CN106608898B

CN106608898B - The complex of water-soluble platinum containing deoxyglucose and Preparation method and use

Info

Publication number: CN106608898B
Application number: CN201510707338.5A
Authority: CN
Inventors: 高清志; 高香倩; 刘冉; 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: 2019-05-28
Anticipated expiration: 2035-10-27
Also published as: CN106608898A

Abstract

The invention discloses the complex of water-soluble platinum containing deoxyglucose and Preparation method and use, the complex of water-soluble platinum containing deoxyglucose is shown in formula (I):

Description

The complex of water-soluble platinum containing deoxyglucose and Preparation method and use

Technical field

The present invention relates to a kind of complex of water-soluble platinum containing deoxyglucose and preparation methods.

Background technique

Platinum class anticarcinogen is the representative a kind of drug of therapeutic field of tumor.It belongs to non-specific cell cycle medicine Object all has therapeutic efficiency to sarcoma, carcinoma, lymthoma and germinoma.It answers extensively in the world at present Representative platinum class anticarcinogen for clinical treatment mainly has, cis-platinum, carboplatin and oxaliplatin.

The fatal defects of platinum-containing anticancer drug are that have extremely strong toxic side effect and drug resistance that is intrinsic and being subsequently formed Property problem.It is metallo-organic compound additionally, due to such drug, all generally existing water solubilitys of platinum class marketed drug are extremely low Characteristic, following table are the water solubility datas of above-mentioned three kinds of listings clinical medicine:

Drug	Cis-platinum	Carboplatin	Oxaliplatin
				Water-soluble (mg/ml)	1.0	17.0	6.0

Studies have shown that tumour includes that tumour cell enters carefully drug the reason of forming drug resistance to platinum series antineoplastic medicament The interception of born of the same parents and outside repulsive interaction are to reduce platinum medicine in savings (the Holzer AK, Manorek of tumour cell GH,Howell SB.Molecular Pharmacology(Internet).2006；70 (4): 1390-4.), therefore how to have It is that exploitation has targeting a new generation platinum class anti-that effect ground, which improves platinum medicine in the selective aggregation of tumour cell and tumor tissues, Cancer drug needs one of the key scientific problems solved.

The tracer 18F-DG (fluoro -2-deoxy-D-glucose) for diagnosing for clinical tumor and checking by stages is clinical Most common imaging agent.Its principle is tumour cell to maintain the needs of fast breeding and transfer, and height expresses glucose transport Albumen (GLUT) is to draw a large amount of glycan molecule nutriment.By injecting the 18F- that radioactive label fluorine atom replaces to patient After DG, drug is accumulated in tumour cell, and the diagnosis of malignant tumour then may be implemented by whole body PET imaging, benign and pernicious Identification, clinical stages, therapeutic evaluation and detection recurrence etc..But 18F-DG is only limited to diagnostic uses and itself does not treat effect Fruit.

Further, since it is too low it is water-soluble not only brought to the stability of medicine preparation and clinical application it is many unfavorable It influences, for example is difficult they to be successfully configured to a kind of convenience and the clinical medicament with suitable concentration.Moreover, too low medicine Object water solubility also directly influences drug in the intracorporal savings of body and metabolism, and the platinum-like compounds containing metallic atom are especially in medicine Excretion of object etc. is influenced more significant by water-soluble, and putting aside platinum medicine in renal tissue and blood cannot be by body Body is discharged in time to be formd platinum medicine generally and has the characteristics that very virulent side effect.It is various below with novel chemical structure Platinum series antineoplastic medicament due to water solubility cannot be improved and thus caused by the sincere drug savings type toxic side effect of weight and It is forced to stop the drug case of clinical test:

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

In conclusion the tumor-targeting and water solubility problems of solution platinum medicine are that platinum class anticarcinogen is ground in the world at present Hair field absorbed most important project (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)。

Patent WO2006091790A1 discloses " platinum complex of minor structure containing sugar and its methods for making and using same ", the change Closing object has antitumor drug effect, but need to be improved to tumor-targeting and selective antitumous effect.

Summary of the invention

The object of the present invention is to provide it is a kind of be capable of that and antitumous effect good to tumor-targeting improve containing deoxyglucose Syrup dissolubility platinum complex.

A second object of the present invention is to provide a kind of preparation methods of complex of water-soluble platinum containing deoxyglucose.

Third object of the present invention is to provide a kind of purposes of complex of water-soluble platinum containing deoxyglucose.

Technical solution of the present invention is summarized as follows:

The complex of water-soluble platinum containing deoxyglucose is shown in formula (I):

Wherein:

X and Y is ligand, and the X and Y are identical or different and respectively represent a NH₃, a C₁-C₈Chain-like alkyl primary Amine, a C₃-C₈Cyclic alkyl primary amine or X and Y are trans--(1R, 2R)-cyclohexanediamine, trans--(1S, 2S)-hexamethylene two together Amine, cis--(1R, 2S)-cyclohexanediamine or cis--(1S, 2R)-cyclohexanediamine, racemization anti-form-1,2- cyclohexanediamine or racemization are suitable Formula -1,2- cyclohexanediamine；

Wherein C₁-C₈The preferred isopropylamine 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.

A is hydrogen atom, C₁-C₈Chain-like alkyl, hydroxyl or C₁-C₈Chain alkoxy；

It may also is that X and Y is identical or different and respectively represents an aromatic amine, at least one C₁-C₄Alkyl Substituted aromatic amine, a molecular formula are R₁-NH-R₂Secondary amine, wherein R₁And R₂It is same or different to respectively indicate C₁-C₈Chain Alkyl or R₁-NH-R₂Collectively constitute C₄-C₈Cyclic alkyl secondary amine, one there are 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 it is non-aromatic Fragrant race's heterocyclic 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.

