CN103848985B - Noval chemical compound and preparation method and purposes containing Sutent analog structure - Google Patents
Noval chemical compound and preparation method and purposes containing Sutent analog structure Download PDFInfo
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- CN103848985B CN103848985B CN201210527560.3A CN201210527560A CN103848985B CN 103848985 B CN103848985 B CN 103848985B CN 201210527560 A CN201210527560 A CN 201210527560A CN 103848985 B CN103848985 B CN 103848985B
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Abstract
The invention discloses the noval chemical compound containing Sutent analog structure and the preparation method and purposes of the compound.The medicine that the noval chemical compound for containing Sutent analog structure is prepared into is more preferable in the effect for the treatment of glaucoma disease and protection nerve than the medicine or medicament of other forms.
Description
Technical field
The invention discloses the preparation method of the noval chemical compound containing Sutent analog structure and the compound and
Purposes.
Background technology
Sutent (Sunitinib, Sutent) is a kind of oral drugs of the treatment tumour of new more targetings.Shu Ni
It is for the primary development goal of Buddhist nun, for treating the gastrointestinal stromal tumors for not responding to or not being resistant to standard treatment and turning
Shifting property clear-cell carcinoma.Sutent can be selectively targeting the acceptor of some albumen, and the latter is considered as in Tumor Growth
Play a part of a kind of molecular switch sample.Application of the medicine in protection nerve and treatment glaucoma, this patent are had been reported that at present
By connecting Sutent analog to a new polymer, make its treat glaucoma the effect of greatly increase.
At present, 6,005 million peoples suffer from glaucoma in the world, wherein 4,005 million peoples are primary open-angles
Glaucoma, 1,005 million peoples are primary angle-closure glaucomas.The main blinding factor of one of glaucoma is exactly intraocular pressure
(intraocular pressure, IOP) is raised.At present, glaucoma mainly is treated in terms of two, first, reducing intraocular
Pressure, its mechanism of action are by promoting aqueous humor drainage, the generation of reduction aqueous humor and hypertonic dehydration effect to reduce intraocular pressure；Second, protect
Optic nerve is protected, Deterioration of Optic Nerve in Glaucoma ultimately results in visual function forfeiture, and optic nerve protection remedy measures include reducing intraocular pressure,
Using calcium antagonist, antioxidant, immunotherapy, supplement and alternative medicine, potential cell repair and gene therapy, not institute
Some optic nerve protection means are used equally for clinic, much still in experimental study stage, its less effective.The easypro Buddhist nun of the present invention replaces
Buddhist nun's analog is coupled segmented copolymer, the new construction containing Sutent analog of preparation can be made to be dissolved in water, very
Good control medicine delivery amount, and then treat glaucoma disease or derivative optic nerve injury illness.
It is simple with polymer when the noval chemical compound containing Sutent analog prepared by this patent is treating glaucoma
Nanometer formulation made of parcel Sutent analog is compared, and the effect of drugs that this patent is invented far surmounts polymer letter
The nanometer formulation of single parcel Sutent analog, medication effect are very good.
The content of the invention
Present disclosure is as follows：
The invention discloses the segmented copolymer of the coupling of the Sutent analog shown in following formula I, its structure are as follows：
Wherein PEG refers to polyethylene glycol, molecular weight 100-100000, molecular weight 100-100000, wherein n not generation
Table stationary digital, for 1-200 integer, preferably 1-100.
The preparation method of present copolymer, it is characterised in that：
1) compound A is obtained with methoxy poly (ethylene glycol) amine and citric acid reactions；
2) compound A and acetylating decanedioic acid react to obtain polymer B, wherein wherein n does not represent stationary digital, are
1-200 integer, preferably 1-100；
3) polymer B and the C of the analog containing Sutent react to obtain final product；
Compound A；
Polymer B；
Sutent analog C
The chemical step optional solvents for wherein synthesizing final product are selected from：Benzene, toluene, pyridine, tetrahydrofuran, chlorine
Imitative, one kind in carbon tetrachloride, dichloromethane, methanol, ethanol, dichloromethane, dimethyl sulfoxide (DMSO), DMF or
It is a variety of.
