CN101935336B - Method for preparing water-soluble taxane medicament and application thereof - Google Patents
Method for preparing water-soluble taxane medicament and application thereof Download PDFInfo
- Publication number
- CN101935336B CN101935336B CN201010268939.8A CN201010268939A CN101935336B CN 101935336 B CN101935336 B CN 101935336B CN 201010268939 A CN201010268939 A CN 201010268939A CN 101935336 B CN101935336 B CN 101935336B
- Authority
- CN
- China
- Prior art keywords
- compound
- injection
- preparation
- agent
- pabc
- 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.)
- Expired - Fee Related
Links
- 0 CC(OCc1ccc(*=C)cc1)=O Chemical compound CC(OCc1ccc(*=C)cc1)=O 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a method for preparing a water-soluble taxane medicament and application thereof. In the water-soluble taxane compounds with a formula I structure, R1 is phenyl or alkoxide, R2 is acetyl or hydrogen atoms, and R3 is directly directed or 4-amino benzyloxy formyl.
Description
Technical field:
The present invention relates to a kind of water soluble drug preparation method and application, particularly a kind of water-soluble taxane class medicine, their preparation method and the application in clinical cancer therapy thereof.
Background technology:
Taxone generally comprises taxol and derivative thereof, Docetaxel and derivative thereof.Taxol is white or off-white powder, and its molecular formula is C
47h
51nO
14, molecular weight is 853.9, fat-soluble strong, is soluble in the organic solvents such as chloroform, ethanol; Docetaxel is white or off-white powder, and its molecular formula is C
43h
55nO
13, fat-soluble stronger, be soluble in chloroform, ethanol, acetone and other organic solvent; The solubleness of taxone is very low, and wherein the solubleness of taxol is less than 0.004g/L, and the solubleness of Docetaxel is less than 0.01g/L.
Taxol (Taxol
) and Docetaxel (Taxotere
) at 1992 and 1996, through united states drug food control office, be approved as PTS respectively, be used for the treatment of ovarian cancer, mammary cancer, skin carcinoma, lung cancer and incidence cancer, its clinical use formulation all adopts intravenous injection.The mechanism of action of taxol and Docetaxel is similar, is to be mainly combined with free microtubule time body, and constantly promotes microtubule polymerization, and then disturb the carrying out of mitotic division and cellular replication; In some tissue culture, can find, Docetaxel has stronger mitotic division restraining effect than taxol.
The water-soluble non-constant of taxol and Docetaxel, this has brought very large problem to exploitation injection.In order to improve the solubleness of taxol in the aqueous solution, in the taxol composition that some intravenous drips are used, applied Cremophor EL (condensation product of polyethoxye Viscotrol C and oxyethane).Cremophor EL has been proved to be larger toxic side effect, after giving dog intravenously administrable, can produce vasorelaxation, expiratory dyspnea, lethargic sleep, ypotension and death, and this solvent has the high sensitization of blood vessel, make paclitaxel injection application clinically be subject to a lot of restrictions.Equally, Docetaxel (Taxotere
) containing Tween-80 (Tween-80) as solubilizing agent in injection liquid, intravenous injection also may produce the reactions such as haemolysis.So people want to provide better clinical application mode by new technology always.Obviously, develop more good water solubility and safety and effective novel taxane class injection, be very important.
By preparing water-soluble prodrug, can solve preferably the water-soluble problem of taxone.More existing researchs and report in this field.Comprise: 2 ' end salify (sulfonation, acidylate, salt, thiosulphate), 2 ' or 7 ' end connects polyamino acid, and connecting arm connects water miscible polymer (PEG is as carrier, amino acid or oligopeptides, oxysuccinic acid or citric acid are as connecting arm).Have patent (China Patent Publication No. CN1895676) report to synthesize and take polyoxyethylene glycol as carrier, oxyacetic acid or lactic acid, as the taxanes water-soluble prodrug of connecting arm, are compared with taxol, and water-soluble and tumour inhibiting rate obviously strengthens.Separately have report (China Patent Publication No. CN101724021A) on taxol 2 ' or 7 ' hydroxyl, to connect polypeptide (Sostatin or its analogue), can increase the water-soluble of medicine, mixture has good targeting simultaneously.
