CN101397301A - Water-soluble derivates containing 10-hydroxycamptothecin and preparation method - Google Patents
Water-soluble derivates containing 10-hydroxycamptothecin and preparation method Download PDFInfo
- Publication number
- CN101397301A CN101397301A CNA2008100702761A CN200810070276A CN101397301A CN 101397301 A CN101397301 A CN 101397301A CN A2008100702761 A CNA2008100702761 A CN A2008100702761A CN 200810070276 A CN200810070276 A CN 200810070276A CN 101397301 A CN101397301 A CN 101397301A
- Authority
- CN
- China
- Prior art keywords
- organic solvent
- hydroxycamptothecine
- acid
- reaction
- dcc
- 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.)
- Pending
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a series of amino-acid ester with molecules internally containing 10-hydroxycamptothecin and derivatives thereof and also discloses water-soluble derivatives forming salts with acids, and a preparation method thereof. The water-soluble derivatives have the formula (I), wherein, A represents saturated hydrocarbons; D represents organic groups containing nitrogen atoms; HB represents the acids forming salt with the organic groups. The compounds have better water-solubility and the arylate can be easily hydrolyzed in the body of human and animals to release the 10-hydroxycamptothecin and the derivatives so as to play the role of anti-cancer.
Description
Technical field
The present invention relates to soluble derivative of a series of hydroxycamptothecin containing amino-acid ester salts and preparation method thereof.
Background technology
The Wall of the U.S. in 1966 etc. separate from the distinctive plant camptotheca acuminata of China (Camptotheca acuminata) first and have obtained camptothecine (Camptothecin, CPT) (J Am Chem Soc.196688:3883-3890), because of its unique chemical structure and notable antitumor activity cause whole world related personnel's attention, but the camptothecine toxic side effect is big, has limited its clinical application.From camplotheca acuminata, isolated 10-hydroxycamptothecine (HCPT) subsequently again, it is wide to show that through clinic trial it has an anticancer spectrum, evident in efficacy, the characteristics that toxic side effect is little particularly have significant curative effect to malignant tumours such as primary liver property liver cancer, gastrointestinal cancer, bladder cancer, head neck skin cancer, leukemia, cervical cancers.But because the water-soluble extreme difference of HCPT can only be made water-soluble injection by following reaction and be used for clinical:
The drug effect of IIa must group---the lactone ring be after hydrolysis becomes corresponding carboxylic acid form IIb, although water soluble, the HCPT more than 95% has lost antitumour activity [Cancer Chemother.Rep.1970,54,461-470; Cancer Chemother.Rep.1972,56 (Part1), 95-101; Cancer Chemother.Rep.1972,56,515-521].Its major cause is that IIb can combine with the albumin (HAS) in the blood plasma, is difficult to bring into play drug effect, and can slow release come out in vivo with the II b of the carboxylic acid form of albumin bound, produces hysteresis toxicity.In order to reach corresponding curative effect, can only increase consumption clinically, so also cause the toxic side effect of HCPT to increase.In order to improve the bioavailability of HCPT, many Pharmaceutical Chemists have carried out structural modification to this medicine.
1994, and the water-soluble irinotecan of drugs approved by FDA (Irinotecan, CPT-11) listing is used for the treatment of colorectal carcinoma, but its synthetic complex process, the production cost height.The water-soluble topotecan of second line treatment medicine (Topotecan) that was used for the ovarian cancer patient in 1996 is got permission listing again, U.S. FDA was ratified its second line treatment medicine as small cell lung cancer (SCLC) again in 1999, but because of its anticancer spectrum narrow, toxic side effect is big, mainly be bone marrow depression, limited its use.Therefore, HCPT is carried out the part modify, when keeping lactonic ring, improve that it is water-soluble significant.
