CN101407516A - Camptothecine derivative having anticancer activity - Google Patents
Camptothecine derivative having anticancer activity Download PDFInfo
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- CN101407516A CN101407516A CNA2008102236564A CN200810223656A CN101407516A CN 101407516 A CN101407516 A CN 101407516A CN A2008102236564 A CNA2008102236564 A CN A2008102236564A CN 200810223656 A CN200810223656 A CN 200810223656A CN 101407516 A CN101407516 A CN 101407516A
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- compound
- tms
- camptothecine
- dimethylamino
- ethyl
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Abstract
The invention relates to camptothecin derivatives with anticancer activity and the preparation and application thereof, and the chemical structure is as shown in the right formula.
Description
Technical field
The present invention relates to anti-cancer drug compounds, more specifically, relate to the new camptothecin derivative of a class, their preparation and application with efficient antitumour activity.
Background technology
(camptothecin is the five rings alkaloid of separation and Extraction from Nyssaceae plant camptotheca acuminata (Camptotheca acuninata) CPT) to camptothecine, is the phytogenic anticarcinogen of unique selective inhibition DNA topoisomerase I (Topo I) effect.At present, camptothecine has become second important cancer therapy drug by plant derivation after taxol in oncotherapy.Toxicity is big because camptothecine exists, weak curative effect has limited its clinical application.At present, developed a part of camptothecin derivative, their toxicity is little, and selectivity is good, for example irinotecan (Irinotecan CPT-11) etc., these camptothecin derivatives have vital role aspect clinical cancer therapy, on the treatment digestive tract tumor, irreplaceable effect is arranged especially, but because the exploitation kind is few, and the medicine that need have higher curative effect, it is low further to seek toxicity, and the camptothecin derivative of high curative effect is the focus and emphasis of studying at present.
Because camptothecine is the five rings alkaloid, 7,9,10,11,12 and lactonic ring all can be modified, therefore, have hundreds of compound (CN101232872,2006-08-08PCT/EP2006/065159 for basic derivative through structural changes according to the female ring of camptothecine, CN1587265, CN1616460).Most of camptothecin derivative all has certain pharmacologically active, and only effect is strong and weak different, but does not also surpass the compound of irinotecan at present in therapeutic action.Univ. of Pittsburgh in 1999 has reported at 7 have the camptothecin derivative of silane (silyl) substituted radical to have the good anticancer activity, its effect approaches irinotecan (PCT WO99/09996), but does not also reach the vivo antitumor effect of irinotecan fully.There is report to show that the camptothecin derivative that the E lactone is opened has also increased antitumour activity (CN101024644) significantly in addition.The present invention has synthesized the camptothecin derivative with new texture that has silane (silyl) substituted radical and E lactone to be opened at 7 according to prior art, and finds that unexpectedly this compounds has better antitumous effect in vivo and in vitro.This compounds belongs to the novel compound of invention at home and abroad also without any report.
Summary of the invention:
The invention provides a kind of new anticancer compound, its chemical structure is as follows:
R1＝TMS，TBDMS，TES
R2＝H，F，Cl，Br，I，NO
2，NH
2，OH，OMe，OAc，
R3＝H，R
4CO-
R4=C1-C4 straight or branched alkyl
R5＝N(Me)
2，
In the structural formula:
R1 represents TMS (TMS), TBDMS (dimethyl t-butylsilane base), or TES (triethyl silyl)
R2 represents 0-3 the identical or different substituting group on 9,10 or 11, and these substituting groups comprise: hydrogen atom, halogen atom (F, Cl, Br, or I), nitro, amino, hydroxyl, alkoxyl group, or ester group, but wherein 10 go up for the compound of hydroxyl not within the scope of the present invention
R3 represents hydrogen atom or R
4CO-;
R4 represents the straight or branched alkyl of C1-C4, methoxyl group alkylidene group, methylamino alkylidene group or dimethylin alkylidene group
