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CN1693309A - N4 (substituted oxycarbonyl) 2',2'-bifluoro-2'-deoxycytidine derivate and application thereof - Google Patents

N4 (substituted oxycarbonyl) 2',2'-bifluoro-2'-deoxycytidine derivate and application thereof Download PDF

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CN1693309A
CN1693309A CNA2005100644438A CN200510064443A CN1693309A CN 1693309 A CN1693309 A CN 1693309A CN A2005100644438 A CNA2005100644438 A CN A2005100644438A CN 200510064443 A CN200510064443 A CN 200510064443A CN 1693309 A CN1693309 A CN 1693309A
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fluoro
hydrate
solvate
deoxyribose cytidine
compound according
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陈耀明
富兰克·热拉
明新
邓盛齐
王俊雄
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Zhengkai Biological Sci & Tech Dev Co Ltd Chengdu
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Zhengkai Biological Sci & Tech Dev Co Ltd Chengdu
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Priority to PCT/CN2005/002430 priority patent/WO2006111058A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical

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Abstract

A N4-(substituted oxycarbonyl)-2',2'-difluoro-2'-deoxycytidine, its derivative, its hydrate, and its solution for treating tumor is prepared through reaction between R-OCOCl and N4-unsubstituted 2',2'-difluoro-2'-deoxycytidine.

Description

N 4-(the oxygen carbonyl of replacement)-2 ', 2 '-two fluoro-2 '-'-deoxycytidine derivatives and application thereof
Technical field
The present invention relates to general formula (I), N 4-(the oxygen carbonyl of replacement)-2 ', 2 '-two fluoro-2 '-'-deoxycytidine derivatives, and the application of this compound in antineoplastic agent.
Particularly, the present invention relates to hydrate or solvate, the invention still further relates to pharmacokinetic properties and have pharmaceutical composition good safety, that contain these compounds with good curing tumour with general formula (I) compound:
R wherein 1The group of representative easy hydrolysis under physiological condition, R 1It is alkyl saturated or unsaturated, straight or branched.
Background technology
Known gemcitabine is useful antineoplastic agent, clinical nonsmall-cell lung cancer, carcinoma of the pancreas, bladder cancer, mammary cancer and other noumenal tumours of being used for.It is the good substrates of thymine deoxyriboside kinase phosphorylation in cell that gemcitabine is done, and changes into following metabolite under the effect of enzyme: gemcitabine-phosphoric acid salt (dFdCMP), gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP) wherein dFdCDP and dFdCTP are active result.DFdCDP suppresses ribonucleotide reductase, thereby has reduced the amount (especially dCTP) that the DNA synthetic is repaired required deoxynucleotide, and low-level dCTP has reversed the normal negative feedback inhibition of deoxidation glycosides kinases, causes dFdCTP more to gather.DFdCDP has suppressed the deamination of dCTP inductive deoxidation born of the same parents ammonia enzyme to dFdCMP simultaneously, and dFdCTP directly suppresses Deoxyribose cytidine and takes off enzyme, thereby make more dFdCMP change into the deamination of active metabolite dFdCMP, and dFdCTP directly suppresses deoxycytidine deaminase, thereby make more dFdCMP change into active metabolite dFdCDP, dFd-CTP dFdCTP then combines with the dCTP competition and enters the DNA chain, be inserted into the site of Deoxyribose cytidine in the DNA chain, and permission guanosine and its pairing, the gemcitabine molecule just " is sheltered " by this guanosine and is made it avoid the reparation that removes of exoribonuclease, the DNA chain is synthetic then stops, and then dna break, necrocytosis.It has tangible cytotoxic activity to the people and the mouse tumour of various cultivations, and its antitumour activity is relevant with drug-fast mode, causes animal dead as administration meeting every day, and antitumour activity seldom, give 1 medicine when per 3～4 days, when non-lethal quantity, the kinds of tumors of mouse is all had good antitumour activity.
