CN106608892B - Fluorine-containing water solubility platinum complex and Preparation method and use - Google Patents

Fluorine-containing water solubility platinum complex and Preparation method and use Download PDF

Info

Publication number
CN106608892B
CN106608892B CN201510706153.2A CN201510706153A CN106608892B CN 106608892 B CN106608892 B CN 106608892B CN 201510706153 A CN201510706153 A CN 201510706153A CN 106608892 B CN106608892 B CN 106608892B
Authority
CN
China
Prior art keywords
fluorine
cyclohexanediamine
containing water
platinum complex
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201510706153.2A
Other languages
Chinese (zh)
Other versions
CN106608892A (en
Inventor
高清志
刘冉
韩建斌
高香倩
刘朋兴
米倩
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tianjin University
Original Assignee
Tianjin University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tianjin University filed Critical Tianjin University
Priority to CN201510706153.2A priority Critical patent/CN106608892B/en
Publication of CN106608892A publication Critical patent/CN106608892A/en
Application granted granted Critical
Publication of CN106608892B publication Critical patent/CN106608892B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

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

Description

Fluorine-containing water solubility platinum complex and Preparation method and use
Technical field
The present invention relates to a kind of fluorine-containing water-soluble platinum complex 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 Identify, clinical stages, therapeutic evaluation and detection recurrence etc..But 18F-DG, which is only limited to diagnostic uses, itself does not have therapeutic effect.
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)。
Chinese patent 201210205475.5 discloses " for the fluorine-containing water-soluble platinum complex of oncotherapy and its preparation Method ", the compound have solved the problems, such as water-soluble, but need to be improved to tumor-targeting and antitumous effect.
Summary of the invention
The object of the present invention is to provide a kind of fluorine-containing water solubilitys for capableing of and antitumous effect good to tumor-targeting raising Platinum complex.
A second object of the present invention is to provide a kind of preparation methods of fluorine-containing water-soluble platinum complex.
Third object of the present invention is to provide a kind of purposes of fluorine-containing water-soluble platinum complex.
Technical solution of the present invention is summarized as follows:
Fluorine-containing water solubility platinum complex, 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.
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.
The preparation method of fluorine-containing water solubility platinum complex (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 in the water of compound and formula (III) compound in the presence of having inorganic base, that is, fluorine-containing water-soluble platinum is made 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；
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 above-mentioned fluorine-containing water-soluble platinum complex and pharmaceutically acceptable auxiliary material.
Application of the above-mentioned fluorine-containing water-soluble platinum complex in preparation prevention and treatment tumour medicine.
Application of the above-mentioned preparation in preparation prevention and treatment tumour medicine.
Advantages of the present invention:
Test proves fluorine-containing water-soluble platinum complex and clinical medicine and Chinese patent 2012102054755 of the invention " the fluorine-containing water-soluble platinum complex and preparation method thereof for oncotherapy " is long-pending compared to having superior tumor selective agents Storage effect, the drug resistance that can be formed and the targeting to tumour cell transmits the repulsive interaction for overcoming tumour to drug. In addition, complex of the invention has higher water solubility compared with clinical medicine, it is easy to clinical preparation.Third, the present invention Provided fluorine-containing water-soluble platinum complex in terms of cytotoxicity with clinical medicine oxaliplatin compared with superiority.To sum up Described, fluorine-containing water-soluble platinum complex provided by the present invention can not only solve existing platinum medicine in default of water solubility And the problem of existing preparation stability difference and the defect of clinical use inconvenience, and can be improved drug to tumour cell Targeting, solve existing clinical medicine in oncotherapy effect, in terms of drug resistance and toxic side effect 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 3.
Fig. 6 is the antitumor drug effect -2 of complex prepared by embodiment 3.
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 6.
Figure 10 is the antitumor drug effect -2 of complex prepared by embodiment 6.
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.
Fluorine-containing water-soluble platinum complex represented by as (I) provided by the present invention by formula, the generation of preferred compound Table citing can also be listed by following table 1, but the present invention covers the citing not limited to the following of fluorine-containing water-soluble complexes.
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 fluorine-containing water solubility platinum complex can be completed by following methods and reaction equation in the present invention.
