CN102492010A - Derivatives of camptothecin 20-site bile acid and preparation method thereof - Google Patents

Derivatives of camptothecin 20-site bile acid and preparation method thereof Download PDF

Info

Publication number
CN102492010A
CN102492010A CN2011104189305A CN201110418930A CN102492010A CN 102492010 A CN102492010 A CN 102492010A CN 2011104189305 A CN2011104189305 A CN 2011104189305A CN 201110418930 A CN201110418930 A CN 201110418930A CN 102492010 A CN102492010 A CN 102492010A
Authority
CN
China
Prior art keywords
nsc
camptothecin derivative
hydrogen
acid
cholic acid
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
Application number
CN2011104189305A
Other languages
Chinese (zh)
Inventor
李庆勇
张宝友
赵腾飞
祖元刚
高文轻
朱翘楚
张黎
孙佰贺
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Northeast Forestry University
Original Assignee
Northeast Forestry University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Northeast Forestry University filed Critical Northeast Forestry University
Priority to CN2011104189305A priority Critical patent/CN102492010A/en
Publication of CN102492010A publication Critical patent/CN102492010A/en
Pending legal-status Critical Current

Links

Landscapes

  • Steroid Compounds (AREA)

Abstract

The invention relates to camptothecin derivatives of a formula (I) and medicines thereof, and relates to a method for preparing the compound and the use of the compounds as medicines in treatment of tumors. In the formula (I), R1 may be hydrogen or ethyl, R2 may be hydrogen and nitro, and the R3 and R4 may be hydrogen and hydroxyl.