USP4966891 discloses the 5-FU precursor that is improving aspect biological transformation ratio and the toxicity.N 4-(the oxygen carbonyl of replacement)-5-fluoro-5 '-'-deoxycytidine derivatives by Ntn hydrolase change into 5-fluoro-5 '-Deoxyribose cytidine (5 '-DFCR), by the cytidine desaminase change into 5-fluoro-5 '-deoxyuridine (5 '-DFUR), change into 5-FU in vivo by the pyrimidine nucleotide Starch phosphorylase then.Derivative capecitabine wherein successfully be developed as real oral antitumor medicine be used for the treatment of various types of mammary cancer and each in period large bowel cancer.The inventor finds N 4Ntn hydrolase isozyme in the oxygen carbonyl gemcitabine precursor that replaces other organs inhuman by mainly concentrating on liver optionally changes into gemcitabine, and N 4-methyl substituted gemcitabine, N 4-benzoylated gemcitabine is all insensitive to monkey and people liver Ntn hydrolase, very difficultly can be converted into gemcitabine, so preferred N 4The oxygen carbonyl gemcitabine that replaces, they can be in human body expeditiously bio-transformation be have 2 of anti-tumor activity ', 2 '-two fluoro-2 '-Deoxyribose cytidine, improved pharmacokinetic properties.The proof inside and outside all can be changed into by Ntn hydrolase have 2 of anti-tumor activity ', 2 '-two fluoro-2 '-Deoxyribose cytidine (gemcitabine).Compounds for treating index of the present invention than gemcitabine and 5 '-deoxidation-5 FU 5 fluorouracil height, and lower to the toxicity of enteron aisle (diarrhoea) and immune response organ (thymus gland and marrow), show that compound provided by the invention might have than higher security.
Technology contents
To illustrate in greater detail each group of the general formula (I) of following definitions below:
R 1Be alkyl (wherein the carbonatoms on the long linear of this alkyl is 3 to 17) saturated or undersaturated, straight or branched, perhaps R 1Be formula-(CH 2) n(wherein when Y was cyclohexyl, n was 0 to 12 integer to-Y base; Perhaps have the lower alkoxy of 1 to 4 carbon atom or Y when being phenyl as Y, n is 2 to 12 integer).
Above-mentioned term " saturated or undersaturated; directly or the alkyl of side chain " (wherein the longest carbonatoms on directly of this alkyl is 3 to 17) " preferably represent n-propyl; 1-sec.-propyl-2-methyl-propyl; 1; 1; 2-trimethylammonium propyl group, normal-butyl, isobutyl-, the 2-ethyl-butyl, 3, the 3-dimethylbutyl, n-pentyl, isopentyl, neo-pentyl, 2-propyl group amyl group, n-hexyl, the 2-ethylhexyl, n-heptyl, allyl group, 2-butylene-1-base, 3-butene-1-Ji, 3-amylene-1-base, 4-amylene-1-base, 3-hexene-1-base, 4-hexene-1-base and 5-hexene-1-base etc.
Term " formula-(CH 2) (wherein when Y was cyclohexyl, n was 0 to 12 integer to the n-Y base; Perhaps have the lower alkoxy of 1 to 4 carbon atom or Y when being phenyl as Y, n is 2 to 12 integer) " preferred representative ring hexyl, cyclohexyl methyl, 2-cyclohexyl ethyl, 3-cyclohexyl propyl group, 4-cyclohexyl butyl, 2-methoxy ethyl, 2-ethoxyethyl group, 2-propoxy-ethyl, 3-methoxy-propyl, 3-ethoxycarbonyl propyl, 4-methoxyl group butyl, 4-oxyethyl group butyl, styroyl, 3-phenyl propyl and 4-phenyl butyl etc.
In the most preferred object lesson of The compounds of this invention, R1 represents n-propyl, normal-butyl, n-pentyl, styroyl and cyclohexyl methyl.
The preferred N of the present invention 4-(the oxygen carbonyl of replacement)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine is:
N 4-(the third oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine
N 4-(butoxy carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine
N 4-(penta oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine
N 4-(styroyl oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine
N 4-[(cyclohexyl methoxy) carbonyl]-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine and hydrate or solvate etc.
N with general formula (I) expression 4-(the oxygen carbonyl of replacement)-2 '; 2 '-two fluoro-2 '-Deoxyribose cytidine and hydrate thereof or solvate can be according to [Transient protection:One-Flask Synthesis of Protected Deoxynucleosides J.Am.Chem.Soc.104; 1316-1319 (1982)] describedly pass through 2 '; 2 '-two fluoro-2 '-Deoxyribose cytidine is with the compound reaction of chlorotriethyl silane protection back with general formula (II) representative, handles through trifluoracetic acid to prepare target compound after sloughing the silanization blocking group.
