 (1H, d, J=7,3 Hz), 7,29 (2H, users), to 6.22 (1H, d, J=7,3 Hz), USD 5.76 (1H, d, J=7,3 Hz), of 4.66 (1H, t, J=6.6 Hz), 4,33 (1H, t, J=4.9 Hz), 3,91-of 3.85 (3H, m), 1,36-0,53 (42H, m); FAB-LRMS m/z 565 (MH+).

Example 36, 37

tert-Butyldimethylsilyl (36a)

Diisobutylaluminum in (18.0 ml, 100 mmol) was dissolved in THF (100 ml), and to the resulting solution under nitrogen atmosphere is added dropwise within 30 minutes was added a solution of chloride tert-butylamine in THF (1,0M, 100 ml). To the mixture was added copper bromide (I) (286 mg, 2.00 mmol), followed by stirring at 70°C for 8 hours. The reaction mixture was cooled, and added to the resulting solution saturated aqueous solution of ammonium chloride and n-pentane. Formed organic layer is washed three times with water and once with saturated saline solution, and rinsed thus layer was dried over anhydrous sodium sulfate. The solvent was removed, followed by purification by distillation under reduced pressure, the resulting compound 36a was obtained as a colourless liquid (boiling point; 27 mm Hg, 100°C fraction of 13.6 g, 68%).

1H-NMR (CDCl3) δ of 3.75 (1H, users), of 1.80 (1H, m)to 0.96 (12H, d, J=5.4 Hz), of 0.91 (9H, s)0,54 (4H, m).

5'-O-(tert-Butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (36)

3',5'-Bis-O-(tert-bout Diisobutylene)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (37)

Compound 36a (1.39 g, 6,92 mmol) was dissolved in dichloromethane (13,8 ml), and to the resulting solution at 0°C was added N-bromosuccinimide (1.20 g, of 6.75 mmol), then the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in DMF (2.3 ml). To the resulting solution was added CNDAC hydrochloride (500 mg, of 1.73 mmol) and imidazole (770 mg, 11.3 mmol), after which the mixture was allowed to mix at room temperature overnight. The reaction mixture was distributed between ethyl acetate and water, and the formed organic layer was washed with saturated saline solution, followed by drying over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on neutral silica gel (0 to 9% methanol/chloroform), in which the connection 36 (425 mg, of 0.94 mmol, 54%), and compound 37 (450 mg, 40%) was obtained as a white foam.

The connection 36

1H-NMR (DMSO-d6) δ to 7.68 (1H, d, J=7,3 Hz), 7,27 (2H, userd), 6,23 (1H, d, J=5,9 Hz), 6,18 (1H, d, J=7,3 Hz), 5,74 (1H, d, J=7,6 Hz), and 4.40 (1H, DD, J=7,6 Hz to 13.2 Hz), of 3.96 (1H, DD, J=3,9 Hz, 11.7 Hz), 3,85-of 3.78 (3H, m), 1,90-1,83 (2H, m)to 0.96 (12H, m)of 0.91 (9H, s), 0,86-0,62 (4H, m); FAB-LRMS (negative) m/z 449 (M-H)-.

The connection 37

1H-NMR (DMSO-d6) δ rate of 7.54 (1H, d, J=7,3 Hz), 7,25 (2H, userd), 6,09 (1H, d, J=7,3 Hz), 5,69 (1H, d, J=7,6 Hz), 4,63 (1H, m), 3,85-of 3.80 (4H, m)to 1.79 (4H, m)of 0.90 (12H, d, J=6.8 Hz), 0.88 to 9H, C)0,63 (8H, m); FAB-LRMS (negative) m/z 647 (M-H)-.

Example 38

Diethyl(3-methylpentan-3-yl)silane (38a)

Procedure for the synthesis of compound 34a was repeated, except that he used a solution of 3-methylpentan-3-nilmanifold in THF (100 ml), which was prepared from magnesium (2,43 g, 100 mmol) and 3-chloro-3-methylpentane (to 13.6 ml, 100 mmol), trichlorosilane (10.0 ml, of 99.1 mmol); and the solution ethylaniline in THF (0,93M, 200 ml, 190 mmol), resulting in compound 38a received in the form of a colorless liquid (boiling point; 39-42 mm Hg, 94-97°C fraction, 8,86 g, 51%).

1H-NMR (CDCl3) δ to 3.52 (1H, users), to 1.37 (4H, m), 1.04 million to 0.97 (9H, m), 0,90 is 0.84 (6H, m), and 0.62 (4H, m).

5'-O-[Diethyl(3-methylpentan-3-yl)silyl]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (38)

The procedure of synthesis of compound 34 was repeated, except that used the compound 38a (3,44 g, 20.0 mmol), N-bromosuccinimide (3,38 g, 19.0 mmol), CNDAC hydrochloride (2.30 g, of 7.97 mmol) and imidazole (1,30 g, 19.0 mmol), resulting in compound 38 was obtained as a white foam (300 mg, 0.71 mmol, 9%).

1H-NMR (DMSO-d6) δ 7,72 (1H, d, J=7,6 Hz), 7,26 (2H, userd), and 6.25 (1H, d, J=5.6 Hz), to 6.19 (1H, d, J=7,6 Hz), 5,74 (1H, d, J=7,3 Hz), 4,30 (1H, DD, J=7,6 Hz, J=13,4 Hz), of 3.96 (1H, DD, J=2.0 Hz, J=11.7 Hz), a 3.87-of 3.77 (3H, m), 1,47 to 1.31 (4H, m), 0,99 (6H, t, J=7.8 Hz), 0,86 (3H, s)0,81 (6H, t, J=7,3 Hz), 0,69 (4H, m); FAB-LRMS m/z 423 (MH+); The analysis. Calculated for C20H34N4O4Si: C, 56,84; H, 8,11; N, 13,26. Found: C, 55,61; H,8,15; N, 13,50.

Example 39

3'-O-(tert-Imidiatelly)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (39)

Compound 35 (600 mg, 1.06 mmol) was dissolved in methanol (1.8 ml)and the resulting solution was added methanesulfonyl acid (137 ml), after which the resulting mixture was stirred at room temperature for 2 hours. Then to the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the formed organic layer was sequentially washed with water and saturated saline solution, followed by drying over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on neutral silica gel (9% methanol/chloroform), resulting in compound 39 was obtained as a white foam (147 mg, 34%).

1H-NMR (DMSO-d6) δ 7,79 (1H, d, J=7,6 Hz), 7,27 (2H, userd), 6,16 (1H, d, J=7,6 Hz), 5,77 (1H, d, J=7,6 Hz), to 5.21 (1H, m)and 4.65 (1H, t, J=6.3 Hz), 3,85-3,59 (3H, m), of 3.60 (1H, m)of 1.34 (2H, q, J=7,6 Hz), and 1.00 (6H, m), 0.88 to (6H, s)of 0.82 (3H, t, J=7,6 Hz), 0,73 (4H, m); FAB-LRMS (negative) m/z 407 (M-H)-.

Example 40

Isobutyleneisoprene (40a)

Diisopropylaniline (16.4 ml, for 96.1 mmol) was dissolved in THF (100 ml), and to the resulting solution under nitrogen atmosphere is added dropwise within 30 minutes solution was added isobutylamine in THF (1,0M, 100 ml). Then to the mixture was added copper bromide (I) (286 mg, 2.00 in the mol), then the mixture was left to mix at 70°C overnight. The reaction mixture was cooled, and the resulting solution was added a saturated aqueous solution of ammonium chloride and n-pentane. Formed organic layer is washed three times with water and once with saturated saline solution, followed by drying over anhydrous sodium sulfate. The solvent was removed, followed by purification by distillation under reduced pressure, the resulting compound 40a was obtained as a colourless liquid (boiling point; 70 mm Hg, 102 to 106°C fraction, compared to 8.26 g, 50%).

1H-NMR (CDCl3) δ 3,49 (1H, m), of 1.80 (1H, m)of 1.05 (12H, m), and 0.98 (6H, m)to 0.88 (2H, m)of 0.56 (2H, m).

3',5'-Bis-O-isobutyleneisoprene-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (40)

Compound 40a (1,53 g of 8.90 mmol) was dissolved in dichloromethane (25 ml), and to the resulting solution at 0°C was added N-bromosuccinimide (1.54 g, 8,68 mmol), after which the resulting mixture was stirred at room temperature for 30 minutes. After the solvent was removed under reduced pressure, the residue was dissolved in DMF (2.3 ml), and to the resulting solution was added CNDAC hydrochloride (500 mg, of 1.73 mmol) and imidazole (770 mg, 11.3 mmol), after which the resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was distributed between ethyl acetate and water, and the formed organic layer PR is mawali saturated salt solution, followed by drying over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on neutral silica gel (5% methanol/chloroform), resulting in compound 40 was obtained as a white foam (910 mg, 88%).

1H-NMR (DMSO-d6) δ the 7.65 (1H, d, J=7,6 Hz), 7,29 (2H, userd), to 6.22 (1H, d, J=7,6 Hz), of 5.75 (1H, d, J=7,6 Hz), and 4.68 (1H, m), 3,98-a-3.84 (4H, m)of 1.84 (2H, m), 1,02 (28H, m)of 0.95 (12H, d, J=6.6 Hz), 0,66 (4H, m); FAB-LRMS m/z 593 (MH+).