Description

20 chlolic acid derivatives of NSC 94600 and preparation method thereof
Technical field
The present invention relates to the preparation method of Cmptothecine derivative and the application in antineoplaston.
Background technology
1966; NSC 94600 has been studied since people such as the U.S. scientist MonroeE.Wall discovery of natural product with its notable antitumor activity; In the time in 38 years, Pharmaceutical Chemists have been made extensive work on the structural modification of NSC 94600 in the past, and countries such as the U.S., Japan, Britain, Canada all actively put in the research and development of camptothecin derivative; And obtained great achievement; A large amount of camptothecin derivatives is designed synthetic, successively has two camptothecin derivative Topotecan, Irinotecan to be approved for antitumor drug and to have gone on the market in all parts of the world, and other tens camptothecin derivatives are in the different steps of development of clinical studies.Camptothecin derivative demonstrates remarkable anti-tumor activity, is being of great use as cancer therapy drug, but because its spinoff receives strict control in clinical application.As everyone knows, NSC 94600,9-nitrocamptothecin and 7-SN 22 etc. have anti-tumor activity, clinically are used to treat cancer of the stomach, intestinal cancer, bladder cancer, lung cancer and white blood disease, but can cause spinoffs such as marrow resistance, vomiting, diarrhoea and severe haemorrhage.As: Iinothecan [CPT-11] puts goods on the market, and in clinical application, shows potential anti-tumor activity, but the same with other antitumor drug, demonstrates violent toxicity, causes the therapeutic action of CPT-11 to be restricted.[referring to the 709th page of " cancer and chemotherapy " 21 volume].
The NSC 94600 indissoluble, photo-thermal is unstable, and spinoff is big.Water insoluble and numerous organic solvents such as NSC 94600,9-nitrocamptothecin and 7-SN 22.In order to improve the camptothecin analogues anti-tumor activity, increase its stability and water-soluble simultaneously, increase bioavailability; Reduce its toxic side effect as much as possible; NSC 94600 and 9-nitrocamptothecin, 7-SN 22 to having serious side effects are modified research, seek good water solubility, and be stable; Toxic side effect is little, and the camptothecine with aequum is delivered to target tissue effectively.
Cholic acid is present unique oral hepatic targeting drug carrier, and it has special movement system in vivo.Cholic acid can be absorbed by liver specifically, and this absorption is through the Na on the liver plasma membrane +Dependency movement system (NTCP) and Na +Dependent/non-dependent movement system (OTAP) realizes.Cholic acid is the specific natural aglucon of endogenic liver cell, has the organ specificity of height.Cholic acid in liver cell by the SUV biosynthesizing; Combine with glycocoll or taurine then; With bile row people small intestine; Be absorbed into liver again, constantly carry out liver sausage and circulate in the human body liver sausage circulation and repeat to participate in round-robin cholic acid total amount 6-15 time every day and reach 17-40g, so have higher turn-over capacity.Cholic acid is that the approach through active transport is absorbed; Be that targeting vector can improve bioavailability of medicament and has good bio-compatibility as endogenic natural aglucon cholic acid with the cholic acid; Being suitable for the carrier as targeted drug, is targeting vector with the cholic acid, not only can realize the liver target of medicine; Reduce toxic side effect, and can improve the bioavailability in vivo of medicine.
In recent years, people are to being that the research of the hepatic targeting drug of carrier deepens continuously with the cholic acid, bibliographical information polypeptide, lipid lowerers, antiviral drug, antitumour drug, antidiabetic drug and nitrate esters medicine etc. and cholic acid bonded hepatic targeting drug arranged.Show that through cell and animal experiment study after medicine and the cholic acid coupling, the liver that has increased medicine to some extent absorbs, and has reduced the toxic side effect of medicine.Some medicine such as cholic acid and nitric acid vinegar conjugates one have advanced people's clinical study stage.Kramer etc. utilize TV as model drug and cholic acid coupling, have investigated the liver target and the anti-tumor activity of conjugates.TV is connected to 3 hydroxyls of cholic acid, obtains cholic acid-TV conjugates.The result shows that former medicine has only faint effect to liver cholic acid transporter, and corresponding cholic acid conjugates strongly inhibited the liver of tca absorb, explaining has stronger interaction between conjugates and cholic acid transporter, medium effective concentration is IC 50=3-5 μ mol/L; Former medicine＞100 μ mol/L are visible, and conjugates has the transport features of cholic acid, and the liver that can increase medicine absorbs, and reaches the target purpose.
