CN1854143A - Preparation method of vinblastine compound and pharmaceutically acceptable salt thereof - Google Patents
Preparation method of vinblastine compound and pharmaceutically acceptable salt thereof Download PDFInfo
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- CN1854143A CN1854143A CN 200510038955 CN200510038955A CN1854143A CN 1854143 A CN1854143 A CN 1854143A CN 200510038955 CN200510038955 CN 200510038955 CN 200510038955 A CN200510038955 A CN 200510038955A CN 1854143 A CN1854143 A CN 1854143A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 150000003839 salts Chemical class 0.000 title claims abstract description 11
- -1 vinblastine compound Chemical class 0.000 title claims description 4
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 title description 8
- 229960003048 vinblastine Drugs 0.000 title description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 241000863480 Vinca Species 0.000 claims description 9
- 229910021630 Antimony pentafluoride Inorganic materials 0.000 claims description 8
- VBVBHWZYQGJZLR-UHFFFAOYSA-I antimony pentafluoride Chemical compound F[Sb](F)(F)(F)F VBVBHWZYQGJZLR-UHFFFAOYSA-I 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 230000002140 halogenating effect Effects 0.000 claims description 7
- 239000003930 superacid Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical class C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 abstract description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract 3
- 235000019256 formaldehyde Nutrition 0.000 abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 9
- 229960002066 vinorelbine Drugs 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 6
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 6
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 4
- 229960004528 vincristine Drugs 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229960004355 vindesine Drugs 0.000 description 3
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 229960000922 vinflunine Drugs 0.000 description 2
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 2
- PPSMYAUEJRADFE-HXUWFJFHSA-N 2-[(5r)-4-[2-[3-(6-methylpyridin-3-yl)oxyphenyl]acetyl]-8-(trifluoromethyl)-1,2,3,5-tetrahydropyrido[2,3-e][1,4]diazepin-5-yl]acetic acid Chemical compound C1=NC(C)=CC=C1OC1=CC=CC(CC(=O)N2[C@@H](C3=CC=C(N=C3NCC2)C(F)(F)F)CC(O)=O)=C1 PPSMYAUEJRADFE-HXUWFJFHSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of vinblastine compounds with a general formula and pharmaceutically acceptable salts thereof. Wherein is 1 or 2; r1Is methyl or formaldehyde; r2Is methoxy or amino; r3Is a hydrogen atom or an acetyl group.
Description
Technical field
The object of the invention is to provide the vinca compound of a kind of general formula (I) and the preparation method of pharmacologically acceptable salt thereof.
Background of invention
The vinca compound has used history that three more than ten years were arranged as anticancer chemotherapeutic clinically, and wherein main is two natural product vinealeucoblastine(VLB) (vinblastine) and vincristine(VCR) (vincristine) and two semi-synthetic derivative vindesines (vindesine) and vinorelbine (vinorelbine)
Vinealeucoblastine(VLB) (vinblastine)
Vincristine(VCR) (vincristine)
Vindesine (vindesine)
Vinorelbine (vinorelbine)
Along with to the structure of vinca compound and deepening continuously of activity research, people more and more intensive expectation obtain the vinca compound of a new generation, make it possess better therapeutic index and lower toxic side effects.The fluorochemical derivative of vinca compound arises at the historic moment thus, and wherein Vinflunine (vinflunine) has entered clinical experimental stage, is expected to become the vinca cancer therapy drug of a new generation.The preparation method of formula (I) compound and pharmacologically acceptable salt thereof is disclosed in two pieces of patents (us5620985 and us6127377) abroad, we are after having carried out careful research to the preparation method, there are many shortcomings in discovery, carries out this reaction about all being adopted in the presence of super acids environment and halogenating agent (as chloroform, NBS) during to formula (I) compound by formula (II) compound in two pieces of patents
Total recovery all has only about 30%, and final product is not very stable.
Summary of the invention
At the deficiencies in the prior art, the invention provides the new preparation method of the vinca compound and the pharmacologically acceptable salt thereof of a kind of general formula (I).
Wherein n is 1 or 2; R
1Be methyl or carboxaldehyde radicals; R
2Be methoxyl group or amino; R
3Be a hydrogen atom or ethanoyl.
The objective of the invention is further to reach by the following technical programs, be characterized in that described reaction comprises the steps: earlier formula (II) compound to be obtained formula (III) compound through halogenating reaction, formula (III) compound transforms an accepted way of doing sth (I) compound again under the super acids environment.
In the formula, R
4Be selected from hydroxyl, R
5Be hydrogen, or R
4, R
5The common a pair of key that forms; R
1, R
2, R
3, n such as claim 1 definition.
