Derivatives of 5'-deoxycitidine containing pharmaceutical compositions

 

(57) Abstract:

The invention relates to derivatives of 5’-deoxycitidine General formula

where R1denotes a hydrogen atom or a group which is easily hydrolyzed under physiological environments; R2denotes a hydrogen atom or a group-CO-OR4where R4denotes a saturated hydrocarbon group with a straight or branched chain, containing from one to fifteen carbon atoms, or a group of the formula -(CH2)n-Y, where Y denotes a cyclohexyl or phenyl, and n is an integer from 0 to 4; R3denotes a hydrogen atom, bromine, iodine, cyano, C1-C4alkyl group which may be substituted atom (s) halogen, vinyl or etinilnoy group which may be substituted atom (s) halogen, C1-C4by alkyl; provided that R2and R3may not simultaneously denote a hydrogen atom. Compounds according to the invention have antitumor activity. The invention also relates to pharmaceutical compositions for the treatment of tumors containing as an active ingredient derived 5’-deoxycitidine, alone or in combination with 5-fluorouracil or its derivatives. 3 N. and 4 C.p. the political songs promoting selective delivery of 5-fluorouracil to the tissues of the tumor.

In particular, the present invention relates to new derivatives of 5’-deoxycitidine General formula (I)

where R1denotes a hydrogen atom or a group which is easily hydrolyzed under physiological environments; R2denotes a hydrogen atom or a group-CO-OR4where R4denotes a saturated hydrocarbon group with a straight or branched chain, containing from one to fifteen carbon atoms, or a group of the formula -(CH2)n-Y, where Y denotes a cyclohexyl or phenyl, and n is an integer from 0 to 4; R3denotes a hydrogen atom, bromine, iodine, cyano, C1-C4alkyl group which may be substituted atom(s) halogen, vinyl or etinilnoy group which may be substituted atom(s) halogen, C1-C4by alkyl; provided that R2and R3may not simultaneously denote a hydrogen atom.

Although 5-fluorouracil (5-FU) or its derivatives suitable for use as anticancer agents in clinical practice for the treatment of various solid tumors, however they generally do not yet have udovletvoriaet rapid inactivation of 5-FU dihydropyrimidin-dehydrogenase (DPD) and/or unsatisfactory delivery of 5-FU to the tissues of the tumor from the point of view of selective delivery to the tumor. Previously, attempts were made to enhance the antitumor activity of 5-FU or its derivative by inhibiting DPD, for example, by co-injection of 5-FU or its derivative with a DPD inhibitor, such as uracil [U.S. patent 4328229], 5-itineraries [WO 92/04901], 5-chloro-2,4-dihydroxypyridine [U.S. patent 5525603] etc., of Such co-administration increased the antitumor activity of 5-FU or its derivative, however, the safety features were not improved due to the poor selectivity of the delivery DPD inhibitor to the tissue tumors (resulting in the level of 5-FU was increased in tumors and in plasma).

In contrast, in accordance with the present izobreteniem it was found that the joint introduction of a new derivative of 5’-deoxycitidine General formula (I) and 5-FU or its derivative leads to a significant improvement of selective delivery of 5-FU to the tissues of the tumor compared with the combination of 5-FU or its derivative with known DPD inhibitors, such as 5-itinerarary, and leads to a significant improvement of antitumor activity in xenograft models of cancer man.

Below is a more detailed definition sootvetstvuyu, which is easily hydrolyzed in the physiological environment.

In the above definition of the concept of "group which is easily hydrolyzed in the physiological environment" preferably denotes acetyl, propionyl, benzoyl, toluoyl, glycyl, alanyl, -alanyl, poured, lysyl, etc.

The definition of R2

R2denotes a hydrogen atom or a group-CO-OR4where R4denotes a saturated hydrocarbon group with a straight or branched chain, containing from one to fifteen carbon atoms, or a group of the formula -(CH2)n-Y, where Y denotes a cyclohexyl or phenyl, and n is an integer from 0 to 4.

In the above definition of the term "saturated" hydrocarbon group with a straight or branched chain, containing from one to fifteen carbon atoms" preferably denotes methyl, ethyl, n-propyl, 1-isopropyl-2-methylpropyl, 1,1,2-trimethylpropyl, n-butyl, isobutyl, 2-ethylbutyl, 3,3-dimethylbutyl, n-pentyl, isopentyl, neopentyl, 2-propylpentyl, n-hexyl, 2-ethylhexyl, n-heptyl, n-octyl etc.

The concept of "group of the formula -(CH2)n-Y, where Y denotes a cyclohexyl or phenyl; n is an integer from 0 to 4" denotes cyclohexyl, cyclohexyl-methyl, 2-cyclohexyl preferred embodiment, in compounds of the present invention R4denotes n-propyl, n-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3-dimethylbutyl, 2-ethylbutyl, phenylethyl and cyclohexylmethyl.

The definition of R3

R3denotes a hydrogen atom, bromine, iodine, cyano, C1-C4alkyl group which may be substituted atom(s) halogen, vinyl or etinilnoy group which may be substituted atom(s) halogen, C1-C4the alkyl, provided that R2and R3may not simultaneously denote a hydrogen atom.

In the above definition WITH1-C4alkyl group which may be substituted atom(s) of the halogen preferably denotes methyl, trifluoromethyl, ethyl, propyl, etc.

The term "vinyl or etinilnoy group [which may be substituted atom(s) halogen, C1-C4the alkyl, cycloalkyl, aralkyl or aromatic ring which may have one or more heteroatom(s)]" preferably denotes vinyl, 1-chloride, 2-bromovinyl, 2-bromo-1-chloride, ethinyl, prop-1-inyl, but-1-inyl, Penta-1-inyl, Gex-1-inyl, 3,3-dimethylbutan-1-inyl, cyclopentylamine, cyclohexylamine, phenylethynyl, 3-phenylprop-1-inyl, pyrid-2-ylethynyl, imidazol-2-ylethynyl and Xenitidis of the present invention are

5’-deoxy-5-ethinicities,

5’-deoxy-5-prop-1-initiatedin,

5-but-1-inyl-5’-deoxycytidine,

5’-deoxy-5-Penta-1-initiatedin,

5’-deoxy-5-Gex-1-initiatedin,

5’-deoxy-5-godcity,

5-bromo-5’-deoxycytidine,

5-(1-vinyl chloride)-5’-deoxycytidine,

5’-deoxy-5-vinyliden,

5’-deoxy-5-triptorelin,

5-(3-benzyloxybenzyl)-5’-deoxycytidine,

5-cyan-5’-deoxycytidine,

5’-deoxy-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-N4-(n-pentyloxybenzoyl)-5-prop-1-icitizen,

5-buta-l-inil-5’-deoxy-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-5-Penta-1-inyl-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-5-Gex-1-inyl-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-5-iodine-N4-(n-pentyloxybenzoyl)citizen,

5-bromo-5’-deoxy-N4-(n-pentyloxybenzoyl)citizen,

5-(1-vinyl chloride)-5’-deoxy-N4-(n-pentyloxybenzoyl)citizen,

N4-(etoxycarbonyl)-5’-deoxy-5-vinyliden,

5’-deoxy-N4-(n-propoxycarbonyl)-5-vinyliden,

N4-(n-butoxycarbonyl)-5’-deoxy-5-vinyliden,

5’-denization,

5’-deoxy-N4-(n-pentyloxybenzoyl)-5-triptorelin,

5-(3-benzyloxybenzyl)-5’-deoxy-N4-(n-pentyloxybenzoyl)citizen,

5-cyan-5’-deoxy-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-5-ethinyl-N4(methoxycarbonyl)citizen,

5’-deoxy-N4-(etoxycarbonyl)-5-ethinicities,

5’-deoxy-5-ethinyl-N4-(n-propoxycarbonyl)citizen,

5’-deoxy-5-ethinyl-N4(isopropoxycarbonyl)citizen,

N4-(n-butoxycarbonyl)-5’-deoxy-5-ethinicities,

5’-deoxy-5-ethinyl-N4(isobutoxide)citizen,

5’-deoxy-5-ethinyl-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-5-ethinyl-N4-[(2-propylpentanoate)carbonyl]citizen,

5’-deoxy-5-ethinyl-N4(isopentylamine)citizen,

5’-deoxy-5-ethinyl-N4-[(2-methylpentane)carbonyl]citizen,

5’-deoxy-5-ethinyl-N4-[(3-methylpentane)carbonyl]citizen,

5’-deoxy-5-ethinyl-N4-(n-hexyloxybenzoyl)citizen,

5’-deoxy-N4-[(2-ethylbutyl)oxycarbonyl]-5-ethinicities,

5’-deoxy-N4-[(2-ethylhexyl)oxycarbonyl]-5-ethinicities,

5’-deoxy-5-azetidin,

N4-[(cyclohexylmethoxy)carbonyl]-5’-deoxy-5-ethinicities,

5’-deoxy-5-ethinyl-N4(neopentylglycol)citizen,

5’-deoxy-N4-[(3,3-Dimethylbutane)carbonyl]-5-ethinicities,

2’,3’-di-O-acetyl-5’-deoxy-5-ethinyl-N4-(n-propoxycarbonyl)citizen,

2’,3’-di-O-acetyl-5’-deoxy-5-ethinyl-N4-(n-pentyloxybenzoyl)citizen,

2’,3’-di-O-acetyl-5’-deoxy-5-vinyliden,

2’,3’-di-O-acetyl-N4-(etoxycarbonyl)-5’-deoxy-5-vinyliden,

2’,3’-di-O-acetyl-5’-deoxy-N4-(n-propoxycarbonyl)-5-vinyliden,

2’,3’-di-O-acetyl-N4-(n-butoxycarbonyl)-5’-deoxy-5-vinyliden,

2’,3’-di-O-acetyl-5’-deoxy-N4-(n-pentyloxybenzoyl)-5-vinyliden,

2’,3’-di-O-acetyl-N4(benzyloxycarbonyl)-5’-deoxy-5-vinyliden,

5’-deoxy-5-ethinyl-N4-(n-decyloxybenzoic)citizen,

5’-deoxy-5-ethinyl-N4-[(2,6-dimethylcyclohexylamine)carbonyl]citizen,

5’-deoxy-5-ethinyl-N4(benzyloxycarbonyl)citizen,

5’-deoxy-5-ethinyl-N4-[(1-isopropyl-2-methylpropoxy)carbonyl]citizen,

5’-deoxy-5-ethinyl-N4-[(3-methoxybenzyloxy)carbonyl]citizen.

