Derivative of 3Т-ethynilcytidine

FIELD: biochemistry.

SUBSTANCE: invention refers to derivatives of 3'-ethynilcytidine represented by the formula (1); (where X is hydrogen atom, alkylcarbonyl group where alkyl fragment is non-branched or branched C1-C6alkyl group which can include as substitute(s) mono-or di-substituted with non-branched or branched C1-C6alkyl group aminogroup or alkoxycarbonyl group where alkoxy-fragment is a branched or non-branched C1-C6 alkoxygroup; One of Y and Z is a hydrogen atom or group (R1)(R2)(R3)Si-, and another is a group (R4)(R5)(R6)Si-; and each R1, R2, R3, R4, R5 and R6 that may be similar or different are non-branched or branched C1-C10 alkyl group or C6-C14aryl group) or to its salts. The invention also refers to the derivative of 3'-ethynilcytidine chosen out of compounds (1)-(17), to the pharmaceutical composition, to oncologic drug, to oral oncologic drug, to the use of derivative of 3'-ethynilcytidine, and to the method of tumor treatment.

EFFECT: new biologically active compounds with antitumor activity.

14 cl, 18 ex, 12 tbl

 

The technical FIELD TO WHICH the INVENTION RELATES

The present invention relates to derivatives of 3'-ethinicities having excellent antitumor effects.

BACKGROUND of INVENTION

Cancer, which is characterized by an abnormal proliferation of cells, remains intractable disease, therefore, urgently needed to develop therapeutic agent effective for treatment. Based on the knowledge that for cell proliferation required biosynthesis of nucleic acids, were conducted intensive studies with the aim of obtaining antagonist metabolism, can inhibit the metabolism of nucleic acids. To the present time have been developed antagonists metabolism on the basis of cytidine that are currently used in the clinic for cancer treatment. For example, as such antagonists can be mentioned cytarabine (non-patent document 1), ancitabine (non-patent document 2) and gemcitabine (patent document 1), which possess antitumor activity through inhibition of DNA synthesis. While containing 3'-ethnicities (ECyd) nucleoside 3'-ethynylpyridine that was developed by Matsuda et al., known as antagonist metabolism of nucleic acids that can inhibit the synthesis of the NC (patent document 2 and non-patent documents 3 and 4).

It is known that ECyd has excellent antitumor effect, more pronounced than any of the medicines on the basis of ftorpirimidinu, in relation to 5 lines of gastric cancer, 3 lines of colon cancer, 2 lines, pancreatic cancer, and 1 line of esophageal cancer, bile duct cancer, lung cancer, breast cancer and kidney cancer, as evidenced by way of application, including its intravenous administration (0.25 mg/kg continuously for 10 days) "Nude" mice with subcutaneously transplanted tumor cells (non-patent documents 5 and 6).

However, with such intravenous drugs there are problems, such as mental and physical pain in cancer patients and higher costs associated with outpatient treatment. If it would be possible to replace such intravenous drug orally injected drugs and to ensure almost the same therapeutic effect, it is considered that the quality of life (QOL) of patients will improve dramatically. However, when administered orally ECyd, most likely, has a significantly less high antitumor effect compared with intravenous administration. Therefore, there is an increased demand for the development of oral input medicines obladaushih the antitumor activity, equivalent received intravenous ECyd.

[Patent document 1] publication of the Japan patent (kokoku) No. 37394/1994

[Patent document 2] JP-B-3142874

[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] Hattori, H. et al. J. Med. Chem. 39, 5005-5011 (1996)

[Non-patent document 4] Hattori, H. et al. J. Med. Chem., 41, 2892-2902 (1998)

[Non-patent document 5] Oncology Report Vol. 3, 1029 to 1034, 1996

[Non-patent document 6] Motohiro Tanaka et al., Cancer &Chemotherapy Vol. 24-4, pp. 476 to 482, 1997

[Non-patent document 7] Ludwig, P. S. et al. Synthesis (2002) 2387-2392

DISCLOSURE of INVENTION

PROBLEMS to BE solved by the PRESENT INVENTION

Given the above, the present invention was the creation of derived ECyd with antitumor effect is large compared to ECyd, by oral administration.

Resolving PROBLEMS

In an attempt to achieve the above objective, the authors of the present invention have conducted extensive studies and found that the derived 3'-ethinicities, represented by the following formula (1)or its salt has an excellent antitumor activity when administered orally. The present invention was completed based on this discovery.

Accordingly, the present invention relates to a derivative of 3'-Atini is cytidine, represented by formula (1):

(in which X represents a hydrogen atom, alkylcarboxylic group in which the alkyl fragment is an unbranched or branched C1-C6alkyl group which may contain a Deputy, or alkoxycarbonyl group in which the alkoxy fragment is an unbranched or branched C1-C6alkoxygroup, which may contain a Deputy; one of Y and Z represents a hydrogen atom or a group (R1)(R2)(R3Si-, and the other is a group (R4)(R5)(R6Si-; and each R1, R2, R3, R4, R5and R6that may be the same or different from each other, represent unbranched or branched C1-C10alkyl group which may contain a Deputy, C3-C6cycloalkyl group which may contain a Deputy, or C6-C14aryl group which may contain a Deputy), or its salt.

The present invention also relates to pharmaceutical compositions containing the compound represented by formula (1)or its salt and a pharmaceutically acceptable carrier.

The present invention also relates to anticancer drugs is a war tool, containing the compound represented by formula (1)or its salt and a pharmaceutically acceptable carrier.

The present invention also relates to oral anticancer drug containing the compound represented by formula (1)or its salt and a pharmaceutically acceptable carrier.

The present invention also relates to the use of compounds represented by formula (1)or salts thereof for the manufacture of a medicinal product, in particular anticancer drugs.

The present invention also relates to a method for treating tumors, which comprises introducing the compound represented by formula (1)or its salt in an effective amount to the needy in this subject.

The EFFECTS of the PRESENT INVENTION

Derived 3'-ethinicities or its salt according to the present invention is applicable as anticancer drugs, which has excellent antitumor activity and excellent absorption by oral administration.

The BEST WAYS of carrying out the INVENTION

Derived 3'-ethinicities or its salt of the present invention is a compound represented by the formula (1), and the compound has a chemical structure in which the silyl group is administered by hydrox the group in the 2'- and/or 5'-position.

One of the known derivatives of 3'-ethinicities containing silyl group in the 2'- or 5'-position, the 4-N-benzoyl-2'-O-(tert-butyldimethylsilyl)-3'-C-trimethylsilylacetamide (non-patent document 7). However, this connection differs structurally derived from 3'-ethinicities of the present invention that contains trimethylsilyloxy group as a substituent in the 3'-position etinilnoy group and contains benzoyloxy group as a substituent in the 4-N position. In addition, the connection specified is disclosed solely as an intermediate product in the synthesis and antitumor activity of this compound was not reported.

Examples of unbranched or branched C1-C6alkyl group" in the "alkylcarboxylic group in which the alkyl fragment is an unbranched or branched C1-C6alkyl group which may contain substituent(s)"represented by X in the formula (1)include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Among them, preferred are non-branched C1-C6alkyl group, and more preferred are methyl and n-hexyl. Examples of the "substituent" in the "alkylcarboxylic group in which the alkyl fragment is neravetla the th or branched C 1-C6alkyl group which may contain substituent(s)"represented by X in the formula (1)include an amino group in which one or two hydrogen atoms substituted unbranched or branched C1-C6alkyl group; for example, methylamino, dimethylamino, diethylamino. Among them, preferred is an amino group in which two hydrogen atoms substituted unbranched or branched C1-C6alkyl group, and more preferred is dimethylamino.

Examples of unbranched or branched C1-C6alkoxygroup" in "alkoxycarbonyl group in which the alkoxy fragment is an unbranched or branched C1-C6alkoxygroup, which may contain a substituent(s)"represented by X in the formula (1)include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy and n-hexyloxy. Among them, preferred are unbranched or branched C1-C4alkoxygroup, and more preferred is tert-butoxy. Examples of the "substituent" in the "alkoxycarbonyl group in which the alkoxy fragment is an unbranched or branched C1-C6alkoxy group which may contain substituent(s)"represented by X in the formula (1)include unbranched or branched C 1-C6alkoxygroup, for example, methoxy, and more preferred is the absence of the Deputy.

Examples of unbranched or branched C1-C10alkyl group" in the "C1-C10alkylcarboxylic group which may contain substituent(s)"represented by R1, R2, R3, R4, R5or R6in the formula (1)include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-hexyl, Texel, n-octyl and n-decyl. Among them, preferred are non-branched C1-C8alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-hexyl, Texel and n-octyl. More preferred examples are methyl, isopropyl, tert-butyl and Texel.

Examples of the "substituent" in the "C1-C10alkylcarboxylic group which may contain substituent(s)"represented by R1, R2, R3, R4, R5or R6in the formula (1)include C3-C6cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C1-C3alkoxygroup, such as methoxy, ethoxy, isopropoxy; C6-C14aryl groups such as phenyl and naphthyl; hydroxy; amino; halogen atoms such as chlorine and bromine; cyano; and nitro.

Examples of "C3-C6cycloalkyl group" "C3-C6 cycloalkyl group which may contain substituent(s)"represented by R1, R2, R3, R4, R5or R6in the formula (1)include cyclopropyl, cyclobutyl, cyclopentyl and tsiklogeksilnogo group.

Examples of the "substituent" in the "C3-C6cycloalkyl group which may contain substituent(s)"represented by R1, R2, R3, R4, R5or R6in the formula (1)include unbranched or branched C1-C3alkyl groups such as methyl, ethyl and isopropyl group; C3-C6cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C1-C3alkoxygroup, such as methoxy, ethoxy, isopropoxy; C6-C14aryl groups such as phenyl and naphthyl; hydroxy; amino; halogen atoms such as chlorine and bromine; cyano; and nitro.

