CN106242972B - Combretastatin prodrug, pharmaceutical preparation and preparation method - Google Patents
Combretastatin prodrug, pharmaceutical preparation and preparation method Download PDFInfo
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- CN106242972B CN106242972B CN201610621678.0A CN201610621678A CN106242972B CN 106242972 B CN106242972 B CN 106242972B CN 201610621678 A CN201610621678 A CN 201610621678A CN 106242972 B CN106242972 B CN 106242972B
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- combretastatin
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- prodrug
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
- C07C69/33—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with hydroxy compounds having more than three hydroxy groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
Abstract
The invention discloses a kind of Combretastatin prodrugs, and disclose preparation method, and the present invention discloses the preparation methods of a kind of preparation containing above-mentioned Combretastatin prodrug and said preparation.Combretastatin lipophilic drugs precursor provided in the present invention can fast hydrolyzing discharge active pharmaceutical ingredient, play drug effect；The nanometer formulation being made of Combretastatin lipophilic drugs precursor then can slow release internal drug, be conducive to extend the circulation of drug in vivo, improve the curative effect of drug, there is good potential applicability in clinical practice and application value.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, are specifically related to a kind of anti-angiogenic medicaments Combretastatin lipophilic drugs
The preparation method of precursor, synthetic method and its nanometer formulation and preparation.
Background technique
The growth and transfer of malignant tumour depend on tumor vessel, and tumour is itself conveying oxygen and nutrients by blood vessel
Matter for the fast breeding of its cell, and causes tumour cell to far-end transfer.With the depth of neonate tumour blood vessel Mechanism Study
Enter, and obtain preferable curative effect in clinical treatment tumour by the drug of target spot of tumor vessel, it was confirmed that by inhibiting swollen
Tumor angiogenesis inhibits the theory of tumour growth.
Combretastatin A-4 4 (Combretastatin, CA4) is separated from the bark of African shrub Combretum Caffrum
A kind of cis-stilbene class natural goods.In the early 1980s, researcher is assessing a series of Combretastatinsization
It is found when closing object to vitro cytotoxicity, CA4 is similar to autumn waters -- limid eyes alkali structure, can be when being much smaller than its maximum tolerated dose (MTD)
Active function is played, is that CA4 and tubulin binding/dissociation are fast, half-life period is shorter, eliminates fast caused (Pettit in vivo
GR,Singh SB,Hamel E,Lin CM,Alberts DS,Garcia-Kendall D,Isolation and
structure of the strong cell growth and tubulin inhibitor combretastatin
A4.Experentia,1989,45:209-211).But the water solubility of CA4 is very poor, bioavilability is lower, to limit
Its clinical application.In order to improve the water solubility of CA4, internal medication is made it easier for, traditional approach is by CA4 design improvement into phosphorus
Acid disodium prodrug (CA4P), phosphate group needs to be converted to CA4 under the action of phosphate in vivo, but turns completely
Change still takes a long time, in addition, pharmacokinetic study shows that the half-life period of CA4P is shorter, eliminates in vivo comparatively fast,
To maintain to block tumor vessel, it is necessary to which medication repeatedly, side effect are larger in the short time.
Nanometer medicine-carried system has good tumor-targeting, can improve the dissolubility of drug, reduces the secondary work of poison of drug
With by the design of reasonable anti-tumor drug administration nano-drug administration system, nano medicament carrying system is obtained in antitumor research
Good application prospect.CA4 and amphipathy macromolecule are assembled altogether in the experiment of our early periods and form nanoparticle, but result
There is drug quick release in display, the nanoparticle for directly containing CA4.
Summary of the invention
In view of the problems of the existing technology, the present invention provides a kind of pharmaceutical release times to extend, the curative effect of drug mentions
High lipophilicity Combretastatin prodrug.
Invention also provides the preparation methods of above-mentioned lipophilicity Combretastatin prodrug, and this method is easy to operate,
It is easily achieved mass production.
The anti-angiogenic medicaments nanometer that the present invention also provides a kind of pharmaceutical release times to extend, the curative effect of drug improves
Grain Combretastatin pharmaceutical preparation.
The present invention also provides a kind of preparation method of above-mentioned Combretastatin pharmaceutical preparation, the present invention by the prodrug with
Advanced nanotechnology combines, and prepares the nanometer system of anti-angiogenic medicaments, delays the release of CA4, when extending the effect of drug
Between, improve the clinical drug effect of drug.
In order to solve the above technical problems, technical solution difference is as follows:
A kind of Combretastatin prodrug, structure are as follows:
The R is the alkanoyl of C1~C10.
Preferably, the R is the alkanoyl of C1~C7.
As further preferred, the Combretastatin prodrug structure is as follows:
Above two Combretastatin prodrug, drug hydrolysis rate is fast, and rate of release significantly delays.
