CN102286050A - Glucose-containing platinum complex for treating tumors and preparation method thereof - Google Patents
Glucose-containing platinum complex for treating tumors and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a glucose-containing platinum complex for treating tumors and a preparation method thereof. The compound is represented by a formula (I). Tests prove that the complex disclosed by the invention and a medicine prepared from the complex have high water solubility and tumor target effect and can be used conveniently in clinic.
Description
Technical field
The present invention relates to a kind of platinum complex, particularly a kind of be used for neoplasm targeted therapy contain glucose platinum complex and preparation method.
Background technology
Why tumour becomes medically is difficult to a kind of disease of curing, and mainly is because pharmacological agent is difficult to realize cancer cell and normal cell are distinguished.The general medicine that has lethality at cancer cell, it also can toxigenicity to normal cell.How accurately and scientifically to find the difference between cancer cells and the normal cell, specific aim, optionally control and kill cancer cell are fundamentally to solve and cure one of key of this disease that threatens human health.
The platinum kind anti-cancer drugs is the representative class medicine in oncotherapy field.It belongs to cell cycle nonspecific agent (CCNSA), to sarcoma, and carcinoma, lymphoma and germinoma all have therapeutic efficiency.The representative platinum kind anti-cancer drugs that is widely used at present clinical treatment in the world mainly contains cis-platinum, carboplatin and oxaliplatin.Cis-platinum is the longest platinum kind anti-cancer drugs of clinical application time with the longest history ((1), Peyrone M.Ann Chemie Pharm (1845), 51:129; (2), Rosenberg, B.﹠amp; Van Camp, L.; Krigas, T. (1965), " Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode ", Nature205 (4972): 698-699), the research of the mechanism of action to it since drugs approved by FDA cis-platinum in 1978 is as the antitumour drug listing is very thorough, this has also driven application and the development of platinum class organometallic compound at the tumour medical field, and the designing and developing of platinum series antineoplastic medicament with new molecular structure laid a good foundation.
The fatal shortcoming of platinum-containing anticancer drug is the resistance problem with extremely strong toxic side effect and inherent and follow-up formation.In addition because this type of medicine is an organometallics, the water-soluble extremely low characteristic of all platinum class marketed drug ubiquities, brought a lot of disadvantageous effects for medicine stability of formulation and clinical application, they successfully are mixed with the suitable formulation of a kind of convenience such as being difficult to.Statistics shows that the sales volume of cis-platinum in the world market has been reduced to 2,400 ten thousand U.S. dollars in 2008 from 3,400 ten thousand U.S. dollars in 2002, presents progressively downward trend, and its major cause is exactly the too big and resistance problem of toxic side effect of medicine.The carboplatin of subsequent development success (U.S. BMS exploitation, Drugs of the Future, (1983), Vol.8, No.6 is 489-491) owing to reduced the reactivity of medicine to DNA from structure, clinical application progressively enlarges in recent years, and the trend that replaces the various clinical applications of cis-platinum is arranged.But, carboplatin does not fundamentally solve the resistance problem that cis-platinum exists, do not change the water-soluble problem of medicine yet, thereby the renal toxicity side effect that the fatal shortcoming that inevitable medicine exists is serious and stability problem ((1), Canetta R, the Rozencweig M of clinical preparation, Carter SK., Carboplatin:the clinical spectrum to date., Cancer Treat Rev. (1985), Sep; 12Suppl A:125-36; (2), Knox, RJ et al, Mechanism of cytotoxicity of anticancer platinum drugs:evidence that cis-diamminedichloropla tinum (II) andcis-diammine-(1,1-cyclobutanedicarboxylato) platinum (II) differ only in the kinetics of their interaction with DNA., Cancer Res. (1986), Apr; 46:1972-9; (3), Overbeck, T, et al. " A comparison of the genotoxic effects of carboplatin and cisplatin in Escherichia Coli " .Mutation Research/DNA Repair. (1996), Volume:362, Issue:3, April 2, pp.249-259; (4), Schnurr, B., Gust, Ronald. " Investigations on the decomposition of carboplatin in infusion solutions " .Mikrochimica Acta. (2002), Volume:140, Issue:1-2, August, pp.69-76).Oxaliplatin (Sanofi-Aventis) is though reduced cis-platinum to a certain extent and the resistance problem of carboplatin existence, but it does not surmount the result of treatment of cis-platinum and carboplatin at the clinical application of kinds of tumors, does not fundamentally solve extremely strong toxic side effect of platinum medicine and extremely low water-soluble problem yet.
The one of the main reasons that causes above-mentioned platinum-containing anticancer drug critical defect is that medicine itself lacks the target function at tumour.The low water solubility problem of medicine has also formed the long and very difficult factor that is increased toxic side effect by kidney eliminating etc. of the residence time of medicine in blood in addition.The target spot guiding problem and the water-soluble problem that solve platinum medicine are one of the absorbed most important problem in present platinum kind anti-cancer drugs research and development field in the world (Galanski, Markus; Keppler, Bernhard K Searching for the Magic Bullet:Anticancer Platinum Drugs Which Can Be Accumulated or Activated in the Tumor Tissue.Anti-Cancer Agents in Medicinal Chemistry, (2007), 7,55-73)
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, provide a kind of and can distinguish cancer cells and normal cell better, when having the target spot guide function, from the water-soluble problem that changes platinum medicine in essence be used for neoplasm targeted therapy contain the glucose platinum complex.
Second purpose of the present invention provides the preparation method who contains the glucose platinum complex who is used for neoplasm targeted therapy.
The 3rd purpose of the present invention provides and contains the medicine that contains the glucose platinum complex that is useful on neoplasm targeted therapy.