A is hydrogen atom, methyl, hydroxyl；

The preparation method of the complex of water-soluble platinum containing deoxyglucose (I), includes the following steps:

Formula (II) compound is reacted with the aqueous solution of formula (III) compound that pH is 7-9 is had adjusted, or by formula (II) it is reacted, that is, is made containing deoxyglucose in the water of compound and formula (III) compound in the presence of having inorganic base Water-soluble platinum complex (I)；The structural formula of (II) are as follows:

In formula (II): X and Y is ligand, and the X and Y are identical or different and respectively represent a NH₃, a C₁-C₈ Chain-like alkyl primary 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- hexamethylene two Amine or racemic cis -1,2- cyclohexanediamine；

Wherein C₁-C₈The preferred isopropylamine 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 X and Y of the invention includes but is not limited to:

X and Y is respectively NH₃, isopropylamine, cyclopropylamine, ring butylamine, cyclopentamine, cyclohexylamine；Or one of X and Y are NH₃, Another is isopropylamine, cyclopropylamine, ring butylamine, cyclopentamine, cyclohexylamine, 2- picoline；1,2- ethylenediamine, 1,3- propane diamine, 2- methyltetramethylene diamines, 1,2- ring butanediamine, 1,2- ring pentanediamine, 1,2- cyclohexanediamine, 1,2- cycloheptyl diamines, 1,2- ring Octamethylenediamine, 1- amino -2- aminomethyl cyclohexane, 1,1- diaminomethyl hexamethylene, 5,5- diaminomethyl -1,3- dioxanes, 2- ammonia Methyi-pyrrofidinium and 2- aminomethyl-pyridine；When containing chiral centre in above-mentioned ligand compound, any optics can be Isomers or racemic mixture；

A₁And A₂It is same or different, respectively represent hydroxyl, nitro, perchlorate or A₁And A₂Sulfate radical is represented jointly Or carbonate；

(III) structural formula are as follows:

In formula (III):

M represents the metallic atom of hydrogen atom or periodic table of elements group ia；Or two M represent a Section II A jointly The metallic atom of race；The preferred hydrogen atom 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；

A is hydrogen atom, C₁-C₈Chain-like alkyl, hydroxyl, C₁-C₈Chain alkoxy；Preferably hydrogen atom, methyl or hydroxyl；

The inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, lithium hydroxide, hydroxide Barium or cesium hydroxide；

Preferably: X and Y is trans--(1R, 2R)-cyclohexanediamine together, trans--(1S, 2S)-cyclohexanediamine, cis-- (1R, 2S)-cyclohexanediamine, cis--(1S, 2R)-cyclohexanediamine, racemization anti-form-1,2- cyclohexanediamine or racemic cis -1,2- ring Hexamethylene diamine.Preferably: trans--(1R, 2R)-cyclohexanediamine.Preferably X and Y is trans--(1R, 2R)-cyclohexanediamine together.

Preparation made of the above-mentioned complex of water-soluble platinum containing deoxyglucose and pharmaceutically acceptable auxiliary material.

Application of the above-mentioned complex of water-soluble platinum containing deoxyglucose in preparation prevention and treatment tumour medicine.

Application of the above-mentioned preparation in preparation prevention and treatment tumour medicine.

Test proves the complex of water-soluble platinum containing deoxyglucose and clinical medicine and leading patent of the invention WO2006091790A1 " platinum complex of dissolubility containing glucose water and preparation method thereof for oncotherapy " is compared with superior Tumor selective agents depot action, can be transmitted by the targeting to tumour cell and tumour be overcome to make the repulsion of drug With and formed drug resistance.In addition, complex of the invention has higher water solubility compared with clinical medicine, it is easy to clinical system Agent.Third, the complex of water-soluble platinum containing deoxyglucose provided by the present invention are difficult to understand with clinical medicine in terms of cytotoxicity Husky benefit platinum, which is compared, has superiority.In conclusion the complex of water-soluble platinum containing deoxyglucose provided by the present invention, it can not only Enough solve the problems, such as existing platinum medicine in default of water solubility and existing preparation stability difference and clinical use are inconvenient Defect, and can be improved drug to the targeting of tumour cell, solve existing clinical medicine in oncotherapy effect, drug resistance Property and toxic side effect in terms of existing for deficiency.

The present invention combines 2-deoxy-D-glucose with the metal platinum complex with therapeutic effect, is making full use of On the basis of 2-deoxy-D-glucose targets neoplastic cells, the anti-tumor drugs targeting with treatment function is developed.

Detailed description of the invention

Fig. 1 is the antitumor drug effect -1 of complex prepared by embodiment 1.

Fig. 2 is the antitumor drug effect -2 of complex prepared by embodiment 1.

Fig. 3 is the antitumor drug effect -1 of complex prepared by embodiment 2.

Fig. 4 is the antitumor drug effect -2 of complex prepared by embodiment 2.

Fig. 5 is the antitumor drug effect -1 of complex prepared by embodiment 4.

Fig. 6 is the antitumor drug effect -2 of complex prepared by embodiment 4.

Fig. 7 is the antitumor drug effect -1 of complex prepared by embodiment 5.

Fig. 8 is the antitumor drug effect -2 of complex prepared by embodiment 5.

Fig. 9 is the antitumor drug effect -1 of complex prepared by embodiment 7.

Figure 10 is the antitumor drug effect -2 of complex prepared by embodiment 7.

Figure 11 is the antitumor drug effect -1 of complex prepared by embodiment 8.

Figure 12 is the antitumor drug effect -2 of complex prepared by embodiment 8.

Specific embodiment

The embodiment of the present invention is in order to make those skilled in the art more fully understand the present invention, but not in any way The limitation present invention.

As the water-soluble platinum complex for oncotherapy represented by (I) provided by the present invention by formula, preferably The representative citing of compound can also be listed by following table 1, but the present invention covers and matches for the water-soluble platinum of oncotherapy Close object citing not limited to the following.

Wherein, deoxyglucose 1- replace the mixture that can be α or β or both；N and X, Y are shown in Table 1:

Table 1:

Ligand 1 in table 1,2- cyclohexanediamine can be trans--(1R, 2R)-cyclohexanediamine, trans--(1S, 2S)-hexamethylene Diamines, cis--(R, S)-cyclohexanediamine or cis--(S, R)-cyclohexanediamine, racemization anti-form-1,2- cyclohexanediamine, racemic cis- Any one among 1,2- cyclohexanediamine.

The specific preparation of the complex of water-soluble platinum containing deoxyglucose can pass through following methods and reaction equation in the present invention To complete.

Method A:

Method B:

In method a, when M is hydrogen atom in (III), reaction can be by using inorganic base appropriate, such as hydrogen-oxygen Change sodium, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, lithium hydroxide and cesium hydroxide etc. adjust reacting solution PH maintains between 7-9 the preparation for completing complex shown in formula (I)；When M is the metallic atom, such as sodium atom, potassium Atom, barium atom or Cs atom, reaction can be gone on smoothly in aqueous solution, when necessary using the water-soluble of a small amount of above-mentioned inorganic base The synthesis of complex shown in formula (I) can be completed in the pH of liquid maintenance reaction solution between 7-9.

In method B, when M is hydrogen atom, reaction can by using the barium hydroxide of equivalent as inorganic base, It completes to prepare cooperation shown in formula (I) with the condensation reaction of metal platinum sulphate cpd shown in formula (II) in aqueous solution Object.When preparing complex of the present invention by method B, prior barium salt obtained can also be used, i.e. two M represent a barium original jointly Son is reacted with metal platinum sulphate complex shown in formula (II) in aqueous solution to complete the preparation process of complex.