Example 41

3'-O-Isobutyleneisoprene-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (41)

Procedure for the synthesis of compound 39 was repeated, except that used the connection 40 (400 mg, 0,675 mmol) and methanesulfonyl acid (87 μl, 1.3 mmol), resulting in compound 41 was obtained as a white foam (263 mg, 93%).

1H-NMR (DMSO-d6) δ 7,79 (1H, d, J=7,6 Hz), 7,27 (2H, userd), x 6.15 (1H, d, J=7,6 Hz), 5,77 (1H, d, J=7,6 Hz), with 5.22 (1H, m), and 4.68 (1H, t, J=6,1 Hz), 3,83 (2H, m), 3,74 (1H, m)to 3.58 (1H, m)of 1.84 (1H, m), 1,02-0,91 (20H, m)that was 0.68 (2H, m); FAB-LRMS (negative) m/z 421 (M-H)-.

Example 42

Diethyl(2-methylpentan-2-yl)silane (42a)

Procedure for the synthesis of compound 34a was repeated, except that he used a solution of chloride of 2-methylpentan-2-limagne in THF (100 ml), prepared from magnesium (2,43 g, 100 mmol) and 2-chloro-2-methylpentane (12.0 g, a 99.0 mmol), trichlorosilane (9,70 ml, for 96.1 mmol); and the solution ethylaniline in THF (0,93M, 200 ml, 1.86 m is ol), resulting compound 42a received in the form of a colorless liquid (boiling point; 40 mm Hg, 100-103°C fraction, 6,62 g, 40%).

1H-NMR (CDCl3) δ 3,47 (1H, m), 1.32 to to 1.21 (4H, m)to 0.96 (6H, t, J=8,1 Hz)to 0.92 (6H, s)to 0.88 (3H, t, J=6.5 Hz), 0,66-0,56 (4H, m).

3',5'-Bis-O-[diethyl(2-methylpentan-2-yl)silyl]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (42)

Procedure for the synthesis of compound 40 was repeated, except that used the compound 42a (2.76 g, 16.0 mmol), N-bromosuccinimide (2,77 g, 15.6 mmol), CNDAC hydrochloride (1,41 g of 4.90 mmol) and imidazole (2,18 g of 32.0 mmol), resulting in compound 42 was obtained as a white foam (1,67 g, 57%).

1H-NMR (DMSO-d6) δ a 7.62 (1H, d, J=7,3 Hz), 7,31 (2H, m), from 6.22 (1H, d, J=7,3 Hz), USD 5.76 (1H, d, J=7,6 Hz), of 4.66 (1H, m), 3,98-a-3.84 (4H, m), 1.26 in (8H, m), 1.06 a-0,84 (30H, m), 0,63 (8H, m); FAB-LRMS m/z 593 (MH+).

Example 43

3'-O-[Diethyl(2-methylpentan-2-yl)silyl]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (43)

Procedure for the synthesis of compound 39 was repeated, except that used the connection 42 (360 mg, 0,607 mmol) and methanesulfonyl acid (80 μl, 1.2 mmol), resulting in compound 43 was obtained as a white foam (55 mg, 11%).

1H-NMR (DMSO-d6) δ 7,71 (1H, d, J=7,3 Hz), 7,27 (2H, userd), 6,17 (1H, d, J=7,3 Hz), 5,78 (1H, d, J=7,3 Hz), 5,19 (1H, m), of 4.66 (1H, t, J=6.3 Hz), 3,85-of 3.54 (4H, m)of 1.28 (4H, m), of 1.03 to 0.97 (6H, m)to 0.88 (6H, s)of 0.82 (3H, t, J=7,6 Hz), 0,73 (4H, m); FAB-LRMS m/z 423 (MH+).

Example 44

Cyclopropylamino episilon (44a)

Procedure for the synthesis of compound 40a was repeated, except that used diisopropylaniline (4,10 ml, 96,0 mmol) and the solution cyclopropylmagnesium in THF (1,0M, 100 ml), resulting in compound 44a was obtained as a colourless liquid (boiling point; 35 mm Hg, 86-89°C fraction, 1.84 g, 50%).

1H-NMR (CDCl3) δ a 3.01 (1H, m)1,07 (14H, m), and 0.62 (2H, m), and 0.28 (2H, m), -0,46 (1H, m).

3',5'-Bis-O-cyclopropanedicarboxylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (44)

Procedure for the synthesis of compound 40 was repeated, except that used cyclopropylacetylene (1,05 g, 6,92 mmol), N-bromosuccinimide (1.20 g, of 6.75 mmol), CNDAC hydrochloride (500 mg, of 1.73 mmol) and imidazole (770 mg, 11.3 mmol), resulting in compound 44 was obtained as a pale yellow liquid (880 mg, 91%).

1H-NMR (CDCl3) δ 7,76 (1H, d, J=7,6 Hz), of 6.26 (1H, d, J=5,9 Hz), 5,74 (1H, d, J=7,6 Hz), a 4.03 (1H, m), 3,68 (1H, t, J=2,9 Hz), 1.04 million (28H, m), 0,67 (4H, m), 0,44 (4H, m), -0,38 (2H, m); FAB-LRMS m/z 561 (MH+).

Example 45

3'-O-Cyclopropanedicarboxylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (45)

Procedure for the synthesis of compound 39 was repeated, except that used the connection 44 (880 mg, 1.57 mmol) and methanesulfonyl acid (203 μl, 3.14 mmol), resulting in compound 45 was obtained as a white foam (240 mg, 38%).

1H-NMR (DMSO-d6) δ 7,79 (1H, d, J=7,3 Hz), 7,26 (2H, userd), 615 (1H, d, J=7,3 Hz), 5,77 (1H, d, J=7,6 Hz), 5,20 (1H, m), and 4.75 (1H, m), 3,85-to 3.73 (3H, m), 3,61 (1H, m), 1,01 (14H, m)to 0.63 (2H, m)to 0.39 (2H, m), -0,35 (1H, m); FAB-LRMS (negative) m/z 405 (M-H)-; The analysis. Calculated for C19H30N4O4Si: C, 56,13; H, 7,44; N, 13,78. Found: C, 55,41; H, 7,37; N, 13,95.

Example 46

3'-O-(tert-Butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (46)

Procedure for the synthesis of compound 39 was repeated, except that used the connection 37 (250 mg, 0,39 mmol) and methanesulfonyl acid (25 μl, 0,39 mmol), resulting in compound 46 was obtained as a white foam (50 mg, 29%).

1H-NMR (DMSO-d6) δ 7,79 (1H, d, J=7,3 Hz), 7,27 (2H, userd), 6,13 (1H, d, J=7,3 Hz), 5,77 (1H, d, J=7,6 Hz), with 5.22 (1H, m), 4,70 (1H, t, J=5,9 Hz), 3,86-with 3.79 (2H, m), 3,74 (1H, DD, J=4.9 Hz, J=12.3 Hz), 3,61 (1H, DD, J=4,2 Hz, J=12.3 Hz), 1,92-to 1.82 (2H, m), and 0.98 (12H, m)of 0.91 (9H, s), 0,86-0,62 (4H, m); FAB-LRMS (negative) m/z 449 (M-H)-.

Example 47

n-Butyldimethylsilyl (47a)

Diisopropylaniline (13.1 ml, with 76.8 mmol) was dissolved in THF (75 ml), and to the resulting solution under nitrogen atmosphere is added dropwise within 10 minutes, the solution was added n-butylacrylamide in THF (0,84M, 100 ml, 84 mmol). Then to the mixture was added copper bromide (I) (286 mg, 2.00 mmol), after which the mixture was stirred at 65°C for 8 hours. The reaction mixture was cooled, and the resulting solution was added a saturated aqueous solution of ammonium chloride and n-pentane. Education is p the organic layer washed three times with water and once with saturated salt solution, washed and thus layer was dried over anhydrous sodium sulfate. The solvent was removed, followed by purification by distillation under reduced pressure, the resulting compound 47a was obtained as a colourless liquid (boiling point; 50 mm Hg, 93,2-95,5°C fraction, 8,43 g, 64%).

1H-NMR (CDCl3) δ is 3.41 (1H, m), 1.41 to of 1.30 (4H, m), 1.06 a-1,01 (14H, m), 0,94 is 0.86 (3H, m), 0,64-0,57 (2H, m).

3',5'-Bis-O-(n-butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (47)

Compound 47a (2.17 g, 12.6 mmol) was dissolved in dichloromethane (25 ml), and to the resulting solution at 0°C was added N-bromosuccinimide (2,19 g, 12.3 mmol), after which the resulting mixture was stirred at room temperature for 30 minutes. After removal of the solvent under reduced pressure the residue was dissolved in DMF (5 ml). Then to the resulting solution was added CNDAC hydrochloride (1,11 g of 3.84 mmol) and imidazole (1,72 g of 25.2 mmol), after which the resulting mixture was stirred at 60°C for 7 hours. The reaction mixture was distributed between ethyl acetate and water, and the formed organic layer was washed with saturated saline solution, followed by drying over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on silica gel (0 to 9% methanol/chloroform), resulting in compound 47 was obtained as a white foam (522 mg, 23%).