Technical scheme of the present invention is summarized as follows:
What be used for neoplasm targeted therapy contains the glucose platinum complex, shown in formula (I):
Wherein:
Glucose 1-position is substituted by α or β or both mixtures; It depends on compound technology and method, but does not influence obtained title complex oncotherapy effect;
X and Y are ligands, and described X and Y are identical or different and represent a NH separately
3, a C
1-C
8Chain-like alkyl primary amine, a C
3-C
8Cyclic alkyl primary amine, aromatic amine, one have a C at least
1-C
4Aromatic amine, a molecular formula that alkyl replaces are R
1-NH-R
2Secondary amine, R wherein
1And R
2Identical or the different C that represents respectively
1-C
8Chain-like alkyl or R
1-NH-R
2The common C that forms
4-C
8Cyclic alkyl secondary amine, a nitrogenous aromatic heterocyclic compounds with 5-8 annular atoms or have a C at least
1-C
4The nitrogenous aromatic heterocyclic compounds that alkyl replaces, sulfur-containing aromatic heterogeneous ring compound or non-aromatic heterogeneous ring compound with 5-8 annular atoms, or X and Y represent that together molecular formula is H
2N-Z-NH
2Diamine compound, wherein Z is C
2-C
8Chain alkylidene group or C
4-C
8Cyclic alkyl; The heteroatoms of heterogeneous ring compound is meant Sauerstoffatom, nitrogen-atoms, and sulphur atom, phosphorus atom etc. are different from the element of carbon atom;
The example of the represented best ligand of X and Y includes but not limited among the present invention: X and Y respectively are NH
3, Isopropylamine, cyclopropylamine, ring butylamine, cyclopentamine, hexahydroaniline; Perhaps X and Y one of them be NH
3, another is an Isopropylamine, cyclopropylamine, ring butylamine, cyclopentamine, hexahydroaniline, 2-picoline; Perhaps X and Y represent that together molecular formula is H
2N-Z-NH
2Diamine compound, for example: 1,1, the 3-propylene diamine, 2-methyl tetramethylene-diamine, 1, the 2-cyclohexanediamine, 1,2-encircles heptamethylene diamine, 1,2-encircles octamethylenediamine, 1-amino-2-aminomethyl hexanaphthene, 1,1-diaminomethyl hexanaphthene, 5,5-diaminomethyl-1,3-diox, 2-aminomethyl-tetramethyleneimine and 2-aminomethyl-pyridine.When containing chiral centre in the above-mentioned ligand compound, can be wherein arbitrary optical isomer or racemic mixture;
N is 1-6.Preferably n is 2-4.Preferably n is 2 or 3.
Described molecular formula is H
2N-Z-NH
2Diamine compound preferably trans-(1R, 2R)-cyclohexanediamine, trans-(1S, 2S)-cyclohexanediamine, cis-(1R, 2S)-cyclohexanediamine, cis-(1S, 2R)-cyclohexanediamine, racemization anti-form-1,2-cyclohexanediamine or racemization cis-1,2-cyclohexanediamine.
Described H
2N-Z-NH
2Preferably select trans-(1R, 2R)-cyclohexanediamine.
Be used for the preparation method who contains glucose platinum complex (I) of neoplasm targeted therapy, comprise the steps:
It is that the aqueous solution of formula (III) compound of 7-9 reacts that formula (II) compound add is regulated pH, or with formula (II) compound and formula (III) compound have mineral alkali in the presence of water in react, promptly make be used for neoplasm targeted therapy contain glucose platinum complex (I); The structural formula of described (II) is:
In the formula (II):
X and Y are ligands, and described X and Y are identical or different and represent a NH separately
3, a C
1-C
8Chain-like alkyl primary amine, a C
3-C
8Cyclic alkyl primary amine, aromatic amine, one have a C at least
1-C
4Aromatic amine, a molecular formula that alkyl replaces are R
1-NH-R
2Secondary amine, R wherein
1And R
2Identical or the different C that represents respectively
1-C
8Chain-like alkyl or R
1-NH-R
2The common C that forms
4-C
8Cyclic alkyl secondary amine, a nitrogenous aromatic heterocyclic compounds with 5-8 annular atoms or have a C at least
1-C
4The nitrogenous aromatic heterocyclic compounds that alkyl replaces, sulfur-containing aromatic heterogeneous ring compound or non-aromatic heterogeneous ring compound with 5-8 annular atoms, or X and Y represent that together molecular formula is H
2N-Z-NH
2Diamine compound, wherein Z is C
2-C
8Chain alkylidene group or C
4-C
8Cyclic alkyl; The heteroatoms of heterogeneous ring compound is meant Sauerstoffatom, nitrogen-atoms, and sulphur atom, phosphorus atom etc. are different from the element of carbon atom;
The example of the represented best ligand of X and Y includes but not limited among the present invention: X and Y respectively are NH
3, Isopropylamine, cyclopropylamine, ring butylamine, cyclopentamine, hexahydroaniline; Perhaps X and Y one of them be NH
3, another is an Isopropylamine, cyclopropylamine, ring butylamine, cyclopentamine, hexahydroaniline, 2-picoline; Perhaps X and Y represent that together molecular formula is H
2N-Z-NH
2Diamine compound, for example: 1,1, the 3-propylene diamine, 2-methyl tetramethylene-diamine, 1, the 2-cyclohexanediamine, 1,2-encircles heptamethylene diamine, 1,2-encircles octamethylenediamine, 1-amino-2-aminomethyl hexanaphthene, 1,1-diaminomethyl hexanaphthene, 5,5-diaminomethyl-1,3-diox, 2-aminomethyl-tetramethyleneimine and 2-aminomethyl-pyridine.When containing chiral centre in the above-mentioned ligand compound, can be wherein arbitrary optical isomer or racemic mixture;
Described molecular formula is H
2N-Z-NH
2Diamine compound preferably trans-(1R, 2R)-cyclohexanediamine, trans-(1S, 2S)-cyclohexanediamine, cis-(1R, 2S)-cyclohexanediamine, cis-(1S, 2R)-cyclohexanediamine, racemization anti-form-1,2-cyclohexanediamine or racemization cis-1,2-cyclohexanediamine.Preferably select trans-(1R, 2R)-cyclohexanediamine.
A
1And A
2Identical or different, representation hydroxy separately, nitro, perchlorate, perhaps A
1And A
2Couple together the representative sulfate radical, carbonate;
The structural formula of described (III) is:
In the formula (III):
Glucose 1-position is substituted by α or β or both mixtures;
M represents the atoms metal of hydrogen atom or periodic table of elements IA family; Perhaps two M represent the atoms metals of an IIA family jointly;
N is 1-6, and preferred n is 2-4, preferably 2 or 3.