R5 represents dimethylamino, 1-morpholinyl, piperidino, or pyrrolidyl
Preferably
R1 represents TMS (TMS), TBDMS (dimethyl t-butylsilane base), or TES (triethyl silyl)
R2 represents 9-H, 9-F, 9-Cl, 9-Br, 9-I, 9-NO
2, 9-NH
2, 9-OH, 9-OMe, 9-OAc, 9-(4 '-piperidinyl piperidine) carbonyl oxygen base; 10-H, 10-F, 10-Cl, 10-Br, 10-I, 10-NO
2, 10-NH
2,, 10-OMe, 10-OAc, 10-(4 '-piperidinyl piperidine) carbonyl oxygen base; Or 11-H, 11-F, 11-Cl, 11-Br, 11-I, 11-NO
2, 11-NH
2, 11-OH, 11-OMe, 11-OAc, 11-(4 '-piperidinyl piperidine) carbonyl oxygen base
R3 represents hydrogen atom or R
4CO-;
R4 represents the straight or branched alkyl of C1-C4, methoxyl group alkylidene group, methylamino alkylidene group or dimethylin alkylidene group
R5 represents dimethylamino, 1-morpholinyl, piperidino, or pyrrolidyl
Particularly preferably be following compound:
Wherein
Compound 1:7-TMS-11-is fluorine-based-17-propionyloxy-21-N[2-(dimethylamino) ethyl] and acid amides E ring open loop camptothecine
Compound 2:7-dimethyl t-butylsilane base-11-is fluorine-based-17-propionyloxy-21-N[2-(dimethylamino) ethyl] and acid amides E ring open loop camptothecine
Compound 3:7-triethyl silyl-11-is fluorine-based-17-propionyloxy-21-N[2-(dimethylamino) ethyl] and acid amides E ring open loop camptothecine
Compound 4:7-TMS-11-is fluorine-based-17-acetoxyl group-21-N[2-(dimethylamino) ethyl] and acid amides E ring open loop camptothecine
Compound 5:7-TMS-11-is fluorine-based-17-propionyloxy-21-N[2-(1-morpholinyl) ethyl] and acid amides E ring open loop camptothecine
Compound 6:7-TMS-11-chloro-17-propionyloxy-21-N[2-(dimethylamino) ethyl] acid amides E ring open loop camptothecine
Compound 7:7-TMS-10-is fluorine-based-17-propionyloxy-21-N[2-(dimethylamino) ethyl] and acid amides E ring open loop camptothecine
Compound 8:7-TMS-10-acetoxyl group-17-propionyloxy-21-N[2-(dimethylamino) ethyl] acid amides E ring open loop camptothecine
Compound 9:7-TMS-10-[(4 '-piperidinyl piperidine) carbonyl oxygen base]-17-propionyloxy-21-N[2-(dimethylamino) ethyl] acid amides E ring open loop camptothecine
Compound 10:7-TMS-10-is fluorine-based-and 11-is fluorine-based-17-propionyloxy-21-N[2-(dimethylamino) ethyl] acid amides E ring open loop camptothecine
Compound 11:7-TMS-9-is fluorine-based-17-propionyloxy-21-N[2-(dimethylamino) ethyl] and acid amides E ring open loop camptothecine
Compound 12:7-TMS-9-hydroxyl-17-propionyloxy-21-N[2-(dimethylamino) ethyl] acid amides E ring open loop camptothecine
The present invention also comprises the form of the medicinal basic or the salt of The compounds of this invention, and their preparation method and purposes.
The present invention also comprises with compound cancer therapy drug of the present invention.
Compound of the present invention can be treated following cancer: lung cancer, liver cancer, cancer of the stomach, esophagus cancer, mammary cancer, ovarian cancer, the cancer of the brain, prostate cancer, the rectum cancer or leukemia.
Compound of the present invention or its pharmacy acceptable salt can be the formed salt of this compound and mineral acid or organic acid.Described salt is selected from hydrochloride, hydrobromate, phosphoric acid salt, vitriol, acetate, trifluoroacetate, Citrate trianion, maleate, oxalate, succinate, benzoate, tartrate, fumarate, mandelate, ascorbate salt, malate, mesylate, tosilate etc.
The present invention also provides the preparation method of compound of the present invention:
As: the method among the embodiment 1, or the preparation method of its pharmacy acceptable salt, this method comprise reacts The compounds of this invention and pharmaceutically acceptable acid to the step that generates pharmacy acceptable salt.
The present invention also comprises the pharmaceutical composition that contains compound of the present invention or its pharmacy acceptable salt.Said composition can be tablet, sugar coated tablet, film coated tablet, enteric coated tablet, slow releasing tablet, capsule, hard capsule, soft capsule, slow releasing capsule, oral liquid, mixture, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, solution, injection, powder injection, lyophilized injectable powder, suppository, ointment, plaster, creme, sprays, aerosol, drops or patch.