Deionized water solution is preferred in the solvent of above-mentioned reaction, and reaction temperature is generally in room temperature or heating as needed It is reacted to 60-90 DEG C.

Compound represented by formula (II) can pass through the cooperation of corresponding cis- platinous chloride and X and Y in method A and B Object, such as: cis- two chloro- (1,2- diaminocyclohexanes) are closed platinum and the silver nitrate of 2 equivalents or the sulfuric acid silver reaction of 1 equivalent and are made It is standby.The reaction preferably carries out in aqueous solution, and the water used is preferably deionized water.Reaction temperature is proper in room temperature.

Such obtained compound (II) is made with compound (III) distilled water or deionized water prepared in advance Solvent is reacted.The compound (III) of every equivalent selects the compound (II) of 0.5-4 equivalent, and optimum condition is 1 to 2 equivalent. Reaction condition is completed under conditions of pH is in 7-9, which can maintain by using alkali appropriate reaction medium and be reached It arrives.The type of the alkali is preferably inorganic base, such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, bicarbonate Sodium.Preferably using the aqueous solution of the about 1N of these alkali.Reaction can carry out within the scope of a wider temperature, example As selected to carry out above-mentioned reaction in 0-100 DEG C of temperature range.Preferably from room temperature to 90 DEG C, and it is with stirring simultaneously It is good.The time change range needed according to different target product reactions is also very wide.According to the property of differential responses object, generally need 1 hour is taken to complete to over 30 days.More often need 10 hours to 15 days time.

Many methods can be used to purify product obtained in above-mentioned reaction (I).Such as mixing after the reaction was completed Object can first pass through the sediment that is filtered to remove and may generate, and then by vacuum distillation concentration, organic solvent is then added, makes Desired target (I) Precipitation.It is typically chosen organic solvent that can be miscible with water, such as a kind of alcohol (such as methanol, second Alcohol, propyl alcohol, butanol, isopropanol etc.), or have with water centainly dissolve each other a kind of ether (such as diethyl ether, methyl tertiary butyl ether(MTBE), four Hydrogen furans, ethylene glycol diethyl ether, glycol dimethyl ether etc.), finally obtained precipitating is collected, such as by filtering, just Complex represented by formula (I) required for available.Purifying and refine product obtained in above-mentioned reaction (I) can also be with With the method for chromatography etc..Such as spent ion exchange resin, or use preparative liquid chromatography.Liquid chromatogram separation and purification generally uses First alcohol and water is used as movement mutually to carry out.

It is any in the compounds of this invention (III) the method C as given by following reaction equations, D or method E, F It is prepared by one kind:

Method C:

Method D:

Method E:

Method F:

It, can be by using halogenated alkyl alcohol and malonate compound for example in method C by taking A is hydrogen atom as an example Dimethyl malenate, diethyl malonate, malonic acid benzhydryl ester, different lactone of malonic acid ring etc. is according to general side known to document Method (such as: Journal of the American Chemical Society, 131 (8), 2786-2787；2009) it makes It is standby.Obtained malonic acid -2- alkyl alcohol derivative and D-2- deoxyglucose can in the presence of a lewis acid in a solvent into Row condensation reaction, to obtain the deoxyglucose glycoside compounds that 2- alkyl replaces malonate.The condition of condensation reaction is needle Deoxyglucose sugar compounds are used with the malonate derivative of 0.1-50 equivalent, or is used on the contrary for malonate derivative The deoxyglucose of 0.1-50 equivalent.The lewis acid used can be BF₃, SnCl₄, FeCl₃, AlCl₃, hydrochloric acid, to toluene sulphur Acid, camphorsulfonic acid etc., lewis acidic amount can be 0.1-10 equivalent relative to deoxyglucose.Used solvent can be Appointing in two kinds of reactants also can be used in tetrahydrofuran, methylene chloride, toluene, glycol dimethyl ether, ethylene glycol diethyl ether etc. One kind of anticipating carries out the reaction as solvent.The temperature of reaction can generally be heated from zero DEG C to 100 DEG C at 60-80 DEG C Complete the reaction.Time required for reacting is different according to the difference of reactant, can complete within general 1 hour to 7 days.It obtains Reaction product can be refined by a series of purification condition, silica gel chromatography generally can be used, or Liquid-phase chromatographic column partition method.The obtained product, the protecting group by removing malonic acid can finally obtain required formula (III) compound represented by.The method of deprotection is different according to the difference of the protecting group used, if using benzyl third Diacid compounds, the method that hydrogenating reduction can be used are deprotected, if using diethyl malonate or malonic acid ring When different lactone is reacted, inorganic base is can be used in methanol-water or THF- aqueous solvent to carry out in deprotection reaction, is had Solvent and the ratio of water are generally 1:1-4:1.Used inorganic base can be sodium hydroxide, potassium hydroxide, barium hydroxide, Lithium hydroxide etc..Reaction temperature is generally room temperature, and the reaction time is generally 1-24 hours.It is deprotected the purification of the compound generated Silica gel chromatography can be used and perhaps ion exchange resin filtration method or completed using liquid chromatography, if with distillation Method directly removes reaction dissolvent, and obtained product will be corresponding metal carboxylate.

As shown in method D, D-2- deoxyglucose can also first be converted to corresponding acetylation deoxyglucose, then again Implement the condensation reaction with 2- substitution malonic ester derivatives, the acetylation of D-2- deoxyglucose can be according to document report Method implement, such as be within heating 1-24 hours using acetic anhydride as acetylation reagent in room temperature in pyridine or at 60 DEG C It is achievable.The reaction condition of each step in method D in addition to acetylation is identical as described in method C.

Preparation method shown in method E and F is by halohydrin elder generation and D-2- deoxyglucose or acetylation deoxyglucose Sugar is condensed in the presence of a lewis acid, is then carried out the substitution reaction with malonic ester derivatives and is finally obtained compound (III) preparation route.The acetylation of D-2- deoxyglucose involved in above-mentioned preparation route, the condensation in the presence of lewis acid Reaction, the position the 2- alkylation substitution reaction and last deprotection reaction of malonate, reaction condition and implementation method and It is identical described in method C and method D.

The malonate intermediate containing substituent A can known operation method according to the literature in the above-mentioned methods And prepare and obtain: Journal of Organic Chemistry, 1998, vol.63,11p.3677-3679；Journal of the American Chemical Society,2004,vol.126,36p.11293–11302。

Major experimental instrument:

Nuclear magnetic resonance spectrometer: BRUKER AVANCE III, 400MHz；Analytical liquid chromatograph: the logical perseverance of Beijing innovation LC3000 type high performance liquid chromatograph, SPD-10ATvp dual wavelength ultraviolet detector, 7725i manual injector, CLASS-VP color Compose work station；Analyze chromatographic column: DaisoGel, C18,4.6 × 250cm, 5 μm of KNAUER Germany；Semi-preparative liquid chromatography instrument: Innovate logical perseverance LC3000 semi-preparative liquid chromatography, SPI001；Half preparation chromatographic column: DaisoGel 250 × 20mmID, C18,10 μ m；Mass spectrograph: Agilent 6310Ion Trap LC/MS；Freeze drier: FD-1c-50 freeze dryer (the rich doctor's health experiment in Beijing Instrument Ltd.).