1means hydroxyamino group, such as acetyl, benzoyl, trimethylsilyl, tert-butyldimethylsilyl etc.

Method AND

The compounds of formula (I), where R1, R2and R3have the above values, can be obtained by the coupling of compounds of formula (II)

[where R1means hydroxyamino group, and R3has the above value], with a compound of General formula (III)

R4OCOX (III)

[where R4has the above meaning; X denotes chlorine or bromine] in the presence of an acid acceptor and optionally with subsequent removal of the release(s) of the group.

Method B

The compounds of formula (I), where R1and R2have the above significance, and R3means etinilnoy or vinyl group [which may be substituted atom (s) halogen, C1-C4the alkyl, cycloalkyl, aralkyl or aromatic ring which may have one or more heteroatom(s)], can be also obtained by the interaction of the compounds of formula (IV)

[where R1and R2have the above values],

with acetylene or vinyl derivative in the presence Method IN

The compounds of formula (I), where R1and R2have the above significance, and R3denotes cyano, can be prepared by the interaction of the compounds of formula (IV)

[where R1and R have the above significance],

cyanide of an alkali metal, and optionally with subsequent removal of the release(s) of the group.

Method D

The compounds of formula (I), where R1and R3have the above significance, and R2denotes a hydrogen atom, can be obtained by the coupling of compounds of formula (V)

[where R1and R3have the above values],

with phosphorylchloride in the presence of an acid acceptor, followed by treatment with ammonia and optionally with subsequent removal of the release (s) of the group.

Method D

The compounds of formula (I), where R1, R2and R3have the above values, can also be obtained by the combination of the compounds of formula (VI)

[where R2and R3have the above value], with a compound of formula (VII)

[where R1has the above value] in the presence of Lewis acid as a catalyst and, if necessary, with subsequent udleadies [which may be substituted atom(s) halogen, C1-C4the alkyl, cycloalkyl, aralkyl or aromatic ring which may have one or more heteros by autom(s)], and R1and R2have the above values, can also be obtained by catalytic hydrogenation of the compounds of formula (VIII)

[where R1means hydroxyamine radical, R3means etinilnoy radical (which may be substituted atom(s) halogen, C1-C4the alkyl, cycloalkyl, aralkyl or aromatic ring which may have one or more heteroatom(s)) and R2has the above value] with Lindlar catalyst and optionally with subsequent removal of the release (s) of the radical(s).

Described in more detail below way to obtain new derivatives of 5’-deoxycitidine formula (I) according to the present invention.

Method AND

Specific examples of compounds of the formula (II) include:

2’,3’-di-O-acetyl-5’-deoxy-5-ethinicities,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-ethinicities,

2’,3’-di-O-acetyl-5’-deoxy-5-prop-1-initiatedin,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-prop-l-initiatedin,

2’,3’-di-O-acetyl-5-but-1-inyl-5’-desal-5’-deoxy-5-Penta-1-initiatedin,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-Penta-1-initiatedin,

2’,3’-di-O-acetyl-5’-deoxy-5-Gex-1-initiatedin,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-Gex-1-initiatedin,

2’,3’-di-O-acetyl-5’-deoxy-5-godcity,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-godcity

2’,3’-di-O-acetyl-5-bromo-5’-deoxycytidine,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5-bromo-5’-deoxycytidine,

2’,3’-di-O-acetyl-5-(1-vinyl chloride)-5’-deoxycytidine,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5-(1-vinyl chloride)-5’-deoxycytidine,

2’,3’-di-O-acetyl-5’-deoxy-5-vinyliden,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-vinyliden,

2’,3’-di-O-acetyl-5’-deoxy-5-triptorelin,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-triptorelin,

2’,3’-di-O-acetyl-5-(3-benzyloxybenzyl)-5’-deoxycytidine,

5-(3-benzyloxybenzyl)-2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxycytidine,

2’,3’-di-O-acetyl-5-cyan-5’-deoxycytidine,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5-cyan-5’-deoxycytidine etc.

The reaction between the above compound of General formula (II) and the above compounds is ontril, chloroform, dichloromethane, etc., in the presence of an acid acceptor, such as triethylamine, pyridine, picoline, 4-(N,N-dimethylamino)pyridine, lutidine, etc., the Reaction can be conducted at a temperature of 0-30C.

At the end of the protective response(s) group(s) may(may) need to be removed(s) by methods well known to specialists in this field, for example, by alkaline or acid hydrolysis or by treatment with anion fluoride.

Method B

Specific examples of compounds of the formula (IV) include:

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-iodine-N4(methoxycarbonyl)citizen,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-N4-(etoxycarbonyl)-5-godcity,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-iodine-N4-(n-propoxycarbonyl)citizen,

N4-(n-butoxycarbonyl)-2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-godcity,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-iodine-N4-(n-pentyloxybenzoyl)citizen,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-iodine-N4(isopentylamine)citizen,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-iodine-N4-(n-hexyloxybenzoyl) citizen,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-iodine-N4-[(2-phenylethane)carbonyl]citizen,

2’,3’-bis-O-(tert-butyldimethylsilyl)-N4-[(cyclohexylmethoxy)carbonyl]-5’-deoxy-5-godcity,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-iodine-N4(neopentylglycol)citizen,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-N4-[(3,3-Dimethylbutane)carbonyl]-5-godcity,

2’,3’-di-O-acetyl-5’-deoxy-5-iodine-N4-(etoxycarbonyl)citizen,

2’,3’-di-O-acetyl-5’-deoxy-5-iodine-N4-(n-propoxycarbonyl)citizen,

2’,3’-di-O-acetyl-N4-(n-butoxycarbonyl)-5’-deoxy-5-godcity,

2’,3’-di-O-acetyl-5’-deoxy-5-iodine-N4-(n-pentyloxybenzoyl)citizen etc.

Specific examples of the acetylene or vinyl derivatives used for this reaction combinations are trimethylsilylacetamide, tert-butyldimethylsilyl, 1-buten, 1-penten, 1 leptin, 1-hexyne, 3-methyl-1-butyn, 3,3-dimethyl-1-butyn, cyclohexylacetate, phenylacetylene, 3-phenyl-1-propyne, tri-n-butyl(vinyl)stannane etc.

The reaction of a combination of compounds of formula (IV) with an acetylene derivative can be carried out in the presence of palladium catalyst, and etc. The reaction of a combination of compounds of formula (IV) with the vinyl derivative can be carried out in the presence of a palladium catalyst such as Tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium chloride, bis(acetonitrile)palladium(II), in the presence of tri-2-furifosmin, triphenylphosphine, etc.,

These reactions can be carried out in a solvent such as chloroform, dichloromethane, tetrahydrofuran, N-organic, N,N-dimethylformamide, etc., the Reaction can be conducted at a temperature of 0 to 80, preferably 10 to 60 SECONDS.

Method IN

The reaction between the above compound of General formula (IV) and the alkali metal cyanide such as sodium cyanide, potassium cyanide, etc. may be carried out in a solvent such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc., the Reaction can be conducted at a temperature of 0-100C, preferably 10-30C.

Method D

Specific examples of compounds of the formula (V) include:

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-itineraries,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-prop-1-injuredin,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5-but-1-inyl-5’-deoxyuridine,

2’,3’-bis-O-(tert-butyldimethylsilyl CLASS="ptx2">2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-iodouridine,

5-bromo-2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxyuridine

2’,3’-bis-O-(tert-butyldimethylsilyl)-5-(1-vinyl chloride)-5’-deoxyuridine,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-vinyluracil,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-triptorelin,

5-(3-benzyloxybenzyl)-2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxyuridine,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5-cyan-5’-deoxyuridine etc.

The above starting materials can be obtained from the known 5-substituted uracil derivative using a method analogous to method D, in which 5-substituted uracile derivative is used instead of 5-substituted casinomaha derived.

The reaction between the above compound of General formula (V) and phosphorylchloride can be carried out in a solvent such as pyridine, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, etc., in the presence of an acid acceptor, such as triethylamine, pyridine, picoline, 4-(N,N-dimethylamino) pyridine, lutidine, imidazole, N-Mei, triazole, etc., at a temperature of 0-30 ° C, followed by treatment of the aqueous ammonia or hatamura 0-30C.

Method D

Specific examples of compounds of the formula (VI) include 5-ethnicity, 5-prop-1-inititation, 5-but-1-inyl-5’-detoxication, 5-Penta-1-inititation, 5-Gex-1-inititation, 5-joltin, 5-bromatosis, 5-(1-vinyl chloride)cytosine, 5-vinicity, 5-cryptometrics, 5-(3-benzyloxybenzyl)cytosine, 5-cianciosi, 5-ethinyl-N4-(n-pentyloxybenzoyl)cytosine, etc.

Specific examples of compounds of General formula (VII) include the well-known 5-deoxy-1,2,3-O-triacetyl-D-ribofuranosyl, 5-deoxy-1,2,3-O-Dibenzoyl-D-ribofuranoside etc.

The compound of formula (VI) may first be converted into trimethylsilyl derived using cilleruelo agent, such as hexamethyldisilazane, followed by conducting the reaction in combination with a compound of formula (VII) in the presence of Lewis acid as a catalyst, such as chloride, tin(IV) chloride titanium(IV), etc., the reaction mix is carried out in a solvent such as acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, nitromethane, toluene, etc. at a temperature of 0 to 30, preferably 0 to 10C.