R 1OCOCl????????????????(II)
Above-mentioned general formula (I) compound can exist with non-solvent form or solvation form (comprising hydrate forms).The hydrate effect can realize in preparation process that perhaps the result as initial anhydrous product moisture absorption can take place gradually.Containing acceptable solvent such as alcoholic acid solvate can for example obtain in the crystallisation process.
By the N shown in the general formula (I) of the present invention's preparation 4-(the oxygen carbonyl of replacement)-2 ', 2 '-two fluoro-2 '-hydrate of '-deoxycytidine derivatives and general formula (I) compound or solvate oral administration and use, in very wide dosage range, in mouse, shown the activity of anti-sarcoma 180, anti-Lewis lung cancer through non-enteron aisle, and be useful antineoplastic agent.They change into expeditiously by the Ntn hydrolase isozyme have 2 of anti-tumor activity ', 2 '-two fluoro-2 '-Deoxyribose cytidine (gemcitabine) and working.
The invention still further relates to pharmaceutical composition, particularly treat the pharmaceutical composition that tumour is used, it is characterized in that containing above-mentioned general formula (I) compound.
N of the present invention 4-(the oxygen carbonyl of replacement)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine can be by various conventional application processes to human oral or non-oral medication.And, N of the present invention 4-(the oxygen carbonyl of replacement)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine can use separately, perhaps prepare with compatible pharmaceutical carrier material.This carrier substance can be the organic or inorganic inert support that is applicable to administration in the intestines, percutaneous dosing or parenteral admin, as water, gelatin, gum arabic, lactose, starch, Magnesium Stearate, talcum, vegetables oil, polyglycol or vaseline.This pharmaceutical composition can be made solid form (for example tablet, dragee, enteric coated tablets, granule, enteric coated particles agent, suppository, glue assist agent or intestines glue to assist agent), semi-solid form (as ointment) or liquid form (as solution, clouding agent or emulsion).This pharmaceutical composition can be sterilization and/or can further contain assistant agent such as sanitas, stablizer, peptizer or emulsifying agent, correctives, be used to change the salt of osmotic pressure or as the material of buffer reagent.This pharmaceutical composition can prepare according to a conventional method.
N of the present invention 4-(the oxygen carbonyl of replacement)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine can use separately, perhaps with two or more different N 4-(the oxygen carbonyl of replacement)-2 ', 2 '-two fluoro-2 '-mixture of Deoxyribose cytidine uses.Weight with pharmaceutical composition is benchmark, N 4-(the oxygen carbonyl of replacement)-2 ', 2 '-two fluoro-2 '-amount of Deoxyribose cytidine is about 0.1 to 99.5%, preferred 0.5 to 95%.
Pharmaceutical composition of the present invention can with other conventional antineoplastic agent mixed preparing.
Experimental section:
1. N of the present invention 4-(the oxygen carbonyl of replacement)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine is as follows to the susceptibility of Ntn hydrolase:
With N of the present invention 4-(the oxygen carbonyl of replacement)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine, N 4-methyl gemcitabine, N 4-benzoyl gemcitabine and monkey or people's liver crude extract was cultivated 120 minutes at 37 ℃.Then by HPLC separated product 2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine, calculate transformation efficiency.As shown in table 1, N 4-methyl substituted gemcitabine, N 4-benzoylated gemcitabine is all insensitive to monkey and people liver Ntn hydrolase; very difficultly can be converted into gemcitabine; compound provided by the invention is extremely sensitive to people liver Ntn hydrolase; illustrate they can be in human body expeditiously bio-transformation be have 2 of anti-tumor activity ', 2 '-two fluoro-2 '-Deoxyribose cytidine.
The transformation efficiency of Ntn hydrolase in table 1. pair monkey and the people liver
Compound embodiment number ??R1 The monkey liver The people liver
??1 N-pentyl ??36 ??95
??2 ??3 ??4 ??N 4-methyl gemcitabine N 4-benzoyl gemcitabine Normal-butyl cyclohexyl methyl styroyl ??25 ??33 ??26 ??0 ??0.7 ??75 ??92 ??83 ??0 ??0.9
2. the pharmacokinetic properties in monkey
Give each group (every group of 2-4 only, 3-4kg) oral The compounds of this invention of monkey.Different time after medication is got blood, is used to measure the haemoconcentration of complete molecule and meta-bolites gemcitabine thereof.