But then, how allowing prodrug in time be degraded in vivo prototype medicine is another important problem.At present noticeable about the Research Thinking of tumor environment target administration, generally comprise the responsive two kinds of strategies of pH sensitivity and enzyme.The latter utilizes distinctive enzyme system in tumor tissues, select the substrate of some these fermentoids as coupler, and be attached between water-soluble macromolecule and cancer therapy drug, because contact agent is selective to tumor tissues, can in tumor tissues, by the distinctive enzyme of tumor tissues, be degraded, and discharge the prototype molecule of cancer therapy drug, thereby bring into play specific antitumous effect.The thinking of this target administration can improve curative effect, and reduces the toxicity of medicine.There is patent (China Patent Publication No. CN1629150) report to synthesize a kind of prodrugs of paclitaxel of polyethylene glycol fatty adoption ester block copolymer, its polymer carrier has biodegradability, after entering in body, under the effect of lipase, medicine is easy to dissociate from combining site.
(the C of cathepsin B
b) be a kind of lysosome L-Cysteine HCL Anhydrous, its molecular weight is 30KDa.In kinds of tumors, due to C
bcan catalysis various kinds of cell epimatrix element degraded, the generation of itself and tumour and shift closely related.C
balso directly activate the cell matrix degraded of lysosome mediation.Only under as the pathologic condition of tumour, rheumatic arthritis one class, C
bjust be present in extracellular.C
bin can specific recognition polypeptide-and HN-Val-Cit-CONH fragment (red part) cut off the amido linkage of Cit carboxyl terminal, can further there is electronic migration in the intermediate PABC-X-Drug of generation, 1,6-occurs and eliminate, thereby discharge medicine.
The present invention proves by a large amount of research work, connects VC or VC-PABC in the middle of PTX and PEG, and the water-soluble of compound increases substantially, and can prepare at an easy rate the water-soluble injection of taxanes; And by research, unexpected discovery, the toxicity of this type of conjugate obviously reduces, and anti-tumor in vivo effect and PTX do not have significant difference, while this means clinical application, can improve dosage, increase curative effect.
Summary of the invention:
The present invention relates to a kind of water soluble drug preparation method and application, particularly a kind of water-soluble taxane class medicine, their preparation method and the application in clinical cancer therapy thereof.
The invention provides a kind of water-soluble taxane compounds with formula I structure,
R wherein
1for phenyl or tert.-butoxy, R
2for ethanoyl or hydrogen atom, R
3for directly connecting or the amino carbobenzoxy of 4-.
Compound of the present invention, is PTX at main active group, and during DTX, can be expressed as:
PEG-VC-PTX：R
1＝Ph，R
2＝Ac，R
3＝none
PEG-VC-DTX：R
1＝Me
3CO，R
2＝H，R
3＝none
PEG-VC-PABC-PTX：R
1＝Ph，R
2＝Ac，R
3＝PABC
PEG-VC-PABC-DTX：R
1＝Me
3CO，R
2＝H，R
3＝PABC
Wherein
Bearing taxanes of the present invention, the compound of preferred following structure
PEG-VC-PTX：
PEG-VC-PABC-PTX：
PEG-VC-DTX：
PEG-VC-PABC-DTX：
The present invention also comprises, the pharmaceutical composition that contains bearing taxanes of the present invention is provided.
Pharmaceutical composition of the present invention, can be any pharmaceutically useful formulation, optimizing injection.
Pharmaceutical composition of the present invention, can add conventional pharmaceutical excipient, as freeze-drying caffolding agent, stablizer, pH adjusting agent, osmotic pressure regulator, wherein freeze-drying caffolding agent is selected from the one or any mixture of N.F,USP MANNITOL, trehalose, sucrose, lactose, glucose, maltose, sorbyl alcohol, sodium-chlor.As injection, after available water for injection, injection physiological saline or glucose for injection solution dilution or redissolution, carry out venoclysis or intravenous injection.