1 H-NMR (DMSO-d6) δ of 7.60 (1H, d, J=7,3 Hz), 7.23 percent (2H, users), 6,18 (1H, d, J=7,3 Hz), 5,69 (1H, d, J=7,3 Hz), 4,60 (1H, t, J=7.8 Hz), 3,93-of 3.64 (4H, m), 1,29-of 1.24 (8H, m), 0,97-0,95 (28H, m), 0,81-of 0.79 (6H, m), 0,71-0,62 (4H, m); FAB-LRMS m/z 593 (MH+).

Example 48

3'-O-(n-Butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (48)

Compound 47 (522 mg, 0,880 mmol) was dissolved in methanol (1.5 ml)and the resulting solution was added methanesulfonyl acid (0.10 ml), the mixture was stirred at room temperature for 30 minutes. Then to the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was sequentially washed with water and saturated saline solution, followed by drying over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on neutral silica gel (11% methanol/chloroform), resulting in compound 48 was obtained as a white foam (179 mg, 48%).

1H-NMR (DMSO-d6) δ 7,79 (1H, d, J=7,4 Hz), 7,26 (2H, userd), 6,16 (1H, d, J=7,3 Hz), 5,77 (1H, d, J=7,4 Hz), to 5.21 (1H, users)and 4.65 (1H, t, J=6.4 Hz), 3,86-of 3.78 (3H, m), of 3.73 of 3.56 (1H, m), 1,01 (14H, m), 0,89 is 0.84 (3H, m), 0.74 and-is 0.69 (2H, m); FAB-LRMS m/z 423 (MH+).

Example 49

Aminobutiramida-n-propylsilane (49a)

The procedure of synthesis of compound 47a was repeated, except that he used a solution of n-propylaniline in THF (1,04M, 100 ml, 104 mmol), is the result of that connection 49a received in the form of a colorless liquid (boiling point; 60 mm Hg, 99,5-103,0°C fraction, 9,38 g, 62%).

1H-NMR (CDCl3) δ of 3.43 (1H, users), 1,53-of 1.40 (2H, m), 1.32 to 0,91 (14H, m), 0,64-0,57 (2H, m).

3',5'-Bis-O-(aminobutiramida-n-propulsion)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (49)

Procedure for the synthesis of compound 47 was repeated, except that used CNDAC hydrochloride (2,22 g of 7.69 mmol) and compound 49a (3,99 g of 25.2 mmol), resulting in compound 49 was obtained as a white foam (1,82 g, 42%).

1H-NMR (DMSO-d6) δ of 7.60 (1H, d, J=7,6 Hz), 7.23 percent (2H, users), 6,18 (1H, d, J=7,4 Hz), 5,69 (1H, d, J=7,6 Hz), 4,59 (1H, t, J=7,3 Hz), 3.96 points-a 3.87 (2H, m), 3,79-to 3.73 (2H, m), 1,40-1,17 (4H, m), 0,99-0,86 (28H, m), 0,68-0,57 (4H, m); FAB-LRMS m/z 565 (MH+).

Example 50

3'-O-(Aminobutiramida-n-propulsion)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (50)

Procedure for the synthesis of compound 48 was repeated, except that used the connection 49 (1,17 g 2,07 mmol), resulting in compound 50 was obtained as a white foam (381 mg, 45%).

1H-NMR (DMSO-d6) δ 7,79 (1H, d, J=7,4 Hz), 7,26 (2H, userd), 6,16 (1H, d, J=7,3 Hz), 5,77 (1H, d, J=7,4 Hz), 5,20 (1H, t, J=5,12)and 4.65 (1H, t, J=6.4 Hz), 3,86 of 3.56 (3H, m), 3,34-of 3.27 (1H, m), 1,46 is 1.34 (2H, m), 1.04 million-0,93 (17H, m)of 0.74 and 0.68 (2H, m); FAB-LRMS m/z 409 (MH+). Analysis. Calculated for C19H32N4O4Si: C, 55,86; H, 7,89; N, 13,71. Found: C, 55,44; H, To 7.84; N, 13,51.

Example 51

Aminobutiramida(2,2-dimethylpropyl)silane (51a)

Magnesium (2,43 g, 100 mmol) and iodine (catalytic amount) to allali to THF (100 ml), and then to the resulting solution was dropwise within 20 minutes was added 1-bromo-2,2-DIMETHYLPROPANE (10,7 ml, 100 mmol), after which the mixture was stirred at room temperature for 1 hour. After completion of the exothermic reaction the mixture was further stirred at 50°C for 5 hours, resulting in a prepared solution of 2,2-dimethylpropyleneurea in THF. Procedure for the synthesis of compound 47a was repeated, except that used the thus prepared mixture, resulting in a compound 51a was obtained as a colourless liquid (boiling point; 40 mm Hg, 120,0 is 122.5°C fraction of 7.65 g, 45%).

1H-NMR (CDCl3) δ of 3.60 (1H, users), 1,03-0,85 (23H, m), 0.67 and to 0.63 (2H, m).

3',5'-Bis-O-[aminobutiramida(2,2-dimethylpropyl)silyl]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (51)

Procedure for the synthesis of compound 47 was repeated, except that used CNDAC hydrochloride (550 mg, 1.92 mmol) and compound 51a (2.35 g, 12.6 mmol), resulting in compound 51 was obtained as a white foam (532 mg, 45%).

1H-NMR (CDCl3) δ 7,73 (1H, d, J=7,4 Hz), to 6.22 (1H, d, J=5.6 Hz), 5,73 (1H, d, J=7,4 Hz), of 4.77 (1H, users), 4,11-3,91 (3H, m), 3.72 points at 3.69 (1H, m), 1,12-0,98 (46H, m), 0,80-0,78 (4H, m); FAB-LRMS m/z 622 (MH+).

Example 52

3'-O-[Aminobutiramida(2,2-dimethylpropyl)silyl]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (52)

Procedure for the synthesis of compound 48 was repeated, except for the m, they used a connection 51 (512 mg, 0,824 mmol), resulting in compound 52 was obtained as a white foam (166 mg, 46%).

1H-NMR (CDCl3) δ for 7.78 (1H, d, J=7,4 Hz), 6,23 (1H, d, J=6.3 Hz), 5,78 (1H, d, J=7,4 Hz), 4.04 the-4,00 (2H, m), 3,85-with 3.79 (1H, m), 3,70-3,66 (1H, m), 1,10-1,00 (23H, m), or 0.57 (2H, users); FAB-LRMS m/z 437 (MH+). Analysis. Calculated for C21H36N4O4Si: C, 57,77; H, 8,31; N, 12,83. Found: C, 57,77; H, 8,35; N, 12,61.

Example 53

(3-Methylbutyl)diisopropylaniline (53a)

Procedure for the synthesis of compound 51a was repeated, except that used 1-bromo-3-methylbutane (of 12.6 ml, 100 mmol), resulting in compound 53 was obtained as a colourless liquid (12,6 g, 73%).

1H-NMR (CDCl3) δ is 3.41 (1H, users), 1,53-of 1.41 (1H, m), 1.30 and to 1.21 (2H, m), 1,10-0,91 (14H, m), 0,90-of 0.82 (6H, m), and 0.61-0,57 (2H, m).

3',5'-Bis-O-[(3-methylbutyl)diisopropylzinc]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (53)

Procedure for the synthesis of compound 47 was repeated, except that used CNDAC hydrochloride (520 mg, of 1.80 mmol) and compound 53a (2.35 g, 12.6 mmol), resulting in compound 53 was obtained as a white foam (515 mg, 46%).

1H-NMR (CDCl3) δ for 7.78 (1H, d, J=7,4 Hz), 6,30 (1H, d, J=5,9 Hz), 5,72 (1H, d, J=7,4 Hz), was 4.76 (1H, t, J=3,7 Hz), 4,01-3,86 (3H, m), 3,64-of 3.60 (1H, m), 1,52-1,49 (2H, m), 1,47 is 1.20 (4H, m), 1.06 a-1,00 (28H, m)to 0.89 (12H, d, J=5,1), 0,73 is 0.65 (4H, m); FAB-LRMS m/z 622 (MH+).

Example 54

3'-O-[(3-Methylbutyl)diisopropylzinc]-2'-cyano-2'-deoxy-1-β-D-Arabi is furnacecitation (54)

Procedure for the synthesis of compound 48 was repeated, except that used the connection 53 (500 mg, 0,805 mmol), resulting in compound 54 was obtained as a white foam (166 mg, 50%).

1H-NMR (DMSO-d6) δ 7,79 (1H, d, J=7,4 Hz), 7,28 (2H, userd), and 6.25 (1H, d, J=7,3 Hz), 5,74 (1H, d, J=7,4 Hz), 4,43 (1H, t, J=7.9 Hz), of 3.96 (1H, d, J=10,2 Hz), a 3.87-of 3.78 (3H, m), 1,50-to 1.38 (1H, m), 1,29-1,22 (2H, m), 1,02 (14H, c)0,86 (6H, d, J=6,4), 0,69-of 0.62 (2H, m); FAB-LRMS m/z 437 (MH+). Analysis. Calculated for C21H36N4O4Si: C, 57,77; H, 8,31; N, 12,83. Found: C, 57,79; H, 8,29; N, 12,83.