Embodiment 1:

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

At room temperature, D-2- deoxyglucose glucosides 1.6g is dissolved in pyridine and acetic anhydride (7ml: 7ml), stirring Overnight, reaction end is monitored with TLC.After the reaction was completed, 100ml ethyl acetate is added, the hydrochloric acid for being 5% with volumetric concentration is water-soluble Water phase is extracted with ethyl acetate (2 × 25ml), merges organic phase by liquid (2 × 25ml) washing.By organic phase successively with saturation chlorine Change aqueous ammonium (1 × 100ml), distilled water (1 × 100ml), saturated sodium bicarbonate aqueous solution (1 × 100ml), saturated sodium-chloride Aqueous solution (1 × 100ml) washing, it is dry with anhydrous sodium sulfate.Solvent is evaporated with Rotary Evaporators, obtains yellowish 3,4,6- Triacetyl-D-2- deoxyglucose crude product.Obtained crude product is dissolved at room temperature in the dry DCM of 20ml, is added Ethylene bromohyrin (2.4g), is cooled to 0 DEG C, and with air in nitrogen displacement flask, boron trifluoride is slowly added dropwise under nitrogen protection Diethyl ether solution (98%, 1ml).Reaction solution is stirred 15 minutes at 0 DEG C, room temperature is then slowly warming up to and stirs 60 minutes, use After the reaction was completed, revolving removes solvent for TLC detection confirmation, 100ml ethyl acetate is added, the hydrochloric acid water for being 5% with volumetric concentration Solution (2 × 25ml) washing, organic phase is successively used saturated aqueous ammonium chloride (1 × 100ml), distilled water (1 × 100ml), Saturated sodium bicarbonate aqueous solution (1 × 100ml), saturated sodium-chloride water solution (1 × 100ml) washing are dry with anhydrous sodium sulfate And solvent is evaporated with Rotary Evaporators.Through silica gel chromatography (petroleum ether: ethyl acetate, 3: 1), obtaining colorless oil mesh 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) 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides)-propane -3,3- dicarboxylate (VI-1) Preparation:

Product 1-O- (3,4,6- triacetyl-D-Glucose glycosides) bromo- ethane of -2- (1.8g) that previous step is reacted It is dissolved in the dry n,N-Dimethylformamide of 5ml, potassium carbonate (3g) is added into reaction solution, diethyl malonate (1.6g), is stirred overnight at room temperature.Reaction end is monitored with TLC, to after the reaction was completed, 100ml acetic acid second be added into reaction solution Then ester is washed with saturated aqueous ammonium chloride (1 × 50ml), water phase is extracted with ethyl acetate (2 × 25ml), merge organic Phase.Organic phase is successively used saturated aqueous ammonium chloride (1 × 100ml), distilled water (1 × 100ml), saturated sodium chloride solution (1 × 100ml) washing, it is then dry with anhydrous sodium sulfate, solvent is evaporated with Rotary Evaporators, obtained light yellow oil is used Silica gel chromatography (petroleum ether: ethyl acetate, 3: 1), obtaining colorless and transparent 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 spectrums: MS, m/z:477.28 [M+H]⁺

(3) 1-O- (D-2- deoxyglucose glucosides)-propane -3,3- dioctyl phthalate preparation

1) by 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides)-propane -3,3- dicarboxylate (2.5g) is dissolved in 5mL methanol.Sodium hydroxide (1.6g) is dissolved in 10mL water, is added in reaction solution at room temperature, so After be warming up to 90 DEG C react about 12 hours.Reaction end is monitored with TLC.

2) to after the reaction was completed, remove methanol with Rotary Evaporators, product is handled using storng-acid cation exchange resin. Colorless viscous shape liquid 1.6g will be obtained after the aqueous solution being obtained by filtration freeze drier drying, crude product is directly used in lower step Reaction.

Mass spectrum: MS, m/z:295.25 [M+H]⁺

(4) cis- [trans--(1R, 2R)-diaminocyclohexane] platinum (II) [1-O- (D-2- deoxyglucose glucosides)-propane- 3,3- dicarboxylic acid esters] preparation:

1) 1-O- (D-2- deoxyglucose glucosides)-propane -3,3- dioctyl phthalate crude product (1.3g) is dissolved in 15mL water, Barium hydroxide octahydrate (about 1.3g is dissolved in 5ml water) is added and adjusts reaction solution pH to 7, is stirred at room temperature 30 minutes.

2) sulfatodiamino cyctohexane platinum (2.1g) is dissolved in 2ml water under nitrogen protection, is added in reaction solution 1), PH to 7 is adjusted with barium hydroxide solution, room temperature, which is protected from light, to be stirred overnight.

3) to after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is lyophilized using freeze drier, with half Prepare the isolated 1.6g final products of high pressure liquid chromatography, white solid.

Nuclear magnetic resoance spectrum (400MHz, D2O), ppm:4.92 (d, J=2.7Hz, 1H), 4.22 (t, J=7.0Hz, 1H), 3.87-3.93 (m, 1H), 3.57-3.74 (m, 4H), 3.47-3.52 (m, 1H), 3.31 (t, J=9.4Hz, 1H), 2.29 (d, J =4.2Hz, 4H), 2.06 (dd, J=13.3Hz, 5.0Hz, 1H), 1.92 (d, J=10.4Hz, 2H), 1.58-1.66 (m, 1H), 1.46 (d, J=9.5Hz, 2H), 1.01-1.05 (m, 4H) mass spectrum: MS, m/z:601.16,602.16,603.16 [M+H]⁺

Embodiment 2:

The preparation of diamino platinum (II) [1-O- (D-2- deoxyglucose glucosides)-propane -3,3- dicarboxylic acid esters]:

1) by the 1-O- of 100mg (D-2- deoxyglucose glucosides)-propane -3,3- dioctyl phthalate crude product be dissolved in 5ml go from Sub- water is added barium hydroxide octahydrate (about 95mg is dissolved into 5ml water) and adjusts reaction solution pH to 8, is stirred at room temperature 30 minutes.

2) diamino platinic sulfate (110mg) is dissolved in 2ml water under nitrogen protection, is added in 1) in reaction solution, PH to 8 is adjusted with barium hydroxide solution, room temperature, which is protected from light, to be stirred overnight.

