CN101948500A - New derivative of camptothecin 20-site coupled bile acid - Google Patents

New derivative of camptothecin 20-site coupled bile acid Download PDF

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CN101948500A
CN101948500A CN201010281844XA CN201010281844A CN101948500A CN 101948500 A CN101948500 A CN 101948500A CN 201010281844X A CN201010281844X A CN 201010281844XA CN 201010281844 A CN201010281844 A CN 201010281844A CN 101948500 A CN101948500 A CN 101948500A
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definition
camptothecin derivative
hydrogen
formula
camptothecine
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李庆勇
祖元刚
高洋
张宝友
何乌娜
赵腾飞
邓晓秋
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Northeast Forestry University
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Northeast Forestry University
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to camptothecin derivatives shown in formula I and II and a drug thereof, in particular to a method for preparing compounds of the invention and an application of compounds as drugs in curing rumours. In the formula I and II, R1 is hydrogen and ethyl, R2 is hydrogen and nitryl, R3 and R4 are hydrogen, hydroxide radical and carbonyl, and R5 is hydroxide radical and carbonyl.

Description

Camptothecine 20 digit pairs are closed the novel derivative of cholic acid
Technical field
The present invention relates to the preparation method of Cmptothecine derivative and the application in antineoplaston.
Background technology
1966, camptothecine has been studied since people such as the U.S. scientist MonroeE.Wall discovery of natural product with its notable antitumor activity, in the past in the time in 38 years, Pharmaceutical Chemists have been made extensive work on the structural modification of camptothecine, the U.S., Japan, Britain, countries such as Canada all actively put in the research and development of camptothecin derivative, and obtained great achievement, a large amount of camptothecin derivatives is designed to synthesize, two camptothecin derivative Topotecan are successively arranged, Irinotecan has been approved for antitumor drug and has 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 side effect is subjected to strict control in clinical application.As everyone knows, camptothecine, 9-nitrocamptothecin and 7-ethyl-camptothecin etc. have anti-tumor activity, clinical cancer of the stomach, intestinal cancer, bladder cancer, lung cancer and the leukemia of being used for the treatment of, but can cause side effects such as marrow resistance, vomiting, diarrhoea and severe haemorrhage.As: Iinothecan[CPT-11] put goods on the market, in clinical application, show potential anti-tumor activity, but the same with other antitumor drug, demonstrate violent toxicity, cause the therapeutic action of CPT-11 to be restricted.[referring to the 709th page of " cancer and chemotherapy " 21 volume].
The camptothecine indissoluble, the photo-thermal instability, side effect is big.Water insoluble and numerous organic solvents such as camptothecine, 9-nitrocamptothecin and 7-ethyl-camptothecin.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, camptothecine and 9-nitrocamptothecin, 7-ethyl-camptothecin with serious side effects are modified research, seek good water solubility, 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 specifically by liver, and this absorption is by 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 by the cholesterol biosynthesizing, combines with glycine or taurine in liver cell then, with bile row people small intestine, is absorbed into liver again, constantly carries out liver sausage and circulates into liver sausage circulation in the human body.Repeat 6-15 every day, participates in round-robin cholic acid total amount and reach 17-40g.Therefore has higher turn-over capacity.Has good bio-compatibility as endogenic natural aglucon 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 by 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 Chlorambucil as model drug and cholic acid coupling, have investigated the liver target and the anti-tumor activity of conjugates.Chlorambucil is connected to 3 hydroxyls of cholic acid, obtains cholic acid-Chlorambucil 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 taurocholate absorb, illustrating 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