Examples of "C6-C14aryl group" in the "C6-C14aryl group which may contain substituent(s)"represented by R1, R2, R3, R4, R5or R6in the formula (1)include phenyl and naphthyl, preferably is phenyl.

Examples of the "substituent" in the "C6-C14aryl group which may contain substituent(s)"represented by R1, R2, R3, R4R 5or R6in the formula (1)include unbranched or branched C1-C3alkyl groups such as methyl, ethyl and isopropyl group; C3-C6cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C1-C3alkoxygroup, such as methoxy, ethoxy, isopropoxy; C6-C14aryl groups such as phenyl and naphthyl; hydroxy; amino; halogen atoms such as chlorine and bromine; cyano; and nitro.

Examples of the groups (R1)(R2)(R3)Si - (R4)(R5)(R6Si-, which are identical to each other or differ from each other and represented by Y and Z in the formula (1)include 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, n-delldimension, (3,3-dimethylbutyl)dimethylsilane, 1,2-dimethylpropyleneurea, di-tert-butylmethylether, di-n-butylmethylether, diethylenediamine, n-activisuspicion, n-activitiesall, cyclohexyldimethylamine, dicyclohexylmethyl, isopropylideneglycerol, triphenylsilane, dimethylphenylsilane, tert-butyldiphenylsilyl, methyldiphenylamine, di is Anil(diphenylmethyl)silyl, pair-tridimensional, biphenylmethanol, biphenyldicarboxylic, three(2-biphenyl)silyl, three(ortho-tolyl)silyl, three(2-methoxyphenyl)silyl, tribenzylamine, benzyldimethylamine, phenethyltrimethoxysilane, (3-phenylpropyl)dimethylsilane, para-(tert-butyl)phenethyltrimethoxysilane, 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, 2-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, aminobutiramida(3-methoxypropyl)silyl, (3-ethoxypropan)diisopropylzinc, [3-(tert-b is talocci)propyl]diisopropylzinc, tert-bathilde(3-ethoxypropan)silyl and 3-phenoxypropylamine. In the preferred (R1)(R2)(R3)Si - (R4)(R5)(R6Si is one or two groups of R1, R2and R3or R4, R5and R6that are identical to each other or differ from each other, represent unbranched or branched C1-C4alkyl group, and the remaining one or two groups that are identical to each other or differ from each other, represent unbranched or branched C2-C8alkyl group or phenyl. Examples of such EliLilly groups include tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl, dimethyl-n-octylsilane, dimethylphenylsilane, dimethylacrylic and tert-butyldiphenylsilyl. In a more preferred (R1)(R2)(R3)Si - (R4)(R5)(R6Si - two groups of R1, R2and R3or R4, R5and R6that are identical to each other or differ from each other, represent unbranched or branched C1-C3alkyl group, and the remaining one group represents an unbranched or branched C2-C8alkyl group. Examples of such EliLilly groups include tert-butyldimethylsilyloxy, triethylsilanol, triisopropylsilyl, Dima is Il-n-octylsilane and dimethylethoxysilane group. In a particularly preferred (R1)(R2)(R3)Si - (R4)(R5)(R6Si - two groups of R1, R2and R3or R4, R5and R6that are identical to each other or differ from each other, represent unbranched or branched C1-C3alkyl group, and the remaining one group represents an unbranched or branched C3-C6alkyl group. Examples of such EliLilly groups include tert-butyldimethylsilyl, triisopropylsilyl and dimethylacrylic.

In the formula (1) one of Y and Z represents a hydrogen atom or a group (R1)(R2)(R3Si-, and the other is a group (R4)(R5)(R6Si-. Preferably one of Y and Z represents a hydrogen atom and the other represents a group (R4)(R5)(R6Si-.

Preferably in the compound of the present invention, represented by formula (1), X represents a hydrogen atom, alkylcarboxylic group in which the alkyl fragment is an unbranched or branched C1-C6alkyl group which may contain substituent(s), or alkoxycarbonyl group in which the alkoxy fragment is an unbranched or branched C1-C6alkoxygroup, Kotor, which may contain a substituent(s); one of Y and Z represents a hydrogen atom or a group (R1)(R2)(R3Si-, and the other is a group (R4)(R5)(R6Si-; and each R1, R2, R3, R4, R5and R6that may be the same or different from each other, represents an unbranched or branched C1-C10alkyl group which may contain substituent(s), C3-C6cycloalkyl group which may contain substituent(s), or C6-C14aryl group which may contain substituent(s).

More preferably in formula (1), X represents a hydrogen atom, alkylcarboxylic group in which the alkyl fragment is an unbranched or branched C1-C6alkyl group, which as a substituent(s) may contain mono - or disubstituted unbranched or branched C1-C6alkyl group, an amino group, or alkoxycarbonyl group in which the alkoxy fragment is an unbranched or branched C1-C6alkoxygroup; one of Y and Z represents a hydrogen atom or a group (R1)(R2)(R3Si-, and the other is a group (R4)(R5)(R6Si-; and each R1, R2, R3, R4, R5and R6 that may be the same or different from each other, represents an unbranched or branched C1-C10alkyl group, a C3-C6cycloalkyl group or a C6-C14aryl group.

Even more preferably, in the formula (1), X represents a hydrogen atom, alkylcarboxylic group in which the alkyl fragment is an unbranched or branched C1-C6alkyl group, which as a substituent(s) may contain dimethylaminopropyl, or alkoxycarbonyl group in which the alkoxy fragment is an unbranched or branched C1-C6alkoxygroup; one of Y and Z represents a hydrogen atom or a group (R1)(R2)(R3Si-, and the other is a group (R4)(R5)(R6Si-; and each R1, R2, R3, R4, R5and R6that may be the same or different from each other, represents an unbranched or branched C1-C10alkyl group, a C3-C6cycloalkyl group or a C6-C14aryl group.

Even more preferably, in the formula (1), X represents a hydrogen atom; one of Y and Z represents a hydrogen atom or a group (R1)(R2)(R3Si-, and the other submitted is a group (R 4)(R5)(R6Si-; and each R1, R2, R3, R4, R5and R6that may be the same or different from each other, represents an unbranched or branched C1-C10alkyl group, a C3-C6cycloalkyl group or a C6-C14aryl group.

Even more preferably, in the formula (1), X represents a hydrogen atom; one of Y and Z represents a hydrogen atom or a group (R1)(R2)(R3Si-, and the other is a group (R4)(R5)(R6Si-; and each R1, R2, R3, R4, R5and R6that may be the same or different from each other, represents an unbranched or branched C1-C8alkyl group or phenyl group.

Even more preferably, in the formula (1), X represents a hydrogen atom; one of Y and Z represents a hydrogen atom and the other represents a group (R4)(R5)(R6Si-; and each R4, R5and R6that may be the same or different from each other, represents an unbranched or branched C1-C8alkyl group or phenyl group.

Even more preferably, in the formula (1), X represents a hydrogen atom; one of Y and Z represents an atom of water is kind, and the other one represents tert-butyldimethylsilyloxy group, triethylsilyl group, triisopropylsilyl group, dimethyl-n-octylsilane group, dimethylphenylsilane group, dimethylethoxysilane group or tert-butyldiphenylsilyl group.

Specific examples of such preferred compounds include derivatives of 3'-ethinicities (1)to(17) or their salts:

(1) 1-[5-O-(tert-butyldimethylsilyl)-3-C-ethinyl-β-D-ribofuranosyl]cytosine,

(2) 1-[5-O-triethylsilyl-3-C-ethinyl-β-D-ribofuranosyl]cytosine,

(3) 1-[5-O-triisopropylsilyl-3-C-ethinyl-β-D-ribofuranosyl]cytosine,

(4) 1-[5-O-(dimethyl-n-octylsilane)-3-C-ethinyl-β-D-ribofuranosyl]cytosine,

(5) 1-[5-O-dimethylphenylsilane-3-C-ethinyl-β-D-ribofuranosyl]cytosine,

(6) 1-[5-O-dimethylacrylic-3-C-ethinyl-β-D-ribofuranosyl]cytosine,

(7) 1-[5-O-(tert-butyldiphenylsilyl)-3-C-ethinyl-β-D-ribofuranosyl]cytosine,

(8) 1-[2,5-bis-O-(tert-butyldimethylsilyl)-3-C-ethinyl-1-β-D-ribofuranosyl]cytosine,

(9) 1-[2-O-(tert-butyldimethylsilyl)-3-C-ethinyl-1-β-D-ribofuranosyl]cytosine,

(10) 1-(2,5-bis-O-triisopropylsilyl-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine,

(11) 1-(2-O-triisopropylsilyl-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine,

(12) 1-(2,5-bis-O-dimethylacrylic-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine,

(13) 1-(2-O-dimethylacrylic-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine,

(14) 1-[5-O-(tert-butyldimethylsilyl is)-3-C-ethinyl-β-D-ribofuranosyl]-4-N-heptanoates,

(15) 1-[5-O-(tert-butyldimethylsilyl)-3-C-ethinyl-β-D-ribofuranosyl]-4-N-(tert-butoxycarbonyl)cytosine,

(16) 1-[5-O-(tert-butyldimethylsilyl)-3-C-ethinyl-β-D-ribofuranosyl]-4-N-(N,N-dimethylglycine)cytosine, and

(17) 1-[5-O-(triisopropylsilyl)-3-C-ethinyl-β-ribofuranosyl]-4-N-(N,N-dimethylglycine)cytosine.