The compound of brand-new can be prepared into the nanometer formulation suitable for being locally administered, microball preparation.Purposes is treated to prepare
The medicine of glaucoma and the medicine of protection nerve.
The preparation method of the present invention is specific as follows：
1) decanedioic acid is flowed back in acetic anhydride, forms acetyl group-decanedioic acid；
2) methoxy poly (ethylene glycol) amine dissolves in a solvent with citric acid, and hybrid reaction is overnight, is dried to obtain compound A；
3) acetyl group-decanedioic acid is mixed with compound A, reacted at 100-200 DEG C, reaction time 10min to 10h；
After the cooling of question response mixture, washing, polymer B is dried to obtain；
4) by Sutent analog C and polymer B as 1-96 hours in solvent, after ultrasonic reaction 1-20 minutes,
Foster to obtain Formulas I polymer in baking oven, then the homogenizer high-speed stirred 1-10 minutes in subzero 30 DEG C of 0-, rotation volatilization obtains
Crude product, post processing obtain the nanometer formulation of end-product Formulas I polymer.
Its reaction equation is as follows：
The polymer containing Sutent analog structure that the present invention obtains, it is easy to dissolve in water, and it partly declines
Phase extends much than Sutent analog, and such noval chemical compound is treating glaucoma kind excellent, makees in protection optic nerve
With obvious.
Nanometer formulation is in the comparison for the treatment of eye disease made of end-product in this patent preparation, the new chemical combination of this patent
The medication effect of thing is very good, surmount completely directly wrapped up by polymer Sutent analog (not with Sutent
Analog be coupled) nanometer formulation.
Brief description of the drawings：
The nuclear magnetic resonance map of the end-product of Fig. 1 embodiments 1.
Nano-particle, decanedioic acid-glycol copolymer directly wrap up Sutent analog and received made of Fig. 2 embodiments 1
The medicine accumulative releasing degree and time chart of the grain of rice and Sutent analog ordinary preparation.
Nano-particle, decanedioic acid-glycol copolymer directly wrap up Sutent analog system made of Fig. 3 embodiments 1
Into nano-particle optic nerve protective effect comparison figure, 3a be embodiment 1 treat after optic nerve, 3b be polymer it is straight
Connect the optic nerve after parcel Sutent analogue treatment.
Embodiment
Specific embodiment is described in further detail to the present invention below, but the present invention not only limits to following examples.
It is as follows to prepare embodiment：
Embodiment 1
1) mixture backflows of the decanedioic acid 52g in 500ml acetic anhydrides, to form acetyl group-decanedioic acid；
2) methoxy poly (ethylene glycol) amine 6g, citric acid 72mg, dicyclohexylcarbodiimide 185mg and pyridine 8mg mixing add
Enter 32ml dichloromethane, be stirred at room temperature overnight；Then washed, and be dried under vacuum with ether, obtain polymer；
3) by the 1) step and the 2) step product mix be put into flask, at 182 DEG C decompression contain intermingle with reaction 1 hour；Wait to gather
Compound is cooled to room temperature and dissolved with chloroform, and with petroleum ether and drying；
4) by 200mg Sutents analog (can be commercially available, can also be according to patent (the 2- indoline of pyrroles's substitution
Ketone kinases inhibitor (notification number：1329390)) voluntarily preparing) stand-by and step 3 700mg polymer is put into 8ml diformazans
24 hours in base sulfoxide and 10ml dichloromethane solution；Ultrasound 5 minutes；Then insert in baking oven 2 hours；In subzero 10 degree
Homogenizer ultrahigh speed stirs 2 minutes, is then put into 1.5% poly-vinyl alcohol solution 500 turns and stirs 3 hours；After being collected by centrifugation
It is lyophilized, produce the nano-particle of end-product.