As seen, 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 test show that this inner complex can be absorbed by tumour cell 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 on a small quantity and get rid of by urine.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 camptothecine, solve its poor solubility, light, thermally labile, the camptothecin derivative of problem such as target is poor, and bioavailability is low, and toxic side effect is big.Improved the target of medicine.
Another object of the present invention provides the preparation method of such camptothecin derivative.
In order to finish purpose of the present invention, the contriver has carried out a large amount of creationary researchs, filling under the antineoplastic pharmacologically active prerequisite of maintenance camptothecine, solve its poor solubility, light, thermally labile, target 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 by 10 hydroxyls of camptothecin derivative and chlolic acid derivatives reaction.
The new camptothecin derivative of the present invention is represented with following logical formula I:
Figure BSA00000270000900021
Figure BSA00000270000900031
Wherein
R 1Be hydrogen, ethyl;
R 2Be hydrogen, nitro;
R 3Be hydrogen, hydroxyl, carbonyl;
R 4Be hydrogen, hydroxyl, carbonyl;
R 5Hydroxyl, carbonyl.
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 III
Figure BSA00000270000900032
Wherein
R 1Definition with claim 2;
R 2Definition with claim 2;
With the Methionin reaction shown in the formula IV
Figure BSA00000270000900041
With the camptothecin derivative shown in the production (V)
Figure BSA00000270000900042
Wherein
R 1Definition with claim 2;
R 2Definition with claim 2;
Camptothecin derivative shown in (V) formula is taken off protecting group to generate (VI) in the methanol solution of hydrochloric acid
Figure BSA00000270000900043
With chlolic acid derivatives shown in (VII) formula
Figure BSA00000270000900051
R wherein 3Definition is with claim 3;
R wherein 4Definition is with claim 3;
R wherein 5Definition is with claim 3;
Generate chlolic acid derivatives Acibenzolar (VIII) with N-maloyl imine reaction.
Figure BSA00000270000900052
R wherein 3Definition is with claim 3;
R wherein 4Definition is with claim 3;
R wherein 5Definition is with claim 3;
Camptothecin derivative shown in (VI) formula and chlolic acid derivatives Acibenzolar shown in (VIII) formula are reacted to generate the described camptothecin derivative of claim 1
Figure BSA00000270000900061
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 camptothecine.There is the activity of the inhibition topoisomerase I of part of compounds to be better than camptothecine in the camptothecin derivative involved in the present invention, the selection activity of topoisomerase I is better than camptothecine.
Embodiment:
Embodiment 1: cholic acid-20-O-Methionin-camptothecine is synthetic:
(1) 20-O-Methionin camptothecine is synthetic:
In the 25ml there-necked flask, add camptothecine 174mg (0.5mmol), (S)-2,6-two t-butoxycarbonyl amino acetate 346mg (1mmol), the 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, followed 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 adds the methanol hydrochloride solution dissolving, and stirring at room 3 hours is followed the tracks of reaction by TLC, and reflection is the back concentrating under reduced pressure fully, uses the chloroform methanol recrystallization.Get yellow solid, yield 87%; Molecular weight 476; Structural formula is as follows:
Figure BSA00000270000900071
(2) the cholic acid Acibenzolar is synthetic:
In the 25ml there-necked flask, add cholic acid 204 (0.5mmol), N-maloyl imines 172.5mg (1.5mmol), the 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol), anhydrous methylene chloride 10ml, stirred 3 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 gets white solid, yield 74%; Molecular weight 505.5; Structural formula is as follows:
Figure BSA00000270000900072
(3) cholic acid-20-O-Methionin camptothecine is synthetic:
In the 25mL round-bottomed flask, add compound 20-O-Methionin camptothecine 95.2mg (0.2mmol), 2mL DMSO and excess of bile acids Acibenzolar, add the 0.1ml triethylamine, stir 4h, follow the tracks of reaction by TLC, back distilled water in reaction solution reacts completely, separate out white solid product, filter oven dry, silica gel column chromatography separating purification.Get compound cholic acid-20-O-Methionin camptothecine (A1), pale yellow powder, 34.6mg, molecular weight are 867, yield 40%.Structural formula is as follows:
(cholic acid) 2-20-O-Methionin camptothecine (A12), pale yellow powder, 87.6mg, molecular weight 1257, yield 35%
Figure BSA00000270000900081
Embodiment 6: Septochol-20-O-Methionin-camptothecine is synthetic:
(1) 20-O-Methionin camptothecine is synthetic:
Method is identical with example 4 (1)
(2) the Septochol Acibenzolar is synthetic:
In the 25ml there-necked flask, add Septochol 196 (0.5mmol), N-maloyl imines 172.5mg (1.5mmol), the 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol), anhydrous methylene chloride 10ml, stirred 3 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 gets white solid 153mg, yield 64.9%; Molecular weight 489; Structural formula is as follows:
Figure BSA00000270000900082
(3) Septochol-20-O-Methionin camptothecine is synthetic:
In the 25mL round-bottomed flask, add compound 20-O-Methionin camptothecine 95.2mg (0.2mmol), 2mL DMSO and excessive Septochol Acibenzolar, add the 0.1ml triethylamine, stir 4h, follow the tracks of reaction by TLC, back distilled water in reaction solution reacts completely, separate out white solid product, filter oven dry, silica gel column chromatography separating purification.Get compound Septochol-20-O-Methionin camptothecine (A2), pale yellow powder, molecular weight are 851, yield 41%.Structural formula is as follows:
Figure BSA00000270000900091
(Septochol) 2-20-O-Methionin camptothecine (A22), pale yellow powder, molecular weight 1225, yield 38%
Figure BSA00000270000900092
Embodiment 7: Felacrinos-20-O-Methionin-camptothecine is synthetic:
(1) 20-O-Methionin camptothecine is synthetic:
Method is identical with example 4 (1)
(2) the Felacrinos Acibenzolar is synthetic:
In the 25ml there-necked flask, add Felacrinos 201mg (0.5mmol), N-maloyl imines 172.5mg (1.5mmol), the 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol), anhydrous methylene chloride 10ml, stirred 3 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 gets white solid, yield 77%; Molecular weight 499; Structural formula is as follows:
Figure BSA00000270000900101
(3) Felacrinos-20-O-Methionin camptothecine is synthetic:
In the 25mL round-bottomed flask, add compound 20-O-Methionin camptothecine 95.2mg (0.2mmol), 2mL DMSO and excessive Felacrinos Acibenzolar, add the 0.1ml triethylamine, stir 4h, follow the tracks of reaction by TLC, back distilled water in reaction solution reacts completely, separate out the white solid thing, filter oven dry, silica gel column chromatography separating purification.Get compound Felacrinos-20-O-Methionin camptothecine (A3), pale yellow powder, molecular weight are 861, yield 42%.Structural formula is as follows:
Figure BSA00000270000900102
(Felacrinos) 2-20-O-Methionin camptothecine (A32), pale yellow powder, molecular weight 1245, yield 34%
Figure BSA00000270000900111
Embodiment 8: gallodesoxycholic acid-20-O-Methionin-camptothecine is synthetic:
(1) 20-O-Methionin camptothecine is synthetic:
Method is identical with example 4 (1)
(2) the gallodesoxycholic acid Acibenzolar is synthetic:
In the 25ml there-necked flask, add gallodesoxycholic acid 196 (0.5mmol), N-maloyl imines 172.5mg (1.5mmol), the 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 286.5mg (1.5mmol), anhydrous methylene chloride 10ml, stirred 3 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 gets white solid, m.p; Yield 74%; Molecular weight 489; Structural formula is as follows:
Figure BSA00000270000900112
(3) gallodesoxycholic acid-20-O-Methionin camptothecine is synthetic:
In the 25mL round-bottomed flask, add compound 20-O-Methionin camptothecine 95.2mg (0.2mmol), 2mL DMSO and excessive gallodesoxycholic acid Acibenzolar, add the 0.1ml triethylamine, stir 4h, follow the tracks of reaction by TLC, back distilled water in reaction solution reacts completely, separate out white solid product, filter oven dry, silica gel column chromatography separating purification.Get compound Septochol-20-O-Methionin camptothecine (A4), pale yellow powder, molecular weight are 851, yield 37%.Structural formula is as follows:
Figure BSA00000270000900121
(Septochol) 2-20-O-Methionin camptothecine (A42), pale yellow powder, molecular weight 1225, yield 36%
Figure BSA00000270000900122
