CN103804418A - Preparation and application of degradable drug carrier material - Google Patents
Preparation and application of degradable drug carrier material Download PDFInfo
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- CN103804418A CN103804418A CN201410092697.XA CN201410092697A CN103804418A CN 103804418 A CN103804418 A CN 103804418A CN 201410092697 A CN201410092697 A CN 201410092697A CN 103804418 A CN103804418 A CN 103804418A
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- carrier material
- drug carrier
- amino acid
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Abstract
The invention discloses degradable drug carrier materials as shown in a formula (I) shown in the specification, wherein R1 and R2 can be the same or different, and selected from hydrogen, C1-C6 alkyls, benzyl, substituted benzyl and the like, respectively; R3 and R4 can be the same or different, and selected from hydrogen, C1-C6 alkyls, phenyl, substituted phenyl, aromatic heterocyclic group and the like, respectively. The invention also relates to a preparation method and application of the drug carrier materials shown in the formula (I). The carrier materials can be taken as medical drug carriers which can be used independently or used together with pharmaceutically acceptable, inert and non-toxic other excipients.
Description
Technical field
The invention belongs to field of medical materials, relate to the preparation of the drug carrier material that a class degradable and degraded product are nontoxic.This carrier is take hexachlorocyclotriphosphazene as raw material, amino acid or amino acid ester are introduced to hexachlorocyclotriphosphazene skeleton by chemical reaction, synthesized and can be used as medical drug carrier material, this solid support material can be used alone or other vehicle acceptable, inertia, nontoxic with pharmacy together with coupling.
Background technology
Its bioavailability is lower or toxicity is larger because the feature (as water-soluble extreme difference or water-soluble extremely strong) of himself causes for most of drug molecule.In order to improve its bioavailability, to reduce toxicity, people are constantly finding and are improving drug utilization degree and fall hypotoxic new way.Wherein liposome and sustained release dosage are to improve drug utilization degree and fall hypotoxic common method.Therefore design prepare there is bio-compatibility, nontoxic drug carrier material has important clinical value.
Group of polyphosphazenes compound is because its degradability and good biocompatibility obtain a wide range of applications (Luten J. at biomedical sector, Van Steenis J.H., Van Someren R., et al.Water-soluble biodegradable cationicpolyphosphazenes for gene delivery.Journal of controlled release.2003,89 (3): 483-497).In addition; group of polyphosphazenes compound in vivo meta-bolites is nontoxic, metabolizable phosphoric acid and amine salt (Harry R.A.; Shawn R.P.Poly[(amino acid ester) phosphazenes]: Synthesis; Crystallinity; and hydrolytic sensitivity in solution and the solid state.Macromoleculars; 1994,27 (5): 1071-1075); Chen Xuesis etc. have been prepared degradable based on oligomerization ethyleneimine and hexachlorocyclotriphosphazene cross-linking compounds, it can be used as the non-viral gene vector (Chen Xuesi etc. of high-efficiency low-toxicity, degradable based on oligomerization ethyleneimine and hexachlorocyclotriphosphazene cross-linking compounds, method for making and application, Chinese patent, CN101735454A). therefore preparation becomes focus containing the new medical material of phosphonitrile skeleton.
Amino acid is the endogenous substance of life entity, has been regarded as the potential source of true tumor material based on amino acid whose polymkeric substance.Bourke S.L. etc. has reported the polyamino acid of sending the good biocompatibility of having of low-molecular weight compound, confirm the polyglutamic acid of comparatively small amt and multipolymer candidate material (the Bourke S.L. as drug delivery, Kohn J.Polymers derived from the amino acid L-tryosine:polycarbonates, polyarylates and copolymers with poly (ethylene glycol) .Adv.Drug Del.Rev., 2003,55,447-466).
Given this, the present invention introduces the endogenous substance of life entity (amino acid, amino acid ester) to have in ring three phosphonitriles of degradability, has prepared the ring three phosphonitrile drug molecule solid support materials of a class containing amino acid fragment.