Example 55

5'-O-(n-Butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (55)

Compound 47a (500 mg, 2,90 mmol) was dissolved in dichloromethane (5.8 ml). To the resulting solution at 0°C was added N-bromosuccinimide (463 mg, 2,60 mmol) and the resulting mixture was stirred at room temperature for 2 hours. After the solvent was removed under reduced pressure, the residue was dissolved in DMF (2.5 ml)and the resulting solution was added CNDAC hydrochloride (500 mg, of 1.73 mmol) and imidazole (531 mg, 7,80 mmol), after which the mixture was allowed to mix at room temperature overnight. The reaction mixture was distributed between ethyl acetate and water. Formed organic layer was washed with saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removed the I solvent the residue was purified by column chromatography on silica gel (0 to 9% methanol/chloroform), resulting compound 55 was obtained as a white foam (351 mg, 48%).

1H-NMR (DMSO-d6) δ 7,76 (1H, d, J=7,4 Hz), 7,26 (2H, userd), of 6.26 (1H, d, J=5,9 Hz), 6,21 (1H, d, J=7,3 Hz), 5,73 (1H, d, J=7,4 Hz), 4,46-to 4.38 (1H, m), 3,95 (1H, d, J=9.6 Hz), 3,86-3,74 (3H, m), 1,36-of 1.30 (4H, m), 1,01 (14H, c)0,86-of 0.83 (3H, m), is 0.69 to 0.63 (2H, m); FAB-LRMS m/z 423 (MH+). Analysis. Calculated for C20H34N4O4Si: C, 56,84; H, 8,11; N, 13,26. Found: C, 56,10; H, A Total Of 8.74; N, 12,89.

Example 56

5'-O-[(3-Methylbutyl)diisopropylzinc]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (56)

Procedure for the synthesis of compound 55 was repeated, except that used CNDAC hydrochloride (491 mg, 1.70 mmol) and compound 53a (541 mg, 2,90 mmol), resulting in compound 56 was obtained as a white foam (379 mg, 51%).

1H-NMR (DMSO-d6) δ 7,76 (1H, d, J=7,4 Hz), 7,28 (2H, userd), and 6.25 (1H, d, J=7,3 Hz), 5,74 (1H, d, J=7,4 Hz), 4,43 (1H, t, J=7.9 Hz), of 3.96 (1H, d, J=10,2 Hz), a 3.87-of 3.78 (3H, m), 1,50-to 1.38 (1H, m), 1,29-1,22 (2H, m), 1,02 (14H, c)0,86 (6H, d, J=6,4), 0,69-of 0.62 (2H, m); FAB-LRMS m/z 437 (MH+). Analysis. Calculated for C21H36N4O4Si: C, 57,77; H, 8,31; N, 12,83. Found: C, 57,38; H, 8,21; N, 12,68.

Example 57

(2-Ethylbutyl)dicyclopropyl (57a)

Magnesium (2,43 g, 100 mmol) and iodine (catalytic amount) were added to THF (100 ml), and to the resulting solution under nitrogen atmosphere is added dropwise within 20 minutes was added 1-bromo-2-ethylbutane (13,8 ml, 100 mmol), after which the mixture was stirred at room temperature is round within 1 hour. After completion of the exothermic reaction the mixture was further stirred at 50°C for 5 hours, resulting in a was prepared solution of 2-ethylbutylamine in THF. Trichlorosilane (2,52 ml to 25.0 mmol) was dissolved in THF (26 ml), and to the resulting solution under nitrogen atmosphere is added dropwise at 0°C was added a solution of cyclopropylmagnesium in THF (0,50M, 100 ml, 50 mmol), after which the mixture was stirred at room temperature for 1 hour. To the mixture was added copper bromide (I) (286 mg, 2.00 mmol)and then dropwise within 30 minutes was added previously obtained a solution of 2-ethylbutylamine in THF (25,0 ml), after which the mixture was stirred at 70°C for 8 hours. The reaction mixture was cooled and was added to the resulting solution saturated aqueous solution of ammonium chloride and n-pentane. Formed organic layer is washed three times with water and once with saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. The solvent was removed, resulting in the connection 57a was obtained as a brown liquid (510 mg, 10%).

1H-NMR (CDCl3) δ 3,61-of 3.60 (1H, m), 1,38-of 1.30 (5H, m), 0,90 is 0.81 (6H, m), of 0.65 to 0.60 (6H, m), 0.37 to 0.31 in (4H, m), -0,45--of 0.51(2H, m).

5'-O-[(2-Ethylbutyl)dicyclopropyl]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (57)

Procedure for the synthesis of compound 55 was repeated, with the exception of the group, what used CNDAC hydrochloride (500 mg, of 1.73 mmol) and compound 57a (510 mg, 2,60 mmol), resulting in compound 57 was obtained as a white foam (309 mg, 40%).

1H-NMR (DMSO-d6) δ 7,74 (1H, d, J=7,4 Hz), 7,28 (2H, userd), and 6.25 (1H, d, J=5,9 Hz), 6,21 (1H, d, J=7,4 Hz), 5,77 (1H, d, J=7,4 Hz), 4,42-4,34 (1H, m), 3,99-of 3.77 (4H, m), 1,54-of 1.39 (1H, m), 1,36-of 1.29 (4H, m), 0,85-to 0.80 (6H, m), 0.60 and 0.50 in (6H, m), 0,40-0,32 (4H, m), -0,38--and 0.46 (2H, m); FAB-LRMS m/z 447 (MH+).

Example 58

Dicyclopentadiene (58a)

Trichlorosilane (2,52 ml to 25.0 mmol) was dissolved in THF (26 ml), and to the resulting solution under nitrogen atmosphere is added dropwise at 0°C was added a solution of cyclopropylmagnesium in THF (0,50M, 100 ml, 50 mmol), after which the mixture was stirred at room temperature for 1 hour. To the mixture was added copper bromide (I) (286 mg, 2.00 mmol)and the resulting solution was dropwise within 30 minutes was added isobutylamine (1,00M, 25,0 ml to 25.0 mmol), after which the mixture was stirred at 70°C for 8 hours. The reaction mixture was cooled, and the resulting solution was added a saturated aqueous solution of ammonium chloride and n-pentane. Formed organic layer is washed three times with water and once with saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. The solvent was removed, followed by purification by distillation under reduced pressure, the che is about connection 58a received in the form of a colorless liquid (boiling point; 20 mm Hg, 95-100°C fraction of 1.46 g, 35%).

1H-NMR (CDCl3) δ of 3.45 (1H, m), 1,91 is 1.86 (1H, m), 0,99-of 0.95 (6H, m), 0,63-0,57 (6H, m), 0,33-0,30 (4H, m), -0,43--of 0.51 (2H, m).

5'-O-Dicyclopentadienyl-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (58)

Procedure for the synthesis of compound 55 was repeated, except that used CNDAC hydrochloride (500 mg, of 1.73 mmol) and compound 58a (438 mg, 2,60 mmol), resulting in compound 58 was obtained as a white foam (247 mg, 34%).

1H-NMR (DMSO-d6) δ of 7.75 (1H, d, J=7,4 Hz), 7,27 (2H, userd), 6,24 (1H, d, J=5.8 Hz), of 6.20 (1H, d, J=7,6 Hz), 5,77 (1H, d, J=7,4 Hz), to 4.41-4,34 (1H, m), 3,98 is 3.76 (4H, m), 1.93 and-is 1.81 (1H, m), 1,03-of 0.94 (6H, m), 0.60 and 0.50 in (6H, m), 0,39-0,33 (4H, m), -0,36--of 0.51 (2H, m); FAB-LRMS m/z 419 (MH+).

Example 59

[3-(tert-Butoxy)propyl]diisopropylaniline (59a)

Procedure for the synthesis of compound 51a was repeated, except that used 1-bromo-3-(tert-butoxy)propane (of 5.40 g, 27.7 mmol), resulting in compound 59a was obtained as a brown liquid (3,10 g, 49%).

1H-NMR (CDCl3) δ 3,44 (1H, users), 1,58-of 1.53 (2H, m)of 1.26 (9H, c), 1,10-0,96 (16H, m), 0,83-0,78 (2H, m).

5'-O-{[3-(tert-Butoxy)propyl]diisopropylphenyl}-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (59)

Procedure for the synthesis of compound 55 was repeated, except that used CNDAC hydrochloride (1,11 g of 3.84 mmol) and compound 59a (2,90 g, 12.6 mmol), resulting in compound 59 was obtained as a white foam (425 mg, 3%).

1H-NMR (CDCl3) δ 7,86 (1H, d, J=7,4 Hz), 6,36 (1H, d, J=6.5 Hz), of 5.81 (1H, d, J=7,4 Hz)and 4.65 (1H, t, J=5,9 Hz), 4,10-3,93 (3H, m), 3,34-3,30 (1H, m), 1,66 is 1.58 (2H, m)and 1.15 (9H, c), 1,06 was 1.04 (16H, m), 0,73 is 0.67 (2H, m,); FAB-LRMS m/z 481 (MH+).