Method E

Specific examples of compounds of the formula (VIII) include:

5’-deoxy-5-ethinicities,

5’-deoxy-N4-(etoxycarbonyl)-5-ethinyl)-5’-deoxy-5-ethinicities,

5’-deoxy-5-ethinyl-N4-(n-pentyloxybenzoyl)citizen,

N4(benzyloxycarbonyl)-5’-deoxy-5-ethinicities,

2’,3’-di-O-acetyl-5’-deoxy-5-ethinicities,

2’,3’-di-O-acetyl-5’-deoxy-5-ethinyl-N4-(etoxycarbonyl)citizen,

2’,3’-di-O-acetyl-5’-deoxy-5-ethinyl-N4-(n-propoxycarbonyl)citizen,

2’,3’-di-O-acetyl-5’-deoxy-5-ethinyl-N4-(n-pentyloxybenzoyl)citizen etc.

Catholic hydrogenation etinilnoy group of compounds of formula (VIII) can be carried out using Lindlar catalyst in accordance with the method, known to specialists in this field [cf. Synthetic Method, 1952, volume 7, R (Interscience Publishers, Inc., New York)].

New derivatives of 5’-deoxycytidine of the present invention can be used as an antitumor agent in conjunction with physiologically acceptable pharmaceutical carriers.

The present invention also relates to pharmaceutical compositions comprising a derivative of 5’-deoxycitidine General formula (I) and 5-fluorouracil (5-FU) or its derivative. When using this composition derived 5’-deoxycitidine potentional antitumor activity of 5-fu or its derivative by the Iceni concentration of 5-FU in plasma.

For combining the derived 5’-deoxycitidine General formula (I) with 5-FU or its derivatives for cancer treatment more effective and safer profile derived 5-FU preferably chosen from the group including:

5-fluoro-1-(2-tetrahydrofuryl)uracil,

1-(n-hexyloxyphenyl)-5-fluorouracil,

5’-deoxy-5-ferritin,

5’-deoxy-5-fluoro-N4-(n-propoxycarbonyl)citizen,

N4-(n-butoxycarbonyl)-5’-deoxy-5-perltidy,

5’-deoxy-5-fluoro-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-5-fluoro-N4(isopentylamine)citizen,

5’-deoxy-5-fluoro-N4-(n-hexyloxybenzoyl)citizen,

5’-deoxy-N4-[(2-ethylbutyl)oxycarbonyl]-5-perltidy,

5’-deoxy-5-fluoro-N4-[(2-phenylethane)carbonyl]citizen,

N4-[(cyclohexylmethoxy)carbonyl]-5’-deoxy-5-perltidy,

5’-deoxy-5-fluoro-N4(neopentylglycol)citizen,

5’-deoxy-N4-[(3,3-Dimethylbutane)carbonyl]-5-perltidy,

5’-deoxy-5-fluoro-N4-(3,5-dimethylbenzoyl)citizen,

5’-deoxy-5-fluoro-N4-(3,5-dichlorobenzoyl)citizen,

2’,3’-O-acetyl-5’-deoxy-5-fluoro-N4-(n-pentyloxy 5-FU or its derivatives.

Therefore, the pharmaceutical composition of the present invention can be obtained by combining the compounds of formula (I) and 5-FU or its derivative in the form of one drug or can be prepared in the form of two separate drugs.

Pharmaceutical composition comprising a compound of formula (I) may be applied before or simultaneously with the introduction of 5-FU or its derivative; preferably 3 hours before or simultaneously with the introduction of 5-FU or its derivative.

In the pharmaceutical compositions of the present invention, including 5-FU or its derivative and derivative 5’-deoxycitidine General formula (I) acceptable molar ratio of the two components is approximately 0.001 to 10 moles, preferably of 0.002 to 0.5 mol of the compounds of formula (I) per mole of 5-FU or its derivative.

The present invention also relates to a kit containing a pharmaceutical composition (component a), which comprises a compound of formula (I), and pharmaceutical composition (component B), which contains 5-FU or its derivative.

Thus, under the scope of the present invention are subject to pharmaceutical compositions containing a compound of the formula (I) and optional 5-FU or it is ka, lung cancer, cervical cancer, bladder cancer and other malignant diseases, etc.

Pharmaceutical compositions and components a and B are set according to the present invention can be applied in any form, for example in the form of tablets, pills, suppositories, capsules, granules, powders or emulsions etc., Pharmaceutically acceptable carriers and excipients suitable for the preparation of pharmaceutical compositions of the present invention, are conventional. Pharmaceutically acceptable materials can be an organic or inorganic inert carrier. suitable for enteral, percutaneous or parenteral administration, such as water, gelatin, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, and petroleum jelly. The pharmaceutical composition according to the present invention can be administered orally, for example in the form of tablets, capsules, pills, powders, granules, solutions, syrups, suspensions or elixirs. The introduction can also be carried out parenterally, for example in the form of sterile solutions, suspensions or emulsions; or locally, for example in the form of solutions, suspensions, ointments, powders or aerosols. Pharmaceuticalstability, emulsifying agents that improve the smell of agents, salts to change the osmotic pressure or substances acting as buffers.

The pharmaceutical composition may be prepared in conventional manner.

The range of doses of the pharmaceutical compositions of the present invention depends on the route of administration, age, weight and condition of the patient and the particular disease to be treated. In the case of oral, rectal or parenteral administration to adult humans approximate daily dose is from about 1 mg to about 2000 mg of the compounds of formula (I) and from about 10 mg to about 4000 mg of 5-FU or its derivative, depending on the type of derivative of 5-FU. Oral introduction is the preferred route of administration of the pharmaceutical compositions of the present invention.

Selective delivery to the tumor to 5-FU in the selective inhibition of DPD tumor compound of formula (I) are illustrated by the following test.

1. Selective inhibition of DPD tumor compound of example 6

The ability of the compounds of example 6 to inhibit the activity of DPD was compared with that of a known inhibitor of DPD Stateline cancer man. After 2 and 8 h after administration of compound A (0.5 mmole/kg) and 5-EC (0.05 µmol/kg) in each group of mice, consisting of three animals were taken for analysis of liver tissue and tumors. Then measured the activity of DPD in these tissues, carrying out the measurement as described in the literature method (Naguib and others, Cancer Research 45, 5405-5412, 1985). 5-PI inhibited the activity of DPD in liver tissue and tumors, while the connection And markedly inhibited the activity of DPD only in tumor tissue (table 1). These results suggest that the compound of example 6 selectively inhibits the activity of DPD in the tumor tissue.

2. Selective increase in the level of 5-FU in tumors with compounds of example 6 in mice treated with torpedinidae

The experiment whose data are shown in table 2, demonstrates that the compound of example 6 selective increases in tumors AUC (area under the curve) for 5-FU in mice treated with torpedinidae. In this study, ftorpirimidinu, such as 5-FU, doxifluridine [5’-deoxy-5-ferritin] and capecitabine (5’-deoxy-5-ferritin-N4-(n-pentyloxybenzoyl)citizen], was introduced deprived hair to the mice BALB/c mice bearing xenograft MKN28 is whether and in plasma at 0.25, of 0.5, 2, 4 and 7 h after injection of ftorpirimidinu (n=3 individuals) and expected AUC of 5-FU. A well-known inhibitor of DPD 5-PI significantly increased the AUC of 5-FU in plasma and tumor tissues from mice treated with 5-FU, and involving capecitabine or doxifluridine. Because increased levels of 5-FU in the plasma leads to systemic toxicity of 5-FU, 5-EU strengthens both the efficacy and toxicity of torpedinidae.

In contrast, the connection And significantly increases the AUC of 5-FU only in tumors, probably due to the fact that the connection And selectively inhibits tumor activity of DPD, which is involved in the catabolism of 5-FU. Thus, the compound of example 6 enhances the effectiveness of torpedinidae, causing only a slight increase their toxicity.

3. Increase protivoopujolevoe activity involving capecitabine compound of example 6

The compound of example 6 was evaluated with respect to its ability to increase the efficiency involving capecitabine in deprived hairline mice of BALB/c mice bearing xenograft RS prostate cancer person. Connection And and capecitabine was administered orally at the same time or sequentially in those is when the tumor has begun to Mature to palpation. On the 75th day tumor volume was again estimated and used to calculate the percent inhibition of tumor growth. As can be seen from table 3, capecitabine inhibited tumor growth to a greater extent when in combination with the compound a was administered either simultaneously or sequentially. Because by itself, the connection And is not cytotoxic (data not shown), it enhances the effectiveness involving capecitabine by inhibiting the activity of DPD.

Below the invention is illustrated in the examples, not limiting its scope.

Getting the original product for example 1.

a) Obtaining 2’,3’-di-O-acetyl-5’-deoxy-5-itineraryday

5-Itinerarary (12 g, 88,2 mmole) suspended in a solution of ammonium sulfate (570 mg, 4.3 mmole) in hexamethyldisilazane (240 ml). The suspension is boiled under reflux for 6 hours After concentrating the reaction mixture under reduced pressure, to the residue was added a solution of 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranoside (27.5 g, 105,8 mmole) in acetonitrile (300 ml). Then to the mixture was added dropwise a solution of anhydrous tin tetrachloride (27,6 g, 105,8 mmole) in nitromethane (60 ml), keeping the temperature below 0C. After stirring the mixture at 0 C for another 4 h was added racemes was filtered to remove insoluble products, which was washed with ethyl acetate. The filtrate and wash were combined, dried over MgSO4and filtered. The filtrate was evaporated under reduced pressure. After purification of the residue by chromatography on silica gel (using a mixture of 1:2 n-hexane:ethyl acetate as eluent) received 2’,3’-di-O-acetyl-5’-deoxy-5-itineraries (13,7 g, yield 48%).

MALDI-MS: (m/z 359 [M+Na]+, 375 [M+K]+.