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.
The compounds of this invention (III) can the method C as given by following reaction equations prepared:
Method C:
Preparation method shown in method C is first to carry out halohydrin in the presence of a lewis acid with acetylation deoxyglucose Then condensation carries out the system that the substitution reaction with malonic ester derivatives finally obtains compound (III) by deprotection reaction Standby route.The acetylation of deoxyglucose involved in above-mentioned preparation route can be implemented according to method reported in the literature, such as It can be completed within 1-24 hours using acetic anhydride as acetylation reagent in room temperature or in 60 DEG C of heating in pyridine.Lewis acid In the presence of the condition of glycoside synthesis reaction be to be spread out using the fluorine-containing malonic acid of 0.1-50 equivalent for deoxyglucose sugar compounds Biology, or the deoxyglucose raw material of 0.1-50 equivalent is used for fluorine-containing malonate derivative on the contrary.The Louis used Acid can be BF3, SnCl4, FeCl3, AlCl3, hydrochloric acid, p-methyl benzenesulfonic acid, camphorsulfonic acid etc., lewis acidic amount is relative to de- Oxygen glucose feed can be 0.1-10 equivalent.Used solvent can be tetrahydrofuran, methylene chloride, toluene, ethylene glycol Dimethyl ether, ethylene glycol diethyl ether etc. also can be used in two kinds of reactants any one carry out the reaction as solvent.Instead The temperature answered generally can complete the reaction in 60-80 DEG C of heating from zero DEG C to 100 DEG C.Time root required for reacting It is different according to the difference of reactant, it can complete within general 1 hour to 7 days.Obtained reaction product can be mentioned by a series of Pure condition is refined, and generally can be used silica gel chromatography or liquid-phase chromatographic column partition method.Glycoside compounds with The 2- position substitution reaction of malonate can according to conventional method known to document (such as: Journal of the American Chemical Society,131(8),2786-2787；2009) sodium hydride, potassium carbonate, saleratus, sodium carbonate, carbonic acid are used Hydrogen sodium etc. is completed in DMF, toluene or tetrahydrofuran equal solvent.Two fluorine substitution reactions of obtained malonate, Representative fluorine substitution reaction reagent Selectflour can be used to carry out.Reaction is generally in THF or DMF or ether By after malonate equivalent or excessive alkali process in solvent, above-mentioned fluorine substitution reaction reagent is added to complete.Made Alkali can be sodium hydride, and the equivalent of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate etc., fluorine substitution reagent is malonate 1-3 times, reaction temperature generally at zero DEG C to 60 DEG C, preferably at room temperature stirring complete.Last deprotection reaction can It is carried out with using inorganic base in methanol-water or THF- aqueous solvent, the ratio of organic solvent and water is 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 To 60 DEG C, the reaction time is generally 1-24 hours.Be deprotected generate compound purification can be used silica gel chromatography or Ion exchange resin filtration method, or completed using liquid chromatography, if directly removing reaction dissolvent, gained with the way of distillation To product will be corresponding metal carboxylate.
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 1.6g is dissolved in pyridine and acetic anhydride (7ml: 7ml), it is stirred Night monitors reaction end with TLC.After the reaction was completed, 100ml ethyl acetate is added, the aqueous hydrochloric acid solution for being 5% with volumetric concentration Water phase is extracted with ethyl acetate (2 × 25ml), merges organic phase by (2 × 25ml) washing.By organic phase successively with saturation chlorination Aqueous ammonium (1 × 100ml), distilled water (1 × 100ml), saturated sodium bicarbonate aqueous solution (1 × 100ml), saturated sodium chloride water Solution (1 × 100ml) washing, it is dry with anhydrous sodium sulfate.Solvent is evaporated with Rotary Evaporators, obtains yellowish 3,4,6- tri- Acetyl group-D-2- deoxyglucose crude product.Obtained crude product is dissolved at room temperature in the dry DCM of 20ml, 2- is added Bromoethanol (2.4g), is cooled to 0 DEG C, and with air in nitrogen displacement flask, the second of boron trifluoride is slowly added dropwise under nitrogen protection Ethereal 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 TLC After the reaction was completed, revolving removes solvent for detection confirmation, 100ml ethyl acetate is added, the aqueous hydrochloric acid solution for being 5% with volumetric concentration (2 × 25ml) washing, organic phase is successively used saturated aqueous ammonium chloride (1 × 100ml), distilled water (1 × 100ml), is saturated Sodium bicarbonate aqueous solution (1 × 100ml), saturated sodium-chloride water solution (1 × 100ml) washing, is dried with anhydrous sodium sulfate and is used in combination Solvent is evaporated by Rotary Evaporators.Through silica gel chromatography (petroleum ether: ethyl acetate, volume ratio, 3: 1), obtaining colorless oil Shape purpose product 1.9g.
Nuclear magnetic resoance spectrum (400MHz, CDCl3), ppm:5.28-5.35 (m, 1H), 4.97-5.02 (m, 2H), 4.24- 4.31 (m, 1H), 4.06-4.11 (m, 2H), 3.91-3.97 (m, 1H), 3.78-3.84 (m, 1H), 3.50 (t, J=6.0Hz, 2H), 2.29 (dd, J=13.0Hz, 5.3Hz, 1H), 2.09 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.80-1.87 (m, 1H) mass spectrum: MS, m/z:397.15,399.23 [M+H]+
