CN1314702C - Cholestrin derivative as nucleoside analog - Google Patents
Cholestrin derivative as nucleoside analog Download PDFInfo
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- CN1314702C CN1314702C CNB200410090653XA CN200410090653A CN1314702C CN 1314702 C CN1314702 C CN 1314702C CN B200410090653X A CNB200410090653X A CN B200410090653XA CN 200410090653 A CN200410090653 A CN 200410090653A CN 1314702 C CN1314702 C CN 1314702C
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Abstract
The present invention discloses a cholesterin derivative of a nucleoside analog, which is characterized in that the cholesterin derivative of the nucleoside analog has a structure of Nu-L-Ch, wherein Nu represents a group of the nucleoside analog; L represents a connection group of an aliphatic chain; moreover, the number of carbon in the L is between 2 and 7; Ch represents a cholesterin group. A highly dispersed transfer system can be formed by the cholesterin derivative of the nucleoside analog, and the transfer system comprises liposome, nonionic surface active agent vesicle, nanometer particles and microemulsion. A self-assembly transfer system can also be formed.
Description
Technical field
The present invention relates to chemistry and biomedicine field, be particularly related to a kind of Cholestrin derivative as nucleoside analog, the transfer system of high dispersing be can prepare by this compound, liposome, nonionogenic tenside vesicle, nanoparticle, micro emulsion and self-assembly transfer system comprised.
Background technology
Nucleosides (Nucleosides) is biological intravital important chemical ingredients, by its carrier that the Nucleotide that obtains and nucleic acid is genetic information that derives.Most important hereditary material DNA and RNA are assembled by Nucleotide exactly.Nucleosides and Nucleotide also participate in many important reactions in the organism.The nucleosides of occurring in nature is by a purine or pyrimidine bases and a five-carbon sugar be combined into.Base comprises VITAMIN B4, guanine, cytosine(Cyt), uridylic, thymus pyrimidine, and five-carbon sugar is ribose and ribodesose, and forms adenosine, guanosine, cytidine and uridine respectively by them, and Desoxyadenosine, pancreatic desoxyribonuclease, Deoxyribose cytidine and deoxythymidine.
(Nucleoside analogues Nu) is the important chemical substance of a class to nucleoside analog.Its constitutional features and nucleoside analogues.People have synthesized multiple nucleoside analog, find wherein to have many pharmacologically actives that have, for example antivirus action, cytotoxicity, immunosuppressive action etc.Active examination mainly concentrates on antiviral and anticancer aspect to nucleoside analog at present.Through forming the phosphorylated nucleosides analogue after the tyrosine phosphorylation effect of virus and human body cell, the latter can suppress virus to antiviral nucleoside analogs by all means in vivo.According to different action functions position, they can be divided into archaeal dna polymerase inhibitor, DNA reductase inhibitor, thymidine kinase inhibitor, RNA enzyme inhibitors, reverse transcriptase inhibitors etc., are used for the treatment of infection such as simplexvirus, cytomegalovirus, varicella virus, influenza virus, hepatitis virus, SARS virus, virus of AIDS (HIV), encephalitis clinically.Because being replicated in the cell of virus finished,, great majority need enter competence exertion antivirus action in the cell so suppressing the antiviral of virus replication birth process.Nucleoside analog water-soluble generally stronger makes intracellular nucleosides material be difficult for oozing out, and this is by the cell instinct decision that earns a bare living.Extraneous simultaneously nucleoside analog cell interior also more difficult to get access, promptly the cell membrane permeability of many nucleoside analogs is bad.Therefore many nucleoside analog drug oral bioavailabilities are poor, IC is little, influenced the performance of antivirus action, and medicine keeps lower concentration also might make virus produce resistance (Yang Daofeng for a long time in cell, Deng. the antiviral nucleoside analogue brief introduction. medical Leader, 2001,20 (2): 122; Plum becomes, etc. the progress of ucleosides antiviral. chemical research and application, 2002,14 (1): 15).Virus of AIDS (HIV) just often entered in lymphsystem and the brain, and has further infected other position at the initial stage of infecting human body.And nucleoside analog is generally water-soluble, it is all difficult to enter lymph and brain, this also is one of reason of acquired immune deficiency syndrome (AIDS) refractory (Yazdanlan M, et al.Blood-brain barrier properties of humanimmunodeficiency virus antiretrovirals.J Pharm Sci, 1999,88:950).Anticancer nucleoside analog generally is a kind of metabolic antagonist, by suppressing the synthetic performance cytotoxicity (Galmarini of nucleic acid, et al.Nucleoside analogues and nucleobase in cancer treatment.Lancet, 2002,3:415).They also need to enter competence exertion effect in the cell equally.Therefore anticancer nucleoside analog also exist bioavailability lower, pass through cytolemma and hemato encephalic barrier than problems such as difficulties.
People have designed bioavailability and the cellular uptake problem that a lot of methods solve nucleoside analog, for example synthetic prodrug and the special drug delivery system of design, and wherein fat-soluble prodrug and liposome administration system are more noticeable.
The microbial film perviousness of medicine is except outside the Pass having with the character of microbial film own and drug molecule amount, and the physicochemical property of medicine are major influence factors.It is generally acknowledged, suitably increase the fat-soluble of medicine and can strengthen the microbial film perviousness.The method that people have attempted the fat-soluble prodrug of synthesis of nucleoside analogue increases its bioavailability and cellular uptake.Because nucleoside analog is connected with hydroxyl or amino usually on the aliphatic chain of non-aromatic ring or ring, people often utilize these hydroxyls or aminoly link to each other with the aliphatic chain group and obtain fat-soluble prodrug.The many bioavailability of fat-soluble enhanced nucleoside analog and cellular uptakes of studies have shown that increase, and the concentration in lymphsystem and brain generally also can improve.These prodrugs can the effect through Perhydrolase or Phospholipid hydrolase discharge former medicine and bring into play antiviral or antitumous effect (Yatvin MB in cell, et al.Improved uptake and retention of lipophilic prodrug to improve treatment of HIV.Adv Drug Del Rev, 1999,39:165; Tan X, et al.Development and optimization ofanti-HIV nucleoside analogs and prodrugs:a review of their cellular pharmacology, structure-activity relationships and pharmacokinetics.Adv Drug Del Rev, 1999,39:117; Wiebe LI, et al.Concepts for the design of anti-HIV nucleoside prodrugsfor treating cephalic HIV infection.Adv Drug Del Rev, 1999,39:63; Hostetler KY, et al.Synthesis and antiretroviral activity of phospholipid analogs ofazidothymidine and other antiviral nucleosides.J Biol Chem, 1990,265:6112).
These phosphatidyls (WO9413324) of studying more employing phospholipid analogues link to each other with the hydroxyl of nucleoside analog.Though increased the fat-soluble of nucleoside analog, can obtain single phosphorylation thing after the prodrug hydrolysis, phospholipid analogues (mainly being phosphatidic acid) is not easy to obtain, and reaction is complicated.Fat-soluble in addition stronger drug administration has certain difficulty.Because fat-soluble medicine is insoluble or be insoluble in water, make its general preparation, can't solve its dispersion and problems of dissolution in the aqueous solution as tablet and injection.Medicine generally need could absorb and enter cell with the molecule aggregates form of molecule or high dispersing state.The intravital environment of people is an aqueous solution form, and it is fat-soluble that microbial film is, and medicine or drug delivery system need can transmit in vivo, and repeatedly pass through microbial film, just can reach effect target sites such as cell.If insoluble fat-soluble medicine can't dissolve or high dispersing, that just can't transmit medicine effectively.
Liposome (Liposomes) is a kind of vesicle that is made of phospholipid bilayer (Vesicles), is a kind ofly can be used as the carrier of a variety of medicines in aqueous solution camber dispersive transfer system.Its high dispersion makes it have effects such as target, slowly-releasing in vivo, oral have a lymph taxis, more portable medicine passes through hemato encephalic barrier, enter (Lasic DDand Papahadjopoulos D.Liposomes revisited.Science in the cell by approach such as fusion, endocytosis easily, 1995,267:1275).The liposome that phosphatide after the modification is formed can also have functions such as long circulation in the body, temperature target, pH target, magnetic target, active target.The part of liposome (eye, nose, skin) administration has good biocompatibility, promotes the effect of drug osmotic.Liposome still is a kind of transfection reagent that often uses in biological chemistry and the molecular biology research field, present still a kind of important carrier (Kikuchi H of gene therapy, et al.Genedelivery using liposome technology.J Control Release, 1999,62:269).
The phospholipid bilayer film of liposome vesicle separates the water and the outside water of internal package, is hydrophobicity in the bilayer.Medicine is wrapped in respectively in interior water or the film according to the difference of its physicochemical property.Usually, water soluble drug is at interior aqueous phase; Fat-soluble medicine is in rete.The preparation of liposome is the process of phospholipid molecule self-assembly in water, and the volume ratio of inside and outside water can not be very big.These factors have determined the encapsulation ratio of most of water soluble drug lower (＜50%), sometimes also can very low (5%), and the medicine of parcel has the possibility that leaks into outer water.If proper fat-soluble group (as aliphatic chain) is arranged, the fat-soluble medicine molecule just can be inserted in the phospholipid bilayer, and binding ratio is more firm, and drug molecule is not easy to take off, so the encapsulation ratio of medicine is higher.Therefore in order to increase the encapsulation ratio of some water soluble drug in liposome, people have often adopted mode (the Gulati M that is prepared into the fat-soluble prodrug that has long aliphatic chain, et al.Lipophilic drug derivatives in liposomes.Int J Pharm, 1998,165:129).
The synthetic nucleoside analog is water-soluble generally stronger, fat-soluble relatively poor at present, the medicine that has even water-soluble and fat-soluble all bad.Therefore their liposome rate is lower, often can't reach administration concentration.If on the basis for preparing the fat-soluble prodrug of nucleoside analog, refabrication becomes liposome, can increase encapsulation ratio, also had the dispersed and fat-soluble prodrug of liposome aqueous solution camber simultaneously and easily penetrated into characteristics (the Tong P of cell, et al.Preparation and in viro antiviral activity ofliposomes of lipophilic esters of acyclovir. Acta Pharmaceutica Sinica, 1991,27:15).
Nonionogenic tenside vesicle (Niosomes) is meant that some nonionogenic tenside (as sorbester p18) is self-assembled into vesicle structure, similar liposome under certain condition in water.It can be used as pharmaceutical carrier equally, has some inside and outside features of similar liposome.It is nano level dispersed solids particle that nanoparticle (Nanoparticles) refers generally to, because its high dispersion, it has characteristics such as the drug bioavailability of raising, intensifier target tropism as pharmaceutical carrier.Solid lipid nanoparticle (SLN) adopts the compatible matrix material of human body to form nanoparticle as main auxiliary material, has the characteristics of common nanoparticle and the characteristics of good biocompatibility, and Recent study is more.Micro emulsion (Microemulsions) is meant the system that the emulsion droplet of particle diameter below 100 nanometers formed, and fat-soluble medicine can be wrapped in the emulsion droplet.Because its high dispersion, it has characteristics such as the drug bioavailability of raising, intensifier target tropism equally as pharmaceutical carrier.
In sum, nucleoside analog is prepared into fat-soluble prodrug, and further is prepared into aqueous solution camber dispersive preparations such as liposome, nonionogenic tenside vesicle, nanoparticle, micro emulsion, help bringing into play drug effect.
Summary of the invention
The inventor has invented a kind of Cholestrin derivative as nucleoside analog, it is characterized in that nucleoside analog connects by being connected base with the cholesterol molecule, and the inventor finds can be prepared easily by above-mentioned Cholestrin derivative as nucleoside analog the transfer system of high dispersing unexpectedly.According to noted earlier, have the high dispersing state and fat-soluble stronger medicine transmits easily in vivo, and the microbial film good penetrability, have target.Therefore the present invention designs first and has prepared the Cholestrin derivative as nucleoside analog that possesses above-mentioned functions, and has prepared the transfer system of its high dispersing.
(Cholesterol, Ch) molecule can derive from and extract and route of synthesis the cholesterol that the present invention relates to.
Contain a free hydroxyl in the cholesterol molecule, need one to connect base (Linker, L) could combine with reactive group such as the hydroxyl in the nucleoside analog, general adopt certain suitable reaction with cholesterol, connect basic molecule, nucleoside analog triplicity, obtain Cholestrin derivative as nucleoside analog.Generally speaking, can combine with nucleoside analog connecting base earlier, combine with cholesterol again, can certainly be with reversed order.Connect with covalent linkage between nucleoside analog group, connection base, the cholesterol group, preferably be connected with ester bond, more preferably connect with ester bond with amido linkage.Connection base among the present invention is that a kind of aliphatic chain connects base, its carbon number is between 2～7, its prototype molecule is preferably from two carboxylic fatty acids of 2～7 carbon numbers, as oxalic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, 2-methyl-2-butene diacid, pyrovinic acid, hydroxy-butanedioic acid, oxosuccinic acid (oxidation succsinic acid), tartrate, aspartic acid, L-glutamic acid, pentanedioic acid, hexanodioic acid, 2,2-dimethylated pentanedioic acid, pimelic acid, more preferably carbon number is two carboxylic fatty acids of 4, as succsinic acid, toxilic acid, fumaric acid.
Being used to described in the present invention prepares the nucleoside analog prototype molecule of Cholestrin derivative as nucleoside analog, aspect molecular characterization, generally contain reactive group, as free hydroxyl or amino, preferably on the aliphatic chain of the non-aromatic ring in the nucleoside analog molecule (or ring) more than one hydroxyl is arranged, more preferably on the aliphatic chain of non-aromatic ring (or ring) hydroxyl is arranged.Nucleoside analog of the present invention does not require it to have special role, but preferably has the medicine of pharmacologically active aspect effect, more preferably has the medicine of antiviral or antitumous effect.Antiviral drug can be selected from acyclovir (ACV), ganciclovir (GCV), Famciclovir (FCV), Penciclovir (PCV), valaciclovir, virazole, Sorivudine, ribavirin, vidarabine, zidovudine (AZT), lamivudine (3TC), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), cidofovir, acyclovir preferably, ganciclovir, Famciclovir, Penciclovir, ribavirin, zidovudine, lamivudine, didanosine, zalcitabine, stavudine, more preferably acyclovir, zidovudine, lamivudine, didanosine, zalcitabine, stavudine.Anticancer medicine can be selected from doxifluridine, cytosine arabinoside, azacitidine.
The synthesis step of the Cholestrin derivative as nucleoside analog among the present invention generally is divided into two stages.At first two carboxylic fatty acids and cholesterol or obtain fatty acid monoester or monoamide with nucleoside analog generation acylation reaction, and then with another reactant reaction, obtain final product.In above-mentioned acylation reaction, can adopt acid anhydrides and hydroxyl or amino acidylate; Or the mode of acyl chlorides and hydroxyl or amino acidylate; Or carboxylic acid elder generation formation activatory intermediate, then with hydroxyl or amino acidylate; Or directly and hydroxyl or amino acidylate by carboxylic acid.By reference pertinent literature method and utilize general professional technique just can obtain highly purified Cholestrin derivative as nucleoside analog.
After obtaining the Cholestrin derivative as nucleoside analog among the present invention, can also it be prepared into alkali salt or hydrochlorate according to service requirements.The salify position generally is on the nucleosides group.Alkali salt can be selected from sodium salt, sylvite, calcium salt, magnesium salts.Acid in the hydrochlorate can be selected from toxilic acid, fumaric acid, succsinic acid, phenylformic acid, Phenylsulfonic acid, formic acid, acetate, propionic acid, oxalic acid, amino acid, citric acid, tartrate, nitric acid, phosphoric acid, hydrochloric acid, sulfuric acid, preferably acetate, succsinic acid, toxilic acid, fumaric acid, phenylformic acid.The method of the salt of preparation Cholestrin derivative as nucleoside analog generally can be dissolved in identical or different organic solvent respectively with Cholestrin derivative as nucleoside analog and corresponding acid or alkali earlier, organic solvent solution with them equates or almost equal mixed according to their molecule moles again, through suitably handling, at last mixing solutions is volatilized, carry out suitable purifying and separate, obtain the salt of Cholestrin derivative as nucleoside analog.
Cholestrin derivative as nucleoside analog among the present invention or its salt have fat-soluble stronger cholesterol group, they can be prepared into liposome, nonionogenic tenside vesicle, nanoparticle, micro emulsion equal altitudes dispersive preparation, the latter can exist with the form of aqueous suspension and administration.These particle dias that contain the high dispersing transfer system of Cholestrin derivative as nucleoside analog are generally less than 1 micron, preferably less than 0.5 micron, more preferably less than 0.2 micron.The preparation method can be with reference to pertinent literature method and professional technique (New RRC ed.Liposome:a practical approach.Oxford:OxfordUniversity Press, 1990; Uchegbu IF and Vyas SP.Non-ionic surfactant basedvesicles (niosomes) in drug delivery.Int J Pharm, 1998,172:33, Cavalli R, et al.Sterilization and freeze-drying of drug-free and drug-loaded solid lipidnanoparticles.Int J Pharm, 1997,148:47; Lu Bin, Zhang Zhengquan. study the formation condition of medicinal micro emulsion with triangle phasor method. Acta Pharmaceutica Sinica, 2001,36:58).
Usually, if adopt film dispersion method to prepare liposome, film materials such as Cholestrin derivative as nucleoside analog and phosphatide can be dissolved in organic solvent jointly, contain in the flask, the decompression rotary evaporation obtains thin film, adds entry or suitable damping fluid then, vibrate with ultrasonic, until forming uniform suspension.If ultrasonic time prolongs, also may obtain the nano level dispersion system.If adopt reverse phase evaporation to prepare liposome, film materials such as Cholestrin derivative as nucleoside analog and phosphatide can be dissolved in organic solvent jointly, add entry or damping fluid, high-speed stirring or the ultrasonic emulsion that is prepared into, the rotary evaporation that reduces pressure then obtains the gel state material, adds entry or suitable damping fluid or do not add then, continue the decompression rotary evaporation, until forming uniform liposome turbid liquor.Liposome turbid liquor can also be selected suitably to write out a prescription and carry out lyophilize or spraying drying under proper condition, forms solid powdery, can guarantee stability of formulation like this, faces with the jolting of the preceding adding aqueous solution to obtain liposome turbid liquor.Use same technology can obtain the nonionogenic tenside vesicle of Cholestrin derivative as nucleoside analog.
Solid lipid nanoparticle in the nano particle preparations is suitable for the Cholestrin derivative as nucleoside analog among the present invention.Usually, Cholestrin derivative as nucleoside analog and normal temperature are solid-state lipid down, as phosphatide, lipid acid, glyceryl ester, common heating and melting adds entry or suitable damping fluid then, under heating state in high pressure dispersing emulsification machine cocycle emulsification repeatedly, form the emulsion droplet of nano-dispersed, cooling rapidly makes it to solidify, and promptly obtains the Cholestrin derivative as nucleoside analog solid lipid nanoparticle.Also can make the Cholestrin derivative as nucleoside analog solid lipid nanoparticle with the micro emulsion method.Cholestrin derivative as nucleoside analog nanoparticle suspension can also be selected suitably, and prescription also carries out lyophilize or spraying drying under proper condition; form solid powdery; can guarantee stability of formulation like this, face with the jolting of the preceding adding aqueous solution and can obtain the nanoparticle suspension.
The preparation of Cholestrin derivative as nucleoside analog micro emulsion can generally comprise emulsifying agent, assistant for emulsifying agent, solubility promoter, oil phase, water with reference to common prescription.Generally after selecting suitable prescription, can easily form micro emulsion.If select suitable prescription, generally comprise emulsifying agent, assistant for emulsifying agent, solubility promoter, oil phase, can also form the self-emulsifying microemulsion system, after adding suitable quantity of water solution, system can be dispersed into micro emulsion voluntarily.
Except the transfer system of the high dispersing of the above-mentioned Cholestrin derivative as nucleoside analog that can obtain easily, the inventor also finds unexpectedly because the Cholestrin derivative as nucleoside analog among the present invention has special physicochemical character, particularly amphipathic, by it self or add an amount of additive after can self-assembly in the aqueous solution, form the transfer system of high dispersing.Therefore contain fat-soluble strong cholesterol group and the bigger nucleosides group of polarity in the Cholestrin derivative as nucleoside analog molecule, have amphipathicly, this physicochemical property are similar to phosphatide and some tensio-active agent.If the molecular structure of amphipathic molecule satisfies certain condition, can in water, be self-assembled into the ordered aggregation of high dispersing by itself, microscler nanoparticle (the Schreier S that obtains of the vesicle that obtains of bilayer, bilayer bending and bilayer stack for example, et al.Surface active drugs:self-association and interaction withmembranes and surfactants.Physicochemical and biological aspects.BiochimBiophys Acta, 2000,1508:210).Cholestrin derivative as nucleoside analog among the present invention has long and fat-soluble stronger cholesterol group and wetting ability nucleosides group, be easier to form bilayer, and further obtain vesicle or microscler nanoparticle, but need to add certain quantity of additive under some condition.Therefore the present invention designs first and has prepared the self-assembly transfer system of being formed or added the high dispersing of an amount of additive by the Cholestrin derivative as nucleoside analog among the present invention.
The preparation method of the self-assembly transfer system of the high dispersing of being made up of Cholestrin derivative as nucleoside analog among the present invention and the preparation method of liposome equal altitudes dispersion system are similar.Normally Cholestrin derivative as nucleoside analog is dissolved in certain organic solvent, can adds suitable additives as required, disperse then.Method comprises film dispersion method, reverse phase evaporation, injection method, compound emulsion method etc.In some cases, additive is optional, and this moment, transfer system all was made up of Cholestrin derivative as nucleoside analog.In some cases, can not form good high dispersing particle with Cholestrin derivative as nucleoside analog separately, need this moment to add suitable additives, help it to form ordered structure.Whether need to add the physicochemical property decision of additive, generally can infer by preliminary experiment according to Cholestrin derivative as nucleoside analog.
The molecule molar ratio that the amount of additive accounts for whole moietys in the high dispersing self-assembly transfer system among the present invention between 0～50%, preferably 0～30%, more preferably 0～15%, all the other compositions are Cholestrin derivative as nucleoside analog.Additive can be selected from phosphatide, polyvalent alcohol esters surface active agent, polyoxyethylene tensio-active agent, double hexadecyl phosphatidic acid, cholesterol and derivative thereof, stearylamine.Phosphatide comprises synthetic phospholipid, semi-synthetic phosphatide, natural phospholipid.Wherein synthetic phospholipid comprise again the phosphatide of modification such as polyglycol derivatization phosphatide, connect the phosphatide of monoclonal antibody.The polyvalent alcohol esters surface active agent is sorbitan fatty acid ester preferably, and is concrete as sorbester p18, span 40, span 20.The polyoxyethylene tensio-active agent is polyoxyethylene polyoxypropylene block copolymer (also claiming poloxamer) preferably, and polysorbate and polyoxyethylene aliphatic alcohol ether are concrete as poloxamer P188, tween 80, polysorbate60, polysorbate40, polysorbas20, Brij35.Cholesterol and derivative thereof comprise the fatty acid ester of cholesterol, cholesterol, the cholesterol of polyglycol derivatization.
The transfer system of high dispersing comprises the self-assembly transfer system; if its composition or surface adsorption have the molecule or the molecule segment of highly-hydrophilic; owing to can form the wetting ability protective layer at external environment or internal milieu; can block interparticle polymerization or block conditioning in vivo and turn usefulness into and obtain long circulating effect (Barenholz Y Liposome application:problems and prospects.Curr Opin ColloidInterface Sci; 2001,6:66).Hydrophilic molecule or molecule segment commonly used are polyoxyethylene glycol (PEG).In the present invention, the transfer system of high dispersing that can adopt the method for the cholesterol of the phosphatide that adds polyglycol derivatization or polyglycol derivatization to prepare the Cholestrin derivative as nucleoside analog of surface hydrophilic comprises its self-assembly transfer system.
The method of the transfer system of the high dispersing of above-mentioned preparation Cholestrin derivative as nucleoside analog is without changing or through after adjusting a little, all applicable to the salt of Cholestrin derivative as nucleoside analog.
Embodiment
The preparation of embodiment 1. acyclovir cholesterol succinates
This product be the succinic acid molecules two ends respectively with the product of acyclovir aliphatic chain hydroxyl and cholesterol acylated hydroxy, English chemical name Succinic acid 2-(2-amino-6-oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester 17-(1,5-dimethyl-hexyl)-10; 13-dimethyl-2,3,4; 7,8,9; 10,11,12; 13,14,15; 16,17-tetradecahydro-1H-cyclopenta[α] phenanthren-3-yl ester, molecular formula C
39H
59N
5O
6, molecular weight 693.93.Ambroid acyl acyclovir (C at first
12H
15N
5O
6), concrete steps are as follows.Get acyclovir (4.5g, 0.02mol), succinyl oxide (10g, 0.1mol), 4-dimethylaminopyridine (DMAP, 0.244g, 2mmol), add 100ml N, dinethylformamide (DMF) charges into nitrogen, and is airtight, room temperature reaction 2 days, the reactant reduction vaporization is removed most of solvent, and remaining liq is poured in the frozen water, get white suspension, regulate pH to 2, suction filtration with 1mol/L hydrochloric acid again, water washing, drying obtains succinyl-acyclovir white powder 6g.The product thin-layer chromatography shows a spot.Fusing point 195-196 ℃.
1H NMR shows, chemical shift 2.61 (4H, OCCH
2CH
2CO), 3.75 (2H, CH
2OCO), 4.22 (2H, OCH
2), 5.40 (2H, NCH
2O), 6.86 (3H, NH
2, COOH), 7.76 (1H, NCHN), 10.59 (1H, OCNHC).Ultimate analysis value C (44.22%) H (4.68%) N (21.69%) is close with theoretical value C (44.31%) H (4.65%) N (21.53%).
The synthesis step of other pair carboxyl fatty acyl acyclovir such as maleoyl acyclovir, fumaryl acyclovir, glutaryl acyclovir is close with the succinyl-acyclovir.
Get succinyl-acyclovir (16.25g, 0.05mol), dicyclohexylcarbodiimide (DCC, 11.33g, 0.055mol), cholesterol (58g, 0.15mol), add 500ml DMF and tetrahydrofuran (THF) (THF) mixed solvent (1: 1), airtight, stirring at room 3 days, remove by filter impurity, the filtrate decompression evaporate to dryness adds the dissolving of 500ml chloroform, order NaCO
3Solution, water washing, the chloroform solution anhydrous magnesium sulfate drying filters, and solvent evaporated is used the Virahol recrystallization, dries, and obtains acyclovir cholesterol succinate white powder 25g.Thin-layer chromatography shows a spot.Fusing point 180-183 ℃.
1H NMR (CDCl
3) show, chemical shift 0.85-1.90 (40H, Cholesterol), 2.20 (2H, CH
2, Cholesterol-α-cycle), 2.63 (4H, OCCH
2CH
2CO), 2.65 (H, OCCH (CH
2)
2-Cholesterol), 5.35 (H, CCHCH
2, Cholesterol-β-cycle), 7.75 (1H, NCHN), 10.65 (1H, OCNHC).Ultimate analysis value C (67.56%) H (8.52%) N (10.28%) is close with theoretical value C (67.50%) H (8.57%) N (10.09%).
The synthesis step of the acyclovir cholesterol derivative molecule of other different connection bases such as acyclovir cholesterol maleic acid ester, acyclovir cholesterol fumarate, acyclovir cholesterol glutarate is close with above-described acyclovir cholesterol succinate synthesis step.
The preparation of embodiment 2. didanosine cholesterol barkites
This product be oxalic acid molecule two ends respectively with the product of didanosine cycloaliphatic ring pendant hydroxyl group and cholesterol acylated hydroxy, chemical name Oxalic acid 17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2; 3,4,7; 8,9,10; 11,12,13; 14,15,16; 17-tetradecahydro-1H-cyclopenta[α] and phenanthren-3-yl ester 5-(6-oxo-1,6-dihydro-purin-9-yl)-tetrahydro-furan-2-ylmethyl ester, molecular formula C
39H
56N
4O
6, molecular weight 676.89.Concrete synthesis step is as follows: get cholesterol (3.86g, 10mmol), oxalyl chloride (5ml) adds the 100ml methylene dichloride, stirring at room 5h, the most of solvent of decompression volatilization adds didanosine (1.18g, 5mmol) and 50ml DMF: THF (1: 1, v/v), airtight, stirring at room 10h, reduction vaporization concentrates, and surplus solution is poured saturated NaHCO under stirring
3In the frozen water solution, filter, be washed to neutrality, filter residue through silicagel column with chloroform: (97: 3, v/v) wash-out obtained thick product to methyl alcohol, gets didanosine cholesterol barkite white powder 2.3g with recrystallizing methanol.Thin-layer chromatography shows a spot.Fusing point 157-160 ℃.
1H NMR (CDCl
3) show, chemical shift 0.85-1.85 (40H, Cholesterol), 2.20 (2H, 34-CH
2), 2.30 (2H, 3-CH
2), 4.00 (H, 23-CH), 4.34 (H, 5-CH), 4.29 (2H, 15-CH
2), 5.37 (H, 36-CH), 7.97 (H, CHN), 8.12 (H, NCHN), 12.70 (H, NH).Ultimate analysis value C (69.06%) H (8.78%) N (8.91%) is close with theoretical value C (69.20%) H (8.34%) N (8.28%).
The preparation of embodiment 3. didanosine cholesterol succinates
This product be the succinic acid molecules two ends respectively with the product of didanosine cycloaliphatic ring pendant hydroxyl group and cholesterol acylated hydroxy, chemical name Succinic acid 17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2; 3,4,7; 8,9,10; 11,12,13; 14,15,16; 17-tetradecahydro-1H-cyclopenta[α] and phenanthren-3-yl ester 5-(6-oxo-1,6-dihydro-purin-9-yl)-tetrahydro-furan-2-ylmethyl ester, molecular formula C
41H
60N
4O
6, molecular weight 704.9.At first the synthetic intermediate Cholesteryl hemisuccinate obtains target product with didanosine (ddI) acidylate again.Concrete synthesis step is as follows: get cholesterol (3.86g, 10mmol), succinyl oxide (3g, 30mmol), DMAP (0.122g, 1mmol) add the 100ml methylene dichloride, 55 ℃ were stirred 3 days, the evaporated under reduced pressure solvent gets the off-white color solid, add ethanol 25ml and be heated to dissolving, pour in the 15%NaCl frozen water solution under stirring, regulate pH to 2.0 with 1mol/L hydrochloric acid, filter, wash with water, filter residue is with dehydrated alcohol: ethyl acetate (10: 1) recrystallization promptly obtains the pure about 4.8g of Cholesteryl hemisuccinate white powder.Remove the hydroxyl inosine (1.18g, 5mmol), Cholesteryl hemisuccinate (4.86g, 10mmol), DCC (1.236g, 6mmol), (610mg 5mmol) adds 50ml DMF: THF (1: 1) to DMAP, and is airtight, 50 ℃ were stirred 2 days, and reduction vaporization concentrates, and surplus solution is poured saturated NaHCO under stirring
3In the frozen water solution, filter, be washed to neutrality, filter residue through silicagel column with chloroform: methyl alcohol (97: 3) wash-out obtains thick product, gets didanosine cholesterol succinate white powder 2.3g with recrystallizing methanol.Thin-layer chromatography shows a spot.Fusing point 188-190 ℃.
1H NMR (CDCl
3) show, chemical shift 0.85-1.85 (40H, Cholesterol), 2.30 (m, 4H, CHCH
2CH), 2.62 (m, 2H, CHCH
2CH), 2.64,2.65 (m, 4H, OCH
2CH
2O), 4.35 (m, 1H, CHO), 4.37 (m, 2H, CH
2O), 4.60 (m, 1H, CHO), 5.35 (d, 1H, CCHCH
2), 6.29 (t, 1H, CHN), 8.11,8.14 (s, 1H, NCHN), 12.71 (s, 1H, NH).Ultimate analysis value C (69.86%) H (8.58%) N (7.95%) is close with theoretical value C (69.77%) H (8.54%) N (7.84%).
The synthesis step of the didanosine cholesterol derivative molecule of other different connection bases such as didanosine cholesterol maleic acid ester, didanosine cholesterol fumarate is close with above-described step.
The preparation of embodiment 4. didanosine cholesterol succinate sodium salts
Molecular formula C
41H
60N
4O
6Na.(7.05g 0.01mol) is dissolved in the 20ml chloroform, adds the methanol solution that contains 0.01mol NaOH, and jolting is ultrasonic, and decompression volatilizes solvent, and recrystallizing methanol obtains didanosine cholesterol succinate sodium salt white crystal to remove hydroxyl inosine cholesterol succinate.This crystal in methyl alcohol solubleness greater than chloroform.Thin-layer chromatography shows a spot.Ultimate analysis value C (67.30%) H (8.21%) N (7.42%) is close with theoretical value C (67.65%) H (8.31%) N (7.70%).Other alkali salt such as sylvite, calcium salt, magnesium salts preparation method are close.
The preparation of embodiment 5. didanosine cholesterol succinate acetate
Molecular formula C
43H
65N
4O
8(7.05g 0.01mol) is dissolved in the 20ml chloroform, adds the acetone soln that contains 0.01mol acetic acid, and jolting is ultrasonic, and decompression volatilizes solvent, and the Virahol recrystallization obtains didanosine cholesterol succinate acetate white solid to remove hydroxyl inosine cholesterol succinate.This solid is soluble in chloroform.Thin-layer chromatography shows a spot.Ultimate analysis value C (67.56%) H (8.52%) N (7.56%) is close with theoretical value C (67.42%) H (8.55%) N (7.31%).Other organic acid salt such as formate, oxalate, maleate preparation method are close.
The preparation of embodiment 6. didanosine cholesterol pimelate
This product be pimelic acid molecule two ends respectively with the product of didanosine cycloaliphatic ring pendant hydroxyl group and cholesterol acylated hydroxy, chemical name Pimelic acid 17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2; 3,4,7; 8,9,10; 11,12,13; 14,15,16; 17-tetradecahydro-1H-cyclopenta[α] and phenanthren-3-yl ester 5-(6-oxo-1,6-dihydro-purin-9-yl)-tetrahydro-furan-2-ylmethyl ester, molecular formula C
44H
66N
4O
6, molecular weight 747.02.The synthesis step of didanosine cholesterol pimelate is as follows: get pimelic acid (16.02g, 10mmol) be dissolved in the 50ml methylene dichloride, reflux, dropwise add thionyl chloride 5ml, backflow 2h, the centre can replenish an amount of thionyl chloride, most of solvent is flung in decompression then, adds 50ml methylene dichloride and cholesterol (3.86g, 10mmol) stirring at room 5h again, continue to add didanosine (1.18g, 5mmol), stirring at room 5h, the evaporated under reduced pressure solvent gets the off-white color solid, add THF and be heated to dissolving in right amount, pour saturated NaHCO under stirring
3In the frozen water solution, filter, be washed to neutrality, filter residue through silicagel column with chloroform: methyl alcohol (95: 5) wash-out obtains thick product, gets didanosine cholesterol pimelate white powder 2.0g with the Virahol recrystallization.Thin-layer chromatography shows a spot.Fusing point 192-195 ℃.Ultimate analysis value C (70.68%) H (8.59%) N (7.85%) is close with theoretical value C (70.74%) H (8.91%) N (7.50%).
The preparation of embodiment 7. zidovudine cholesterol succinates
This product be the succinic acid molecules two ends respectively with the product of zidovudine cycloaliphatic ring pendant hydroxyl group and cholesterol acylated hydroxy, molecular formula C
41H
61N
5O
7, molecular weight 735.96.Acyclovir cholesterol succinate among the synthesis step of zidovudine cholesterol succinate and the embodiment 1 is similar, product results of elemental analyses C (66.58%) H (8.59%) N (9.09%), close with theoretical value C (66.91%) H (8.35%) N (9.52%), the thin-layer chromatography result shows a point.
The preparation of embodiment 8. lamivudine cholesterol succinates
This product be the succinic acid molecules two ends respectively with the product of lamivudine cycloaliphatic ring pendant hydroxyl group and cholesterol acylated hydroxy; English chemistry Succinic acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-[1 by name; 3] oxathiolan-2-ylmethyl ester 17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2; 3; 4,7,8; 9; 10,11,12; 13; 14,15,16; 17-tetradecahydro-1H-cyclopenta[α] phenanthren-3-yl ester, molecular formula C
39H
59N
3O
6S, molecular weight 697.97.The synthesis step of lamivudine cholesterol succinate is similar to the didanosine cholesterol succinate among the embodiment 3, product results of elemental analyses C (67.58%) H (8.46%) N (6.38%), close with theoretical value C (67.11%) H (8.52%) N (6.02%), the thin-layer chromatography result shows a point.
The preparation of embodiment 9. cytosine arabinoside cholesterol maleic acid esters
This product be toxilic acid molecule two ends respectively with the product of 4 arylamine of cytosine arabinoside and cholesterol acylated hydroxy; English chemistry 3-[1-by name (3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-ylcarbamoyl]-acrylic acid 17-(1; 5-dimethyl-hexyl)-10; 13-dimethyl-2,3,4; 7; 8,9,10; 11; 12,13,14; 15; 16,17-tetradecahydro-1H-cyclo-penta[α] phenanthren-3-yl ester, molecular formula C
40H
59N
3O
8, molecular weight 709.91.The synthesis step of cytosine arabinoside cholesterol maleic acid ester is as follows: get cytosine arabinoside (300mg, 1.23mmol) be dissolved in 2ml water, add 15ml and be dissolved with maleic anhydride (287mg, 2.47mmol) dioxane, stirring at room 2 days, solvent is flung in decompression, and residue washs with normal hexane, and, obtain N with ethanol water (1: 1) recrystallization
4-toxilic acid-cytosine arabinoside monoesters.(1.21g 5mmol) is dissolved in 20ml DMF to this intermediate, adds 20ml then and is dissolved with cholesterol (stirring at room 3 days is poured saturated NaHCO under stirring for 3.86g, THF solution 10mmol)
3In the frozen water solution, filter, be washed to neutrality, filter residue through silicagel column with chloroform: methyl alcohol (90: 10) wash-out obtains thick product, gets cytosine arabinoside cholesterol maleic acid ester white powder 2.5g with ethyl alcohol recrystallization.Thin-layer chromatography shows a spot.Fusing point 142-145 ℃.Product results of elemental analyses C (67.88%) H (8.76%) N (5.65%) is close with theoretical value C (67.67%) H (8.38%) N (5.92%).
The preparation of embodiment 10. acyclovir cholesterol succinate liposomes
Get acyclovir cholesterol succinate (20mg), soybean phospholipid (0.1g) in the 250ml flask, with the dissolving of 20ml methylene dichloride, the decompression rotary evaporation obtains one deck alicyclic organic soluble film, the phosphate buffer 1 0ml that adds pH7.4, vibration, most of film comes off, and is ultrasonic at 50 ℃, until obtaining even suspension, microscopically is observed, and most of particle dia is acyclovir cholesterol succinate liposome less than 1 micron.
The preparation of embodiment 11. acyclovir cholesterol succinate nonionogenic tenside vesicles
Get acyclovir cholesterol succinate (30mg), sorbester p18 (0.08g) in the 250ml flask, dissolve with the 20ml methylene dichloride, the decompression rotary evaporation obtains one deck alicyclic organic soluble film, adds the phosphate buffer 1 0ml of pH7.4, vibration, most of film comes off, 50 ℃ ultrasonic, until the even suspension that obtains acyclovir cholesterol succinate nonionogenic tenside vesicle, the laser light scattering particle-size analyzer detects, and median size is 325 nanometers.
The preparation of embodiment 12. didanosine cholesterol succinate long circulating liposomess
Remove hydroxyl inosine cholesterol succinate (50mg), soybean phospholipid (0.1g), PEGization DSPE (PEG-DSPE) (0.01g) in flask, use the 20ml chloroform: isopropyl ether (1: 1, v/v) dissolving, add an amount of distilled water, ultrasonicly make it become emulsion, the decompression rotary evaporation, obtain the gel state material, add less water, continue the decompression rotary evaporation, the gel state material comes off and is dispersed into even suspension, and microscopically is observed, most of particle dia is didanosine cholesterol succinate long circulating liposomes less than 1 micron.
The preparation of embodiment 13. didanosine cholesterol succinate solid lipid nanoparticles
Remove hydroxyl inosine cholesterol succinate (60mg), glyceryl monostearate (0.8g), tween 80 (0.02g) and in beaker, be heated to 80C, add the 80 ℃ of water (10ml) that contain sodium lauryl sulphate (10mg) gradually, keep temperature-resistant, be transparent liquid.Again it is injected in 0 ℃ of water of high-speed stirring with syringe, is transparent liquid.Under atomic force microscope, observe, mostly be the following particle of 100 nanometers.But this didanosine cholesterol succinate solid lipid nanoparticle suspension normal temperature is placed and was not seen that precipitation separated out in 7 days.This solid lipid nanoparticle suspension is lyophilized into pressed powder after adding due care agent, face with before adding entry, didanosine cholesterol succinate solid lipid nanoparticle suspension.
The preparation of embodiment 14. acyclovir cholesterol succinate self-assembly transfer systems
Get the acyclovir cholesterol succinate and be dissolved in tetrahydrofuran (THF) (5%, w/w), be injected into microsyringe in the water of stirring, the about 100 μ l/min of injection speed are to obtaining even little suspension, decompression can be flung to organic solvent, and can be under heating condition further concentrated product, product is after the phospho-wolframic acid negative staining, the particle transmission electron microscope is observed down, be nano level granular or club shaped structure, be acyclovir cholesterol succinate self-assembly transfer system.
The preparation of embodiment 15. didanosine cholesterol succinate self-assembly transfer systems
To contain didanosine cholesterol succinate (5%, w/w) and poloxamer P188 (1%, w/w) tetrahydrofuran solution, be injected into microsyringe in the water of stirring, the about 100 μ l/min of injection speed, to obtaining even little suspension, decompression can be flung to organic solvent, and can be under heating condition further concentrated product.Product is used transmission electron microscope observing after the phospho-wolframic acid negative staining, be nano level granular or club shaped structure (seeing Figure of description 1 and accompanying drawing 2), and particle diameter is didanosine cholesterol succinate self-assembly transfer system between the 20-1000 nanometer.
Fig. 1 lower concentration (0.47mg/ml) didanosine cholesterol succinate self-assembly transfer system negative staining transmission electron microscope photo
Fig. 2 high density (11.88mg/ml) didanosine cholesterol succinate self-assembly transfer system negative staining transmission electron microscope photo.
Claims (12)
1. Cholestrin derivative as nucleoside analog, its constitutional features is:
Nu-L-Ch
Wherein Nu is the nucleoside analog group, and L is that aliphatic chain connects base, and Ch is the cholesterol group, and satisfies:
(1) the prototype molecule of Nu is a nucleoside analog, but does not comprise Levovirin, and is connected with hydroxyl on the aliphatic chain of non-aromatic ring or ring;
(2) the prototype molecule of L is the two carboxylic fatty acids of carbon number between 2～7;
(3) connect with ester bond between Nu, L and the Ch.
2. Cholestrin derivative as nucleoside analog as claimed in claim 1, wherein nucleoside analog prototype molecule is the medicine with antiviral or antitumous effect.
3. Cholestrin derivative as nucleoside analog as claimed in claim 2, medicine wherein antiviral or antitumous effect is selected from acyclovir, ganciclovir, Famciclovir, Penciclovir, valaciclovir, virazole, Sorivudine, ribavirin, vidarabine, zidovudine, lamivudine, didanosine, zalcitabine, stavudine, cidofovir, doxifluridine, cytosine arabinoside, azacitidine.
4. the transfer system of a high dispersing is characterized in that it comprises the Cholestrin derivative as nucleoside analog of claim 1, and is selected from liposome, nonionogenic tenside vesicle, nanoparticle, micro emulsion or self-assembly transfer system.
5. the transfer system of high dispersing as claimed in claim 4, wherein particle dia is less than 1 micron.
6. the transfer system of high dispersing as claimed in claim 4, wherein particle dia is less than 0.5 micron.
7. the transfer system of high dispersing as claimed in claim 4, wherein particle dia is less than 0.2 micron.
8. the transfer system of high dispersing as claimed in claim 4, the molecule molar ratio that the amount of additive accounted for whole moietys during the particle of wherein self-assembly transfer system was formed is between 0～50%, and all the other compositions are the Cholestrin derivative as nucleoside analog of claim 1.
9. the transfer system of high dispersing as claimed in claim 4, the molecule molar ratio that the amount of additive accounted for whole moietys during the particle of wherein self-assembly transfer system was formed is between 0～30%, and all the other compositions are the Cholestrin derivative as nucleoside analog of claim 1.
10. the transfer system of high dispersing as claimed in claim 4, the molecule molar ratio that the amount of additive accounted for whole moietys during the particle of wherein self-assembly transfer system was formed is between 0～15%, and all the other compositions are the Cholestrin derivative as nucleoside analog of claim 1.
11. the transfer system of high dispersing as claimed in claim 4, the particle of wherein self-assembly transfer system all is made up of the Cholestrin derivative as nucleoside analog of claim 1.
12. as the transfer system of claim 8,9 or 10 high dispersing, additive wherein is selected from phosphatide, polyvalent alcohol esters surface active agent, polyoxyethylene tensio-active agent, double hexadecyl phosphatidic acid, cholesterol and derivative thereof, stearylamine.
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| CN100525836C (en) * | 2006-04-28 | 2009-08-12 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Double-head radical lipid prodrug |
| CN100462103C (en) * | 2006-09-01 | 2009-02-18 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Cholesterol phosphononucleoside analogue |
| CN103864881B (en) * | 2012-03-31 | 2016-01-13 | 广西师范大学 | Oleanolic Acid-uridine conjugate and its preparation method and application |
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|---|---|---|---|---|
| CN1178535A (en) * | 1995-01-16 | 1998-04-08 | 联邦科学技术研究组织 | Therapeutic compound-fatty acid conjugates |
| CN1416431A (en) * | 2000-03-15 | 2003-05-07 | Icn药品公司 | Nucleoside compounds and uses thereof |
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| CN1178535A (en) * | 1995-01-16 | 1998-04-08 | 联邦科学技术研究组织 | Therapeutic compound-fatty acid conjugates |
| CN1416431A (en) * | 2000-03-15 | 2003-05-07 | Icn药品公司 | Nucleoside compounds and uses thereof |
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