3) to after the reaction was completed, remove and precipitate using centrifuge, supernatant is collected, with half preparation HPLC refining spearation and is made It is lyophilized with freeze drier, obtains 115mg 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), 3.29 (t, J=9.4Hz, 1H), 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:533.10,534.12,535.11 [M+H]⁺

Embodiment 3:

The preparation of diisopropylamino platinum (II) [1-O- (D-2- deoxyglucose glucosides)-propane -3,3- dicarboxylic acid esters]:

3) to after the reaction was completed, remove and precipitate using centrifuge, supernatant is collected, with half preparation HPLC refining spearation and is made It is lyophilized with freeze drier, obtains 134mg 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),3.22-3.32(m,1H), 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 spectrums: MS, m/z:603.19,604.17,605.18 [M+H]⁺

Embodiment 4:

Cis- [trans--(1R, 2R)-diaminocyclohexane] platinum (II) [1-O- (D-2- deoxyglucose glucosides)-propane -3- hydroxyl Base -3,3- dicarboxylic acid esters] preparation::

1) 1-O- of 100mg (D-2- deoxyglucose glucosides)-propane -3- hydroxyl -3,3- dioctyl phthalate crude product is dissolved in 5ml Deionized water, be added barium hydroxide octahydrate (about 90mg is dissolved into 5ml water) adjust reaction solution pH to 8, be stirred at room temperature 30 Minute.

2) diamino platinic sulfate (100mg) is dissolved in 2ml water under nitrogen protection, is added in 1) in reaction solution, PH to 8 is adjusted with barium hydroxide solution, room temperature, which is protected from light, to be stirred overnight.

3) to after the reaction was completed, remove and precipitate using centrifuge, supernatant is collected, with half preparation HPLC refining spearation and is made It is lyophilized with freeze drier, obtains 120mg final products, white solid.

Nuclear magnetic resoance spectrum (400MHz, D2O), ppm:4.91 (d, J=2.7Hz, 1H), 4.21 (t, J=7.0Hz, 1H), 3.87-3.93 (m, 1H), 3.57-3.74 (m, 4H), 3.47-3.52 (m, 1H), 2.29 (d, J=4.2Hz, 4H), 2.06 (dd, J =13.3Hz, 5.0Hz, 1H), 1.92 (d, J=10.4Hz, 2H), 1.58-1.66 (m, 1H), 1.46 (d, J=9.5Hz, 2H), 1.01-1.05 (m, 4H) mass spectrum: MS, m/z:617.16,618.16,619.15 [M+H]⁺

Embodiment 5:

Nuclear magnetic resoance spectrum (400MHz, D2O), ppm:4.91 (s, 1H), 3.83-3.90 (m, 1H), 3.62-3.80 (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:549.10,550.12,551.11 [M+H]⁺

Embodiment 6:

The system of diisopropylamino platinum (II) [1-O- (D-2- deoxyglucose glucosides)-propane -3- hydroxyl -3,3- dicarboxylic acid esters] It is standby:

3) to after the reaction was completed, remove and precipitate using centrifuge, supernatant is collected, with half preparation HPLC refining spearation and is made It is lyophilized with freeze drier, obtains 122mg final products, white solid.

Nuclear magnetic resoance spectrum (400MHz, D2O), ppm:4.93 (d, J=4.0Hz, 1H), 4.83 (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:619.19,620.17,621.19 [M+H]⁺

Embodiment 7:

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

At room temperature, D-2- deoxyglucose glucosides 1.6g is dissolved in pyridine and acetic anhydride (7ml: 7ml), stirring Overnight, reaction end is monitored with TLC.After the reaction was completed, 100ml ethyl acetate is added, the hydrochloric acid for being 5% with volumetric concentration is water-soluble Water phase is extracted with ethyl acetate (2 × 25ml), merges organic phase by liquid (2 × 25ml) washing.By organic phase successively with saturation chlorine Change aqueous ammonium (1 × 100ml), distilled water (1 × 100ml), saturated sodium bicarbonate aqueous solution (1 × 100ml), saturated sodium-chloride Aqueous solution (1 × 100ml) washing, it is dry with anhydrous sodium sulfate.Solvent is evaporated with Rotary Evaporators, obtains yellowish 3,4,6- Triacetyl-D-2- deoxyglucose crude product.Obtained crude product is dissolved at room temperature in the dry DCM of 20ml, is added 3- bromopropyl alcohol (2.5g), is cooled to 0 DEG C, and with air in nitrogen displacement flask, boron trifluoride is slowly added dropwise under nitrogen protection Diethyl ether solution (98%, 1ml).Reaction solution is stirred 15 minutes at 0 DEG C, room temperature is then slowly warming up to and stirs 2 hours, use After the reaction was completed, revolving removes solvent for TLC detection confirmation, 100ml ethyl acetate is added, the hydrochloric acid water for being 5% with volumetric concentration Solution (2 × 25ml) washing, organic phase is successively used saturated aqueous ammonium chloride (1 × 100ml), distilled water (1 × 100ml), Saturated sodium bicarbonate aqueous solution (1 × 100ml), saturated sodium-chloride water solution (1 × 100ml) washing are dry with anhydrous sodium sulfate And solvent is evaporated with Rotary Evaporators.Through silica gel chromatography (petroleum ether: ethyl acetate, 3: 1), obtaining colorless oil mesh 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- dicarboxylate:

It is dry that 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides) bromo- propane of -3- (2.0g) is dissolved in 15ml N,N-Dimethylformamide in, potassium carbonate (2.6g) is added into reaction solution, diethyl malonate (1.55g) stirs in room temperature It mixes overnight.Reaction end is monitored with TLC, to after the reaction was completed, 100ml ethyl acetate be added into reaction solution, with saturation chlorination Aqueous ammonium (1 × 50ml) washing, water phase is extracted with ethyl acetate (2 × 25ml), merges organic phase.Organic phase is successively used Saturated aqueous ammonium chloride (1 × 100ml), distilled water (1 × 100ml), saturated sodium chloride solution (1 × 100ml) washing, then It is dry with anhydrous sodium sulfate, solvent is evaporated with Rotary Evaporators, obtained light yellow oil silica gel chromatography (stone Oily ether: ethyl acetate, 3: 1), obtaining colorless and transparent oily purpose product 2.3g.

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, 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) 1-O- (D-2- deoxyglucose glucosides)-butane -4,4- dioctyl phthalate

By 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides)-butane -4,4- dicarboxylate (2.0g) It is dissolved in 5mL methanol.Sodium hydroxide (1.4g) is dissolved in 10mL water, is added in reaction solution, then heats up at room temperature It is reacted 24 hours to 60 DEG C.Reaction end is monitored with HPLC.To after the reaction was completed, methanol be removed with Rotary Evaporators, using strong Acid cation exchange resin handles product.Liquid phase color will be prepared through half after the aqueous solution being obtained by filtration freeze drier drying Compose isolated colorless viscous shape liquid 1.4g.