Specific examples of such preferred compounds include derivatives of 3'-ethinicities or their salts:

(1) 1-[5-O-(tert-butyldimethylsilyl)-3-C-ethinyl-1-β-D-ribofuranosyl]cytosine,

(3) 1-(5-O-triisopropylsilyl-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine,

(6) 1-(5-O-dimethylacrylic-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine,

(9) 1-[2-O-(tert-butyldimethylsilyl)-3-C-ethinyl-1-β-D-ribofuranosyl]cytosine,

(11) 1-(2-O-triisopropylsilyl-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine, and

(13) 1-(2-O-dimethylacrylic-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine.

The salt derivative of 3'-ethinicities of the present invention is not imposed specific restrictions, as the salt is pharmaceutically acceptable. Examples of the salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; and organic acid salts such as acetate, propionate, tartrate, fumarate, maleate, malate, citrate, methanesulfonate, para-toluensulfonate and triptorelin. Depending on the characteristics of the substituent(s) derived 3'-ethinicity is on the present invention can form optical isomers or geometrical isomers, and the present invention includes such optical isomers and geometrical isomers, provided that supported stereostructure skeleton 3'-ethinicities specified in the formula (1). Such isomers can be used after separation or used as a mixture. Derived 3'-ethinicities the present invention also encompasses amorphous particles, polymorphs and a solvate such as a hydrate.

Derived 3'-ethinicities or its salt according to the present invention can be obtained in accordance with the following reaction scheme, which includes stages 1-7:

(where the values of X, Y and Z are defined above).

(Stage 1)

In stage 1 interact with the 3'-ethinicities represented by the formula (2)or its salt with the well-known tizanidine silylium agent such as tizamidine silicalite, tizamidine silicrylic or tizamidine silylated presented (R1)(R2)(R3Si-W or (R4)(R5)(R6Si-W (where W represents a halogen atom, triftormetilfullerenov, acetaminoph, and the like, and R1-R6defined above), the result can be obtained compound represented by the formula (1a).

The interaction may be carried out in accordance with the well-known ability is BOM. The solvent used in the reaction, specific limitations are not imposed, and can be used any solvent provided that it is inert in the reaction. Examples of the solvent include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N,N-dimethylformamide and dimethylsulfoxide. These solvents can be used individually or in combination. If necessary, the interaction may be carried out in the presence of a base. 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 base can be used as the solvent per se.

Tizamidine silicalite, which is used in the reaction and presents (R1)(R2)(R3Si-W or (R4)(R5)(R6Si-W, can be obtained by a commonly known method. For example, carry out the interaction of trigalogenmetany, monoalkylphenols or dialkylaminoalkyl with alkyllithium or a Grignard reagent of interest, thereby obtaining trisemester silane, not only the frame (R 1)(R2)(R3Si-H or (R4)(R5)(R6Si-H, which then interact electrophilic reagent, such as N-bromosuccinimide or N-chlorosuccinimide. Upon receipt trisemester silane represented by (R1)(R2)(R3Si-H or (R4)(R5)(R6Si-H, can be used an additive, such as copper bromide. If necessary tizamidine silane represented by (R1)(R2)(R3Si-H or (R4)(R5)(R6Si-H, and tizamidine silicalite presented (R1)(R2)(R3Si-W or (R4)(R5)(R6Si-W, can be isolated/purified. Alternatively, the obtained silane or silanolate can be used in stage 1 without cleaning.

In the reaction mentioned above (R1)(R2)(R3Si-W or (R4)(R5)(R6Si-W is used in amounts of from about 0.5 to about 10 mol, preferably about 1 to about 5 mol, and the base is used in amounts of from about 0.5 to about 100 mol, preferably from about 1 to about 10 mol, relative to 1 mole of the compound represented by formula (2). The reaction temperature is from -30 to 100°C, preferably from 0 to 30°C, and the duration of reaction is from 0.1 to 100 hours, the site is preferably from 1 to 20 hours. If necessary, obtained during the reaction of the compound represented by formula (1a)can be isolated/purified. Alternatively, the connection can be used in the next stage without treatment.

(Stage 2)

In stage 2 interact derived 3'-ethinicities represented by the formula (1a), with the above-mentioned tizanidine silylium agent represented by (R1)(R2)(R3Si-W or (R4)(R5)(R6Si-W, in the presence of a base to obtain the compound represented by formula (1b). The interaction may be carried out by, similar to that described in stage 1.

(Stage 3)

By analogy with stage 1 on stage 3 carry out the interaction of 3'-ethinicities represented by the formula (2)mentioned above tizanidine silylium agent represented by (R1)(R2)(R3Si-W or (R4)(R5)(R6Si-W, in the presence of a base to obtain the compound represented by formula (1b). The reaction temperature is from -30 to 150°C, preferably from 0 to 100°C, and the duration of reaction is from 0.1 to 100 hours, preferably from 1 to 40 hours. If necessary, obtained during the reaction of the compound represented by formula (1b)can be isolated/purified. Alternatively, the connection can be used with etousa stage without treatment.

(Stage 4)

In stage 4, the compound represented by formula (1c)are derived from the 3'-ethinicities represented by the formula (1b), in an acidic environment. In relation to acid-specific no restrictions, provided that it is able to remove Deputy Y. Examples of the acid include inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids such as triperoxonane acid, acetic acid, propionic acid, formic acid, methanesulfonate acid and para-toluensulfonate acid. These acids may be mixed with water. If necessary, can 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 can be used individually or in combination. The reaction temperature is from -30 to 150°C, preferably from 0 to 100°C, and the duration of reaction is from 0.1 to 100 hours, preferably from 1 to 20 hours.

(Stage 5)

At stage 5 the derived 3'-ethinicities represented by the formula (1a), modify the group X in a compound represented by the formula (3a).

In that case, if X is a containing alkyl group, carbonyl group, then the modification is carried out by condensation with galogenangidridy X-V (where V denotes a halogen atom), with an acid anhydride X-O-X or carboxylic acid X-OH. No restrictions on the solvent used in the reaction, there may be used any solvent provided that it is inert in the reaction. Examples of the solvent include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N,N-dimethylformamide, dimethylsulfoxide and water. These solvents can be used individually or in combination. If you use gelegenheid X-V or an acid anhydride X-O-X, you can use the base. 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. The base can be used as the solvent per se. In relation to the condensation reaction with the carboxylic acid X-OH specific no restrictions, provided that the reaction occurs amide formation from carboxylic acid and amine. For example, can be used STRs is about using mixed anhydrides, the method using a condensing agent, and the like. Examples of the base used in the method using mixed anhydrides 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. The base can be used as the solvent per se. As a reagent to obtain a mixed anhydride with a carboxylic acid X is OH may be used isobutylparaben, pivaloyloxy, and the like. If using a condensing agent may be used carbodiimide compounds such as dicyclohexylcarbodiimide or hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; or 1,1'-carbonyldiimidazole or similar connection. Examples of contributing condensing means includes a hydrate of 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboximide and 4-(N,N-dimethylamino)pyridine. If necessary, the reaction can be used a basis. Examples of the base include organic amines such as trimethylamine, triethylamine, Tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lucid the n and kallidin; and inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate. The base can be used as the solvent per se.

If the reaction is gelegenheid X-V or an acid anhydride X-O-X, halogenmethyl X-V or an acid anhydride X-O-X is used in amounts of from about 0.5 to about 20 mol, preferably from about 1 to about 10 mol, relative to 1 mole of the compound represented by formula (1a), and the base is used in amounts of from about 0 to about 100 mol, preferably from about 1 to about 20 mol. The reaction temperature is from -30 to 100°C, preferably from -10 to 30°C, and the duration of reaction is from 0.1 to 100 hours, preferably from 1 to 72 hours. If condensation with carboxylic acid X-OH is carried out by the method using mixed anhydride, the carboxylic acid X-OH is used in amounts of from about 0.5 to about 20 mol, preferably from about 1 to about 10 mol; reagent to obtain a mixed anhydride is used in an amount of from about 0.5 to about 20 mol, preferably from about 1 to about 10 mol; and the base is used in amounts of from about 0.5 to about 100 mol, site is preferably from about 1 to about 20 mol, relative to 1 mole of the compound represented by formula (1a). The reaction temperature is from -30 to 100°C, preferably from -10 to 30°C, and the duration of reaction is from 0.1 to 100 hours, preferably from 1 to 72 hours. If you use a condensing agent, the carboxylic acid X-OH is used in amounts of from about 0.5 to about 20 mol, preferably from about 1 to about 10 mol; condensing agent is used in amounts of from about 0.5 to about 20 mol, preferably from about 1 to about 10 mol; promoting the condensation product is used in amounts of from about 0.1 to about 40 mol, preferably from about 1 to about 10 mol; and the base is used in an amount of from 0 to about 100 mol, preferably from 0 to about 20 mol, relative to 1 mole of compound represented by the formula (1a). The reaction temperature is from -30 to 100°C, preferably from -10 to 30°C, and the duration of reaction is from 0.1 to 100 hours, preferably from 1 to 72 hours. If necessary, obtained by any of these methods, the compound represented by formula (3a)can be isolated/purified. Alternatively, the connection can be used in the next stage without holding to clean the key.

If the group X is alkoxycarbonyl group, the reaction at the stage 5 specific restriction is not imposed, provided that it is a typical reaction. In one typical way to interact derived 3'-ethinicities represented by the formula (1a)or its salt with dialkylammonium, alkylhalogenide, alkyl(para-nitrophenyl)carbonate, complex alkilany ether 1H-imidazole-1-carboxylic acid, and the like, which presents X-Q (where Q is alkoxycarbonylmethyl X-O, halogen atom, 4-nitrophenylacetate, 1H-imidazol-1-ilen group, and the like). The interaction may be carried out in accordance with the well-known manner. In regard to the solvent used in the reaction, a specific no restrictions and can be used any solvent provided that it is inert in the reaction. Examples of the solvent include dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and water. These solvents can be used individually or in combination. If necessary, the interaction may be carried out in the presence of a base. 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 base can be used as the solvent per se.