The present invention also comprises the application of bearing taxanes of the present invention in preparing antitumor drug.
The present invention also comprises the preparation method of bearing taxanes of the present invention, it is characterized in that, comprises the following steps:
R wherein
1for phenyl or tert.-butoxy, R
2for ethanoyl or hydrogen atom, R
3for directly connecting or the amino carbobenzoxy of 4-.
Wherein react at DMF or CHCl
3in solvent, carry out, with Et
3for urging deprotection agent and acid binding agent, at DCC, there is condensation reaction under the effect of EDCHCl condensing agent in N, DIEA or DBU, generates target product.
Its Chinese style III compound is prepared by following steps,
A. compound VII and VIII generate compound VI under the effect of condensing agent
B. compound is under the effect of condensing agent and to aminobenzyl alcohol reacting generating compound V
C. compound generates compounds Ⅳ with p-nitrophenyl chloroformate ester generation transesterify under the effect of organic bases
D. compounds Ⅳ and taxol or Docetaxel are at DMAP, and pyridine, generates compound III-a under the organic base catalytic effects such as triethylamine
E. compound VI and taxol or Docetaxel reacting generating compound III-b under the effect of condensing agent
The most preferred preparation method of the present invention in an embodiment.
The invention has the advantages that: 1) the present invention by introducing water-soluble macromolecule polyoxyethylene glycol (PEG) in chemical structure, solved well the low problem of solubleness of taxone, because medicine has water-soluble, can directly be prepared into injection liquid or injectable sterile powder, prescription can not contain a large amount of tensio-active agents (being different from Cremophor EL and Tween-80 in existing preparation), therefore do not produce relevant toxic side effect, particularly anaphylaxis and hemolytic action etc.; Do not need containing organic solvent (being different from the ethanol in existing preparation), avoided toxic side effect that organic solvent brings and pungency etc. yet; 2) the present invention has adopted the thinking of tumor environment target administration, at chemistry between PEG and taxone molecule, connect coupler α-amino-isovaleric acid-guanidine propylhomoserin dipeptides (Val-Cit), and contact agent VC is selective to tumor tissues, can be by the distinctive enzyme (C of cathepsin B of tumor tissues in tumor tissues
b) institute degrades, and discharge the prototype molecule of taxone, thereby bring into play specific antitumous effect.The thinking of this target administration can improve curative effect, and reduces the toxicity of this type of medicine.
Accompanying drawing explanation:
The structure iron of Fig. 1 PEG-VC-PTX
The structure iron of Fig. 2 PEG-VC-PABC-PTX
The structure iron of Fig. 3 PEG-VC-DTX
The structure iron of Fig. 4 PEG-VC-PABC-DTX
The antitumor drug effect experimental result 1 of compound of the present invention after Fig. 5 drug administration by injection
The antitumor drug effect experimental result 2 of compound of the present invention after Fig. 6 drug administration by injection
The body weight change result 1 of nude mice after Fig. 7 drug administration by injection
The antitumor drug effect experimental result 4 of compound of the present invention after Fig. 8 drug administration by injection
The antitumor drug effect experimental result 5 of compound of the present invention after Fig. 9 drug administration by injection
The body weight change result 2 of nude mice after Figure 10 drug administration by injection
Embodiment:
Further illustrate by the following examples the present invention, but not as restriction of the present invention.
The preparation of embodiment 1:PEG-VC-PTX
The preparation of PEG-succinic acid:
By PEG (20gl), Succinic anhydried (0.40g) and triethylamine (1mL) add CH
2cl
2(100mL), backflow 2h, adds 100mL distilled water, with CH
2cl
2extraction (50mL * 2), merges CH
2cl
2layer, anhydrous sodium sulfate drying, filters, concentrated, adds a large amount of ether to make to separate out solid, and suction filtration is dried, and obtaining product is white solid, 15.10g, productive rate 74.02%.