A kind of preparation method of above-mentioned Combretastatin prodrug, comprising: Combretastatin A-4 4 is corresponding with the alkanoyl
Carboxylic acid, acyl chlorides or acid anhydrides carry out esterification, obtain the Combretastatin prodrug.
Preferably, be prepared using the carry out esterification of the carboxylic acid corresponding with the alkanoyl of Combretastatin A-4 4,
In reaction process, catalyst, condensing agent etc. can be added as needed, for example 1- (3- dimethylamino-propyl) -3- ethyl can be used
The hydrochloride of carbodiimide is as condensing agent, and 4-dimethylaminopyridine is as catalyst, while using N, N- diisopropyl second
Hydrochloric acid in amine and in the hydrochloride of 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide.
As further preferred, the molar ratio of the Combretastatin A-4 4 and carboxylic acid, catalyst, condensing agent is 1:1~1.5:
0.5~1.5:1~1.5.
A kind of Combretastatin nanometer formulation, including Combretastatin prodrug and amphipathy macromolecule material, the Kang Pu
The structure of auspicious spit of fland prodrug is as follows:
The R is the alkanoyl of C1~C10.
Preferably, the R is the alkanoyl of C1~C10.
Preferably, the structure of the Combretastatin prodrug is as follows:
Above two Combretastatin pharmaceutical preparation, drug hydrolysis rate is fast, and 8h is releasable about 90% active medicine；Together
When rate of release of the drug in nanoparticle significantly delay, be conducive to the long circulating of drug in vivo, play long-time drug effect.
Preferably, the amphipathy macromolecule material is selected from polyethylene glycol-polylactic acid (PEG-PLA), polyethylene glycol
The poly- cream of lactic-co-glycolic acid (PEG-PLGA), methoxy polyethylene glycol-polylactic acid (mPEG-PLA) or methoxy poly (ethylene glycol)-
Any one in acid-hydroxyacetic acid (mPEG-PLGA).
As further preferred, in described PEG-PLA, PEG-PLGA, mPEG-PLA or mPEG-PLGA, the molecular weight of PEG
For 2k~8k, the molecular weight of mPEG is 2k~8k, and the molecular weight of PLA is 2k~16k, and the molecular weight of PLGA is 2k~16k.
As further preferred, the amphipathy macromolecule material is mPEG5k-PLA16k。
Preferably, the Combretastatin nanometer formulation is pulvis or tablet, injection, pill.
A method of Combretastatin nanometer formulation described in any of the above-described technical solution being prepared, by Combretastatin prodrug
In organic solvent with the dissolution of amphipathy macromolecule material, it is then added in water, removes organic solvent, obtain Combretastatin and receive
Metric system agent.
Preferably, the organic solvent is acetone.
The present invention provides a kind of synthesis of Combretastatin lipophilic drugs precursor and its nanometer formulations.It is provided in the present invention
Combretastatin lipophilic drugs precursor can fast hydrolyzing discharge active pharmaceutical ingredient, play drug effect.Relative to unmodified health
Puri spit of fland composition nanoparticle quick release, the present invention in nanoparticle can slow release internal drug, be conducive to extend medicine
The circulation of object in vivo improves the anti-angiogenesis curative effect of drug, has good potential applicability in clinical practice and application value.
Detailed description of the invention
Fig. 1 is butyric acid-CA4 synthetic route chart；
Fig. 2 is enanthic acid-CA4 synthetic route chart；
Fig. 3 is nanoparticle electron microscope in embodiment 4；
Fig. 4 is the grain-size graph of nanoparticle in embodiment 3,4,5；
Fig. 5 is CA4 prodrug hydrolysis rate figure in test case 1；
Fig. 6 is nanoparticle In-vitro release curves in test case 2；
In figure, CA4 indicates that Combretastatin A-4 4, DCM indicate that methylene chloride, EDCHCl indicate 1- (3- dimethylamino third
Base) -3- ethyl carbodiimide hydrochloride, DMAP indicate 4-dimethylaminopyridine, DIEA indicate n,N-diisopropylethylamine.
Specific embodiment
Invention is further described in detail with reference to the accompanying drawings and detailed description, but the present invention is not limited by it
System.
Embodiment 1
It takes butyric acid (51.7 μ L, 0.57mmol), CA4 (compound 1,180mg, 0.57mmol), EDCHCl (163mg,
0.855mmol), DMAP (76.6mg, 0.627mmol), DIEA (188.9 μ L, 1.14mmol) are dissolved in 4ml DCM, at room temperature
It is stirred overnight, ethyl acetate is added, respectively successively with 5% citric acid, saturation NaHCO3, saturated common salt water washing organic phase, have
Machine is mutually dried, filtered with anhydrous sodium sulfate, and solvent is removed under reduced pressure after collecting filtrate；Solid isolates and purifies (second with column chromatography chromatogram
Acetoacetic ester: n-hexane=1:3), obtain target product butyric acid-CA4 coupling compounds 2 (280mg, yield 93%).Synthesize road
Line is as shown in Figure 1.
The 1H NMR nuclear magnetic data and mass spectrometric data of product butyric acid-CA4 is as follows:
1H NMR(400MHz,CDCl3):δ1.00-1.04(t,3H),1.73-1.78(m,2H),2.49-2.53(t,2H),
3.71 (s, 6H), 3.80 (s, 3H), 3.83 (s, 3H), 6.45-6.45 (d, 2H, J=1.2), 6.51 (s, 2H), 6.83-6.85
(d, 1H, J=8.4), 7.00-7.01 (d, 1H, J=1.6), 7.10-7.12 (q, 1H)
HR-ESI Qq-LTMS: calculated value: [C22H26O6]+[M+H]+=387.1802；Detected value: 387.1811.
Embodiment 2
It takes enanthic acid (80.8 μ L, 0.57mmol), CA4 (180mg, 0.57mmol), EDCHCl (163mg,
0.855mmol), DMAP (76.6mg, 0.627mmol), DIEA (188.9 μ L, 1.14mmol) are dissolved in 4mL DCM, at room temperature
It is stirred overnight, ethyl acetate is added, respectively successively with 5% citric acid, saturation NaHCO3, saturated common salt water washing organic phase, have
Machine is mutually dried, filtered with anhydrous sodium sulfate, and solvent is removed under reduced pressure after collecting filtrate；Solid isolates and purifies (second with column chromatography chromatogram
Acetoacetic ester: n-hexane=1:3), obtain target product enanthic acid-CA4 coupling compounds 3 (260mg, yield 85%).Synthesize road
Line is as shown in Figure 2.
1H NMR(400MHz,CDCl3):δ0.88-0.91(t,3H),1.26-1.41(m,6H),1.70-1.74(t,2H),
2.51-2.54 (t, 2H), 3.71 (s, 6H), 3.80 (s, 3H), 3.84 (s, 3H), 6.45-6.45 (d, 2H, J=1.6), 6.51
(s, 2H), 6.83-6.85 (d, 1H, J=8.4), 7.00-7.00 (d, 1H, J=1.6), 7.10-7.12 (q, 1H)
HR-ESI Qq-LTMS: calculated value [C25H32O6]+[M+H]+=429.2212；Detected value: 429.2282.
Embodiment 3
By CA4 (CA4 content 0.5mg) and mPEG5k-PLA16k(20 times of drug quality) are dissolved in 1mL acetone, uniformly
After be added drop-wise in 10mL water, after being added dropwise, decompression removal acetone, CA4 Nano medication (being denoted as 1-NP) can be obtained.
Embodiment 4
By butyric acid-CA4 conjugate 2 (being counted according to CA4, the amount of CA4 is 0.5mg) and mPEG prepared by embodiment 15k-PLA16k
(20 times of CA4 prodrug quality) are dissolved in 1mL acetone, are added drop-wise in 10mL water after uniform, after being added dropwise, decompression removal third
Butyric acid-CA4 Nano medication (2-NP) can be obtained in ketone, pattern such as Fig. 3 under 2-NM Electronic Speculum, observes nanoparticle in preferable circle
Shape, it is uniform in size.
Embodiment 5
Enanthic acid-CA4 conjugate 3 (according to CA4, the amount 0.5mg of CA4) and mPEG prepared by embodiment 25k-PLA8k(CA4
20 times of prodrug quality) it is dissolved in 1mL acetone, it is added drop-wise in 10mL water after uniform, after being added dropwise, decompression removal acetone,
Enanthic acid-CA4 Nano medication (3-NP) can be obtained.
DLS (dynamic light scattering, Dynamic Light Scattering) measures the nanometer prepared in each embodiment 1,2,3
The partial size of grain is as shown in Figure 4 and Table 1.The partial size of 1-NP, 2-NP, 3-NP nanoparticle prepared in embodiment 3,4,5 as the result is shown
In 30nm or so, and particle diameter distribution is relatively narrow, and preferable uniformity is presented.
1 particle size of table
Below by way of the vitro characteristics of test case the present invention is furture elucidated the Combretastatin precursor and its nanoparticle:
Test case 1: drug hydrolysis rate
CA4 medicine precursor compound 2, the compound 3 prepared in Example 1,2, is dissolved in DMSO (CA4 equal parts respectively
2mg/mL), then with HEPES (4- hydroxyethyl piperazineethanesulfonic acid, pH 8.0) 0.5mg/mL (CA4 equal parts) are diluted to, are placed in 37
DEG C, at regular intervals, 100 μ L fluid analysis are taken out, draws drug hydrolysis curve.As shown in figure 5, CA4 prodrug chemical combination
Object 2, compound 3 can fast hydrolyzing, 8h be in an in vitro environment releasable about 90% active medicine.