Described mineral alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta or cesium hydroxide.
Described M is hydrogen atom, sodium atom, potassium atom, lithium atom or caesium atom; Or two M represent a barium atom jointly.
Containing the medicine that contains the glucose platinum complex that is used for neoplasm targeted therapy is to use the glucose platinum complex that contains that is used for neoplasm targeted therapy to add that pharmaceutically acceptable carrier or thinner make according to ordinary method.
Advantage of the present invention:
Evidence title complex of the present invention and by the water-soluble height of title complex drug prepared of the present invention has tumour target effect and clinical easy to use.
Embodiment
Embodiments of the invention are in order to make those skilled in the art understand the present invention better, but do not limit the present invention in any way.
The glucose platinum complex that contains that is used for neoplasm targeted therapy of the present invention designs as biological targets at tumor tissues and the peculiar a kind of nutrition transmission passage of cell.Medicine of the present invention can optionally be discerned the cancer cells with this specific channel and reach the purpose of kill cancer cell pointedly.In addition, medicine provided by the present invention can solve the problem of existing platinum medicine and stability of formulation difference and the defective of clinical use inconvenience.
Containing in the title complex provided by the invention to become the D-of tumour-specific nutritive ingredient glucose structure.This structure design has scientific basis, also is to make the platinum complexes that is provided in this invention have one of key of tumor-targeting function.Scientist discovers as far back as the seventies, and tumour cell has the nutritional needs different with normal cell and at special absorption channel (Lee, the S.G.﹠amp of these nutrition; Lipmann, F. (1977) Proc.Natl Acad.Sci.USA 74,163-167.), the glucose that this achievement in research also finds to have special three-dimensional arrangement be tumour cell one of the nutrition of special demand.Then invented with the radioactive fluorine atom according to these results of study scientist and to have replaced second hydroxyl of glucose and the glucose-derivative that generates, be commonly called as the compound of 18FDG.This compound is widely used in the lesions position that detects tumour patient, its root be exactly according to tumour cell at glucose with special three-dimensional arrangement with it as the specificity nutrition source of tumour cell and the principle ((1) that optionally absorbs and in tumour cell, accumulate, Kim, J.et al " 5-thio-D-glucose selectively potentiates hyperthermic killing of hypoxic tumor cells " Science, vol.200, pp.206-207,1978, (2), Bessell, E.et al " The use of deoxyfluoro-d-glucopyranoses and related compounds... " Biochem.J., vol.128, pp.199-204,1972).
The D-glucose with special three-dimensional arrangement that the present invention can optionally be discerned by tumour cell and absorb combines with chemotherapeutics that can kill cancer cell DNA, thereby the platinum antineoplastic complex with tumour target effect (I) that can provide among the present invention has been provided.
The present invention utilizes the characteristics of the highly water-soluble of D-glucose simultaneously, the platinum complexes that making among the present invention is provided has highly water-soluble, solved organometallic compound and generally be difficult to be dissolved in the difficult problem of water, and then solved water-soluble extremely low being not easy of existing metal platinum series antineoplastic medicament by the defective of clinical application.
Medicine of the present invention can be treated the animal that suffers from tumour, and Mammals especially is comprising the medicine of title complex shown in of the present invention the containing (I) of using effective dose for above-mentioned animal.
As provided by the present invention by formula (I) represented be used for neoplasm targeted therapy contain the glucose platinum complex, the representativeness of its preferred compound can also be listed by following table 1 for example, but the glucose platinum complex that contains that is used for neoplasm targeted therapy that the present invention is contained is not limited to following giving an example.
Table 1:
Wherein, when part is 1, can trans-(1R during the 2-cyclohexanediamine, 2R)-cyclohexanediamine, trans-(1S, 2S)-cyclohexanediamine, cis-(1R, 2S)-cyclohexanediamine, cis-(1S, 2R)-cyclohexanediamine, the racemization anti-form-1,2-cyclohexanediamine or racemization cis-1,2-cyclohexanediamine, preferably trans-(1R, 2R)-cyclohexanediamine.
Concrete preparation can utilize following method and reaction formula to finish.
Method A:
Method B:
In method A, when M is hydrogen atom in the formula (III), reaction can be by using suitable mineral alkali, sodium hydroxide for example, potassium hydroxide, yellow soda ash, sodium bicarbonate, the preparation that salt of wormwood, lithium hydroxide and cesium hydroxide wait the pH of the conditioned reaction aqueous solution to maintain to come compound shown in the perfect (I) between the 7-9; When M is atoms metal, for example: sodium atom, potassium atom, lithium atom, barium atom or caesium atom, reaction can be carried out in the aqueous solution smoothly, and the pH that uses the aqueous solution of a spot of above-mentioned mineral alkali to keep reaction soln in case of necessity gets final product the synthetic of title complex shown in the perfect (I) between 7-9.
In method B, when M was hydrogen atom, the hydrated barta that reaction can be by using equivalent was as mineral alkali, and the condensation reaction of finishing in the aqueous solution with the metal platinum sulphate cpd shown in the formula (II) comes title complex shown in the preparation formula (I).When preparing title complex of the present invention by method B, can also use the barium salt that makes in advance, promptly two M represent a barium atom jointly, react the preparation process of finishing title complex with the metal platinum sulphate complex shown in the formula (II) in the aqueous solution.
The solvent of above-mentioned reaction preferably uses deionized water solution, and temperature of reaction is generally in room temperature or be heated to 60 to 90 ℃ as required and react.
The represented compound of method A and B Chinese style (II) can be by the title complex with X and Y of suitable-platinum dichloride accordingly, for example: suitable-two chloro-(1, the 2-diamino-cyclohexane) close platinum and 2 normal Silver Nitrates or 1 normal Sulfuric acid disilver salt and react and prepare.This reaction is preferably in the aqueous solution to be carried out, and the water of use is deionized water preferably.Temperature of reaction is proper in room temperature.