Meta-bolites in the HPLC separated plasma also calculates its concentration.As shown in table 2, compound of the present invention has high-caliber C MaxWith blood plasma active metabolite gemcitabine.These results show that these compounds provided by the present invention can be used for the treatment of human various tumours effectively.
The pharmacokinetic properties of table 2 in monkey
Compound (embodiment number) Gemcitabine in the blood plasma
C max(μg/ml) AUC (μ g hour/ml)
??1 3.36 ??3.96
??2 ??3 ??4 ??2.17 ??2.48 ??2.01 ??3.20 ??3.49 ??2.97
The anti-tumor activity of The compounds of this invention is as follows:
2. anti-sarcoma 180 test
With sarcoma 180 cell (2X106), in D 0(my god) to inject small white mouse (20-24g) subcutaneous.By D 1Begin oral The compounds of this invention, once a day, serve on seven days.D 14Put to death animal, the taking-up tumour is also weighed.The inhibition percentage of tumor growth is calculated by following formula:
Suppress %=(1-T/C) * 100
The tumor weight of T=test group, the tumor weight of C=control group.
The effect of the anti-murine sarcoma 180 of table 3
Compound (embodiment number) Dosage (mmol/kg/ days) Inhibiting rate %
??1? ? ??2 ??0.5 ??1.5 ??0.5 ??1.5 ??61 ??83 ??49 ??77
3. anti-Lewis lung cancer test
To N of the present invention 4-(the oxygen carbonyl of replacement)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine, 2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine, 5 '-anti-tumor activity of deoxidation-5 FU 5 fluorouracil compares research.With Lewis lung cancer cell (106), with D 0It is subcutaneous that it is inoculated in small white mouse.By D 1It beginning, oral above-claimed cpd, once a day, continuous 14 days.Measure effective dose (ED 50, i.e. the dosage of tumor suppression 50%) and poisonous dosage.Test records therapeutic index (poisonous dosage/ED 50) list in table 4, by table 4 as seen, compounds for treating index of the present invention than gemcitabine and 5 '-deoxidation-5 FU 5 fluorouracil height, and lower to the toxicity of enteron aisle (diarrhoea) and immune response organ (thymus gland and marrow), show that compound provided by the invention might have than higher security.
Table 4
Compound (instance number) Do not cause the maximal dose of diarrhoea Thymus gland reduces 50% Medullary cell reduces by 50%
1 gemcitabine 5 '-deoxidation-5 FU 5 fluorouracil ??19 ??12.3 ??7 ??15.2 ??10 ??9 ??10.6 ??11.5 ??8.6
Behind the tumor inoculation 15 days, instantiation compound, gemcitabine and 5 '-deoxidation-5 FU 5 fluorouracil ED 50Be respectively 0.25,1.05 and 0.47mmol/kg/ days.
4. acute toxicity test
Give the oral representative compound of small white mouse (example 1-4), measure their acute toxicity (LD 50).Record each LD by test 50Value is all greater than 1000mg/kg.
Embodiment
Following embodiment will illustrate in greater detail the present invention, rather than limit its scope in all senses.