Example 60

Aminobutiramida(3-methoxypropyl)silane (60a)

1-Bromo-3-methoxypropane (9,18 g, 60,0 mmol) was dissolved in THF (55 ml)and the resulting solution was added magnesium (1,53 g, a 62.9 mmol) and iodine (catalytic amount), after which the mixture was stirred at room temperature for 20 minutes and at 55°C for 5 minutes. The resulting mixture is added dropwise within 5 minutes was added to diisopropylaniline (8,88 ml, with 52.0 mmol) in THF (65 ml), then stirred at room temperature for 1 hour. After completion of the exothermic reaction the mixture was further stirred at 50°C for 1.5 hours, and then to the resulting solution was added a saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with pentane, and then washed with water six times and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, resulting in the connection 60a was obtained as a yellow liquid (10.1 g, 89%).

1H-NMR (CDCl3) δ 3,44 (1H, users), the 3.35 (2H, t, J=6.6 Hz), 1.60-to 1,72 (2H, m), 0,97-1,03 (14H, m), 0,58-of 0.64 (2H, m).

5'-O-[Aminobutiramida(3-methoxypropyl)silyl]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (60)

Compound 60a (565 mg ,00 mmol) was dissolved in dichloromethane (6 ml), to the resulting solution at 0°C was added N-bromosuccinimide (534 mg, 3.00 mmol), after which the resulting mixture was stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure. The residue was dissolved in DMF (4.5 ml)and the resulting solution was added CNDAC hydrochloride (866 mg, 3.00 mmol) and imidazole (511 mg, 7,51 mmol), after which the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added methanol (0.1 ml)and the resulting mixture was separated between ethyl acetate and water. Formed organic layer was washed with saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was recrystallized from tert-butyl methyl ether, resulting in compound 60 was obtained as a white powder (820 mg, 62%).

1H-NMR (DMSO-d6) δ of 7.75 (1H, d, J=7,6 Hz), 7,27, 7,25 (each 1H, each users), and 6.25 (1H, d, J=5,9 Hz), 6,21 (1H, d, J=7,3 Hz), 5,73 (1H, d, J=7,6 Hz), of 4.38 is 4.45 (1H, m), 3,76-of 3.97 (4H, m), with 3.27 (2H, t, J=6.9 Hz), 3,20 (3H, c)and 1.51-to 1.61 (2H, m), 1,01 (14H, c), and 0.62 to 0.69 (2H, m).

Example 61

(3-Ethoxypropan)diisopropylaniline (61a)

1-Bromo-3-ethoxypropan (5,85 g 35,0 mmol) was dissolved in THF (30 ml). To the resulting solution was added magnesium (900 mg, up 37.0 mmol) and iodine (catalytic amount) and the resulting mixture was stirred at room temperature during 30 minutes and at 60°C for 10 minutes. The resulting mixture was added dropwise to diisopropylaniline (5,12 ml, 30.0 mmol) in THF (40 ml), after which the mixture was stirred at room temperature for 15 minutes and at 60°C for 1.5 hours. To the resulting solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with pentane, and then washed with water six times and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the resulting compound 61a was obtained as a yellow liquid (6,52 g, 92%).

1H-NMR (CDCl3) δ 3,36 of 3.75 (5H, m), 1,61-1,72 (2H, m)to 1.21 (3H, t, J=7.0 Hz), 0,97-1,03 (14H, m), 0,57 is 0.65 (2H, m).

5'-O-[(3-Ethoxypropan)diisopropylzinc]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (61)

Connection 61a (809 mg, 4.00 mmol) was dissolved in dichloromethane (8 ml), and to the resulting solution at 0°C was added N-bromosuccinimide (712 mg, 4.00 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure. The residue was dissolved in DMF (4.5 ml)and the resulting solution was added CNDAC hydrochloride (1.26 g, 4,36 mmol) and imidazole (681 mg, 10.0 mmol), after which the mixture was stirred at room temperature for 3 hours. After the reaction mixture was added methanol, and the resulting mixture was distributed between ethyl acetate and water. Formed organic layer about ivali saturated salt solution six times, and then washed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was recrystallized from tert-butyl methyl ether, resulting in the compound 61 was obtained as a white powder (1.10 g, 68%).

1H-NMR (DMSO-d6) δ of 7.75 (1H, d, J=7,4 Hz), 7,27, 7,25 (each 1H, each users), 6,21 (1H, d, J=5,9 Hz), 6,21 (1H, d, J=7,4 Hz), 5,73 (1H, d, J=7,4 Hz), 4,37 is 4.45 (1H, m), 3,76-3,98 (4H, m)to 3.38 (2H, q, J=6.9 Hz), 1,50-to 1.61 (2H, m), 1,01 (14H, c)of 0.62 and 0.68 (2H, m); FAB-LRMS (negative) m/z 451 (M-H)-.

Example 62

3'-O-[(3-Ethoxypropan)diisopropylzinc]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (62)

Connection 61a (1,82 g 8,99 mmol) was dissolved in dichloromethane (18 ml), and to the resulting solution at 0°C was added N-bromosuccinimide (1.60 g, 8,99 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in DMF (5 ml). Then to the resulting solution was added CNDAC hydrochloride (866 mg, 3.00 mmol) and imidazole (1,23 g of 18.1 mmol) and the resulting mixture was stirred at room temperature for 20 minutes and at 55°C for 2 hours. After the reaction mixture was added methanol, and the resulting mixture was distributed between ethyl acetate and water. Formed organic layer was washed with saturated saline solution six times, and then washed so about the time the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was dissolved in methanol (5 ml)and the resulting solution was added methanesulfonyl acid (0.33 ml, 4.5 mmol) and the mixture was stirred at 0°C for 30 minutes. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, after which the formed organic layer was washed with water and saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was purified by column chromatography on neutral silica gel (6-10% methanol/chloroform), resulting in compound 62 was obtained as a white foam (310 mg, 23%).

1H-NMR (DMSO-d6) δ 7,79 (1H, d, J=7,6 Hz), 7,29, 7,24 (each 1H, each users), 6,16 (1H, d, J=7,3 Hz), 5,77 (1H, d, J=7,6 Hz), to 5.21 (1H, t, J=5.4 Hz), 4,63-of 4.66 (1H, m), 3,79-a 3.87 (2H, m), 3,56-of 3.77 (2H, m), 3,39 (2H, q, J=7,1 Hz), 1,52 is 1.60 (2H, m)a 1.08 (3H, t, J=7,1 Hz), 1,01 (14H, c)of 0.67 to 0.70 (2H, m); FAB-LRMS (negative) m/z 451 (M-H)-.

Example 63

5'-O-[tert-Bathilde(3-ethoxypropan)silyl]-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (63)

Magnesium (330 mg, 13.5 mmol) and iodine (catalytic amount) were added to THF (13.5 ml), and to the resulting solution under nitrogen atmosphere is added dropwise within 20 minutes was added 1-bromo-3-ethoxypropan (2.25 g, 13.5 mmol) and the resulting mixture was stirred at room temperature for 1 hour. After the evershine exothermic reaction the mixture was further stirred at 50°C for 4 hours. In nitrogen atmosphere at 0°C the mixture was added dropwise to tert-butyldichlorosilane (1.06 g, of 6.75 mmol) and copper bromide (I) (20 mg, 0.14 mmol) in THF (6.75 ml), after which the mixture was stirred at 70°C for 8 hours. The reaction mixture was cooled, and the resulting solution was added a saturated aqueous solution of ammonium chloride and n-pentane. Formed organic layer is washed three times with water and once with saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of the solvent the obtained yellow liquid was dissolved in dichloromethane (7,4 ml), and to the resulting solution at 0°C was added N-bromosuccinimide (642 mg, 3.61 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in DMF (3.3 ml)and the resulting solution was added CNDAC hydrochloride (530 mg, of 1.85 mmol) and imidazole (378 mg, 5,55 mmol), after which the mixture was allowed to mix at 60°C overnight. Then to the reaction mixture was added methanol, and the resulting mixture was distributed between ethyl acetate and water. Formed organic layer was washed with saturated saline solution, and then rinsed thus the organic layer was dried over anhydrous sodium sulfate. After removal of solvent the residue was purified through to Nochnoi chromatography on neutral silica gel (0-5% methanol/chloroform), resulting compound 63 was obtained as a yellow foam (310 mg, 23%).

1H-NMR (DMSO-d6) δ 7,71 (1H, d, J=7,6 Hz), 7,29, 7,25 (each 1H, each users), 6,27 (1H, m), of 6.20 (1H, d, J=7,6 Hz), 5,73 (1H, d, J=7,6 Hz), to 4.38 (1H, m), of 3.94 (1H, DD, J=2,2, J=11.7 Hz), 3,86 of 3.75 (3H, m), 3,37 (4H, q, J=7,1 Hz), 3,29 (2H, q, J=7,1 Hz), and 3.16 (1H, d, J=5.4 Hz), and 1.56 (4H, m)of 1.07 (6H, t, J=7,1 Hz)of 0.91 (9H, c)0,63 (4H, m); FAB-LRMS m/z 509 (MH+).

Structural formulas of compounds 1-63 obtained in the above examples, are shown in tables 1-11.