Summary of the invention
The object of the invention is to: the Preparation method and use of a class containing phosphonitrile and amino acid whose drug carrier material is provided.The amino acid whose ring three phosphonitrile compounds that contain as shown in general formula (I) are synthesized.
Wherein: R
1, R
2, R
3and R
4the group of representative is as described in the following:
R
1, R
2can be identical, also can be different; Be selected from respectively hydrogen, C
1～C
6alkyl, benzyl, substituted benzyl etc.; R
3and R
4can be identical, also can be different, be selected from respectively hydrogen, C
1～C
6alkyl, phenyl, substituted-phenyl or aromatic heterocyclic etc.
Such can be separately containing cyclotrinitrile phosphide of amino acid fragment or in conjunction with one or more pharmaceutically acceptable, inertia, nontoxic vehicle as drug carrier material.
According to the present invention, shown in described formula (I) containing amino acid whose ring three phosphonitrile compounds preferably from following any compound:
| Code name | R 1 | R 2 | R 3 | R 4 |
| P-1 | H | H | H | H |
| P-2 | H | H | CH 3 | CH 3 |
| P-3 | H | H | CH 2CH 3 | CH 2CH 3 |
| P-4 | CH 3 | CH 3 | H | H |
| P-5 | CH 3 | CH 3 | CH 3 | CH 3 |
| P-6 | CH 3 | CH 3 | CH 2CH 3 | CH 2CH 3 |
| P-7 | (CH 3) 2CH | (CH 3) 2CH | CH 3 | CH 3 |
| P-8 | (CH 3) 2CHCH 2 | (CH 3) 2CHCH 2 | CH 3 | CH 3 |
| P-9 | PhCH 2 | PhCH 2 | CH 3 | CH 3 |
Shown in formula of the present invention (I) containing the ring three phosphonitrile compounds of amino acid fragment, be take hexachlorocyclotriphosphazene and amino acid or amino acid ester as raw material, adopt conventional reaction to prepare under low temperature or reflux conditions.
If need, any functional group in formula (I) can be protected.
According to the present invention, described temperature of reaction is-20
oc is to refluxing.
According to the present invention, described organic solvent is benzene,toluene,xylene, hexanaphthene, tetrahydrofuran (THF), chloroform, methylene dichloride, DMF or ionic liquid.More preferably tetrahydrofuran (THF).
According to the present invention, described alkaline acid binding agent is mineral alkali or organic bases.Described organic bases is preferably triethylamine, tripropyl amine, DMAP etc.; Described mineral alkali is preferably salt of wormwood, sodium hydride, sodium carbonate etc.
Of the present invention as shown in general formula containing the ring three phosphonitrile compounds of amino acid fragment, can be separately or in conjunction with one or more pharmaceutically acceptable, inertia, nontoxic vehicle as drug carrier material.After this solid support material carrying medicament, can make different pharmaceutical dosage form (as solid oral agent, oral liquid or liquid infusion agent etc.).
Concrete embodiment
Below in conjunction with embodiment, patent of the present invention is further described.It should be noted that: following embodiment can not be served as the protection domain restriction to patent of the present invention, and any improvement of making on basis of the present invention is all without prejudice to spirit of the present invention.
Wherein the building-up process of target compound is all with the representative explanation in embodiment, the same representation compound of building-up process of remaining compound.
Instrument and reagent:
AVANCE III type nuclear magnetic resonance analyser (CDCl
3, TMS is interior mark), ion trap mass spectrometer (DECAX-30000LCQ Deca XP).
Hexachlorocyclotriphosphazene, amino acid, amino acid ester hydrochloride, tetrahydrofuran (THF), toluene, normal hexanes etc. are commercially available analytical reagent, and tetrahydrofuran (THF) passes through sodium Metal 99.5 and benzophenone reflow treatment before use, toluene passes through sodium Metal 99.5 reflow treatment before use, process hydrolith reflow treatment before triethylamine uses.
The reaction of embodiment 1. hexachlorocyclotriphosphazenes and glycine methyl ester
Method one: by toluene dry 250mL, the glycine methyl ester hydrochloride of 27g (0.2mol) and 22g (0.2mol) triethylamine join in the single necked round bottom flask of 500mL successively, more than reflux 6h, system is cooled to room temperature, filters to get filtrate.Dry to the tripolyphosphazene of 10g (0.03mol) and 100mL tetrahydrofuran (THF) is joined in the single necked round bottom flask of 500mL, under-5 ℃ of stirrings, above-mentioned filtrate is slowly added dropwise to wherein,-5 ℃ of reactions rise to room temperature reaction 10h after 5 hours naturally, then 40 ℃ of reaction 40h, system is filtered after being down to room temperature, filtrate vacuum concentration, residue washs repeatedly with normal hexane, after dry, obtain milky elastomerics (P-2), 14g, productive rate: 70%.
Method two: the glycine methyl ester hydrochloride of 27g (0.2mol) and 10g (0.03mol) tripolyphosphazene, tetrahydrofuran (THF) that 250mL is dry are joined at the bottom of the single port garden of 500mL in flask, zero degree is slowly added dropwise to the tetrahydrofuran solution dry 100mL that is dissolved with the triethylamine that 22g (0.2mol) is dry wherein under stirring, at this temperature, react 10h, change 36 ℃ of reaction 48h into, system is filtered after being down to room temperature, filtrate vacuum concentration, residue washs repeatedly with normal hexane, after being dried, obtains milky elastomerics.
The reaction of embodiment 2. hexachlorocyclotriphosphazenes and glycine ethyl ester
Method one: by toluene dry 250mL, the glycine ethyl ester hydrochloride of 30g (0.2mol) and 22g (0.2mol) triethylamine join in the single necked round bottom flask of 500mL successively, more than reflux 6h, system is cooled to room temperature, filters to get filtrate.Dry to the tripolyphosphazene of 10g (0.03mol) and 100mL tetrahydrofuran (THF) is joined in the single necked round bottom flask of 500mL, under-5 ℃ of stirrings, above-mentioned filtrate is slowly added dropwise to wherein,-5 ℃ of reactions rise to room temperature reaction 10h after 5 hours naturally, then 36 ℃ of reaction 40h, system is filtered after being down to room temperature, filtrate vacuum concentration, and residue washs repeatedly with normal hexane, after lyophilize, obtain white solid (P-3) 17g, productive rate: 76%.
Method two: the glycine methyl ester hydrochloride of 30g (0.2mol) and 10g (0.03mol) tripolyphosphazene, tetrahydrofuran (THF) that 250mL is dry are joined at the bottom of the single port garden of 500mL in flask, zero degree is slowly added dropwise to the tetrahydrofuran solution dry 100mL that is dissolved with the triethylamine that 22g (0.2mol) is dry wherein under stirring, at this temperature, react 10h, change 36 ℃ of reaction 48h into, system is filtered after being down to room temperature, filtrate vacuum concentration, residue washs repeatedly with normal hexane, obtains white solid after lyophilize.
Other compound is synthetic according to the reaction process of hexachlorocyclotriphosphazene and glycine methyl ester (ethyl ester).Its structure is passed through
1h NMR and ESI-MS characterize.Optimize to obtain compound
1h NMR describes with the form of list.
Table 1-optimize compound structure, numbering and
1h NMR data
Claims (5)
1. the degradable drug carrier material shown in a class formula I,
Wherein: R
1, R
2, R
3and R
4the group of representative is as described in the following:
R
1, R
2can be identical, also can be different; Be selected from respectively hydrogen, C
1～C
6alkyl, benzyl, substituted benzyl etc.; R
3and R
4can be identical, also can be different, be selected from respectively hydrogen, C
1～C
6alkyl, phenyl, substituted-phenyl or aromatic heterocyclic etc.
2. such drug carrier material according to claim 1 is selected from following arbitrary compound:
3. such drug carrier material according to claim 1, is characterized in that such drug carrier material is take hexachlorocyclotriphosphazene, amino acid or amino acid ester as raw material, in dry organic solvent, by low temperature or back flow reaction preparation.
4. in drug carrier material according to claim 1, any one compound can be separately as pharmaceutical carrier or with other pharmaceutically acceptable, inertia, nontoxic vehicle together coupling as pharmaceutical carrier.
5. drug carrier material according to claim 1, drug molecule can be made the different formulation such as oral preparation or injection liquid after being loaded on carrier.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1150391A (en) * | 1994-04-20 | 1997-05-21 | 耐克麦德瑟鲁塔公司 | Dendrimeric compounds |
| CN101735454A (en) * | 2009-11-12 | 2010-06-16 | 中国科学院长春应用化学研究所 | Degradable crosslinking compound based on oligopolyethyleneimine and hexachlorocyclotriphosphazene, preparation method and application thereof |
| US20100249226A1 (en) * | 2007-04-18 | 2010-09-30 | Nanohybrid Co., Ltd | Tumor selective and biodegradable cyclotriphosphazene-platinum(ii) conjugate anticancer agent, and preparation method thereof |
| CN102408445A (en) * | 2011-06-15 | 2012-04-11 | 东北林业大学 | Hexaminoacid ester phenoxyl cyclotriphosphazene, its fluorescent nano-microsphere and preparation method thereof |
-
2014
- 2014-03-13 CN CN201410092697.XA patent/CN103804418A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1150391A (en) * | 1994-04-20 | 1997-05-21 | 耐克麦德瑟鲁塔公司 | Dendrimeric compounds |
| US20100249226A1 (en) * | 2007-04-18 | 2010-09-30 | Nanohybrid Co., Ltd | Tumor selective and biodegradable cyclotriphosphazene-platinum(ii) conjugate anticancer agent, and preparation method thereof |
| CN101735454A (en) * | 2009-11-12 | 2010-06-16 | 中国科学院长春应用化学研究所 | Degradable crosslinking compound based on oligopolyethyleneimine and hexachlorocyclotriphosphazene, preparation method and application thereof |
| CN102408445A (en) * | 2011-06-15 | 2012-04-11 | 东北林业大学 | Hexaminoacid ester phenoxyl cyclotriphosphazene, its fluorescent nano-microsphere and preparation method thereof |
Non-Patent Citations (7)
| Title |
|---|
| ARLIN L. WEIKEL等: "Synthesis and Characterization of Methionine- and Cysteine-Substituted Phosphazenes", 《MACROMOLECULES》 * |
| H. R. ALLCOCK等: "Hydrolysis Pathways for Aminophosphazenes", 《INORG. CHEM.》 * |
| HARRY R. ALLCOCK等: "Poly[ (amino acid ester)phosphazenes]: Synthesis, Crystallinity, and Hydrolytic Sensitivity in Solution and the Solid State", 《MACROMOLECULES》 * |
| JESSICA L. NICHOL等: "Biodegradable alanine and phenylalanine alkyl ester polyphosphazenes as potential ligament and tendon tissue scaffolds", 《POLYM. CHEM.》 * |
| S. LAKSHMI等: "Biodegradable polyphosphazenes for drug delivery applications", 《ADVANCED DRUG DELIVERY REVIEWS》 * |
| UDAYA S. TOTI等: "Thermosensitive and biocompatible cyclotriphosphazene micelles", 《JOURNAL OF CONTROLLED RELEASE》 * |
| 关丽娟等: "一种新型端氨基环磷腈衍生物的合成", 《北京化工大学学报》 * |
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Application publication date: 20140521 |
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