Embodiment 1
Preparation N 4-(penta oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine
2 ', 2 '-two fluoro-2 '-(0.76g is 2.89mmol) with twice of anhydrous pyridine (5ml) azeotropic decompression rotary distillation for Deoxyribose cytidine, be dissolved in anhydrous pyridine (5ml) then, (2.2ml 13.1mmol), stirred 1 hour under the room temperature to add chlorotriethyl silane in above-mentioned reaction solution.Then, in above-mentioned reaction solution, add amyl chlorocarbonate (5ml), continue under the room temperature to stir 2 hours.Reacted the back reduction vaporization to doing, residuum is dissolved in mixed solvent methylene chloride (26ml, 1: 1), adds trifluoracetic acid (1.36ml) under room temperature, stirs 30 minutes.Reaction solution is used 5%NaHCO respectively with methylene dichloride (20ml) dilution 3The aqueous solution (13ml) and water (15ml) washing, the organic layer anhydrous Na 2SO 4Drying is filtered and the decompression rotary evaporation is extremely done.Oily residuum silica gel column chromatography separating purification obtains N with methylene chloride (20: 1) washing separation 4-(penta oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine (665mg, yield 61%): fusing point 59-60 ℃.UV(MeOH)：λ max242nm(ε＝11500)； 1H-NMR(DMSO-d 6)：δ10.82(s，1H，NH)；δ?8.21(d，1H，H-6)；δ7.09(d，1H，H-5)；δ6.32(d，1H，H-1′)；δ6.14(t，1H，OH-3′)；δ5.30(m，1H，OH-5′)；δ4.23(m，1H，H-3′)；δ4.10(m，2H，OCH 2)；δ3.88(m，1H，H-4′)；δ3.78(m，1H，H-5′)；δ3.64(m，1H，H-5′)；δ1.60(m，2H，CH 2)；δ1.30(m，4H，2?CH 2)；0.87(m，3H，CH3). 13C-NMR(DMSO-d 6)：δ153.19(s，C-2)；δ163.42(s，C-4)；δ94.87(s，C-5)；δ144.33(s，C-6)；δ84.07(m，C-1′)；δ122.94(t，C-2′)；δ68.39(m，C-3′)；δ80.98(m，C-4′)；δ58.80(m，C-5′)；δ154.03(s，CO)；δ65.37，27.88，27.38，21.74(m，4CH 2)；δ13.87(m，CH3). 19F-NMR(DMSO-d 6)：δ117.36。Results of elemental analyses: C47.66%; H5.80%; N11.11%.
Obtain following compounds (R according to method similar to Example 1 1With the R in the general formula (I) 1Identical).
Embodiment 2
Preparation N 4(the third oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine
According to method similar to Example 1, just use propyl chloroformate as acylating agent, obtain noncrystalline powder shape title compound (yield 75%);
1H-NMR(DMSO-d 6)：δ10.93(s，1H，NH)；δ8.35(d，1H，H-6)；δ7.12(d，1H，H-5)；δ6.35(d，1H，H-1′)；δ6.17(t，1H，OH-3′)；δ5.38(m，1H，OH-5′)；δ4.43(m，1H，H-3′)；δ4.18(m，2H，OCH 2)；δ3.98(m，1H，H-4′)；δ3.68(m，1H，H-5′)；δ3.57(m，1H，H-5′)；δ1.70(m，2H，CH 2)；0.90(m，3H，CH3). 13C-NMR(DMSO-d 6)：δ154.20(s，C-2)；δ163.85(s，C-4)；δ93.12(s，C-5)；δ144.46(s，C-6)；δ84.26(m，C-1′)；δ122.74(t，C-2′)；δ68.57(m，C-3′)；δ81.47(m，C-4′)；δ59.08(m，C-5′)；δ153.98(s，CO)；δ64.67，22.56(m，2CH 2)；δ14.48(m，CH 3)。Results of elemental analyses; C44.72%; H4.81%; N11.96%.
Embodiment 3
Preparation N 4-(butoxy carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine
According to method similar to Example 1, just use butyl chlorocarbonate as acylating agent, obtain noncrystalline powder shape title compound (yield 58%);
1H-NMR(DMSO-d 6)：δ11.01(s，1H，NH)；δ8.25(d，1H，H-6)；δ7.20(d，1H，H-5)；δ6.28(d，1H，H-1′)；δ6.09(t，1H，OH-3′)；δ5.36(m，1H，OH-5′)；δ4.39(m，1H，H-3′)；δ4.08(m，2H，OCH 2)；δ3.88(m，1H，H-4′)；δ3.70(m，1H，H-5′)；δ3.49(m，1H，H-5′)；δ1.70-1.62(m，4H，CH 2)；0.87(m，3H，CH 3)。Results of elemental analyses: C42.34%; H5.24%; N11.48%.
Embodiment 4
Preparation N 4-(cyclohexyl methoxycarbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine
According to method similar to Example 1, just use chloroformic acid cyclohexyl methyl esters as acylating agent, obtain noncrystalline powder shape title compound (yield 46%);
1H-NMR(DMSO-?d 6)：δ10.87(s，1H，NH)；δ8.21(d，1H，H-6)；δ7.05(d，1H，H-5)；δ6.46(d，1H，H-1′)；δ6.20(t，1H，OH-3′)；δ5.41(m，1H，OH-5′)；δ4.45(m，1H，H-3′)；δ4.19(m，1H，OCH)；δ3.91(m，1H，H-4′)；δ3.62(m，1H，H-5′)；δ3.59(m，1H，H-5′)；δ1.70-1.40(m，11H，5CH 2，CH)。Results of elemental analyses: C50.72%; H5.70%; N10.41%.