Table 1
ConnectionThe structural formula
1
2
3
4
5
6

Table 2
The connection is giving The structural formula
7
8
9
10
11
12

Table 3
ConnectionThe structural formula
13
14
15
16
17
18

Table 4
ConnectionThe structural formula
19
20
21
22
23
24

Table 5
ConnectionThe structural formula
25
26
27
28
29
30

Table 6
ExampleThe structural formula
31
32
33
34
35
36

Table 7
ExampleThe structural formula
37
38
39
40
41
42

Table 8
ExampleThe structural formula
43
44
45
46
47

Table 9
ExampleThe structural formula
48
49
50
51
52
53

Table 10
ExampleThe structural formula
54
55
56
57
58
59

Table 11
ExampleThe structural formula
60
61
62
63

Example pharmacological test 1

Antitumor test using subcutaneous implantation of the "Nude" mouse by oral administration CNDAC compound

Cancer cells human colon strain KM20C subcutaneously vaccinated mice BALB/cA Jcl-nu (CLEA Japan, Inc.), and the resulting tumor tissue was cut into slices with a thickness of 2 mm, Each of the fragments subcutaneously implanted in the back of the mouse BALB/cA Jcl-nu 6 weeks of age. On day 14 after implantation were measured at the largest and smallest diameters of the obtained tumor, and tumor volume was calculated from the following equation. Mice were divided into groups (6 animals per group) so that the groups were approximately equal in value to the average volume of the tumor.

(Equation 1) Vt=1/2(Vl)·(Vs)2

In this equation Vt denotes tumor volume, Vl denotes the largest diameter of the tumor, and Vs represents the smallest diameter of the tumor.

Each CNDAC compound was dissolved or suspended in 0.5% solution is hydroxypropylmethylcellulose, which balanced 100 mm citrate buffer (pH 6,0). From the next day after the groups are formed, the mixture is administered orally to each mouse once a day for the next 14 days at a dose that is equivalent, in molar ratio, 18 mg/kg/day CNDAC.

On day 29 after the formation of the groups was measured at the largest and smallest diameters of subcutaneously implanted tumors in each mouse, as well as, to assess the antitumor effect of the compounds, using the following equations to calculate the relative tumor volume (RTV) and the rate of inhibition (IR). The results of the tests are presented in table 12.

(Equation 2) RTV=Vt1/Vt2

In this equation RTV denotes the indicator of tumor volume, Vt1 denotes tumor volume measured on the day of analysis, and Vt2 represents the tumor volume measured on the day of formation of the group.

(Equation 3) IR (%)=[1-(RTVtest)/(RTVcont)]×100

In this equation IR denotes the index of inhibition of tumor growth, RTVtest represents the average RTV group, which was administered the drug and RTVcont represents the median RTV in the untreated group.

Table 12
Example No.IR (%)
1 75
265
382
682
779
1068
1869
1989
2185
2483
2785
3189
3285
CNDAC46

As shown in table 12, the compounds of the present invention exhibit excellent anti-tumor effect compared to CNDAC.

Example pharmacological test 2

Pharmacokinetic test CNDAC compound on the Donryu rats

CNDAC compound orally was administered to Donryu rats (Charles River Laboratories Japan, Inc., 5 weeks of age), and then measured the levels of CNDAC in the blood. CNDAC compound possessing excellent absorption ability when administered orally and formed what about the transformer in active CNDAC in the body, was chosen on the basis of levels of CNDAC in the blood.

In particular, from the evening of the day before the test day Donryu rats did not receive food. On the morning of the test day, each CNDAC compound (equimolar amount, up to 30 mg/kg CNDAC) was dissolved or suspended in 0.5% solution of hydroxypropylmethylcellulose, balanced 100 mm citrate buffer (pH 5.0), and then administered orally, and then from the caudal Vena cava after 15 and 30 minutes, and after 1, 2, 4 and 8 hours after administration blood samples were taken, resulting in the obtained serum samples from 3 animals at each time point). The levels of compounds and CNDAC in each serum sample was measured using HPLC. To calculate the area under the curve of concentration of CNDAC in blood (AUC) from 0 to 8 hours, and the following equation was determined bioavailability (BA), which specifies the number of CNDAC, get into the blood from the total number of CNDAC compound. The results of the tests are shown in table 13.

(Equation 4) BA=[(AUCtest)/(AUCcont)]·100 (%)

In this equation VA denotes the bioavailability, AUCtest AUC denotes the level of CNDAC in the blood by oral administration CNDAC compound (in an amount equivalent to 30 mg/kg CNDAC), and AUCcont represents the AUC level CNDAC in the blood with the introduction of CNDAC into the tail vein (in an amount equivalent to 30 mg/kg CNDAC).

Table 13
Example No.BA (%)
219,4
320,6
622,9
1019,3
1945,1
2122,8
2319,3
2421,0
2542,6
2623,5
27to 25.3
3141,4
3224,2
CNDAC
P-CNDAC
9,2
14,6

As shown in table 13, the compounds of the present invention exhibit excellent bioavailability in comparison with the known CNDAC compound when administered orally - P-CNDAC.

Example pharmacological test 3

Pharmacokinetic test CNDAC compound on rats SD(IGS)

CNDAC sedimentwater orally to rats SD (IGS) (Charles River Laboratories Japan, Inc., age 8 weeks), and then measured the levels of CNDAC in the blood. CNDAC compound possessing excellent absorption ability when administered orally and is easily transformed into an active CNDAC in the body, was chosen on the basis of levels of CNDAC in the blood.

On the morning of the test day, each CNDAC compound (equimolar amount, up to 10 mg/kg CNDAC) was dissolved or suspended in 0.5% solution of hydroxypropylmethylcellulose, balanced 100 mm citrate buffer (pH 5.0), and then administered orally, and then from the carotid artery after 30 minutes and after 1, 2, 4, 6 and 8 hours after administration blood samples were taken, resulting in the obtained serum samples (from 2-3 animals at each time point). The levels of compounds and CNDAC in each serum sample was measured using LC/MS. To calculate the area under the curve of concentration of CNDAC in blood (AUC) from 0 to 8 hours. The results of the tests are shown in table 14.

Table 14
Example No.AUC 0-8 h
(ng·h/ml)
191163
451210
CNDAC492
-CNDAC 956

As shown in table 14, the compounds of the present invention show higher AUC compared with the known CNDAC compound for oral administration - P-CNDAC.

Example pharmacological test 4

Antitumor test using subcutaneous implantation of the "Nude" mouse by oral administration CNDAC, P-CNDAC or connection 19 in equitoxic dose

Cancer cells human colon strain KM20C subcutaneously has perestal mice BALB/cA Jcl-nu (CLEA Japan, Inc.), and the resulting tumor tissue was cut into slices with a thickness of 2 mm, Each of the fragments subcutaneously implanted in the back of the mouse BALB/cA Jcl-nu 6 weeks of age. On the 15th day after implantation were measured at the largest and smallest diameters of the obtained tumor, and tumor volume was calculated from the following equation. Mice were divided into groups (6 animals per group) so that the groups were approximately equal in value to the average volume of the tumor.

(Equation 5) Vt=1/2(Vl) · (Vs)2

In this equation Vt denotes tumor volume, Vl denotes the largest diameter of the tumor, and Vs represents the smallest diameter of the tumor.

CNDAC, P-CNDAC or compound 19 was dissolved or suspended in 0.5% solution of hydroxypropylmethylcellulose that balanced 100 mm citrate buffer (pH 6,0). With the following the day after the groups are formed, the mixture is administered orally to each mouse once a day for the next 14 days in equitoxic dose.

The largest and smallest diameters of subcutaneously implanted tumors in each mouse was measured twice a week, then, to assess the antitumor effect of the compounds of the following equations to calculate the relative tumor volume (RTV) as an indicator, showing the growth of the tumor. The results of the tests shown in the drawing.

(Equation 6) RTV=Vt1/Vt2

In this equation RTV denotes the indicator of tumor volume, Vt1 denotes tumor volume measured on the day of analysis, and Vt2 represents the tumor volume measured on the day of formation of the group.

As shown in the drawing, equitations the dose of a compound 19 significantly reduces tumor volume compared to CNDAC and P-CNDAC. While CNDAC and P-CNDAC not cause the disappearance of the tumor, the connection 19 removes the tumor in three cases out of all six, confirming that the compound of the present invention shows superior antitumor effect.

Example compositions 1

Pills

tr>
Table 15
Connection 350 mg
Corn starch50 mg
Microcrystalline cellulose50 mg
Hydroxypropylcellulose15 mg
Lactose47 mg
Talc2 mg
Magnesium stearate2 mg
Ethylcellulose30 mg
Unsaturated glycerides2 mg
Titanium dioxide2 mg

Tablets (250 mg/tablet) were prepared in accordance with the above formulation using a conventional method.

Example composition 2

Granules

Table 16
Connection 19300 mg
Lactose540 mg
Corn starch100 mg
Hydroxypropylcellulose50 mg
Talc10 mg

Pellets (1000 mg/sachet) were prepared in accordance with the above R is captures using a conventional method.

An example of the composition 3

Capsules

Table 17
The connection 20100 mg
Lactose30 mg
Corn starch50 mg
Microcrystalline cellulose10 mg
Magnesium stearate3 mg

Capsules (193 mg/capsule) were prepared in accordance with the above formulation using a conventional method.

An example of the composition 4

Injection

Table 18
Connection 21100 mg
Sodium chloride3.5 mg
Distilled water for injectionThe corresponding dose
(2 ml/ampoule)

The solution for injection were prepared in accordance with the above formulation using a conventional method.

