CN104877142A - Preparation method of novel high molecular polymer and novel use of novel high molecular polymer in medical treatment - Google Patents
Preparation method of novel high molecular polymer and novel use of novel high molecular polymer in medical treatment Download PDFInfo
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- CN104877142A CN104877142A CN201410456440.8A CN201410456440A CN104877142A CN 104877142 A CN104877142 A CN 104877142A CN 201410456440 A CN201410456440 A CN 201410456440A CN 104877142 A CN104877142 A CN 104877142A
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Abstract
The invention discloses a novel high molecular polymer and its preparation method and novel use in medical treatment. The novel high molecular polymer is a novel polymer structure. In an eye disease-treatment drug screening animal model test, the novel high molecular polymer has substantial and positive effects superior to those of other drugs.
Description
Technical field
The invention discloses a kind of structure containing novel high dimeric molecule and this high dimeric molecule, the purposes of preparation method and Xin.
Background technology
The many treatment difficulties of modern eye disease, pathogenic factor is varied, wherein angle, room narrow or close be a kind of producing cause fail to understand, may be genetic, also may be insecondary a kind of ophthalmic disease, majority directly translates into the associated conditions such as angle, room is narrow, angle, room obstruction, the angle closedown of acute and chronic room.Or closedown narrow for angle, room at present, way is clinically Direct Surgery, but surgical disruption is comparatively large, and later stage ratio is easier to send out again, and sufferer misery is larger.Medicine clinically for temporary treatment is miotic, and this measure effect is very limited.The present inventor is surprised to find that the high dimeric molecule that a class is new is applied to angle, room disease, and the structure of this kind of high dimeric molecule proposes first, at present without the application of this type of medicine of report in the disease of angle, room.
Summary of the invention
Content of the present invention is as follows: the invention discloses a kind of high dimeric molecule, and the purposes of this high dimeric molecule is that treatment angle, room is narrow or close and the purposes of relative disease.Its synthesis step is as follows:
1) 0-48 hour is reacted by the solvent orange 2 A of one mole of connector B3 PH6.5-8 in 0-30 degree of the hydrophilic polymer B2 of the x containing double-active group mole and activation, the active group of one of them active group of hydrophilic compounds and the non-primary amine groups of connector B3 obtain containing primary amine groups-(B2) x-B3, then add solvent B vacuum-drying;
2) by (B2) x-B3 compound containing primary amine groups of obtaining in the upper step of 1 mole with y mole containing carboxyl or containing hydrophobic polymer B4 0-90 degree concentrating under reduced pressure in the solvent C of PH6.5-8 of ethanoyl, adding after 0-48 hour that solvent C suction filtration is dry must compound-(B2) x-B3-(B4) y;
3) anthracycline antibiotics 0-35 degree in solvent C of general-(B2) x-B3-(B4) y compound and X mole reacts 0-48 hour, volatile dry both (B1-B2) x-B3-(B4) y.
Solvent orange 2 A in wherein said chemical step 1-3 is selected from benzene, toluene, methyl ether, ether, pyridine, trifluoroacetic acid, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, dimethyl sulfoxide (DMSO), N, one or more in dinethylformamide, solvent B is selected from acetic acid, formic acid, methyl ether, ether, benzene, toluene, pyridine, trifluoroacetic acid, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, dimethyl sulfoxide (DMSO), N, one or more in dinethylformamide, solvent C is selected from acetonitrile, acetic acid, formic acid, methyl ether, ether, benzene, toluene, pyridine, trifluoroacetic acid, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, dimethyl sulfoxide (DMSO), N, one or more in dinethylformamide.
The invention discloses following formula height dimeric molecule
Wherein B1 is anthracycline antibiotics, and B2 is one section of hydrophilic polymer segment, and B3 is the connection compound of a branch-like, and B4 is one section of hydrophobic polymer fragment, and x is the integer between 2 to 30, and y is the integer between 1-30, between B1B2B3B4 structure, chemical reaction occurs.The wherein preferred aclarubicin of B1, Dx, pirarubicin, idarubicin, pidorubicin, daunorubicin or carminomycin; Wherein B2 preferably polyethylene alcohol, polyoxyethylene glycol, polypyrrole alkane ketone, polyethers, polyoxyethylene block copolymer, or their multipolymer; Wherein B3 preferably containing primary amine groups and there is the branch-like compound of other active groups; Wherein B4 preferred polyester, condensing model or their multipolymer.The wherein preferred polyoxyethylene glycol of B2.Wherein B3 is preferably as follows structure:
The wherein preferred polylactic-co-glycolic acid of B4, poly-sebacic acid.
Preferred structure of the present invention is as follows:
(anthracycline antibiotics-polyoxyethylene glycol) x-connector B3-(polylactic-co-glycolic acid) y
The wherein preferred 1-20 of x preferred 2-20, y.
Compound of the present invention can be prepared into and be suitable for muscle, vein or the nanometer formulation of topical, microball preparation or implant preparation, described local is head administration, topical cutaneous administration, local tumor site-specific delivery of drugs, ear nasal administration, intravitreal injection administration or eyeground administration.The purposes of compound of the present invention, purposes is the narrow or purposes in closing in treatment angle, room and the purposes of relative disease.High dimeric molecule of the present invention has the structure of anthracycline antibiotics, therefore also may be used for the indication of anthracycline antibiotics medicine, owing to having biodegradable component, therefore being used for the treatment of similar and cancer, has extraordinary curative effect during the diseases such as tumour.
Accompanying drawing illustrates:
fig. 1nucleus magnetic resonance
figurespectrum embodiment 1.
fig. 2nucleus magnetic resonance
figurespectrum embodiment 3.
Embodiment
Preparation embodiment is as follows:
Embodiment 1
Compound (one) (being purchased) of 1 mole and compound (two) (being purchased) of 2 moles are at 20 degree, PH is in the methanol solution of 7, stirring reaction obtains compound (three) after 24 hours, then insert methyl ether, vacuum-freeze-dry, (4) containing PLGA structure (are purchased, its molecular formula x, y representative about 50, note x herein, y is different from the x in the claims in the present invention, y) (1 mole) and compound (three) PH be 7.3 dimethyl sulfoxide (DMSO) and methanol solution in react 6 hours, concentrating under reduced pressure crystallization in ethanolic soln obtains compound (five), compound (five) 4g and compound (six) 0.9g (being purchased) reacts to obtain product (seven) in the mixing solutions of methylene dichloride and methyl alcohol, then get freeze-drying compound (seven) 100mg, be placed in 300ml dimethyl sulphoxide solution, under homogenizer 3000 rpms, high-speed stirring 3 minutes, the polyvinyl alcohol solution then liquid being placed in 3% stirs volatilization 5 hours, the then centrifugation 20 minutes of 5000 rpms, abandon supernatant, distilled water is added in sample, repeated centrifugation 3 times again, abandon supernatant freeze-drying and be prepared into nanometer formulation.
Embodiment 2
Compound (one) (being purchased) of 1 mole and compound (two) (being purchased) of 2 moles are at 35 degree, PH is in the methanol solution of 7.3, stirring reaction obtains compound (three) after 24 hours, then insert methyl ether, vacuum-freeze-dry, (4) (being purchased) (1 mole) containing PLGA structure and compound (three) PH be 7.1 dimethyl sulfoxide (DMSO) and methanol solution in react 10 hours, concentrating under reduced pressure crystallization in ethanolic soln obtains compound (five), compound (five) 6g and compound (six) 0.3g (being purchased) reacts to obtain product (seven) in the mixing solutions of methylene dichloride and methyl alcohol, then Weigh Compound G200mg, put into test tube to heat, after there is molten state, taking-up is placed in 28G syringe needle, be placed in 100 degree of oil baths 1 hour, then take out fast and put into baking oven, modulate 80 degree, take out after spending the night, it is taken out from syringe needle, intercept suitable length 0.2cm, implant preparation for subsequent use.
Following formula is shown in embodiment 1-2 reaction:
Compound (one)
Compound (two)
Compound (three)
Compound (four)
Compound (five)
Compound (six)
Compound (seven)
Embodiment 3
Compound (one) (being purchased) of 1 mole and compound (two) (being purchased) of 2 moles are at 25 degree, PH is in the methanol solution of 6.8, stirring reaction obtains compound (three) after 24 hours, then insert methyl ether, vacuum-freeze-dry, (4) (being purchased) (1 mole) containing PLGA structure and compound (three) PH be 7.2 dimethyl sulfoxide (DMSO) and methanol solution in react 12 hours, concentrating under reduced pressure crystallization in methyl alcohol and alcohol mixed solution obtains compound (five), compound (five) 5g and compound (six) 0.4g (being purchased) reacts to obtain product (seven) in the mixing solutions of methylene dichloride and methyl alcohol, then get freeze-drying compound (seven) 120mg, be placed in 200ml dimethyl sulfoxide (DMSO) and methylene dichloride mixing solutions, under homogenizer 5000 rpms, high-speed stirring 1 minute, the polyvinyl alcohol solution then liquid being placed in 2% stirs volatilization 5 hours, the then centrifugation 30 minutes of 4000 rpms, abandon supernatant, distilled water is added in sample, repeated centrifugation 2 times again, abandon supernatant freeze-drying and be prepared into nanometer formulation.
Embodiment 4
Compound (one) (being purchased) of 1 mole and compound (two) (being purchased) of 2 moles are at 35 degree, PH is in the methanol solution of 7.2, stirring reaction obtains compound (three) after 24 hours, then insert acetone and methylene dichloride mixing solutions, vacuum-freeze-dry, (4) (being purchased) (1 mole) containing PLGA structure and compound (three) PH be 7 dimethyl sulfoxide (DMSO) and ethanolic soln in react 12 hours, concentrating under reduced pressure crystallization in ethanolic soln obtains compound (five), compound (five) 5.6g and compound (six) 0.2g (being purchased) reacts to obtain product (seven) in the mixing solutions of methylene dichloride and methyl alcohol, then Weigh Compound G200mg, put into test tube to heat, after there is molten state, taking-up is placed in 28G syringe needle, be placed in 97 degree of oil baths 1 hour, then take out fast and put into baking oven, modulate 83 degree, take out after spending the night, it is taken out from syringe needle, intercept suitable length 0.2cm, implant preparation for subsequent use.
Following formula is shown in embodiment 3-4 reaction:
Compound (one)
Compound (two)
Compound (three)
Compound (four)
Compound (five)
Compound (six)
Compound (seven)
The sample prepared by embodiment 1-4 is compared with the polymkeric substance of other various structures or the effect experimental of medicine.Be specially:
First group is embodiment 1 sample sets;
Second group is embodiment 2 sample sets;
3rd group is embodiment 3 sample sets;
4th group is embodiment 4 sample sets;
5th group is polymer P LGA-PEG group;
6th group is polymer P LGA group;
7th group is polyoxyethylene glycol group;
8th group is Dx ordinary preparation group;
9th group is pirarubicin ordinary preparation group;
Carry out drug action test respectively.
Wherein the 5th group, the 6th group PLGA-PEG and PLGA used all buys in poly sci tech (molecular weight is same as embodiment).7th group, the 8th group, the 9th group of medicine used and polyoxyethylene glycol (molecular weight is same as embodiment) are all bought in sigma aldrich.
Investigate medicine to angle, room narrow or close therapeutic action:
Laboratory animal and grouping: animal rearing controls at 22 degrees Celsius in envrionment temperature, humidity is in the Animal House of 55%, male Wistar rat, body weight 200g-250g.Before modeling, by animal random packet: namely control group and model group (for judging modeling whether success), first group to the 9th group be intraocular injection group, positive drug group pilocarpine eye drop group.All medicines all after modeling all in day administration of the 1st weekly, wherein positive control drug Per-Hop behavior 2 times, all animals all continue medication 4 weeks, each group of intraocular injection is intraocular injection administration (dosage is 10ug/200g mouse body weight), wherein pilocarpine eye drop group is according to eye drop administration mode, be specially to specifications to people measure conversion to the dosage of mouse, every day eye drip three times.
The foundation of animal model: all mouse all set right eye as experimental eye, left eye is contrast eye.First mouse is anaesthetized, then with compound tropicamide eye drops, mydriasis is carried out to rat, then put 1% content in tetracaine hydrochloride eye drops 1 time in conjunctiva of right eye capsule, then carry out a surface anesthesia, under optical operation microscope with disposable syringe syringe needle carry out corneoscleral junction puncture of anterior chamber and suction before aqueous humor, make obliteratio camerae anterior.Adopt multiwavelength laser machine to carry out light to angle, room to coagulate, optical maser wavelength 532 nanometer, spot diameter 50 microns, power 0.40W, carry out 3 episclera vein blood vessel light simultaneously and coagulate.Postoperative by utilizing slit lamp and anterior ocular segment OCT optical coherence tomography to observe postoperative conjunctiva, cornea and angle, anterior chamber room, thus judge whether to cause the model that angle, room is narrow or close, take photo angulometer to measure, record various medication for the change at angle, room and analyze.
Morphological observation before and after the treatment of angle, testing index room: often will organize each five of mouse in after administration the 28th day, and by anterior ocular segment OCT optical coherence tomography, carry out vertical scan direction and scanning of making film, then uses angulometer to exist
figuresheet is measured angle, room, records simultaneously and analyze.Simultaneously with ultrasonic investigation cardiac toxic.
Experimental result: medicine to the treatment of angle, room disease,
following tablefor treating angle, the room angle of latter each group.Compare with control group, the room angle number of model group is obviously on the low side, display modeling success; Compare with model group, medicine is respectively organized treatment situation and is referred to
table 1.
table 1different dosing group is on the impact of angle, room angle
* P<0.05 is compared with model group.
Claims (9)
1. a new high dimeric molecule, its structure is as follows::
Wherein B1 is anthracycline antibiotics, and B2 is one section of hydrophilic polymer segment, and B3 is the connection compound of a branch-like, and B4 is one section of hydrophobic polymer fragment, and x is the integer between 2 to 30, and y is the integer between 1-30, between B1B2B3B4 structure, chemical reaction occurs.
2. the high dimeric molecule of claim 1, the wherein preferred aclarubicin of B1, Dx, pirarubicin, idarubicin, pidorubicin, daunorubicin or carminomycin; Wherein B2 preferably polyethylene alcohol, polyoxyethylene glycol, polypyrrole alkane ketone, polyethers, polyoxyethylene block copolymer, or their multipolymer; Wherein B3 preferably containing primary amine groups and there is the branch-like compound of other active groups; Wherein B4 preferred polyester, condensing model or their multipolymer.
3. claim 1-2, the wherein preferred polyoxyethylene glycol of B2; Wherein B3 is preferred:
; The wherein preferred polylactic-co-glycolic acid of B4, poly-sebacic acid.
4. the high dimeric molecule of claim 1-3, preferred structure is as follows:
(anthracycline antibiotics-polyoxyethylene glycol) x-B3-(polylactic-co-glycolic acid) y
The wherein preferred 1-20 of x preferred 2-20, y.
5. the purposes of the high dimeric molecule of claim 1, purposes be treatment angle, room narrow in and the purposes of relative disease.
6. the purposes of the high dimeric molecule of claim 1, purposes is during treatment angle, room is closed and the purposes of relative disease.
7. the compound of claim 1 can be prepared into and be suitable for muscle, vein or the nanometer formulation of topical, microball preparation or implant preparation; Described local is topical cutaneous administration, local tumor site-specific delivery of drugs, head administration, ear nasal administration, eye drops.
8., as the preparation method of the high dimeric molecule of claim 1-4, it is characterized in that:
1) 0-48 hour is reacted by the solvent orange 2 A of one mole of connector B3 PH6.5-8 in 0-30 degree of the hydrophilic polymer B2 of the x containing double-active group mole and activation, the active group of one of them active group of hydrophilic compounds and the non-primary amine groups of connector B3 obtain containing primary amine groups-(B2) x-B3, then add solvent B vacuum-drying;
2) by (B2) x-B3 compound containing primary amine groups of obtaining in the upper step of 1 mole with y mole containing carboxyl or containing hydrophobic polymer B4 0-90 degree concentrating under reduced pressure in the solvent C of PH6.5-8 of ethanoyl, adding after 0-48 hour that solvent C suction filtration is dry must compound-(B2) x-B3-(B4) y;
3) anthracycline antibiotics 0-35 degree in solvent C of general-(B2) x-B3-(B4) y compound and X mole reacts 0-48 hour, volatile dry both (B1-B2) x-B3-(B4) y.
9. the method for claim 8, solvent orange 2 A in wherein said chemical step 1-3 is selected from benzene, toluene, methyl ether, ether, pyridine, trifluoroacetic acid, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, dimethyl sulfoxide (DMSO), N, one or more in dinethylformamide, solvent B is selected from acetic acid, formic acid, methyl ether, ether, benzene, toluene, pyridine, trifluoroacetic acid, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, dimethyl sulfoxide (DMSO), N, one or more in dinethylformamide, solvent C is selected from acetonitrile, acetic acid, formic acid, methyl ether, ether, benzene, toluene, pyridine, trifluoroacetic acid, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, dimethyl sulfoxide (DMSO), N, one or more in dinethylformamide.
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| CN103169718A (en) * | 2011-12-21 | 2013-06-26 | 张雅珍 | Application of anthracene nucleus antibiotic and its pharmaceutical salt for treating neovascular glaucoma |
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| CN103169718A (en) * | 2011-12-21 | 2013-06-26 | 张雅珍 | Application of anthracene nucleus antibiotic and its pharmaceutical salt for treating neovascular glaucoma |
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| CLAUDIA RYPPA等: "In Vitro and in ViWo Evaluation of Doxorubicin Conjugates with the Divalent Peptide E-[c(RGDfK)2] that Targets Integrin αvβ3", 《BIOCONJUGATE CHEM》 * |
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Application publication date: 20150902 |