Alkylhalogenide X-Q, used in the reaction, can be obtained by a commonly known method. For example, halogenfree can be obtained in the reaction between triphosgene and relevant alkilany alcohol. By analogy alkyl(para-nitrophenyl)carbonate X-Q, used in the reaction, can be obtained by a commonly known method. For example, the carbonate can be obtained in the reaction between para-nitrophenylacetate and relevant alkilany alcohol. In addition, complex alkilany ester 1H-imidazole-1-carboxylic acid X-Q, used in the reaction, can be obtained by a commonly known method. For example, the ester can be obtained in the reaction between 1,1'-carbonyl diimidazol and relevant alkilany alcohol. If necessary, alkylhalogenide, alkyl(para-nitrophenyl)carbonate and complex alkilany ester 1H-imidazole-1-carboxylic acid represented by X-Q, can be isolated/purified. Alternatively, these compounds can be used to stage 5 without cleaning.

In the reaction mentioned above, the soybean is inania X-Q is used in amounts of from about 0.5 to about 20 mol, preferably from about 1 to about 10 mol; and the base is used in amounts of from about 0.5 to about 100 mol, preferably from about 1 to about 20 mol, relative to 1 mole of the compound represented by formula (1a). The reaction temperature is from -30 to 100°C, preferably from -10 to 30°C, and the duration of reaction is from 0.1 to 100 hours, preferably from 1 to 72 hours. If necessary, obtained in the reaction of the compound represented by formula (3a)can be isolated/purified. Alternatively, the connection can be used in the next stage without treatment.

(Stage 6)

By analogy with stage 5 stage 6 derived 3'-ethinicities represented by the formula (1b), modify the group X, thereby obtaining the compound represented by formula (3b).

(Stage 7)

By analogy with the stage 5 to stage 7, a derivative of 3'-ethinicities represented by the formula (1c), modify the group X, thereby obtaining the compound represented by formula (3c).

Thus obtained compound of the present invention can be converted into its salts, especially pharmaceutically acceptable salt, a well-known method.

The compound or its salt of the present invention can be isolated and purified overall the known method of separation/purification, such as concentration, extraction with solvent, filtration, recrystallization or chromatography.

As described by way of examples, the compound or its salt according to the present invention exhibits an excellent antitumor effect by oral administration. Thus, it is an effective drug, particularly an antitumor drug to humans and mammals.

When using the compounds of the present invention as a drug compound is mixed with a pharmaceutically acceptable carrier, and in accordance with the preventive and therapeutic purposes can be selected a number of input forms. Can use different input forms, and examples include oral medications, injectable forms, suppositories, ointments and plasters. Among them, preferably used oral forms. These forms of medicines can be obtained from any pharmaceutical techniques well known in the art.

Be used pharmaceutically acceptable carrier can be any organic or inorganic carriers which are traditionally used as materials for the preparation of drugs. In solid dosage is ormah carrier included in the composition in the form of foundations, lubricants, binders, powder or similar additives. In liquid formulations, the carrier included in the composition in the form of a solvent that promotes dissolution means, a suspending agent, giving isotonicity agent, buffer, soothing agent, or similar additives. Optionally, the composition may also include other additives such as preservative, antioxidant, coloring and sweetener.

In the preparation of solid dosage forms for oral administration the compound of the present invention is mixed with the base and optional additives such as a binder, baking powder, lubricant, coloring and sweetener/flavoring, and convert the mixture in the traditional way into tablets, coated tablets, granules, powder, capsules, and the like. These supplements can be commonly used in the art, and examples include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid (base); water, ethanol, propanol, simple syrup, liquid glucose, liquid starch, liquid gelatin, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone (binder);dry starch, sodium alginate, powdered agar, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride of stearic acid and lactose (leavening agents); purified talc, salts of stearic acid, borax and polyethylene glycol (lubricant), silicon oxide and iron oxide (dyes); and sucrose, orange peel, citric acid and tartaric acid (sweeteners/flavorings).

In the preparation of liquid dosage forms for oral administration the compound of the present invention is mixed with additives such as sweetening agents, buffer, stabilizer and flavoring, and convert the mixture of the traditional way in a liquid dosage form for oral administration, syrup, elixir and the like. In this case, the sweetener/flavoring may be the same as described above. Examples of the buffer include sodium citrate, and examples of the stabilizer include tragakant, acacia and gelatin.

In the preparation of injectable form of the compound of the present invention is mixed with additives such as a pH Adjuster, buffer, stabilizer, giving isotonicity agent and a local anesthetic, and convert the mixture in the traditional way in injectable forms for subcutaneous, intramuscular and intravenous. In this case, examples of the pH regulator and buffer include sodium citrate, sodium acetate and phosphate n is sodium, 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 giving isotonicity agent include sodium chloride and glucose.

In the preparation of a medicinal product in the form of a suppository, the compound of the present invention is mixed with a known in the art carrier for the preparation of medicines, such as polyethylene glycol, lanolin, cocoa butter and triglyceride fatty acid, and optionally surface-active agent such as Tween™, and convert the mixture in the traditional way in suppositories.

In the preparation of ointments compound of the present invention is mixed, in accordance with the requirements, with commonly used additives, such as base, stabilizer, humectant, preservative, and the like, the mixture is produced and converted into medicine in the traditional way. Examples of ointment bases include liquid paraffin, white petrolatum, bleached beeswax, octyldodecyl alcohol and paraffin. Examples of the preservative include methyl-para-hydroxybenzoate, ethyl-para-hydroxybenzoate and propyl-para-hydroxybenzoate.

In the preparation of a medicinal product in the form of a patch mentioned above, ointment, cream, the spruce, paste or similar material in the traditional way put on a standard substrate. Examples of suitable substrates include woven and non-woven material made of cotton, staple fiber, or synthetic fiber; and film and sheet foam, made of soft vinyl chloride, polyethylene or polyurethane.

A single dose of the compounds of the present invention, be incorporated as part of any of the above forms of medicines varies depending on the condition of patients who need to enter the compound of the present invention, the form of drugs or other factors. Typically, a single dose is preferably from about 0.05 to 1000 mg for oral dosage forms, approximately from 0.01 to 500 mg injectable forms and from about 1 to 1000 mg for suppositories. Daily dose medications in any of the above dosage forms varies depending on the condition, body weight, age, sex, and the like, of the patient, and therefore it may not necessarily be determined immediately. However, as a rule, the daily dose for an adult is approximately from 0.05 to 5000 mg, preferably from 0.1 to 1,000 mg Daily dose is preferably administered once a day or fractional approximately two to four times in the TCI.

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

EXAMPLES

The present invention will be further described in detail with reference to comparative examples, examples (demos), examples of pharmacological tests and preparatory examples. However, one should not be construed as limiting the present invention.

Example 1

1-[5-O-(tert-Butyldimethylsilyl)-3-C-ethinyl-β-D-ribofuranosyl]cytosine (compound 1)

tert-Butyldimethylsilyloxy (12.5 g, of 82.5 mmol) was gradually added while cooling on ice to a solution of 3'-ethinicities (hereafter in this document referred to ECyd) (20 g, 75 mmol) and imidazole (12.8 g, 188 mmol) in N,N-dimethylformamide (hereinafter in this document called DMF) (75 ml), and p is remedial the mixture for 5 hours at room temperature. After completion of the reaction the solvent evaporated under reduced pressure, and was added to the residue ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate (100 ml) and saturated saline (100 ml), and dried over magnesium sulfate. The magnesium sulfate was removed by filtration. The filtrate was stirred at room temperature, and was collected in the precipitated crystals by filtration to obtain compound 1 (11,5 g, 52%).

Example 2

1-[5-O-Triethylsilyl-3-C-ethinyl-β-D-ribofuranosyl]cytosine (compound 2)

Repeating the procedure of example 1 except that instead of used in example 1 tert-butyldimethylsilyloxy used triethylsilane, and synthesized compound 2.

Example 3

1-[5-O-Triisopropylsilyl-3-C-ethinyl-β-D-ribofuranosyl]cytosine (compound 3)

Repeating the procedure of example 1 except that instead of used in example 1 tert-butyldimethylsilyloxy used triisopropylsilane, and synthesized compound 3.

Example 4

1-[5-O-(Dimethyl-n-octylsilane)-3-C-ethinyl-β-D-ribofuranosyl]cytosine (compound 4)

Repeating the procedure of example 1 except that instead of used in example 1 tert-butyldimethylsilyloxy used dimethyl-n-octylsilane, and synthesized compound 4.

Example 5

1-[5-O-Dee ethylvanillin-3-C-ethinyl-β-D-ribofuranosyl]cytosine (compound 5)

Repeating the procedure of example 1 except that instead of used in example 1 tert-butyldimethylsilyloxy used dimethylphenylsilane, and synthesized compound 5.

Example 6

1-[5-O-Dimethylacrylic-3-C-ethinyl-β-D-ribofuranosyl]cytosine (compound 6)

Repeating the procedure of example 1 except that instead of used in example 1 tert-butyldimethylsilyloxy used dimethylethoxysilane, and synthesized the compound 6.

Example 7

1-[5-O-(tert-Butyldiphenylsilyl)-3-C-ethinyl-β-D-ribofuranosyl]cytosine (compound 7)

Repeating the procedure of example 1 except that instead of used in example 1 tert-butyldimethylsilyloxy used tert-butyldiphenylsilyl, and synthesized the compound 7.