(2) 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-2- deoxyglucose glucosides) bromo- ethane of -2- that previous step is reacted (1.8g) 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, volume ratio, 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- (3,4,6- triacetyl-D-2- deoxyglucose glucosides) the fluoro- 3,3- dicarboxylate of-propane -3- (VII-1) preparation
1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides)-propane -3,3- dicarboxylate 2.5g is dissolved In 20mL dry tetrahydrofuran, it is cooled to 0 DEG C.With air in nitrogen displacement flask, it is slowly added under nitrogen protection 235mg sodium hydride solid (60%).Reaction solution is warming up to room temperature, stirs 1 hour.2g Selectflour is added, reacts liquid chamber Temperature reaction 2 hours, revolving removes solvent.100ml ethyl acetate is added into reaction solution, then uses saturated aqueous ammonium chloride (1 × 50ml) washing, water phase is extracted with ethyl acetate (2 × 25ml), organic phase is merged.Organic phase is successively used into saturated ammonium chloride Aqueous solution (1 × 100ml), distilled water (1 × 100ml), saturated sodium-chloride water solution (1 × 100ml) washing, then with anhydrous sulphur Sour sodium is dry, is evaporated solvent with Rotary Evaporators, obtained light yellow oil silica gel chromatography (petroleum ether: second Acetoacetic ester, 3: 1), obtaining colorless and transparent oily purpose product 2.1g.
Nuclear magnetic resoance spectrum (400MHz, CDCl3), ppm:5.10-5.20 (m, 1H), 4.50 (t, J=9.9Hz, 1H), 4.88 (d, J=3.3Hz, 1H), 4.25-4.39 (m, 5H), 3.94-4.08 (m, 3H), 3.56-3.62 (m, 1H), 2.55-2.67 (m, 2H), 2.21 (dd, J=13.0Hz, 5.2Hz, 1H), 2.09 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H), 1.73-1.80 (m, 1H), 1.28-1.33 (m, 6H) mass spectrum: MS, m/z:495.19 [M+H]+
(4) preparation of the fluoro- 3,3- dioctyl phthalate (III-1) of 1-O- (D-2- deoxyglucose glucosides)-propane -3-
1) by 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides) the fluoro- 3,3- dicarboxylate of-propane -3- (2.3g) is dissolved in 5mL methanol.Sodium hydroxide (1.5g) 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 1.5g 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:313.10 [M+H]+
(5) cis- [trans--(1R, 2R)-diaminocyclohexane] platinum (II) [1-O- (D-2- deoxyglucose glucosides)-propane- Fluoro- 3, the 3- dicarboxylic acid esters of 3-] (I-1) preparation:
1) fluoro- 3,3- dioctyl phthalate (III-1) crude product (1.3g) of 1-O- (D-2- deoxyglucose glucosides)-propane -3- is molten Solution is added barium hydroxide octahydrate (about 1.3g is dissolved in 5ml water) and adjusts reaction solution pH to 7, be stirred at room temperature in 15mL water 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:4.90 (d, J=2.6Hz, 1H), 3.61-3.82 (m, 7H), 3.18- 3.27 (m, 2H), 2.30 (s, 2H), 1.91-2.02 (m, 3H), 1.45-1.59 (m, 3H), 0.98-1.19 (m, 4H) mass spectrum: MS, m/z:619.16,620.14,621.17 [M+H]+
Embodiment 2:
The system of diamino platinum (II) [fluoro- 3, the 3- dicarboxylic acid esters of 1-O- (D-2- deoxyglucose glucosides)-propane -3-] (I-2) It is standby:
1) fluoro- 3,3- dioctyl phthalate (III-1) crude product of the 1-O- of 110mg (D-2- deoxyglucose glucosides)-propane -3- is molten In the deionized water of 5ml, barium hydroxide octahydrate (about 98mg is dissolved into 5ml water) is added and adjusts reaction solution pH to 8, room temperature is stirred It mixes 30 minutes.
2) diamino platinic sulfate (115mg) 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 100mg final products, white solid.
Nuclear magnetic resoance spectrum (400MHz, D2O), ppm:4.92 (s, 1H), 3.80-3.90 (m, 1H), 2.60-3.80 (m, 6H), 2.20-2.40 (m, 2H), 2.00-2.10 (m, 1H), 1.55-1.66 (m, 1H) mass spectrum: MS, m/z:551.09, 552.10,553.07,[M+H]+
Embodiment 3:
Diisopropylamino platinum (II) [fluoro- 3, the 3- dicarboxylic acid esters of 1-O- (D-2- deoxyglucose glucosides)-propane -3-] (I-3) Preparation:
1) fluoro- 3,3- dioctyl phthalate (III-1) crude product of the 1-O- of 100mg (D-2- deoxyglucose glucosides)-propane -3- is molten In the deionized water of 5ml, barium hydroxide octahydrate (about 100mg is dissolved into 5ml water) is added and adjusts reaction solution pH to 8, room temperature Stirring 30 minutes.
2) diisopropylamino platinic sulfate (130mg) 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 154mg final products, white solid.
Nuclear magnetic resoance spectrum (400MHz, D2O), ppm:4.91 (d, J=4.0Hz, 1H), 4.82 (br, 4H), 4.06 (t, J= 8.0Hz, 1H), 3.40-3.90 (m, 6H), 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: 621.16,6322.18,623.15,[M+H]+
Embodiment 4:
(1) preparation of 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides) bromo- propane of -3- (V-4):
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, volume ratio, 3: 1), obtaining nothing Color oily purpose product 2.1g.
Nuclear magnetic resoance spectrum (400MHz, CDCl3), ppm:5.24-5.31 (m, 1H), 4.95-5.02 (m, 2H), 4.29 (dd, J=12.2Hz, 4.6Hz, 1H), 4.07 (dd, J=12.2Hz, 1.9Hz, 1H), 3.95-3.98 (m, 1H), 3.80-3.85 (m, 1H), 3.47-3.54 (m, 3H), 2.23 (dd, J=12.9Hz, 5.2Hz, 1H), 2.10-2.16 (m, 2H), 2.09 (s, 3H), 2.04(s,3H),2.00(s,3H),1.79-1.86(m,1H).
(2) 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides)-butane -4,4- dicarboxylate (VI-4) Preparation:
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, CD3Cl3), ppm:5.27-5.33 (m, 1H), 4.93-5.01 (m, 2H), 4.18- 4.31 (m, 6H), 4.04 (dd, J=12.2Hz, 1.8Hz, 1H), 3.93-3.96 (m, 1H), 3.63-3.69 (m, 1H), 3.34- 3.43 (m, 2H), 2.24 (dd, J=12.7Hz, 5.2Hz, 1H), 2.08 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 1.94- 1.98 (m, 1H), 1.78-1.86 (m, 1H), 1.60-1.68 (m, 2H), 1.28 (t, J=7.1Hz, 6H)
(3) the fluoro- 4,4- dicarboxylate (VII-4) of 1-O- (3,4,6- triacetyl-D-Glucose glycosides)-butane -4- Preparation
By 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides) the fluoro- 4,4- dicarboxylate of-butane -4- 2.5g is dissolved in the dry tetrahydrofuran of 20mL, is cooled to 0 DEG C.With air in nitrogen displacement flask, delay under nitrogen protection It is slow that 255mg sodium hydride solid (60%) is added.Reaction solution is warming up to room temperature, stirs 1 hour.2.1g SelectFlour is added, Reaction solution reacts at room temperature 2 hours, and revolving removes solvent.100ml ethyl acetate is added into reaction solution, then uses saturated ammonium chloride Aqueous solution (1 × 50ml) washing, water phase is extracted with ethyl acetate (2 × 25ml), merges organic phase.By organic phase successively with full With aqueous ammonium chloride solution (1 × 100ml), distilled water (1 × 100ml), saturated sodium-chloride water solution (1 × 100ml) is washed, 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 2.6g.Mass spectrum: MS, m/z:837.18 [M+H]+(4)1- The preparation of the fluoro- 4,4- dioctyl phthalate (III-4) of O- (D-2- deoxyglucose glucosides)-butane -4-
By 1-O- (3,4,6- triacetyl-D-2- deoxyglucose glucosides) the fluoro- 4,4- dicarboxylate of-butane -4- (2.0g) is dissolved in 5mL methanol.Sodium hydroxide (1.4g) is dissolved in 10mL water, is added in reaction solution at room temperature, so After be warming up to 60 DEG C react 24 hours.Reaction end is monitored with HPLC.To after the reaction was completed, remove methanol with Rotary Evaporators, Product is handled using storng-acid cation exchange resin.It will partly be prepared after the aqueous solution being obtained by filtration freeze drier drying The isolated colorless viscous shape liquid 1.4g of liquid chromatogram.Mass spectrum: MS, m/z:327.09 [M+H]+
(5) cis- [trans--(1R, 2R)-diaminocyclohexane] platinum (II) [1-O- (D-2- deoxyglucose glucosides)-butane- Fluoro- 4, the 4- dicarboxylic acid esters of 4-] (I-4) preparation:
4) the fluoro- 4,4- dioctyl phthalate (III-4) (1.3g) of 1-O- (D-2- deoxyglucose glucosides)-butane -4- is dissolved in 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 points Clock.5) sulfatodiamino cyctohexane platinum (1.7g) is dissolved in 2ml water under nitrogen protection, is added in reaction solution 1), uses hydrogen Barium oxide solution adjusts pH to 7, and 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:5.95 (br, 1H), 5.71 (br, 1H), 5.25 (br, 1H), 4.90- 5.10(m,2H),3.80-4.00(m,1H),3.50-3.80(m,5H),3.20-3.40(m,2H),2.70-2.90(m,1H), 2.20-2.40 (br, 2H), 2.10 (dd, J=4.0,12.0Hz, 1H), 1.93 (br, 2H), 1.55-1.75 (m, 3H), 1.35- 1.50 (m, 2H), 0.90-1.30 (m, 4H) mass spectrum: MS, m/z:633.14,634.15,635.17 [M+H]+
Embodiment 5:
The system of diamino platinum (II) [fluoro- 4, the 4- dicarboxylic acid esters of 1-O- (D-2- deoxyglucose glucosides)-butane -4-] (I-5) It is standby:
1) fluoro- 4,4- dioctyl phthalate (III-4) crude product of the 1-O- of 100mg (D-2- deoxyglucose glucosides)-butane -4- is molten In the deionized water of 5ml, barium hydroxide octahydrate (about 98mg is dissolved into 5ml water) is added and adjusts reaction solution pH to 8, room temperature is stirred It mixes 30 minutes.
2) diamines platinic sulfate (120mg) 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 110mg final products, white solid.
Nuclear magnetic resoance spectrum (400MHz, D2O), ppm:4.95 (d, J=4.0Hz, 1H), 3.85-3.98 (m, 1H), 3.70- 3.82 (m, 1H), 3.45-3.72 (m, 5H), 2.33-2.45 (m, 2H), 2.20-2.33 (m, 2H), 2.09 (dd, J=4.0, 16.0Hz, 1H), 1.50-1.69 (m, 3H) mass spectrum: MS, m/z:549.10,550.09,551.08 [M+H]+
Embodiment 6:
Diisopropylamino platinum (II) [fluoro- 4, the 4- dicarboxylic acid esters of 1-O- (D-2- deoxyglucose glucosides)-butane -4-] (I-6) Preparation:
1) the fluoro- 4,4- dioctyl phthalate (III-4) of the 1-O- of 100mg (D-2- deoxyglucose glucosides)-butane -4- is dissolved in 5ml Deionized water, be added barium hydroxide octahydrate (about 100mg is dissolved into 5ml water) adjust reaction solution pH to 8, be stirred at room temperature 30 Minute.
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 130mg final products, white solid.
Nuclear magnetic resoance spectrum (400MHz, D2O), ppm:4.92 (d, J=4.0Hz, 1H), 4.81 (br, 4H), 3.80-3.90 (m,1H),3.60-3.80(m,3H),3.45-3.60(m,3H),2.80-2.95(m,2H),2.30-2.53(m,2H),2.08 (dd, J=4.0,16.0Hz, 1H), 1.50-1.70 (m, 3H), 1.23 (s, 6H), 1.21 (s, 6H) mass spectrums: MS, m/z: 633.17,634.18,635.20 [M+H]+
Experimental example 1:
For fluorine-containing water-soluble platinum complex more of the invention and marketed drug cis-platinum, carboplatin and oxaliplatin are water-soluble Property in terms of difference, in following tests, respectively on the representative fluorine-containing water-soluble platinum complex of the present invention and three kinds City's drug has carried out the saturated solution Solute mass measurement of various drugs in 100g water at room temperature, and it is fluorine-containing that table 2 lists the present invention Water-soluble platinum complex solubility in water and with platinum antineoplastic clinical medicine cis-platinum, the difference of carboplatin and oxaliplatin Not.