Yu-Ling Leu (J.Med.Chem.2008,51,1740-1746) reported that the introducing glucoside is to obtain its water-soluble prodrug on HPCT virtue hydroxyl.This prodrug complicated process of preparation, water-soluble increase is little.WO2005062985 provides 10 of hydroxycamptothecine and derivative thereof; fatty acid ester, aryl esters, virtue or the fragrant heteroaromatic carboxylate of the two acidylates of 20 (S); and the Lv Wei of China etc. have synthesized the carbonic ether (CN 1673225) and the carboxylicesters (CN1673226) of the single acidylate of 10,20 (S) or two acidylates.They are hydrolyzed the activeconstituents that discharges in blood plasma be hydroxycamptothecine, but these compounds well do not solve the water miscible problem of HCPT.
In order to solve the water-soluble problem of HCPT, we have designed general formula (I) compound, and this compounds not only has good water-solubility, and can discharge parent drug HCPT after in entering body, produce drug effect.
Summary of the invention
The technical problem to be solved in the present invention is, the salt of 10-amino acid ester that is provided at widely used hydroxycamptothecine of China and derivative thereof provides its corresponding preparation method simultaneously as prodrug.This class medicine has good water-solubility, can decompose after in entering body to discharge 10-hydroxycamptothecine and derivative thereof, produces antitumous effect.
The general formula that the present invention relates to is:
Wherein, A is saturated hydrocarbon polymer, has following structure:
Wherein, m=0,1,2,3; N=0,1,2,3; M and n can be identical, also can be different; R
1=H, Me, Et; R
2=H, Me, Et; R
1With R
2Can be identical, also can be different;
D represents to contain the organic group of nitrogen-atoms, D=NR
3R
4: R wherein
3, R
4Expression H, C
1-6Straight chain or containg branched alkyl radical, R
3, R
4Can be identical or different;
HB is meant and can be used as medicinal mineral acid example hydrochloric acid, phosphoric acid, sulfuric acid or carbonic acid; Or can be used as medicinal organic acid such as acetate, lactic acid, methylsulfonic acid, Succinic Acid, Citric Acid, fumaric acid, toxilic acid or oxysuccinic acid.
The preparation method of above-mentioned general formula (I) compound comprises:
A. hydroxycamptothecine in pyridine with contain the benzoylchloride hydrochloride reactant salt of tertiary amine, also can in organic solvent, add DMAP or tertiary amine, stirred 1-50 hour at-20~50 ℃, formation is as the compound of general formula (I).
B. hydroxycamptothecine in organic solvent with amino by the amino acid of benzyl or CBZ or BOC protection at DCC; or DCC/DMAP; or under the effect of other corresponding active substances; form ester in temperature of reaction-20~50 a ℃ following reaction; in organic solvent, slough again blocking group and with corresponding sour salify, form compound as general formula (I).
C. by 10-hydroxycamptothecine (II a) in organic solvent with the amino acid that contains disubstituted amido at DCC, or DCC/DMAP, or the effect of other corresponding active substances forms ester down, the reaction times is more than 1 hour, temperature of reaction-20~50 ℃.
Used organic solvent is halogen-containing organic solvent dichloromethane, chloroform or chlorobenzene; Or not halogen-containing organic solvent-benzene, toluene, hexane or hexanaphthene; Or contain other heteroatomic organic solvent pyridines, acetonitrile, acetone, DMF, DMSO, THF or ether.
The derivative (I) that contains 10-hydroxycamptothecine of the present invention can be used for preparing the medicine to people and animal generation antitumour activity.
The present invention forms by chemical reaction (structural modification) and to contain amino acid whose derivative under the prerequisite that does not change the intrinsic pharmacologically active of 10-hydroxycamptothecine, and makes prodrug with corresponding sour salify, improves that it is water-soluble thereby reach, and reduces the purpose of toxic side effect.
Embodiment
Following embodiment can make those skilled in the art more fully understand the present invention, but does not limit the present invention in any way.