The compound (III) that resulting compound like this (II) and prepared beforehand are good reacts with distilled water or deionization water as solvent.Every normal compound (III) is selected the normal compound of 0.5-4 (II) for use, and optimum condition is 1 to 2 equivalent.Reaction conditions is to finish under the condition of about pH=7-9, and this condition can reach by the potential of hydrogen of using suitable alkali to regulate and keep reaction medium.The kind of this alkali is mineral alkali preferably, sodium hydroxide for example, potassium hydroxide, hydrated barta, yellow soda ash, salt of wormwood, sodium bicarbonate.Preferably use the aqueous solution of about 1N of these alkali.Reaction can be carried out in than wide temperature range at one, and the temperature range that for example is chosen in 0-100 ℃ is carried out above-mentioned reaction.Preferably from room temperature to 90 ℃, and follow simultaneously and stir to well.Time variation range according to different target product reaction needed is also very wide.According to the character of differential responses thing, generally need 1 hour to finishing over 30 days.Need 10 hours to 15 days time under the more situation.
The resultant (I) that a lot of methods can be used to purify and obtain in the above-mentioned reaction.Mixture after for example reaction is finished can concentrate by underpressure distillation then earlier by removing by filter the throw out that may generate, and adds organic solvent then, and desired target (I) precipitation is separated out.The organic solvent that general selection can be dissolved each other with water, for example a kind of alcohol (methyl alcohol for example, ethanol, propyl alcohol, butanols, Virahol etc.), perhaps a kind of ether of necessarily dissolving each other (diethyl ether is for example arranged with water, methyl tertiary butyl ether, tetrahydrofuran (THF), ethylene glycol diethyl ether, glycol dimethyl ether etc.), the precipitation that will obtain collects at last, for example by filtering, just can obtain the represented title complex of needed formula (I).Purify and refining above-mentioned reaction in the resultant (I) that obtains also can be with the method for chromatogram etc.For example spent ion exchange resin is perhaps used preparative liquid chromatography.The liquid chromatography separation and purification generally uses the first alcohol and water to carry out as mobile phase.
The compounds of this invention (III) can be by the given method C of following reaction formula, D or method E, and any one among the F is prepared:
Method C:
Method D:
Method E:
Method F:
In method C, replace the malonic ester derivative as 2-position with the sugar reaction, can be by using for example dimethyl malonate of haloalkyl alcohol and malonic ester compound, diethyl malonate, the propanedioic acid benzhydryl ester, the different lactones of propanedioic acid ring etc. according to the known general method of document (for example: Journal of the American Chemical Society, 131 (8), 2786-2787; 2009) synthetic simply.The propanedioic acid that obtains-2-alkyl alcohol and D-glucose can carry out condensation reaction in solvent in the presence of Lewis acid, thereby obtain the glucoside compound that the 2-alkyl replaces malonic ester.The condition of condensation reaction is to use the normal malonate derivative of 0.02-50 at the glucosylation compound, and the Lewis acid of use can be BF
3, SnCl
4, FeCl
3, AlCl
3, hydrochloric acid, tosic acid, camphorsulfonic acid etc., lewis acidic amount can be the 0.1-10 equivalent with respect to glucose.Employed solvent can be a tetrahydrofuran (THF), methylene dichloride, and toluene, glycol dimethyl ether, ethylene glycol diethyl ethers etc. also can use in two kinds of reactants any one to be used as solvent and carry out this reaction.The temperature of reaction can generally can be finished this reaction 60-80 ℃ of heating from 0 ℃ to 100 ℃.React the needed time according to the difference of reactant and difference can be finished in general 1 hour to 7 days.The reaction product that obtains can be made with extra care by a series of purification condition, generally can use the silica gel column chromatography partition method, perhaps the liquid-phase chromatographic column partition method.This product that obtains just can obtain the represented compound of needed formula (III) at last through the protecting group of removing propanedioic acid.The method of deprotection is according to the difference of the protecting group of using and difference; if use phenmethyl propanedioic acid compound; can use the method for hydrogenating reduction to carry out deprotection; if use diethyl malonate or the different lactone of propanedioic acid ring to react; can use mineral alkali at methanol-water during deprotection; perhaps carry out in the THF-water solvent, the ratio of organic solvent and water is generally 1: 1-4: 1.Employed inorganic salt can be sodium hydroxide, potassium hydroxide, hydrated barta, lithium hydroxide etc.Temperature of reaction is generally room temperature, and the reaction times was generally 1-24 hour.The purification of the compound that deprotection generates can be used silica gel chromatography or ion exchange resin filtration method, perhaps uses liquid phase chromatography to finish, if directly remove reaction solvent with distillation method, resulting resultant will be the corresponding metal carboxylate salt.
Shown in method D; D-glucose can also change into corresponding acetyl glucose earlier; and then the condensation reaction of enforcement and 2-position replacement malonic ester derivative; the acetylize of D-glucose can be implemented simply according to the method for bibliographical information, for example adopts the acetyl acid anhydride can finish in 1-24 hour in room temperature or 60 ℃ of heating as acetylation reagent in pyridine.Basic identical described in the reaction conditions of each step among the method D except that acetylize and the method C.
Preparation method shown in method E and the F carries out condensation with glucose or acetyl glucose earlier with halohydrin in the presence of Lewis acid, carry out obtaining at last with the substitution reaction of malonic ester derivative the preparation route of compound (III) then.Relate to the acetylize of glucose in the above-mentioned preparation route, the condensation reaction under Lewis acid exists, that is narrated in the 2-position substitution reaction of malonic ester and the last deprotection reaction, its reaction conditions and implementation method and method C and method D is identical.
Compound provided by the invention has good antineoplastic activity.This anti-tumor activity can with the cis-platinum that is widely used at present, carboplatin or oxaliplatin compare favourably, it is active even be higher than these existing platinum-containing anticancer drugs.In addition, title complex provided by the present invention can form strong drug-fast mouse Leukemia-L1210 bacterial strain at the antitumous effect of cis-platinum and have more effective lethal effect, and this is because title complex provided by the present invention has special highly selective and the target effect at tumour cell.Title complex provided by the present invention is compared with existing platinum antineoplastic medicine aspect water-soluble, all has the raising more than tens times, this highly water-soluble characteristics can increase and improve the drainage of medicine at kidney in theory, alleviate the general high kidney toxic side effect that exists of platinum medicine, thereby this highly water-soluble characteristic makes the application clinically of the easy preparationization of these compounds more convenient simultaneously.
Anti-tumor complex of the present invention, its route of administration has no particular limits.Its dosage not only depends on patient's age, and the body weight and the state of an illness also depend on kind, character and the severity of tumour.But in general, for the adult patient, the amount of preferably using this title complex every day be 10 milligrams to one the gram between.Be generally each to three weeks once or medication several times.
Below further specify the present invention with specific embodiment.
Embodiment 1:
(1) 1-O-D-glucoside-2-bromo-ethane preparation:
1) at ambient temperature glucose (2.7g) is joined in the ethylene bromohyrin (10ml), be cooled to 0 ℃ after with air in the nitrogen replacement flask, under nitrogen protection, slowly drip boron trifluoride diethyl ether solution (98%, 1ml).
2) reaction solution was stirred 15 minutes at 0 ℃, slowly be warmed up to room temperature then and stirred 30 minutes, reaction solution is heated to 80 ℃ then, 80 ℃ of reactions 5 hours.
After reaction is finished, revolve to steam to remove and desolvate, use silica gel column chromatography (methylene dichloride: methyl alcohol, 6: 1) that resultant of reaction is implemented simple purification, obtain thick product 2.3g.
Mass spectrum: MS, m/z:287.23[M+H]
+
(2) preparation of 1-O-(2,3,4,6-is tetra-acetylated-D-glucoside)-2-bromo-ethane:
At ambient temperature, product 1-O-D-glucoside-2-bromo-ethane 2.3g that previous step reaction is obtained is dissolved in pyridine (7ml: 7ml), stirring is spent the night, usefulness TLC monitoring reaction terminal point with diacetyl oxide.After reaction is finished, add the 100ml ethyl acetate, with volumetric concentration be 5% aqueous hydrochloric acid (2 * 25ml) washings, with water with ethyl acetate (2 * 25ml) extractions, merging organic phase.Organic phase is used saturated aqueous ammonium chloride successively, and (1 * 100ml), (1 * 100ml), (1 * 100ml), (anhydrous sodium sulfate drying is used in 1 * 100ml) washing to saturated sodium-chloride water solution to saturated sodium bicarbonate aqueous solution to distilled water.With the solvent evaporate to dryness, obtain the thick product of little yellow with Rotary Evaporators.The thick product that obtains obtains colorless oil purpose product 2.5g through silica gel chromatography (sherwood oil: ethyl acetate, 3: 1).
Nuclear magnetic resonance spectrum (400MHz, CDCl3), ppm:
5.45 (1H, triplet, J=9.6Hz)
5.15 (1H, doublet, J=4Hz)
5.02 (1H, triplet .J=9.6Hz)
(4.80-4.83 1H, multiplet)
(4.19-4.23 1H, multiplet)
(4.04-4.15 2H, multiplet)
(3.92-4.00 1H, multiplet)
(3.75-3.85 1H, multiplet)
3.49 (2H, triplet, J=6Hz)
(1.91-2.11 12H, multiplet)
Mass spectrum: MS, m/z:455.15[M+H]
+
(3) 1-O-(2,3,4,6-is tetra-acetylated-D-glucoside)-propane-3, the preparation of 3-dicarboxylate:
Previous step is reacted the product 1-O-(2,3,4 that obtains; 6-is tetra-acetylated-the D-glucoside)-2-bromo-ethane (2.5g) is dissolved in 5ml exsiccant N, in the dinethylformamide, adds salt of wormwood (3g) in reaction solution; diethyl malonate (1.76g), stirred overnight at room temperature.With TLC monitoring reaction terminal point, after question response is finished, in reaction solution, add the 100ml ethyl acetate, use then saturated aqueous ammonium chloride (1 * 50ml) washing, with water with ethyl acetate extraction (2 * 25ml), merge organic phase.Organic phase is used saturated aqueous ammonium chloride (1 * 100ml) successively, distilled water (1 * 100ml), saturated nacl aqueous solution (1 * 100ml) washing, use anhydrous sodium sulfate drying then, with Rotary Evaporators with the solvent evaporate to dryness, the faint yellow oily thing that obtains obtains water white transparency oily purpose product 2.6g with silica gel chromatography (sherwood oil: ethyl acetate, 3: 1).
Nuclear magnetic resonance spectrum (400MHz, CDCl3), ppm:
5.42 (1H, triplet, J=9.6Hz)
(4.96-5.10 2H, multiplet)
(4.78-4.90 1H, multiplet)
(4.03-4.33 5H, multiplet)
(3.92-4.02 1H, multiplet)
(3.71-3.87 1H, multiplet)
(3.71-3.87 1H, multiplet)
3.55 (1H, triplet, J=8Hz)
(3.40-3.50 1H, multiplet)
(2.13-2.28 2H, multiplet)
(1.94-2.14 12H, multiplet)
(1.15-1.35 6H, multiplet)
Mass spectrum: MS, m/z:535.34[M+H]
+
(4) 1-O-D-glucoside-propane-3, the 3-dioctyl phthalate
1) with 1-O-(2,3,4,6-is tetra-acetylated-D-glucoside)-propane-3,3-dicarboxylate (2.6g) is dissolved in the 5mL methyl alcohol.Sodium hydroxide (1.6g) is dissolved in the 10mL water, joins in the reaction solution under the room temperature, be warming up to 60 ℃ of reactions 24 hours then.With TLC monitoring reaction terminal point.
2) after question response is finished, remove methyl alcohol, use the storng-acid cation exchange resin treating product with Rotary Evaporators.The aqueous solution that filtration is obtained obtains colourless viscous liquid 1.3g after with the freeze drier drying, and thick product is directly used in the next step.
Mass spectrum: MS, m/z:311.25[M+H]
+
(5) suitable-[trans-(1R, 2R)-diamino-cyclohexane] preparation of platinum (II) (1-O-D-glucoside-propane-3,3-dicarboxylic acid esters):
1) with 1-O-D-glucoside-propane-3, the thick product of 3-dioctyl phthalate (1.3g) is dissolved in the 15mL water, adds barium hydroxide octahydrate (about 1.3g is dissolved in the 5ml water) conditioned reaction liquid pH to 7, stirring at room 30 minutes.