Embodiment 9: cholic acid-20-O-Methionin-7-ethyl-camptothecine is synthetic:
(1) 20-O-Methionin-7-ethyl-camptothecin is synthetic:
In the 25ml there-necked flask, add 7-ethyl-camptothecin 188mg (0.5mmol), (S)-2,6-two t-butoxycarbonyl amino acetate 346mg (1mmol), the 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, followed 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 adds the methanol hydrochloride solution dissolving, and stirring at room 3 hours is followed the tracks of reaction by TLC, and the back concentrating under reduced pressure that reacts completely is used the chloroform methanol recrystallization.Get yellow solid, yield 87%; Molecular weight 504; Structural formula is as follows:
(2) the cholic acid Acibenzolar is synthetic:
Method is identical with example 4 (2)
(3) cholic acid-20-O-Methionin-7-ethyl-camptothecin is synthetic:
In the 25mL round-bottomed flask, add compound 20-O-Methionin-7-ethyl-camptothecin 100mg (0.2mmol), 2mL DMSO and excess of bile acids Acibenzolar, add the 0.1ml triethylamine, stir 4h, follow the tracks of reaction by TLC, back distilled water in reaction solution reacts completely, separate out white solid product, filter oven dry, silica gel column chromatography separating purification.Get compound cholic acid-20-O-Methionin-7-ethyl-camptothecin, pale yellow powder, molecular weight are 895, yield 33%.Structural formula is as follows:
Figure BSA00000270000900132
(cholic acid) 2-20-O-Methionin-7-ethyl-camptothecin, pale yellow powder, molecular weight 1285, yield 35%
Figure BSA00000270000900141
Embodiment 8: Felacrinos-20-O-Methionin-9-nitrocamptothecin is synthetic:
(1) 20-O-Methionin-9-nitrocamptothecin is synthetic:
In the 25ml there-necked flask, add 9-nitrocamptothecin 196mg (0.5mmol), (S)-2,6-two t-butoxycarbonyl amino acetate 346mg (1mmol), the 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, followed 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 adds the methanol hydrochloride solution dissolving, and stirring at room 3 hours is followed the tracks of reaction by TLC, and the back concentrating under reduced pressure that reacts completely is used the chloroform methanol recrystallization.Get yellow solid, yield 76%; Molecular weight 521; Structural formula is as follows:
Figure BSA00000270000900142
(2) the Felacrinos Acibenzolar is synthetic:
Method is identical with example 8 (2)
(3) Felacrinos-20-O-Methionin-9-nitrocamptothecin is synthetic:
In the 25mL round-bottomed flask, add compound 20-O-Methionin-9 nitrocamptothecin 14.2mg (0.2mmol), 2mL DMSO and excessive Felacrinos Acibenzolar, add the 0.1ml triethylamine, stir 4h, follow the tracks of reaction by TLC, back distilled water in reaction solution reacts completely, separate out white solid product, filter oven dry, silica gel column chromatography separating purification.Get compound Felacrinos-20-O-Methionin-9-nitrocamptothecin, pale yellow powder, molecular weight are 906, yield 32%.Structural formula is as follows:
Figure BSA00000270000900151
(Felacrinos) 2-20-O-Methionin-9-nitrocamptothecin, pale yellow powder, molecular weight 1290, yield 38%
Figure BSA00000270000900152
The mensuration of extracorporeal anti-tumor effect:
The cell in vegetative period (BEL7402, HCT116, SMMC7721) of taking the logarithm is inoculated in to cultivate in 96 well culture plates and was paved with to cell 95% in about 24 hours.Negative control group, positive controls and administration group are established in experiment, and the positive control medicine is a camptothecine.After the dosing, cultivate 72h in 37 ℃, 5%CO2 incubator, stop cultivating, each hole adds 5mg/ml MTT solution 20 μ l, put and cultivate 4h in the incubator, abandoning supernatant, every hole adds DMSO 100 μ l, puts micropore vibrator gentle agitation 10 minutes, the bluish voilet material is fully dissolved, use microplate reader detecting wavelength 492nm then, under the reference wavelength 630nm condition, measure the absorbance (OD value) in every hole.The experiment triplicate is averaged, and with the inhibiting rate of following formula computerized compound to tumour cell, calculates IC50 with NOSA 2.3 software Bliss methods.The result is as shown in table 1
Figure BSA00000270000900161
A:BEL 7402 is that liver cancer cell HCT116 is that colon cancer cell SMMC7721 is a liver cancer cell
Table 1 camptothecine novel derivative anti tumor activity in vitro.

