CN101787064A - Cytarabine prodrug derivatives and purposes thereof in resisting cancers and tumors - Google Patents

Cytarabine prodrug derivatives and purposes thereof in resisting cancers and tumors Download PDF

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CN101787064A
CN101787064A CN200910001175A CN200910001175A CN101787064A CN 101787064 A CN101787064 A CN 101787064A CN 200910001175 A CN200910001175 A CN 200910001175A CN 200910001175 A CN200910001175 A CN 200910001175A CN 101787064 A CN101787064 A CN 101787064A
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cytosine arabinoside
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arabinoside derivative
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CN101787064B (en
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高峰
徐峻
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Abstract

The invention relates to novel anti-tumor cytarabine prodrug derivatives through chemically modifying the N4 and O5 positions of cytarabine to prevent N4 amino being metabolized to lose efficacies and result in toxicity and let O5 hydroxy be easily phosphorylated for activation and introducing multifunctional groups of aspirins to the prodrug modules of the cytarabine to increase the drug functions for improving the anti-solid tumor activities. The invention also provides multiple synthesis routes of the cytarabine prodrug derivatives, a cytarabine prodrug derivative preparation and a preparation method thereof in detail and proves the purposes of the cytarabine prodrug derivatives at the aspect of resisting cancers and tumors through a great amount of experimental data. The cytarabine prodrug derivatives have a multi-targeting function and the advantages of increasing bioavailability, reducing multiple drug resistance and increasing solubility and ester dissolution.

Description

Cytosine arabinoside derivative and in anticancer purposes in antitumor
Technical field
The present invention relates to medicine technology field, particularly relate to cytosine arabinoside derivative and synthetic route thereof, the invention still further relates to cytosine arabinoside derivative formulations and preparation method thereof and cytosine arabinoside derivative and preparation thereof in anticancer purposes in antitumor.
Background technology
Cancer is the topmost disease of present harm humans life and health, and the existing means of treatment cancer mainly comprise: the also usefulness of excision, radiation therapy, chemotherapy or these methods.Chemotherapy has obtained using and being used for widely the treatment for cancer of number of different types.Yet, thereby all only limiting to delay the deterioration of cancer, the used cancer therapy drug of most of chemotherapy prolongs patient's life, be difficult to reach the purpose of healing.Though the pathogeny of all kinds of cancers has nothing in common with each other, they are the big class syndrome with common trait in fact.Cancer cells is vigorous except metabolism, the differentiation constantly, with Normocellular physiological differences be not very big.This optionally removes cancer cells for exploitation and does not does not kill and wound Normocellular medicine is a great challenge.Another big challenge of cancer therapy drug exploitation is the cancer cells resistance, i.e. the resistance resistance that after chemotherapy after a while, causes, and the exhausted chemotherapeutics is even increase dosage also no longer works to cancer cells.The transfer of tumour cell also often makes and can't treat with chemotherapy.Up to the present, there is not a kind of cancer therapy drug can cure all cancers.The new type anticancer medicine of seeking efficient, highly selective, low toxicity, have no drug resistance and being badly in need of still has challenge.The chemotherapy cancer therapy drug all can produce severe side effect mostly, thereby causes chemotherapy not proceed.Therefore, existing medicine is subjected to great restriction when the different types of tumour of treatment.So, seek new type anticancer medicine efficient, low toxicity and still press for safeguarding human health.
Cytosine arabinoside is the analogue of cytidine(C, the inhibitor of DNA polymerase.It can stop DNA synthetic, also can mix DNA, disturbs duplicating of DNA, and cytidylic acid(CMP) capable of blocking in addition is reduced into deoxycytidylic acid (Sylvester, R.K., Fisher, A.J., and Lobell, M., Drug Intelligence﹠amp; Clinical Pharmacy:Vol.21, No.2, pp.177-180 (1987); Boyer et al., NovelCytarabine Monophospate Prodrugs, United States Patent Application Publication, Pub.No.:US 2007/0037774A1, (Feb.15,2007); Colon-Cesario, M., Wang, J., Ramos, X., Garcia, H.G., Davila, J.J., Laguna, J., Rosado, C., and Pena de Ortiz, S., J.Neurosci., 26 (20): 5524-5533 (2006)).
At present, cytosine arabinoside is mainly used in the treatment of acute leukemia.Best to the acute myeloblastic leukemia curative effect, also effective to acute monocytic leukemia and acute lymphoblastic leukemia, malignant lymphoma, lung cancer, digestive tract cancer, incidence cancer there is certain curative effect, viral keratitis and epidemic conjunctivitis etc. also there is certain curative effect, yet, invalid to most noumenal tumours.The activity of cytosine arabinoside is not very high, in order to improve curative effect, the general equal and other drug of cytosine arabinoside, as: methoxy daunorubicin, all-trans-retinoic acid associating white arsenic, pirarubicin, topotecan-etoposide-endoxan, fludarabine etc. merge use.Cytosine arabinoside has side effects such as bone marrow depression, digestive tract reaction, and a few patients can have side effect (Bolwell, B.J., Cassileth, P.A., Gale, R.P.Leukemia.2 (5): 253-60 (1988) such as abnormal liver function, heating, fash; Kimby, E., Nygren, P., Glimelius, B.Acta Oncol.40 (2-3): 231-52 (2001); Stamatopoulos, K.Leukemia Research, Volume 22, and Issue 8, pp 759-761, (2003); Burnett, A.K., Milligan, D., Prentice, A.G., Goldstone, A.H., McMullin, M.F., Hills, R.K., Wheatley, K.Cancer.109 (6): 1007-10 (2007)).
Cytosine arabinoside is an antimetabolite, earlier through Deoxyribose cytidine enzyme catalysis phosphorylation, changes activated cytosine arabinoside acid in cell, further transfers corresponding bisphosphate and ara-CTP to again and works.Cytosine arabinoside mainly by with the DNA building-up process in the competition of required dCTP, and inhibition DNA polymerase, disturb Nucleotide to mix DNA, and can suppress ribonucleotide reductase, stop Nucleotide to change deoxynucleotide into, but RNA and proteinic synthetic nothing are significantly acted on, belong to the cell cycle specific agents that acts on the S phase, the most responsive to the effect that is in S propagation phase cell, and G1/S and S/G2 transition period also had effect.Disappear from blood rapidly after the intravenous injection, 40% can pass through hemato encephalic barrier, medicine main in vivo in liver metabolism be the ara U of non-activity, 70%～90% by renal excretion.In order to develop, must seek new drug to liver target to noumenal tumour such as the medicable PTS of liver cancer.Obviously, the medicine of hepatitis virus resisting can be used as fabulous reference.For example, Mi Fuding and Adefovir (adefovir, PMEA) oneself goes through as hepatitis B virus medicine (Starrett, et al., " Synthesis, oralbioavailability determination, and in vitro evaluation of prodrugs of the antiviralagent 9-[2-(phosphonomethoxy) ethyl] adenine (PMEA); " J Med Chem., 37 (12): 1857-64 (1994); Shaw, et al., " Pharmacokinextics and Metabolism ofSelected Prodrugs of PMEA in Rats, " Drug Metabolism Dis., 25 (3): 362-366 (1997); Wacher, V.J., et al., Advanced Drug Delivery Reviews 46:89-102 (2001); Wacher, et al., " Active Secretion and Enterocytic Drug Metabolism Barriers to DrugAbsorption, " Adv.Drug Del.Rev., 46:89-102 (2001); Murono, et al., " Preventionand inhibition of nasopharyngeal carcinoma growth by antiviral phosphonatednucleoside analogs, " Cancer Res., 61 (21): 7875-7 (2001)).2003, MetabasisTherapeutics, the scientist K.Raja Reddy of Inc company, Mark D.Erion, Michael C.Matelich, Joseph J.Kopcho proposes with prodrug (the United States Patent 7,214,668 of cyclic phosphoric acid ucleosides as anti-cancer treatment drug; ), after compound enters liver, be dissociated into acyclic phosphoric acid nucleoside analog derivative and have anticancer activity by the CYP 3A4 metabolic enzyme catalysis of liver.2007, MetabasisTherapeutics, Inc company proposes patent application (the Novel Cytarabine Monophospate Prodrugs of new cyclic phosphoric acid cytosine arabinoside derivative as anticancer prodrug again, United States Patent ApplicationPublication, Pub.No.:US 2007/0037774A 1, Boyer et al., Feb.15,2007; Phosphonic acid based prodrugs of PMEA and its analogues, United States Patent7,214,668, Reddy, et al.May 8,2007).The core of these patent applications be cyclic phosphoric acid is inserted on the ribose ring of cytosine arabinoside-OCH2-ribose position on, i.e. O5 position, and amino without polishing on the cytosine arabinoside cytosine(Cyt) ring.
Cytosine arabinoside generally can not be used for the treatment of liver cancer, and its reason is that after its Cyd skeleton structure enters liver the amino (see figure 1) of its N4 was lost efficacy by metabolism and caused toxicity; Be that the structural O5 hydroxyl of its glucoside (see figure 1) must be activated by phosphorylation on the other hand, and this activation process is too slow in liver.
Summary of the invention
The present invention is intended to overcome the deficiency of above-mentioned prior art, a kind of efficient, low toxicity is provided, have no drug resistance, can be by rapid activated cytosine arabinoside derivative, and provide the synthetic route of cytosine arabinoside derivative and the preparation method of cytosine arabinoside derivative formulations, the present invention that cytosine arabinoside derivative and preparation thereof the experimental data in the application of anticancer anti-tumor aspect also is provided.
Cytosine arabinoside derivative of the present invention is characterized in that: described cytosine arabinoside derivative is the compound with following general formula (I):
Figure G2009100011753D0000041
General formula-I
Wherein, X be OH, O-P (O) (OR) 2With in the phosphate any one, described phosphate comprises single phosphate, bisphosphate base and triphosphoric acid base; R is H, C 1-16Alkyl, cycloalkyl, any one in benzyl, phenyl and the aromatic ring yl;
Wherein, A is second medicine base or the functional group in many targets medicine, represents with any one structural formula in the following formula:
Figure G2009100011753D0000042
R 1Be in H, alkyl, alkane thiazolinyl, alkane alkynyl and the aromatic base any one; R 2Be in nitro, amino, substituted-amino, halogen atom base, itrile group, carboxyl and the amide group any one;
Wherein, L is a connector element, represents with any one following structural unit:
Figure G2009100011753D0000043
Figure G2009100011753D0000051
Wherein, n=0,1-5; M=0,1-18; Curve
Figure G2009100011753D0000052
Represent that above-mentioned connector element L is adjacent group and links to each other with covalent linkage; Two groups among the described connection L on phenyl ring or the cyclohexane ring are that ortho position, a position or contraposition link to each other.
Each group in above-mentioned definition can and then replace, and wherein can contain heteroatoms.
The cytosine arabinoside prodrug derivant of general formula of the present invention (I) comprises the representative compounds with following structural formula:
Figure G2009100011753D0000053
Figure G2009100011753D0000071
For clarity but and unrestricted the present invention, remove illustrate in addition, all scientific and technical terminologies used in the present invention and the same meaning that the technician often uses and understands in field of the present invention.Patent application that the present invention quoted or the application of having delivered and other papers all belong to original quoting and do not add modification.
This patent used " one " or " a kind of " or " class " mean minimum one/kind/class or one/kind/class or one/kind/more than the class.
The present invention's used " alkyl " means various saturated straight chain, the band side chain or cyclic hydrocarbon groups, and the spy comprises contains ten or ten little alkyl that carbon is following.For example methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, heptyl, octyl group and nonyl etc. only are some exemplary in this definition.
The present invention's used " thiazolinyl " is identical with above-mentioned " alkyl " definition, but wherein must the rarest carbon-carbon double bond (C=C), so comprising, the used thiazolinyl of the present invention contains two to straight chain, that have branched chain or the cyclic of ten carbon atoms and contain the alkyl of a carbon-carbon double bond at least, as vinyl, propenyl, butenyl and pentenyl etc.
Used " alkynyl " of the present invention is abovementioned alkyl or thiazolinyl and contains at least one carbon carbon triple bond, so, alkynyl comprises and contains two to ten carbon atoms and contain at least one carbon carbon triple-linked straight chain, that have branched chain or cyclic alkyl or alkynyl, as ethynyl, proyl, butynyl and pentynyl etc.
" saturated " among the present invention means and do not contain unsaturated link(age) in this group, as carbon-carbon double bond or carbon carbon triple bond; " unsaturated " then refers to contain in this group one or more carbon-carbon double bond or carbon carbon triple bond.
The present invention's used " cycloalkyl " is for the cyclic hydrocarbon group and preferentially select the cycloalkyl that contains three to eight carbon for use.Therefore cyclopropane, tetramethylene, pentamethylene, hexanaphthene, suberane and cyclooctane are the exemplary under this definition.Contain one or two carbon-carbon double bond in the cycloalkyl and promptly form " cycloalkenyl group ".Also can have alkyl, thiazolinyl, alkynyl and other groups on the cycloalkyl.
" aromatic base " used in the present invention is for cyclic conjugated aroma system and can contain one or more non-carbon atom (other heteroatomss such as nitrogen beyond the de-carbon) in ring, as phenyl, naphthyl and pyridyl etc.
" heterocyclic radical " also used always among the present invention refers to cyclic group and the compound that any a plurality of atom constitutes by covalent linkage, and contains a non-carbon atom at least.Refer in particular to heterocyclic group and comprise and contain nitrogen, five yuan and six-membered cyclic system such as phonetic azoles, pyrroles, pyridine or pyrimidine etc. of sulphur or the non-carbon atom of oxygen.
" alkoxyl group " among the present invention refers to Sauerstoffatom is connected formed alkyl oxidation base with straight chain or branched alkyl.The example of this type of alkoxy grp comprises methoxyl group, oxyethyl group, propoxy-or isopropoxy etc.
Similarly, " alkylthio " refers to sulphur atom is connected formed alkyl sulfuration base with straight chain or branched alkyl.The example of this type of alkylthio group comprises methylthio group, ethylmercapto group, rosickyite base or iprotiazem base etc.
" halogen atom base " among the present invention is fluorine, chlorine, bromine, iodine.
" amino acid " among the present invention refers to natural and non-natural amino acid of replacing, pure L-or D-form or racemic mixture, with and the group of deriving out by amino and carboxyl.
What be worth especially further specifying is, above-mentioned defined various substituting groups also comprise them by the group that further replaces and constitute, and wherein these new substituting groups also can contain other group.For example the hydrogen atom on alkyl or the aromatic base is replaced by amino, halogen or other groups promptly becomes the new group that belongs in above-mentioned each definition.
Used " phosphoric acid " or " phosphoric acid ester " is to be connected with four Sauerstoffatoms on the pentavalent phosphorus atom of highest oxidation state among the present invention, a Sauerstoffatom links to each other with phosphorus atom with two keys, two Sauerstoffatoms link to each other with phosphorus atom with singly-bound, and, can hydrogen atom, negative charge or various as defined above alkyl, aromatic base etc. on these two Sauerstoffatoms, as-P (=O) (O-) 2,-P (O) (OR) 2Another one Sauerstoffatom on the phosphorus atom links to each other with the derivative among the present invention.
" many targets medicine " among the present invention refers to that more than one structural unit in the molecule is by having biological drug effect to a plurality of targetings.
" multi-functional " among the present invention refers to that different groups have more than a kind of biological function in the molecule." medicine base " among the present invention or " functional group " refer to that this group is medicine or the non-pharmaceutical group with certain biological function.Among the present invention, the cytosine arabinoside derivative is to insert the acetylsalicylic acid group on the structural formula of cytosine arabinoside.Acetylsalicylic acid (Aspirin, have another name called acetylsalicylic acid) be a multifunctional medical, have antithrombotic (Antithrombus), anticonvulsion (Antieclampsia), dementia resisting (Antidementia), anti-cataract (Anticataract), anticancer functional characteristicss such as (Anticancer), be to be raw material, make it with the preparation of diacetyl oxide direct reaction and get with the Whitfield's ointment.Acetylsalicylic acid is most widely used in the world analgesic, analgesia and antiphlogiston, also be as a comparison with the standard preparation of estimating other drug.Have antithrombotic effect in vivo, it can suppress hematoblastic release reaction, suppresses hematoblastic gathering, is used to prevent the outbreak of cardiovascular and cerebrovascular diseases clinically.
" connector element " among the present invention (Linker) refers to this connector element two groups or medicine base or functional group be coupled together to form molecule among the present invention.
After " prodrug " among the present invention refers to that the cytosine arabinoside derivative among the present invention is used in the body, rupture in vivo or to increase certain structural unit formed and then play the compound of biological action.
Employed curve among the present invention
Figure G2009100011753D0000101
Be a kind of method for expressing commonly used in the pharmaceutical chemistry, represent this group or medicine base or functional group to be connected with corresponding atom in the general formula (I) by this place.
The organic solvent of mentioning among the present invention comprises: phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus (PyBOP), 4-Dimethylamino pyridine (DMAP), N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), poly ethylene glycol (PEG) and tetrahydrofuran (THF) (THF).
Another technical problem that the present invention solves has provided the synthetic route of the cytosine arabinoside derivative of general formula (I), and its technical scheme is as follows respectively:
1. the synthetic route of cytosine arabinoside derivative comprises the steps:
(1) Whitfield's ointment is mixed with aliphatic dihydroxy alcohol, drip 3～5 vitriol oils then, be heated to 80 ℃ of reactions 4～12 hours, after reaction finished, evaporated under reduced pressure or purify by column chromatography chromatogram obtained first intermediate product (B);
(2) first intermediate product (B) is dissolved in CH 2Cl 2Or tetrahydrofuran (THF), adding anhydride compound and DMAP then, stirring reaction is 24 hours under heating reflux reaction 5～12 hours or the room temperature, and second intermediate product (C) that obtains is directly used in next step reaction without being further purified;
(3) cytosine arabinoside, second intermediate product (C), PyBOP and DMAP are dissolved in DMF, stirring at room 12～24 hours, reaction solution is directly maybe poured this reaction solution in the water into by the column chromatography chromatogram cytosine arabinoside derivative obtain general formula (I) of purifying, with ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the cytosine arabinoside derivative of general formula (I).
Described aliphatic dihydroxy alcohol is ethylene glycol, butyleneglycol, 1,6-hexylene glycol, 1,8-ethohexadiol, decamethylene-glycol and 1, any one in 12-12 glycol; Described anhydride compound is any one in Succinic anhydried, Tetra hydro Phthalic anhydride, Pyroglutaric acid and the glycol ether acid anhydride.(with reference to synthetic route 1,2,7～24)
2. the synthetic route of cytosine arabinoside derivative may further comprise the steps:
(1) Whitfield's ointment and yellow soda ash are dissolved in the 3-propylene chlorohydrin, reflux 2.5 hours, and the reaction solution that obtains is poured layering in the cold water into, uses NaHCO 3The solution washing organic layer is to weakly alkaline, and organic layer with after a small amount of saturated brine washing, adds anhydrous sodium sulfate drying again, filters, and the filtrate decompression evaporate to dryness obtains the 3rd intermediate product (D), is directly used in next step reaction;
(2) the 3rd intermediate product (D) is dissolved in CH 2Cl 2Or in the tetrahydrofuran (THF), add anhydride compound and DMAP then, and stirring reaction is 24 hours under the room temperature, filtering reacting liquid, and the filtrate decompression evaporate to dryness, the 4th intermediate product (E) that obtains is directly used in next step reaction;
(3) cytosine arabinoside, the 4th intermediate product (E), PyBOP and DMAP are dissolved in DMF, stirring at room 12～24 hours, reaction solution directly obtains the cytosine arabinoside derivative of general formula (I) by the column chromatography chromatogram purification or this reaction solution of elder generation is poured in the water, with ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the cytosine arabinoside derivative of general formula (I).
Described anhydride compound is any one in Succinic anhydried, Tetra hydro Phthalic anhydride, Pyroglutaric acid and the glycol ether acid anhydride.(with reference to synthetic route 3)
3. the synthetic route of cytosine arabinoside derivative may further comprise the steps:
(1) wintergreen oil and aminopropanol are dissolved in the dioxane, stirring at room 12 hours, rotary evaporation removes and desolvates, add saturated brine, behind hydrochloric acid adjusting PH to 4-5, repeatedly with ethyl acetate extraction, the acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness, gained the 5th intermediate product (F) is directly used in next step reaction.
(2) the 5th intermediate product (F) is dissolved in CH 2Cl 2Or in the tetrahydrofuran (THF), add anhydride compound and DMAP then, and stirring reaction is 24 hours under the room temperature, filtering reacting liquid, and the filtrate decompression evaporate to dryness, the 6th intermediate product (G) of the thick product of gained is directly used in next step reaction without being further purified;
(3) with cytosine arabinoside, the 6th intermediate product (G), PyBOP and DMAP are dissolved in DMF, stirring at room 12～24 hours, the reaction solution that obtains directly obtain product by the column chromatography chromatogram purification or reaction solution are poured in the water, use ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the cytosine arabinoside derivative of general formula (I).
Described anhydride compound is any one in Succinic anhydried, Tetra hydro Phthalic anhydride, Pyroglutaric acid and the glycol ether acid anhydride.(with reference to synthetic route 4,6)
4. the synthetic route of cytosine arabinoside derivative may further comprise the steps:
(1) o-methoxybenzoic acid and SOCl 2Be dissolved in methylene dichloride, reflux 4 hours, rotary evaporation removes and desolvates and excessive SOCl 2The 7th intermediate product (H) that obtains need not be further purified, and is directly used in next step reaction;
(2) aminopropanol is dissolved in the methylene dichloride, when being chilled to 0 ℃, drips the 7th intermediate product (H) that is dissolved in methylene dichloride, 0.5 hour dropwise, then stirring at room is 5 hours, and the enriching hcl acidifying is to pH=5, and rotary evaporation removes and desolvates, the product that obtains adds the less water dissolving, ethyl acetate extraction repeatedly, acetic acid ethyl fluid washs with saturated brine, anhydrous sodium sulfate drying, filtration, rotary evaporation removes and desolvates, and gained the 8th intermediate product (J) is directly used in next step reaction without purification;
(3) the 8th intermediate product (J) is dissolved in the tetrahydrofuran (THF), adds anhydride compound and DMAP then, stirring reaction is 24 hours under the room temperature, filter, and evaporated under reduced pressure filtrate, gained the 9th intermediate product (K) is directly used in next step reaction without purification;
(4) with cytosine arabinoside, the 9th intermediate product (K), PyBOP and DMAP are dissolved in DMF, stirring at room 12～24 hours, reaction solution directly obtain product by the column chromatography chromatogram purification or reaction solution are poured in the water, use ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the cytosine arabinoside derivative of general formula (I).
Described anhydride compound is a Succinic anhydried, any one in Tetra hydro Phthalic anhydride, Pyroglutaric acid and the glycol ether acid anhydride.(with reference to synthetic route 5)
5. the synthetic route of cytosine arabinoside derivative comprises the steps:
(1) aliphatic dibasic acid is joined SOCl 2In, adding DMF, reflux was reacted 3 hours, revolved SOCl 2, the tenth intermediate product (M) that obtains need not be further purified, and is directly used in next step reaction;
(2) o-Nitraniline is dissolved in benzene and adds pyridine again, be added drop-wise in the tenth intermediate product (M) that is dissolved in benzene, reaction 4h boils off solvent, and reactant is soluble in water, regulate pH value to acid, filtering-depositing, washing is dissolved in precipitation in the Virahol, recrystallization is separated out solid the 11 intermediate product (N);
(3) with cytosine arabinoside, solid the 11 intermediate product (N), PyBOP and DMAP are dissolved in DMF, stirring at room 12 hours, reaction solution is poured in the water, separates out solid, purifies by column chromatography chromatogram again, obtains the cytosine arabinoside derivative of general formula (I).
Described aliphatic dibasic acid is oxalic acid, Succinic Acid, 1,6-hexylene glycol and 1, any one in the 8-suberic acid.(with reference to synthetic route 25)
6. the synthetic route of cytosine arabinoside derivative may further comprise the steps:
(1) with o-Carboxynitrobenzene and SOCl 2Be dissolved in DMF, back flow reaction 2 hours, the 12 intermediate product (S) that obtains need not be further purified, and is directly used in next step reaction.
(2) the 12 intermediate product (S) is dissolved in tetrahydrofuran (THF), drops in the aqueous solution of amino-acid compound, simultaneously the dropping sodium aqueous solution, control PH=8～9, controlled temperature dropwised about 10 ℃ in 30 minutes, stirred 40 minutes and regulated pH value to 3, the pressure reducing and steaming tetrahydrofuran (THF), aqueous solution ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, concentrated is placed recrystallization, filter, get the 13 intermediate product (T) of faint yellow solid; Described amino-acid compound is L-Ala or hexosamine;
(3) cytosine arabinoside, the 13 intermediate product (T), PyBOP and DMAP are dissolved in DMF; Stirring at room 12 hours, reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the 14 intermediate product (U);
(4) the 14 intermediate product (U) further is dissolved in tetrahydrofuran (THF), catalytic hydrogenolysis stirs, and filters, and filtrate is spin-dried for, and obtains the cytosine arabinoside derivative of highly purified general formula (I).(with reference to synthetic route 26,27)
7. the synthetic route of cytosine arabinoside derivative may further comprise the steps:
(1) nitrobenzoic acid or nicotinic acid, amino-hexanol, PyBOP and DMAP are dissolved in DMF, stirring at room 12 hours, reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the 15 intermediate product (V);
(2) the 15 intermediate product (V) is dissolved in the tetrahydrofuran (THF), adds Tetra hydro Phthalic anhydride and DMAP then, heating reflux reaction 12 hours, the 16 intermediate product (W) that obtains be without being further purified,
Be directly used in next step reaction;
(3) cytosine arabinoside, the 16 intermediate product (W), PyBOP and DMAP are dissolved in DMF, stirring at room 12 hours, reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the 17 intermediate product (Y);
(4) the 17 intermediate product (Y) further is dissolved in tetrahydrofuran (THF), catalytic hydrogenolysis stirs, and filters, and filtrate is spin-dried for, and obtains the cytosine arabinoside derivative of highly purified general formula (I).(with reference to synthetic route 28,29)
The preparation method of cytosine arabinoside derivative formulations of the present invention is characterized in that:
(1) the cytosine arabinoside derivative of general formula (I) is dissolved into any one or the multiple combination solvent in water, physiological saline, cyclodextrin aqueous solution, water miscible organic solvent, non-ionic tenside, water miscible lipoid, lipid acid, fatty acid ester and the phosphatide and makes formulation soln;
(2) described formulation soln is made the cytosine arabinoside derivative formulations with the dilution of physiological saline or glucose injection again.
Described organic solvent can be ethanol, propylene glycol, glycerine, glyceryl ester, poly ethylene glycol (PEG), N, any one in dinethylformamide (DMF) and the dimethyl sulfoxide (DMSO) (DMSO) or multiple combination solvent.
Cytosine arabinoside derivative formulations of the present invention is characterized in that: be the product that the preparation method by above-mentioned cytosine arabinoside derivative formulations prepares.
Cytosine arabinoside derivative of the present invention is in anticancer purposes in antitumor.The cytosine arabinoside derivative of general formula (I) can be used for treating or alleviating the cancer of a certain tissue or organ.Cancer comprises but is not only limited to leukemia, solid knurl, lung cancer, colorectal carcinoma, liver cancer, central nerve neuroma, ovarian cancer and kidney.
Cytosine arabinoside derivative formulations of the present invention is in anticancer purposes in antitumor.Cancer comprises leukemia, solid knurl, lung cancer, colorectal carcinoma, liver cancer, central nerve neuroma, ovarian cancer and kidney.Cytosine arabinoside derivative formulations of the present invention also can be used in the anti-tumor chemotherapeutic with other chemotherapy drugs in combination, can include but not limited to alkylating agent, vegetable alkaloids, antibiotic antitumor sulfonamides medicine, platinum medicine, anti-metabolism and other known cancer therapy drug with the antitumor drug that the preparation of cytosine arabinoside derivative of the present invention is united use.In the drug combination therapeutic process of indication of the present invention, comprise the utilization cytosine arabinoside derivative that at least a the present invention exemplified.
With cytosine arabinoside derivative of the present invention is that composition is prepared into medicinal preparations, can be used for oral or the parenteral route administration.The parenteral route administration of indication herein is meant in subcutaneous intracutaneous, intravenously, intra-arterial, intramuscular, the atrium, in the synovial membrane, breastbone inner injection or instillation.
The present invention adopts new designing technique design to design the cytosine arabinoside derivative.The reason that cytosine arabinoside (with reference to Fig. 1) can not be used for the treatment of liver cancer is on the one hand after its Cyd skeleton structure enters liver, its N4 amino was lost efficacy by metabolism and caused toxicity, be that the structural O5 hydroxyl of its glucoside must be activated by phosphorylation on the other hand, and this activation process is too slow in liver.
The design of cytosine arabinoside derivative of the present invention is by to N4, chemically modified is carried out in the O5 position, avoid N4 amino to be lost efficacy and cause toxicity by metabolism, allow the O5 hydroxyl be activated by phosphorylation easily, the acetylsalicylic acid multifunctional medical is entered into the prodrugs of cytosine arabinoside, to increase the activity that its pharmic function improves solid tumor resisting, designed novel antineoplastic prodrug derivant.It is multi-functional that cytosine arabinoside derivative of the present invention has many targets, and main beneficial effect is: increase bioavailability, reduce multiple drug resistance (many targets designing technique), increase solubleness, increase the ester dissolubility.The present invention provides the multiple synthetic route of the cytosine arabinoside derivative of general formula (I) in detail, cytosine arabinoside derivative formulations and preparation method thereof, and proved the purposes of cytosine arabinoside derivative of the present invention at anticancer anti-tumor aspect by great deal of experiment data.
Description of drawings
Fig. 1 represents the structure and the N4 of cytosine arabinoside, and O5 modifies the synoptic diagram of position.
Fig. 2 represents the structural representation of representative cytosine arabinoside derivative of the present invention.
Fig. 3 represents that cytosine arabinoside derivative of the present invention suppresses the drug level-inhibiting rate graphic representation of BEL-7402 hepatoma cell strain.
Embodiment
The synthetic route of representative cytosine arabinoside derivatives more of the present invention is listed below, and other cytosine arabinoside derivatives in the patent of the present invention obtain by identical or similar method is synthetic.
Synthetic route 1:
Synthetic (route 1) of the first intermediate product B1: with Whitfield's ointment (13.8g, 100mmol) be dissolved in 40 milliliters of butyleneglycols, Dropwise 5 drips the vitriol oil then, back flow reaction 4 hours, reaction finishes the back evaporated under reduced pressure, and the intermediate product B1 that wins is directly used in next step reaction
Synthetic (route 1) of the second intermediate product C1: with the first intermediate product B1 (2.1g, 100mmol) be dissolved in 10 milliliters of tetrahydrofuran (THF)s, add Succinic anhydried (1.0g then, 100mmol) and DMAP (1.2g, 100mmol), stirring reaction is 24 hours under the room temperature, filtering reacting liquid, the filtrate decompression evaporate to dryness, the gained second intermediate product C1 is directly used in next step reaction.
Synthetic (route 1) of cytosine arabinoside derivative 1: with cytosine arabinoside (2.43g, 100mmol), the second intermediate product C1 (3.1g, 100mmol), and PyBOP (5.7g, 110mmol) and DMAP (0.12g, 10mmol) be dissolved among the DMF (10ml), stirred 24 hours under the room temperature.Reaction solution is by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=10/1), obtain cytosine arabinoside derivative 1 (42mg).LC (UV 254nm) purity 95%.LC-MS m/z 536[M+H] +(molecular formula C 24H 29N 3O 11, molecular weight 535); 1H NMR (600MHz, DMSO-d 6) δ 10.90 (s, 1H), 10.56 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.54 (t, 1H), 7.15 (d, 1H), 6.99 (m, 2H), 6.05 (d, 1H), 5.48 (t, 2H), 5.06 (t, 1H), 4.34 (t, 2H), 4.09 (t, 3H), 3.62 (t, 1H), 3.33 (t, 1H), 2.69 (d, 2H), 2.58 (d, 2H), 2.50 (s, 2H), 1.78 (d, 2H), 1.73 (d, 2H).
Synthetic route 2:
Figure G2009100011753D0000171
Synthetic (route 2) of the first intermediate product B2: with Whitfield's ointment (13.8g, 100mmol) be dissolved in 40 milliliters of butyleneglycols, Dropwise 5 drips the vitriol oil then, back flow reaction 4 hours, reaction finishes the back evaporated under reduced pressure, and the intermediate product B2 that wins is directly used in next step reaction.
Synthetic (route 2) of the second intermediate product C2: with the first intermediate product B2 (2.1g, 100mmol) be dissolved in 10 milliliters the tetrahydrofuran (THF), add then Pyroglutaric acid (1.14g, 100mmol) and DMAP (1.2g, 100mmol), stirring reaction 24 hours at room temperature.Filter reaction mixture, filtrate is evaporate to dryness under reduced pressure, and the gained second intermediate product C2 is directly used in next step reaction.
Synthetic (route 2) of cytosine arabinoside derivative 2: with cytosine arabinoside (2.43g, 100mmol), the second intermediate product C2 (3.24g, 100mmol), PyBOP (5.7g, 110mmol) and DMAP (0.12g 10mmol) is dissolved among the DMF (10ml).Stirred 24 hours under the room temperature.Reaction solution is by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=10/1), obtain cytosine arabinoside derivative 2 (93.9mg), LC (UV 254nm) purity＞95%.LC-MS m/z 550[M+H] +(molecular formula C 25H 31N 3O 11, molecular weight 549).
Synthetic route 3:
Synthetic (route 3) of the 3rd intermediate product D3: (82.8g, 600mmol), (31.8g 300mmol) is dissolved in the 3-propylene chlorohydrin (180ml) reflux 2.5 hours to yellow soda ash to Whitfield's ointment.Reaction solution is poured layering in the cold water into, uses NaHCO 3The solution washing organic layer is to weakly alkaline, and organic layer with after a small amount of saturated brine washing, adds anhydrous sodium sulfate drying again, filter, and the filtrate decompression evaporate to dryness, the 3rd intermediate product D3 is directly used in next step reaction.
Synthetic (route 3) of the 4th intermediate product E3: with the 3rd intermediate product D3 (1.96g, 100mmol) be dissolved in 10 milliliters of tetrahydrofuran (THF)s, add Succinic anhydried (1.0g then, 100mmol) and DMAP (1.2g, 100mmol), stirring reaction is 24 hours under the room temperature, filtering reacting liquid, the filtrate decompression evaporate to dryness, the 4th intermediate product E3 is directly used in next step reaction.
Synthetic (route 3) of cytosine arabinoside derivative 3: with cytosine arabinoside (2.43g, 100mmol), the 4th intermediate product E3 (2.96g, 100mmol), and PyBOP (5.7g, 110mmol) and DMAP (0.12g, 10mmol) be dissolved among the DMF (10ml), stirred 24 hours under the room temperature.Reaction solution is by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=10/1), obtain cytosine arabinoside derivative 3 (20mg).LC (UV 254nm) purity 94%.LC-MS m/z 522[M+H] +(molecular formula C 23H 27N 3O 11, molecular weight 521).
Synthetic route 4:
Synthetic (route 4) of the 5th intermediate product F4: (20g, 130mmol), (15g 200mmol) is dissolved in the dioxane (50ml) stirring at room 12 hours to aminopropanol to wintergreen oil.Rotary evaporation removes and desolvates, and adds saturated brine, behind hydrochloric acid adjusting PH to 4-5, uses ethyl acetate extraction ten times.The acetic acid ethyl fluid anhydrous sodium sulfate drying filters, the filtrate decompression evaporate to dryness, and gained the 5th intermediate product F4 is directly used in next step reaction.
Synthetic (route 4) of the 6th intermediate product G: with the 5th intermediate product F4 (1.95g, 100mmol) be dissolved among 10 milliliters of THF, add Succinic anhydried (1.3g then, 130mmol) and DMAP (1.56g, 130mmol), stirring reaction is 24 hours under the room temperature, filtering reacting liquid, the filtrate decompression evaporate to dryness, gained the 6th intermediate product G is directly used in next step reaction without being further purified.
Synthetic (route 4) of cytosine arabinoside derivative 4: with cytosine arabinoside (2.43g, 100mmol), the 6th intermediate product G (2.95g, 100mmol), and PyBOP (5.7g, 110mmol) and DMAP (0.12g, 10mmol) be dissolved among the DMF (10ml), stirred 24 hours under the room temperature.Reaction solution is by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=10/1), obtain cytosine arabinoside derivative 4 (75mg), LC (UV 254nm) purity 92%.LC-MS m/z 521[M+H] +(molecular formula C 23H 28N 4O 10, molecular weight 520).
Synthetic route 5:
The synthetic route of the 7th intermediate product H5 (route 5): o-methoxybenzoic acid (20g, 131.6mmol), SOCl 2(15ml), be dissolved in methylene dichloride (50ml), reflux 4 hours.Rotary evaporation removes and desolvates and excessive SOCl 2Obtaining the 7th intermediate product H5 need not be further purified, and is directly used in next step reaction.
The synthetic route of the 8th intermediate product J5 (route 5): with aminopropanol (12.4g, 164mmol) be dissolved in the methylene dichloride (70ml), when being chilled to 0 ℃, drip the 7th intermediate product H5 (14g that is dissolved in methylene dichloride (10ml), 82mmol), dropwised in 0.5 hour.Then stirring at room is 5 hours.The enriching hcl acidifying is to pH=5, and rotary evaporation removes and desolvates.Product adds the less water dissolving, ethyl acetate extraction 4 times, and acetic acid ethyl fluid washs with saturated brine, and anhydrous sodium sulfate drying filters, and rotary evaporation removes and desolvates, and gained the 8th intermediate product J5 is directly used in next step reaction without purification.
The synthetic route of the 9th intermediate product K5 (route 5): with the 8th intermediate product J5 (2.09g, 10mmol) be dissolved among 10 milliliters of THF, add succinic anhydride (1.00g then, 10mmol) and DMAP (1.2g, 10mmol), stirring reaction is 24 hours under the room temperature, filters, evaporated under reduced pressure filtrate, gained the 9th intermediate product K5 is directly used in next step reaction without purification.
Synthetic (route 5) of cytosine arabinoside derivative 5: with cytosine arabinoside (2.43g, 10mmol), the 9th intermediate product K5 (3.09g, 10mmol), PyBOP (5.7g, 11mmol) and DMAP (0.12g 1mmol) is dissolved in DMF (10ml), stirring at room 24 hours.Reaction solution is by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=10/1), obtain cytosine arabinoside derivative 5 (38.7mg); LC (UV 254nm) purity＞90%.LC-MS m/z 535[M+H] +(molecular formula C 24H 30N 4O 10, molecular weight 534).
Synthetic route 6:
Figure G2009100011753D0000211
Synthetic (route 6) of the 5th intermediate product F6: (20g, 130mmol), (15g 200mmol) is dissolved in the dioxane (50ml) stirring at room 12 hours to aminopropanol to wintergreen oil.Rotary evaporation removes and desolvates, and adds saturated brine, behind hydrochloric acid adjusting PH to 4-5, uses ethyl acetate extraction ten times.The acetic acid ethyl fluid anhydrous sodium sulfate drying filters, the filtrate decompression evaporate to dryness, and gained the 5th intermediate product F6 is directly used in next step reaction.
Synthetic (route 6) of the 6th intermediate product G6: with the 5th intermediate product F6 (1.95g, 10mmol) be dissolved in 10 milliliters of THF, add Pyroglutaric acid (1.14g then, 10mmol) and DMAP (1.2g, 10mmol), room temperature reaction 24 hours, filter, evaporated under reduced pressure filtrate, the 6th intermediate product G6 is not purified for gained, is directly used in next step reaction.
Synthetic (route 6) of cytosine arabinoside derivative 6: with cytosine arabinoside (2.43g, 10mmol), the 6th intermediate product G6 (3.09g, 10mmol), PyBOP (5.7g, 11mmol) and DMAP (0.12g 1mmol) is dissolved in DMF (10ml), stirring at room 24 hours.Reaction solution is by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=10/1), obtain cytosine arabinoside derivative 6 (82.2mg), LC (UV 254nm) purity＞95%).LC-MS m/z 535[M+H] +(molecular formula C 24H 30N 4O 10, molecular weight 534).
Synthetic route 7:
Figure G2009100011753D0000221
Synthetic (route 7) of the first intermediate product B7: with Whitfield's ointment (27.6g, 200mmol) be dissolved in the ethylene glycol of 70 grams, drip the 3ml vitriol oil then, back flow reaction 4 hours, reaction finishes the back evaporated under reduced pressure, and the intermediate product B7 that wins of institute (glycol salicylate) is directly used in next step reaction.Synthetic (route 7) of the second intermediate product C7: the first intermediate product B7 (glycol salicylate) (2.7g, 15mmol), Pyroglutaric acid (1.7g, 15mmol) and DMAP (0.2g 1.5mmol) is dissolved in CH 2Cl 2(30ml), reflux is 5 hours.The second intermediate product C7 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 7) of cytosine arabinoside derivative 7: cytosine arabinoside (2.5g, 10mmol), the second intermediate product C7 (3g, 10mmol), PyBOP (5.2g, 10mmol) and DMAP (0.2g 2mmol) is dissolved in DMF (25ml), stirring at room 12 hours.Reaction solution is used ethyl acetate extraction with the water suspendible, and extraction liquid is with column chromatography chromatogram purify (silica gel, developping agent: methylene chloride=10/1), obtain cytosine arabinoside derivative 7 (23.7mg), LC (UV 254nm) purity 95%.LC-MS m/z 522[M+H] +(molecular formula C 23H 27N 3O 11, molecular weight 521).
Synthetic route 8:
Figure G2009100011753D0000231
Synthetic (route 8) of the first intermediate product B8: with Whitfield's ointment (27.6g, 200mmol) be dissolved in the ethylene glycol of 70 grams, drip the 3ml vitriol oil then, back flow reaction 4 hours, reaction finishes the back evaporated under reduced pressure, and the intermediate product B8 that wins of institute (glycol salicylate) is directly used in next step reaction.
Synthetic (route 8) of the second intermediate product C8: the first intermediate product B8 (glycol salicylate) (8.7g, 47mmol), Succinic anhydried (4.8g, 48mmol) and DMAP (0.6g 5mmol) is dissolved in CH 2Cl 2(50ml), reflux is 5 hours.The second intermediate product C8 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 8) of cytosine arabinoside derivative 8: cytosine arabinoside (2.5g, 10mmol), the second intermediate product C8 (5g, 15mmol), PyBOP (5.2g, 10mmol) and DMAP (0.2g 2mmol) is dissolved in DMF (25ml), stirring at room 12 hours.Reaction solution is used ethyl acetate extraction with the water suspendible, and extraction liquid is with column chromatography chromatogram purify (silica gel, developping agent: methylene chloride=10/1), obtain cytosine arabinoside derivative 8 (298.3mg), LC (UV 254nm) purity 95%.LC-MS m/z 508[M+H] +(molecular formula C 22H 25N 3O 11, molecular weight 507).
Synthetic route 9:
Figure G2009100011753D0000241
Synthetic (route 9) of the first intermediate product B9: with Whitfield's ointment (13.8g, 100mmol) with 1,6-hexylene glycol (23.6g, 200mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 5 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B9.
Synthetic (route 9) of the second intermediate product C9: with the first intermediate product B9 (2.4g 10mmol) is dissolved in THF (30ml), add then Pyroglutaric acid (1.6g, 13mmol) and DMAP (1.7g, 13mmol), heating reflux reaction 12 hours.The second intermediate product C9 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 9) of cytosine arabinoside derivative 9: with cytosine arabinoside (2.4g, 10mmol), the second intermediate product C9 (3.5g, 10mmol), PyBOP (5.7g, 11mmol), and DMAP (0.12g 1mmol) is dissolved in DMF (10ml), stirring at room 24 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=10/1), obtain cytosine arabinoside derivative 9 (67.8mg).LC (UV 254nm) purity 95%.LC-MS m/z 578[M+H] +(molecular formula C 27H 35N 3O 11, molecular weight 577).
Synthetic route 10:
Figure G2009100011753D0000251
Synthetic (route 10) of the first intermediate product B10: with Whitfield's ointment (6.9g, 50mmol) with 1,8-ethohexadiol (14.6g, 100mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 12 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B10.
Synthetic (route 10) of the second intermediate product C10: with the first intermediate product B 10 (1.33g 5mmol) is dissolved in THF (100ml), add then Pyroglutaric acid (0.74g, 6.5mmol) and DMAP (0.79g, 6.5mmol), heating reflux reaction 12 hours.The second intermediate product C10 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 10) of cytosine arabinoside derivative 10: with cytosine arabinoside (1.2g, 5mmol), the second intermediate product C10 (1.9g, 5mmol), PyBOP (3.1g, 5mmol), and DMAP (60mg 0.5mmol) is dissolved in DMF (10ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=15/1), obtain cytosine arabinoside derivative 10 (44.7mg).LC (UV 254nm) purity 96%.LC-MS m/z 606[M+H] +(molecular formula C 29H 39N 3O 11, molecular weight 605).
Synthetic route 11:
Figure G2009100011753D0000261
Synthetic (route 11) of the first intermediate product B11: with Whitfield's ointment (13.8g, 100mmol) with 1,10-decanediol (34.8g, 200mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 12 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B11.
Synthetic (route 11) of the second intermediate product C11: with the first intermediate product B11 (2.9g 10mmol) is dissolved in THF (100ml), add then Pyroglutaric acid (1.4g, 12mmol) and DMAP (1.5g, 12mmol), heating reflux reaction 12 hours.The second intermediate product C11 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 11) of cytosine arabinoside derivative 11: with cytosine arabinoside (2.4g, 10mmol), the second intermediate product C11 (4.1g, 10mmol), PyBOP (5.7g, 11mmol) and DMAP (0.12g 1mmol) is dissolved in DMF (10ml), stirring at room 24 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=25/1), obtain cytosine arabinoside derivative 11 (88.8mg).LC (UV 254nm) purity 96%.LC-MS m/z 634[M+H] +(molecular formula C 31H 43N 3O 11, molecular weight 633).
Synthetic route 12:
Synthetic (route 12) of the first intermediate product B12: with Whitfield's ointment (3.45g, 25mmol) with 1,12-12 glycol (10.1g, 50mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 5 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B12.
Synthetic (route 12) of the second intermediate product C12: with the first intermediate product B12 (0.966g 3mmol) is dissolved in THF (30ml), add then Pyroglutaric acid (0.455g, 3.9mmol) and DMAP (0.475g, 3.9mmol), heating reflux reaction 12 hours.The second intermediate product C12 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 12) of cytosine arabinoside derivative 12: with cytosine arabinoside (0.729g, 3mmol), the second intermediate product C12 (1.308g, 3mmol), and PyBOP (1.848g, 3.3mmol) and DMAP (0.06g, 0.5mmol) be dissolved in DMF (10ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=15/1), obtain cytosine arabinoside derivative 12 (20.9mg).LC (UV 254nm) purity 80%.LC-MS m/z 662[M+H] +(molecular formula C 33H 47N 3O 11, molecular weight 661).
Synthetic route 13:
Figure G2009100011753D0000281
Synthetic (route 13) of the first intermediate product B13: with Whitfield's ointment (3.45g, 25mmol) with 1,6-hexylene glycol (5.9g, 50mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 5 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B13.
Synthetic (route 13) of the second intermediate product C13: with the first intermediate product B13 (0.65g 2.74mmol) is dissolved in THF (30ml), add then the glycol ether acid anhydride (0.38g, 3.29mmol) and DMAP (0.4g, 3.29mmol), heating reflux reaction 12 hours.The second intermediate product C13 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 13) of cytosine arabinoside derivative 13: with cytosine arabinoside (0.67g, 2.74mmol), the second intermediate product C13 (0.97g, 2.74mmol), PyBOP (1.5g, 2.9mmol) and DMAP (0.05g, 0.41mmol) be dissolved in DMF (10ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=15/1), obtain cytosine arabinoside derivative 13 (50.5mg).LC (UV 254nm) purity 91%.LC-MS m/z 580[M+H] +(molecular formula C 26H 33N 3O 12, molecular weight 579).
Synthetic route 14:
Figure G2009100011753D0000291
Synthetic (route 14) of the first intermediate product B14: with Whitfield's ointment (6.9g, 50mmol) with 1,8-ethohexadiol (14.6g, 100mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 12 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B14.
Synthetic (route 14) of the second intermediate product C14: with the first intermediate product B14 (0.48g 1.8mmol) is dissolved in THF (30ml), add then the glycol ether acid anhydride (0.25g, 2.2mmol) and DMAP (0.27g, 2.2mmol), heating reflux reaction 12 hours.The second intermediate product C14 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 14) of cytosine arabinoside derivative 14: with cytosine arabinoside (0.44g, 1.8mmol), the second intermediate product C14 (0.69g, 1.8mmol), PyBOP (0.94g, 1.8mmol) and DMAP (0.022g, 0.18mmol) be dissolved in DMF (5ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=15/1), obtain cytosine arabinoside derivative 14 (22.9mg).LC (UV 254nm) purity 85%.LC-MS m/z 608[M+H] +(molecular formula C 28H 37N 3O 12, molecular weight 607).
Synthetic route 15:
Figure G2009100011753D0000301
Synthetic (route 15) of the first intermediate product B15: with Whitfield's ointment (13.8g, 100mmol) with 1,10-decanediol (34.8g, 200mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 12 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B15.
Synthetic (route 15) of the second intermediate product C15: with the first intermediate product B15 (2.7g 9.2mmol) is dissolved in THF (50ml), add then the glycol ether acid anhydride (1.4g, 12mmol) and DMAP (1.5g, 12mmol), heating reflux reaction 12 hours.The second intermediate product C15 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 15) of cytosine arabinoside derivative 15: with cytosine arabinoside (1.3g, 5mmol), the second intermediate product C15 (2.1g, 5mmol), and PyBOP (2.9g, 5.5mmol), and DMAP (0.06g 0.5mmol) is dissolved in DMF (10ml), stirring at room 24 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=25/1), obtain cytosine arabinoside derivative 15 (120.6mg).LC (UV 254nm) purity 93%.LC-MS m/z 636[M+H] +(molecular formula C 30H 41N 3O 12, molecular weight 635).
Synthetic route 16:
Figure G2009100011753D0000311
Synthetic (route 16) of the first intermediate product B16: with Whitfield's ointment (3.45g, 25mmol) with 1,12-12 glycol (10.1g, 50mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 5 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B16
Synthetic (route 16) of the second intermediate product C16: with the first intermediate product B16 (0.966g, 3mmol) be dissolved in THF (30ml), add glycol ether acid anhydride (0.452g then, 3.9mmol) and DMAP (0.475g, 3.9mmol), heating reflux reaction 12 hours, the second intermediate product C16 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 16) of cytosine arabinoside derivative 16: cytosine arabinoside (0.729g, 3mmol), the second intermediate product C16 (1.314g, 3mmol), and PyBOP (1.848g, 3.3mmol) and DMAP (0.06g, 0.5mmol) be dissolved in DMF (30ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=15/1), obtain cytosine arabinoside derivative 16 (26.6mg).LC (UV 254nm) purity 80%.LC-MS m/z 664[M+H] +(molecular formula C 32H 45N 3O 12, molecular weight 663).
Synthetic route 17:
Figure G2009100011753D0000321
Synthetic (route 17) of the first intermediate product B17: with Whitfield's ointment (13.8g, 100mmol) with 1,6-hexylene glycol (23.6g, 200mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 5 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B 17.
Synthetic (route 17) of the second intermediate product C17: with the first intermediate product B17 (1.5g 6.3mmol) is dissolved in THF (30ml), add then Tetra hydro Phthalic anhydride (1.05g, 6.3mmol) and DMAP (0.84g, 6.9mmol), heating reflux reaction 12 hours.The second intermediate product C17 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 17) of cytosine arabinoside derivative 17: with cytosine arabinoside (1.5g, 6.3mmol), the second intermediate product C17 (2.43g, 6.3mmol), PyBOP (3.28g, 6.3mmol) and DMAP (0.08g, 0.65mmol) be dissolved in DMF (10ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=30/1), obtain cytosine arabinoside derivative 17 (66.1mg).LC (UV 254nm) purity 96%.LC-MS m/z 612[M+H] +(molecular formula C 30H 33N 3O 11, molecular weight 611).
Synthetic route 18:
Figure G2009100011753D0000331
Synthetic (route 18) of the first intermediate product B18: with Whitfield's ointment (6.9g, 50mmol) with 1,8-ethohexadiol (14.6g, 100mmol) mix, drip 3 vitriol oils then, be heated to 80 ℃ of reactions 5 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/l), obtain the first intermediate product B18.
Synthetic (route 18) of the second intermediate product C18: with the first intermediate product B18 (2.00g, 7.5mmol) be dissolved in THF (100ml), add then Tetra hydro Phthalic anhydride (1.45g, 9.8mmol) and DMAP (1.20g, 9.8mmol), heating reflux reaction 12 hours.The second intermediate product C18 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 18) of cytosine arabinoside derivative 18: with cytosine arabinoside (1.82g, 7.5mmol), the second intermediate product C18 (3.11g, 7.5mmol), PyBOP (4.3g, 8.3mmol) and DMAP (91.5mg, 0.75mmol) be dissolved in DMF (15ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=15/1), obtain cytosine arabinoside derivative 18 (78.8mg).LC (UV 254nm) purity 99%.LC-MS m/z 640[M+H] +(molecular formula C 32H 37N 3O 11, molecular weight 639).
Synthetic route 19:
Synthetic (route 19) of the first intermediate product B19: with Whitfield's ointment (13.8g, 100mmol) with 1,10-decanediol (34.8g, 200mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 5 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B19.
Synthetic (route 19) of the second intermediate product C19: with the first intermediate product B19 (3.0g 10mmol) is dissolved in THF (100ml), add then Tetra hydro Phthalic anhydride (1.8g, 12mmol) and DMAP (1.5g, 12mmol), heating reflux reaction 12 hours.The second intermediate product C19 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 19) of cytosine arabinoside derivative 19: with cytosine arabinoside (2.4g, 10mmol), the second intermediate product C19 (4.4g, 10mmol), PyBOP (5.7g, 11mmol), and DMAP (0.12g 1mmol) is dissolved in DMF (10ml), stirring at room 24 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=25/1), obtain cytosine arabinoside derivative 19 (48mg).LC (UV 254nm) purity 94%.LC-MS m/z 668[M+H] +(molecular formula C 34H 41N 3O 11, molecular weight 667).
Synthetic route 20:
Figure G2009100011753D0000351
Synthetic (route 20) of the first intermediate product B20: with Whitfield's ointment (1.38g, 10mmol) with 1,12-12 glycol (4.04g, 20mmol) mix, drip 3 vitriol oils then, be heated to 80 ℃ of reactions 5 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B20.
Synthetic (route 20) of the second intermediate product C20: with the first intermediate product B20 (1.96g, 6.1mmol) be dissolved in THF (40ml), add Tetra hydro Phthalic anhydride (0.9g then, 6.1mmol) and DMAP (0.74g, 6.1mmol), heating reflux reaction 12 hours, the second intermediate product C20 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 20) of cytosine arabinoside derivative 20: with cytosine arabinoside (1g, 4.1mmol), the second intermediate product C20 (2.76g, 6.1mmol), PyBOP (2.35g, 4.5mmol) and DMAP (0.05g, 0.41mmol) be dissolved in DMF (10ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=15/1), obtain cytosine arabinoside derivative 20 (18.1mg).LC (UV 254nm) purity 96%.LC-MS m/z 696[M+H] +(molecular formula C 36H 45N 3O 11, molecular weight 695).
Synthetic route 21:
Figure G2009100011753D0000361
Synthetic (route 21) of the first intermediate product B21: with Whitfield's ointment (13.8g, 100mmol) with 1,6-hexylene glycol (23.6g, 200mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 5 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B21.
Synthetic (route 21) of the second intermediate product C21: with the first intermediate product B21 (7.2g 30mmol) is dissolved in THF (20ml), add then acid anhydrides (5.6g, 36mmol) and DMAP (4.4g, 36mmol), heating reflux reaction 12 hours.The second intermediate product C21 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 21) of cytosine arabinoside derivative 21: with cytosine arabinoside (2.4g, 10mmol), the second intermediate product C21 (3.9g, 10mmol), PyBOP (5.7g, 11mmol), and DMAP (0.12g 1mmol) is dissolved in DMF (10ml), stirring at room 24 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=10/1), obtain cytosine arabinoside derivative 21 (151.3mg).LC (UV 254nm) purity 96%.LC-MS m/z 618[M+H] +(molecular formula C 30H 39N 3O 11, molecular weight 617).
Synthetic route 22:
Figure G2009100011753D0000371
Synthetic (route 22) of the first intermediate product B22: with Whitfield's ointment (6.9g, 50mmol) with 1,8-ethohexadiol (14.6g, 50mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 5 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B22.
Synthetic (route 22) of the second intermediate product C22: with the first intermediate product B22 (1.4g 5.3mmol) is dissolved in THF (20ml), add then acid anhydrides (0.97g, 6.3mmol) and DMAP (0.77g, 6.3mmol), heating reflux reaction 12 hours.The second intermediate product C22 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 22) of cytosine arabinoside derivative 22: with cytosine arabinoside (1.7g, 6.9mmol), the second intermediate product C22 (2.2g, 5.3mmol), PyBOP (3.6g, 6.9mmol), and DMAP (0.12g 1mmol) is dissolved in DMF (10ml), stirring at room 24 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=25/1), obtain cytosine arabinoside derivative 22 (129.2mg).LC (UV 254nm) purity 98%.LC-MS m/z 646[M+H] +(molecular formula C 32H 43N 3O 11, molecular weight 645).
Synthetic route 23:
Figure G2009100011753D0000381
Synthetic (route 23) of the first intermediate product B23: with Whitfield's ointment (13.8g, 100mmol) with 1,10-decanediol (34.8g, 200mmol) mix, Dropwise 5 drips the vitriol oil then, is heated to 80 ℃ of reactions 12 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B23.
Synthetic (route 23) of the second intermediate product C23: with the first intermediate product B23 (3.0g 10mmol) is dissolved in THF (100ml), add then acid anhydrides (2.0g, 13mmol) and DMAP (1.6g, 13mmol), heating reflux reaction 12 hours.The second intermediate product C23 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 23) of cytosine arabinoside derivative 23: with cytosine arabinoside (3.2g, 13mmol), the second intermediate product C23 (4.5g, 10mmol), PyBOP (7.8g, 15mmol), and DMAP (0.12g 1mmol) is dissolved in DMF (10ml), stirring at room 24 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=25/1), obtain cytosine arabinoside derivative 23 (98.3mg).LC (UV 254nm) purity 91%.LC-MS m/z 674[M+H] +(molecular formula C 34H 47N 3O 11, molecular weight 673).
Synthetic route 24:
Figure G2009100011753D0000391
Synthetic (route 24) of the first intermediate product B24: with Whitfield's ointment (1.38g, 10mmol) with 1,12-12 glycol (4.04g, 20mmol) mix, drip 3 vitriol oils then, be heated to 80 ℃ of reactions 5 hours, after reaction finishes, by column chromatography chromatogram purification (silica gel, developping agent: petrol ether/ethyl acetate=5/1), obtain the first intermediate product B24.
Synthetic (route 24) of the second intermediate product C24: with the first intermediate product B24 (0.8g 2.5mmol) is dissolved in THF (30ml), add then acid anhydrides (0.5g, 3.2mmol) and DMAP (0.4g, 3.2mmol), heating reflux reaction 12 hours.The second intermediate product C24 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 24) of cytosine arabinoside derivative 24: with cytosine arabinoside (0.9g, 3.9mmol), the second intermediate product C24 (1.5g, 3.2mmol), PyBOP (2.0g, 3.9mmol), and DMAP (0.012g 0.1mmol) is dissolved in DMF (10ml), stirring at room 24 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=25/1), obtain cytosine arabinoside derivative 24 (26.6mg).LC (UV 254nm) purity 84%.LC-MS m/z 702[M+H] +(molecular formula C 36H 51N 3O 11, molecular weight 701).
Synthetic route 25:
Figure G2009100011753D0000401
Synthetic (route 25) of the tenth intermediate product M25: with 1, (3.48g 20mmol) joins SOCl to the 8-suberic acid 2(15ml), add DMF (1), reflux was reacted 3 hours.Revolve SOCl 2, the tenth intermediate product M25 that obtains need not be further purified, and is directly used in next step reaction.
Synthetic (route 25) of the 11 intermediate product N25: with o-Nitraniline (2.76g, 20mmol) be dissolved in benzene (20ml) and add pyridine (8ml) again, under the room temperature o-Nitraniline is added drop-wise to the tenth intermediate product M25 (4.04g that is dissolved in benzene (40ml), 20mmol), reaction 4h boils off solvent.Reactant is soluble in water, regulate pH value to acid, filtering-depositing, washing is dissolved in precipitation in the Virahol, and recrystallization is separated out khaki color solid the 11 intermediate product N25.
Synthetic (route 25) of cytosine arabinoside derivative 25: cytosine arabinoside (0.42g, 1.7mmol), the 11 intermediate product N25 (0.5g, 1.7mmol), PyBOP (0.97g, 1.87mmol) and DMAP (0.021g, 0.17mmol) be dissolved in DMF (5ml), stirring at room 12 hours.Reaction solution is poured in the water, separates out solid, and solid is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=15/1), obtain cytosine arabinoside derivative 25 (31.3mg).LC (UV 254nm) purity 95%.LC-MS m/z 520[M+H] +(molecular formula C 23H 29N 5O 9, molecular weight 519).
Synthetic route 26:
Synthetic (route 26) of the 12 intermediate product S26: with o-Carboxynitrobenzene (3.34g, 20mmol) and SOCl 2(12ml) be dissolved in DMF (10ml), back flow reaction 2 hours.The 12 intermediate product S26 that obtains need not be further purified, and is directly used in next step reaction.
Synthetic (route 26) of the 13 intermediate product T26: with the 12 intermediate product S26 (3.6g, 20mmol) be dissolved in THF (20ml), drop to L-Ala (1.8g, in aqueous solution 20mmol), while dropping sodium (0.8g, 20mmol) the aqueous solution, control PH=8-9, controlled temperature is about 10 ℃.30min dropwises, and stirs 40min.Adjusting PH=3, pressure reducing and steaming THF, aqueous solution ethyl acetate extraction three times, the acetic acid ethyl fluid anhydrous sodium sulfate drying concentrates, and places recrystallization, filters, and gets the 13 intermediate product T26 of faint yellow solid.
Synthetic (route 26) of the 14 intermediate product U26: with cytosine arabinoside (1.56g, 6mmol), the 13 intermediate product T26 (1.43g, 6mmol), and PyBOP (3.12g, 6mmol) and DMAP (0.07g, 0.6mmol) be dissolved in DMF (10ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, and the acetic acid ethyl fluid anhydrous sodium sulfate drying filters, and the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=6/1), obtain the 14 intermediate product U26.
Synthetic (route 26) of cytosine arabinoside derivative 26: (about 40mg 0.086mmol) is dissolved in THF (30ml) and adds catalytic amount Pd/C, feeds hydrogen with the 14 intermediate product U26, stir 2h, filter, filtrate is spin-dried for, and obtains cytosine arabinoside derivative 26 (24.7mg).LC (UV 254nm) purity 94%.LC-MS m/z 434[M+H] +(molecular formula C 19H 23N 5O 7, molecular weight 433).
Synthetic route 27:
Figure G2009100011753D0000421
Synthetic (route 27) of the 12 intermediate product S27: with o-Carboxynitrobenzene (1.67g, 10mmol) and SOCl 2(10ml) be dissolved in DMF (10ml), back flow reaction 2 hours, the 12 intermediate product S27 that obtains need not be further purified, and is directly used in next step reaction.
Synthetic (route 27) of the 13 intermediate product T27: with the 12 intermediate product S27 (1.8g, 10mmol) be dissolved in THF (20ml), drop to hexosamine (1.5g, in aqueous solution 12mmol), while dropping sodium (0.96g, 24mmol) the aqueous solution, control PH=8-9, controlled temperature is about 10 ℃.30min dropwises, and stirs 40min.Regulate PH=3, pressure reducing and steaming THF, aqueous solution ethyl acetate extraction three times, the acetic acid ethyl fluid anhydrous sodium sulfate drying, decompression is spin-dried for, column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=10/1), obtain the 13 intermediate product T27.
Synthetic (route 27) of the 14 intermediate product U27: with cytosine arabinoside (2.4g, 10mmol), the 13 intermediate product T27 (2.8g, 10mmol), and PyBOP (5.7g, 11mmol) and DMAP (0.12g, 1mmol) be dissolved in DMF (10ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, and the acetic acid ethyl fluid anhydrous sodium sulfate drying filters, and the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=10/1), obtain the 14 intermediate product U27.
Synthetic (route 27) of cytosine arabinoside derivative 27: (about 40mg 0.08mmol) is dissolved in THF (30ml) and adds catalytic amount Pd/C, feeds hydrogen with the 14 intermediate product U27, stir 2h, filter, filtrate is spin-dried for, and obtains cytosine arabinoside derivative 27 (36.2mg).LC (UV 254nm) purity 97%.LC-MS m/z 476[M+H] +(molecular formula C 22H 29N 5O 7, molecular weight 475).
Synthetic route 28:
Figure G2009100011753D0000431
Synthetic (route 28) of the 15 intermediate product V28: with o-Carboxynitrobenzene (1.67g, 10mmol), amino-hexanol (1.17g, 10mmol), PyBOP (5.72g, 10mmol) and DMAP (0.12g 1mmol) is dissolved in DMF (10ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, and the acetic acid ethyl fluid anhydrous sodium sulfate drying filters, and the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=50/1), obtain the 15 intermediate product V28.Synthetic (route 28) of the 16 intermediate product W28: with the 15 intermediate product V28 (2.1g, 8mmol) be dissolved in 40 milliliters of tetrahydrofuran (THF)s, add then Tetra hydro Phthalic anhydride (1.48g, 10mmol) and DMAP (1.22g, 10mmol), heating reflux reaction is 12 hours.The 16 intermediate product W28 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 28) of the 17 intermediate product Y28: with cytosine arabinoside (1g, 4.1mmol), the 16 intermediate product W28 (1.86g, 4.5mmol), PyBOP (2.35g, 4.5mmol) and DMAP (0.05g, 0.4mmol) be dissolved in DMF (10ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, and the acetic acid ethyl fluid anhydrous sodium sulfate drying filters, and the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=10/1), obtain the 17 intermediate product Y28.
Synthetic (route 28) of cytosine arabinoside derivative 28: (50mg 0.1mmol) is dissolved in THF (30ml) and adds catalytic amount Pd/C, feeds hydrogen, stirs 2h, filters, and filtrate is spin-dried for, and obtains cytosine arabinoside derivative 28 (45.1mg) with the 17 intermediate product Y28.LC (UV 254nm) purity 94%.LC-MS m/z 610[M+H] +(molecular formula C 30H 35N 5O 9, molecular weight 609).
Synthetic route 29:
Figure G2009100011753D0000441
Synthetic (route 29) of the 15 intermediate product V29: with nicotinic acid (1.35g, 11mmol), 6-amino-1-hexanol B (1.17g, 10mmol), PyBOP (5.72g, 11mmol) and DMAP (0.12g 1mmol) is dissolved in DMF (10ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, and the acetic acid ethyl fluid anhydrous sodium sulfate drying filters, and the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=15/1), obtain the 15 intermediate product V29.Synthetic (route 29) of the 16 intermediate product W29: with the 15 intermediate product V29 (1.14g, 5.1mmol) be dissolved in 40 milliliters of tetrahydrofuran (THF)s, add then Tetra hydro Phthalic anhydride (0.83g, 5.6mmol) and DMAP (0.68g, 5.6mmol), heating reflux reaction 12 hours.The 16 intermediate product W29 that obtains is directly used in next step reaction without being further purified.
Synthetic (route 29) of cytosine arabinoside derivative 29: cytosine arabinoside (1g, 4.1mmol), the 16 intermediate product W29 (1.89g, 5.1mmol), PyBOP (2.35g, 4.5mmol) and DMAP (0.05g, 0.41mmol) be dissolved in DMF (10ml), stirring at room 12 hours.Reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness is again by column chromatography chromatogram purification (silica gel, developping agent: methylene chloride=15/1), obtain cytosine arabinoside derivative 29 (32.1mg).LC (UV 254nm) purity 92%.LC-MS m/z 596[M+H] +(molecular formula C 29H 33N 5O 9, molecular weight 595).
Synthetic drugs cytotoxicity test operation procedure
Cytosine arabinoside derivative of the present invention and preparation thereof are to the restraining effect test of tumour cell
1. test materials
1) cell strain:
The HL-60 cell strain, suspension growth is cultivated with the RPMI1640 cell culture medium that contains 10% foetal calf serum (Hyclone company), and conventional the cultivation keeps initial cell concentration at 3*10 5About/ml, went down to posterity in three days one time 1: 3.Test (the 5*10 that goes down to posterity the day before yesterday 5/ ml), cell concn is at 7.5～10*10 during experiment 5Between/the ml.
BEL-7402 cell strain and HT-29 cell strain, adherent growth is cultivated with the D-MEM cell culture medium of 10% foetal calf serum (Hyclone company), and the conventional initial cell concentration of cultivating is at 3*10 5About/ml, went down to posterity once in 2～3 days 1: 3.Experiment is gone down to posterity 1: 2 the day before yesterday, and cell concn is at 5～10*10 during experiment 5Between/the ml.
2) dissolving of medicine and dilution: according to the weight and the molecular weight of the cytosine arabinoside derivative that provides, at first add DMSO 100～200 μ l, add physiological saline (NS) then, making the drug level that obtains after the dilution is 5mM (noticing that the DMSO final concentration is no more than 10%).
3) D-MEM or RPMI 1640 cell culture mediums, Gibco company
4) foetal calf serum, Hyclone company
5) cell dissociation buffer, 0.25%Trypsin+0.02%EDTA
6) PBS phosphate buffered saline buffer
7) MTT liquid, MTT dry powder (Sigma) fully dissolves with PBS and to be made into 5mg/ml, packing behind the 0.22 μ m filtering with microporous membrane ,-20 ℃ of preservations
8) 10% acidifying SDS, 0.01N HCl
9) centrifuge tube, suction pipe etc. (BD company), 96 orifice plates (Costar company)
2. step:
1) cell inoculation: the back 24 hours cell that goes down to posterity, growth conditions is good.Conventional harvested cell, adjusting cell concn with fresh medium is 2 * 10 5/ ml (attached cell)～3 * 10 5/ ml (suspension cell).
Attached cell inoculates 100 μ l/ holes, 37 ℃, 5%CO 2Discard old nutrient solution after cultivating 24h in the incubator, add fresh medium 95 μ l/ holes.
Suspension cell direct inoculation 95 μ l/ holes.
2) drug treating: each medicine is established 6 concentration gradients, and each concentration is established 3 multiple holes, and medicine blank group is established 5 multiple holes.The Ara-C contrast is done in each test simultaneously.HT-29 and BEL-7402 cell add that drug concentrations is followed successively by 5,2.5,1.25,0.625,0.3125,0.16mM, every hole 5 μ l, final concentration is followed successively by 0.25,0.125,0.0625,0.03125,0.016,0.008mM, and control group adds 5 μ l physiological saline; The HL60 cell adds drug concentrations and is followed successively by 5 * 10 -3, 2.5 * 10 -3, 1.25 * 10 -3, 0.625 * 10 -3, 0.3125 * 10 -3, 0.16 * 10 -3MM, corresponding final concentration is followed successively by 2.5 * 10 -4, 1.25 * 10 -4, 6.25 * 10 -5, 3.125 * 10 -5, 1.6 * 10 -5, 8 * 10 -6MM, control group add 5 μ l physiological saline.
3) cell cultures and detection: after adding medicine, 37 ℃, 5%CO 2Cultivate 72h in the incubator, every then hole adds MTT 10 μ l, continues to cultivate 4h, and every hole adds 100 μ l 10%SDS (containing 0.01NHCl) dissolving, measure each hole absorbancy (A) with Bio-rad 680 type ELISA readout instruments behind the 24h, the detection wavelength is that 570nm, reference wavelength are 630nm.
4) calculate: the absorbancy at first average each multiple hole (removing the too data of great disparity), calculate the inhibiting rate (IR) under each drug level of every kind of cell, IR (%)=(1-A n/ A 0) * 100%, A nBe experimental port mean light absorbency, A 0Be medicine blank hole mean light absorbency.Use EXCEL software, draw the drug level effect curve, select reasonable calculation method to calculate the drug level (IC of 50% cell survival 50).
Fig. 3 is drug level-inhibiting rate graphic representation that cytosine arabinoside derivative of the present invention suppresses the BEL-7402 hepatoma cell strain.JF007, JF017, JF019, JF020 and JF029 are respectively according to synthetic route 7,17,19,20 and 29 synthetic cytosine arabinoside derivatives.
Table 1 has been enumerated the biological activity that representative cytosine arabinoside derivative suppresses different tumour cells.Wherein, JF002, JF003, JF004 and JF006 are respectively according to synthetic route 2,3,4 and 6 synthetic cytosine arabinoside derivatives.
Table 1
Figure G2009100011753D0000481
Evidence, cytosine arabinoside derivative of the present invention has the biological activity of solid tumor resisting.

Claims (24)

1. cytosine arabinoside derivative, it is characterized in that: described cytosine arabinoside derivative is the compound with following general formula (I):
Figure F2009100011753C0000011
General formula-I
Wherein, X be OH, O-P (O) (OR) 2With in the phosphate any one, described phosphate comprises single phosphate, bisphosphate base and triphosphoric acid base;
R is H, C 1-16In alkyl, cycloalkyl, benzyl, phenyl and the aromatic ring yl any one;
Wherein, A is second medicine base or the functional group in many targets medicine, represents with any one structural formula in the following formula:
Figure F2009100011753C0000012
R 1Be in H, alkyl, alkane thiazolinyl, alkane alkynyl and the aromatic base any one; R 2Be in nitro, amino, substituted-amino, halogen atom base, itrile group, carboxyl and the amide group any one;
L is a connector element, represents with any one following structural unit:
Figure F2009100011753C0000013
Figure F2009100011753C0000021
Wherein, n=0,1-5; M=0,1-18; Curve
Figure F2009100011753C0000022
Represent that above-mentioned connector element L is adjacent group and links to each other with covalent linkage; Two groups among the described connector element L on phenyl ring or the cyclohexane ring are that ortho position, a position or contraposition link to each other.
2. cytosine arabinoside derivative according to claim 1 is characterized in that: the cytosine arabinoside derivative of the X=OH in the described general formula (I).
3. cytosine arabinoside derivative according to claim 1 and 2 is characterized in that: the structural formula of described cytosine arabinoside derivative is any one of following structural formula:
Figure F2009100011753C0000023
Figure F2009100011753C0000031
Figure F2009100011753C0000041
4. the synthetic route of cytosine arabinoside derivative comprises the steps:
(1) Whitfield's ointment is mixed with aliphatic dihydroxy alcohol, drip 3～5 vitriol oils then, be heated to 80 ℃ of reactions 4～12 hours, after reaction finished, evaporated under reduced pressure or purify by column chromatography chromatogram obtained first intermediate product (B);
(2) first intermediate product (B) with step (1) is dissolved in CH 2Cl 2Or tetrahydrofuran (THF), adding anhydride compound and DMAP then, stirring reaction is 24 hours under heating reflux reaction 5～12 hours or the room temperature, and second intermediate product (C) that obtains is directly used in next step reaction without being further purified;
(3) cytosine arabinoside, second intermediate product (C), PyBOP and DMAP are dissolved in DMF, stirring at room 12～24 hours, reaction solution is directly maybe poured this reaction solution in the water into by the column chromatography chromatogram cytosine arabinoside derivative obtain general formula (I) of purifying, with ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the cytosine arabinoside derivative of general formula (I).
5. the synthetic route of cytosine arabinoside derivative according to claim 4 is characterized in that: described aliphatic dihydroxy alcohol is ethylene glycol, butyleneglycol, 1,6-hexylene glycol, 1,8-ethohexadiol, decamethylene-glycol and 1, any one in 12-12 glycol; Described anhydride compound is any one in Succinic anhydried, Tetra hydro Phthalic anhydride, Pyroglutaric acid and the glycol ether acid anhydride.
6. the synthetic route of cytosine arabinoside derivative may further comprise the steps:
(1) Whitfield's ointment and yellow soda ash are dissolved in the 3-propylene chlorohydrin, reflux 2.5 hours, and the reaction solution that obtains is poured layering in the cold water into, uses NaHCO 3The solution washing organic layer is to weakly alkaline, and organic layer with after a small amount of saturated brine washing, adds anhydrous sodium sulfate drying again, filters, and the filtrate decompression evaporate to dryness obtains the 3rd intermediate product (D), is directly used in next step reaction;
(2) the 3rd intermediate product (D) is dissolved in CH 2Cl 2Or in the tetrahydrofuran (THF), add anhydride compound and DMAP then, and stirring reaction is 24 hours under the room temperature, filtering reacting liquid, and the filtrate decompression evaporate to dryness, the 4th intermediate product (E) that obtains is directly used in next step reaction;
(3) cytosine arabinoside, the 4th intermediate product (E), PyBOP and DMAP are dissolved in DMF, stirring at room 12～24 hours, reaction solution is directly maybe poured this reaction solution in the water into by the column chromatography chromatogram cytosine arabinoside derivative obtain general formula (I) of purifying, with ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the cytosine arabinoside derivative of general formula (I).
7. the synthetic route of cytosine arabinoside derivative according to claim 6 is characterized in that: described anhydride compound is any one in Succinic anhydried, Tetra hydro Phthalic anhydride, Pyroglutaric acid and the glycol ether acid anhydride.
8. the synthetic route of cytosine arabinoside derivative may further comprise the steps:
(1) wintergreen oil and aminopropanol are dissolved in the dioxane, stirring at room 12 hours, rotary evaporation removes and desolvates, add saturated brine, behind hydrochloric acid adjusting PH to 4～5, repeatedly with ethyl acetate extraction, the acetic acid ethyl fluid anhydrous sodium sulfate drying, filter, the filtrate decompression evaporate to dryness, gained the 5th intermediate product (F) is directly used in next step reaction;
(2) the 5th intermediate product (F) is dissolved in CH 2Cl 2Or in the tetrahydrofuran (THF), add anhydride compound and DMAP then, and stirring reaction is 24 hours under the room temperature, filtering reacting liquid, and the filtrate decompression evaporate to dryness, the 6th intermediate product (G) of gained is directly used in next step reaction without being further purified;
(3) cytosine arabinoside, the 6th intermediate product (G), PyBOP and DMAP are dissolved in DMF, stirring at room 12～24 hours, reaction solution directly obtains the cytosine arabinoside derivative of general formula (I) by the column chromatography chromatogram purification or reaction solution is poured in the water, with ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the cytosine arabinoside derivative of general formula (I).
9. the synthetic route of cytosine arabinoside derivative according to claim 8 is characterized in that: described anhydride compound is any one in Succinic anhydried, Tetra hydro Phthalic anhydride, Pyroglutaric acid and the glycol ether acid anhydride.
10. the synthetic route of cytosine arabinoside derivative may further comprise the steps:
(1) o-methoxybenzoic acid and SOCl 2Be dissolved in methylene dichloride, reflux 4 hours, rotary evaporation removes and desolvates and excessive SOCl 2The 7th intermediate product (H) that obtains;
(2) aminopropanol is dissolved in the methylene dichloride, when being chilled to 0 ℃, drips the 7th intermediate product (H) that is dissolved in methylene dichloride, 0.5 hour dropwise, then stirring at room is 5 hours, and the enriching hcl acidifying is to pH=5, and rotary evaporation removes and desolvates, the product that obtains adds the less water dissolving, ethyl acetate extraction repeatedly, acetic acid ethyl fluid washs with saturated brine, anhydrous sodium sulfate drying, filtration, rotary evaporation removes and desolvates, and gained the 8th intermediate product (J) is directly used in next step reaction without purification;
(3) the 8th intermediate product (J) is dissolved in the tetrahydrofuran (THF), adds anhydride compound and DMAP then, stirring reaction is 24 hours under the room temperature, filter, and evaporated under reduced pressure filtrate, gained the 9th intermediate product (K) is directly used in next step reaction without purification;
(4) cytosine arabinoside, the 9th intermediate product (K), PyBOP and DMAP are dissolved in DMF, stirring at room 12～24 hours, reaction solution directly obtains product by the column chromatography chromatogram purification or reaction solution is poured in the water, with ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the cytosine arabinoside derivative of general formula (I).
11. the synthetic route of cytosine arabinoside derivative according to claim 10 is characterized in that: described anhydride compound is any one in Succinic anhydried, Tetra hydro Phthalic anhydride, Pyroglutaric acid and the glycol ether acid anhydride.
12. the synthetic route of cytosine arabinoside derivative comprises the steps:
(1) aliphatic dibasic acid is joined SOCl 2In, adding DMF, reflux was reacted 3 hours, revolved SOCl 2, the tenth intermediate product (M) that obtains need not be further purified, and is directly used in next step reaction;
(2) o-Nitraniline is dissolved in benzene and adds pyridine again, be added drop-wise in the tenth intermediate product (M) that is dissolved in benzene, reaction 2～4h boils off solvent, and reactant is soluble in water, regulate pH value to acid, filtering-depositing, washing is dissolved in precipitation in the Virahol, recrystallization is separated out solid the 11 intermediate product (N);
(3) with cytosine arabinoside, solid the 11 intermediate product (N), PyBOP and DMAP are dissolved in DMF, stirring at room 12 hours, reaction solution is poured in the water, separates out solid, purifies by column chromatography chromatogram again, obtains the cytosine arabinoside derivative of general formula (I).
13. the synthetic route of cytosine arabinoside derivative according to claim 12 is characterized in that: described aliphatic dibasic acid is oxalic acid, Succinic Acid, 1,6-hexylene glycol and 1, any one in the 8-suberic acid.
14. the synthetic route of cytosine arabinoside derivative may further comprise the steps:
(1) o-Carboxynitrobenzene and SOCl2 are dissolved in DMF, back flow reaction 2 hours, the 12 intermediate product (S) that obtains need not be further purified, and is directly used in next step reaction.
(2) the 12 intermediate product (S) is dissolved in tetrahydrofuran (THF), drops in the aqueous solution of amino-acid compound, simultaneously the dropping sodium aqueous solution, control PH=8～9, controlled temperature dropwised about 10 ℃ in 30 minutes, stirred 40 minutes and regulated pH value to 3, the pressure reducing and steaming tetrahydrofuran (THF), aqueous solution ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, concentrated is placed recrystallization, filter, get solid the 13 intermediate product (T);
Described amino-acid compound is L-Ala or hexosamine;
(3) cytosine arabinoside, the 13 intermediate product (T), PyBOP and DMAP are dissolved in DMF, stirring at room 12 hours, reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the 14 intermediate product (U);
(4) the 14 intermediate product (U) is dissolved in tetrahydrofuran (THF), catalytic hydrogenolysis stirs, and filters, and filtrate is spin-dried for, and obtains the cytosine arabinoside derivative of highly purified general formula (I).
15. the synthetic route of cytosine arabinoside derivative may further comprise the steps:
(1) nitrobenzoic acid or nicotinic acid, amino-hexanol, PyBOP and DMAP are dissolved in DMF, stirring at room 12 hours, reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the 15 intermediate product (V);
(2) the 15 intermediate product (V) is dissolved in the tetrahydrofuran (THF), adds Tetra hydro Phthalic anhydride and DMAP then, heating reflux reaction 12 hours, the 16 intermediate product (W) that obtains is directly used in next step reaction without being further purified;
(3) cytosine arabinoside, the 16 intermediate product (W), PyBOP and DMAP are dissolved in DMF, stirring at room 12 hours, reaction solution is poured in the water, ethyl acetate extraction three times, acetic acid ethyl fluid anhydrous sodium sulfate drying, filtration, the filtrate decompression evaporate to dryness is purified by column chromatography chromatogram again, obtains the 17 intermediate product (Y);
(4) the 17 intermediate product (Y) is dissolved in tetrahydrofuran (THF), catalytic hydrogenolysis stirs, and filters, and filtrate is spin-dried for, and obtains the cytosine arabinoside derivative of highly purified general formula (I).
16. the preparation method of cytosine arabinoside derivative formulations is characterized in that:
(1) the cytosine arabinoside derivative of general formula (I) is dissolved into any one or the multiple combination solvent in water, physiological saline, cyclodextrin aqueous solution, water miscible organic solvent, non-ionic tenside, water miscible lipoid, lipid acid, fatty acid ester and the phosphatide and makes formulation soln;
(2) described formulation soln is made the cytosine arabinoside derivative formulations with the dilution of physiological saline or glucose injection again.
17. preparation method according to the cytosine arabinoside derivative formulations of claim 16, it is characterized in that: described organic solvent is ethanol, propylene glycol, glycerine, glyceryl ester, poly ethylene glycol, N, any one in dinethylformamide and the dimethyl sulfoxide (DMSO) or multiple combination solvent.
18. the cytosine arabinoside derivative formulations is characterized in that: be the product that the preparation method by the cytosine arabinoside derivative formulations of claim 16 prepares.
19. the cytosine arabinoside derivative of claim 1 is in anticancer purposes in antitumor.
20. in anticancer purposes in antitumor, it is characterized in that: cancer comprises leukemia, solid knurl, lung cancer, colorectal carcinoma, liver cancer, central nerve neuroma, ovarian cancer, kidney according to the cytosine arabinoside derivative of claim 19.
21. the cytosine arabinoside derivative formulations of claim 18 is in anticancer purposes in antitumor.
22. in anticancer purposes in antitumor, it is characterized in that: cancer comprises leukemia, solid knurl, lung cancer, colorectal carcinoma, liver cancer, central nerve neuroma, ovarian cancer and kidney according to the cytosine arabinoside derivative formulations of claim 21.
23. the cytosine arabinoside derivative formulations of claim 21 is in anticancer purposes in antitumor, it is characterized in that: described cytosine arabinoside derivative formulations and other chemotherapy drugs in combination medications, described other chemotherapeutics comprise alkylating agent, vegetable alkaloids, antibiotic antitumor sulfonamides medicine, platinum medicine, anti-metabolism and other known cancer therapy drug.
24. in anticancer purposes in antitumor, it is characterized in that: in the drug combination process, comprise at least a cytosine arabinoside derivative of utilization with structural formula of claim 5 according to the cytosine arabinoside derivative formulations of claim 23.
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WO2011113175A1 (en) * 2010-03-15 2011-09-22 Gao Feng Cytarabine prodrug derivatives and use for resisting cancer or tumor thereof
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CN104995625A (en) * 2012-12-18 2015-10-21 弗·哈夫曼-拉罗切有限公司 Prediction of molecular bioactivation
CN107137417A (en) * 2016-03-01 2017-09-08 长春诺赛生物科技有限公司 One kind is used to treat cachectic pharmaceutical composition and its application
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