Test case 2: extracorporeal releasing experiment
Each 10mL of 1-NP, 2-NP, the 3-NP prepared in Example 3~5 is placed in the bag filter that molecular weight is 14kDa,
Release conditions are the phosphate buffer (Tween 80 containing 0.2%) of 50mL, pH 7.4, and 37 DEG C, different time points take out extraneous phosphorus
Acid buffer measures CA4 content with HPLC, to obtain the release in vitro situation of drug in nanoparticle.The release profiles of drug
As shown in fig. 6, as the result is shown with free drug CA4 composition nanoparticle 1-NP compared with, to CA4 carry out it is structurally-modified after 2-NP
Obviously slow down with 3-NP rate of release, for 24 hours, 1-NP release rate is up to 91%, and the release rate of 2-NP and 3-NP is respectively 37% He
4.6%.It is experimentally confirmed that effectively delaying rate of release of the drug in nanoparticle to the structure of modification of CA4, being conducive to drug and exist
Intracorporal long circulating plays long-time drug effect.
Claims (5)
1. a kind of preparation method of Combretastatin nanometer formulation, which is characterized in that the Combretastatin nanometer formulation includes health
The structure of Puri spit of fland prodrug and amphipathy macromolecule material, the Combretastatin prodrug is as follows:
The R is the alkanoyl of C1~C10；
Any one of the amphipathy macromolecule material in PEG-PLA, PEG-PLGA, mPEG-PLA, mPEG-PLGA；
The preparation method of the Combretastatin nanometer formulation is to dissolve Combretastatin prodrug and amphipathy macromolecule material
In organic solvent, it is then added in water, removes organic solvent, obtain Combretastatin nanometer formulation.
2. the preparation method of Combretastatin nanometer formulation according to claim 1, which is characterized in that the Combretastatin medicine
The structure of object precursor is as follows:
3. the preparation method of Combretastatin nanometer formulation according to claim 1, which is characterized in that the amphipathy macromolecule
In material, the molecular weight of PEG is 2k~8k, and the molecular weight of mPEG is 2k~8k, and the molecular weight of PLA is 2k~16k, point of PLGA
Son amount is 2k~16k.
4. the preparation method of Combretastatin nanometer formulation according to claim 3, which is characterized in that the amphipathy macromolecule
Material is mPEG5k-PLA16k。
5. the preparation method of Combretastatin nanometer formulation according to claim 1 or claim 2, which is characterized in that the Combretastatin
Nanometer formulation is pulvis or tablet, injection, pill.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000067801A2 (en) * | 1999-05-06 | 2000-11-16 | University Of Kentucky Research Foundation | Prodrugs of chemotherapeutic agents with oxaalkanoic acids |
| WO2006089207A2 (en) * | 2005-02-18 | 2006-08-24 | Abraxis Bioscience, Inc. | Drugs with improved hydrophobicity for incorporation in medical devices |
| CN1857736A (en) * | 2006-03-16 | 2006-11-08 | 上海交通大学 | Polyglycol modified antitumor compound and its preparing method |
| WO2007059118A1 (en) * | 2005-11-14 | 2007-05-24 | Abraxis Bioscience, Inc. | Combretastatin derivatives and related therapeutic methods |
| CN106580945A (en) * | 2015-10-14 | 2017-04-26 | 上海天氏利医药科技有限公司 | Combretastatin A4 derivative and preparation thereof |
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2016
- 2016-07-29 CN CN201610621678.0A patent/CN106242972B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000067801A2 (en) * | 1999-05-06 | 2000-11-16 | University Of Kentucky Research Foundation | Prodrugs of chemotherapeutic agents with oxaalkanoic acids |
| WO2006089207A2 (en) * | 2005-02-18 | 2006-08-24 | Abraxis Bioscience, Inc. | Drugs with improved hydrophobicity for incorporation in medical devices |
| WO2007059118A1 (en) * | 2005-11-14 | 2007-05-24 | Abraxis Bioscience, Inc. | Combretastatin derivatives and related therapeutic methods |
| CN1857736A (en) * | 2006-03-16 | 2006-11-08 | 上海交通大学 | Polyglycol modified antitumor compound and its preparing method |
| CN106580945A (en) * | 2015-10-14 | 2017-04-26 | 上海天氏利医药科技有限公司 | Combretastatin A4 derivative and preparation thereof |
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