People such as Monte form glycine cholic acid-cis-platinum inner complex with glycine cholic acid and cis-platinum coupling, in vivo tests show this inner complex can by tumour cell absorb and absorbed dose apparently higher than former medicine.As natural cholic acid, can advance the circulation of people's liver sausage, increase the little intestinal absorption and the choleresis of former medicine,, have only a small amount of through the urine eliminating.Simultaneously, also can effectively suppress the growth of external and interior tumor cell, have certain anti-tumor activity.Referring to [2006 15 the 3rd phases of volume of Chinese Journal of New Drugs].
Summary of the invention
The object of the present invention is to provide the antineoplastic pharmacologically active of a kind of abundant maintenance NSC 94600, solve its poor solubility, light, thermally labile, the camptothecin derivative of problem such as target property is poor, and bioavailability is low, and toxic side effect is big.Improved the target property of medicine.
Another object of the present invention provides the preparation method of such camptothecin derivative.
In order to accomplish the object of the invention, the contriver has carried out a large amount of creationary researchs, is filling under the antineoplastic pharmacologically active prerequisite of maintenance NSC 94600; Solve its poor solubility; Light, thermally labile, target property is poor, and bioavailability is low; Problems such as toxic side effect is big have finally been found and can have been generated the camptothecin derivative with liver target through 20 hydroxyls of camptothecin derivative and chlolic acid derivatives reaction.
The new camptothecin derivative of the present invention is represented with formula (I):
Wherein
R 1Be hydrogen, ethyl;
R 2Be hydrogen, nitro;
R 3Be hydrogen, hydroxyl;
R 4Be hydrogen, hydroxyl.
The preparation method 1 of the camptothecin derivative that the present invention is new:
It is characterized in that the camptothecin derivative shown in the formula (II)
Figure BDA0000120351070000022
Wherein
R 1And R 2Definition with claim 2;
With the bromoacetic acid reaction shown in the formula (III)
Figure BDA0000120351070000031
With the camptothecin derivative shown in the production (IV)
Figure BDA0000120351070000032
Wherein
R 1And R 2Definition with claim 2;
With the chlolic acid derivatives shown in (V) formula
Figure BDA0000120351070000033
R wherein 3And R 4Definition is with claim 3;
Reflect to generate the described camptothecin derivative of claim 1 with camptothecin derivative shown in the formula (IV)
Figure BDA0000120351070000034
R wherein 3And R 4Definition is with claim 3.
The present invention also comprise described in claim 1 to 4 compound preparation in the antitumor drug purposes and contain antitumor drug just like compound described in the claim 1 to 4.
Advantage of the present invention: camptothecin derivative of the present invention has not only kept the stability of reactive site lactonic ring; And good water solubility; Greatly reduce the toxicity that camptothecine compounds brings because of the water surrounding that is insoluble to body fluid; Increase bioavailability of medicament, fully kept the antineoplastic pharmacologically active of NSC 94600.There is the activity of the inhibition topoisomerase I of part of compounds to be superior to NSC 94600 in the camptothecin derivative involved in the present invention, the selection activity of topoisomerase I is superior to NSC 94600.
Embodiment:
Embodiment 1: cholic acid-O-acetate-20-O-NSC 94600 (A1) is synthetic:
(1) bromoacetic acid-20-O-NSC 94600 is synthetic:
In the 25ml there-necked flask, add NSC 94600 174mg (0.5mmol); Bromoacetic acid 138mg (1mmol); 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol), 4-Dimethylamino pyridine (DMAP) 18mg (0.17mmol), anhydrous methylene chloride 10ml; Stirred 3.5 hours under the room temperature, follow the tracks of reaction by TLC.In reaction solution, add chloroform 20ml after reacting completely, use 50ml water, the saturated NaHCO of 50ml successively 3Solution washing 3 times, anhydrous MgSO 4Drying, decompress filter is removed MgSO 4Back concentrating under reduced pressure, silica gel column chromatography gets yellow solid, yield 90%; Molecular weight 469.3; Structural formula as
Figure BDA0000120351070000041
(2) cholic acid-O-acetate-20-O-NSC 94600 is synthetic:
In the 25mL round-bottomed flask, add compound bromoacetic acid-20-O-NSC 94600 46.8mg (0.1mmol), 1mL DMSO and excess of bile acids add the 0.1ml triethylamine; Stirring at room 4h follows the tracks of reaction by TLC, and back zero(ppm) water in reaction solution reacts completely; Separate out white solid product; Filter oven dry, silica gel column chromatography separating purification.Get compound cholic acid-O-acetate-20-O-NSC 94600 (A1).Pale yellow powder; Molecular weight is 796; Yield 68%.Structural formula is following:
Figure BDA0000120351070000051
Embodiment 2: Septochol-O-acetate-20-O-NSC 94600 (A2) is synthetic:
(1) bromoacetic acid-20-O-NSC 94600 is synthetic:
Method is identical with instance 1 (1)
(2) Septochol-O-acetate-20-O-NSC 94600 is synthetic:
In the 25mL round-bottomed flask, add compound bromoacetic acid-20-O-NSC 94600 46.8mg (0.1mmol), 1mL DMSO and excessive Septochol add the 0.1ml triethylamine; Stirring at room 4h follows the tracks of reaction by TLC, and back zero(ppm) water in reaction solution reacts completely; Separate out white solid product; Filter oven dry, silica gel column chromatography separating purification.Get compound Septochol-O-acetate-20-O-NSC 94600 (A2).Pale yellow powder; Molecular weight is 780.9; Yield 64%.Structural formula is following:
Embodiment 3: Ursodeoxycholic Acid (UDCA)-O-acetate-20-O-NSC 94600 (A3) is synthetic:
(1) bromoacetic acid-20-O-NSC 94600 is synthetic:
Method is identical with instance 1 (1)
(2) Ursodeoxycholic Acid (UDCA)-O-acetate-20-O-NSC 94600 is synthetic:
In the 25mL round-bottomed flask, add compound bromoacetic acid-20-O-NSC 94600 46.8mg (0.1mmol), 1mL DMSO and excessive Ursodeoxycholic Acid (UDCA) add the 0.1ml triethylamine; Stirring at room 4h follows the tracks of reaction by TLC, and back zero(ppm) water in reaction solution reacts completely; Separate out white solid product; Filter oven dry, silica gel column chromatography separating purification.Get compound Ursodeoxycholic Acid (UDCA)-O-acetate-20-O-NSC 94600 (A3).Pale yellow powder; Molecular weight is 780.9; Yield 65%.Structural formula is following:
Figure BDA0000120351070000061
Embodiment 4: gallodesoxycholic acid-O-acetate-20-O-NSC 94600 (A4) is synthetic:
(1) bromoacetic acid-20-O-NSC 94600 is synthetic:
Method is identical with instance 1 (1)
(2) gallodesoxycholic acid-O-acetate-20-O-NSC 94600 is synthetic:
In the 25mL round-bottomed flask, add compound bromoacetic acid-20-O-NSC 94600 46.8mg (0.1mmol), 1mL DMSO and excessive gallodesoxycholic acid add the 0.1ml triethylamine; Stirring at room 4h follows the tracks of reaction by TLC, and back zero(ppm) water in reaction solution reacts completely; Separate out white solid product; Filter oven dry, silica gel column chromatography separating purification.Get compound gallodesoxycholic acid-O-acetate-20-O-NSC 94600 (A4).Pale yellow powder; Molecular weight is 780.9; Yield 66%.Structural formula is following:
Figure BDA0000120351070000062
Embodiment 5: cholic acid-O-acetate-20-O-7-ethyl-NSC 94600 (A5) is synthetic:
(1) bromoacetic acid-20-O-7-ethyl-NSC 94600 is synthetic:
In the 25ml there-necked flask, add 7-ethyl-NSC 94600 186mg (0.5mmol); Bromoacetic acid 138mg (1mmol); 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol), 4-Dimethylamino pyridine (DMAP) 18mg (0.17mmol), anhydrous methylene chloride 10ml; Stirred 3.5 hours under the room temperature, follow the tracks of reaction by TLC.In reaction solution, add chloroform 20ml after reacting completely, use 50ml water, the saturated NaHCO of 50ml successively 3Solution washing 3 times, anhydrous MgSO 4Drying, decompress filter is removed MgSO 4Back concentrating under reduced pressure behind the silica gel column chromatography, gets yellow solid, yield 90%; Molecular weight 497.35; Structural formula is following:
Figure BDA0000120351070000071
(2) cholic acid-O-acetate-20-O-7-ethyl-NSC 94600 is synthetic:
In the 25mL round-bottomed flask, add compound bromoacetic acid-20-O-7-ethyl-NSC 94600 49.6mg (0.1mmol), 1mL DMSO and excess of bile acids add the 0.1ml triethylamine; Stirring at room 4h follows the tracks of reaction by TLC, and back zero(ppm) water in reaction solution reacts completely; Separate out white solid product; Filter oven dry, silica gel column chromatography separating purification.Get compound cholic acid-O-acetate-20-O-7-ethyl-NSC 94600 (A5).Pale yellow powder; Molecular weight is 824.9; Yield 60%.Structural formula is following:
Figure BDA0000120351070000072
Embodiment 6: cholic acid-O-acetate-20-O-9-nitro-NSC 94600 (A6) is synthetic:
(1) bromoacetic acid-20-O-9-nitro-NSC 94600 is synthetic:
In the 25ml there-necked flask, add 9-nitro-NSC 94600 196mg (0.5mmol); Bromoacetic acid 138mg (1mmol); 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol), 4-Dimethylamino pyridine (DMAP) 18mg (0.17mmol), anhydrous methylene chloride 10ml; Stirred 3.5 hours under the room temperature, follow the tracks of reaction by TLC.In reaction solution, add chloroform 20ml after reacting completely, use 50ml water, the saturated NaHCO of 50ml successively 3Solution washing 3 times, anhydrous MgSO 4Drying, decompress filter is removed MgSO 4Back concentrating under reduced pressure.Get yellow solid, yield 89%; Molecular weight 514.2; Structural formula is following:
Figure BDA0000120351070000081
(2) cholic acid-O-acetate-20-O-9-nitro-NSC 94600 is synthetic:
In the 25mL round-bottomed flask, add compound bromoacetic acid-20-O-9-nitro-NSC 94600 51.3mg (0.1mmol), 1mL DMSO and excess of bile acids add the 0.1ml triethylamine; Stirring at room 4h follows the tracks of reaction by TLC, and back zero(ppm) water in reaction solution reacts completely; Separate out white solid product; Filter oven dry, silica gel column chromatography separating purification.Get compound cholic acid-O-acetate-20-O-9-nitro-NSC 94600 (A6).Pale yellow powder; Molecular weight is 841.9; Yield 61%.Structural formula is following:
Figure BDA0000120351070000082

Claims (6)

1. described camptothecin derivative is represented with formula (I):
Figure FDA0000120351060000011
Wherein
R 1Be hydrogen, ethyl;
R 2Be hydrogen, nitro;
R 3Be hydrogen, hydroxyl;
R 4Be hydrogen, hydroxyl.
2. camptothecin derivative according to claim 1, wherein R 1Be hydrogen, ethyl; R 2Be hydrogen, nitro.
3. camptothecin derivative according to claim 1, wherein R 3Be hydrogen, hydroxyl; R 4Be hydrogen, hydroxyl.
4. the preparation method of the described camptothecin derivative of claim 1:
It is characterized in that the camptothecin derivative shown in the formula (II)
Figure FDA0000120351060000012
Wherein
R 1And R 2Definition with claim 2;
With the bromoacetic acid reaction shown in the formula (III)
Figure FDA0000120351060000021
With the camptothecin derivative shown in the production (IV)
Figure FDA0000120351060000022
Wherein
R 1And R 2Definition with claim 2;
With the chlolic acid derivatives shown in (V) formula
Figure FDA0000120351060000023
R wherein 3And R 4Definition is with claim 3;
Reflect to generate the described camptothecin derivative of claim 1 with camptothecin derivative shown in the formula (IV)
Figure FDA0000120351060000024
(VII)
R wherein 3And R 4Definition is with claim 3.
5. the compound of claim 1-4 is as the purposes in the preparation antitumor drug.
6. the compound of claim 1-4 is used to treat the application of activeconstituents of the medicine of tumour as preparation.
CN2011104189305A 2011-12-15 2011-12-15 Derivatives of camptothecin 20-site bile acid and preparation method thereof Pending CN102492010A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2011104189305A CN102492010A (en) 2011-12-15 2011-12-15 Derivatives of camptothecin 20-site bile acid and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2011104189305A CN102492010A (en) 2011-12-15 2011-12-15 Derivatives of camptothecin 20-site bile acid and preparation method thereof

Publications (1)

Publication Number Publication Date
CN102492010A true CN102492010A (en) 2012-06-13

Family

ID=46183878

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2011104189305A Pending CN102492010A (en) 2011-12-15 2011-12-15 Derivatives of camptothecin 20-site bile acid and preparation method thereof

Country Status (1)