The preparation of Fmoc-Val-Cit:
Fmoc-Val (5.06g) and HOSu (1.72g) are dissolved in THF (100mL), add DCC (3.08g), reaction 1h, adds Cit (2.74g) and NaHCO
3(1.32g), reaction 4h..In reaction system, add aqueous citric acid solution (30%, 75mL), with ethyl acetate extraction (50mL * 2), merge organic phase, washing (50mL * 2), pressure reducing and steaming solvent adds ether (80mL) that product is separated out, suction filtration in gelatin material, ether is washed, dry to obtain white solid, 4.64g, productive rate 62.67%.
The preparation of Fmoc-Val-Cit-PTX:
By Fmoc-Val-Cit (99mg), EDCHCl (77mg), PTX (171mg), DIEA (66 μ L) and DMAP (2.4mgl) are added to CH
2cl
2(10mL) in, reaction 3h, with saturated common salt washing, anhydrous sodium sulfate drying, filtering and concentrating, dodges post (CHCl
3: CH
3oH=50: 1 → 35: 1) obtain white solid 224mg, productive rate 84.06%.
The preparation of PEG-VC-PTX:
By PEG-succinic acid (518mg), EDCHCl (36mg), Fmoc-Val-Cit-2 '-PTX (123mg, 0.092mmol), DIEA (28 μ L) is added to DMF (10mL), reaction 6h, pressure reducing and steaming DMF, dodges post (CHCl
3: CH
3oH=10: 1 → 5: 1) separation obtains white solid, 358.mg, productive rate 62.63%
The preparation of embodiment 2:PEG-VC-PABC-VC-PTX
The preparation of Fmoc-Val-Cit-PABOH:
By Fmoc-Val-Cit (1.04g), EEDQ (0.52g) and PABOH (0.26mg) are added to CH
2cl
2in, reaction 10h, decompression pressure reducing and steaming solvent, adds ether, stirs, suction filtration, ether is washed, and dries to obtain light violet magenta solid, 1.10g, productive rate 81.84%.
The preparation of Fmoc-Val-Cit-PABC-PNP:
Fmoc-Val-Cit-PABOH (0.30g) and PNPCOCl (0.10gl) are added in THF (15mL), stir the lower triethylamine (300uL) that drips, then under room temperature, reaction is spent the night.Dodge the separated (CHCl of post
3: CH
3oH=20: 1 → 10: 1) obtain pink spumescence solid, 0.20g, productive rate 52.31%.
The preparation of Fmoc-Val-Cit-PABC-PTX:
By Fmoc-Val-Cit-PABC-PNP (160mg), PTX (214mg) and DMAP (31mg, 0.25mmol) are added to CH successively
2cl
2(20mL), in, under room temperature, react 100h.Dodge post (CHCl
3: CH
3oH=30: 1 → 20: 1) separation obtains peach spumescence solid 182mg, productive rate 58.87%.
The preparation of PEG-VC-PABC-PTX:
By PEG-succinic acid (689mg), EDCHCl (47mg), Fmoc-Val-Cit-PABC-2 '-PTX (182mg), DIEA (80 μ L) is added to DMF (10mL), reaction 6h, pressure reducing and steaming DMF, dodges post (CHCl
3: CH
3oH=10: 1 → 5: 1) separation obtains white solid white solid, 231mg, productive rate 29.65%.
The preparation of embodiment 3:PEG-VC-DTX
The preparation of PEG-succinic acid:
By PEG (20gl), Succinic anhydried (0.40g) and triethylamine (1mL) add CH
2cl
2(100mL), backflow 2h, adds 100mL distilled water, with CH
2cl
2extraction (50mL * 2), merges CH
2cl
2layer, anhydrous sodium sulfate drying, filters, concentrated, adds a large amount of ether to make to separate out solid, and suction filtration is dried, and obtaining product is white solid, 15.10g, productive rate 74%.