Pharmaceutical composition of the present invention, as dosage form, the significant quantity of the The compounds of this invention that contains in every dose is 0.1mg-1000mg, described every dose refers to, and each preparation unit is as every of tablet, capsular every, also can refer to each taking dose, as take 100mg at every turn.
But pharmaceutical composition of the present invention can use solid carrier when solid that is prepared into pulvis, tablet dispersion powder, capsule, cachet, suppository and ointment or semisolid pharmaceutical formulation.Spendable solid-state carrier is preferably one or more materials that are selected from thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, the swelling agent etc., or can be encapsulating substance.In powderous preparations, in carrier, contain 5% or 10% to 70% micronize activeconstituents.The specific examples of suitable solid-state carrier comprises that magnesiumcarbonate, Magnesium Stearate, talcum, sucrose, lactose, pectin, dextrin, starch, gelatin, Huang have a liking for glue, methylcellulose gum, Xylo-Mucine, lower boiling wax, theobroma oil etc.Because they are easy to administration, tablet, pulvis, cachet rubber alloy capsule are represented best oral solid formulation.
Liquid preparation of the present invention comprises solution, suspension and emulsion.For example, the injectable formulation of parenteral administration can be water or water-propylene glycol solution form, regulates its degree of oozing such as grade, and pH etc. make the physiological condition that is suitable for live body.Liquid preparation also can be made into the solution form in polyoxyethylene glycol, the aqueous solution.Can add appropriate colouring agent, seasonings, stablizer and thickening material again by activeconstituents is dissolved in the water, prepare oral aqueous solution.Micronized activeconstituents can be dispersed in to prepare in viscous substance such as natural or synthetical glue, methylcellulose gum, Xylo-Mucine and other the known suspension agent and be suitable for oral aqueous suspensions.
In order to be easy to administration and dosage homogeneous, it is particularly advantageous that the said medicine preparation is mixed with dosage unit form.The dosage unit form of preparation refers to be suitable for the physical sepn unit as single dose, and each unit contains the activeconstituents of the good predetermined amount of the calculating that produces desired result of treatment.This dosage unit form can be packaged form, as tablet, capsule be contained in tubule or bottle in pulvis, be contained in the pipe or the bottle in ointment, gel or creme.
Though the amount of contained activeconstituents can change in the dosage unit form, generally, be adjusted in the 1-1000mg scope according to the effectiveness of selected activeconstituents.
Below data declaration is of the present invention by experiment has a mind to effect:
The antitumour activity test:
1. camptothecin derivative is in external cytotoxicity:
Experimental technique: mtt assay
1) gets and be in one bottle in cell in good condition exponential phase of growth, add 0.25% tryptic digestive juice (MX-1 and OV-3 cell),, use suspension for the CCRF cell.Digestion comes off attached cell, counting 4-5 * 10
-4Individual/mL, make cell suspension.
2) obtained cell suspension is inoculated on 96 orifice plates, and constant temperature CO is put in the 200L/ hole
2Cultivated 24 hours in the incubator.
3) change liquid, adding is subjected to the reagent thing, and cultivated 48 hours in the 20L/ hole.
4) MTT is added in 96 orifice plates, the 20L/ hole, reaction is 4 hours in the incubator
5) supernatant liquor is removed in suction, adds DMSO, the 150L/ hole, and jolting is 5 minutes on the dull and stereotyped shaking table.
6) be the light absorption value that the 570nm place measures every hole with enzyme-linked immunosorbent assay instrument at wavelength.
The subject cell strain:
MX-1: human breast cancer cell; CCRF: human leukemia cell; OV-3: Proliferation of Human Ovarian Cell
Experimental result
Because irinotecan is that medicine obviously acts on IC before the medicine in external nothing
50More than 100, be converted into active drug in its body.
IC
50For suppressing the concentration of 50% cell growth.
Because irinotecan is that medicine obviously acts in external nothing before the medicine, be converted into active drug in vivo.
IC
50For suppressing the concentration of 50% cell growth.
2. camptothecin derivative is in vivo to the effect of human implantation's tumor treatment:
Experimental technique:
Laboratory animal is a nude mice, 5 every group.If control group and treatment group.