1H-NMR: (270 MHz; CDCl3): of 1.47 (3H, d, J=6,6), 2,10 (3H, s), 2,12 (3H, s), 3,23 (1H, s), 4,19-to 4.28 (1H, m), 5,01-of 5.05 (1H, m), and 5.30-of 5.34 (1H, m), 5,90 (1H, d, J=4,95), EUR 7.57 (1H, s), a 8.34 (1H, br.s).

b) Obtain 2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-itineraryday

To a solution of 2’,3’-di-O-acetyl-5’-deoxy-5-itineraryday (13,7 g, 40,7 mmole) dissolved in methanol (100 ml), under stirring at 0C was added dropwise a solution of sodium hydroxide (3.3 g, 81,4 mmole) in water (10 ml). After stirring at 0C for a further 30 min the pH value of the reaction mixture is brought to 7 with 1N. aqueous hydrochloric acid. Then the mixture was evaporated under reduced pressure.

The residue was dissolved in DMF (250 ml) and to the solution under stirring was added imidazole (41,6 g, 610 mm) and tert-butyldimethylchlorosilane (30,7 g, 203 mmole). The mixture continued to stir for 23 hours, the Reaction mixture was soap the ski layers were washed with brine, dried over PA2SO4, was filtered and was evaporated under reduced pressure. After purification of the residue by chromatography on silica gel (using a mixture of 3:1 n-hexane:ethyl acetate as eluent) received 2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-itineraries (14.9 g, yield 76%).

BT-MS: (m/z 481 [M+H]+.

1H-NMR: (270 MHz; CDCl3): 0,10-0,13 (N, m) 0,91 (N, m) of 1.40 (3H, d, J=6,6), 3,21 (1H, s), to 3.58 (1H, dd, J=4,29, 6,6), 4,08-4,17 (2H, m), 5,62 (1H, d, J=2,64), to 7.68 (1H, s), 8,24 (1H, br.s).

The following compounds were obtained in the same way as described above, using appropriate well-known 5-substituted derivatives of uracil.

2’,3’ -bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-iodouridine

BT-MS: (m/z 583 [M+H]+, 605[M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): -0,09 (3H, s) -0,03 (3H, s) 0,00 (3H, s), of 0.02 (3H, s), 0.75 in (N, s) 0,81 (N, s) of 1.24 (3H, d, J=6,6 in), 3.75 (1H, dd, J=4,6, 4,0), 3,86 (1H, m), 4,36 (1H, dd, J=5,3, 5,0), 5,59 (1H, d, J=5,6), to $ 7.91 (1H, s), of 11.69 (1H, br.s).

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-trichlormethiazide

BT-MS: (m/z 525 [M+H]+.

1H-NMR: (400 MHz; D13): 0,00 (6N, s) 0,02 (3H, s), is 0.06 (3H, s), or 0.83 (N, s), or 0.83 (N, s) of 1.32 (3H, d, J=5,9), 3,47 (1H, m), of 4.05 (1H, m), 4,16 (1H, m), 5,54 (1H, d, J=2,2), to 7.84 (1H, s), 8,43 (1H, br.s).

2’,3’-bis-O-(tert-butyldimethylsilyl)-5-(3-b is-0,09-0,01 (N, m), 0.77-a 0,82 (N, m) of 0.90 (3H, d, J=6,3), with 3.27 (1H, m), and 3.31 (1H, d, J=16.5 in), 3,61 (1H, d, J=16.5 in), 3,86 (1H, m), 3,95 (1H. m), 4,94 (2H, s), of 5.50 (1H, d, J=2,0), 6,68-of 6.78 (4H, m), 7,12-7,34 (6H, m), 8,54 (1H, br.s).

The following compounds can be obtained, similarly to that described above, using appropriate well-known 5-substituted uralovich derivatives:

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-prop-1-injuredin,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5-but-1-inyl-5’-deoxyuridine,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-Penta-1-injuredin,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-Gex-1-injuredin,

5-bromo-2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxyuridine

2’,3’-bis-O-(tert-butyldimethylsilyl)-5-(1-vinyl chloride)-5’-deoxyuridine,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-vinyluracil.

Example 1

Obtain 2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-ethinicities

To the solution containing dimethylaminopyridine (19,0 g, 155,5 mmole) in acetonitrile (120 ml) and pyridine (of 12.6 ml, 155,6 mmole), in an ice bath is added dropwise in an atmosphere of AG was added phosphorylchloride (14.4 g, 93,8 mm). After stirring the mixture for 1 h at room temperature was added a solution of 2’,3’-bis-O-(tert-BU is th bath. The mixture was stirred at room temperature for 2 h Then the reaction mixture in one portion was added 25% aqueous ammonia solution (10 ml), keeping the temperature below 10C. To the reaction mixture was added to the second portion of 25% aqueous ammonia solution (65 ml), keeping the temperature below 10C. The mixture was stirred at room temperature for 45 minutes Then the reaction mixture was diluted with water (200 ml) at room temperature and was extracted three times with ethyl acetate. The combined organic layers are successively washed with 1N. aqueous solution of hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over MgSO4, was filtered and was evaporated under reduced pressure. After purification of the residue by chromatography on silica gel (using a mixture of 2:1 n-hexane:ethyl acetate as eluent) received 2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-ethnicities (14.8 g, yield 99%).

MALDI-MS: (m/z 502[M+Na]+, 518 [M+K]+.

1H-NMR: (400 MHz; CDCl3): of 0.05 (3H, s), is 0.06 (3H, s), 0,12 (3H, s), 0,24 (3H, s), 0,89 (N, s) 0,92 (N, s) of 1.41 (3H, d, J=6,35), to 3.36 (1H, s), of 3.46 (1H, dd, J=3,91, 7,81), 4,19-4,26 (2H, m), to 5.57 (1H, s), 5,79 (1H, br.s), EUR 7.57 (1H, br.s), 7,80 (1H, s).

The following compounds were obtained by the method, anaitides

BT-MS: (m/z 582 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): 0,00 (3H, s), of 0.02 (3H, s), is 0.06 (3H, s), and 0.08 (3H, s), 0,82 (N, s) 0,88 (N, s) of 1.30 (3H, d, J=6,6), of 3.78 (1H, dd, J=4,6, 4,3), 3,93 (1H, m), 4,33 (IH, dd, J=4,9, 4,6), 5,67 (1H, d, J=5.0) and to 6.67 (1H, br.s), 7,87 (2H, br.s).

Example 3

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-trifluoromethyl-citadin

BT-MS: (m/z 524 [M+H]+.

1H-NMR: (400 MHz; D13): 0,00 (6N, s), and 0.08 (3H, s), 0,19 (3H, s), 0,84 (N, s), 0,87 (N, s) of 1.35 (3H, d, J=6,6), to 3.38 (1H, m), is 4.15 (1H, m), is 4.21 (1H, m), the 5.51 (1H, s), of 7.97 (1H, s).

Example 4

5-(3-benzyloxybenzyl)-2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxycytidine

BT-MS: (m/z) 652 [M+H]+.

1H-NMR: (270 MHz; DCl3): -0,01 (3H, s) 0,00 (3H, s), and 0.09 (3H, s) and 0.22 (3H, s), 0,86 (N, s), 0,90 (N, s) of 1.10 (3H, d, J=6,6), 3,37 (1H, m), 3,57.(2H, s), 4,08-4,18 (2H, m), of 5.03 (2H, s), 5,59 (1H, s), 6.75 in-6,90 (3H, m), 7,11 (1H, s), 7,26 (1H, m), 7,31-7,44 (5H, m).

Example 5

2’,3’-bis-O-(tert-butyldimethylsilyl)-5-cyan-5’-detoxicated

BT-MS: (m/z 481 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): -0,04 (3H, s) 0,00 (3H, s), 0.02 (3H, s), 0,76 (N, s) 0,82 (N, s) to 1.21 (3H, d, J=6,3), 3,81 (1H, m), of 4.05 (1H, t, J=5.0) and 4,71 (1H, t, J=5.0) and the 5.65 (1H, d, J=5,3), 6,41 (1H, s), 7,69 (1H, br.s), a 7.85 (1H, br.s).

The following compounds can be obtained in a manner analogous to example 5:

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-about the(tert-butyldimethylsilyl)-5’-deoxy-5-Penta-1-initiatedin,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-Gex-1-initiatedin,

5-bromo-2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxycytidine,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5-(1-vinyl chloride)-5’-deoxycytidine,

2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-vinyliden.

Example 6

Obtaining 5’-deoxy-5-ethinyl-N4-(n-pentyloxybenzoyl)cytidine

a) 2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-ethnicities (45 mg, and 0.09 mmole) was dissolved in dichloromethane (1 ml) and pyridine (33 μl, 0,42 mm). To the mixture in an ice bath in an atmosphere of AG was added dropwise n-interharmonic (42 mg, of 0.28 mmole). The reaction mixture was stirred at room temperature for 2 hours was Added water and the reaction mixture was stirred for 30 minutes, the Reaction mixture was distributed between dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over Na2SO4and filtered. The filtrate is ’evaporated under reduced pressure.

After purification of the residue by chromatography on silica gel (using a mixture of 4:1 n-hexane:ethyl acetate as eluent) received 2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-ethinyl-N4-(n-pentyloxy the -0,27 (N, m), and 0.09 to 0.92 (N, m), 1,26-of 1.42 (7H, m), 1,64-of 1.74 (2H, m), 3.25 to 3,51 (2H, m), 4,15-to 4.23 (4H, m), 5,55-the ceiling of 5.60 (1H, m), 7.62mm (0.5 H, br.s), 7,73 (0.5 H, br.s), 8,00 (0.5 H, br.s) to 12.3 (0.5 H, br.s).

b) To a solution of 2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-ethinyl-N4-(n-pentyloxybenzoyl)cytidine (19 mg, 0.03 mmole) in tetrahydrofuran (500 μl) at room temperature in an atmosphere of AG was added dropwise tetrabutylammonium fluoride (93 μl, and 0.09 mmole) [1.0 M solution in tetrahydrofuran]. After stirring the mixture for 2 h at room temperature the reaction mixture was evaporated under reduced pressure. The residue was distributed between dichloromethane and water. The aqueous layer was re-extracted with dichloromethane. The combined organic layers were dried over Na2SO4, was filtered and was evaporated under reduced pressure. After purification of the residue by chromatography on silica gel (using a mix of 20:1 dichloromethane:methanol as eluent) has received a 5’-deoxy-5-ethinyl-N4-(n-pentyloxybenzoyl)citizen (compound A) (9 mg, yield 81%).