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, contained using the present invention Fluorine water-soluble platinum complex implements treatment, and is compared with the platinum series antineoplastic medicament of clinical use, and it is a kind of to verify the present invention Fluorine-containing water solubility platinum complex is to the therapeutic effects of bearing animals and complex of the invention to the toxic side effect of experimental animal. 5%V/V mannitol aqueous solution is used for fluorine-containing water-soluble platinum complex of the invention, then uses 5%V/V sweet cis-platinum Dew sugar alcohol normal saline solution prepares corresponding injection.Isosorbide-5-Nitrae day is via intraperitoneal injection drug after tumor cell transplantation, Every group of experimental animal number is 6.
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] X100
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:
Table 3:
* the 1 day to the 7th day changes of weight of note
Experimental example 3: inhibited proliferation of the fluorine-containing water solubility platinum complex to cancer cell
Fluorine-containing water-soluble platinum complex of the invention is drug through the invention to the inhibition of tumour cell and lethal effect With DNA of tumor cell formed chain in and interchain linkage, thus inhibit DNA of tumor cell synthesis and duplication and realize.
Experiment is for the fluorine-containing water-soluble platinum complex of the present invention to the Proliferation Ability of different types of human tumor cells below Effect 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)
The antitumor drug effect of platinum complex prepared by embodiment 1 is shown in Fig. 1 and Fig. 2；Platinum complex prepared by embodiment 2 resists Tumour drug effect is shown in Fig. 3 and Fig. 4；The antitumor drug effect of platinum complex prepared by embodiment 3 is shown in Fig. 5 and Fig. 6；Prepared by embodiment 5 The antitumor drug effect of platinum complex is shown in Fig. 7 and Fig. 8；The antitumor drug effect of platinum complex prepared by embodiment 6 is shown in Fig. 9 and Figure 10. In order to more clearly show the drug effect trend of complex, standard error of mean label is omitted in the curve in all figures.
Experimental example 4:
The anticancer drug effect of the fluorine-containing water-soluble platinum complex of the present invention and leading patents (201210205475.5) and Tumor-targeting compares
(1) test method: using MCF-7 Human Breast Cancer Cells, by 1 drug of the embodiment of the present invention and disclosed in advance contains Have glucose, the corresponding complex of galactolipin and mannose under same concentrations (50 μM) and same time condition (for 24 hours) into Row Cytotoxic evaluation.According to the method in experimental example 3 while obtaining tumor control rate data, using atomic absorption spectrum The method of test, evaluates drug concentration of each complex in tumour cell, compares relative medicine under the same conditions with this Effect is put aside in targeting for tumour cell.
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. BioTEK ELX808), low temperature refrigerator (Japanese MDF-V5410), superclean bench (Suzhou Medical Instruments Factory), micropipettor (French GILSON), automatic pure water steam Evaporate device (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, fluorine-containing water-soluble platinum complex provided by the present invention and in advance disclosed structure similar medicine It compares, no matter in terms of depot action in tumour cell of antitumor drug effect and drug all shows more superior effect.
Using fluorine-containing water-soluble platinum complex of the invention, the drug for preventing and treating tumour can be prepared.These drugs Preparation usually using the fluorine-containing water-soluble platinum complex provided by the present invention of one or several kinds of effective doses, cooperate pharmacy Acceptable carrier or diluent and complete.These pharmaceutically acceptable pharmaceutic adjuvant such as starch, glucose, dextrin, fruit Sugar and maltose, lactose, gelatin, sucrose, hydroxylated cellulose, hydroxypropyl methyl cellulose, silica, stearic acid hydroxyacetic acid Sodium starch, 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: fluorine-containing water-soluble platinum complex provided by the invention has good anti-tumor activity.Institute of the present invention The fluorine-containing water-soluble platinum complex provided is for including intestinal cancer, breast cancer, prostate cancer, the antitumor pharmacodynamic test of lung cancer etc. In, anti-tumor activity can compare favourably with the cis-platinum that is widely used at present, carboplatin or oxaliplatin, and activity is even higher than These existing platinum-containing anticancer drugs.In addition, complex provided by the present invention is capable of forming by force for the antitumaous effect of cis-platinum The mouse Leukemia-L1210 tumour cell of strong drug resistance has more effective lethal effect.This is because provided by the present invention Fluorine-containing water solubility platinum complex in terms of water solubility compared with existing platinum antineoplastic drug, all with tens times of raising, this Kind of highly-water-soluble feature can theoretically increase and improve drug in the excretion of kidney, mitigate platinum medicine generally there are height Kidney toxic side effect, while so that these compounds is easy formulation and clinically application more convenient for this highly-water-soluble characteristic.
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 (9)