Transplantation tumor is got eugonic tumor tissues, is cut into thin piece with sterile scissors, the tumor tissues of every inoculation 50mg.
Treatment is beginning in the tenth day after transplantation tumor, and this moment, tumor weight was about 300mg.
Route of administration is intravenous injection, and dosage regimen is to be administered once every day, successive administration 4 days,
Every other day claim the nude mice body weight and measure gross tumor volume.
Tried transplantation tumor:
MX-1: human breast cancer cell
A549: human lung carcinoma cell
HT29: human colon cancer cell
Experimental result:
Tumour inhibiting rate (%)=(control group knurl weight-treatment group knurl is heavy)/control group knurl heavy * 100%
Tumour disappears: visual inspection exists less than tumour
Tumor recurrence: observed tumour and exist in 50 days after treatment
Every group of 5 nude mices, treatment are beginning in the tenth day after transplantation tumor
Body weight change is that body weight is measured in the 3rd day after drug withdrawal, and this moment, body weight was in lower-most point.Body weight * 100% before body weight change (%)=(body weight after body weight before the treatment-treatment group)/treatment
Embodiment
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
The concrete preparation method of compound 1:
The preparation of midbody compound C:
Compd B (250mg 0.75mmol) is dissolved among DME (2.5ml) and the DMF (1.0ml). 0 ℃ add in this solution 60% NaH (32mg, 0.78mmol), add again after 10 minutes LiBr (150mg, 1.75mmol).After 15 minutes, at ambient temperature, (420mg 2.24mmol) is added into compd A, is heated to 65 ℃ and stirred 20 hours in this temperature then.Final solution is poured the 20mL saturated aqueous common salt into, uses ethyl acetate extraction, uses anhydrous Na
2SO
4Dry.Obtain pure product Compound C 283mg (85%) with the silica gel column chromatography separation.
The preparation of midbody compound E:
(37mg, 0.084mmol), (42mg 0.12mmol) is heated to 70 ℃ to Compound C in benzene, and reacts 12 hours under the irradiation of 275W GE fluorescent lamp for Compound D (0.25mmol) and hexa methyl ditin hexamethylditin.Final product obtains pure product compd E 30mg (67%) with the silica gel column chromatography separation.
The preparation of midbody compound F:
(20mg 0.04mmol) is heated to 50 ℃ of reactions 20 hours to compd E in 48%HBr (1mL).Pour saturated NaHCO then lentamente into
3(10mL).Use ethyl acetate extraction, use anhydrous Na
2SO
4Dry.Obtain pure product compound F 17-hydroxy-corticosterone 13mg (83%) with the silica gel column chromatography separation.
The preparation of midbody compound H:
Compound F 17-hydroxy-corticosterone (8.8mg, 0.02mmol) with compound G (0.1mmol) and 0.5mL methanol mixed, reaction is after 12 hours down in 80 ℃, and system becomes clarification, and reaction mixture is dropwise added in the ether, separates out yellow mercury oxide, leaches precipitation, washs with cold diethyl ether.Product is dissolved in the minimum of chloroform, separates obtaining pure product compound H (10.2mg, 96%) with alumina column chromatography.
The preparation of compound 1:
(10mg 0.019mmol) is dissolved in the 0.2mL pyridine compound H, adds the 0.02mL propionic anhydride, and heating makes temperature maintenance at 40 ℃, stirs 12 hours.Boil off low boiling point solvent, residuum is poured ether into, separates out faint yellow solid, separates obtaining pure product compound 1 11mg (99%) with silica gel column chromatography.
Embodiment 2
The preparation of compound 2-3:
The preparation method is identical with embodiment 1, and the starting raw material A that only is to use is and they substituting group corresponding compounds separately, specific as follows shown in:
The preparation of compound 4:
(10mg 0.019mmol) is dissolved in the 0.2mL pyridine compound H, adds the 0.02mL diacetyl oxide, and heating makes temperature maintenance at 40 ℃, stirs 12 hours.Boil off low boiling point solvent, residuum is poured ether into, separates out faint yellow solid, separates obtaining pure product compound 4 11mg (99%) with silica gel column chromatography.
