CN106608898B - The complex of water-soluble platinum containing deoxyglucose and Preparation method and use - Google Patents
The complex of water-soluble platinum containing deoxyglucose and Preparation method and use Download PDFInfo
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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
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；
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；
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]:
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 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:
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:4.91 (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:
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 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]:
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) 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:
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) 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),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:
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: 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 (10)
1. the complex of water-soluble platinum containing deoxyglucose, it is characterized in that shown in formula (I):
Wherein:
X and Y is ligand, and the X and Y are identical or different and respectively represent a NH3, an isopropylamine, a C3-C6Ring
Shape kiber alkyl 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- hexamethylene
Diamines；
N is 2 or 3.
A is hydrogen atom, C1-C8Chain-like alkyl, hydroxyl or C1-C8Chain alkoxy.
2. the complex of water-soluble platinum containing deoxyglucose according to claim 1, it is characterized in that the X and Y are anti-together
Formula-(1R, 2R)-cyclohexanediamine.
3. the complex of water-soluble platinum containing deoxyglucose according to claim 1, it is characterized in that the A is hydrogen atom, first
Base or hydroxyl.
4. the preparation method of the complex of water-soluble platinum containing deoxyglucose (I) described in claim 1, it is characterized in that including as follows
Step:
Formula (II) compound is reacted with the aqueous solution for having adjusted formula (III) compound that pH is 7-9, or formula (II) is changed
It closes object and formula (III) compound to be reacted in water in the presence of having inorganic base, that is, is made water-soluble containing deoxyglucose
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, an isopropylamine, one
A C3-C6Cyclic 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 racemic cis -1,
2- cyclohexanediamine；
A1And A2It is same or different, respectively represent hydroxyl, nitro, perchlorate or A1And A2Sulfate radical or carbon are represented jointly
Acid group；
The structural formula of (III) 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 group iia jointly
Metallic atom；
N is 2 or 3.
A is hydrogen atom, C1-C8Chain-like alkyl, hydroxyl or C1-C8Chain alkoxy；
5. according to the method described in claim 4, it is characterized in that the M is that hydrogen atom, sodium atom or two M represent one jointly
Barium atom.
According to the method for claim 4,6. it is characterized in that the inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate, carbon
Sour hydrogen sodium, potassium carbonate, lithium hydroxide, barium hydroxide or cesium hydroxide.
7. according to the method described in claim 4, it is characterized in that the X and Y are trans--(1R, 2R)-cyclohexanediamine, institute together
Stating A is hydrogen atom, methyl or hydroxyl.
8. preparation made of claims 1 or 2 water-soluble platinum containing deoxyglucose complex and pharmaceutically acceptable auxiliary material.
9. claims 1 or 2 water-soluble platinum containing deoxyglucose complex is in the application of preparation prevention and treatment tumour medicine.
10. the preparation of claim 8 is in the application of preparation prevention and treatment tumour medicine.
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