The objective of the invention is further to reach by the following technical programs, be characterized in the preparation of general formula (III) compound, the super acids of reacting used is the mixture that hydrofluoric acid and antimony pentafluoride are formed; Used halogenating agent is selected from the mixture of tetracol phenixin and methylene dichloride, and its ratio is 1: 1 (V/V).The temperature maintenance of reaction is at-80 degree～-30 degree.
The objective of the invention is further to reach by the following technical programs, be characterized in the preparation of general formula (I) compound, the super acids of reacting used is the mixture that hydrofluoric acid and antimony pentafluoride are formed; Used halogenating agent is a chloroform.The temperature maintenance of reaction is at-80 degree～-30 degree.
The objective of the invention is further to reach by the following technical programs, be characterized in that the pharmacologically acceptable salt of general formula (I) compound can be obtained by freeze-drying or recrystallization.
The objective of the invention is further to reach by the following technical programs, be characterized in that the pharmacologically acceptable salt of general formula (I) compound is obtained by recrystallization, used solvent is selected from the mixture of acetone or acetone and ether solvent; Used ether is selected from ether, isopropyl ether, t-butyl methyl ether.Wherein the ratio of acetone and ethers can adopt the arbitrary proportion that those skilled in the art are familiar with.
Specific embodiment
Further specify the present invention below by embodiment; the preparation method of the embodiment of the invention is only used for illustrating the present invention rather than limitation of the present invention; any simple modifications to invention preparation method under design prerequisite of the present invention all belongs to claimed scope of the present invention, except as otherwise noted.
Embodiment one
4 '-deoxidation-20 ', the preparation of 20 '-2 chlorine vinealeucoblastine(VLB)
The anhydrous hydrofluoric acid of 60g (0.28mol) antimony pentafluoride and 80ml (4mol) is put in the reactor of tetrafluoroethylene together, be cooled to-60 degree, stir the tetracol phenixin that adds 1.63ml (17mmol) down, begin to drip 13.75g (17mmol) 3 ' after adding, the 25ml dichloromethane solution of 4 '-F 81097, keep temperature of reaction to be no more than-40 degree after .30 minute, reaction solution carefully is punched into 1.5 liters of 3M NaCO that contain the 200ml methylene dichloride
3In the solution, after the static layering, water layer 100ml dichloromethane extraction merges organic layer, saturated common salt water washing, anhydrous MgSO
4Drying concentrates, and column chromatography gets title compound 9g.(yield 60%)
Embodiment two
4 '-deoxidation-20 ', the preparation of 20 '-2 fluorine vinealeucoblastine(VLB)
The 500ml hydrofluoric acid solution of 750g (3.45mol) antimony pentafluoride is put in the tetrafluoroethylene reactor, be added dropwise to 110g (0.12mol) 4 '-deoxidation-20 ' again, the chloroformic solution of the 250ml of 20 '-2 chlorine vinealeucoblastine(VLB), temperature is-35 degree in dropwising and kept in 30 minutes, and then stirs under this temperature and continued 30 minutes.Under-30 degree, slowly add 200ml acetone, finished in 30 minutes.Under-25 degree, slowly add 150ml water again, added in 15 minutes.Naturally be warmed up to 20 degree, add the 900ml methylene dichloride, add 650ml water subsequently, layering, water layer 100ml dichloromethane extraction, merge organic phase and fully neutralize with 10% the KOH of 600ml, the ammoniacal liquor that organic phase adds 400ml after the layering stirs and spends the night, and uses twice of 400ml water washing, concentrating under reduced pressure behind the anhydrous magnesium sulfate drying, column chromatography, eluent are toluene/acetone (60/40), collect and merge positive component after concentrating under reduced pressure get the 90g target compound.(yield 85%)
Embodiment three
4 '-deoxidation-20 ', the preparation of 20 '-dichloro vinorelbine
The anhydrous hydrofluoric acid of 30g (0.14mol) antimony pentafluoride and 40ml (2mol) is put in the reactor of tetrafluoroethylene together, be cooled to-60 degree, stir the tetracol phenixin that adds 0.8ml (8.5mmol) down, begin to drip the 12.5ml dichloromethane solution of 6.6g (8.5mmol) vinorelbine after adding, keep temperature of reaction to be no more than-40 degree.After 30 minutes, reaction solution carefully is punched into the 3MNaCO that 700ml contains the 100ml methylene dichloride
3In the solution.After the static layering, water layer 50ml dichloromethane extraction merges the water washing of organic layer saturated common salt, anhydrous MgSO
4Drying concentrates, and column chromatography gets title compound 4.7g.(yield 65%)
Embodiment four
4 '-deoxidation-20 ', the preparation of 20 '-difluoro vinorelbine
The 100ml hydrofluoric acid solution of 150g (0.69mol) antimony pentafluoride is put in the reactor of tetrafluoroethylene, be cooled to-45 degree, be added dropwise to 20.2g (24mmol) 4 '-deoxidation-20 ' again, the chloroformic solution of the 50ml of 20 '-2 chlorine vinorelbines, temperature is-35 degree in dropwising and kept in 30 minutes, and then stirs under this temperature and continued 30 minutes.Under-30 degree, slowly add 40ml acetone, finished in 30 minutes.Under-25 degree, slowly add 30ml water again, added in 15 minutes.Naturally be warmed up to 20 degree, add the 180ml methylene dichloride, add 130ml water subsequently, layering, water layer 20ml dichloromethane extraction, merge organic phase and fully neutralize with 10% the KOH of 120ml, the ammoniacal liquor that organic phase adds 80ml after the layering stirs and spends the night, and uses twice of 80ml water washing, concentrating under reduced pressure behind the anhydrous magnesium sulfate drying, column chromatography, eluent are toluene/acetone (60/40), collect and merge positive component after concentrating under reduced pressure get target compound 80g (yield 82%)
Embodiment five
4 '-deoxidation-20 ', the preparation of 20 '-difluoro vinorelbine bitartrate
With 4 '-deoxidation-20 ', 20 '-difluoro vinorelbine (18.0 grams, 22.03mmol) joins in the acetone (300ml), add tartrate (6.6 grams, 44mmol), stir molten clear, stir and drip ether (300ml) down, in 0-5 ℃ of crystallization, filter the dry target compound that gets then: 21 gram (yields: 85.3%).