Embodiment 5
Preparation N 4-(benzene ethoxycarbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine
According to method similar to Example 1, just use the chloroformic acid phenethyl ester as acylating agent, obtain noncrystalline powder shape title compound (yield 46%);
1H-NMR(DMSO-d 6)：δ10.81(s，1H，NH)；δ8.40(d，1H，H-6)；δ7.50-7.20(m，5H，ArH)；57.16(d，1H，H-5)；δ6.37(d，1H，H-1′)；δ6.21(t，1H，OH-3′)；δ5.33(m，1H，OH-5′)；δ4.40(m，1H，H-3′)；δ4.23(m，2H，0CH 2)；δ3.92(m，1H，H-4′)；δ3.61(m，1H，H-5′)；δ3.52(m，1H，H-5′)；δ2.21(m，2H，CH 2)。Results of elemental analyses: C52.59%; H4.63%; N10.15%.
The following example has illustrated compound formulation provided by the present invention.
Embodiment 6
The gelatine capsule that contains following ingredients according to known method preparation own separately:
N 4-(penta oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine 100mg
Starch 100mg
Magnesium Stearate 10mg
210mg
Embodiment 7
The tablet that contains following ingredients according to known method preparation own separately:
N 4-(penta oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine 100mg
Starch 25mg
Lactose 50mg
HPMC 5mg
Magnesium Stearate 10mg
190mg
Embodiment 8
The formulation that contains the exsiccant parenteral of following ingredients according to known method preparation own separately:
(1) with the N of total amount 1g 4-(penta oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine is dissolved in the distilled water of 100ml, and solution is through sterile filtration, then under aseptic condition in dress as 20 the aseptic shape bottles.This solution is through lyophilize, in every bottle the aseptic xeraphium of 50mg.
(2) the pure N of 50mg will be housed 4-(penta oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-each phial of Deoxyribose cytidine or ampere seal, and heat sterilization.
Before use, add an amount of aseptic water-containing solvent (as water), above-mentioned dry formulation is mixed with injection, or adds isotonic sodium chlorrde solution or 5% dextrose, above-mentioned dry formulation is mixed with the medicament that parenteral is taken.

Claims (10)

1, the compound of general formula (I) or its hydrate or solvate:
Figure A2005100644430002C1
R wherein 1The group of representative easy hydrolysis under physiological condition, R 1It is alkyl saturated or unsaturated, straight or branched.
2, compound according to claim 1, wherein R 1Representative contain 17 carbon atoms nearly alkyl, contain 17 carbon atoms nearly alkenyl, contain 17 carbon atoms nearly cycloalkyl, contain the aralkyl of 17 carbon atoms nearly or contain the nearly aryl of 10 carbon atoms.
3, compound according to claim 1, wherein R 1Be selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, n-pentyl, isopentyl, neo-pentyl, 3,3-dimethylbutyl, n-hexyl, 2-ethyl-butyl, phenmethyl, styroyl and cyclohexyl methyl.
4, compound according to claim 1, it is N 4-(the third oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine or its hydrate or its solvate.
5, compound according to claim 1, it is N 4-(butoxy carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine or its hydrate or its solvate.
6, compound according to claim 1, it is N 4-(penta oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine or its hydrate or its solvate.
7, compound according to claim 1, it is N 4-(styroyl oxygen carbonyl)-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine or its hydrate or its solvate.
8, compound according to claim 1, it is N 4-[(cyclohexyl methoxy) carbonyl]-2 ', 2 '-two fluoro-2 '-Deoxyribose cytidine or its hydrate or its solvate.
9, a kind of pharmaceutical composition for the treatment of tumour is characterized in that containing general formula (I) compound or its hydrate or solvate as activeconstituents.
10, each described compound is used to prepare the purposes of antineoplastic agent among the claim 1-8.
CNA2005100644438A 2005-04-18 2005-04-18 N4 (substituted oxycarbonyl) 2',2'-bifluoro-2'-deoxycytidine derivate and application thereof Pending CN1693309A (en)

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PCT/CN2005/002430 WO2006111058A1 (en) 2005-04-18 2005-12-31 N4- (substituted oxycarbonyl)-2’,2’-difluoro-2’-deoxycytidines and uses thereof

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