Claims (6)

1. described camptothecin derivative is represented with following logical formula I (II):
Figure FSA00000270000800011
Wherein
R 1Be hydrogen, ethyl;
R 2Be hydrogen, nitro;
R 3Be hydrogen, hydroxyl, carbonyl;
R 4Be hydrogen, hydroxyl, carbonyl;
R 5Be hydroxyl, carbonyl.
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, carbonyl; R 4Be hydrogen, hydroxyl, carbonyl; R 5Hydroxyl, carbonyl.
4. the preparation method of the described camptothecin derivative of claim 1:
It is characterized in that the camptothecin derivative shown in the formula III
Figure FSA00000270000800021
Wherein
R 1Definition with claim 2;
R 2Definition with claim 2;
With the Methionin reaction shown in the formula IV
Figure FSA00000270000800022
With the camptothecin derivative shown in the production (V)
Figure FSA00000270000800023
Wherein
R 1Definition with claim 2;
R 2Definition with claim 2;
Camptothecin derivative shown in (V) formula is taken off protecting group to generate (VI) in the methanol solution of hydrochloric acid
Wherein
R 1Definition with claim 2;
R 2Definition with claim 2;
With the chlolic acid derivatives shown in (VII) formula
Figure FSA00000270000800032
R wherein 3Definition is with claim 3;
R wherein 4Definition is with claim 3;
R wherein 5Definition is with claim 3;
Generate chlolic acid derivatives Acibenzolar (VIII) with N-maloyl imine reaction.
Figure FSA00000270000800033
R wherein 3Definition is with claim 3;
R wherein 4Definition is with claim 3;
R wherein 5Definition is with claim 3;
Again camptothecin derivative shown in (VI) formula and chlolic acid derivatives Acibenzolar shown in (VIII) formula are reacted to generate the described camptothecin derivative of claim 1
5. the described compound of claim 1-4 is as the purposes of raw material in the preparation antitumor drug.
6. the described compound of claim 1-4 is used to prepare the application of the activeconstituents of the medicine for the treatment of tumour.
CN201010281844XA 2010-09-15 2010-09-15 New derivative of camptothecin 20-site coupled bile acid Pending CN101948500A (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102492010A (en) * 2011-12-15 2012-06-13 东北林业大学 Derivatives of camptothecin 20-site bile acid and preparation method thereof
CN102492009A (en) * 2011-12-15 2012-06-13 东北林业大学 Camptothecin 20- position cholic acid derivative and preparation method thereof
CN102516347A (en) * 2011-12-15 2012-06-27 东北林业大学 Camptothecin 20-site cholic acid derivative and preparation method thereof
CN107266520A (en) * 2017-06-28 2017-10-20 湖南华腾制药有限公司 A kind of camptothecine and birch acid conjugate and preparation method thereof
CN109172527A (en) * 2018-09-11 2019-01-11 中国科学院长春应用化学研究所 A kind of camptothecine prodrug and preparation method thereof and nanoparticle and its application based on cationic amino acid modification
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1665831A (en) * 2002-07-08 2005-09-07 普利瓦研究院有限公司 Novel compounds, compositions as carriers for steroid/nonsteroid anti-inflammatory, antienoplastic and antiviral active molecules
WO2005118612A1 (en) * 2004-06-04 2005-12-15 Sonus Pharmaceuticals, Inc. Cholesterol/bile acid/bile acid derivative-modified therapeutic anti-cancer drugs
CN101490077A (en) * 2006-07-17 2009-07-22 诺瓦提斯公司 Sulphonylaminocarbonyl derivatives of bile acid amides for use as immunomodulators

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1665831A (en) * 2002-07-08 2005-09-07 普利瓦研究院有限公司 Novel compounds, compositions as carriers for steroid/nonsteroid anti-inflammatory, antienoplastic and antiviral active molecules
WO2005118612A1 (en) * 2004-06-04 2005-12-15 Sonus Pharmaceuticals, Inc. Cholesterol/bile acid/bile acid derivative-modified therapeutic anti-cancer drugs
CN101490077A (en) * 2006-07-17 2009-07-22 诺瓦提斯公司 Sulphonylaminocarbonyl derivatives of bile acid amides for use as immunomodulators

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
《Journal of Molecular Structure: THEOCHEM》 20050520 Min-Jie Li et al QSAR studies of 20(S)-camptothecin analogues as antitumor agents 163-170 1-6 第723卷, 第1-3期 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102492010A (en) * 2011-12-15 2012-06-13 东北林业大学 Derivatives of camptothecin 20-site bile acid and preparation method thereof
CN102492009A (en) * 2011-12-15 2012-06-13 东北林业大学 Camptothecin 20- position cholic acid derivative and preparation method thereof
CN102516347A (en) * 2011-12-15 2012-06-27 东北林业大学 Camptothecin 20-site cholic acid derivative and preparation method thereof
CN107266520A (en) * 2017-06-28 2017-10-20 湖南华腾制药有限公司 A kind of camptothecine and birch acid conjugate and preparation method thereof
CN109172527A (en) * 2018-09-11 2019-01-11 中国科学院长春应用化学研究所 A kind of camptothecine prodrug and preparation method thereof and nanoparticle and its application based on cationic amino acid modification
CN109172527B (en) * 2018-09-11 2021-01-08 中国科学院长春应用化学研究所 Camptothecin prodrug based on cationic amino acid modification, preparation method thereof, nano drug-loaded particles and application thereof
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

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