Example 8

1-[2,5-bis-O-(tert-Butyldimethylsilyl)-3-C-ethinyl-1-β-D-ribofuranosyl]cytosine (compound 8)

ECyd (5,00 g, to 18.7 mmol) was dissolved in DMF (19 ml)was added to a solution of imidazole (3,82 g, or 56.1 mmol) and tert-butyldimethylsilyl (6.20 g, 41,1 mmol)and then stirred for 4 hours at room temperature under a stream of nitrogen. The solvent is evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent evaporated. OS is atok was purified column chromatography on silica gel (0-5% methanol/chloroform). Then the product was led from hexane/ether to obtain compound 8 (6,36 g, 12.8 mmol, 69%) as a white solid.

Example 9

1-[2-O-(tert-Butyldimethylsilyl)-3-C-ethinyl-1-β-D-ribofuranosyl]cytosine (compound 9)

Compound 8 (2.00 g, a 4.03 mmol) was dissolved in tetrahydrofuran (hereafter in this document referred THF) (20 ml)was added to a solution of 80% water triperoxonane acid (20 ml)and then stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue three times together boiled with ethanol, and the product was distributed between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline and then dried over anhydrous sodium sulfate. The solvent is evaporated, and the residue was purified column chromatography on silica gel (0-6% methanol/chloroform), and then was led from hexane/ether to obtain compound (9) (645 mg, 1,69 mmol, 42%) as a white solid.

Example 10

1-(2,5-bis-O-Triisopropylsilyl-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine (compound 10)

ECyd (5,00 g, to 18.7 mmol) was dissolved in DMF (19 ml)was added to a solution of imidazole (5.73 g, 84,2 mmol) and triisopropylsilane (12,8 ml, to 59.8 mmol)and then stirred overnight at room temperature under a stream is the monk. The solvent is evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent evaporated. The residue was purified column chromatography on silica gel (0-6% methanol/chloroform) to obtain compound 10 (of 5.05 g, to 8.70 mmol, 46%) as a colourless foam.

Example 11

1-(2-O-Triisopropylsilyl-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine (compound 11)

ECyd (4,01 g, 15 mmol) was dissolved in DMF (30 ml)was added to a solution of imidazole (6,39 g, for 93.9 mmol) and triisopropylsilane (8,02 ml, 37.5 mmol)and then stirred under a stream of nitrogen for 3 hours at room temperature and then for 24 hours at 50°C. the Reaction mixture was distributed between ethyl acetate and water, the organic layer washed five times with water, and then dried over anhydrous sodium sulfate. The solvent is evaporated, and got to 10.1 g of residue. to 1.9 g of the obtained residue was dissolved in methanol (5.2 ml)was added to a solution of water (of 0.58 ml) and methanesulfonyl acid (347 μl, 4.76 mmol)and then stirred for 1 hour at 40°C. the Reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate, the organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is evaporated, and the people headed the remainder were led from tert-butyl methyl ether/water/isopropyl ether. The obtained crystals were again led from methanol/water/triethylamine to obtain the compound (11) (961 mg, 80%) as a white solid.

Example 12

1-(2,5-bis-O-Dimethylacrylic-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine (compound 12)

ECyd (2.67 g, 10 mmol) was dissolved in DMF (100 ml)was added to a solution of imidazole (4,50 g, 66 mmol) and dimethylethoxysilane (5,90 g, 33 mmol)and then stirred for 48 hours at room temperature under a stream of nitrogen. The solvent is evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent evaporated. The residue was purified column chromatography on silica gel (0-3% methanol/chloroform) to obtain compound 12 (4,34 g, 79%) as a colourless foam.

Example 13

Triperoxonane salt of 1-(2-O-dimethylacrylic-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine (compound 13)

Compound 12 (2.0 g, 3.6 mmol) was dissolved in THF (20 ml)was added to a solution of 80% water triperoxonane acid (20 ml)and then stirred for 4 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue three times together boiled with ethanol. To the boiling residue was added chloroform, and was collected in the precipitate white solid way of the filter with connection 13 (1.54 g, 81%) as a white solid.

Example 14

1-(2-O-Dimethylacrylic-3-C-ethinyl-1-β-D-ribofuranosyl)cytosine (compound 14)

Compound 13 (1.0 g, 1.9 mmol) was dissolved in a mixture of 5% methanol/chloroform (100 ml), and washed with a solution of saturated aqueous sodium bicarbonate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is evaporated, and the residue was led from hexane/ether to obtain compound 14 (690 mg, 1,68 mmol, 88%) as a white solid.

Example 15

1-[5-O-(tert-Butyldimethylsilyl)-3-C-ethinyl-β-D-ribofuranosyl]-4-N-heptanoates (compound 15)

To a mixture of dioxane (14 ml) and water (5 ml) was added compound 1 (1.27 g, 3.3 mmol) and the anhydride heptane acid (1.8 ml, 6.8 mmol)and the mixture was stirred over night at 100°C. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 ml), and neutralized organic layer 1 N. aqueous sodium hydroxide. The resulting mixture was washed with saturated saline (50 ml), then dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on silica gel (mixture of 4% methanol/chloroform). The eluate was concentrated, and the residue is recrystallized from isopropanol/hexa is and getting connection 15 (0.55 g, 33%).

Example 16

1-[5-O-(tert-Butyldimethylsilyl)-3-C-ethinyl-β-D-ribofuranosyl]-4-N-(tert-butoxycarbonyl)cytosine (compound 16)

When cooled on ice to a tetrahydrofuran (20 ml) was added compound 1 (1.65 g, 4.3 mmol) and di-tert-BUTYLCARBAMATE (1.4 g, 6.5 mmol)and the mixture was stirred over night at 50°C. the Reaction mixture was concentrated, and the residue was purified by chromatography on silica gel (mixture of 4% methanol/chloroform). The eluate was concentrated, and the residue was recrystallized from hexane to obtain compound 16 (0.52 g, 26%).

Example 17

1-[5-O-(tert-Butyldimethylsilyl)-3-C-ethinyl-β-D-ribofuranosyl]-4-N-(N,N-dimethylglycine)cytosine (compound 17)

To DMF (20 ml) cooled on ice was added compound 1 (1.9 g, 5 mmol), N,N-dimethylglycine (1.0 g, 10 mmol), N,N-dimethylaminopyridine (0.1 g, 0.8 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.9 g, 10 mmol)and the mixture was stirred over night at 40°C. the Reaction mixture was concentrated, and was added to the residue ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate (50 ml) and saturated saline (50 ml), then dried over sodium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated. The residue was purified by chromatography on silica gel (mixture of 4% methanol/chloroform). The eluate was concentrated, and precrystallization and the residue from hexane to obtain compound 17 (0,46 g, 20%).

Example 18

1-[5-O-(Triisopropylsilyl)-3-C-ethinyl-β-ribofuranosyl]-4-N-(N,N-dimethylglycine)cytosine (compound 18)

Repeating the procedure of example 17 except that instead of used in example 17 compound 1 used the connection 3, and synthesized the compound 18 (yield: 47%).

Structure and physical properties of the compounds obtained in the examples described above, are presented in tables 1-5.

Table 1
ExampleStructureData instrumental analysis
1Properties: colorless powder (ethyl acetate); TPL: 251 to 256°C (decomposition),1H-NMR (DMSO-d6) δ 7,80 (1H, d, J=7,6 Hz), 7,19
(2H, s, disappeared in D2O)to 5.93 (1H, d, J=7,1 Hz), by 5.87 (1H, s, disappeared in D2O), of 5.75 (1H, d, J=6,8 Hz, disappeared in D2O)5,70 (1H, d, J=7,6 Hz), a 4.03 (1H, DD, J=6,8 Hz and 7.1 Hz), of 3.77-3,93 (3H, m), 3,55 (1H, s)to 0.89 (9H, s), and 0.09 (3H, s), and 0.08 (3H, s)
2Properties: colorless powder (ethyl acetate); tel: 202 to 204°C;1H-NMR (DMSO-d6) δ to 7.84 (1H, d, J =7,3 Hz), 7,22 (2H, s, disappeared in D2O)5,94 (1H, IS, J=7,0 Hz), by 5.87 (1H, s, disappeared in D2O), of 5.75 (1H, d, J=6.8 Hz, disappeared in D2O)5,73 (1H, d, J=7,3 Hz), 4,07 (1H, DD, J=6,8 Hz and 7.3 Hz), 3.75 to of 3.95 (3H, m), 3,55 (1H, s), 0,90-1,00 (9H, m)of 0.55 and 0.68 (6H, m)

Table 2
ExampleStructureData instrumental analysis
3Properties: colorless powder (methanol/ethyl acetate); TPL: >219°C (decomposition)1H-NMR (DMSO-d6) δ 7,72 (1H, d, J=7,6 Hz), 7,12 (2H, user. with that he disappeared in D2O)5,90 (1H, d, J=7,2 Hz), by 5.87 (1H, s, disappeared in D2O)5,79 (1H, d, J=6,6 Hz, disappeared in D2O)5,71 (1H, d, J=7,6 Hz), a 4.03 (1H, DD, J=6,GC, 7,2 Hz), 3,86-3,98 (3H, m), 3,54 (1H, s), 0,90-1,18 (21H, m)
4Properties: colorless powder; TPL,: (ethyl acetate); TPL: 175 to 177°C (decomposition)1H-NMR (DMSO-d6) δ 7,81 (1H, d, J=7,6 Hz), 7,18 (2H, user. with that he disappeared in D2O)5,91 (1H, d, J=6.8 Hz), 5,86 (1H, s, disappeared in D2O)5,72 (1H, d, J=6,8 Hz, disappeared in D2O)5,70 (1H, d, J=7,6 Hz), a 4.03 (1H, t, J=6.8 Hz), 3,65-of 3.95 (3H, m), 3,53 (1H, s), 1,15-1,35 (12H, m), is 0.84 (3H, t, J=6.6 Hz), 0,50-0,65 (2H, m), and 0.08 (6H, s)
5 Properties: colorless powder (ethyl acetate); TPL: 171 to l73°C;1H-NMR (DMSO-d6) δ 7,72 (1H, d, J=7,6 Hz), 7,38-of 7.60 (5H, m), 7,19 (2H, user. with that he disappeared in D2O)5,91 (1H, d, J=6.8 Hz), 5,88 (1H, s, disappeared in D2O), USD 5.76 (1H, d, J=6,8 Hz, disappeared in D2O)to 5.58 (1H, d, J=7,6 Hz), of 4.05 (1H, t, J=6.8 Hz), 3.75 to 3,90 (3H, m), 3,54 (1H, s)0,39 (3H, s), and 0.37 (3H, s)
6Properties: colorless powder (ethyl acetate/n-hexane); TPL: >197°C (decomposition);1H-NMR (DMSO-d6) δ 7,74 (1H, d, J=7,6 Hz), 7,19 (2H, user. with that he disappeared in D2O)5,90 (1H, d, J=6.8 Hz), 5,86 (1H, s, disappeared in D2O), of 5.75 (1H, d, J=6,8 Hz, disappeared in D2O)5,71 (1H, d, J=7,6 Hz)to 4.01 (1H, t, J=6.8 Hz), 3.75 to 3,90 (3H, m), 3,55 (1H, s), 1,52-of 1.65 (1H, m), 0,82-of 0.87 (12H, m)0,12 (3H, s)of 0.11 (3H, s)

Table 3
ExampleStructureData instrumental analysis
7Properties: colorless powder (H2O); TPL,: 210 to 213°C1H-NMR (DMSO-d6) δ 7,35-of 7.70 (11H, m), to 7.15 (2H, user. with that he disappeared in D2O)to 5.93 (1H, d, J=6.8 Hz), of 5.92 (1H, s, disappeared in D2O), by 5.87 (1H, d, J=6,8 Hz, disappeared in D2 O), lower than the 5.37 (1H, d, J= 7,6 Hz), of 4.12 (1H, t, J=6,8gts), 3,80-to 4.15 (3H, m), 3,60 (1H, s)of 1.02 (9H, s)
8Properties: colorless solid;1H-NMR (DMSO-d6) δ a 7.85 (1H, d, J=7,3 Hz), 7,20 (2H, user. C)the 6.06 (1H, d, J=7,3 Hz), USD 5.76 (1H, s), 5,73 (1H, d, J=7,3 Hz), 4,17 (1H, d, J=7,6 Hz), of 3.97 (1H, s), 3,90 (1H, m), 3,80 (1H, m)to 3.64 (1H, s)to 0.92 (9H, s)to 0.80 (9H, ), 0,12, 0,11, 0,01, -0,12 (each 3H, each C); FAB-LRm/z497 (MN+).
9Properties: colorless solid;1H-NMR (DMSO-d6) δ 7,86 (1H, d, J=7,3 Hz), 7.18 in, 7,14 (each 1H, each user. C), by 5.87 (1H, d, J=6.9 Hz), 5,74 (1H, d, J=7,3 Hz), the 5.65 (1H, s), 5,09 (1H, t, J=4.6 Hz), 4,32 (1H, d, J=6.9 Hz), 3,89-3,91 (1H, m), 3,61-3,88 (2H, m), of 3.56 (1H, s)to 0.80 (9H, s)of 0.03 (3H, s), -0,89 (3H, s); FAB-LRm/z382 (MN+); Analytical calculated for C17H27N3O5Si·0,7 H2O: C, 51,81; H, 7,26; N, 10,66, Found: C, 52,06; H, To 7.09; N, 10,65.
10Properties: colorless foam;1H-NMR (DMSO-d6) δ 7,71 (1H, d, J=7,3 Hz), 7,18 (2H, user. C)5,96 (1H, d, J=6,1 Hz), 5,74 (1H, s), 5,71 (1H, d, J=7,3 Hz), 4,30 (1H, d, J= 6.3 Hz), of 3.94 (3H, m), 3,62 (1H, s), 2.49 USD (9H, s), 1.06 a-0,95 (42H, m); FAB-LRm/z580 (MN+); Analytical calculated for C29H53N3O5Si:C, 60,06; H, Of 9.21; N, 7,25 Found: C, 59,08; H, 9,23; N, 7,15.
11Properties: colorless solid;1H-NMR (DMSO-d6) δ to 7.84 (1H, d, J=7,3 Hz), 7.18 in, 7,14 (each 1H, each user. C)5,88 (1H, d, J=6.3 Hz), 5,73 (1H, d, J=7,3 Hz), 5,64 (1H, s), 5,10 (1H, t, J=4.6 Hz), 4,50-a 4.53 (1H, m), a 3.87-to 3.89 (1H, m), 3,61-to 3.73 (2H, m), of 3.56 (1H, s), 0,95-1,05 (21H, m)

Table 4
ExampleStructureData instrumental analysis
12Properties: colorless foam; TPL: 106 to 108°C1H-NMR (DMSO-d6) δ for 7.78 (1H, d, J= 7,3 Hz), 7,19 2H, user. C), 6,03 (1H, d, J=7,3 Hz), 5,73 (1H, d, J=7,3 Hz), the 5.65 (1H, s), 4,13 (2H, d, J=7,6 Hz), 3,95 (1H, s), 3,90 (1H, DD, J=2.3 Hz, J=11.5 Hz), 3,81 (1H, DD, J=2.3 Hz, J=11.5 Hz), 3,63 (1H, s), 1,58 (2H, m), 0,80 (24H, m), 0,15, 0,14, 0,08, -0,10 (each 3H, each s); FAB-LRMSm/z552 (MH+); Analytical calculated for C27H49N3O5Si2: C, 58,76; H, OF 8.95; N, TO 7.61. Found: C, 58,48; H, 8,93; N, A 7.85.
13Properties: colorless solid; TPL: 182°C1 H-NMR (DMSO-d6) δ which 9.22 (1H, user. C)8,44 (1H, user. C)8,23 (1H, d, J=7.9 Hz), 6,09 (1H, d, J=7.9 Hz), to 5.85 (1H, d, J=6.3 Hz), 4,32 (1H, d, J=6.3 Hz), with 3.89 (1H, m), 3,74 (2H, m), 3,66 (1H, s)of 1.55 (1H, m)0,79 (12H, m), 0,14, -0,01 (each 3H, each s); FAB-LRMS (negative)m/z522 (M-N)-; Analytical calculated for C21H32F3N3O7Si·0,7 H2O: C, 47,04; H, 6,28; N, 7,84. Found: C, 47,59; H, 6,27; N, 8,11.
14Properties: colorless solid; TPL: 218°C1H-NMR (DMSO-d6) δ a 7.85 (1H, d, J=7,3 Hz), 7,17 (2H, user. d, J=11,9 Hz), 5,86 (1H, d, J=6.9 Hz), 5,74 (1H, d, J=7,3 Hz), to 5.57 (1H, s), 5,10 (1H, m)to 4.33 (1H, d, J=6.9 Hz), with 3.89 (1H, m)to 3.67 (2H, m), 3,57 (1H, s)of 1.53 (1H, m), 0,78 (12H, m), 0,10, -0,06 (each 3H, each s); FAB-LRMSM/Z410 (MH+); Analytical calculated for C19H31N3O5Si·0,6 H2O: C, 54,29; H, 7,72; N, 10,00. Found: C, 54,18; H, Of 7.69; N, Becomes 9.97.
15Properties: colorless powder (isopropanol/hexane); TPL: 134 to 137°C;1H-NMR (DMSO-d6) δ 10,90 (1H, s, disappeared in D2O), 8,24 (1H, d, J=7,6 Hz), 7,24 (1H, d, J=7,6 Hz), 6,00 (1H, s, disappeared in D2O)5,94 (1H, d, J=6.3 Hz), of 5.83 (1H, d, J=6.3 Hz, disappeared in D2O), 4.09 to (1H, t, J=6.3 Hz), 3,82-Android 4.04 (3H, m)to 3.58 (1H, s), of 2.38 (2H, t, J=7,3 Hz), 1,49-and 1.54 (2H, m), 1,17 is 1.34 (6H, m), 0.79, which is of 0.93 (12H, m), 0,11 (3H, s), and 0.09 (3H, s)

Table 5
ExampleStructureData instrumental analysis
16Properties: colorless powder (hexane); TPL: 103 to 110°C;1H-NMR (DMSO-d6) δ; the 10.40 (1H, s, disappeared in D2O, 8,18 (1H, d, J=7.8 Hz), 7,00 (1H, d, J=7,3 Hz), 5,98 (1H, s, disappeared in D2O)to 5.93 (1H, d, J=6,4 Hz, disappeared in D2O)5,80 (1H, d, J=7.8 Hz), 4,08 (1H, DD, J=6,4 Hz and 7.3 Hz), 3,8-4,00 (3H, m), of 3.56 (1H, s)of 1.44 (9H, s)to 0.89 (9H, s)of 0.10 (3H, s), and 0.09 (3H, s)
17Properties: colorless powder (hexane);; TPL: 180 to 185°C;1H-NMR (DMSO-d6) δ;10,38 (1H, s, disappeared in D2O)of 8.27 (1H, d, J=7,3 Hz), 7,22 (1H, d, J=7,3 Hz), by 5.87-6,05 (3H, m, 2H disappeared in D2O), 3,82-4,06 (4H, m), 3,57 (1H, s), 3,14 (2H, s)to 0.89 (9H, s)of 0.10 (3H, s), and 0.09 (3H, s)
18Properties: colorless powder (diisopropyl ether); TPL: 146 to l48°C;1H-NMR (DMSO-d6) δ;accounted for 10.39 (1H, s, disappeared on D2O)to 8.20 (1H, d, J=7,6 Hz), 7.23 percent (1H, d, J=7,6 Hz), 6,03 (1H, s, disappeared in D2O)of 5.99 (1H, d, J=5,9 Hz), of 5.89 (1H, d, J=5.4 Hz), 3,94-to 4.14 (4H, m), 3,85 (1H, s), and 3.16 (2H, s), and 2.27 (6H, s), 0,9-1,20 (21H, m)

Pharmacological test

The antitumor effect of the compounds of the present invention when administered orally Donryu rats with subcutaneously implanted tumor cells

Cell lines of Yoshida sarcoma (ascitic tumor rats), administered intraperitoneally subcultivation in Donryu rats (Charles River Laboratories Japan, Inc.), implanted under the skin of the back of Donryu rats (5 weeks of age) in an amount of 2×104cells/0,2 ml After 4 days after implantation, each rat was weighed, and divided the rats into groups so that the average body weight between groups was approximately equal to (7 rats per group).

Each derived ECyd was dissolved or suspended in 0.5% solution of hydroxypropylmethylcellulose, oral and injected the resulting solution or suspension of each rat daily since split into groups once a day for 7 days at a dose of 12 µmol/kg/day. Derived ECyd was evaluated three times. As a control in each test used ECyd in amounts equimolar with respect to the derived ECyd.

In 7 days after splitting into groups of rats of groups with the introduction of pharmaceuticals measured the mass of the tumor. The tumor weight was also measured in rats, which the pharmaceutical agent is not injected (group without treatment). Expected average weight of the tumors in the group with the introduction of the headlight is aceticism means and in the group without treatment. The degree of inhibition of tumor growth (IR) was determined using the following equation, thereby evaluating the antitumor effect.

IR(%)=[1-(TWtest)/(TWcont)]×100 (equation 1)

[where TWtest and TWcont represent the average tumor weight in the group with the introduction of pharmaceuticals and in the group without treatment, respectively].

The test results presented in table 6.

Table 6
Connection # IR (%)
194,6
3for 93.4
999,6
1188,3
1291,5
1399,8
1499,8
ECyd46,6

As shown in table 6, it was found that oral administration of the compound of the present invention has excellent antitumor effect compared with ECyd.

Separately, the compound of the present invention peroral what about was administered to male Donryu rats, and he measured the content of ECyd in the serum. It was found that, compared with ECyd compound of the present invention is found in the blood in very high concentrations. For example, in very high concentrations in the blood were found connection 1, 3, 4, 9, 11, 12, 14, 15, 17 and 18.

Sample preparation 1

Tablets

Table 7
Connection 150 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, each weighing 250 mg and containing the above companies shall stand, got the usual way.

Example preparation of 2

Granules

Table 8
Connection 9300 mg
Lactose540 mg
Corn starch100 mg
Hydroxypropylcellulose50 mg
Talc10 mg

Pellets (1000 mg/sachet)containing the above composition was obtained in the usual way.

Example preparation of 3

Capsules

Table 9
Connection 11100 mg
Lactose30 mg
Corn starch50 mg
Microcrystalline cellulose10 mg
Magnesium stearate3 mg

Capsules, each weighing 193 mg and containing the above composition was obtained in the usual way.

Example preparation of 4

The injectable form

Table 10
Connection 2100 mg
Sodium chloride3.5 mg
Distilled water
for injection
An appropriate number of
(2 ml/ampoule)

Injectable liquid containing the above composition was obtained in the usual way.

Sample preparation 5

Syrup

Table 11
Connection 3200 mg
Purified sucrose60 g
Ethyl-para-hydroxybenzoate5 mg
Butyl-para-hydroxybenzoate5 mg
FlavorThe appropriate number
DyeThe appropriate number
Purified water The appropriate number

The syrup containing the above composition was obtained in the usual way.

Example 6 preparation

Suppositories

Table 12
The connection 14300 mg
Witepsol W-35 (registered trademark, a mixture of mono-, di-, and triglycerides of saturated fatty acids (lauric - stearic), production Dynamite Novel)1400 mg

Suppositories containing the above composition was obtained in the usual way.

APPLICABILITY IN an INDUSTRIAL environment

Derived 3'-ethinicities or its salt of the present invention is an antitumor drug, which has excellent antitumor activity and excellent absorption when administered orally. Therefore, can be solved the problems associated with intravenous drugs to patients, i.e. mental and physical pain and the extremely high cost of outpatient treatment, and thus it is expected a significant improvement in quality of life (QOL) of patients.

1. Derived 3'-ethinicities represented by the formula (1):

(in which X represents a hydrogen atom, alkylcarboxylic group in which the alkyl fragment is an unbranched or branched C1-C6alkyl group, which as a substituent(s) may contain mono - or disubstituted unbranched or branched C1-C6alkyl group, an amino group, or alkoxycarbonyl group in which the alkoxy fragment is an unbranched or branched C1-C6alkoxygroup;
one of Y and Z represents a hydrogen atom or a group (R1)(R2)(R3Si-, and the other is a group (R4)(R5)(R6Si-; and each R1, R2, R3, R4, R5and R6that may be the same or different from each other, represent unbranched or branched C1-C10alkyl group or a C6-C14aryl group) or its salt.

2. Derived 3'-ethinicities or its salt according to claim 1, where in formula (1), X represents a hydrogen atom, alkylcarboxylic group in which the alkyl fragment is an unbranched or branched C1-C6alkyl group, which as a Deputy may contain dimethylaminopropyl, or alkoxycarbonyl group in which the alkoxy fragm the NT represents an unbranched or branched C 1-C6alkoxygroup; one of Y and Z represents a hydrogen atom or a group (R1)(R2)(R3Si-, and the other is a group (R4)(R5)(R6Si-; and each R1, R2, R3, R4, R5and R6that may be the same or different from each other, represent unbranched or branched C1-C10alkyl group or a C6-C14aryl group.

3. Derived 3'-ethinicities or its salt according to claim 1, where in formula (1), X represents a hydrogen atom; one of Y and Z represents a hydrogen atom or a group (R1)(R2)(R3Si-, and the other is a group (R4)(R5)(R6Si-; and each R1, R2, R3, R4, R5and R6that may be the same or different from each other, represent unbranched or branched C1-C10alkyl group or a C6-C14aryl group.

4. Derived 3'-ethinicities or its salt according to claim 1, where in formula (1), X represents a hydrogen atom; one of Y and Z represents a hydrogen atom or a group (R1)(R2)(R3Si-, and the other is a group (R4)(R5)(R6Si-; and each R1, R2, R3, R4, R5and R6that may be the same and or different from each other, are unbranched or branched C1-C8alkyl group or phenyl group.

5. Derived 3'-ethinicities or its salt according to claim 1, where in formula (1), X represents a hydrogen atom; one of Y and Z represents a hydrogen atom and the other represents a group (R4)(R5)(R6Si-; and each R4, R5and R6that may be the same or different from each other, represent unbranched or branched C1-C8alkyl group or phenyl group.

6. Derived 3'-ethinicities or its salt according to claim 1, where in formula (1), X represents a hydrogen atom; one of Y and Z represents a hydrogen atom and the other represents a tert-butyldimethylsilyloxy group, triethylsilyl group, triisopropylsilyl group, dimethyl-n-octylsilane group, dimethylphenylsilane group, dimethylethoxysilane group or tert-butyldiphenylsilyl group.

7. Derived 3'-ethinicities, selected from the following compounds (1)to(17)or its salt:
(1) 1-[5-O-(tert-butyldimethylsilyl)-3-ethinyl-β-D-ribofuranosyl]cytosine,
(2) 1-[5-O-triethylsilyl-3-With-ethinyl-β-D-ribofuranosyl]cytosine,
(3) 1-[5-O-triisopropylsilyl-3-With-ethinyl-β-D-ribofuranosyl]cytosine,
(4) 1-[5-O-(dimethyl-n-octylsilane)-3-ethinyl-β-D-ribofuranosyl]cytosine,
(5) -[5-O-dimethylphenylsilane-3-With-ethinyl-β-D-ribofuranosyl]cytosine,
(6) 1-[5-O-dimethylacrylic-3-With-ethinyl-β-D-ribofuranosyl]cytosine,
(7) 1-[5-O-(tert-butyldiphenylsilyl)-3-ethinyl-β-D-ribofuranosyl]cytosine,
(8) 1-[2,5-bis-O-(tert-butyldimethylsilyl)-3-ethinyl-1-β-D-ribofuranosyl]cytosine,
(9) 1-[2-O-(tert-butyldimethylsilyl)-3-ethinyl-1-β-D-ribofuranosyl] cytosine,
(10) 1-(2,5-bis-O-triisopropylsilyl-3-With-ethinyl-1-β-D-ribofuranosyl)cytosine,
(11) 1-(2-O-triisopropylsilyl-3-With-ethinyl-1-β-D-ribofuranosyl)cytosine,
(12) 1-(2,5-bis-O-dimethylacrylic-3-With-ethinyl-1-β-D-ribofuranosyl)cytosine,
(13) 1-(2-O-dimethylacrylic-3-With-ethinyl-1-β-D-ribofuranosyl)cytosine,
(14) 1-[5-O-(tert-butyldimethylsilyl)-3-ethinyl-β-D-ribofuranosyl]-4-N-heptanoates,
(15) 1-[5-O-(tert-butyldimethylsilyl)-3-ethinyl-β-D-ribofuranosyl]-4-N-(tert-butoxycarbonyl)cytosine,
(16) 1-[5-O-(tert-butyldimethylsilyl)-3-ethinyl-β-D-ribofuranosyl]-4-N-(N,N-dimethylglycine)cytosine, and
(17) 1-[5-O-(triisopropylsilyl)-3-ethinyl-β-ribofuranosyl]-4-N-(N,N-dimethylglycine)cytosine.