Embodiment six
4 '-deoxidation-20 ', the preparation of 20 '-difluoro vinorelbine bitartrate
With 4 '-deoxidation-20 ', 20 '-difluoro vinorelbine (18.0 gram, 22.03mmol) and tartrate (6.6 grams, 44mmol) join in the water (100ml), stirs molten clearly, lyophilize gets target compound: 25 restrain (yields: 102%).
Experiment one
Stability relatively
Claims (6)
1. the preparation method of a general formula (I) vinca compound and pharmacologically acceptable salt thereof:
In the formula, n is 1 or 2, preferred n=1; R
1Be methyl or carboxaldehyde radicals, preferable methyl; R
2Be methoxy or amino, preferred methoxyl group; R
3Be a hydrogen atom or ethanoyl, preferred ethanoyl.
2. preparation method according to claim 1, it is characterized in that described reaction comprises the steps: earlier formula (II) compound to be obtained formula (III) compound through halogenating reaction, formula (III) compound transforms an accepted way of doing sth (I) compound again under the super acids environment.
In the formula, R
4Be selected from hydroxyl, R
5Be hydrogen, or R
4, R
5The common a pair of key that forms; R
1, R
2, R
3, n such as claim 1 definition.
3. preparation method according to claim 2 is characterized in that in the preparation of general formula (III) compound, and the super acids of reacting used is the mixture that hydrofluoric acid and antimony pentafluoride are formed; Used halogenating agent is selected from the mixture of tetracol phenixin and methylene dichloride, and its ratio is 1: 1 (V/V).
4. preparation method according to claim 2 is characterized in that in the preparation of general formula (I) compound, and the super acids of reacting used is the mixture that hydrofluoric acid and antimony pentafluoride are formed; Used halogenating agent is a chloroform.
5, preparation method according to claim 1 is characterized in that the pharmacologically acceptable salt of general formula (I) compound can be obtained by freeze-drying or recrystallization.
6, preparation method according to claim 5 is characterized in that the pharmacologically acceptable salt of general formula (I) compound is obtained by recrystallization, and used solvent is selected from the mixture of acetone or acetone and ether solvent; Used ether is selected from ether, isopropyl ether, t-butyl methyl ether.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510038955 CN1854143A (en) | 2005-04-19 | 2005-04-19 | Preparation method of vinblastine compound and pharmaceutically acceptable salt thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510038955 CN1854143A (en) | 2005-04-19 | 2005-04-19 | Preparation method of vinblastine compound and pharmaceutically acceptable salt thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1854143A true CN1854143A (en) | 2006-11-01 |
Family
ID=37194632
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510038955 Pending CN1854143A (en) | 2005-04-19 | 2005-04-19 | Preparation method of vinblastine compound and pharmaceutically acceptable salt thereof |
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| Country | Link |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008092335A1 (en) | 2007-01-29 | 2008-08-07 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Novel vinblastine derivatives, their preparation, use and pharmaceutical compositions comprising the said derivatives |
-
2005
- 2005-04-19 CN CN 200510038955 patent/CN1854143A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008092335A1 (en) | 2007-01-29 | 2008-08-07 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Novel vinblastine derivatives, their preparation, use and pharmaceutical compositions comprising the said derivatives |
| US8168647B2 (en) | 2007-01-29 | 2012-05-01 | Shanghai Institute Of Materia Medica Chinese Academy Of Sciences | Vinblastine derivatives, their preparation, use and pharmaceutical compositions comprising the said derivatives |
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