BT-MS: (m/z 366 [M+H]+.

1H-NMR: (400 MHz; DMSO-d6): to 0.88 (3H, t, J=6,84), 1.30 AND 1.32 TO (7H, m), 1,59-to 1.63 (2H, m), 3,67-3,71 (1H, m), 3,90-4,46 (5H, m), 5,07 (1H, m), 5,42 (1H, m), to 5.66 (1H, m), 7,89 (0.5 H, br.s), 8,14 (0.5 H, br.s), at 9.53 (0.5 H, br.s) to 11.7 (0.5 H, br.s).

The following compounds (example is bonyl)citadin

BT-MS: (m/z 370 [M+H]+.

1H-NMR: (270 MHz; D13): of 0.91 (3H, t, J=6,93), OF 1.16 (3H, t, J=7,5), OF 1.36 (4H, m), of 1.41 (3H, d, J=6,6), 1,72 (2H, m), 2,47 (2H, q, J=7,5). up 3.22 (1H, br.s) 3,93 (1H, m), of 4.16 (2H, t, J=6,93), 4,28 (2H, m), 4,49 (1H, br.s), to 5.66 (1H, d, J=3,63), 7,37 (1H, br.s), 12,46 (1H, br.s).

Example 8

5’-deoxy-5-iodine-N4-(n-pentyloxybenzoyl)citadin

BT-MS: (m/z 468 [M+H]+, 490 [M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): of 1.36 (3H, t, J=7,0), 1,76-1,78 (7H, m), is 2.09 (2H, m), 4,18 (1H, m), 4,36 (1H, m), of 4.54 (2H, t, J=5,9), 5,54 (1H, br.d, J=5.0) and of 5.84 (1H, br.d, J=5.0) and 6,09 (1H, d, J=4,3), of 8.47 (1H, s), 12,24 (1H, br.s).

Example 9

5’-deoxy-N4-(n-pentyloxybenzoyl)-5-triptorelin

BT-MS: (m/z 410 [M+H]+.

1H-NMR: (270 MHz; Dl3): from 0.88 to 0.94 (3H, m), 1.32 to 1.39 in (4H, m), of 1.42 (3H, d, J=6,6), 1,68 is 1.75 (2H, m), 3,09-3,30 (1H, m), 3,92 (1H, m), 4,15-4,27 (5H, m), 5,67 (1H, d, J=3.3V), 8,05-8,31 (1H, m), USD 12.6 (1H, br.s).

Example 10

5-(3-benzyloxybenzyl)-5’-deoxy-N4-(n-pentyloxybenzoyl)citadin

BT-MS: (m/z 538 [M+H]+.

1H-NMR: (270 MHz; Dl3): of 0.90 (3H, t, J=6,9), WAS 1.04 (3H, d, J=6,6), 1,26-OF 1.39 (4H, m), 1,72 (2H, m), and 3.16 (1H, br.s) to 3.67 (1H, d, J=16.5 in), 3,71 (1H, m in), 3.75 (3H, d, J=16.5 in), 4,10 (2H, m), of 4.16 (2H, t, J=6,9), and 4.40 (1H, br.s) 5,04 (2H, s), 5,62 (1H, d, J=3.3V), 6,79 (1H, d, J=7,6), at 6.84-6.89 in (2H, m), 6,97 (1H, br.s), 7,22-the 7.43 (6H, m), 12,41 (1H, br.s).

Example 11

5-cyan-5’-deoxy-N4-(n-pentyloxybenzoyl)citadin

Example 12

5’-deoxy-5-ethinyl-N4-(n-propoxycarbonyl)citadin

BT-MS: (m/z 338 [M+H]+, 360 [M+Na]+.

1H-NMR: (270 MHz; DMSO-d3): of 0.91 (3H, t, J=7,3), IS 1.31 (3H, d, J=6,3), and 1.63 (2H, sextet, J=7,3), of 3.69 (1H, dt, J=5,9, 5,3), 3,91 (1H, quin., J=5,9), a 4.03 (2H, t, J=6,6), 4,13 (1H, dt, J=5,0, 4,3), 4,35 (1H, br.s) of 5.05 (1H, d, J=5,9), 5,41 (1H, d, J=5,3), to 5.66 (1H, d, J=4,0), 8,01 (1H, br.s).

Example 13

5’-deoxy-5-ethinyl-N4(isopropoxycarbonyl)citadin

BT-MS: (m/z 338 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): 1,24 (6N, d, J=5,9), IS 1.31 (3H, d, J=6,6), 3,68 (1H, dt, J=5,9, 5,6), 3,90 (1H, quin., J=5,9), of 4.12 (1H, m), 4,30 (1H, s), is 4.85 (1H, m), of 5.05 (1H, d, J=5,9), of 5.40 (1H, d, J=5,3), to 5.66 (1H, d, J=3.6), and 8,02 (1H, br.s).

Example 14

N4(isobutoxide)-5’-deoxy-5-ethinicities

BT-MS: (m/z 352 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): 0,91 (6N, d, J=6,6), OF 1.30 (3H, d, J=6,3), at 1.91 (2H, m), 3,68 (1H, dt, J=5,9, 5,3), OF 3.84 (2H, d, J=6,6), with 3.89 (1H, quin., J=6,3), 4,11 (1H, m), 4,30 (1H, s), of 5.03 (1H, d, J=5,9), 5,38 (1H, d, J=5,3), to 5.66 (1H, d, J=4.0) is, of 7.96 (1H, s).

Example 15

5’-deoxy-5-ethinyl-N4-[(2-methylpentane)carbonyl]citizen

BT-MS: (m/z 380 [M+H]+, 402[M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): 0,85-0,93 (7H, m) is 1.31 (3H, d, J=6,3), 1,28-1,37 (3�P CLASS="ptx2">Example 16

5’-deoxy-5-ethinyl-N4-[(3-methylpentane)carbonyl]citizen

BT-MS: (m/z 380 [M+H]+.

1H-NMR: (270 MHz; CDCl3): 0,86-0,98 (6N, m), 1,15-of 1.80 (8H, m), 3.25 to 3,26 (1H, m), 3,53 (1H, br.s), 3,90-of 3.95 (1H, m), 4,25-4,37 (4H, m), 5,33 (1H, br.s), 5,71 (1H, d, J=4,28), 7,69 (1H, br.s), 8,13 (1H, br.s).

Example 17

5’-deoxy-5-ethinyl-N4-[(2-propylpentanoate)carbonyl]citizen

MALDI-MS: (m/z) 408,5 [M+H]+, 430,5 [M+Na]+, 446 [M+K]+.

1H-NMR: (270 MHz; DMSO-d6): 0,87 (6N, br. m) of 1.29 (11N, br. m) of 1.66 (1H, br. m), of 3.69 (1H, br. m), 3,94 to 4.5 (5H, br. m), is 5.06 (1H, br. m), 5,42 (1H, br. m), to 5.66 (1H, br. m), of 7.90 (0.5 H, br.s), 8,14 (0.5 H, br.s), at 9.53 (0.5 H, br.s).

Example 18

5’-deoxy-5-ethinyl-N4-(n-octyloxyphenyl)citadin

BT-MS: (m/z 408 [M+H]+, 430 [M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): 0,86 (3H, t, J=5.0) AND OF 1.26 (10H, m) is 1.31 (3H, d, J=6,0), TO 1.60 (2H, m), of 3.69 (1H, dt, J=5,9, 5,6), 3,90 (1H, quin., J=6,3), 4,06 (2H, t, J=6,3), of 4.13 (1H, m), 4,35 (1H, br.s) of 5.05 (1H, d, J=5,9), 5,41 (1H, d, J=5,3), to 5.66 (1H, d, J=4,0), 8,02 (1H, br.s).

Example 19

5’-deoxy-N4-[(2-ethylhexyl)oxycarbonyl]-5-ethinicities

BT-MS: (m/z 408 [M+H]+.

1H-NMR: (270 MHz; Dl3): from 0.88 to 0.94 (6N, m), 1.30 and 1.41 for (N, m) of 3.25 (1H, d, J=3,63), 3,53 (1H, m), 3,92-of 3.94 (1H, m), 4,15-4,37 (4H, m), 5,32 (1H, m), 5,70 (1H, dt, J=br4.61), 7,86 (1H, br.s) to 8.14 (1H, br.s).

Example 20

5’-deoxy-5-ethinyl-N4Example 21

N4(cyclohexyloxycarbonyl)-5’-deoxy-5-ethinicities

BT-MS: (m/z 378 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): of 1.06 to 1.48 (N, m), 1.69 in (2H, m) to 1.86 (2H, m), 3,65-and 3.72 (1H, m), 3,88-3,93 (1H, m), 4,13-br4.61 (3H, m), is 5.06 (1H, d, J=6,27), 5,42 (1H, d, J=4,95), to 5.66 (1H, d, J=3,63), of 7.9 and 8.1 (1H, m), and 9.4 (0.5 H, br.s), and 11.8 (0.5 H, br.s).

Example 22

N4-[(cyclohexylmethoxy)carbonyl)]-5’-deoxy-5-ethinicities

BT-MS: (m/z 392 [M+H]+, 414 [M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): 0,86-1,25 (5H, m) is 1.31 (3H, d, J=6,3), 1,61-1,72 (6H, m), of 3.69 (1H, dt, J=5,9, 5,6), THE 3.89 (2H, d, J=6,3), 3,90 (IH, m), 4,14 (1H, m), 4,36 (1H, br.s) of 5.05 (1H, d, J=5,9), 5,41 (1H, d, J=5,3), to 5.66 (1H, d, J=4,0), 8,02 (1H, br.s).

Example 23

5’-deoxy-5-ethinyl-N4(neopentylglycol)citadin

BT-MS: (m/z 366 [M+H]+, 388 [M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): 0,93 (N, s) of 1.30 (3H, br.d) 3,67-4,27 (5,5 H, br.m), 4,47 (0.5 H, br.s) of 5.06 (1H, br.m), of 5.39 (1H, br.m), 5,43 (1H, br.m), 7,88 (0.5 H, br.s), 8,16 (0.5 H, br.s), 9,56 (0.5 H, br.s), of 11.69 (0.5 H, br.s).

Example 24

5’-deoxy-N4-[(3,3-Dimethylbutane)carbonyl)-5-ethinicities

BT-MS: (m/z 380 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): 1,01 (N, s) of 1.39 (3H, br.d), and 1.63 (5H, br.s).

Example 25

5’-deoxy-5-ethinyl-N4(treeselectionmodel)citadin

MALDI-MS: (m/z 478 [M+H]+, 516 [M+K]+.

1H-NMR: (270 MHz; DMSO-d6): of 0.85 (3H, d, J=4,6), 1,24 (20N, m) of 1.30 (3H, d, J=6,3), to 1.60 (2H, m), 3,68 (1H, dt, J=5,9, 5,6), 3,90 (1H, quin., J=6,3), of 4.05 (2H, t, J=6,6), 4,13 (1H, dt, J=5,0, 4,3), 4,34 (1H, br.s) of 5.05 (1H, d, J=5,9), of 5.40 (1H, d, J=5,3), the 5.65 (1H, d, J=3.6), and of 8.00 (1H, br.s).

Example 26

N4-(n-butoxycarbonyl)-5’-deoxy-5-ethinicities

BT-MS: (m/z 352 [M+H]+, 374[M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): to 0.89 (3H, t, J=7,2), 1,28-OF 1.41 (5H, m), 1,53-of 1.64 (2H, m), 3,64-3,71 (1H, m), 3,85-to 3.92 (1H, m), a 4.03-to 4.15 (3H, m), 4,34 (1H, s), 5,04 (1H, d, J=5,9), of 5.39 (1H, d, J=5,3), 5,64 (1H, d, J=3.6), and of 8.06 (1H, br.s).

Example 27

5’-deoxy-5-ethinyl-N4-(n-hexyloxybenzoyl)citadin

BT-MS: (m/z 380 [M+H]+, 402[M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): of 0.95 (3H, t, J=6,6), 1,38-1,40 (N, m), 1,63-1,71 (2H, m), 3,74-of 3.80 (1H, m), 3,94-a 4.03 (1H, m), 4,14 (2H, t, J=6,6), 4,19-4,24 (1H, m), 4,43 (1H, s), 5,13 (1H, d, J=5,9), 5,49 (1H, d, J=5,3), 5,74 (1H, d, J=4.0) is, of 8.09 (1H, br.s).

Example 28

5’-deoxy-5-ethinyl-N4-(n-decyloxybenzoic)citadin

MS: BT-MS: (m/z 436 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): d of 0.85 (3H, t, J=6,4), 1,15-1,42 (17H, m), 1,60 (2H, m), of 3.69 (2h, m), 3,90 (1H, m), of 4.05 (2H, t, J=6,6), of 4.13 (1H, m), 4,34 (1H, br.s) 5,04 (1H, d, J=5,6), of 5.40 (1H, d, J=4,9), to 5.66 (1H, d, J=3.6), and 8,01 (1H, br.s).

+.

1H-NMR: (270 MHz; DMSO-d6): d 0,83 (36N, t, J=6,3), 1,20-1,50 (N, m), 1,55-1,75 (2H, m), 3,68 (1H, m), 3,93 (1H, m), 4,12-4,20 (2H, m), 4,45 (0,7 N, s), a 4.86 (0,3 H, s), 5,04 (1H, d, J=5,6), 5,43 (1H, br.s), 5,67 (1H, br.s) of 7.96 (0,3 H, br.s), 8,14 (0,7 H, br.s), 9,50 (0,7 H, br.s) 12,00 (0,3 H. br.s).

Example 30

5’-deoxy-5-ethinyl-N4(benzyloxycarbonyl)citadin

MS: BT-MS: (m/z 386 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6):d of 1.30 (3H, d, J=6,3), of 3.69 (1H, m), with 3.89 (1H, m), 4,13 (1H, m), 4,35 (1H, br.s) of 5.05 (1H, d, J=5,9), 5,14 (2H, s), 5,41 (1H, d, J=5,3), to 5.66 (1H, d, J=3,6), 7,31 was 7.45 (5H, m), 8,01 (1H, br.s).

Example 31

5’-deoxy-5-ethinyl-N4-[(1-isopropyl-2-methylpropoxy)carbonyl]citizen

MS: BT-MS: (m/z 394 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): d 0,93 (N, d, J=6,6), of 1.40 (3H, d, J=6,6), of 1.97 (2H, m) to 3.33 (1H, d, J=3,6), 3,55 (1H, s), 3,91 (1H, m), 4,30 (1H, m), 4,36 (1H, m), to 4.62 (1H, m), of 5.40 (1H, s), 5,72 (1H, d, J=4,3), of 7.69 (1H, s), 8,11 (1H, s).

Example 32

5’-deoxy-5-ethinyl-N4-[(3-methylbenzylamino)carbonyl]citizen

MS:BT-MS: (m/z 416 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): d is 1.31 (3H, d, J=6,0), 3,70 (1H, m), 3,76 (3H, s), 3,90 (1H, m), 4,14 (1H, m), 4.26 deaths (0.5 N, br.s) of 4.44 (0.5 H, br.s) of 5.06 (2H, s), 5,16 (1H, br.s) 5,41 (1H, br.s), to 5.66 (1H, m), 6,91 (1H, d, J=7,9), 7,00 (2H, m), 7,30 (1H, dd, J=7,9, 7,9), 7,89 (0.5 H, br.s), 8,14 (0.5 H, br.s), 9,72 (0.5 H, br.s) to 11.7 (0.5 H, br.s).

Example 33

5’-deoxy-5-ethinyl-N4(methoxycarbonyl)citadin

MS: BTN, m), 4,34 (1H, s), of 5.05 (1H, d, J=5,9), of 5.40 (1H, d, J=5,3), to 5.66 (1H, d, J=4.0) is, of 8.00 (1H, br.s).

Example 34

5’-deoxy-5-ethinyl-N4(ethoxycarbonyl)citadin

MS: BT-MS: (m/z 324 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): d of 1.23 (3H, t, J=6,93), is 1.31 (3H, d, J=6,27), of 3.69 (1H, m), 3,90 (1H, m), 4,08-to 4.14 (3H, m), 4,35 (1H, br.s) of 5.05 (1H, d, J=5,94), of 5.40 (1H, d, J=5,27), to 5.66 (1H, d, J=3,63), 8,02 (1H, br.s).

Example 35

5’-deoxy-N4-(n-pentyloxybenzoyl)citadin

MS: BT-MS: (m/z 342 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): to 0.88 (3H, t, J=6,9), IS 1.31 (4H, m), 1,32 (3H, d, J=6,3) 1,55-to 1.63 (2H, m), 3,63 (1H, dt, J=5,6, 5,6), 3,93 (1H, quin., J=6,3), 3,98 (1H, m) to 4.01 (2H, t, J=6,9), 5,04 (1H, d, J=5,9), 5,42 (1H, d, J=4,6), 5,73 (1H, d, J=3,0), 7,07 (1H, d, J=7,6), of 7.97 (1H, d, J=7,6), 10,66 (1H, br.s).

Example 36

5’-deoxy-N4-(n-pentyloxybenzoyl)-5-vinyliden

MS: LC-MS: (m/z 368 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): to 0.88 (3H, t, J=7,1), 1,31 (7H, m), of 1.61 (2H, m), 3,74 (1H, m), 3,91 (1H, m), 4,06 (2H, t, J=6,4) 4,22 (1H, m), to 5.08 (1H, d, J=5,3), 5,20 (1H, d, J=11,3), of 5.40 (1H, d, J=4,9), 5,69 (1H, d, J=4,0), 5,88 (1H, d, J=17,9), to 6.57 (1H, dd, J=11,3, 17,9), 7,78 (1H, s), 11,88 (1H, s).

Example 37

5’-deoxy-N4(benzyloxycarbonyl)-5-vinyliden

MS: BT-MS: (m/z 388 [M+H]+, 410 [M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): of 1.30 (3H, d, J=6,3), to 3.73 (1H, m), 3,92 (1H, m) to 4.23 (1H, m) to 5.13 (2H, s), 5,04 with 5.22 (2H, m), 5,42 (1H, d, J=5,3) 5,69 (1H, d, J=4,3), 5,6�)-5’-deoxy-5-vinyliden

MS: BT-MS: (m/z 326 [M+H]+, 348 [M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): of 1.23 (3H, t, J=7,26), OF 1.32 (3H, d, J=6,27), 3,70 is 3.76 (1H, m), 3,89-of 3.94 (1H, m), 4,11 (2H, q, J=7,26), 4,22 (1H, m), 5,09 (1H, d, J=5,61) 5,18 with 5.22 (1H, m), 5,42 (1H, d, J=5,61), 5,69 (1H, d, J=3,96), 5,85-of 5.92 (1H, m), to 6.57 (1H, dd, J=11.8 in, 17,82), 7,79 (1H, s), 11,88 (1H, br.s).

Example 39

5’-deoxy-5-iodine-N4-[(2-(phenylethane)carbonyl]citizen

MS: BT-MS: (m/z 502 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): of 1.30 (3H, d, J=6,3), 2,96 (2H, t, J=7,1), of 3.69 (1H, m), 3,88 (1H, m), 4,17 (1H, m), the 4.29 (2H, t, J=7,1) 5,07 (1H, d, J=5,9), 5,38 (1H, d, J=5,3), 5,62 (1H, d, J=4,6), 7,19-to 7.35 (5H, m), 8,01 (1H, s), 11,70 (1H, br. s).