The preparation of Fmoc-Val-Cit:
Fmoc-Val (5.06g) and HOSu (1.72g) are dissolved in THF (100mL), add DCC (3.08g), reaction 1h, adds Cit (2.74g) and NaHCO
3(1.32g), reaction 4h..In reaction system, add aqueous citric acid solution (30%, 75mL), with ethyl acetate extraction (50mL * 2), merge organic phase, washing (50mL * 2), pressure reducing and steaming solvent adds ether (80mL) that product is separated out, suction filtration in gelatin material, ether is washed, dry to obtain white solid, 4.64g, productive rate 63%.
The preparation of Fmoc-Val-Cit-DTX:
Fmoc-Val-Cit (99mg) successively, EDCHCl (77mg), DIEA (66 μ L), DMAP (2.4mgl), and DTX (167mg) is added to CH
2cl
2(10mL) in, reaction 6h, with saturated common salt washing, anhydrous sodium sulfate drying, filtering and concentrating, dodges post (CHCl
3: CH
3oH=50: 1 → 35: 1) obtain white solid 210mg, productive rate 79%.
The preparation of PEG-VC-DTX:
By PEG-succinic acid (518mg), EDCHCl (36mg), Fmoc-Val-Cit-2 '-DTX (123mg, 0.092mmol), DIEA (28 μ L) is added to DMF (10mL), reaction 6h, pressure reducing and steaming DMF, dodges post (CHCl
3: CH
3oH=10: 1 → 5: 1) separation obtains white solid, 337mg, productive rate 59%
The preparation of embodiment 4:PEG-VC-PABC-VC-DTX
The preparation of Fmoc-Val-Cit-PABOH:
By Fmoc-Val-Cit (1.04g), EEDQ (0.52g) and PABOH (0.26mg) are added to CH
2cl
2in, reaction 10h, decompression pressure reducing and steaming solvent, adds ether, stirs, suction filtration, ether is washed, and dries to obtain light violet magenta solid, 1.10g, productive rate 82%.
The preparation of Fmoc-Val-Cit-PABC-PNP:
Fmoc-Val-Cit-PABOH (0.30g) and PNPCOCl (0.10g) are added in THF (15mL), stir the lower triethylamine (300uL) that drips, then under room temperature, reaction is spent the night.Dodge the separated (CHCl of post
3: CH
3oH=20: 1 → 10: 1) obtain pink spumescence solid, 0.20g, productive rate 52%.
The preparation of Fmoc-Val-Cit-PABC-DTX:
By Fmoc-Val-Cit-PABC-PNP (160mg), DTX (210mg) and DMAP (31mg, 0.25mmol) are added to CH successively
2cl
2(20mL), in, under room temperature, react 100h.Dodge post (CHCl
3: CH
3oH=30: 1 → 20: 1) separation obtains peach spumescence solid 190mg, productive rate 62%.
The preparation of PEG-VC-PABC-DTX:
By PEG-succinic acid (689mg), EDCHCl (47mg), Fmoc-Val-Cit-PABC-2 '-DTX (176mg), DIEA (80 μ L) is added to DMF (10mL), reaction 6h, pressure reducing and steaming DMF, dodges post (CHCl
3: CH
3oH=10: 1 → 5: 1) separation obtains white solid, 263mg, productive rate 34%.
The preparation of embodiment 5 injections (take PEG-VC-PABC-PTX as example)
Get this product 0.22g, be dissolved in 50ml physiological saline or 5% glucose solution, regulate to wait and ooze.Solution after filtering with microporous membrane, sealing, both every bottle containing the colourless extremely micro-yellow transparent solution with taxol note 30mg.
Embodiment 6: the preparation of freeze-dried powder (take PEG-VC-PABC-PTX as example)
Get 0.22g this product, be dissolved in 10ml distilled water, add the lactose of 0.1g, solution filters through millipore filtration, puts pre-freeze in-70 ℃ of refrigerators and more than 4 hours, then puts freeze-drying in freeze drier, sealing, both every bottle containing the micro-yellow water soluble powder injection extremely of the white with taxol note 30mg.
Embodiment 7
Adopt two kinds of different cell line mcf-7s and Hela, by SRB method, carry out the cytotoxic mensuration of sample, calculate IC
50value, the results are shown in Table 1 (unit is nmol/L).Wherein PTX is by commercial preparation prescription preparaton (containing Cremophor EL and ethanol, lower same).Result is visible, and the cytotoxicity of three kinds of PTX prodrugs is less than contrast PTX group.
Table 1 cell in vitro poison test-results
Select MCF-7 cell, in the oxter, left side of female nude mice, inoculate, every mouse inoculation 10
6cell, inoculates administration after 9 days.Administration component is 5 groups, is respectively: 5% glucose, and PTX, PEG-PTX, PEG-VC-PTX, PEG-VC-PABC-PTX, dosage is 15mg PTX/Kg, 5 every group.Administration is 5 times altogether, and delivery time is 1 day.Survey every other day body weight and knurl volume.When the 6th administration, put to death, get tumor tissue, weigh, take pictures, claim to go knurl body weight.The results are shown in Figure 5, Fig. 6 and Fig. 7.Result is visible, and three kinds of PTX prodrugs toxicity in whole animal is less than contrast PTX group.In three kinds of PTX prodrugs, the antitumor action of PEG-VC-PABC-PTX is the strongest, there is no significant difference with PTX group.
Embodiment 9
Select MCF-7 cell, in the oxter, left side of female nude mice, inoculate, every mouse inoculation 10
6cell, inoculates administration after 9 days.Administration component is 5 groups, is respectively: 5% glucose, PTX (10mg/kg), PEG-VC-PABC-PTX (10mg/kg, 15mg/kg, 20mg/kg), 5 every group.Administration is 5 times altogether, and delivery time is 1 day.Survey every other day body weight and knurl volume size.When the 6th administration, put to death, get tumor tissue, weigh, take pictures, claim to go knurl body weight.The results are shown in Figure 8, Fig. 9 and Figure 10.Result is visible, when the dosage of PEG-VC-PABC-PTX, brings up to after 15mg/kg, and antitumor action is better than PTX group, and toxicity is lower than PTX group; When the dosage of PEG-VC-PABC-PTX, bring up to after 20mg/kg, toxicity and PTX organize in suitable situation, and antitumor action significantly strengthens.
Claims (10)
1. the water-soluble taxane compounds with formula I structure,
R wherein
1=Ph, R
2=Ac, R
3=PABC,
2. the pharmaceutical composition that contains bearing taxanes claimed in claim 1.
3. pharmaceutical composition according to claim 2, is characterized in that, is injection.
4. pharmaceutical composition according to claim 3, is characterized in that, can add conventional pharmaceutical excipient, and auxiliary material is selected from: freeze-drying caffolding agent, stablizer, pH adjusting agent, osmotic pressure regulator.
5. pharmaceutical composition according to claim 4, is characterized in that, freeze-drying caffolding agent is selected from: the one or any mixture of N.F,USP MANNITOL, trehalose, sucrose, lactose, glucose, maltose, sorbyl alcohol, sodium-chlor.
6. pharmaceutical composition according to claim 2, is characterized in that, is injection, with water for injection, injection physiological saline or glucose for injection solution dilution or after redissolving, carries out venoclysis or intravenous injection.
7. the application of bearing taxanes claimed in claim 1 in preparing antitumor drug.
8. the preparation method of bearing taxanes claimed in claim 1, is characterized in that, comprises the following steps:
R wherein
1=Ph, R
2=Ac, R
3=PABC,
9. preparation method claimed in claim 8, is characterized in that, wherein reacts at DMF or CHCl
3in solvent, carry out, with Et
3for urging deprotection agent and acid binding agent, at DCC, there is condensation reaction under the effect of EDCHCl condensing agent in N, DIEA or DBU, generates target product.
10. preparation method claimed in claim 8, is characterized in that, wherein formula III compound is prepared by following steps,
A. compound VI I and VIII generate compound VI under the effect of condensing agent
B. compound is under the effect of condensing agent and to aminobenzyl alcohol reacting generating compound V
C. compound generates compound IV with p-nitrophenyl chloroformate ester generation transesterify under the effect of organic bases
D. compound IV and taxol or Docetaxel are at DMAP, and pyridine, generates compound III under the katalysis of triethylamine
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010268939.8A CN101935336B (en) | 2010-09-01 | 2010-09-01 | Method for preparing water-soluble taxane medicament and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010268939.8A CN101935336B (en) | 2010-09-01 | 2010-09-01 | Method for preparing water-soluble taxane medicament and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101935336A CN101935336A (en) | 2011-01-05 |
| CN101935336B true CN101935336B (en) | 2014-04-09 |
Family
ID=43388929
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010268939.8A Expired - Fee Related CN101935336B (en) | 2010-09-01 | 2010-09-01 | Method for preparing water-soluble taxane medicament and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101935336B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104650179A (en) * | 2015-02-06 | 2015-05-27 | 东南大学 | Novel platinum prodrug capable of being cracked by lysosomal enzyme |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104055787B (en) * | 2013-07-25 | 2017-04-26 | 北京蓝贝望生物医药科技股份有限公司 | Medicinal water-soluble antifungal macromolecular compound |
| CN104177474B (en) * | 2014-08-22 | 2017-09-15 | 亚飞（上海）生物医药科技有限公司 | A kind of Docetaxel derivative of tumor microenvironment targeted activation and application thereof |
| CN104262455B (en) * | 2014-08-22 | 2017-05-03 | 亚飞（上海）生物医药科技有限公司 | Tumor microenvironment targeted activation docetaxel derivatives, preparation thereof and uses of the derivatives |
| JP6854759B2 (en) | 2014-08-22 | 2021-04-07 | ヤフェイ シャンハイ バイオログ メディスン サイエンス アンド テクノロジー カンパニー リミテッド | Small molecule target conjugates specifically activated by the tumor microenvironment and their use |
| WO2017028766A1 (en) * | 2015-08-14 | 2017-02-23 | 江苏恩华络康药物研发有限公司 | Method for preparing water-soluble taxane derivative and intermediate |
| CN105622924B (en) * | 2016-02-03 | 2017-11-24 | 华东师范大学 | A kind of block polymer of cathepsin B's cleavable and its preparation method and application |
| CN107365284A (en) * | 2017-08-16 | 2017-11-21 | 桂林茗兴生物科技有限公司 | A kind of method that taxol is extracted from Chinese yew |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1259875A (en) * | 1997-06-11 | 2000-07-12 | 伦敦大学药学院 | Pharmaceutical compositions contg. anti-body-enzyme conjugates in combination with prodrugs |
| CN1125097C (en) * | 2000-07-05 | 2003-10-22 | 天津大学 | Precursor of polyglycol carried taxusol or polyene taxusol |
| CN100361985C (en) * | 2004-10-26 | 2008-01-16 | 中国科学院长春应用化学研究所 | Paclitaxol predrug of biodegradable polymer and its synthesis method |
-
2010
- 2010-09-01 CN CN201010268939.8A patent/CN101935336B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1259875A (en) * | 1997-06-11 | 2000-07-12 | 伦敦大学药学院 | Pharmaceutical compositions contg. anti-body-enzyme conjugates in combination with prodrugs |
| CN1125097C (en) * | 2000-07-05 | 2003-10-22 | 天津大学 | Precursor of polyglycol carried taxusol or polyene taxusol |
| CN100361985C (en) * | 2004-10-26 | 2008-01-16 | 中国科学院长春应用化学研究所 | Paclitaxol predrug of biodegradable polymer and its synthesis method |
Non-Patent Citations (4)
| Title |
|---|