Embodiment 2
1) methoxy poly (ethylene glycol) amine 3.5g, citric acid 52mg, dicyclohexylcarbodiimide 220mg and pyridine 7mg are mixed
20ml dichloromethane is added, is stirred at room temperature overnight；Then washed, and be dried under vacuum with ether；
2) acetyl group-decanedioic acid 20g (commercially available) and the 1st step product mix are put into flask, react 1.5 at 176 DEG C
Hour；Thing to be polymerized is cooled to room temperature and dissolved with chloroform, and with petroleum ether and be dried to obtain polymer (structure or with self-control
Slightly different, molecular weight or different because of commercially available quality)；
3) 30mg Sutents analog and polymer 140mg are put into and mixed by 0.5ml methanol and 1ml dichloromethane
Solution in；Ultrasound 2 minutes；Then insert in baking oven 24 hours；In minus 20 degrees, homogenizer high-speed stirred 3 minutes, product
600 turns are put into 5% cholic acid solution to stir 2 hours；Freezed after being collected by centrifugation, produce the microballoon of noval chemical compound.
Effect experiment is as follows：
By embodiment 1-2 samples prepared and similar with the Sutent that decanedioic acid-glycol copolymer directly wraps up
The nanoparticle pharmaceutical group (chemical coupling reaction not occurring, Sutent analog does not have structure change) of thing, Sutent is similar
Thing ordinary preparation (powder-injection) carries out stability test, drug release in vitro experiment and the medicine of letter out eye and neuroprotection respectively
Imitate Experiment on Function.
Stability test：
By receiving for the Sutent analog of the sample of 1 group of preparation of embodiment and decanedioic acid-glycol copolymer parcel
Grain of rice medicine group, Sutent analog ordinary preparation take same amount to determine absorbance respectively (in terms of Sutent analog).
Then three groups are put into 20 degree of incubators 3 months, then take out measure absorbance, as a result visible embodiment 1-2 groups and common system
The absorbance of the Sutent analog of agent group is front and rear without change, and the nanoparticle group absorbance wrapped up declines 18.5%.
Drug release in vitro is tested：
By 1 group of embodiment, the nanoparticle pharmaceutical group for the Sutent analog that decanedioic acid-glycol copolymer directly wraps up
And Sutent analog ordinary preparation component also known as takes the medicine of equivalent (in terms of Sutent analog, every group contains 10mg
Sutent analog), then by each group medicine as in test tube, after being soaked with PBS, in shaking table under 37 degrees Celsius
Shake, after timing sampling, the medicament contg percentage of release is calculated in the content of ultraviolet specrophotometer measure medicine, and after recording
Than, do releasing curve diagram, abscissa be the time (my god), ordinate for release percentage.See Fig. 2, it is seen that embodiment release
Medicine is more permanent, makes drug half-life longer.
Solubility test in water：
By embodiment 1-2 groups, the nanoparticle pharmaceutical for the Sutent analog that decanedioic acid-glycol copolymer directly wraps up
Group and Sutent analog ordinary preparation component also known as take the medicine of equivalent, and (in terms of Sutent analog, every group contains
100mg Sutents analog), it is respectively put into test tube, with 10mlPBS buffer solutions and shakes, dissolving is observed after static
Situation.The record dissolved state of 3 minutes and 20 minutes, it is as a result as follows.
The solubility of table 1 compares
To the Experiment on therapy of rat angle-closure glaucoma：
1.1 experimental animals and packet
Experiment uses Thirty male rats, body weight 200g or so.Before modeling, animal is grouped at random：That is blank
Control group；Model group；Embodiment 1-2 groups, polymer directly wrap up Sutent analog group, common Sutent analog system
Agent group was administered once every 5 days intraocular injections, dosage 0.1mg injections/kg；Positive drug group selection pilocarpinum eye drops,
It is administered once a day, one time one drop.All administrations continue 15 days.
The foundation of 1.2 animal models
Experiment before intraperitoneal injection the chloraldurate of rat 4% (200mg.kg-1), then with 1% lidocaine local anaesthesia
Cornea of rats.During high intraocular pressure, keep making animal continuous narcosis every 0.2 milliliter of 4% chloraldurate of half an hour intraperitoneal injection
State.Rat right eye intraocular pressure is raised using pulley suture system, while left side eyeball compares.By surgical sutures both ends
It is respectively an identical heavy counterweight, a circle is hitched among suture and is used for after the rat canthus limbus of sclera 2 millimeters, the weight at both ends
Code is by pulley to the continual and steady pressure of rat eye.Counterweight pressure is 20 grams, continuous 6 hours, causes rat angle-closure
Glaucoma model.Raising is pressed and recorded to the 15th day measure rathole.
1.3 experimental result
Experimental result is shown in Table 1
The intraocular pressure result (mmHg, n=10) of glaucoma rat under each group drug treatment of table 2
The * P ＜ 0.05**P ＜ 0.01 compared with model group
Protective effect experiment to optic nerve：
2.1 experimental animals and packet
Experiment uses Adult female rats, body weight 200g or so.Animal is grouped at random：That is blank control group；
Model group；Embodiment 1-2 groups, polymer directly wrap up Sutent analog group, and common Sutent analog formulations group is every
It is administered once every 5 days intraocular injections, dosage 0.1mg injections/kg, terminates observation after 20 days.
The foundation of 2.2 animal models
The water of rat 6% is injected intraperitoneally before carrying out the preparation experiment of nerve injury model in method according to Chen Xiaorui et al. reports
Chloral (200mg.kg-1) anesthesia is closed, eye part cleaning-sterilizing, goes in ring and cuts off outer canthus portion bulbar conjunctiva, opens Tenons capsules, passivity
Suspensorium is separated, pulls eyeball, exposure optic nerve forward, eye scissors enters vertical cut-out optic nerve in socket of the eye from after ball and made at 2mm
Into optic nerve injury, optical fundus blood vessel is avoided damage to.Ensure uniformity, all optic nerve transections wound is all in identical position, seam
Bulbar conjunctiva is closed, also receives eyeball, applies Antibiotic Eye Ointment.There are within postoperative 2 days Marcus-gun pupils, eyeball is without obvious prominent, eyelid
Closure is complete, and eyeground is successful model without obvious bleeder.Vacation hinders eye and only separates exposed optic nerve, not all right cross-section wound.Administration 20
Eyeball is won after it.After disconnected neck is put to death, whole eyeball (retaining ball optic nerve 2mm) is won, makes sample row electron microscopic observation.Knot
Fruit sees Fig. 3, it is seen that the neural action effect of embodiment protection is much better than polymer and directly wraps up Sutent analog guarantor
Protect the effect of nerve.
Claims (8)
1. the segmented copolymer containing Sutent analog in the structure being shown below, its structure are as follows：
2. the copolymer of claim 1, wherein PEG refer to polyethylene glycol, molecular weight 100-100000, wherein n are 1-200
Integer.
3. the preparation method of copolymer as claimed in claim 1, it is characterised in that：
1) compound A is obtained with methoxy poly (ethylene glycol) amine and citric acid reactions；
2) compound A and acetylating decanedioic acid react to obtain polymer B, and wherein n is 1-200 integer；
3) polymer B reacts to obtain final product with Sutent analog C；
4. the method for claim 3, wherein the chemical step 1-3 is selected from from solvent：Benzene, toluene, pyridine, tetrahydrofuran,
One or more in chloroform, carbon tetrachloride, dichloromethane, methanol, ethanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide.
5. the copolymer of claim 1 is prepared into the nanometer formulation suitable for being locally administered, microball preparation.
6. the purposes of the copolymer of claim 1, purposes treats the medicine of glaucoma to prepare.
7. the purposes of the copolymer of claim 1, purposes protects the medicine of nerve to prepare.
8. the purposes of the copolymer of claim 1, purposes reduces the medicine of intraocular pressure to prepare.
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| WO2016100392A1 (en) | 2014-12-15 | 2016-06-23 | The Johns Hopkins University | Sunitinib formulations and methods for use thereof in treatment of ocular disorders |
| CN104610231B (en) * | 2015-01-28 | 2016-08-17 | 广州葳澜生物科技有限公司 | A kind of Sutent prodrug |
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| EP2313411A1 (en) * | 2008-06-10 | 2011-04-27 | Plexxikon, Inc. | 5h-pyrr0l0 [2,3-b]pyrazine derivatives for kinase modulation, and indications therefor |
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