1. fluorine-containing water solubility platinum complex, 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.
2. fluorine-containing water-soluble platinum complex according to claim 1, it is characterized in that the X and Y be together it is trans--(1R, 2R)-cyclohexanediamine.
3. the preparation method of fluorine-containing water-soluble platinum complex (I) described in claim 1, it is characterized in that including the following steps:
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, fluorine-containing water solubility platinum complex is made (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.
4. according to the method described in claim 3, 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 3,5. 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.
6. according to the method described in claim 3, it is characterized in that the X and Y are trans--(1R, 2R)-cyclohexanediamine together.
7. a kind of preparation, it is characterised in that preparation is by fluorine-containing water-soluble platinum complex of any of claims 1 or 2 and pharmaceutically may be used The auxiliary material of receiving is made.
8. a kind of application of fluorine-containing water-soluble platinum complex of any of claims 1 or 2, it is characterised in that claims 1 or 2 institute The fluorine-containing water-soluble platinum complex stated is applied to prepare the drug of anti-curing oncoma.
9. a kind of application of preparation as claimed in claim 7, it is characterised in that by formulation application as claimed in claim 7 in preparation The drug of anti-curing oncoma.
CN201510706153.2A 2015-10-27 2015-10-27 Fluorine-containing water solubility platinum complex and Preparation method and use Active CN106608892B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510706153.2A CN106608892B (en) 2015-10-27 2015-10-27 Fluorine-containing water solubility platinum complex and Preparation method and use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510706153.2A CN106608892B (en) 2015-10-27 2015-10-27 Fluorine-containing water solubility platinum complex and Preparation method and use