Mass spectrum: MS, m/z:309.12 [M+H]⁺

(4) cis- [trans--(1R, 2R)-diaminocyclohexane] platinum (II) [1-O- (D-2- deoxyglucose glucosides)-butane- 4,4- dicarboxylic acid esters] preparation:

4) 1-O- (D-2- deoxyglucose glucosides)-butane -4,4- dioctyl phthalate (1.3g) is dissolved in 15mL water, is added eight Hydronium(ion) barium monoxide (about 1.3g is dissolved in 5ml water) adjusts reaction solution pH to 7, is stirred at room temperature 30 minutes.

5) sulfatodiamino cyctohexane platinum (1.7g) is dissolved in 2ml water under nitrogen protection, is added in reaction solution 1), PH to 7 is adjusted with barium hydroxide solution, room temperature, which is protected from light, to be stirred overnight.

6) to after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is lyophilized using freeze drier, with half Prepare the isolated 1.5g final products of high pressure liquid chromatography, white solid.

Nuclear magnetic resoance spectrum (400MHz, D2O), ppm:4.96 (d, J=2.3Hz, 1H), 3.91-3.98 (m, 1H), 3.66- 3.82 (m, 4H), 3.48-3.60 (m, 2H), 3.29 (t, J=9.4Hz, 1H), 2.12-2.37 (m, 5H), 1.91 (d, J= 11.9Hz, 2H), 1.61-1.69 (m, 3H), 1.45 (d, J=8.1Hz, 2H), 0.98-1.16 (m, 4H) mass spectrum: MS, m/z: 615.20,616.17,617.18 [M+H]⁺

Embodiment 8:

The preparation of diamino platinum (II) [1-O- (D-2- deoxyglucose glucosides)-butane -4,4- dicarboxylic acid esters]:

1) by the 1-O- of 100mg (D-2- deoxyglucose glucosides)-butane -4,4- dioctyl phthalate crude product be dissolved in 5ml go from Sub- water is added barium hydroxide octahydrate (about 100mg is dissolved into 5ml water) and adjusts reaction solution pH to 8, is stirred at room temperature 30 minutes.

2) diamines platinic sulfate (100mg) is dissolved in 2ml water under nitrogen protection, is added in 1) in reaction solution, used Barium hydroxide solution adjusts pH to 8, and room temperature, which is protected from light, to be stirred overnight.

3) to after the reaction was completed, remove and precipitate using centrifuge, supernatant is collected, with half preparation HPLC refining spearation and is made It is lyophilized with freeze drier, obtains 108mg 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), 3.28 (t, J=8.0Hz, 1H), 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:531.13,532.11, 533.10[M+H]⁺

Embodiment 9:

The preparation of diisopropylamino platinum (II) [1-O- (D-2- deoxyglucose glucosides)-butane -4,4- dicarboxylic acid esters]:

2) diisopropylamine platinic sulfate (120mg) is dissolved in 2ml water under nitrogen protection, is added to reaction solution in 1) In, pH to 8 is adjusted with barium hydroxide solution, room temperature, which is protected from light, to be stirred overnight.

3) to after the reaction was completed, remove and precipitate using centrifuge, supernatant is collected, with half preparation HPLC refining spearation and is made It is lyophilized with freeze drier, 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), 3.28 (t, J=8.0Hz, 1H), 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:615.17,616.18,617.18 [M+H]⁺

Embodiment 10:

Cis- [trans--(1R, 2R)-diaminocyclohexane] platinum (II) [1-O- (D-2- deoxyglucose glucosides)-butane -4- first Base -4,4- dicarboxylic acid esters] preparation:

1) 1-O- (D-2- deoxyglucose glucosides)-butane -4- methyl -4,4- dioctyl phthalate (1.4g) is dissolved in 15mL water In, barium hydroxide octahydrate (about 1.4g is dissolved in 5ml water) is added and adjusts reaction solution pH to 7, is stirred at room temperature 30 minutes.

2) sulfatodiamino cyctohexane platinum (1.9g) is dissolved in 2ml water under nitrogen protection, is added in reaction solution 1), PH to 7 is adjusted with barium hydroxide solution, room temperature, which is protected from light, to be stirred overnight.

3) to after the reaction was completed, be removed and precipitated using centrifuge, supernatant is collected, is lyophilized using freeze drier, with half Prepare the isolated 1.7g final products of high pressure liquid chromatography, white solid.

Nuclear magnetic resoance spectrum (400MHz, D2O), ppm:4.96 (d, J=2.3Hz, 1H), 3.91-3.98 (m, 1H), 3.66- 3.82 (m, 4H), 3.48-3.60 (m, 2H), 2.12-2.37 (m, 5H), 1.91 (d, J=11.9Hz, 2H), 1.61-1.69 (m, 3H), 1.45 (d, J=8.1Hz, 2H), 1.30 (s, 3H), 0.98-1.16 (m, 4H) mass spectrum: MS, m/z:629.20,630.17, 631.18[M+H]⁺

Embodiment 11:

The preparation of diamino platinum (II) [1-O- (D-2- deoxyglucose glucosides)-butane -4- methyl -4,4- dicarboxylic acid esters]:

1) by the 1-O- of 100mg (D-2- deoxyglucose glucosides)-butane -4,4- dioctyl phthalate crude product be dissolved in 5ml go from Sub- water is added barium hydroxide octahydrate (about 120mg is dissolved into 5ml water) and adjusts reaction solution pH to 8, is stirred at room temperature 30 minutes.

2) diamines platinic sulfate (130mg) is dissolved in 2ml water under nitrogen protection, is added in 1) in reaction solution, used Barium hydroxide solution adjusts pH to 8, and room temperature, which is protected from light, to be stirred overnight.

3) to after the reaction was completed, remove and precipitate using centrifuge, supernatant is collected, with half preparation HPLC refining spearation and is made It is lyophilized with freeze drier, obtains 138mg 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), 1.27 (s, 3H) mass spectrums: MS, m/z:545.13,546.11,547.10 [M+H]⁺

Embodiment 12:

The system of diisopropylamino platinum (II) [1-O- (D-2- deoxyglucose glucosides)-butane -4- methyl -4,4- dicarboxylic acid esters] It is standby:

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), 1.25 (s, 3H), 1.21 (s, 6H) mass spectrums: MS, m/z:629.22,630.18,631.23 [M+H]⁺

Experimental example 1: for platinum complex more of the present invention and marketed drug cis-platinum, carboplatin and oxaliplatin are in water solubility The difference of aspect is carried out for representative platinum complex of the invention and three kinds of marketed drugs respectively in following tests The saturated solution Solute mass of various drugs measures in 100g water at room temperature, and table 2 lists platinum complex of the invention in water Solubility and with platinum antineoplastic clinical medicine cis-platinum, the difference of carboplatin and oxaliplatin.