Embodiment 1
The preparation of hydroxycamptothecine 10-(γ-N, N-diethylin) butyric ester hydrochloride
Under the exsiccant nitrogen gas stream, in 25ml exsiccant three-necked bottle, add the 80mg10-hydroxycamptothecine, the 4ml anhydrous pyridine at room temperature is stirred to dissolving fully.300mg (γ-N, N-diethylin) butyryl chloride hydrochloride is dissolved in the 5ml exsiccant methylene dichloride, slowly drips, reaction is 2-3 hour under the room temperature.Reaction is finished, and adds water number and drip in reaction solution, stirs 5 minutes, adds the 15ml ether, separates out solid, filters, and washes solid with ether.Solid is dissolved in methyl alcohol, ends when dripping ether to muddiness, static crystallization, suction filtration washes with ether; Behind the recrystallization, drying under reduced pressure obtains faint yellow solid 60mg as stated above, and m.p221-223 ℃, yield 54%.IR(KBr,cm
-1):3559,3435,2942,2646,1774,1743,1653,1602,1587,1462,1437,1346,1234,1194,1161,1141,1107,1068。
13C-NMR(500Hz),δ:7.745(C-18),8.369(C-28),18.267(C-25),30.311(C-19),30.535(C-24),46.098(C-27),49.175(C-5),50.138(C-26),65.222(C-17),72.334(C-20),96.680(C-14),119.094(C-9),119.117(C-16),125.911(C-11),128.203(C-8),130.289(C-12),130.376(C-6),131.133(C-7),145.225(C-13),145.837(C-3),148.827(C-10),149.948(C-15),152.485(C-2),156.709(C-22),171.055(C-23),172.376(C-21)。
Embodiment 2
The preparation of hydroxycamptothecine 10-(gamma-amino) butyric ester acetate
The 280mg γ-An Jidingsuan and the 250mgDCC of CBZ protection are dissolved in 10mlCH
2Cl
2In, add 40mgDMAP, stir 10min under the room temperature, add 0.5ml pyridine and 150mg HCPT again.Reaction was filtered more than 10 hours, and it is acidity that filtrate is washed till water layer with the sour water of pH3.Use saturated NaHCO again
3Be washed till water layer for alkalescence, be washed to neutrality with saturated common salt at last.With the organic layer anhydrous Na
2SO
4Drying, the evaporate to dryness organic solvent.With the THF dissolving, add 0.5ml acetate, a little 10% palladium-carbon feeds the hydrogen hydrogenolysis, reacts about 1 hour, filters, and adds the ether crystallization, obtains faint yellow solid 100mg, yield 46%.IR(KBr,cm
-1):3428,2927,1745,1657,1623,1591,1504,1235,1193,1162,1109,1047。ESI-MS:450(M
+-AcOH)
Embodiment 3
The preparation of HCPT-gamma-aminobutyric acid ester hydrochloride
The gamma-aminobutyric acid and the 250mgDCC of 230mgBoc protection are dissolved in 10mlCH
2Cl
2In, add 40mgDMAP, stir 10min.Add 0.5ml pyridine and 150mgHCPT, reaction was used the acid rinsing of pH3 more than 10 hours after reaction is finished, be washed till water layer for acid, it is alkaline washing to water layer with saturated NaHCO3 again, is neutral with saturated common salt water washing to water layer at last, organic layer anhydrous Na SO4 drying.Wave organic solvent and obtain the 200mg faint yellow solid, yield 85%.This solid is dissolved in the mixed solution of ethyl acetate and methylene dichloride, and the ice bath cooling drips the saturated ethyl acetate solution of HCl down, after reaction is finished, filters, and filter cake is water-soluble, adds acetone, and crystallization filters and obtains HCPT-gamma-aminobutyric acid ester hydrochloride 20mg.Yield 11%.ESI-MS:450(M
+-AcOH)
Embodiment 4
The preparation of hydroxycamptothecine 10-(γ-N, N-dimethylamino) butyric ester hydrochloride