Country Link
CN (1) CN102492010A (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11826430B2 (en) 2019-05-14 2023-11-28 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11834458B2 (en) 2021-03-23 2023-12-05 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11952349B2 (en) 2019-11-13 2024-04-09 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US12006314B2 (en) 2021-05-03 2024-06-11 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005118612A1 (en) * 2004-06-04 2005-12-15 Sonus Pharmaceuticals, Inc. Cholesterol/bile acid/bile acid derivative-modified therapeutic anti-cancer drugs
CN101948500A (en) * 2010-09-15 2011-01-19 东北林业大学 New derivative of camptothecin 20-site coupled bile acid

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005118612A1 (en) * 2004-06-04 2005-12-15 Sonus Pharmaceuticals, Inc. Cholesterol/bile acid/bile acid derivative-modified therapeutic anti-cancer drugs
CN101948500A (en) * 2010-09-15 2011-01-19 东北林业大学 New derivative of camptothecin 20-site coupled bile acid

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
《Journal of Molecular Structure: THEOCHEM》 20050520 Min-Jie Li等 "QSAR studies of 20(S)-camptothecin analogues as antitumor agents" 第169页3.3节及表3 1-6 第723卷, 第1-3期 *
MIN-JIE LI等: ""QSAR studies of 20(S)-camptothecin analogues as antitumor agents"", 《JOURNAL OF MOLECULAR STRUCTURE: THEOCHEM》, vol. 723, no. 13, 20 May 2005 (2005-05-20) *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11826430B2 (en) 2019-05-14 2023-11-28 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11952349B2 (en) 2019-11-13 2024-04-09 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11834458B2 (en) 2021-03-23 2023-12-05 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US12006314B2 (en) 2021-05-03 2024-06-11 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds

Similar Documents

Publication Publication Date Title
CN102516347A (en) Camptothecin 20-site cholic acid derivative and preparation method thereof
CN101948500A (en) New derivative of camptothecin 20-site coupled bile acid
CN103751795B (en) Preparation and application of hyaluronic acid-antitumor drug conjugate and composite nanoparticle composition
Zhao et al. Dual-active targeting liposomes drug delivery system for bone metastatic breast cancer: Synthesis and biological evaluation
CN101967173A (en) Novel camptothecin derivative coupled with cholic acid at position 10
CN111330014B (en) Acid-responsive cross-linked polymer prodrug and preparation method and application thereof
CN102492009A (en) Camptothecin 20- position cholic acid derivative and preparation method thereof
CN101967172A (en) Novel derivates of camptothecin 10-position coupled bile acid
CN102532237A (en) Camptothecin tenth-position cholic acid coupling compound and preparation method thereof
CN106831805A (en) A kind of camptothecine adriamycin prodrug and its preparation method and application
CN102492010A (en) Derivatives of camptothecin 20-site bile acid and preparation method thereof
CN110591078A (en) Preparation method of reduction/pH dual-responsiveness adriamycin prodrug
CN111529715B (en) Dextran-docosahexaenoic acid coupling polymer and synthesis method and application thereof
CN102225961A (en) Novel berberine 9-position coupled cholic acid derivative and preparation method thereof
CN103130854A (en) Vitamin E succinic acid esterification gemcitabine prodrug and application
CN106631957A (en) Antitumor compound targeting FAP-alpha enzyme and preparation method and application thereof
CN110665009B (en) Nanometer gemcitabine for promoting normalization of tumor blood vessels and application thereof
CN113230417B (en) Preparation and application of glucose and triphenyl phosphonium modified brain tumor targeted liposome
CN107951839B (en) Polyion micelle shielding system with reversible charges and preparation method thereof
CN102225962A (en) New derivative bonded by berberine and cholic acid at 9th position of berberine and preparation method thereof
CN104610415A (en) Liver-targeting platinum anticancer drug and synthetic method thereof
CN102229636A (en) New derivatives of berberine coupled with cholic acid at ninth position through ester bond and preparation methods thereof
US9655975B2 (en) Prodrug using nitroimidazole
CN110075314B (en) Amphiphilic drug conjugate and preparation method of nanoparticle preparation thereof
CN101402640B (en) Diester camptothecin derivative, preparation method and uses thereof

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

Application publication date: 20120613