2) under nitrogen protection, sulfatodiamino cyctohexane platinum (1.7g) is dissolved in the 2ml water, joins 1) reaction solution in, regulate pH to 7 with barium hydroxide solution, the room temperature lucifuge stirs spends the night.
3) after question response is finished, use whizzer to remove precipitation, collect supernatant liquor, use the freeze drier freeze-drying, obtain 1.5g the finished product, white solid with partly preparing the high pressure liquid chromatography separation.
Nuclear magnetic resonance spectrum (400MHz, D2O), ppm:
4.80 (0.8H, doublet, J=3.6Hz)
4.25 (0.2H, doublet, J=7.2Hz)
(4.18 1H, multiplet)
(3.12-3.90 8H, multiplet)
(2.30-2.45 2H, multiplet)
(2.20-2.30 2H, multiplet)
(1.82-1.96 2H, multiplet)
1.44 (2H, double peak, J=9.6Hz)
(1.15-1.24 2H, multiplet)
(0.95-1.15 2H, multiplet)
Mass spectrum: MS, m/z:618.36[M+H]
+
Embodiment 2:
(1) preparation of 1-O-D-glucoside-3-bromo-propane:
At ambient temperature glucose (1.8g) is joined 3-bromopropyl alcohol (8mL), is cooled to 0 ℃, with air in the nitrogen replacement flask, under nitrogen protection with the diethyl ether solution that slowly splashes into boron trifluoride (98%, 0.7mL).Reaction solution was stirred 15 minutes at 0 ℃, rose to stirring at room 30 minutes, be heated to 80 ℃ then, 80 ℃ of reactions 5 hours.After reaction is finished, revolve to steam to remove and desolvate, after use silica gel column chromatography (methylene dichloride: methyl alcohol, volume ratio 6: 1) carries out simple purification, obtain thick product 2g.
Mass spectrum: MS, m/z:301.23[M+H]
+
(2) preparation of 1-O-(2,3,4,6-is tetra-acetylated-D-glucoside)-3-bromo-propane:
At ambient temperature, the thick product 2g of 1-O-D-glucoside-3-bromo-propane that previous step reaction is obtained is dissolved in pyridine (6ml: 6ml), stirring is spent the night, usefulness TLC monitoring reaction terminal point with diacetyl oxide.After reaction is finished, add the 100ml ethyl acetate, with volumetric concentration be 5% aqueous hydrochloric acid (2 * 25ml) washings, with water with ethyl acetate (2 * 25ml) extractions, merging organic phase.Organic phase is used saturated aqueous ammonium chloride successively, and (1 * 100ml), (1 * 100ml), (1 * 100ml), (anhydrous sodium sulfate drying is used in 1 * 100ml) washing to saturated sodium-chloride water solution to saturated sodium bicarbonate aqueous solution to distilled water.With the solvent evaporate to dryness, obtain the thick product of little yellow with Rotary Evaporators.Arrive thick product through silica gel chromatography (sherwood oil: ethyl acetate, 3: 1), obtain colorless oil purpose product 2.1g.
Nuclear magnetic resonance spectrum (400MHz, CDCl3), ppm:
5.47 (1H, triplet, J=9.6Hz)
(5.00-5.15 2H, multiplet)
(4.85-4.95 1H, multiplet)
(4.20-4.40 1H, multiplet)
(4.07-4.18 1H, multiplet)
(4.00-4.07 1H, multiplet)
(3.80-3.95 1H, multiplet)
(3.40-3.70 3H, multiplet)
(1.90-2.30 14H, multiplet)
Mass spectrum: MS, m/z:469.15[M+H]
+
(3) 1-O-(2,3,4,6-is tetra-acetylated-D-glucoside)-butane-4, the preparation of 4-dicarboxylate:
1-O-(2,3,4,6-is tetra-acetylated-D-glucoside)-3-bromo-propane (2.1g) is dissolved in 15ml exsiccant N, in the dinethylformamide, adds salt of wormwood (2.5g) in reaction solution, diethyl malonate (1.45g) is in stirred overnight at room temperature.With TLC monitoring reaction terminal point, after question response is finished, in reaction solution, add the 100ml ethyl acetate, with saturated aqueous ammonium chloride (1 * 50ml) washing, with water with ethyl acetate extraction (2 * 25ml), merge organic phase.Organic phase is used saturated aqueous ammonium chloride (1 * 100ml) successively, distilled water (1 * 100ml), saturated nacl aqueous solution (1 * 100ml) washing, use anhydrous sodium sulfate drying then, with Rotary Evaporators with the solvent evaporate to dryness, the faint yellow oily thing that obtains obtains water white transparency oily purpose product 2.2g with silica gel chromatography (sherwood oil: ethyl acetate, 3: 1).
Nuclear magnetic resonance spectrum (400MHz, CD3Cl3), ppm:
5.45 (1H, triplet, J=9.6Hz)
(4.95-5.15 2H, multiplet)
(4.75-4.93 1H, multiplet)
(4.13-4.35 5H, multiplet)
(4.03-4.11 1H, multiplet)
(3.93-4.02 1H, multiplet)
(3.60-3.80 1H, multiplet)
(3.39-3.50 1H, multiplet)
3.25-3.38 (1H, triplet, J=8Hz)
(1.80-2.30 14H, multiplet)
(1.50-1.75 2H, multiplet)
(1.10-1.45 6H, multiplet)
Mass spectrum: MS, m/z:549.50[M+H]
+
(4) 1-O-D-glucoside-butane-4, the preparation of 4-dioctyl phthalate:
1) 1-O-(2,3,4,6-is tetra-acetylated-D-glucoside)-butane-4,4-dicarboxylate (2.2g) is dissolved in the 5mL methyl alcohol.Sodium hydroxide (1.26g) is dissolved in the 10mL water, slowly joins in the reaction solution, be warming up to 60 ℃ of reactions 24 hours then in room temperature.With TLC monitoring reaction terminal point.