Table 2:

Experimental example 2:

In following tests, the female CDF1 kind mouse of 8-9 week old, 20-25 grams of the weight of animals average out to are used.Use L1210 Tumour cell (10⁵Every mouse of cell) it is inoculated in peritonaeum.For the animal model for tumour of production, using of the invention Platinum complex implements treatment, and is compared with the platinum series antineoplastic medicament of clinical use, verifies platinum complex of the present invention to swollen The toxic side effect of the therapeutic effect of tumor animal and platinum complex of the invention to experimental animal.For platinum complex of the invention Using 5%V/V mannitol aqueous solution, the corresponding note of 5%V/V mannitol normal saline solution preparation is then used for cis-platinum Penetrate liquid.Isosorbide-5-Nitrae day is 6 via intraperitoneal injection drug, every group of experimental animal number after tumor cell transplantation.

Above-mentioned experimental animal is purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., and tumour cell L1210-mouse is white Blood disease cell is purchased from the beautiful commerce and trade Co., Ltd of Town in Shanghai.

The calculation method that animal lifespan extends (ILS) is 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 the animal survival day for the treatment of Weighting mediant, experimental result is listed in Table 3 below:

Table 3:

* the 1 day to the 7th day changes of weight of note

Experimental example 3:

Inhibited proliferation of present invention water-soluble platinum containing the deoxyglucose complex to cancer cell

The complex of water-soluble platinum containing deoxyglucose of the invention is to pass through this to the inhibition of tumour cell and lethal effect Invention drug and DNA of tumor cell are formed in chain and interchain linkage, thus inhibit DNA of tumor cell synthesis and duplication and realize 's.

Experiment is thin to different types of human tumour for the method for the present invention water-soluble platinum containing deoxyglucose complex below The proliferation inhibiting effect of born of the same parents has carried out experimental verification.

(1) test method:

Cell culture fluid:

Using contain 10% N of fetus serum (fetal bovine serum), 1mM Sodium Pyruvate, 2mML- glutamine, 50U/ml penicillin, the cell culture fluid of 50 μ g/ml streptomysins (streptomycin).

Major experimental instrument: MCO-15A type carbon dioxide incubator (Japanese SANYO company), inverted phase contrast microscope (Olympus, Japan), full-automatic microplate reader (U.S. BioTEK ELX808), low temperature refrigerator (Japanese MDF-V5410), ultra-clean work Make platform (Suzhou Medical Instruments Factory), micropipettor (French GILSON), automatic pure water distiller (Shanghai 1810B).

Experiment reagent:

MTS:CellTiter96Aqueous MTS Reagent Powder, Promega company

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

DPBS:Sigma-Aldrich company

Tumour 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 (gland cancer)；H460- Non-small cell lung carcinoma (large cell carcinoma) and animal tumor cell: L1210-mouse leukemia cell is purchased from the beautiful commerce and trade Co., Ltd of Town in Shanghai.

Cytotoxicity test:

Cytotoxicity experiment uses MTS test method.Logarithmic phase tumour cell is collected, concentration of cell suspension, every hole are adjusted 100 μ l are added, bed board makes cell tune density to be measured to the hole 1000-10000/, (edge hole is filled with sterile PBS).In 5%CO2, 37 DEG C of incubations, until cell monolayer is paved with bottom hole (96 hole flat underside), the drug of addition various concentration gradient, every 100 μ l of hole, if 5 A multiple holes.It is incubated for 96 hours under the conditions of 5%CO2,37 DEG C, is observed under inverted microscope.To 2ml MTS, (2mg/ml, DPBS match System) 100 μ l PMS (1mg/ml, DPBS are prepared) is added in solution, it mixes, MTS working solution is made.Above-mentioned tissue culture plate centrifugation After discard culture solution, carefully rush 2-3 after with PBS, before detect absorbance, the 100 μ l culture mediums of every hole addition into 96 orifice plates, 20 μ lMTS working solutions are added, at 37 DEG C, after being incubated for 2h under the conditions of 5%CO2, detect OD value (OD value) at 490nm.

Control group: not adding tested active constituent under above-mentioned similarity condition, finally obtains tumour cell and examines at 490nm Survey OD value.

Inhibitory activity IC50 of the drug to tumour cell:

Cell inhibitory rate calculates: drug is calculated according to the following formula to the inhibiting rate of growth of tumour cell:

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

2) cell survival rate under each drug concentration is found out, is mapped with this to drug concentration.On resulting curve, cell Survival rate concentration corresponding when being 50% is exactly IC50 value.

The experiment of above-mentioned each drug concentration repeats 5 groups, and average OD value is taken to calculate cell survival rate.

(2) experimental result:

The tumour cell title that various symbols represent in figure is as follows: du145-human prostata cancer；MCF-7-human breast carcinoma； SKOV3-human ovarian cancer；HT-29-human colon carcinoma；A549-Non-small cell lung carcinoma (gland cancer)；H460- Non-small cell lung carcinoma (large cell carcinoma)

Fig. 1 is the antitumor drug effect -1 of complex prepared by embodiment 1.Fig. 2 is complex antineoplastic prepared by embodiment 1 Effect -2.Fig. 3 is the antitumor drug effect -1 of complex prepared by embodiment 2.Fig. 4 is the antitumor drug effect-of complex prepared by embodiment 2 2.Fig. 5 is the antitumor drug effect -1 of complex prepared by embodiment 4.Fig. 6 is the antitumor drug effect -2 of complex prepared by embodiment 4. Fig. 7 is the antitumor drug effect -1 of complex prepared by embodiment 5.Fig. 8 is the antitumor drug effect -2 of complex prepared by embodiment 5.Fig. 9 The antitumor drug effect -1 of complex prepared for embodiment 7.Figure 10 is the antitumor drug effect -2 of complex prepared by embodiment 7.Figure 11 The antitumor drug effect -1 of complex prepared for embodiment 8.Figure 12 is the antitumor drug effect -2 of complex prepared by embodiment 8.

Experimental example 4:

Present invention water-soluble platinum containing deoxyglucose complex is anti-with leading patents (WO2006091790A1's) Cancer drug effect and tumor-targeting compare

(1) test method: using MCF-7 Human Breast Cancer Cells, by the water-soluble containing deoxyglucose of various embodiments of the present invention Property platinum complex and it is disclosed in advance contain glucose, the corresponding complex of galactolipin and mannose is in same concentrations (50 μ M) and under same time condition (for 24 hours) Cytotoxic evaluation is carried out.Tumor control rate number is being obtained according to the method in experimental example 3 According to while, using atomic absorption spectrum test method, drug concentration of each complex in tumour cell is evaluated, with this Comparison relative medicine is directed to the targeting savings effect of tumour cell under the same conditions.