Publications (2)

Publication Number Publication Date
CN106608892A CN106608892A (en) 2017-05-03
CN106608892B true CN106608892B (en) 2019-06-14

Family

ID=58614198

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510706153.2A Active CN106608892B (en) 2015-10-27 2015-10-27 Fluorine-containing water solubility platinum complex and Preparation method and use

Country Status (1)

Country Link
CN (1) CN106608892B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109553595B (en) * 2017-09-27 2021-05-28 上虞京新药业有限公司 Preparation method of chiral gamma-butyrolactone and intermediate thereof
CN111450326A (en) * 2020-03-09 2020-07-28 西南交通大学 Drug coating for selenazolidone-loaded blood vessel stent and preparation method thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0167071A2 (en) * 1984-06-30 1986-01-08 BEHRINGWERKE Aktiengesellschaft Derivatives of cis-platin(II) complexes with diamino sugars as ligands, method for their preparation and the pharmaceutical compositions obtained
WO2006091790A1 (en) * 2005-02-23 2006-08-31 Xenoport, Inc. Platinum-containing compounds exhibiting cytostatic activity, synthesis and methods of use
CN101429218A (en) * 2007-11-09 2009-05-13 百博方舟（北京）科技有限责任公司 Preparation of novel organic platinum complex and uses thereof
CN102276657A (en) * 2011-06-24 2011-12-14 天津大学 Complex containing mannose meal for targeting treatment of tumors and preparation method thereof
CN102276656A (en) * 2011-06-24 2011-12-14 天津谷堆生物医药科技有限公司 Fluorine contained water-soluble platinum complex for treating tumour and preparation method thereof
CN102603804A (en) * 2012-02-10 2012-07-25 昆明贵研药业有限公司 Novel platinum complex, preparation method and applications of platinum complex
CN102702293A (en) * 2011-06-24 2012-10-03 天津谷堆生物医药科技有限公司 Water soluble platinum complex for tumor therapy and preparation method of water soluble platinum complex