An example of the composition 5

Syrup

Table 19
Connection 27200 mg
Purified sucrose60 g
ethyl para-hydroxybenzoate5 mg
butyl para-hydroxybenzoate5 mg
Flavoring additiveThe appropriate number
DyeThe appropriate number
Purified waterThe appropriate number

The syrup prepared in accordance with the above formulation using a conventional method.

An example of the composition 6

Suppositories

Table 20
The connection 32300 mg
Witepsol W-35 (registered trademark, a mixture of mono-, di - and triglycerides of saturated fatty acids - lauric and stearic, product of Dynamite Nobel Co.)1400 mg

Suppositories prigoda ivali in accordance with the above formulation using a conventional method.

1. Pyrimidine nucleoside compound represented by the following formula (1):

in which one of X and Y is cyano and the other is a hydrogen atom;
R1represents a hydrogen atom, a group (R3)(R4)(R5Si - or carbonyl group, including C1-C6 alkyl group, which monogamist amino group;
R2represents a hydrogen atom or a group (R6)(R7)(R8Si-, provided that at least one of R1and R2is not hydrogen; or
R1and R2together form a 6-membered cyclic group,- Si (R9)(R10)-, where each R9and R10represents a C1-C6 linear or branched alkyl group;
R3, R4and R5represent a C1-C10 linear or branched alkyl group which may be substituted by C1-C6 alkoxygroup, or C3-C6 cycloalkyl group;
R6, R7and R8represent a C1-C10 linear or branched alkyl group which may be substituted by C1-C6 alkoxygroup, C3-C6 cycloalkyl group or phenyl,
or its pharmacologically acceptable salt.

2. Pyrimidine nucleoside compound or its pharmacologically acceptable salt according to claim 1, where one of X and Y is cyano and the other is an atom is odorata; R1represents a hydrogen atom, a group (R3)(R4)(R5Si - or carbonyl group, including C1-C6 alkyl group, which monogamist amino group; R2represents a hydrogen atom or a group (R6)(R7)(R8Si-, provided that at least one of R1and R2is not hydrogen; or R1and R2together form a 6-membered cyclic group,- Si (R9)(R10)-; R3, R4and R5represent a C1-C8 linear or branched alkyl group which may be substituted linear or branched C1-C6 alkoxygroup, or C3-C6 cycloalkyl group; R6, R7and R8represent a C1-C8 linear or branched alkyl group which may be substituted linear or branched C1-C6 alkoxygroup, C3-C6 cycloalkyl group or phenyl.

3. Pyrimidine nucleoside compound or its pharmacologically acceptable salt according to claim 1, where one of X and Y is cyano and the other is a hydrogen atom; R1is a hydrogen atom, valley group or group (R3)(R4)(R5Si-; R2is a hydrogen atom or a group (R6)(R7)(R8)Si (in the case when R1is a hydrogen atom or valley group, R2is not a hydrogen atom); and R 3, R4, R5, R6, R7and R8that may be the same or different from each other, are C1-C8 linear or branched alkyl group or C3-C6 cycloalkyl group.

4. Pyrimidine nucleoside compound or its pharmacologically acceptable salt according to claim 1, where one of X and Y is cyano and the other is a hydrogen atom; R1is a hydrogen atom, L-valley group or group (R3)(R4)(R5Si-; R2is a hydrogen atom or a group (R6)(R7)(R8)Si (in the case when R1is a hydrogen atom or L-valley group, R2is not a hydrogen atom); and any R3, R4and R5and any R6, R7and R8that may be the same or different from each other are C3-C8 linear or branched alkyl group or cyclopropene group, and other groups which may be the same or different from each other, represent a C1-C4 linear or branched alkyl group.

5. Pyrimidine nucleoside compound or its pharmacologically acceptable salt according to claim 1, where one of X and Y is cyano and the other is a hydrogen atom; R1is a hydrogen atom, L-valley group, triisopropylsilyl group of diethylether pisellino group, dimethylethoxysilane group or dimethyl-n-octylsilane group; R2is a hydrogen atom, a tert-butyldimethylsilyloxy group, triisopropylsilyl group, diethylethanolamine group, cyclopropanecarbonitrile group or dimethylethoxysilane group (in the case when R1is a hydrogen atom or L-valley group, R2is not a hydrogen atom).

6. Pyrimidine nucleoside compound selected from the following (a)to(k), or its pharmacologically acceptable salt:
(a) 5'-O-triisopropylsilyl-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;
(b) 5'-O-diethylenediamine-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;
(c) 5'-O-dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;
(d) 5'-O-(dimethyl-n-octylsilane)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;
(e) 3'-O-dimethylacrylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;
(f) 3'-O-diethylenediamine-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;
(g) 3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;
(h) 3'-O-triisopropylsilyl-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;
(i) 3'-O-dimethylacrylic-5'-O-(L-felled)-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine;
(j) 5'-O-(L-felled)-3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-deoxy-1-β-D-arabinofuranose is cytosine; and
(k) 3'-O-cyclopropanedicarboxylic-2'-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine.

7. The antitumor agent comprising an effective amount of the pyrimidine nucleoside compound according to any one of claims 1 to 6, or its pharmacologically acceptable salt and a pharmaceutically acceptable carrier.

8. The use of pyrimidine nucleoside compounds according to any one of claims 1 to 6, or its pharmacologically acceptable salts for the manufacture of a medicinal product for the treatment of tumors.

9. A method of treating tumors, comprising introducing an effective amount of the pyrimidine nucleoside compound according to any one of claims 1 to 6, or its pharmacologically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to the method of producing 2'-desoxy-β-L-thymidine, which involves reacting 5'-O-trityl- or 5'-O-dimethoxytrityl- substituted 2,2' -anhydro-1 -β-L- arabinofuranosylthymine with a reducing agent RedAl and a complexing agent 15-crown-5-ether in a polar solvent 1,2-dimethoxyethane (DME) or tetrahydrofuran, obtaining 5'-O-trityl- or 5'-O-dimethoxytrityl- substituted 2,2'-desoxy-β-L-thymidine, subjected to protection removal if necessary. The invention also relates to the method of producing 2'-desoxy-β-L-thymidine, which involves reacting L-arabinose with cyanamide with subsequent reaction of the intermediate product - L-arabinofuranosylaminooxazoline - with a cycling or condensing agent, forming 2,2' -anhydro-1-β-L-arabinofuranosylthymine; reaction of the latter with a reducing agent RedAl and a complexing agent 15-crown-5-ether in a polar solvent 1,2-dimethoxyethane (DME) or tetrahydrofuran, obtaining 2'-desoxy-β-L-thymidine, where L-arabinofuranosylaminooxazoline can be protected by trityl or dimethoxytrityl in position 5' before or after reaction with the cycling or condensing agent; and protection removal of optionally protected 2'-desoxy-β-L-thymidine, if this is necessary or desired. Use in the given methods of such a reducing agent as Red-Al, and such a complexing agent as 15-crown -5-ether, causes a reaction of intramolecular protection and production of the required nucleoside product with good output.

EFFECT: compound is of great importance as an antiviral or antineoplastic preparation.

13 cl, 29 dwg, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining enriched with β-anomer 2'-desoxy-2',2'-difluorocytidine of formula (I)

, which includes stages: (i) interaction of enriched with α-anomer compound of 1-halogenribofuranose of formula (III) with nucleic base of formula (IV) in solvent obtaining enriched with β-anomer nucleoside of formula (II) , with constant removal of formed in reaction process silylhalogenide of formula R3SiX (V) by distillation using carrier or running inert gas through reaction mixture; and (ii) removal of protective group from enriched with β-anomer nucleoside of formula (II). Invention also relates to method of obtaining hydrate of enriched with β-anomer 2'-desoxy-2',2'-difluorocytidine of formula (I), which at stage (ii) after removal of protective group additionally includes stages of dissolving formula (I) nucleoside in water; heating of obtained solution to temperature from 40 to 60°C; cooling of solution to temperature ranging from 10 to 25°C with or without mixing and without changing pH; and filtering of deposited solid substances.

EFFECT: method improvement.

17 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to (2'R)-2'-dezoxy-2'-fluoro-2'-C-methylnucleoside (β-D or (β-L) , where X represents O; R1 and R7 independently represent H; R3 represents hydrogen and R4 represents NH2; or its pharmaceutically acceptable salt. The invention also pertains to the method of producing the said compounds, which involves glycosylation of N4-benzoylcytosine with a compound of formula 1-4, where R represents methyl, Pg is chosen from C(O)Ph, CH2Ph or both Pg groups can be included in 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene); with further removal of protection of 3'-OPg and 5'-OPg and N-benzoyl of the obtained product.

EFFECT: invented compounds or their pharmaceutically acceptable salts are used as active ingredients against Flaviviridae family viruses in pharmaceutical compositions and liposomal pharmaceutical compositions.

4 cl, 9 tbl, 5 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: claimed invention relates to method of gemcitabine hydrochloride purification, which includes enriching gemcitabine hydrochloride with its p-anomer, according to which solution of gemcitabine hydrochloride in water is taken with ratio of water to gemcitabine hydrochloride from 3:1 to 12:1 (wt/vol); solution is processed with activated coal, activated coal being taken in amount from 0.1 to 10 wt % of gemcitabine hydrochloride amount in solution; activated coal is removed from solution with formation of filtered solution; concentration of gemcitabine hydrochloride in filtered solution is increased until ratio of filtered solution to gemcitabine hydrochloride equals from 1:1 to 1:5 (wt/vol), efficient for gemcitabine hydrochloride sedimentation; deposited gemcitabine hydrochloride is isolated; and in case admixture content in deposited gemcitabine hydrochloride is not reduced to required level, stages (a)-(e) are repeated. Claimed invention also relates to method of obtaining gemcitabine hydrochloride using claimed purification method.

EFFECT: creation of efficient method of gemcitabine hydrochloride purification.

5 cl, 1 tbl, 5 dwg, 8 ex

FIELD: medicine, pharmacology, bioorganic chemistry, pharmacy.

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

EFFECT: enhanced and valuable medicinal properties of agent.

83 cl, 6 tbl, 11 ex

FIELD: organic chemistry, biochemistry, medicine, virology.

SUBSTANCE: invention relates to derivatives of 2'=amino-2'-deoxynucleosides of the formula:

wherein R means hydrogen atom (H), alkyl, aminoalkyl; R1 means -(R2NR3) wherein R2 and/or R3 means H, -OH, -NH2, alkyl, benzyl under condition that R doesn't represent H or methyl when R2 and R3 mean H. Compounds elicit an antiviral activity with respect to measles and Marburg viruses exceeding that of ribavirin.

EFFECT: valuable properties of compounds.

4 tbl, 2 dwg, 18 ex

The invention relates to a derivative of gemcitabine formula (I), where R1, R2, R3independently selected from hydrogen and C18and C20saturated and monounsaturated acyl groups, provided that R1, R2, R3can't all be hydrogen

The invention relates to the chemistry of nucleosides, in particular to an improved method for the preparation of 3'-azido-2',3'-dideoxythymidine (azidothymidine, AZT), used in medicine as an antiviral drug for the treatment of patients suffering from acquired immunodeficiency syndrome (AIDS)

The invention relates to a method for obtaining enriched beta-anomer nucleoside of the formula I, where T is fluorine and R is the corresponding nucleoside described in paragraph 1 of the formula
The invention relates to the synthesis of nucleosides and relates to an improved method for the preparation of 3'-azido-2',3'-dideoxythymidine with the ability to suppress the reproduction of human immunodeficiency virus and finds application in medical practice for the treatment of AIDS

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on CDK1 kinase. In formula I , R1 is hydrogen or R2-(X)n-; X is a lower alkylene or cyclic lower alkylene; R2 denotes ; where denotes phenyl; cycloalkyl containing 3-6 carbon atoms; 4-6-member heterocycloalkyl ring having 3-5 carbon atoms and 1-2 oxygen atoms; R5, R6 and R7 are independently selected from a group containing hydrogen or halide; R4 is hydrogen or -(O)k(CH2CH2O)y-R10; R19 is hydrogen; R20 is hydrogen or -C(O)-R11; R10 and R11 is a lower alkyl; n and k are equal to 0 or 1; y is an integer from 0 to 3.

EFFECT: obtaining a pharmaceutical composition with inhibitory effect on CDK1 kinase, containing one or more of the disclosed compounds.

15 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts and esters. The disclosed compounds have inhibitory effect on cyclin-dependant kinase. In formula I R1 denotes , R3 is selected from a group consisting of H, CO2R6, C(O)R6, SO2R6 and SO2NR5R6, R5 and R6 are each independently selected from a group which includes H and (lower)alkyl, R2 is phenyl which contains one, two or three substitutes independently selected from a group which includes halogen or -O-(lower)alkyl.

EFFECT: preparation of a pharmaceutical composition which contains an effective amount of a formula I compound as an active ingredient.

6 cl, 1 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to experimental medicine and can be applied for amplification of apoptosis or cytolytic activity in cells of mammals. Method and application by invention include bringing mammalian cells in contact with effective quantity of Apo- 2-ligand receptors agonist and resting or unprocessed NK-cells, said agonist is selected from Apo-2-ligand polypeptide, agonistic DR5 antibody and agonistic DR4 antibody.

EFFECT: application of inventions allows amplification of apoptosis and cytolysis induction in tumour cells due to activation by Apo-2-ligand receptors agonist of resting NK-cells.

26 cl, 1 tbl, 18 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, pharmaceutical industry and deals with novel medications used for treatment of dysplastic processes of the cervix and rectum mucosa. Medication for treatment of dysplastic processes of the cervix and rectum mucosa, in form of suppository is characterised by the following: it contains 3,3'-diindolylmethane, epigallocatechin-3-gallate, as well as catalyst of epigallocatechin-3-gallate inhibiting activity with respect to DNA-methyltransferases, representing cations Mg2+ in form of pharmaceutically acceptable magnesium salt, lipophilic base, which contains hard fat, polyvinylpyrrolidone and butylhydroxyanisol and/or butylhydroxytoluol.

EFFECT: medication has efficient impact in case of severe forms of dysplastic injuries.

4 cl, 3 dwg, 5 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to biotechnology and immunology. An antibody against angiopoietin-2 is proposed. Versions of the antibody are disclosed, which are produced by hybridome ATCC PTA-7258, ATCC PTA-7259, ATCC PTA-7260. The corresponding coding nucleic acid and expression vector are disclosed. A host cell which produces the antibody based on the said vector is described. The disclosed antibodies have Kd of the order of 10-10-10-12 M, for the antibody 3.19.3 (from ATCC PTA-7260) IC50=99 nM. The said antibody properties can be used in treating human tumours.

EFFECT: design of a method of treating pathological angiogenesis based on an antibody and use of the antibody to prepare a medicinal agent for treating pathological angiogenesis.

33 cl, 18 dwg, 18 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of general formula: , where R1 - C1-C6alkyl, C1-C6alkoxy, halogen, CN, C(O)NH2 or OCH2CH2OCH3; R2-C1-C6alkyl, possibly substituted with halogen, a halogen, C1-C6alkoxy, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, where n equals 1 or 2; m equals 2 or 3; R6 -R7 -C1C6alkyl, and R8 -OCH2CH2OCH3; or R7 and R8 together with the nitrogen atom to which they are bonded form a 6-member heterocycle which additionally contains one oxygen atom or one nitrogen atom, which in the latter case is substituted with C1-C4alkyl; or R1 and R2 together form a 5-member heterocyclic ring system containing two oxygen atoms as heteroatoms; R3 - hydrogen or C1-C6alkyl; R4 - hydrogen, halogen or C1-C6alkoxy; or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these compounds.

EFFECT: obtaining novel compounds with kinase inhibiting properties, particularly CDK2, or angiogenesis inhibiting properties and can be used in treating malignant growths, particularly in mammary glands, large intestines, lungs and prostate glands.

60 cl, 7 tbl, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): or pharmaceutically acceptable salts thereof, where X is CH; R1 is phenyl or a 6-member heteroaryl which contains 1 or 2 nitrogen atoms as heteroatoms, independently and optionally substituted with up to five groups J; R2 and R3 each independently represents hydrogen, halogen, -V-R or -V-Ra; R5 is R; R is H or an optionally substituted C1-6aliphatic group, where the substitutes are selected from -OR0, phenyl, substituted R0, -N(R0)2; where each independent R0 is selected from hydrogen, halogen, C1-6aliphatic group; Ra is morpholine, V is a bond or Q; Q is -NR5-; each J group independently represents a halogen, -N(R5)2. The invention also relates to a pharmaceutical composition with protein kinase inhibiting properties, and to methods of inhibiting Aurora A protein kinase using the said compounds.

EFFECT: obtaining novel compounds and pharmaceutical compositions based on the said compounds, which can be used in medicine to treat or alleviating a proliferative disorder, such as cancer, in a patient.

25 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel 1,2,3-triazole derivatives of general formula: , where X denotes O or N-OH; R1 is hydrogen, fluorine, chlorine, bromine, phenyl or C1-4-alkyl, unsubstituted or substituted 1-3 times with fluorine, chlorine and bromine; R2 - R5 hydrogen; pharmaceutically acceptable salts and stereoisomers thereof and a pharmaceutical composition containing the said compounds.

EFFECT: obtaining compounds which can be used as oestrogen receptor selective modulators for treating or preventing different conditions related to oestrogen function, including: bone loss, bone fracture, osteoporosis, metastatic bone disease, Piaget's disease, periodontal disease etc.

5 cl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology, and can be used for conservative treatment and relapse prevention of virus-associated precancer and early cancer cervix. Photodynamic therapy is carried out for this purpose. A compound photosense is used as a photosensitiser. The energy density of laser radiation is 150 J/cm2. At that the cervical canal is affected with a quartz light guide with a cylindrical diffuser. The vaginal area of cervix is affected with microlens.

EFFECT: method enables to achieve treatment effect equivalent to surgical due to neutralisation of etiological factor of cervical carcinogenesis, to carry out surgical service at aggravated somatic status, to avail of the opportunity of full generative function.

2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and deals with anticancer therapeutic medicine, which presents composition, containing α,α,α-trifluorothymidine (FTD) and 5-chlor-6-(1-(2-iminopyrrolidine)methyl)uracyl hydrochloride in molar ratio 1:0.5, and which is introduced to patient, who needs it, in dose, as in dose for FTD, 20-70 mg/m2 /day two times per day - four times per day.

EFFECT: invention ensures anticancer therapeutic medicine of increased efficiency and safety.

12 cl, 2 ex, 2 dwg

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