Example 40

5’-deoxy-5-iodine-N4(isopropoxycarbonyl)citadin

MS: MALDI-TOF: m/z 462,5 [M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): 1,24 (6N, d, J=6,3), of 1.30 (3H, d, J=6,3), of 3.69 (1H, m), 3,88 (1H, m), 4,17 (1H, m), to 4.87 (1H, m), 5,07 (1H, d, J=5,6), 5,38 (1H, d, J=5,3), 5,62 (1H, d, J=4,3), 8,02 (1H, s), 11,77 (1H, br. s).

Example 41

N4(cyclohexyloxycarbonyl)5’-deoxy-5-godcity

MC: LC-MS: (m/z) 479,9 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): 1,23-1,42 (6N, m) of 1.29 (3H, d, J=6,3), to 1.70 (2H, m), 1,89 (2H, m), of 3.69 (1H, m), 3,88 (1H, m), 4,16 (1H, m), 4,60 (1H, m), of 5.05 (1H, d, J=5,9), lower than the 5.37 (1H, d, J=5,3), 5,62 (1H, d, J=4,3), of 8.00 (1H, s).

The following compounds can be obtained in a manner analogous to example 6:

5’-deoxy-N-(n-pentyloxybenzoyl)-5-prop-l-INELS-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-5-Gex-1-inyl-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-5-bromo-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-5-(1-vinyl chloride)-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-N4-(n-pentyloxybenzoyl)-5-vinyliden,

5’-deoxy-5-ethinyl-N4(isopentylamine)citizen and

5’-deoxy-N4-[(2-ethylbutyl)oxycarbonyl]-5-ethinicities.

Example 42

Obtain 2’,3’-di-O-acetyl-5’-deoxy-5-Ittihadiya

5-joltin (1.0 g, 4,22 mmole) and a catalytic amount (NH4)2SO4suspended in a solution of toluene (10 ml) and hexamethyldisilazane (20 ml). The suspension is kept at 110S for 18 hours to obtain a transparent solution. After concentrating the reaction solution under reduced pressure, to the residue was added acetonitrile (25 ml) and 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose (1,32 g of 5.06 mmole). Then within 5 min to the mixture was added dropwise anhydrous tin tetrachloride (of 0.58 ml of 5.06 mmole) in nitromethane (5 ml). During the addition the temperature of the mixture was maintained below 0C, cooling on ice. After stirring the mixture for 2 hours at a temperature of 0-5S to the MCA is stirred at room temperature for 30 minutes The reaction mixture was filtered to remove insoluble product, which was washed CH2CL2. The filtrate and wash were combined and washed with water and saturated aqueous sodium bicarbonate, then dried over Na2SO4and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified using the rapid chromatography on SiO2(eluent 5% MEOH/CH2Cl2) to give 5’-deoxy-2’,3’-di-O-acetyl-5-godcity in the form of a colorless solid (1.22 g, yield 66%).

BT-MS: (m/z 438 [M+H]+, 460 [M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): of 1.32 (3H, d, J=6,3), 2,04 (3H, s), of 2.06 (3H, s), was 4.02 (1H, quin., J=6,3), 5,14 (1H, t, J=6,6), of 5.48 (1H, dd, J=6,6, 4,3), 5,69 (1H, d, J=4,0), 6,78 (1H, br.s), 8,01 (1H, br.s), 8,11 (1H, s).

Example 43

Obtain 2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-iodine-N4-(n-pentyloxybenzoyl)cytidine

a) 5’-deoxy-2’,3’-di-O-acetyl-5-godcity (200 mg, and 0.46 mmole) was dissolved in methanol (5 ml). To this solution at 0 C was added dropwise a solution of sodium hydroxide (1 mol/l). After stirring for 10 min the pH value of the reaction mixture is brought to 7 with 1N. hydrochloric acid solution. The reaction mixture was evaporated under reduced pressure.

To the residue was added the Reaction mixture was stirred at 50C for 1 h The mixture was extracted with dichloromethane, washed with water and then dried over Na2SO4and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified using the rapid chromatography on SiO2(eluent from 70% tO/n-hexane to 100% EtOA) to give 5’-deoxy-2’,3’-di-O-(tert-butyldimethylsilyl)-5-godcity in the form of a colorless solid (176,5 mg, yield 66%).

BT-MS: (m/z 582 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): 0,00 (3H, s), of 0.02 (3H, s), is 0.06 (3H, s), and 0.08 (3H, s), 0,82 (N, s) 0,88 (N, s) of 1.30 (3H, d, J=6,6), of 3.78 (1H, dd, J=4,6, 4,3), 3,93 (1H, m) to 4.33 (1H, dd, J=4,9, 4,6), 5,67 (1H, d, J=5.0) and to 6.67 (1H, br.s), 7,87 (2H, br.s).

b) To a stirred solution of 5’-deoxy-2’,3’-bis-O-(tert-butyldimethylsilyl)-5-Ittihadiya (116 mg, 0.200 mmole) in CH2CL2(2 ml) was added at room temperature in the atmosphere of AG pyridine (84 μl, 1.00 mmol), N,N-dimethylaminopyridine (6 mg, 0.05 mmole) and n-interharmonic (95 μl, 0,600 mmole). After stirring for 30 min the reaction mixture was distributed between dichloromethane and water, the organic phase was separated and the aqueous phase was extracted with CH2CL2(15 ml x 4). The combined organic phase was washed with water and brine, dried over Na2SO4and filtered. The filtrate was evaporated under reduced pressure to the bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-iodine-N4-(n-pentyloxybenzoyl)citizen in the form of a colorless amorphous solid (132,4 mg, yield 91%).

BT-MS: (m/z) 696 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): 0,00 (3H, s), of 0.03 (3H, s), 0,05 (3H, s), of 0.07 (3H, s), 0,77 (N, s) 0,81 (N, s), 1,20-of 1.27 (10H, m), 1,46-of 1.55 (2H, m), 3,74 (IH, dd, J=4,6, 4,6), 3,89-4,01 (3H, m), 4,37 (1H, dd, J=4,5, 4,6), of 5.55 (1H, d, J=4,6), 7,92 (1H, s), 11,70 (1H, br.s).

Example 44

Obtain 2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-[(trimethylsilyl)ethinyl]-N4-(n-pentyloxybenzoyl)cytidine

To a solution containing 2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-iodine-N4-(n-pentyloxybenzoyl)citizen (130 mg, of 0.18 mmole) in CH2Cl2(2 ml) and Et3N (2 ml) was added CuI (10,7 mg, 0,1056 mmole), Pd(PPh3)2Cl2(2.6 mg, 0,0036 mmole) and trimethylsilylacetamide (58,6 μl, 0.40 mmole) and stirred for 2 h at room temperature in an atmosphere of AG in the dark. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (25 ml x 3), washed with 2% aqueous solution of disodium salt add (10 ml x 2), water and brine, dried over Na2SO4and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified using the rapid chromatography on SiO2(eluent 10% tO/n-hexane),l)citizen in the form of a colorless amorphous solid (30,2 g, yield 26%).

BT-MS: (m/z) 666[M+H]+, 688[M+Na]+.

1H-NMR: (270 MHz; DMSO-d6): -0,18 (3H, s), -0,16 (3H, s) -0,14 (3H, s) -0,12 (3H, s) 0,00 (N, s), 0,64 (N, s) of 0.65 (3H, s), 0.67 and (N, s), 1,01 (4H, m) to 1.14 (3H, d, J=6,6), OF 1.40 (2H, m) to 3.58 (1H, t, J=4,9), with 3.79 (1H, m), a 3.87 (2H, m), 4,20 (1H, m), 5,43 (1H, d, J=3.6), and 7,88 (1H, br.s).

Example 45

Obtaining 5’-deoxy-2’,3’-bis-O-(tert-butyldimethylsilyl)-5-cuantitativa

To a stirred solution of 5’-deoxy-2’,3’-bis-O-(tert-butyldimethylsilyloxy)-5-Ittihadiya (153 mg, to 0.263 mmole) in DMF (5 ml) was added at room temperature NaCN (to 34.3 mg, 0,70 mmole). After stirring for 1 day, the reaction mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc and then washed with water and brine. The extract was dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified using the rapid chromatography on SiO2(eluent EtOAc) to give 5’-deoxy-2’,3’-bis-O-(tert-butyldimethylsilyl)-5-tiansition as a pale yellow solid (71,1 mg, yield 56%)

BT-MS: (m/z 481 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): -0,04 (3H, s) 0,00 (3H, s), of 0.02 (3H, s), 0,76 (N, s) 0,82 (N, s) to 1.21 (3H, d, J=6,3), 3,81 (1H, m), of 4.05 (1H, t, J=5.0) and 4,71 (1H, t, J=5.0) and the 5.65 (1H, d, J=5,3), 6,41 (1H, s), 7,69 (1H, br.s), 7 which is,3’-di-O-acetyl-5’-deoxy-5-Ittihadiya, Ro 09-4620, (1.6 g, 3,66 mmole) in 10 ml DMF was added in an atmosphere of AG at room temperature PD2(dba)3(67 mg, 0,073 mmole) and tri-2-furifosmin (85 mg, 0,366 mmole) and tri-n-butyl(vinyl)stannane (2.1 ml, 7,318 mmole). After stirring for 19 h to the reaction mixture was added tri-n-butyl(vinyl)stannane (2.1 ml, 7,318 mmole) and the reaction mixture was heated with stirring to 40 ° C for 24 hours the Solvent was removed under vacuum and the residue was purified column chromatography on silica gel (eluent: a mixture of 95:5 ethyl acetate:~CH2CL2:Meon), obtaining 2’,3’-di-O-acetyl-5’-deoxy-5-vinylidene (1.13 g, 92%) as colorless solids

MS:BT-MS: (m/z 338 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): of 1.33 (3H, d, J=6,3), WAS 2.05 (3H, s), of 2.06 (3H, s), of 4.05 (1H, quin., J=6,3), 5,14 (1H, d, J=10,8), 5,16 (1H, t, J=6,6), 5,54 (1H, d, J=17,2), of 5.53 (1H, dd, J=6,9, 5,9), 5,73 (1H, d, J=4,3), 6,55 (1H, dd, J=17,2, 10,8), 7,20 (1H, br.s), EUR 7.57 (1H, br.s), 7,88 (lH, s).

Example 47

Obtaining 5’-deoxy-5-vinylidene

To a solution of 2’,3’-di-O-acetyl-5’-deoxy-5-vinylidene (111 mg, 3,29 mmole) in 5 ml of methanol at room temperature was added 1N. NaOH (0,32 ml of 0.32 mmole). After stirring for 1 h to the reaction mixture were added 1N. Model HC1 (about 0.3 ml) and then the reaction mixture was concentrated at lower levels is 2About:MEON, stepwise gradient) to give 5’-deoxy-5-vinylidene (82 g, 98%) as a colourless solid.

MS: LC-MS: (m/z) 253,9 [M+H]+.

1H-NMR: (270 MHz; DMSO-d6): of 1.29 (3H, d, J=6,3), 3,68 (1H, m), 3,86 (1H, m), 4,08 (1H, m), equal to 4.97 (1H, d, J=5,9), 5,12 (1H, d, J=11,1), 5,28 (1H, d, J=5,3), of 5.50 (1H, d, J=17,2), 5,70 (1H, d, J=3.6), and to 6.58 (1H, dd, J=11,1, 17,2), 7,10 (1H, br.s), 7,42 (1H, br.s) of 7.64 (1H, s).

The following are examples of pharmaceutical preparations containing the compound described in this invention.

If necessary, make the tablet with a film coating, comprising hypromellose, talc and dye.

If necessary, make the tablet with a film coating, comprising hypromellose, talc and dye.

1. Derivatives of 5’-deoxycitidine General formula (I)

where R1denotes a hydrogen atom or a group which is easily hydrolyzed under physiological environments;

R2denotes a hydrogen atom or a group-CO-OR4where R4denotes a saturated hydrocarbon group with a straight or branched chain, containing from one to fifteen carbon atoms, or a group of the formula -(CH2)n-Y, where Y denotes a cyclohexyl or phenyl, the4alkyl group which may be substituted atom(s) halogen, vinyl or etinilnoy group which may be substituted atom(s) halogen, C1-C4the alkyl, provided that R2and R3may not simultaneously denote a hydrogen atom.

2. Connection on p. 1, where R3denotes a hydrogen atom, bromine, iodine, trifluoromethyl, ethyl, propyl, cyano, vinyl, 1-chloride, ethinyl, prop-1-inyl, but-1-inyl, Penta-1-inyl, Gex-1-inyl or bromamines.

3. Connection under item 1 or 2, selected from the group including

5’-deoxy-5-ethinicities,

5’-deoxy-5-prop-1-initiatedin,

5-but-1-inyl-5’-deoxycytidine,

5’-deoxy-5-Penta-1-initiatedin,

5’-deoxy-5-Gex-1-initiatedin,

5’-deoxy-5-godcity,

5-bromo-5’-deoxycytidine,

5-(1-vinyl chloride)-5’-deoxycytidine,

5’-deoxy-5-vinyliden,

5’-deoxy-5-triptorelin,

5-(3-benzyloxybenzyl)-5’-deoxycytidine,

5-cyan-5’-deoxycytidine,

5’-deoxy-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-N4-(n-pentyloxybenzoyl)-5-prop-1-icitizen,

5-but-1-inyl-5’-deoxy-N4-(n-pentyloxybenzoyl)citizen,

5’-arbonyl)citizen,

5’-deoxy-5-iodine-N4-(n-pentyloxybenzoyl)citizen,

5-bromo-5’-deoxy-N4-(n-pentyloxybenzoyl)citizen,

5-(1-vinyl chloride)-5’-deoxy-N4-(n-pentyloxybenzoyl)citizen,

N4-(etoxycarbonyl)-5’-deoxy-5-vinyliden,

5’-deoxy-N4-(n-propoxycarbonyl)-5-vinyliden,

N4-(n-butoxycarbonyl)-5’-deoxy-5-vinyliden,

5’-deoxy-N4-(n-pentyloxybenzoyl)-5-vinyliden,

N4(benzyloxycarbonyl)-5’-deoxy-5-vinyliden,

5’-deoxy-N4-(n-pentyloxybenzoyl)-5-triptorelin,

5-(3-benzyloxybenzyl)-5’-deoxy-N4-(n-pentyloxybenzoyl)citizen,

5-cyan-5’-deoxy-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-5-ethinyl-N4(methoxycarbonyl)citizen,

5’-deoxy-N4-(etoxycarbonyl)-5-ethinicities,

5’-deoxy-5-ethinyl-N4-(n-propoxycarbonyl)citizen,

5’-deoxy-5-ethinyl-N4(isopropoxycarbonyl)citizen,

N4-(n-butoxycarbonyl)-5’-deoxy-5-ethinicities,

5’-deoxy-5-ethinyl-N4(isobutoxide)citizen,

5’-deoxy-5-ethinyl-N4-(n-pentyloxybenzoyl)citizen,

5’-deoxy-5-ethinyl-N4-[(2-methylpentane)carbonyl]citizen,

5’-deoxy-5-ethinyl-N4-[(3-methylpentane)carbonyl]citizen,

5’-deoxy-5-ethinyl-N4-(n-hexyloxybenzoyl)citizen,

5’-deoxy-N4-[(2-ethylbutyl)oxycarbonyl]-5-ethinicities,

5’-deoxy-N4-[(2-ethylhexyl)oxycarbonyl]-5-ethinicities,

5’-deoxy-5-ethinyl-N4-[(2-phenylethane)carbonyl]citizen,

N4(cyclohexyloxycarbonyl)-5’-deoxy-5-ethinicities,

N4-[(cyclohexylmethoxy)carbonyl]-5’-deoxy-5-ethinicities,

5’-deoxy-5-ethinyl-N4(neopentylglycol)citizen,

5’-deoxy-N4-[(3,3-Dimethylbutane)carbonyl]-5-ethinicities,

2’,3’-di-O-acetyl-5’-deoxy-5-ethinyl-N4-(n-propoxycarbonyl)citizen,

2’,3’-di-O-acetyl-5’-deoxy-5-ethinyl-N4-(n-pentyloxybenzoyl)citizen,

2’,3’-di-O-acetyl-5’-deoxy-5-vinyliden,

2’,3’-di-O-acetyl-N4-(etoxycarbonyl)-5’-deoxy-5-vinyliden,

2’,3’-di-O-acetyl-5’-deoxy-N4-(n-propoxycarbonyl)-5-vinyliden,

2’,3’-di-O-acetyl-N4-(n-butoxycarbonyl)-5’-deoxy-5-vinyliden,

2’,3’-di-O-acetyl-5’-deoxy-N45’-deoxy-5-ethinyl-N4-(n-decyloxybenzoic)citizen,

5’-deoxy-5-ethinyl-N4-[(2,6-dimethylcyclohexylamine)carbonyl]citizen,

5’-deoxy-5-ethinyl-N4(benzyloxycarbonyl)citizen,

5’-deoxy-5-ethinyl-N4-[(1-isopropyl-2-methylpropoxy)carbonyl]citizen,

5’-deoxy-5-ethinyl-N4-[(3-methoxybenzyloxy)carbonyl]citizen.

4. Connection at one PM.1, 2 or 3, intended for the treatment of tumors.

5. Pharmaceutical composition for treating tumors containing compound on PP.1, 2 or 3 as an active ingredient.

6. Pharmaceutical composition for treating tumors containing compound on PP.1, 2 or 3 as an active ingredient and 5-fu or its derivative.

7. The pharmaceutical composition according to p. 6, where a derivative of 5-fluorouracil selected from the group consisting of 5’-deoxy-5-ferritin, 5’-deoxy-5-fluoro-N4-(n-pentyloxybenzoyl)citizen.

 

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< / BR>
where R1represents a methyl group, R2represents a methyl group, R4represents a hydroxy-group and X represents a methylene group; R1represents a methyl group, R2represents a hydrogen atom, R4represents a hydroxy-group and X represents a methylene group; R1represents a methyl group, R2represents a methyl group, R4represents a hydrogen atom and X represents a methylene group; R1represents a hydrogen atom, R2represents a hydrogen atom, R4represents a hydroxy-group and X represents a methylene group; or R1represents a methyl group, R2represents a methyl group, R4represents a hydroxy-group and X represents a sulfur atom

The invention relates to substituted ammonium salts of 5'-H-phosphonate 3'-azido-3'-deoxythymidine General formula (1), where RR'R N are L-alanine, ethanolamine, triethanolamine, 6-aminocaproic acid, pyridoxine or dimethylaminoethanol, which are selective inhibitors of the production of human immunodeficiency virus HIV-1 and HIV-2

The invention relates to a method for producing 5'-deoxy-5-ptoluidine formula I, including (a) the interaction of 2',3'-O-isopropylidene-5-ptoluidine formula II with a functional derivative of a sulfonic acids R-SO3H, where R is a (C1-C4)alkyl, triptorelin, unsubstituted, mono-, di - or tizamidine phenyl group, (b) interaction of a derivative of formula IV with iodide of alkaline or alkaline earth metal, (C) hydrolysis of a derivative of formula V in an acidic environment, and (d) recovering a derivative of formula VI with hydrogen or a hydrogen donor

The invention relates to certain nucleoside derivative, which was found to possess valuable properties for the treatment of tumors

The invention relates to intermediate compounds used in the synthesis of CIS-nucleosides, their analogues and derivatives of nucleosides of high purity, the method of obtaining these intermediate compounds

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