Under the exsiccant nitrogen gas stream, in 25ml exsiccant three-necked bottle, add the 100mg10-hydroxycamptothecine, the 4.5ml anhydrous pyridine at room temperature is stirred to dissolving fully.300mg (γ-N, N-dimethylamino) butyryl chloride hydrochloride is dissolved in the 5ml exsiccant methylene dichloride, slowly drips, reaction is 2-3 hour under the room temperature, filters, and the solid drying under reduced pressure obtains the 130mg crude product.The fine powder of crude product is dispersed in the methyl alcohol, stirs 2-5min, filter, drying under reduced pressure obtains faint yellow solid 90mg, yield 64%, m.p247-250 ℃.IR(KBr,cm
-1):3582,3435,3035,2964,2676,1757,1663,1634,1606,1554,1503,1467,1230,1190,1158,1143,1130。
13C-NMR(500Hz),δ:6.670(C-1),18.615(C-2),29.758(C-3),30.283(C-4),42.237(C-5),48.919(C-6),55.998(C-7),64.985(C-8),
72.764(C-9),97.881(C-10),117.590(C-11),118.216(C-12),125.172(C-13),126.737(C-14),
127.615(C-15),128.001(C-16),130.790(C-17),143.074(C-18),143.404(C-19),144.977(C-20),149235(C-21),149986(C-22),156.187(C-23),171.537(C-24),173531(C-25)。
Embodiment 5
The preparation of hydroxycamptothecine 10-(γ-N, N-dimethylamino) butyric ester hydrochloride
In the exsiccant three-necked bottle, add 90mg γ-N, N-dimethylamino butyrates hydrochlorate, 180mgDCC and 60mgDMAP, in the mixed solvent of 10ml methylene dichloride and 1ml pyridine, stir 15min, add 100mg HCPT again, at room temperature reacted 2-3 days, column chromatography purification, obtain the 50mg faint yellow solid, m.p:247-250 ℃, yield 35%.
ESI-MS:478(M
+)
Embodiment 6
The preparation of hydroxycamptothecine 10-(γ-morpholine) butyric ester hydrochloride
Under the exsiccant nitrogen gas stream, in 25ml exsiccant three-necked bottle, add the 80mg10-hydroxycamptothecine, the 4ml anhydrous pyridine at room temperature is stirred to dissolving fully.350mg γ-morpholine butyryl chloride hydrochloride is dissolved in the 10ml exsiccant methylene dichloride, slowly drips, reaction is 2-3 hour under the room temperature.After reacting completely, in reaction solution, add water number and drip, stirred 5 minutes, add the 15ml ether, separate out solid, filter, wash solid with ether.Solid is dissolved in methyl alcohol, ends when dripping ether to muddiness, stirring and crystallizing, suction filtration, with the ether flushing, drying under reduced pressure obtains faint yellow solid 25mg, yield 20%.IR(KBr,cm
-1):3425,2929,2614,1747,1658,1602,1503,1463,1366,1233,1193,1158。1046。ESI-MS:520(M
+-HCl)。
Claims (5)
1. a series of derivatives that contain 10-hydroxycamptothecine is characterized in that this derivative has following general formula (I):
Wherein, A is saturated hydrocarbon polymer, has following structure:
Wherein, m=0,1,2,3; N=0,1,2,3; M and n are identical or different; R
1=H, Me, Et; R
2=H, Me, Et; R
1With R
2Identical or different;
D represents to contain the organic group of nitrogen-atoms, D=NR
3R
4: R wherein
3, R
4Expression H, C
1-6Straight chain or containg branched alkyl radical, R
3With R
4Identical or different;
HB is meant and can be used as medicinal mineral acid example hydrochloric acid, phosphoric acid, sulfuric acid or carbonic acid; Or can be used as medicinal organic acid such as acetate, lactic acid, methylsulfonic acid, Succinic Acid, Citric Acid, fumaric acid, toxilic acid or oxysuccinic acid.
2. the described derivative synthesizing process that contains 10-hydroxycamptothecine of claim 1 is characterized in that this method is:
By 10-hydroxycamptothecine in organic solvent with the acyl chloride hydrochloride that contains tertiary amine 1:1-8 in molar ratio, with Duo than the acyl chloride hydrochloride that contains tertiary amine under the effect of the pyridine of one times of mole or DMAP or tertiary amine, under temperature of reaction-20~50 ℃, reaction forms the ester that contains tertiary amine;
Used organic solvent is halogen-containing organic solvent dichloromethane, chloroform or chlorobenzene; Or not halogen-containing organic solvent-benzene, toluene, hexane or hexanaphthene; Or containing other heteroatomic organic solvent pyridines, acetonitrile, acetone, DMF, DMSO, THF or ether, consumption of organic solvent is as the criterion with the 10-hydroxycamptothecine that dissolving participates in reaction.
3. the described derivative synthesizing process that contains 10-hydroxycamptothecine of claim 1 is characterized in that this method is:
By 10-hydroxycamptothecine in organic solvent with the amino of mol ratio 1:1-3 by the amino acid of benzyl or carbobenzoxy-(Cbz) CBZ or tertbutyloxycarbonyl BOC protection at equimolar DCC, or DCC/DMAP, or other are similar under the effect of active substance of DCC sample effect, temperature of reaction-20~50 ℃ down reaction form ester, in organic solvent, slough again blocking group and with corresponding sour salify;
Used organic solvent is halogen-containing organic solvent dichloromethane, chloroform or chlorobenzene; Or not halogen-containing organic solvent-benzene, toluene, hexane or hexanaphthene; Or contain other heteroatomic organic solvent pyridines, acetonitrile, acetone, DMF, DMSO, THF or ether; Consumption of organic solvent is as the criterion with the 10-hydroxycamptothecine that dissolving participates in reaction.
4. the described derivative synthesizing process that contains 10-hydroxycamptothecine of claim 1 is characterized in that this method is:
By 10-hydroxycamptothecine in organic solvent with the amino acid that contains tertiary amine of mol ratio 1:1-3 at equimolar DCC, or DCC/DMAP, or other are similar under the effect of active substance of DCC sample effect, under temperature of reaction-20~50 ℃, form the ester that contains tertiary amine;
Used organic solvent is halogen-containing organic solvent dichloromethane, chloroform or chlorobenzene; Or not halogen-containing organic solvent-benzene, toluene, hexane or hexanaphthene; Or contain other heteroatomic organic solvent pyridines, acetonitrile, acetone, DMF, DMSO, THF or ether; Consumption of organic solvent is as the criterion with the 10-hydroxycamptothecine that dissolving participates in reaction.