2) after question response is finished, remove methyl alcohol, use the storng-acid cation exchange resin treating product with Rotary Evaporators.The aqueous solution that obtains is used the freeze drier drying, obtain the colourless viscous liquid of 1.2g.Thick product is directly used in next step reaction.Mass spectrum: MS, m/z:325.15[M+H]
+
(5) suitable-[trans-(1R, 2R)-diamino-cyclohexane] preparation of platinum (II) (1-O-D-glucoside-butane-4,4-dicarboxylic acid esters):
1) with 1-O-D-glucoside-butane-4, the thick product of 4-dioctyl phthalate (1.2g) was dissolved in the 15mL water, adds barium hydroxide octahydrate (1.23g is dissolved in the 5ml water) conditioned reaction liquid pH to 8, stirring at room 30 minutes.
2) under nitrogen protection, sulfatodiamino cyctohexane platinum (1.5g) is dissolved in the 2ml water, joins 1) in reaction solution in, regulate pH to 8 with barium hydroxide solution, the room temperature lucifuge stirs spends the night.
3) after question response is finished, use whizzer to remove precipitation, collect supernatant liquor, HPLC separates and the freeze-drying of use freeze drier with partly preparing, and obtains the 1.5g the finished product, white solid.
Nuclear magnetic resonance spectrum (400MHz, D2O), ppm:
4.86 (0.8H, doublet, J=3.6Hz)
4.40 (0.2H, doublet, J=7.2Hz)
(3.30-3.90 9H, multiplet)
(2.30-2.50 4H, multiplet)
1.95 (2H, double peak, J=12Hz)
(1.60-1.80 2H, multiplet)
1.49 (2H, double peak, J=8Hz)
(1.13-1.33 2H, multiplet)
(0.92-1.11 2H, multiplet)
Mass spectrum: MS, m/z:632.65[M+H]
+
Embodiment 3:
The preparation of diamino platinum (II) (1-O-D-glucoside-propane-3,3-dicarboxylic acid esters):
1) with 1-O-D-glucoside-propane-3 of 100mg, the thick product of 3-dioctyl phthalate is dissolved in the deionized water of 5ml, adds barium hydroxide octahydrate (about 100mg is dissolved in the 5ml water) conditioned reaction liquid pH to 9, stirring at room 30 minutes.
2) under nitrogen protection, diamines platinic sulfate (125mg) is dissolved in the 2ml water, joins 1) in the reaction solution, regulate pH to 9 with barium hydroxide solution, the room temperature lucifuge stirs spends the night.
3) after question response is finished, use whizzer to remove precipitation, collect supernatant liquor, HPLC is refining to be separated and the freeze-drying of use freeze drier with partly preparing, and obtains the 120mg the finished product, white solid.
Nuclear magnetic resonance spectrum (400MHz, D2O), ppm:
4.81 (0.8H, doublet, J=3.6Hz)
4.25 (0.2H, doublet, J=7.2Hz)
(2.90-4.10 9H, multiplet)
(2.10-2.60 2H, multiplet)
Mass spectrum: MS, m/z:538.11[M+H]
+
Embodiment 4:
Diamino platinum (II) (1-O-D-glucoside-butane-4,4-dicarboxylic acid esters):
1) with 1-O-D-glucoside-butane-4 of 100mg, the thick product of 4-dioctyl phthalate is dissolved in the deionized water of 5ml, adds barium hydroxide octahydrate (98mg is dissolved in the 5ml water) conditioned reaction liquid pH to 9, stirring at room 30 minutes.
2) under nitrogen protection, diamines platinic sulfate (120mg) is dissolved in the 2ml water, joins 1) in the reaction solution, regulate pH to 9 with barium hydroxide solution, the room temperature lucifuge stirs spends the night.
3) after question response is finished, use whizzer to remove precipitation, collect supernatant liquor, HPLC is refining to be separated and the freeze-drying of use freeze drier with partly preparing, and obtains the 110mg the finished product, white solid.
Nuclear magnetic resonance spectrum (400MHz, D2O), ppm:
4.87 (0.9H, doublet, J=3.6Hz)
4.42 (0.1H, doublet, J=7.2Hz)
(3.35-3.95 9H, multiplet)
(2.30-2.55 2H, multiplet)
(1.60-1.80 2H, multiplet)
Mass spectrum: MS, m/z:552.56[M+H]
+
Experiment 1
Contain glucose platinum complex and marketed drug cis-platinum for what the present invention relatively was used for neoplasm targeted therapy, carboplatin and the oxaliplatin difference aspect water-soluble, in following test, carried out the saturated solution solute quality determination of various medicines in the 100g water under the room temperature at the representational platinum complex of the present invention and three kinds of marketed drug respectively, table 2 enumerated of the present invention contain the glucose platinum complex in water solubleness and with platinum antineoplastic clinical medicine cis-platinum, the difference of carboplatin and oxaliplatin.
Table 2:
Experiment 2
In order to test the target that contains the glucose platinum complex that the present invention is used for neoplasm targeted therapy, in following test, adopt the title complex of the present invention and the cisplatin medicine of same concentrations to carry out the drug absorption test experiments at colon-cancer cell HT29.50 μ M cisplatin medicines and title complex of the present invention (in the table 1 21 and 22) are adopted in experiment respectively, and (part was trans-(1R, 2R)-diamino-cyclohexane), with HT29 colon-cancer cell co-cultivation 1 hour and 3 hours.Behind the centrifugal collecting cell,, use the 150mM salt solution, the HEPES of 50mM (pH7.2) and 0.5% Tween 20 lysing cell and supersound process with the PBS rinse after ice-cold three times.Get the 200ul lysate and carry out Atomic Absorption Spectrometry, the content of metal platinum in more every milligram of protein ingredient: experimental result is listed in the table 3:
Table 3:
Experiment 3
In following test, test animal is the 8-9 female CDF1 kind mouse in age in week, the weight of animals average out to 20-25 gram.With L1210 cell (10
5Every mouse of cell) by the intraperitoneal inoculation, table 3 has illustrated used title complex and experimental result in the test.For title complex of the present invention and carboplatin, use the 5%V/V mannitol aqueous solution, then use 5%V/V mannitol normal saline solution for cis-platinum.Every group of laboratory animal number was 6 via intraperitoneal injection drug in the 1st, 4 day behind tumor cell transplantation.