8. Pharmaceutical composition having antitumor activity, containing a derivative of 3'-ethinicities or its salt according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

9. The antitumor drug containing derivative of 3'-ethinicities or its salt according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

10. Oral anticancer Le is arctonoe means, containing derivative of 3'-ethinicities or its salt according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

11. The use of derivative 3'-ethinicities or its salt according to any one of claims 1 to 7 for the production of anticancer drugs.

12. The application of claim 11, where the drug is an oral anticancer drug.

13. A method of treating tumors, characterized in that it includes the introduction of derivative 3'-ethinicities or its salt according to any one of claims 1 to 8 in an effective amount to the needy in this subject.

14. A method of treating a tumor in item 13, where the introduction of means oral administration.



 

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SUBSTANCE: water-salt mixture of vitamins B1 and B12 is prepared, for which the analysed vitamin solutions with pharmacopoeial purity are put into a measuring flask, while stirring, brought to the mark using a saturation solution of a salting-out agent in form of ammonium sulphate. The vitamins are extracted with chemically pure isopropyl alcohol by adding to the obtained water-salt mixture of vitamins isopropyl alcohol in volume ratio of the water-salt mixture of vitamins to isopropyl alcohol equal to 20:1, extracted for 5-7 minutes and after stratification of the system, the aqueous phase is separated from the organic phase. Optical density of the water-salt mixture is measured on a UV spectrophotometre at wavelengths 246 nm and 360 nm (thickness of the light-absorbing layer equal to 1 cm). Molar concentration of vitamins B1 (CB1) and B12 (CB12) is calculated using equations: CB1=6.17·10-5·A246-4.21·10-5·A360 CB12=3.36·10-5·A360, where A426 and A360 are optical density of the solution of mixtures of vitamins B1 and B12 at 246 nm and 360 nm, respectively.

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FIELD: chemistry.

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EFFECT: high distribution and concentration coefficients, faster and safer process.

1 ex, 1 tbl

FIELD: chemistry.

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1 ex, 1 tbl

FIELD: medicine.

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15 cl, 6 tbl

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FIELD: chemistry.

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10 cl, 2 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula (IX) or to their pharmaceutically acceptable salts having inhibitory activity to hepatitis C, to the related pharmaceutical composition and to their application for making a medical product. In compound of formula (IX) , R1 and R2 independently represent H, phosphate or acyl; X represents O; base* represents pyrimidine base; R12 represents C(Y3)3; Y3 represents H and R13 represents fluorine.

EFFECT: higher efficiency of the composition and treatment method.

31 cl, 14 dwg, 26 ex

FIELD: medicine.

SUBSTANCE: invention relates to method of obtaining gemcitabine hydrochloride, characterised by the following: 2,2-dimethyl-[1,3]-dioxolane-4-carbaldehyde is subjected to interaction with ethyl bromodifluoracetate in presence of zinc in organic solvent medium processing reaction mixture with ultrasound for 5-60 minutes, obtained ethyl 3-hydroxy-2,2-difluoro-3-[2,2-dimethyl-[1,3]dioxolane-4-yl]propionate is subjected to hydrolysis and cyclisation by means of ion-exchange resin in water-alcohol medium obtaining (4R,5R)-4-hydroxy-5-hydroxymethyl-3,3-difluorodihydrofuran-2(3H)-on, which is processed with solution of trimethylchlorosilane in dichloromethane obtaining (4R,5R)-4-trimethylsilyloxy-5-((trimethylsilyloxy)methyl)-3,3-difluorodihydrofuran-2(3H)-on, which is subjected to reduction by means of lithium diisopropylalumohydride in organic solvent medium at cooling to -70°C obtaining (4R,5R)-2-hydroxy-4-(trimethylsilyloxy)-5-((thrimethylsilyloxy)methyl)-3,3-difluorotetrahydrofurane, which is converted into (4R,5R)-2-methylsulphonyloxy-4-(trimethylsilyloxy)-5-((trimethylsilyloxy)methyl)-3,3-difluorotetrahydrofurane by processing with methane sulphonylchloride in solvent medium at cold, obtained (4R,5R)-2-methylsulphonyloxy-4-(trimethylsilyloxy)-5-((trimethylsilyloxy)methyl)-3,3- difluorotetrahydrofurane after optic isomer separation is processed with bis-trimethylsilylacetylcytozine in water-free dichlorethane and boil with trifluoromethane sulphonyloxymethylsilane with further cooling and separation of obtained gemcitabine in form of base or hydrochloride, as well as method of gemcitabine hydrochloride purification by its re-crystallisation from water solution with processing with ultrasound.

EFFECT: invention results in increase of ratio 3-(R)-hydroxy-isomer to 3(S)-hydroxy-isomer.

6 cl, 2 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to anhydrous polymorphic salt representing hemisulphate 1-[4(S)-azido-2(S),3(R)-dihydroxy-4-(hydroxymethyl)-1-(R)-cycloamyl]- cytosine of formula (Ia) possessing extra stability and improved physical properties that facilitates production, transportation of compound and preparation of compositions on the basis of compounds of formula I . Invention also refers to various crystal forms of compounds of formula (Ia), characterised by certain values of lattice constant D (interplanar spacing), to methods of their production from compounds of formula (I), to pharmaceutical compositions on the basis of compounds of formula (Ia) and to method of disease treatment caused by C hepatitis virus, including injection if such treatment is required, of therapeutically effective amount of compound of formula (Ia).

EFFECT: production of compound possessing extra stability and improved physical properties that facilitates production, transportation of compound and preparation of compositions on its basis.

14 cl, 5 dwg, 1 tbl, 9 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention pertains to nucleoside derivatives with general formula (I) , where R1 represents hydrogen; COR5, where R5 is chosen from C1-18 alkyl, phenyl, CH2OPh and CH2Ph; C(=O)OR5, where R5 represents C1-18 alkyl; or COCH(R6)NHR7, where R6 represents C1-5 alkyl, and R7 represents R5OCO, where R5 is C1-18 alkyl, R2 represents hydrogen; COR5 , where R5 is chosen from C1-18 alkyl, C1-18 alkenyl, phenyl or CH2OPh; C(=O)OR5, where R5 is chosen from C1-18 alkyl, C1-18 alkenyl, substituted with low alkyl; C(=O)NHR5, where R5 represents C1-18 alkenyl; or COCH(R6)NHR7, where R6 is chosen from side-chains of natural amino acid and C1-5alkyl, and R7 is chosen from hydrogen and R5OCO, where R5 is C1-18 alkyl; R3 and R4 are the same and are chosen from hydrogen; COR5, where R5 is chosen from C1-18 alkyl, or phenyl; C(=O)OR5, where R5 is C1-18 alkyl, or R3 and R4 together represent C(CH3)2; or their pharmaceutical acidic additive salts; under the condition that, at least one of R1, R2, R3 or R4 is not hydrogen. The invention also relates to pharmaceutical compositions, which have antiviral activity to HCV.

EFFECT: obtaining of a range of new biologically active substances.

15 cl, 2 tbl, 9 ex

FIELD: organic chemistry, antiviral agents.

SUBSTANCE: invention relates to a method for synthesis of β-L-5-fluoro-2',3'-dideoxy-2',3'-didehydrocytidine (β-L-FD4C) that is used as an antiviral agent. This method can be used in the large-scale manufacture of β-L-FD4C and it displays the effectiveness, high economy and ecology acceptable.

EFFECT: improved method of synthesis.

23 cl, 1 tbl, 1 ex

FIELD: organic chemistry, biochemistry.

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

EFFECT: valuable properties of analogues.

15 cl, 3 tbl, 4 dwg, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medications and deals with composition for enhancing growth of hematopoetic stem cells CD34+, which contains efficient amount of immunomodelling compound, which represents 4-(amino)-2-(2,6-dioxo(3-pyperidyl))isoindoline-1,3-dione or 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)pyperidine-2,6-dione or its pharmaceutically acceptable salt and efficient amount of valproic acid or trichostatin A or their pharmaceutically acceptable salt. Invention also relates to method of enhancing growth of hematopoetic stem cells CD34+, method of treatment, prevention or controlling hematological disease or disorder, method of transplantation and recovery of bone marrow, method of treatment, prevention or controlling solid tumour, method of treatment, prevention or controlling leukoses and myelomas, method of treatment, prevention or controlling myelodysplastic syndrome and method of increasing expression of embryonic hemoglobin in cells.

EFFECT: compositions by the invention synergistically increase growth of hematopoetic stem cells CD34+.

23 cl, 16 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing N-{5-[4-(4-methyl piperazinomethyl)benzoylamido]-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula (I) (Imatibin) in form of a free base or acid addition salt. Said compounds have anti-tumour activity and can be used, for example, when treating leukaemia. The method involves reduction of N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula (IV) in the presence of a chemical reducing agent, reaction of the obtained N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula (II) with a dihydro-halide salt of 4-(4-methylpiperazinomethyl)benzoylhalide of formula (III) in the presence of an inert organic solvent which is not a base-acid acceptor to obtain a hydro-halide salt of imitinib of formula (I), where n equals 1, 2 or 3 and Hal denotes bromine, chlorine, fluorine or iodine in hydrated form, which, if needed, optionally undergoes further conversion to a free base or some other acid addition salt.

EFFECT: method simplifies the production and extraction process, the process takes place under mild conditions, the obtained hydrohalide salt of imatibin is virtually not soluble in organic solvents and can be easily extracted from the reaction mass.

39 cl, 3 ex

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