| Gene M.Dubowchik et al.Cathepsin B-Labile Dipeptide Linkers for Lysosomal Release of Doxorubicin from Internalizing Immunoconjugates:Model Studies of Enzymatic Drug Release and Antigen-Specific In Vitro Anticancer Activity.《Bioconjugate Chem》.2002,第13卷855-869. * |
| Marcin Dyba et al.Small Molecule Toxins Targeting Tumor Receptors.《Current Pharmaceutical Design》.2004,第10卷2311-2334. * |
| 张学农等.紫杉烷类新剂型的研究进展及其临床应用.《国外医学药学分册》.2002,第29卷(第6期),321-325. * |
| 涂龙霞等.组织蛋白酶B在紫杉醇诱导胃癌BGC-823细胞凋亡中的作用.《中国医药导报》.2009,第6卷(第36期),33-34. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104650179A (en) * | 2015-02-06 | 2015-05-27 | 东南大学 | Novel platinum prodrug capable of being cracked by lysosomal enzyme |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101935336A (en) | 2011-01-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101935336B (en) | Method for preparing water-soluble taxane medicament and application thereof | |
| CN103804472B (en) | A kind of taxone precursor | |
| AU2009250393B2 (en) | Polymer derivative of Docetaxel, method of preparing the same and uses thereof | |
| CN1761485B (en) | Micellar preparation containing sparingly water-soluble anticancer agent and novel block copolymer | |
| CN1125097C (en) | Precursor of polyglycol carried taxusol or polyene taxusol | |
| CN1895676B (en) | Prodrug of taxol or polyene-taxol with carbowax as carrier | |
| KR102190093B1 (en) | Biodegradable amphiphilic polymers specifically targeting ovarian cancer, polymer cyclists prepared therefrom, and uses | |
| CN107335060A (en) | A kind of small molecule conjugate and its nano prodrug system based on rgd peptide-chemotherapeutics | |
| CN108066770A (en) | Amphipathic nature polyalcohol prodrug of reduction response release active compound and preparation method thereof | |
| CN109303780A (en) | A kind of amphiphilic polymer prodrug and preparation method thereof restoring response type 7-Ethyl-10-hydroxycamptothecin | |
| CN100374443C (en) | Hydrophilic polymer-thunder good vine extract binding substance and its medicinal composition | |
| Arpicco et al. | Preparation and characterization of novel poly (ethylene glycol) paclitaxel derivatives | |
| CN105233298A (en) | Paclitaxel phospholipid compound and drug combination and application thereof | |
| CN103370329A (en) | Amphiphilic cyclic phosphazene trimer, hydrophobic pharmaceutical formulation micellized by amphiphilic cyclic phosphazene trimer, and preparation methods thereof | |
| US9789198B2 (en) | Low molecular weight polyethylene glycol drug conjugates having improved drug biological activity | |
| CN108727208A (en) | A kind of connexon compound, polyethylene glycol-connexon conjugate and its derivative and polyethylene glycol-connexon-drug conjugates | |
| CN108863992B (en) | Preparation method and application of polyamino polycarboxylic acid modified cabazitaxel compound | |
| CN103819429B (en) | Aminopolycanboxylic acid modifies the Preparation method and use of paclitaxel analog compound | |
| ES2771423T3 (en) | Composition of Cabazitaxel | |
| CN103183722B (en) | Glyoxalase I inhibitor, preparation method and medical application thereof | |
| CN102626521B (en) | Segmented copolymer - docetaxel combination, preparation thereof and preparation method thereof | |
| CN102336904A (en) | Multivalent polyglycol (PEG) modifier for camptothecin and derivatives thereof and application of multivalent PEG modifier | |
| CN103980232A (en) | 10-acetyldocetaxel and application thereof | |
| US20070048252A1 (en) | Conjugates of the hydrophilic polymer and the molecules from boxwood extraction, and pharmaceutical compositions of the conjugates | |
| CN110025574A (en) | A kind of reduction response type amphipathic stem polymer prodrug and its preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140409 Termination date: 20170901 |