The method of calculation that the animal life-span prolongs (ILS) are as follows:
ILS％＝[(St/Su)-1]X100
Wherein, the weighting mediant of St=animals survived day of receiving treatment; The weighting mediant of the animals survived day that Su=does not receive treatment
Experimental result is listed in the table 4:
Table 4:
Annotate the 1st day to the 7th day body weight change of *
Utilize metal platinum complex of the present invention, can prepare the medicine that is used for oncotherapy.The metal platinum complex provided by the present invention of one or several effective doses is used in the preparation of these medicines usually, cooperates pharmaceutically acceptable carrier or thinner and finishes.These pharmaceutically acceptable pharmaceutical excipients are starch for example, glucose, dextrin, fructose and maltose, lactose, gelatin, sucrose, hydroxylated cellulose, Vltra tears, silicon-dioxide, the stearic acid sodium starch glycollate, water, ethanol, sodium-chlor etc. can be selected according to different formulation needs.In addition, according to the needs on the medication preparation, these pharmaceutical excipients can also comprise a spot of acid-base modifier, stablizer etc.
Claims (10)
1. what be used for neoplasm targeted therapy contains the glucose platinum complex, it is characterized in that with shown in the formula (I):
Wherein:
Glucose 1-position is substituted by α or β or both mixtures;
X and Y are ligands, and described X and Y are identical or different and represent a NH separately
3, a C
1-C
8Chain-like alkyl primary amine, a C
3-C
8Cyclic alkyl primary amine, aromatic amine, one have a C at least
1-C
4Aromatic amine, a molecular formula that alkyl replaces are R
1-NH-R
2Secondary amine, R wherein
1And R
2Identical or the different C that represents respectively
1-C
8Chain-like alkyl or R
1-NH-R
2The common C that forms
4-C
8Cyclic alkyl secondary amine, a nitrogenous aromatic heterocyclic compounds with 5-8 annular atoms or have a C at least
1-C
4The nitrogenous aromatic heterocyclic compounds that alkyl replaces, sulfur-containing aromatic heterogeneous ring compound or non-aromatic heterogeneous ring compound with 5-8 annular atoms, or X and Y represent that together molecular formula is H
2N-Z-NH
2Diamine compound, wherein Z is C
2-C
8Chain alkylidene group or C
4-C
8Cyclic alkyl;
N is 1-6.
2. according to claim 1 be used for neoplasm targeted therapy contain the glucose platinum complex, it is characterized in that described n is 2-4.
3. according to claim 2 be used for neoplasm targeted therapy contain the glucose platinum complex, it is characterized in that described n is 2 or 3.
4. according to claim 1 be used for neoplasm targeted therapy contain the glucose platinum complex, it is characterized in that described molecular formula is H
2N-Z-NH
2Diamine compound be trans-(1R, 2R)-cyclohexanediamine, trans-(1S, 2S)-cyclohexanediamine, cis-(1R, 2S)-cyclohexanediamine, cis-(1S, 2R)-cyclohexanediamine, racemization anti-form-1,2-cyclohexanediamine or racemization cis-1,2-cyclohexanediamine.
5. according to claim 4 be used for neoplasm targeted therapy contain the glucose platinum complex, it is characterized in that described H
2N-Z-NH
2For trans-(1R, 2R)-cyclohexanediamine.
6. the preparation method who contains glucose platinum complex (I) who is used for neoplasm targeted therapy of claim 1 is characterized in that comprising the steps:
It is that the aqueous solution of formula (III) compound of 7-9 reacts that formula (II) compound add is regulated pH, or with formula (II) compound and formula (III) compound have mineral alkali in the presence of water in react, promptly make be used for neoplasm targeted therapy contain glucose platinum complex (I); The structural formula of described (II) is:
In the formula (II):
X and Y are ligands, and described X and Y are identical or different and represent a NH separately
3, a C
1-C
8Chain-like alkyl primary amine, a C
3-C
8Cyclic alkyl primary amine, aromatic amine, one have a C at least
1-C
4Aromatic amine, a molecular formula that alkyl replaces are R
1-NH-R
2Secondary amine, R wherein
1And R
2Identical or the different C that represents respectively
1-C
8Chain-like alkyl or R
1-NH-R
2The common C that forms
4-C
8Cyclic alkyl secondary amine, a nitrogenous aromatic heterocyclic compounds with 5-8 annular atoms or have a C at least
1-C
4The nitrogenous aromatic heterocyclic compounds that alkyl replaces, sulfur-containing aromatic heterogeneous ring compound or non-aromatic heterogeneous ring compound with 5-8 annular atoms, or X and Y represent that together molecular formula is H
2N-Z-NH
2Diamine compound, wherein Z is C
2-C
8Chain alkylidene group or C
4-C
8Cyclic alkyl;
A
1And A
2Identical or different, representation hydroxy separately, nitro, perchlorate, perhaps A
1And A
2Couple together the representative sulfate radical, carbonate;
The structural formula of described (III) is:
In the formula (III):
Glucose 1-position is substituted by α or β or both mixtures;
M represents the atoms metal of hydrogen atom or periodic table of elements IA family; Perhaps two M represent the atoms metals of an IIA family jointly;
N is 1-6.
7. the preparation method who contains the glucose platinum complex who is used for neoplasm targeted therapy according to claim 6 is characterized in that described mineral alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta or cesium hydroxide, and described n is 2-4.
8. the preparation method who contains the glucose platinum complex who is used for neoplasm targeted therapy according to claim 6 is characterized in that described molecular formula is H
2N-Z-NH
2Diamine compound be trans-(1R, 2R)-cyclohexanediamine, trans-(1S, 2S)-cyclohexanediamine, cis-(1R, 2S)-cyclohexanediamine, cis-(1S, 2R)-cyclohexanediamine, racemization anti-form-1,2-cyclohexanediamine or racemization cis-1,2-cyclohexanediamine.
9. the preparation method who contains the glucose platinum complex who is used for neoplasm targeted therapy according to claim 6 is characterized in that described M is hydrogen atom, sodium atom, potassium atom, lithium atom or caesium atom; Or two M represent a barium atom jointly.
10. contain the medicine that contains the glucose platinum complex that is used for neoplasm targeted therapy, it is characterized in that adding that with the glucose platinum complex that contains that is used for neoplasm targeted therapy of one of claim 1-5 pharmaceutically acceptable carrier or thinner make.
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