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0167071A2 (en) * 1984-06-30 1986-01-08 BEHRINGWERKE Aktiengesellschaft Derivatives of cis-platin(II) complexes with diamino sugars as ligands, method for their preparation and the pharmaceutical compositions obtained
WO2006091790A1 (en) * 2005-02-23 2006-08-31 Xenoport, Inc. Platinum-containing compounds exhibiting cytostatic activity, synthesis and methods of use
CN101429218A (en) * 2007-11-09 2009-05-13 百博方舟（北京）科技有限责任公司 Preparation of novel organic platinum complex and uses thereof
CN102276657A (en) * 2011-06-24 2011-12-14 天津大学 Complex containing mannose meal for targeting treatment of tumors and preparation method thereof
CN102276656A (en) * 2011-06-24 2011-12-14 天津谷堆生物医药科技有限公司 Fluorine contained water-soluble platinum complex for treating tumour and preparation method thereof
CN102702293A (en) * 2011-06-24 2012-10-03 天津谷堆生物医药科技有限公司 Water soluble platinum complex for tumor therapy and preparation method of water soluble platinum complex
CN102718824A (en) * 2011-06-24 2012-10-10 天津谷堆生物医药科技有限公司 Fluorine-containing water-soluble platinum complex for cancer treatment and preparation method thereof
CN102603804A (en) * 2012-02-10 2012-07-25 昆明贵研药业有限公司 Novel platinum complex, preparation method and applications of platinum complex

Also Published As

Publication number Publication date
CN106608892A (en) 2017-05-03

Similar Documents

Publication Publication Date Title
CN102702293B (en) Water soluble platinum complex for tumor therapy and preparation method of water soluble platinum complex
WO2017148193A1 (en) Tetravalent platinum complex containing bioactive group and preparation method therefor
CN102718824B (en) Fluorine-containing water-soluble platinum complex for cancer treatment and preparation method thereof
CN102286050A (en) Glucose-containing platinum complex for treating tumors and preparation method thereof
WO2009043296A1 (en) Gambogic glycoside derivatives and analogs, the preparation and the application thereof
CN102276674A (en) Galactose-containing platinum complex for tumour targeted therapy and preparation method thereof
CN109438522A (en) 5 FU 5 fluorouracil-platinum (IV) complex, intermediate, preparation method and application
CN102276657A (en) Complex containing mannose meal for targeting treatment of tumors and preparation method thereof
CN106608892B (en) Fluorine-containing water solubility platinum complex and Preparation method and use
JPH01294683A (en) Novel platinum complex, antitumor agent containing said complex as active ingredient and intermediate for preparing the same compound
KR102640022B1 (en) Cyclobutane dicarboxylic acid platinum complex, its intermediate, its preparation method, pharmaceutical composition and use
CN106608898B (en) The complex of water-soluble platinum containing deoxyglucose and Preparation method and use
CN106608897B (en) Chlorinated water dissolubility platinum complex and Preparation method and use
CN115838386A (en) Preparation method of arundoin-platinum (IV) complex and application of arundoin-platinum (IV) complex in tumor drugs
CN113549122B (en) Glycosylated tetravalent platinum compound targeting GLUTs, synthetic method and application thereof
CN112940059B (en) Glycosyl modified naphthalimide-polyamine conjugate, preparation method and application thereof
CN102716145A (en) Application of sugar-containing platinum complex in preparation of medicines for preventing and treating tumor
CN114524716A (en) Beta-elemene vinylation coupled derivative, preparation thereof and application thereof in preparing antitumor drugs
CN110218230B (en) Vitamin C coupled platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and application
CN104788498B (en) A kind of platinum (II) complex using chiral bicyclic diamines as carrier ligand and its preparation method and application
CN116178464B (en) Sugar-targeted GSH response type epothilone B nano prodrug, preparation method and application
CN103435586B (en) Containing the polyamine derivative and its preparation method and application of flavones structure
CN113416216B (en) High-activity Pt complex and preparation method and application thereof
CN113072594A (en) Carbon glycoside glycosylated tetravalent platinum compound, synthetic method and application thereof
CN117624250A (en) Platinum (IV) prodrug with novel NF- κB inhibitor as ligand and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant