CN106608897A

CN106608897A - Fluorine-containing water-soluble platinum complex and its preparation method and use

Info

Publication number: CN106608897A
Application number: CN201510705072.0A
Authority: CN
Inventors: 高清志; 高香倩; 刘冉; 刘朋兴; 韩建斌; 米倩
Original assignee: Tianjin University
Current assignee: Tianjin University
Priority date: 2015-10-27
Filing date: 2015-10-27
Publication date: 2017-05-03
Anticipated expiration: 2035-10-27
Also published as: CN106608897B

Abstract

The invention discloses a fluorine-containing water-soluble platinum complex and its preparation method and use. The fluorine-containing water-soluble platinum complex is shown in the formula (I). A test result shows that the fluorine-containing water-soluble platinum complex has excellent tumor-selective drug accumulation effects and prevents rejection-caused tumor resistance to drugs by targeting delivery to tumor cells. Compared with clinical drugs, the complex has high water solubility and is suitable for clinical preparation. Compared with a clinical drug oxaliplatin, the complex has superiority in cytotoxicity. The fluorine-containing water-soluble platinum complex solves the problem the existing platinum drug has poor water solubility, poor stability and clinical use inconvenience, improves drug targeting effects on tumor cells, and solve the problem that the existing clinical drugs has deficiency in tumor treatment effects, resistance to drugs and toxic or side effect.

Description

Chloride water solublity platinum complex and Preparation method and use

Technical field

The present invention relates to a kind of chloride water solublity platinum complex and preparation method.

Background technology

Platinum class anticarcinogen is the representative class medicine of therapeutic field of tumor.Which belongs to cell cycle nonspecific agent (CCNSA), right Sarcoma, carcinoma, lymphoma and germ cell tumor all have therapeutic efficiency.It is widely used in the world facing at present The representative platinum class anticarcinogen of bed treatment mainly has, cisplatin, carboplatin and oxaliplatin.

The fatal defects of platinum-containing anticancer drug are with extremely strong toxic and side effects and intrinsic and drug resistance problems that are being subsequently formed. It is metallo-organic compound additionally, due to such medicine, the extremely low characteristic of all platinum class marketed drug generally existing water solublity, following table It is the water solubility data of above-mentioned three kinds of listings clinical medicine：

Medicine	Cisplatin	Carboplatin	Oxaliplatin
				Water solublity (mg/ml)	1.0	17.0	6.0

Research shows, includes that tumor cell enters the resistance of cell to medicine the reason for tumor forms drug resistance to platinum series antineoplastic medicament Only effect and outside repulsive interaction so as to reduce platinum medicine tumor cell savings (Holzer AK, Manorek GH, Howell SB.Molecular Pharmacology(Internet).2006；70(4):1390-4.), therefore how platinum class to be effectively improved Medicine is that exploitation needs to solve with targeting a new generation platinum-containing anticancer drug in the selective aggregation of tumor cell and tumor tissues One of key scientific problems.

The tracer 18F-DG (fluoro -2-deoxy-D-glucose) for diagnosing for clinical tumor and checking by stages is clinical the most frequently used Developer.Its principle is tumor cell to maintain the needs of fast breeding and transfer, high expression glucose transporter (GLUT) To draw substantial amounts of glycan molecule nutrient substance.By injecting after the 18F-DG that radioactive label fluorine atom replaces to patient, medicine exists Tumor cell is accumulated, and the diagnosis of malignant tumor then can be realized by whole body PET imagings, and benign and pernicious discriminating is clinical to divide Phase, therapeutic evaluation and detection recurrence etc..But 18F-DG is only limited to diagnostic uses itself does not have therapeutic effect.

Further, since too low water solublity stability not only to medicine preparation and clinical practice bring many adverse effects, Such as it is difficult to they are successfully configured to a kind of convenience and the clinical medicament with suitable concn.And, too low medicine is water-soluble Property also directly influences savings and metabolism of the medicine in body, and the platinum-like compounds containing metallic atom are especially in the excretion of medicine Etc. aspect affected more notable by water miscible, platinum medicine of the savings in renal tissue and blood can not be discharged in time by body Define platinum medicine generally have very strong toxic and side effects the characteristics of.The following is the various platinum antineoplastics with novel chemical structure Medicine due to water solublity can not be improved and thus the sincere medicine savings type toxic and side effects of caused weight and be forced stop clinical trial Medicine case：

(list of references：Status of platinum drugs in the clinic and in clinical trials,Dalton Transactions,2010,39, 8113-8127.)

In sum, the tumor-targeting and water solubility problems for solving platinum medicine is that platinum class anticarcinogen researches and develops field in the world at present Absorbed most important problem (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).

Chinese patent ZL201210206008.4 discloses " the chloride water solublity platinum complex and its preparation side for oncotherapy Method ", the compound have solved water miscible problem, but tumor-targeting and antitumous effect are need to be improved.

The content of the invention

It is an object of the invention to provide a kind of chloride water-soluble platinum for being capable of and antitumous effect good to tumor-targeting raising coordinates Thing.

Second object of the present invention is to provide a kind of preparation method of chloride water solublity platinum complex.

Third object of the present invention is to provide a kind of purposes of chloride water solublity platinum complex.

Technical scheme is summarized as follows：

Chloride water solublity platinum complex, is shown in formula (I)：

Wherein:

X and Y are ligands, and the X and Y is identical or different and each represents a NH₃, a C₁-C₈Chain-like alkyl primary amine, One C₃-C₈Cyclic alkyl primary amine or X and Y are trans-(1R, 2R)-cyclohexanediamine together, trans-(1S, 2S)-hexamethylene Diamidogen, cis-(1R, 2S)-cyclohexanediamine or cis-(1S, 2R)-cyclohexanediamine, racemization anti-form-1,2- cyclohexanediamine Or racemic cis -1,2- cyclohexanediamine；

Wherein C₁-C₈The preferred 2-aminopropane. of chain-like alkyl primary amine；C₃-C₈Cyclic alkyl primary amine, wherein it is preferred that C₃-C₆Cyclic alkyl primary amine；

N is 1-6, n preferably 2 or 3.

Can also be：X and Y is identical or different and each represents an aromatic amine, at least one C₁-C₄Alkyl replaces Aromatic amine, molecular formula be R₁-NH-R₂Secondary amine, wherein R₁And R₂Identical or difference represents C respectively₁-C₈Chain-like alkyl Or R₁-NH-R₂Collectively constitute C₄-C₈Cyclic alkyl secondary amine, one have nitrogenous aromatic heterocyclic compounds or at least one C₁-C₄Alkyl-substituted nitrogenous aromatic heterocyclic compounds, one have sulfur-containing aromatic heterocyclic compound or sulfur-bearing non-aromatic it is miscellaneous Cycle compound or X and Y mono- are reinstated shown in structural formula (VIII)：

Wherein D is C₀Or C₁Alkylidene；B is C₂-C₈Alkylidene；

X and Y are preferred together：Trans-(1R, 2R)-cyclohexanediamine.

The preparation method of chloride water solublity platinum complex (I), comprises the steps：

Formula (II) compound is reacted with have adjusted the aqueous solution of formula (III) compound that pH is 7-9, or by formula (II) Compound is reacted in the water having in the presence of inorganic base with formula (III) compound, that is, make chloride water solublity platinum complex (I)；The structural formula of (II) is：

In formula (II)：X and Y are ligands, and the X and Y is identical or different and each represents a NH₃, a C₁-C₈Chain Kiber alkyl amine, a C₃-C₈Cyclic alkyl primary amine or X and Y are trans-(1R, 2R)-cyclohexanediamine together, trans-(1S, 2S)-cyclohexanediamine, cis-(1R, 2S)-cyclohexanediamine or cis-(1S, 2R)-cyclohexanediamine, racemization anti-form-1,2- Cyclohexanediamine or racemic cis -1,2- cyclohexanediamine；

Wherein C₁-C₈The preferred 2-aminopropane. of chain-like alkyl primary amine；C₃-C₈The preferred C of cyclic alkyl primary amine₃-C₆Cyclic alkyl primary amine；

Wherein D is C₀Or C₁Alkylidene；B is C₂-C₈Alkylidene；

Optimal example represented by the X and Y of the present invention is included but is not limited to：

X and Y are respectively NH₃, 2-aminopropane., cyclopropylamine, ring butylamine, Aminocyclopentane, cyclohexylamine；Or one of X and Y are NH₃, Another is 2-aminopropane., cyclopropylamine, ring butylamine, Aminocyclopentane, cyclohexylamine, 2- picolines；1，2-diaminoethane, 1,3- third Diamidogen, 2- methyltetramethylene diamidogen, 1,2- ring butanediamine, 1,2- ring pentanediamine, 1,2- cyclohexanediamine, 1,2- cycloheptyl Diamidogen, 1,2- ring octamethylenediamine, 1- amino -2- aminomethyl cyclohexanes, 1,1- diaminomethyl hexamethylene, 5,5- diaminomethyl -1, 3- dioxs, 2- aminomethyls-pyrrolidine and 2- aminomethyl-pyridines；When chiral centre is contained in above-mentioned ligand compound, can be with It is any of which optical isomer or racemic mixture；

A₁And A₂It is identical or different, respective representation hydroxy, nitro, perchlorate, or A₁And A₂Represent jointly sulfate radical or Carbonate；

(III) structural formula is：

In formula (III)：

M represents the metallic atom of hydrogen atom or periodic table of elements group ia；Or two M represent a group iia jointly Metallic atom；The preferred hydrogen atoms of M, sodium atom or two M represent a barium atom jointly；

N is 1-6；It is preferred that 2,3 or 4；Preferably 2 or 3；

The inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, Lithium hydrate, barium hydroxide Or Cesium hydrate.；

Preferably：X and Y are trans-(1R, 2R)-cyclohexanediamine together, and trans-(1S, 2S)-cyclohexanediamine is suitable Formula-(1R, 2S)-cyclohexanediamine, cis-(1S, 2R)-cyclohexanediamine, racemization anti-form-1,2- cyclohexanediamine or racemization it is suitable Formula -1,2- cyclohexanediamine.Preferably：Trans-(1R, 2R)-cyclohexanediamine.Preferably X and Y together for it is trans-(1R, 2R)-cyclohexanediamine.

Above-mentioned chloride water solublity platinum complex and preparation made by pharmaceutically acceptable adjuvant.

Above-mentioned chloride water solublity platinum complex is preparing the application of preventing and treating tumour medicine.

Above-mentioned preparation is preparing the application of preventing and treating tumour medicine.

Advantages of the present invention：

Test proves that the chloride water solublity platinum complex of the present invention is public with clinical medicine and Chinese patent ZL201210206008.4 Open " chloride water solublity platinum complex for oncotherapy and preparation method thereof " to compare with superior tumor selective agents Depot action, can transmit the drug resistance for overcoming tumor to form the repulsive interaction of medicine by the targeting to tumor cell. In addition, the coordination compound of the present invention compared with clinical medicine with higher water solublity, it is easy to clinical preparation.3rd, the present invention The chloride water solublity platinum complex for being provided in terms of cytotoxicity compared with clinical medicine oxaliplatin with superiority.To sum up institute State, chloride water solublity platinum complex provided by the present invention can not only solve existing platinum medicine and deposit in default of water solublity Preparation stability difference problem and the inconvenient defect of Clinical practice, and the targeting of drug on tumor cell can be improved Property, solve the deficiency that existing clinical medicine is present in terms of oncotherapy effect, drug resistance and toxic and side effects.

2-deoxy-D-glucose is combined by the present invention with the metal platinum complex with therapeutic effect, is making full use of 2- deoxidations On the basis of-D-Glucose targets neoplastic cells, exploitation is with the anti-tumor drugs targeting for controlling treatment functions.

Description of the drawings

Fig. 1 is coordination compound antitumor drug effect -1 prepared by embodiment 1.

Fig. 2 is coordination compound antitumor drug effect -2 prepared by embodiment 1.

Fig. 3 is coordination compound antitumor drug effect -1 prepared by embodiment 2.

Fig. 4 is coordination compound antitumor drug effect -2 prepared by embodiment 2.

Fig. 5 is coordination compound antitumor drug effect -1 prepared by embodiment 5.

Fig. 6 is coordination compound antitumor drug effect -2 prepared by embodiment 5.

Fig. 7 is coordination compound antitumor drug effect -1 prepared by embodiment 6.

Fig. 8 is coordination compound antitumor drug effect -2 prepared by embodiment 6.

Specific embodiment

Embodiments of the invention are in order that those skilled in the art more fully understands the present invention, but limits this never in any form Invention.

As the water-soluble platinum coordination compound for oncotherapy by represented by formula (I) provided by the present invention, its preferred compound Representative citing can also be listed by table 1 below, but the covered chloride water solublity platinum complex of the present invention is not limited to following act Example.

Wherein, deoxyglucose 1- positions replacement can be the mixture of α or β or both；N, and X, Y be shown in

Table 1：

Ligand 1 in table 1,2- cyclohexanediamine can be trans-(1R, 2R)-cyclohexanediamine, trans-(1S, 2S)-ring Hexamethylene diamine, cis-(R, S)-cyclohexanediamine or cis-(S, R)-cyclohexanediamine, racemization anti-form-1,2- cyclohexanediamine, Racemic cis -1, any one among 2- cyclohexanediamine.

The concrete preparation of chloride water solublity platinum complex in the present invention can be completed by following methods and reaction equation.

Method A：

Method B：

In method a, when in (III), M is hydrogen atom, reaction can be by using appropriate inorganic base, such as hydroxide Sodium, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, Lithium hydrate and Cesium hydrate. etc. are adjusting reacting solution The preparation that pH maintains between 7-9 to complete coordination compound shown in formula (I)；When M is the metallic atom, such as sodium atom, Potassium atom, barium atom or Cs atom, reaction can be smoothed out in aqueous, if necessary using the water of a small amount of above-mentioned inorganic base Solution maintains the pH of reaction solution that the synthesis of coordination compound shown in formula (I) can be completed between 7-9.

In method B, when M is hydrogen atom, reaction can be by using the barium hydroxide of equivalent as inorganic base, in water Complete with the condensation reaction of the metal platinum sulphate cpd shown in formula (II) to prepare the coordination compound shown in formula (I) in solution. When coordination compound of the present invention is prepared by method B, can also represent a barium atom jointly using the obtained M of barium salt, i.e., two in advance, The preparation process for being reacted in aqueous to complete coordination compound with the metal platinum sulphate complex shown in formula (II).

The solvent of above-mentioned reaction is preferably used deionized water solution, and reaction temperature is typically heated to 60-90 in room temperature or as needed DEG C reacted.

Compound in method A and B represented by formula (II) can pass through the coordination compound of corresponding cis- platinous chloride and X and Y, For example：Cis- two chloro- (1,2- diamino-cyclohexane) are closed the silver sulfate reaction of the silver nitrate or 1 equivalent of platinum and 2 equivalents and are prepared. The reaction is preferably carried out in aqueous, and the water for using is preferably deionized water.Reaction temperature is proper in room temperature.

Compound (II) and compound (III) distilled water or the deionization water as solvent for preparing in advance obtained by so Reacted.Per equivalent compound (III) from 0.5-4 equivalent compound (II), optimum condition be 1 to 2 work as Amount.Reaction condition is completed under conditions of 7-9 in pH, the condition reaction medium can be maintained by using appropriate alkali and Reach.The species of the alkali is preferably inorganic base, such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, Sodium bicarbonate.The aqueous solution of the about 1N of these alkali is used preferably.Reaction can be entered within the scope of the relatively wide temperature OK, for example select in 0-100 DEG C of temperature range carrying out above-mentioned reaction.Preferably from room temperature to 90 DEG C, and while adjoint stir Mix preferably.It is also very wide according to the time change scope that different target product reactions needs.According to the property of differential responses thing, one As need 1 hour to completing over 30 days.The time of 10 hours to 15 days is needed more often.

The product (I) that many methods are obtained in being used to purify above-mentioned reaction.Such as mixture after the completion of reacting can be with First pass through and be filtered to remove the precipitate that may be generated, then concentrated by vacuum distillation, be subsequently adding organic solvent, make desired Target (I) Precipitation.Be typically chosen can be miscible with water organic solvent, for example a kind of alcohol (such as methanol, ethanol, third Alcohol, butanol, isopropanol etc.), or have a kind of ether (such as diethyl ether, methyl tertiary butyl ether(MTBE), the tetrahydrochysene furan for necessarily dissolving each other with water Mutter, ethylene glycol diethyl ether, glycol dimethyl ether etc.), finally the precipitation for obtaining is collected, such as by filtering, it is possible to The coordination compound represented by formula (I) required for obtaining.The product (I) obtained in purification and refined above-mentioned reaction can also be used The method of chromatograph etc..Such as spent ion exchange resin, or use preparative liquid chromatography.Liquid chromatograph separation and purification generally uses first Alcohol and water is carried out as mobile phase.

The compounds of this invention (III) can be prepared by method C given by following reaction equations：

Method C：

Preparation method shown in method C is first to be condensed halohydrin with acetylation deoxyglucose in the presence of a lewis acid, so Carry out afterwards finally obtaining the syntheti c route of compound (III) with the substitution reaction of malonic ester derivatives through deprotection reaction.On The acetylation of the deoxyglucose being related in stating syntheti c route, can implement according to the method for document report, for example, adopt in pyridine Be completed in room temperature or by heating 1-24 hours at 60 DEG C as acetylation reagent with acetic anhydride.Glucosides in the presence of lewis acid The condition of synthetic reaction is the fluorine-containing malonate derivative that 0.1-50 equivalents are used for deoxyglucose sugar compounds, or phase purl The deoxyglucose raw material of 0.1-50 equivalents is used to fluorine-containing malonate derivative.The lewis acid for using can be BF₃, SnCl₄, FeCl₃, AlCl₃, hydrochloric acid, p-methyl benzenesulfonic acid, camphorsulfonic acid etc., lewis acidic amount relative to deoxyglucose raw material can be 0.1-10 equivalents.The solvent for being used can be tetrahydrofuran, dichloromethane, toluene, glycol dimethyl ether, ethylene glycol diethyl Ether etc. can also carry out the reaction as solvent using any one in two kinds of reactants.The temperature of reaction can from zero DEG C to 100 DEG C, typically the reaction can be completed in 60-80 DEG C of heating.Reaction required for time according to the different and different of reactant, Can complete within general 1 hour to 7 days.The product for obtaining can be refined by a series of purification condition, typically may be used To use silica gel chromatography, or liquid-phase chromatographic column partition method.The 2- positions substitution reaction of glycoside compounds and malonate can With according to conventional method known to document (for example：Journal of the American Chemical Society,131(8),2786-2787； 2009) use sodium hydride, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate etc. molten in DMF, toluene or tetrahydrofuran etc. Complete in agent.Two chlorine substitution reactions of resulting malonate, it is possible to use representational chlorine substitution reaction reagent N CS Come carry out.Reaction typically in THF or DMF or ether solvent by the alkali process of malonate equivalent or excess after, Add above-mentioned chlorine substitution reaction reagent to complete.The alkali for being used can be sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, carbon Sour hydrogen sodium etc., it is 1-3 times of malonate that chlorine replaces the equivalent of reagent, reaction temperature typically at zero DEG C to 60 DEG C, preferably in room temperature Under the conditions of stir and complete.Last deprotection reaction can using inorganic base in methanol-water, or carrying out in THF- aqueous solvents, The ratio of organic solvent and water is generally 1:1-4:1.The inorganic base for being used can be sodium hydroxide, potassium hydroxide, barium hydroxide, Lithium hydrate etc..Reaction temperature is generally room temperature to 60 DEG C, and the response time is generally 1-24 hours.The compound that deprotection is generated Purification can use silica gel chromatography or ion exchange resin Filtration, or using liquid chromatography completing, if used The way of distillation directly removes reaction dissolvent, and resulting product would is that corresponding metal carboxylate.

Major experimental instrument：

Nuclear magnetic resonance spectrometer：BRUKER AVANCE III, 400MHz；Analytical liquid chromatograph：The logical perseverance LC3000 types of Beijing innovation High performance liquid chromatograph, SPD-10ATvp dual wavelength ultraviolet detectors, 7725i manual injectors, the work of CLASS-VP chromatographs Stand；Analysis chromatographic column：DaisoGel, C18,4.6 × 250cm, 5 μm of KNAUER Germany；Semi-preparative liquid chromatography instrument： The logical perseverance LC3000 semi-preparative liquid chromatographies of innovation, SPI001；Half preparative hplc post：DaisoGel 250×20mmID,C18, 10μm；Mass spectrograph：Agilent 6310Ion Trap LC/MS；Freezer dryer：FD-1c-50 freeze dryers (the rich doctor in Beijing Health experimental apparatus company limited).

Embodiment 1：

(1) preparation of 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides) the bromo- ethane of -2- (V-1)：

At ambient temperature, in D-2- deoxyglucose 1.6g being dissolved in pyridine and acetic anhydride (7ml: 7ml), it is stirred overnight, Reaction end is monitored with TLC.After the completion of reaction, 100ml ethyl acetate is added, with the aqueous hydrochloric acid solution that volumetric concentration is 5% (2 × 25ml) is washed, and water is mutually extracted with ethyl acetate (2 × 25ml), merges organic faciess.Organic faciess are used saturation successively Aqueous ammonium chloride solution (1 × 100ml), distilled water (1 × 100ml), saturated sodium bicarbonate aqueous solution (1 × 100ml), saturation Sodium-chloride water solution (1 × 100ml) is washed, and uses anhydrous sodium sulfate drying.Solvent is evaporated with Rotary Evaporators, obtains micro- Huang Color 3,4,6- triacetyl-D-2- deoxyglucose crude products.The crude product for obtaining is dissolved in into the DCM of 20ml dryings at room temperature In, ethylene bromohyrin (2.4g) is added, 0 DEG C is cooled to, with air in nitrogen displacement flask, slowly Deca three under nitrogen protection The diethyl ether solution (98%, 1ml) of boron fluoride.Reactant liquor is stirred 15 minutes at 0 DEG C, room temperature is then slowly warmed up to and is stirred 60 minutes, after the completion of confirming reaction with TLC detections, revolving removed solvent, adds 100ml ethyl acetate, uses volumetric concentration Aqueous hydrochloric acid solution (2 × 25ml) washing for 5%, organic faciess is used saturated aqueous ammonium chloride (1 × 100ml) successively, is steamed Distilled water (1 × 100ml), saturated sodium bicarbonate aqueous solution (1 × 100ml), saturated sodium-chloride water solution (1 × 100ml) washing, Solvent is evaporated with anhydrous sodium sulfate drying and with Rotary Evaporators.Jing silica gel chromatographies (petroleum ether: ethyl acetate, body Product ratio, 3: 1), obtain colorless oil purpose product 1.9g.

Nuclear magnetic resoance spectrum (400MHz, CDCl3), ppm：5.28-5.35(m,1H),4.97-5.02(m,2H),4.24-4.31(m, 1H), 4.06-4.11 (m, 2H), 3.91-3.97 (m, 1H), 3.78-3.84 (m, 1H), 3.50 (t, J=6.0Hz, 2H), 2.29 (dd, J= 13.0Hz, 5.3Hz, 1H), 2.09 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.80-1.87 (m, 1H). mass spectrum：MS, m/z： 397.15,399.23[M+H]⁺

(2) preparation of 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides)-propane -3,3- dicarboxylates (VI-1)：

Product 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides) the bromo- ethane of -2- (1.8g) that previous step reaction is obtained It is dissolved in the DMF of 5ml dryings, addition potassium carbonate (3g) in reactant liquor, diethyl malonate (1.6g), It is stirred overnight at room temperature.Reaction end is monitored with TLC, after the completion of question response, 100ml ethyl acetate is added in reactant liquor, so Washed with saturated aqueous ammonium chloride (1 × 50ml) afterwards, water is mutually extracted with ethyl acetate (2 × 25ml), merge organic faciess. Organic faciess are used saturated aqueous ammonium chloride (1 × 100ml), distilled water (1 × 100ml), saturated nacl aqueous solution (1 successively × 100ml) washing, then with anhydrous sodium sulfate drying, solvent is evaporated with Rotary Evaporators, the pale yellow oil for obtaining is used Silica gel chromatography (petroleum ether: ethyl acetate, volume ratio, 3: 1), obtain water white transparency oily purpose product 2.6g.

Nuclear magnetic resoance spectrum (400MHz, CDCl3), ppm：5.21-5.28 (m, 1H), 4.98 (t, J=9.8Hz, 1H), 4.90 (d, J=3.2Hz, 1H), 4.14-4.32 (m, 5H), 3.92-4.04 (m, 2H), 3.68-3.74 (m, 1H), 3.52 (t, J=7.3Hz, 1H), 3.39-3.49(m,1H),2.16-2.24(m,3H),2.08(s,3H),2.03(s,3H),2.00(s,3H),1.76-1.83(m,1H), 1.27 (t, J=7.1Hz, 6H). mass spectrum：MS, m/z：477.28[M+H]⁺

(3) 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides) the chloro- 3,3- dicarboxylates (VII-1) of-propane -3- Preparation

1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides)-propane -3,3- dicarboxylate 2.5g are dissolved in into 20mL In dry tetrahydrofuran, 0 DEG C is cooled to.With air in nitrogen displacement flask, 235mg hydrogenations are slowly added under nitrogen protection Sodium solid (60%).Reactant liquor is warming up to room temperature, stirs 1 hour.Add 770mgN- chlorosuccinimides, reactant liquor room temperature Reaction 2 hours, revolving remove solvent.100ml ethyl acetate is added in reactant liquor, then with saturated aqueous ammonium chloride (1 × 50ml) washing, water is mutually extracted with ethyl acetate (2 × 25ml), merges organic faciess.Organic faciess are used saturation chlorination successively Aqueous ammonium (1 × 100ml), distilled water (1 × 100ml), saturated sodium-chloride water solution (1 × 100ml) washing, Ran Houyong Solvent is evaporated by anhydrous sodium sulfate drying with Rotary Evaporators, the pale yellow oil for obtaining silica gel chromatography (oil Ether: ethyl acetate, 3: 1), obtain water white transparency oily purpose product 2.4g.

Nuclear magnetic resoance spectrum (400MHz, CDCl3), ppm：5.12-5.19 (m, 1H), 4.50 (t, J=9.9Hz, 1H), 4.88 (d, J=3.3Hz, 1H), 4.25-4.39 (m, 5H), 3.94-4.08 (m, 3H), 3.56-3.62 (m, 1H), 2.55-2.67 (m, 2H), 2.21 (dd, J=13.0Hz, 5.2Hz, 1H), 2.09 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H), 1.73-1.80 (m, 1H), 1.28-1.33 (m, 6H). mass spectrum：MS, m/z：511.19[M+H]⁺

(4) preparation of the chloro- 3,3- dioctyl phthalate (III-1) of 1-O- (D-2- deoxyglucose glucosides)-propane -3-

1) by 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides)-propane -3- chloro- 3,3- dicarboxylates (2.3g) It is dissolved in 5mL methanol.Sodium hydroxide (1.5g) is dissolved in 10mL water, is added under room temperature in reactant liquor, then It is warming up to 90 DEG C to react about 12 hours.Reaction end is monitored with TLC.

2) after the completion of question response, methanol is removed with Rotary Evaporators, process product using storng-acid cation exchange resin.To filter The aqueous solution freezer dryer for obtaining obtains colorless viscous shape liquid 1.6g after being dried, and crude product is directly used in the next step.

Mass spectrum：MS, m/z：329.10[M+H]⁺

(5) it is cis-【Trans-(1R, 2R)-diamino-cyclohexane】Platinum (II)【1-O- (D-2- deoxyglucose glucosides)-propane -3- Chloro- 3,3- dicarboxylic acid esters】(I-1) preparation：

1) by 1-O- (D-2- deoxyglucose glucosides)-propane -3- chloro- 3,3- dioctyl phthalate crude products (1.3g) is dissolved in 15mL water, Add barium hydroxide octahydrate (about 1.3g is dissolved in 5ml water) reactant liquor pH to be adjusted to 7, be stirred at room temperature 30 minutes.