The preparation of compound 5:
Compound F 17-hydroxy-corticosterone (8.8mg, 0.02mmol) with compound G1 (0.1mmol) and 0.5mL methanol mixed, reaction is after 12 hours down in 80 ℃, and system becomes clarification, and reaction mixture is dropwise added in the ether, separates out yellow mercury oxide, leaches precipitation, washs with cold diethyl ether.Product is dissolved in the minimum of chloroform, separates obtaining pure product compound with alumina column chromatography.Further this compound is dissolved in the 0.2mL pyridine, adds the 0.02mL diacetyl oxide, heating makes temperature maintenance at 40 ℃, stirs 12 hours.Boil off low boiling point solvent, residuum is poured ether into, separates out faint yellow solid, separates obtaining pure product compound 5 10mg (94%) with silica gel column chromatography.
Embodiment 3
Contain the preparation of the tablet of compound 1
Prescription compound 1 50 grams
Microcrystalline Cellulose 80.0 grams
Lactose 100.0 grams
Secondary calcium phosphate 18.0 grams
Starch 8.0 grams
Magnesium Stearate 30.0 grams
Pregelatinized Starch 20.0 grams
Propyl cellulose E50 60 grams
Acid methyl cellulose sodium 1.0 grams
Become 1000 50mg/ sheets through pelletizing press sheet.
Embodiment 4
Capsular preparation
Prescription compound 1 50 grams
Microcrystalline Cellulose 80.0 grams
Lactose 100.0 grams
Secondary calcium phosphate 18.0 grams
Starch 8.0 grams
Magnesium Stearate 30.0 grams
Pregelatinized Starch 20.0 grams
Propyl cellulose E50 60 grams
Acid methyl cellulose sodium 1.0 grams
1000 of mixing dress glue capsules contain the 50mg/ grain.
Claims (10)
1, a kind of anticancer compound, its chemical structure is as follows:
R1＝TMS，TBDMS，TES
R2＝H，F，Cl，Br，l，NO
2，NH
2，OH，OMe，OAc，
R3＝H，R
4CO-
R4=C1-C4 straight or branched alkyl
R5＝N(Me)
2，
Wherein
R1 represents TMS (TMS), TBDMS (dimethyl t-butylsilane base), or TES (triethyl silyl)
R2 represents 0-3 the identical or different substituting group on 9,10 or 11, and these substituting groups comprise: hydrogen atom, halogen atom (F, Cl, Br, or I), nitro, amino, hydroxyl, alkoxyl group, or ester group, but wherein 10 go up for the compound of hydroxyl not within the scope of the present invention
R3 represents hydrogen atom or R
4CO-;
R4 represents the straight or branched alkyl of C1-C4, methoxyl group alkylidene group, methylamino alkylidene group or dimethylin alkylidene group
R5 represents dimethylamino, 1-morpholinyl, piperidino, or pyrrolidyl.
2, the compound of claim 1, wherein
R1 represents TMS (TMS), TBDMS (dimethyl t-butylsilane base), or TES (triethyl silyl)
R2 represents 9-H, 9-F, 9-Cl, 9-Br, 9-I, 9-NO
2, 9-NH
2, 9-OH, 9-OMe, 9-OAc, 9-(4 '-piperidinyl piperidine) carbonyl oxygen base; 10-H, 10-F, 10-Cl, 10-Br, 10-I, 10-NO
2, 10-NH
2,, 10-OMe, 10-OAc, 10-(4 '-piperidinyl piperidine) carbonyl oxygen base; Or 11-H, 11-F, 11-Cl, 11-Br, 11-I, 11-NO
2, 11-NH
2, 11-OH, 11-OMe, 11-OAc, 11-(4 '-piperidinyl piperidine) carbonyl oxygen base R3 represents hydrogen atom or R
4CO-;
R4 represents the straight or branched alkyl of C1-C4, methoxyl group alkylidene group, methylamino alkylidene group or dimethylin alkylidene group
R5 represents dimethylamino, 1-morpholinyl, piperidino, or pyrrolidyl.
3, the compound of claim 1 is
Compound 1:7-TMS-11-is fluorine-based-17-propionyloxy-21-N[2-(dimethylamino) ethyl] and acid amides E ring open loop camptothecine
Compound 2:7-dimethyl t-butylsilane base-11-is fluorine-based-17-propionyloxy-21-N[2-(dimethylamino) ethyl] and acid amides E ring open loop camptothecine
Compound 3:7-triethyl silyl-11-is fluorine-based-17-propionyloxy-21-N[2-(dimethylamino) ethyl] and acid amides E ring open loop camptothecine
Compound 4:7-TMS-11-is fluorine-based-17-acetoxyl group-21-N[2-(dimethylamino) ethyl] and acid amides E ring open loop camptothecine
Compound 5:7-TMS-11-is fluorine-based-17-propionyloxy-21-N[2-(1-morpholinyl) ethyl] and acid amides E ring open loop camptothecine
Compound 6:7-TMS-11-chloro-17-propionyloxy-21-N[2-(dimethylamino) ethyl] acid amides E ring open loop camptothecine
Compound 7:7-TMS-10-is fluorine-based-17-propionyloxy-21-N[2-(dimethylamino) ethyl] and acid amides E ring open loop camptothecine
Compound 8:7-TMS-10-acetoxyl group-17-propionyloxy-21-N[2-(dimethylamino) ethyl] acid amides E ring open loop camptothecine
Compound 9:7-TMS-10-[(4 '-piperidinyl piperidine) carbonyl oxygen base]-17-propionyloxy-21-N[2-(dimethylamino) ethyl] acid amides E ring open loop camptothecine
Compound 10:7-TMS-10-is fluorine-based-and 11-is fluorine-based-17-propionyloxy-21-N[2-(dimethylamino) ethyl] acid amides E ring open loop camptothecine
Compound 11:7-TMS-9-is fluorine-based-17-propionyloxy-21-N[2-(dimethylamino) ethyl] and acid amides E ring open loop camptothecine
Compound 12:7-TMS-9-hydroxyl-17-propionyloxy-21-N[2-(dimethylamino) ethyl] acid amides E ring open loop camptothecine.
4, the pharmacy acceptable salt of the compound of claim 1, can be the formed salt of this compound and mineral acid or organic acid, described salt be selected from hydrochloride, hydrobromate, phosphoric acid salt, vitriol, acetate, trifluoroacetate, Citrate trianion, maleate, oxalate, succinate, benzoate, tartrate, fumarate, mandelate, ascorbate salt, malate, mesylate, tosilate.
5, contain the compound of claim 1 or the pharmaceutical composition of its pharmacy acceptable salt.
6, the composition of claim 6, oral preparations are selected from that tablet, capsule, oral liquid, granule, injection are selected from, solution, powder injection, lyophilized injectable powder, liposome.
7, the compound of claim 1 or its pharmacy acceptable salt application in the anticancer disease drug of preparation.
8, the application of claim 7, described cancer is: lung cancer, liver cancer, cancer of the stomach, esophagus cancer, mammary cancer, ovarian cancer, the cancer of the brain, prostate cancer, the rectum cancer or leukemia.
9, the preparation method of the compound of claim 1 or its pharmacy acceptable salt is characterized in that, comprises described compound of claim 1 and pharmaceutically acceptable acid are reacted the step that generates pharmacy acceptable salt.
10, the preparation method of the compound of claim 1 or its pharmacy acceptable salt, route is as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008102236564A CN101407516A (en) | 2008-10-06 | 2008-10-06 | Camptothecine derivative having anticancer activity |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008102236564A CN101407516A (en) | 2008-10-06 | 2008-10-06 | Camptothecine derivative having anticancer activity |
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| Publication Number | Publication Date |
|---|---|
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Family
ID=40570747
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|---|---|---|---|
| CNA2008102236564A Pending CN101407516A (en) | 2008-10-06 | 2008-10-06 | Camptothecine derivative having anticancer activity |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012136144A1 (en) * | 2011-04-07 | 2012-10-11 | Lei Xiaoguang | Camptothecin derivatives having anti-tumor activity |
-
2008
- 2008-10-06 CN CNA2008102236564A patent/CN101407516A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012136144A1 (en) * | 2011-04-07 | 2012-10-11 | Lei Xiaoguang | Camptothecin derivatives having anti-tumor activity |
| CN102731516A (en) * | 2011-04-07 | 2012-10-17 | 雷晓光 | Novel camptothecin derivatives having antineoplastic activity |
| CN102731516B (en) * | 2011-04-07 | 2014-07-02 | 宁波天衡药业股份有限公司 | Novel camptothecin derivatives having antineoplastic activity |
| US9006439B2 (en) | 2011-04-07 | 2015-04-14 | Ningbo Team Pharmaceutical Co., Ltd | Camptothecin derivatives having anti-tumor activity |
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