Cell culture fluid:

Major experimental instrument: Shimadzu AAS tester (AA-6800), MCO-15A type carbon dioxide incubator (Japanese SANYO Company), inverted phase contrast microscope (Olympus, Japan), full-automatic microplate reader (U.S. BioTEKELX808), low temperature refrigerator (day This MDF-V5410), superclean bench (Suzhou Medical Instruments Factory), micropipettor (French GILSON), automatic pure water distiller (Shanghai 1810B).

(2) experimental result: table -4 lists the targeting that drug is directed to tumour cell and different pharmaceutical in same concentration Under the conditions of antitumor drug effect comparative test result.

Table 4

Experimental result shows, the complex of water-soluble platinum containing deoxyglucose provided by the present invention and in advance disclosed structure Similar medicine is compared, and no matter is all shown in terms of depot action in tumour cell of antitumor drug effect and drug more superior Effect.

Using the complex of water-soluble platinum containing deoxyglucose of the invention, the drug for preventing and treating tumour can be prepared. The preparation of these drugs cooperates medicine usually using the metal platinum complex provided by the present invention of one or several kinds of effective doses It learns acceptable carrier or diluent and completes.These pharmaceutically acceptable pharmaceutic adjuvant such as starch, glucose, dextrin, Fructose and maltose, lactose, gelatin, sucrose, hydroxylated cellulose, hydroxypropyl methyl cellulose, silica, stearic acid hydroxyl second Acid-starch sodium, water, ethyl alcohol, sodium chloride etc. can need to be selected according to different dosage forms.In addition, according to the need in medicine preparation It wants, these pharmaceutic adjuvants can also include a small amount of acid-base modifier, stabilizer etc..

Experiments have shown that: the complex of water-soluble platinum containing deoxyglucose provided by the invention has good anti-tumor activity. The complex of water-soluble platinum containing deoxyglucose provided by the present invention is for including intestinal cancer, breast cancer, prostate cancer, lung cancer etc. Antitumor pharmacodynamic test in, anti-tumor activity can be with the cis-platinum that is widely used at present, and carboplatin or oxaliplatin are mutually equal to Beauty, activity are even higher than these existing platinum-containing anticancer drugs.In addition, provided by the present invention water-soluble containing deoxyglucose The mouse Leukemia-L1210 tumour cell that platinum complex is capable of forming strong drug resistance for the antitumaous effect of cis-platinum has more Effective lethal effect.This is because the complex of water-soluble platinum containing deoxyglucose provided by the present invention in terms of water solubility with Existing platinum antineoplastic drug is compared, all with tens times of raising, this highly-water-soluble feature can theoretically increase and Drug is improved in the excretion of kidney, mitigate platinum medicine generally there are high kidney toxic side effect, while this highly-water-soluble characteristic These compounds are made to be easy formulation and clinically application more convenient.

Complex of the invention, since its water-soluble administration route for having high is not particularly limited, dosage is not It is only dependent upon the age of patient, weight and the state of an illness, additionally depends on the type of tumour, property and severity.But in general, For adult patient, the amount preferably used daily is between 10 milligrams to 1 gram.It is generally each to using once in three weeks or several times Medicine.

Claims

1. containing deoxyglucose water-soluble platinum complex, it is characterized in that shown in formula (I):

in:

X and Y are ligands, said X and Y being the same or different and each representing one _NH3 , one isopropylamine, one C3 _- _C6 cyclic alkyl primary amine or X and Y together are trans-(1R , 2R)-cyclohexanediamine, trans-(1S,2S)-cyclohexanediamine, cis-(1R,2S)-cyclohexanediamine or cis-(1S,2R)-cyclohexanediamine , racemic trans-1,2-cyclohexanediamine or racemic cis-1,2-cyclohexanediamine;

n is 2 or 3.

A is a hydrogen atom, a C ₁ -C ₈ chain alkyl group, a hydroxyl group or a C ₁ -C ₈ chain alkoxy group.

2 . The deoxyglucose-containing water-soluble platinum complex according to claim 1 , wherein the X and Y together are trans-(1R, 2R)-cyclohexanediamine. 3 .

3. The water-soluble platinum complex containing deoxyglucose according to claim 1, wherein the A is a hydrogen atom, a methyl group or a hydroxyl group.

4. the preparation method containing deoxyglucose water-soluble platinum complex (I) according to claim 1 is characterized in that comprising the steps:

reacting a compound of formula (II) with an aqueous solution of a compound of formula (III) adjusted to pH 7-9, or reacting a compound of formula (II) with a compound of formula (III) in water in the presence of an inorganic base, That is, the water-soluble platinum complex (I) containing deoxyglucose is prepared; the structural formula of the (II) is:

In formula (II): X and Y are ligands, said X and Y being the same or different and each representing an NH ₃ , an isopropylamine, a C ₃ -C ₆ cyclic alkyl primary amine or X and Y together as trans-(1R,2R)-cyclohexanediamine, trans-(1S,2S)-cyclohexanediamine, cis-(1R,2S)-cyclohexanediamine or cis-(1S,2R )-cyclohexanediamine, racemic trans-1,2-cyclohexanediamine or racemic cis-1,2-cyclohexanediamine;

A ₁ and A ₂ are the same or different, and each represents a hydroxyl group, a nitro group, a perchlorate group, or A ₁ and A ₂ jointly represent a sulfate group or a carbonate group;

The structural formula of described (III) is:

In formula (III):

M represents a hydrogen atom or a metal atom of Group IA of the periodic table; or two M together represent a metal atom of Group IIA;

n is 2 or 3.

A is a hydrogen atom, a C ₁ -C ₈ chain alkyl group, a hydroxyl group or a C ₁ -C ₈ chain alkoxy group;

5. The method according to claim 4, wherein the M is a hydrogen atom, a sodium atom or two M together represent a barium atom.

6. method according to claim 4 is characterized in that described inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, lithium hydroxide, barium hydroxide or cesium hydroxide.

7. The method according to claim 4, wherein the X and Y together are trans-(1R,2R)-cyclohexanediamine, and the A is a hydrogen atom, a methyl group or a hydroxyl group.

8. The preparation of claim 1 or 2 containing a deoxyglucose water-soluble platinum complex and a pharmaceutically acceptable adjuvant.

9. The application of claim 1 or 2 containing deoxyglucose-containing water-soluble platinum complexes in the preparation of medicines for preventing and treating tumors.

10. The application of the preparation of claim 8 in the preparation of a tumor-prevention drug.