2) under nitrogen protection sulfatodiamino cyctohexane platinum (2.1g) is dissolved in 2ml water, is added in reactant liquor 1), uses hydrogen Barium oxide solution adjusts pH to 7, and room temperature lucifuge is stirred overnight.

3) after the completion of question response, removed using centrifuge and precipitated, collect supernatant, using freezer dryer lyophilizing, prepared with half high The isolated 1.6g final products of pressure liquid chromatography, white solid.

Nuclear magnetic resoance spectrum (400MHz, D2O), ppm：5.73(br,1H),5.66(br,1H),5.14(br,1H), 4.96(br,1H),4.92(s,1H),3.50-3.90(m,7H),3.00-3.30(m,2H),2.32(br,2H),1.95-2.05(m, 1H), 1.93 (br, 2H), 1.50-1.62 (m, 1H), 1.46 (br, 2H), 1.18 (br, 2H), 1.03 (br, 2H). mass spectrum：MS, m/z： 637.10,636.08,635.17[M+H]⁺

Embodiment 2：

Diaminourea platinum (II)【1-O- (D-2- deoxyglucose glucosides) chloro- 3, the 3- dicarboxylic acid esters of-propane -3-】(I-2) preparation：

1) 1-O- (D-2- deoxyglucose glucosides) the chloro- 3,3- dioctyl phthalate crude products of-propane -3- of 110mg are dissolved in into the deionization of 5ml Water, adds barium hydroxide octahydrate (about 98mg is dissolved in 5ml water) to adjust reactant liquor pH to 8, is stirred at room temperature 30 points Clock.

2) under nitrogen protection diaminourea platinic sulfate (115mg) is dissolved in 2ml water, in being added to 1) in reactant liquor, uses hydrogen Barium oxide solution adjusts pH to 8, and room temperature lucifuge is stirred overnight.

3) after the completion of question response, removed using centrifuge and precipitated, collect supernatant, HPLC refining spearations are prepared and using freezing with half Drying machine lyophilizing, obtains 100mg final products, white solid.

Nuclear magnetic resoance spectrum (400MHz, D2O), ppm：4.92(s,1H),3.80-3.90(m,1H),3.60-3.80(m,2H),3.40-3.60 (m, 2H), 2.61 (s, 2H), 2.20-2.40 (m, 2H), 2.00-2.10 (m, 1H), 1.55-1.66 (m, 1H). mass spectrum：MS, m/z： 568.09,567.16,569.07,[M+H]⁺

Embodiment 3：

Diisopropylamino platinum (II)【1-O- (D-2- deoxyglucose glucosides) chloro- 3, the 3- dicarboxylic acid esters of-propane -3-】(I-3) preparation：

1) 1-O- (D-2- deoxyglucose glucosides) the chloro- 3,3- dioctyl phthalate crude products of-propane -3- of 100mg are dissolved in into the deionization of 5ml Water, adds barium hydroxide octahydrate (about 100mg is dissolved in 5ml water) to adjust reactant liquor pH to 8, is stirred at room temperature 30 points Clock.

2) under nitrogen protection diisopropylamino platinic sulfate (130mg) is dissolved in 2ml water, in being added to 1) in reactant liquor, PH to 8 is adjusted with barium hydroxide solution, room temperature lucifuge is stirred overnight.

3) after the completion of question response, removed using centrifuge and precipitated, collect supernatant, HPLC refining spearations are prepared and using freezing with half Drying machine lyophilizing, obtains 154mg final products, white solid.

Nuclear magnetic resoance spectrum (400MHz, D2O), ppm：4.91 (d, J=4.0Hz, 1H), 4.82 (br, 4H), 4.06 (t, J=8.0Hz, 1H),3.80-3.90(m,1H),3.62-3.80(m,3H),3.40-3.58(m,2H),2.80-2.95(m,2H),2.30-2.50(m,

2H), 2.06 (dd, J=4.0,12.0Hz, 1H), 1.60 (dt, J=4.0,12.0Hz, 1H), 1.23 (s, 6H), 1.22 (s, 6H). mass spectrum： MS, m/z：638.16,637.15,639.15,[M+H]⁺

Embodiment 4：

(1) preparation of 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides) the bromo- propane of -3-：

At ambient temperature, it is in D-2- deoxyglucose glucosides 1.6g being dissolved in pyridine and acetic anhydride (7ml: 7ml), stirred At night, reaction end is monitored with TLC.After the completion of reaction, 100ml ethyl acetate is added, with the hydrochloric acid water that volumetric concentration is 5% Solution (2 × 25ml) is washed, and water is mutually extracted with ethyl acetate (2 × 25ml), merges organic faciess.Organic faciess are used successively Saturated aqueous ammonium chloride (1 × 100ml), distilled water (1 × 100ml), saturated sodium bicarbonate aqueous solution (1 × 100ml), Saturated sodium-chloride water solution (1 × 100ml) is washed, and uses anhydrous sodium sulfate drying.Solvent is evaporated with Rotary Evaporators, is obtained Slightly yellow 3,4,6- triacetyls-D-2- deoxyglucose crude products.The crude product for obtaining is dissolved in into 20ml dryings at room temperature In DCM, 3- bromopropyl alcohols (2.5g) are added, 0 DEG C is cooled to, with air in nitrogen displacement flask, is slowly dripped under nitrogen protection Plus the diethyl ether solution (98%, 1ml) of boron trifluoride.Reactant liquor is stirred 15 minutes at 0 DEG C, then room temperature is slowly warmed up to simultaneously Stirring 2 hours, after the completion of confirming reaction with TLC detections, revolving removes solvent, adds 100ml ethyl acetate, dense with volume Aqueous hydrochloric acid solution (2 × 25ml) washing for 5% is spent, organic faciess is used saturated aqueous ammonium chloride (1 × 100ml) successively, Distilled water (1 × 100ml), saturated sodium bicarbonate aqueous solution (1 × 100ml), saturated sodium-chloride water solution (1 × 100ml) are washed Wash, solvent is evaporated with anhydrous sodium sulfate drying and with Rotary Evaporators.Jing silica gel chromatographies (petroleum ether: ethyl acetate, 3: 1), obtain colorless oil purpose product 2.1g.

Nuclear magnetic resoance spectrum (400MHz, CDCl3), ppm：5.24-5.31 (m, 1H), 4.95-5.02 (m, 2H), 4.29 (dd, J= 12.2Hz, 4.6Hz, 1H), 4.07 (dd, J=12.2Hz, 1.9Hz, 1H), 3.95-3.98 (m, 1H), 3.80-3.85 (m, 1H), 3.47-3.54 (m, 3H), 2.23 (dd, J=12.9Hz, 5.2Hz, 1H), 2.10-2.16 (m, 2H), 2.09 (s, 3H), 2.04 (s, 3H), 2.00(s,3H),1.79-1.86(m,1H).

(2) preparation of 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides)-butane -4,4- dicarboxylates (VI-4)：

1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides) the bromo- propane of -3- (2.0g) is dissolved in into 15ml dryings In DMF, in reactant liquor potassium carbonate (2.6g), diethyl malonate (1.55g) is added to stir in room temperature Mix overnight.Reaction end is monitored with TLC, after the completion of question response, 100ml ethyl acetate is added in reactant liquor, saturation chlorine is used Change aqueous ammonium (1 × 50ml) washing, water is mutually extracted with ethyl acetate (2 × 25ml), merge organic faciess.By organic faciess according to Secondary use saturated aqueous ammonium chloride (1 × 100ml), distilled water (1 × 100ml), saturated nacl aqueous solution (1 × 100ml) are washed Wash, then with anhydrous sodium sulfate drying, solvent is evaporated with Rotary Evaporators, the pale yellow oil silica gel column chromatography for obtaining Purification (petroleum ether: ethyl acetate, 3: 1), obtain water white transparency oily purpose product 2.3g.

Nuclear magnetic resoance spectrum (400MHz, CD3Cl3), ppm：5.27-5.33(m,1H),4.93-5.01(m,2H),4.18-4.31(m, 6H), 4.04 (dd, J=12.2Hz, 1.8Hz, 1H), 3.93-3.96 (m, 1H), 3.63-3.69 (m, 1H), 3.34-3.43 (m, 2H), 2.24 (dd, J=12.7Hz, 5.2Hz, 1H), 2.08 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 1.94-1.98 (m, 1H), 1.78-1.86 (m, 1H), 1.60-1.68 (m, 2H), 1.28 (t, J=7.1Hz, 6H).

(3) preparation of the chloro- 4,4- dicarboxylates (VII-4) of 1-O- (3,4,6- triacetyls-D-Glucose glycosides)-butane -4-

1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides)-butane -4,4- dicarboxylate 2.5g are dissolved in into 20mL In dry tetrahydrofuran, 0 DEG C is cooled to.With air in nitrogen displacement flask, 255mg hydrogenations are slowly added under nitrogen protection Sodium solid (60%).Reactant liquor is warming up to room temperature, stirs 1 hour.Add 790mgN- chlorosuccinimides, reactant liquor room temperature Reaction 2 hours, revolving remove solvent.100ml ethyl acetate is added in reactant liquor, then with saturated aqueous ammonium chloride (1 × 50ml) washing, water is mutually extracted with ethyl acetate (2 × 25ml), merges organic faciess.Organic faciess are used saturation chlorination successively Aqueous ammonium (1 × 100ml), distilled water (1 × 100ml), saturated sodium-chloride water solution (1 × 100ml) washing, Ran Houyong Solvent is evaporated by anhydrous sodium sulfate drying with Rotary Evaporators, the pale yellow oil for obtaining silica gel chromatography (oil Ether: ethyl acetate, 3: 1), obtain water white transparency oily purpose product 2.6g.

Nuclear magnetic resoance spectrum (400MHz, CDCl3), ppm：5.27-5.33(m,1H),4.93-5.01(m,2H),4.18-4.31(m, 6H), 4.04 (dd, J=12.2Hz, 1.8Hz, 1H), 3.93-3.96 (m, 1H), 3.63-3.69 (m, 1H), 3.34-3.43 (m, 1H), 2.24 (dd, J=12.7Hz, 5.2Hz, 1H), 2.08 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 1.94-1.98 (m, 1H), 1.78-1.86 (m, 1H), 1.60-1.68 (m, 2H), 1.28 (t, J=7.1Hz, 6H). mass spectrum：MS, m/z：853.18[M+H]⁺ (4) preparation of the chloro- 4,4- dioctyl phthalate (III-4) of 1-O- (D-2- deoxyglucose glucosides)-butane -4-

Will be 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides) chloro- 4, the 4- dicarboxylates (2.0g) of-butane -4- molten Solution is in 5mL methanol.Sodium hydroxide (1.4g) is dissolved in 10mL water, is added under room temperature in reactant liquor, Ran Housheng Temperature is reacted 24 hours to 60 DEG C.Reaction end is monitored with HPLC.After the completion of question response, methanol is removed with Rotary Evaporators, made Product is processed with storng-acid cation exchange resin.After the aqueous solution freezer dryer being filtrated to get is dried, Jing partly prepares liquid phase Chromatographic isolation obtains colorless viscous shape liquid 1.4g.

Mass spectrum：MS, m/z：343.09[M+H]⁺

(5) it is cis-【Trans-(1R, 2R)-diamino-cyclohexane】Platinum (II)【1-O- (D-2- deoxyglucose glucosides)-butane -4- Chloro- 4,4- dicarboxylic acid esters】(I-4) preparation：

4) by 1-O- (D-2- deoxyglucose glucosides)-butane -4- chloro- 4,4- dioctyl phthalate (1.3g) is dissolved in 15mL water, is added Barium hydroxide octahydrate (about 1.3g is dissolved in 5ml water) adjusts reactant liquor pH to 7, is stirred at room temperature 30 minutes.

5) under nitrogen protection sulfatodiamino cyctohexane platinum (1.7g) is dissolved in 2ml water, is added in reactant liquor 1), uses hydrogen Barium oxide solution adjusts pH to 7, and room temperature lucifuge is stirred overnight.

6) after the completion of question response, removed using centrifuge and precipitated, collect supernatant, using freezer dryer lyophilizing, prepared with half high The isolated 1.5g final products of pressure liquid chromatography, white solid.

Nuclear magnetic resoance spectrum (400MHz, D2O), ppm：5.82(br,1H),5.64(br,1H),5.13(br,1H), 4.90-5.10(m,2H),3.80-4.00(m,1H),3.50-3.80(m,5H),3.20-3.40(m,2H), 2.70-2.90 (m, 1H), 2.20-2.40 (m, 2H), 2.10 (dd, J=4.0,12.0Hz, 1H), 1.93 (br, 2H), 1.40-1.70 (m, 5H), 0.90-1.30 (m, 4H). mass spectrum：MS, m/z：649.14,650.15,651.17 [M+H]⁺

Embodiment 5：

Diaminourea platinum (II)【1-O- (D-2- deoxyglucose glucosides) chloro- 4, the 4- dicarboxylic acid esters of-butane -4-】(I-5) preparation：

1) 1-O- (D-2- deoxyglucose glucosides) the chloro- 4,4- dioctyl phthalate crude products of-butane -4- of 100mg are dissolved in into the deionization of 5ml Water, adds barium hydroxide octahydrate (about 98mg is dissolved in 5ml water) to adjust reactant liquor pH to 8, is stirred at room temperature 30 points Clock.

2) under nitrogen protection diamidogen platinic sulfate (120mg) is dissolved in 2ml water, in being added to 1) in reactant liquor, uses hydrogen-oxygen Change barium solution and adjust pH to 8, room temperature lucifuge is stirred overnight.

3) after the completion of question response, removed using centrifuge and precipitated, collect supernatant, HPLC refining spearations are prepared and using freezing with half Drying machine lyophilizing, obtains 110mg final products, white solid.

Nuclear magnetic resoance spectrum (400MHz, D2O), ppm：4.95 (d, J=4.0Hz, 1H), 3.85-3.98 (m, 1H), 3.70-3.82 (m, 1H), 3.45-3.72 (m, 5H), 2.33-2.45 (m, 2H), 2.20-2.33 (m, 2H), 2.09 (dd, J=4.0,16.0Hz, 1H), (1.50-1.69 m, 3H). mass spectrum：MS, m/z：565.10,566.05,567.08 [M+H]⁺

Embodiment 6：

Diisopropylamino platinum (II)【1-O- (D-2- deoxyglucose glucosides) chloro- 4, the 4- dicarboxylic acid esters of-butane -4-】(I-6) preparation：

1) by the 1-O-D- deoxyglucoses glucosides-butane -4- fluoro- 4 of 100mg, 4- dioctyl phthalate crude products are dissolved in the deionized water of 5ml, Add barium hydroxide octahydrate (about 100mg is dissolved in 5ml water) reactant liquor pH to be adjusted to 8, be stirred at room temperature 30 minutes.

2) under nitrogen protection diamidogen platinic sulfate (130mg) is dissolved in 2ml water, in being added to 1) in reactant liquor, uses hydrogen-oxygen Change barium solution and adjust pH to 8, room temperature lucifuge is stirred overnight.

3) after the completion of question response, removed using centrifuge and precipitated, collect supernatant, HPLC refining spearations are prepared and using freezing with half Drying machine lyophilizing, obtains 130mg final products, white solid.

Nuclear magnetic resoance spectrum (400MHz, D2O), ppm：4.95 (d, J=4.0Hz, 1H), 4.81 (br, 4H), 3.80-3.90 (m, 1H), 3.60-3.80 (m, 3H), 3.45-3.60 (m, 3H), 2.80-2.95 (m, 2H), 2.30-2.53 (m, 2H), 2.08 (dd, J=4.0, 16.0Hz, 1H), 1.50-1.70 (m, 3H), 1.23 (s, 6H), 1.21 (s, 6H). mass spectrum：MS, m/z：549.13,650.18, 651.20[M+H]⁺

Experimental example 1:

For comparison platinum complex of the present invention and marketed drug cisplatin, the difference of carboplatin and oxaliplatin in terms of water solublity, In following tests, be respectively directed to representational platinum complex of the invention and three kinds of marketed drug carried out it is each in 100g water under room temperature The saturated solution Solute mass of kind of medicine is determined, table 2 list dissolubility of the chloride water solublity platinum complex of the invention in water with And the difference with platinum antineoplastic clinical medicine cisplatin, carboplatin and oxaliplatin.

Table 2：

Experimental example 2:

In following tests, using the female CDF1 kinds Mus of 8-9 week old, 20-25 gram of the weight of animals average out to.It is swollen with L1210 Oncocyte (10⁵Every mouse of cell) it is inoculated with intraperitoneal.It is for the animal model for tumour for making, chloride using the present invention Water-soluble platinum coordination compound implements treatment, and is compared with the platinum series antineoplastic medicament of Clinical practice, verifies the coordination compound of the present invention Toxic and side effects of the therapeutic effect and chloride water solublity platinum complex of the invention to bearing animals to laboratory animal.For the present invention Coordination compound use 5%V/V mannitol aqueous solutions, for cisplatin then using 5%V/V mannitols normal saline solution prepare phase The injection answered.After tumor cell transplantation, via intraperitoneal injection drug, every group of laboratory animal number is 6 in Isosorbide-5-Nitrae day.

Above-mentioned laboratory animal is purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., and tumor cell L1210-mouse leukemia is thin Born of the same parents are purchased from the beautiful commerce and trade company limited of Town in Shanghai.

The computational methods that animal lifespan extends (ILS) are as follows：

ILS%=[(St/Su) -1] X 100

Wherein, St=receives the weighting mediant of the animal survival day for the treatment of；Su=does not receive in the weighting of the animal survival day treated Between number

Experimental result is listed in table -3：

Table 3：

The note body weight change of * the 1 day to the 7th day

Experimental example 3：

Inhibited proliferation of the water-soluble platinum coordination compound effective ingredient of the present invention to cancerous cell

The chloride water solublity platinum complex of the present invention is thin by medicine of the present invention and tumor to the suppression of tumor cell and lethal effect Born of the same parents DNA formed chain in and interchain linkage, so as to suppress DNA of tumor cell synthesis and replicate and realize.

Hereinafter experiment is for propagation of the chloride water solublity platinum complex effective ingredient of the invention to different types of human tumor cells Inhibition has carried out experimental verification.

(1) test method：

Cell culture fluid：

Using containing 10% N of fetus serum (fetal bovine serum), 1mM Sodium Pyruvates, 2mML- glutamine, 50U/ml penicillins, the cell culture fluid of 50 μ g/ml streptomycins (streptomycin).

Major experimental instrument：MCO-15A type CO2 gas incubator (Japanese SANYO companies), inverted phase contrast are micro- Mirror (Olympus, Japan), full-automatic microplate reader (U.S. BioTEK ELX808), cryogenic refrigerator (day This MDF-V5410), superclean bench (Suzhou Medical Instruments Factory), micropipettor (French GILSON), from Dynamic pure water distillator (Shanghai 1810B).

Experiment reagent：

MTS:CellTiter96Aqueous MTS Reagent Powder, Promega companies

PMS:Phenazine methosulfate (PMS), Sigma-Aldrich companies

DPBS:Sigma-Aldrich companies

Tumor cell：

Human tumor cells used in following active testing experiment：Du145-human prostata cancer；MCF-7-human breast carcinoma； SKOV3-human ovarian cancer；HT-29-human colon carcinoma；A549-Non-small cell lung carcinoma (adenocarcinoma)；H460- people is non- Small cell lung cancer (large cell carcinoma), and animal tumor cell：L1210-mouse leukemia cell is purchased from the beautiful commerce and trade of Town in Shanghai Company limited.

Cytotoxicity test：

Cytotoxicity experiment adopts MTS method of testings.Logarithmic (log) phase tumor cell is collected, concentration of cell suspension is adjusted, per hole 100 μ l, bed board are added to make cell to be measured adjust density to 1000-10000/ holes, (edge hole is filled with aseptic PBS). 5%CO2,37 DEG C of incubations, is paved with bottom hole (96 hole flat underside) to cell monolayer, adds the medicine of variable concentrations gradient, Per 100 μ l of hole, if 5 multiple holes.In 5%CO2, it is incubated 96 hours under the conditions of 37 DEG C, observes under inverted microscope.To 100 μ l PMS (1mg/ml, DPBS are prepared) are added in 2ml MTS (2mg/ml, DPBS are prepared) solution, is mixed, is made MTS Working solution.Culture fluid is discarded after above-mentioned Tissue Culture Plate centrifugation, is carefully rushed after 2-3 time with PBS, before detection absorbance, 100 μ l culture medium are added in 96 orifice plates per hole, 20 μ lMTS working solutions is added, at 37 DEG C, is incubated under the conditions of 5%CO2 After educating 2h, OD values (optical density value) are detected at 490nm.

Matched group：Without tested active component under above-mentioned similarity condition, finally obtain tumor cell and examine at 490nm Survey OD values.

Inhibitory activity IC50 of drug on tumor cell：

Cell inhibitory rate is calculated：The suppression ratio of drug on tumor cell growth is calculated by following equation：

1) cell survival rate (%)=treatment group OD values/matched group OD value × 100%

2) cell survival rate under each drug level is obtained, drug level is mapped with this.On the curve of gained, cell survival When rate is 50%, corresponding concentration is exactly IC50 values.

The experiment of above-mentioned each drug level repeats 5 groups, takes average OD values and calculates cell survival rate.

(2) experimental result：

The tumor cell title that various symbols are represented in figure is as follows：Du145-human prostata cancer；MCF-7-people's mammary gland Cancer；SKOV3-human ovarian cancer；HT-29-human colon carcinoma；A549-Non-small cell lung carcinoma (adenocarcinoma)； H460- Non-small cell lung carcinomas (large cell carcinoma)

The antitumor drug effect of platinum complex prepared by embodiment 1 is shown in Fig. 1 and Fig. 2；The antitumor of platinum complex prepared by embodiment 2 Drug effect is shown in Fig. 3 and Fig. 4；The antitumor drug effect of platinum complex prepared by embodiment 5 is shown in Fig. 5 and Fig. 6；Platinum prepared by embodiment 6 The antitumor drug effect of coordination compound is shown in Fig. 7 and Fig. 8.In order to more clearly show the drug effect trend of coordination compound, the curve in all figures Standard error of mean labelling is eliminated

Experimental example 4：

The anticancer drug effect and tumor of the chloride water solublity platinum complex of the present invention and leading patents (ZL201210206008.4) Targeting compares

(1) test method：Using MCF-7 Human Breast Cancer Cells, by 1 medicine of the embodiment of the present invention and disclosed in advance contain There is the corresponding coordination compound of glucose, galactose and mannose under same concentrations (50 μM) and same time condition (24h) Carry out Cytotoxic evaluation.According to the method in experimental example 3 while tumor control rate data are obtained, using atomic absorption light The method of spectrum test, evaluates drug level of each coordination compound in tumor cell, contrasts relative medicine under the same conditions with this For the targeting savings effect of tumor cell.

Cell culture fluid：

Major experimental instrument：Shimadzu AAS tester (AA-6800), MCO-15A type CO2 gas incubator (days This SANYO companies), inverted phase contrast microscope (Olympus, Japan), full-automatic microplate reader (U.S. BioTEK ELX808), cryogenic refrigerator (Japanese MDF-V5410), superclean bench (Suzhou Medical Instruments Factory), micro shifting Liquid device (French GILSON), automatic pure water distillator (Shanghai 1810B).

(2) experimental result：Table -4 lists targeting and different pharmaceutical of the medicine for tumor cell under same concentration conditions The comparative test result of antitumor drug effect.

Table 4

Experimental result shows, chloride water solublity platinum complex provided by the present invention compared with leading disclosed structure similar medicine, More superior effect is shown in terms of the depot action in tumor cell all in antitumor drug effect and medicine.

Using the coordination compound of the present invention, the medicine of prevention and treatment tumor can be prepared.The preparation of these medicines is usually used one kind Or the metal platinum complex provided by the present invention of several effective doses, coordinate pharmaceutically acceptable carrier or diluent and complete. These pharmaceutically acceptable pharmaceutic adjuvant such as starch, glucose, dextrin, Fructose and maltose, Lactose, gelatin, sucrose, Hydroxylated cellulose, hydroxypropyl methyl cellulose, silicon dioxide, stearic acid sodium starch glycollate, water, ethanol, Sodium Chloride etc. Can need to be selected according to different dosage forms.In addition, according to the needs in medicine preparation, these pharmaceutic adjuvants can also include A small amount of acid-base modifier, stabilizer etc..

Experiment is proved：The platinum complex that the present invention is provided has good anti-tumor activity.Provided by the present invention chloride and D-2- The platinum complex of deoxyglucose for include intestinal cancer, breast carcinoma, carcinoma of prostate, pulmonary carcinoma etc. the antitumor test of pesticide effectiveness in, Its anti-tumor activity can be compared favourably with the cisplatin being widely used at present, carboplatin or oxaliplatin, and its activity is even above these Existing platinum-containing anticancer drug.In addition, coordination compound provided by the present invention can form strong drug resistance for the antitumaous effect of cisplatin The Mus Leukemia-L1210 tumor cells of property have more effective lethal effect.This is because provided by the present invention chloride water-soluble Property platinum complex in terms of water solublity compared with existing platinum antineoplastic medicine, it is all with tens times to hundreds of times of raising, this Highly-water-soluble feature can increase and improve excretion of the medicine in kidney in theory, mitigate the high kidney poison that platinum medicine generally there are Side effect, while this highly-water-soluble characteristic makes these compounds easily formulation and application clinically is more convenient.

The coordination compound of the present invention, has no particular limits due to possessing high water solublity its route of administration, and its dosage not only depends on The age of patient Yu, body weight and the state of an illness, additionally depend on the species of tumor, property and the order of severity.But generally, for Adult patient, the amount for preferably using daily are between 10 milligrams to 1 gram.It is generally each to once in three weeks or medication several times.

Claims

1. chloride water solublity platinum complex, is characterized in that shown in formula (I)：

Wherein:

X and Y are ligands, and the X and Y is identical or different and each represents a NH₃, 2-aminopropane., a C₃-C₆ Cyclic alkyl primary amine or X and Y are trans-(1R, 2R)-cyclohexanediamine together, and trans-(1S, 2S)-cyclohexanediamine is suitable Formula-(1R, 2S)-cyclohexanediamine or cis-(1S, 2R)-cyclohexanediamine, racemization anti-form-1,2- cyclohexanediamine or racemization it is suitable Formula -1,2- cyclohexanediamine；

N is 2 or 3.

2. chloride water solublity platinum complex according to claim 1, is characterized in that the X and Y are trans-(1R, 2R) together - cyclohexanediamine.

3. the preparation method of the chloride water solublity platinum complex (I) described in claim 1, is characterized in that comprising the steps：

In formula (II)：X and Y are ligands, and the X and Y is identical or different and each represents a NH₃, 2-aminopropane., One C₃-C₆Cyclic alkyl primary amine or X and Y are trans-(1R, 2R)-cyclohexanediamine together, trans-(1S, 2S)-hexamethylene Diamidogen, cis-(1R, 2S)-cyclohexanediamine or cis-(1S, 2R)-cyclohexanediamine, racemization anti-form-1,2- cyclohexanediamine Or racemic cis -1,2- cyclohexanediamine；

The structural formula of (III) is：

In formula (III)：

M represents the metallic atom of hydrogen atom or periodic table of elements group ia；Or two M represent a group iia jointly Metallic atom；

N is 2 or 3.

4. method according to claim 3, is characterized in that the M represents a barium jointly for hydrogen atom, sodium atom or two M Atom.

5. method according to claim 3, is characterized in that the inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate, carbonic acid Hydrogen sodium, potassium carbonate, Lithium hydrate, barium hydroxide or Cesium hydrate..

6. method according to claim 3, is characterized in that the X and Y are trans-(1R, 2R)-cyclohexanediamine together.

7. 1 or 2 chloride water solublity platinum complex of claim and preparation made by pharmaceutically acceptable adjuvant.

8. 1 or 2 chloride water solublity platinum complex of claim is preparing the application of preventing and treating tumour medicine.

9. the preparation of claim 7 is preparing the application of preventing and treating tumour medicine.