5. according to the described derivative that contains 10-hydroxycamptothecine of claim 1, it is characterized in that described compound (I) hydrolyzable in animal and human body discharges antitumour activity medicine hydroxycamptothecine.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNA2008100702761A CN101397301A (en) | 2008-09-10 | 2008-09-10 | Water-soluble derivates containing 10-hydroxycamptothecin and preparation method |
CN2009101762711A CN101654456B (en) | 2008-09-10 | 2009-09-08 | Water-soluble derivants containing 10-hydroxycamptothecine and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNA2008100702761A CN101397301A (en) | 2008-09-10 | 2008-09-10 | Water-soluble derivates containing 10-hydroxycamptothecin and preparation method |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101397301A true CN101397301A (en) | 2009-04-01 |
Family
ID=40516167
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2008100702761A Pending CN101397301A (en) | 2008-09-10 | 2008-09-10 | Water-soluble derivates containing 10-hydroxycamptothecin and preparation method |
CN2009101762711A Expired - Fee Related CN101654456B (en) | 2008-09-10 | 2009-09-08 | Water-soluble derivants containing 10-hydroxycamptothecine and preparation method thereof |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2009101762711A Expired - Fee Related CN101654456B (en) | 2008-09-10 | 2009-09-08 | Water-soluble derivants containing 10-hydroxycamptothecine and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (2) | CN101397301A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102190622A (en) * | 2010-03-15 | 2011-09-21 | 李勤耕 | Water-soluble derivatives of edaravone, preparation method and application thereof |
CN103848840A (en) * | 2012-12-03 | 2014-06-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Camptothecin derivatives and medical application thereof |
CN103864810A (en) * | 2012-12-07 | 2014-06-18 | 天津科技大学 | Preparation method of novel 10-hydroxycamptothecine 10-position derivatives and application in antitumor drugs |
CN106588946A (en) * | 2017-01-25 | 2017-04-26 | 郑州大学 | 10-HCPT (10-hydroxycamptothecine) derivative, synthesis method and application thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6019790A (en) * | 1983-07-14 | 1985-01-31 | Yakult Honsha Co Ltd | Novel camptothecin derivative |
-
2008
- 2008-09-10 CN CNA2008100702761A patent/CN101397301A/en active Pending
-
2009
- 2009-09-08 CN CN2009101762711A patent/CN101654456B/en not_active Expired - Fee Related
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102190622A (en) * | 2010-03-15 | 2011-09-21 | 李勤耕 | Water-soluble derivatives of edaravone, preparation method and application thereof |
CN102190622B (en) * | 2010-03-15 | 2015-01-07 | 李勤耕 | Water-soluble derivatives of edaravone, preparation method and application thereof |
CN103848840A (en) * | 2012-12-03 | 2014-06-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Camptothecin derivatives and medical application thereof |
CN103864810A (en) * | 2012-12-07 | 2014-06-18 | 天津科技大学 | Preparation method of novel 10-hydroxycamptothecine 10-position derivatives and application in antitumor drugs |
CN106588946A (en) * | 2017-01-25 | 2017-04-26 | 郑州大学 | 10-HCPT (10-hydroxycamptothecine) derivative, synthesis method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN101654456A (en) | 2010-02-24 |
CN101654456B (en) | 2013-01-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2561356T3 (en) | Camptothecin derivatives with antitumor activity | |
PT749432E (en) | 9-DEOXOTAXANE COMPOUNDS | |
JP2024506819A (en) | Camptothecin compounds, their preparation methods and their applications | |
WO2013000286A1 (en) | Bufogenin derivatives, preparation methods, compositions containing such derivatives and uses thereof | |
JP2010540471A (en) | Gambogic acid glycoside derivatives and analogs, and their production and application | |
JP6196616B2 (en) | 10-methoxycamptothecin derivative, process for its production and use | |
WO2021026016A1 (en) | Fused polycyclic dimers | |
CN101654456B (en) | Water-soluble derivants containing 10-hydroxycamptothecine and preparation method thereof | |
RU2411244C2 (en) | Camptotecin derivatives and application thereof | |
CN101495485B (en) | Camptothecin derivatives with antitumor activity | |
CN102336904B (en) | Multivalent polyglycol (PEG) modifier for camptothecin and derivatives thereof and application of multivalent PEG modifier | |
JP6043729B2 (en) | New camptothecin derivatives | |
ES2395930T3 (en) | Stereoselective procedure and crystalline forms of a camptothecin | |
WO2021024256A1 (en) | Anticancer agents | |
CN105777769A (en) | 7-ethyl-10-hydroxycamptothecin derivatives, and preparation and application thereof | |
CN117427176A (en) | Drug conjugate and application thereof | |
CN104098594A (en) | Biotin-podophyllotoxin esterified derivative and pharmaceutical composition thereof, as well as preparation methods and applications of derivative and pharmaceutical composition | |
JP2010500970A (en) | Camptothecin derivatives having antitumor activity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |