CN101343276A - Camptothecin derivative and its preparation - Google Patents
Camptothecin derivative and its preparation Download PDFInfo
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- CN101343276A CN101343276A CNA2008100647425A CN200810064742A CN101343276A CN 101343276 A CN101343276 A CN 101343276A CN A2008100647425 A CNA2008100647425 A CN A2008100647425A CN 200810064742 A CN200810064742 A CN 200810064742A CN 101343276 A CN101343276 A CN 101343276A
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Abstract
The invention relates to camptothecin derivates in formulas of (I), (II) and (III) as well as acceptable salt in medicine, relating to a method for preparing the compounds as well as applications thereof in tumor therapy particularly by using the compounds as medicines. In the formulas of (I), (II) and (III), R1 is hydrogen and ethyl; R2 is hydrogen and nitryl; R3 is oxhydryl, amido, an amine compound, and a compound containing one or a plurality of five-membered or six-membered nitrogen heterocyclic rings as well as derivates thereof; R4 is hydrogen and oxhydryl; and n can be 2, 3 and 4.
Description
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, 10-hydroxycamptothecine and 7--ethyl-19 hydroxycamptothecine 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, 10-hydroxycamptothecine and 7-ethyl 10 hydroxycamptothecines.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 10-hydroxycamptothecine, 7-ethyl 10-hydroxycamptothecine 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.
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 toxic side effect is big.
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, problems such as toxic side effect is big have finally been found and can have been given birth to the camptothecin derivative that 10 haloalkanes replace by 10 hydroxyls of camptothecin derivative and haloalkane reaction, and generated 20 bit esterified camptothecin derivatives by 20 hydroxyls of camptothecine and halogenated carboxylic acid reaction.This derivative again with the nitrogen heterocyclic ring salify or with contain amino compound and carry out chemically modified and form and have active camptothecin derivative, or adopt the described preparation method 2 of claim 8 to obtain having the new water soluble camptothecin derivatives of required pharmacological action.
The new camptothecin derivative of the present invention is represented with following general formula (I), (II), (III):
R wherein
1Be hydrogen, ethyl.
R wherein
2Be hydrogen, nitro.
R wherein
4Be hydrogen, hydroxyl.
R wherein
3Be
Above pyridine and the position and the derivative of para-orientation therebetween.
R wherein
3Be
More than five, hexa-atomic nitrogen-containing heterocycle compound.
R wherein
3Be
R wherein
3Be
-NH
2
-OH
-NH(CH
2)mOH
m＝1，2，3，4，5
-NHCH
2COOC
2H
5
Wherein n is 2,3,4 alkyl chain, and structure is-CH
2CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH
2CH
2-.
The preparation method 1 of the water soluble camptothecin derivatives that the present invention is new:
I is characterized in that the camptothecin derivative shown in the formula (IV)
Wherein
R
1Definition with claim 2;
R
2Definition with claim 3;
R
4Definition with claim 4;
React with the haloalkane shown in the formula V or with the halogenated carboxylic acid shown in the formula (VI)
BrCH
2CH
2Br，BrCH
2CH
2CH
2Br，BrCH
2CH
2CH
2CH
2Br；
(V)
BrCH
2CH
2Cl，BrCH
2CH
2CH
2Cl，BrCH
2CH
2CH
2CH
2Cl；
ClCH
2COOH，CH
3ClCH
2COOH；
(VI)
BrCH
2COOH，CH
3BrCH
2COOH；
With the camptothecin derivative shown in production (VII), (VIII), (IX)
Wherein
R
1Definition with claim 2;
R
2Definition with claim 3;
R
4Definition with claim 4
N is 2,3,4;
R
5Be Br, Cl;
R in the camptothecin derivative of formula (VII), (VIII), (IX) and the claim 5 then
3Pairing nitrogen heterocyclic ring and derivative thereof, and all Ammonia derivatives reactions generate the described water soluble camptothecin derivatives of claim 1.
The preparation method 2 of the water soluble camptothecin derivatives that the present invention is new:
It is characterized in that R in the claim 5
3Pairing nitrogen heterocyclic ring and derivative thereof, and all Ammonia derivatives and formula V shown in haloalkane under weak basic condition or with the halogenated carboxylic acid shown in the formula (VI), react
BrCH
2CH
2Br，BrCH
2CH
2CH
2Br，BrCH
2CH
2CH
2CH
2Br；
(V)
BrCH
2CH
2Cl，BrCH
2CH
2CH
2Cl，BrCH
2CH
2CH
2CH
2Cl；
ClCH
2COOH，CH
3ClCH
2COOH；
(VI)
BrCH
2COOH，CH
3BrCH
2COOH；
Compound shown in difference production (X) or formula (XI), (XII)
Wherein
R
5Be Br, Cl;
N is 2,3,4;
R
3Definition with claim 4,5,6,7;
Then the compound of formula (X) or formula (XI), (XII) respectively with the camptothecin derivative reaction shown in (IV) of formula, generate the described water soluble camptothecin derivatives of claim 1.
Wherein
R
1Definition with claim 2;
R
2Definition with claim 3;
R
4Definition with claim 4;
The present invention also comprise described in claim 1 to 6 compound preparation in the antitumor drug purposes and contain antitumor drug just like compound described in the claim 1 to 6.
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:
10-O-(3-pyridinium salt) propyl group camptothecine
(1) 10-O-(3-bromine) propyl group camptothecine is synthetic
Add 10-hydroxycamptothecine 182.18mg (0.5mmol) in the 25mL round-bottomed flask, 1.5mL DMSO and 345.94mg (2.5mmol) Anhydrous potassium carbonate after the stirring and dissolving, adds 1,3-dibromopropane 0.86mL (10.01mmol), N
2Be heated to 60 ℃ under the protection; stir 72h; follow the tracks of reaction by TLC; with in the reaction solution impouring water, separate out solid after reacting completely, filter; gained solid volume fraction is 8: 2 trichloromethane and a dissolve with methanol; through silica gel column chromatography separating purification, (100: 1-100: 3) gradient elution obtains compound 10-O-(3-bromine) propyl group camptothecine with trichloromethane-methyl alcohol.This compound molecular weight is: 484.06, and structural formula is as follows:
(2) 10-O-(3-pyridinium salt-1) propyl group camptothecine is synthetic
In the 25mL round-bottomed flask, add compound 10-O-(3-bromine) propyl group camptothecine 97.07mg (0.2mmol), 1.5mL DMSO and excess pyridine, be heated to 50 ℃, stir 12h, follow the tracks of reaction by TLC, product unfolded Rf value in methyl alcohol is zero, in reaction solution, add trichloromethane after reacting completely, separate out yellow solid product, filter, use the trichloromethane thorough washing, 60 ℃ of vacuum-dryings get product.Compound 10-O-(3-pyridinium salt-1) propyl group camptothecine pale yellow powder, 92.54mg, m.p.＞250 ℃, molecular weight is 484.19, yield 95.6%.Structural formula is as follows:
Embodiment 2:
10-O-(3-(3-ethanoyl) pyridinium salt-1) propyl group camptothecine
(1) synthetic method of 10-O-(3-bromine) propyl group camptothecine is identical with embodiment 1 (1)
(2) 10-O-(3-(3-ethanoyl) pyridinium salt-1) propyl group camptothecine is synthetic
In the 25mL round-bottomed flask, add compound 10-O-(3-bromine) propyl group camptothecine 97.07mg (0.2mmol) and excessive 3-acetylpyridine; be heated to 50 ℃; stir 12h; follow the tracks of reaction by TLC, product unfolded Rf value in methyl alcohol is zero, and the back that reacts completely adds trichloromethane in reaction solution; separate out yellow solid product; filter, use the trichloromethane thorough washing, 60 ℃ of vacuum-dryings get product 10-O-(3-(3-ethanoyl) pyridinium salt-1) propyl group camptothecine.This compound is a pale yellow powder, 95.10mg, and molecular weight is: 526.20; M.p.192 ℃, yield 90.4%.Structural formula is as follows:
Embodiment 3:
10-O-(3-(3-hydroxyl) pyridinium salt-1) propyl group camptothecine
(1) synthetic method of 10-O-(3-bromine) propyl group camptothecine is identical with embodiment 1 (1)
(2) 10-O-(3-(3-hydroxyl) pyridinium salt-1) propyl group camptothecine is synthetic
In the 25mL round-bottomed flask, add compound 10-O-(3-bromine) propyl group camptothecine 97.07mg (0.2mmol), 1.5mL DMSO and excessive 3-phenolic hydroxyl group pyridine, be heated to 50 ℃ of reactants dissolved, stir 12h, follow the tracks of reaction by TLC, product unfolded Rf value in methyl alcohol is zero, back an amount of trichloromethane of adding in reaction solution reacts completely, separate out yellow solid product, filter, with the trichloromethane and the methyl alcohol mixed liquor thorough washing of suitable proportion, 60 ℃ of vacuum-dryings get product 10-O-(3-(3-hydroxyl) pyridinium salt-1) propyl group camptothecine.This compound is a pale yellow powder, 80.4mg, and m.p.293 ℃, molecular weight is: 500.18; Yield 80.4%.Structural formula is as follows:
Embodiment 4:
10-O-(3-pyrimidine salt) propyl group camptothecine
(1) synthetic method of 10-O-(3-bromine) propyl group camptothecine is identical with embodiment 1 (1)
(2) 10-O-(3-pyrimidine salt-1) propyl group camptothecine is synthetic
In the 25mL round-bottomed flask, add compound 10-O-(3-bromine) propyl group camptothecine 145.5mg (0.3mmol), 1.5mL DMSO and 72.7 μ L pyrimidines, be heated to 40 ℃ of reactants dissolved, stir 24h, follow the tracks of reaction by TLC, product unfolded Rf value in methyl alcohol is zero, in reaction solution, add an amount of trichloromethane and acetone after reacting completely, separate out yellow solid product, filter, trichloromethane and methyl alcohol mixed liquor thorough washing with suitable proportion wash with anhydrous diethyl ether then.Compound 10-O-(3-pyrimidine salt-1) propyl group camptothecine is a pale yellow powder, 50.1mg, and m.p.203 ℃, molecular weight is: 485.18; Yield 91.5%; Structural formula is as follows:
Embodiment 5:
The preparation of 1O-O-(3-triazine salt-1) propyl group camptothecine
(1) synthetic method of 10-O-(3-bromine) propyl group camptothecine is identical with embodiment 1 (1)
(2) 10-O-(3-triazine salt-1) propyl group camptothecine is synthetic
In the 25mL round-bottomed flask, add compound 10-O-(3-bromine) propyl group camptothecine 145.5mg (0.3mmol), 1.5mL DMSO and 1,3,5 ,-triazine 81mg (1m mol) is heated to 40 ℃, stir 24h, follow the tracks of reaction by TLC, product unfolded Rf value in methyl alcohol is zero, and the back that reacts completely adds entry in reaction solution, separate out pale brown look solid product, filter, solid concentrates with chloroform and methyl alcohol mixed liquor dissolving, go up the silica gel chromatographic column separation then and obtain compound 10-O-(3-triazine salt-1) propyl group camptothecine alkali pale yellow powder, 15.4mg, m.p.＞265 ℃, molecular weight is: 486.50 yields 10.6%.Structural formula is as follows:
Embodiment 6:
10-O-propyl group-inosine camptothecine
(1) synthetic method of 10-O-(3-bromine) propyl group camptothecine is identical with embodiment 1 (1)
(2) 10-O-propyl group-inosine camptothecine is synthetic
In the 25mL round-bottomed flask, add compound 10-O (3-bromine) propyl group camptothecine 145.5mg (0.3mmol), 1.5mL DMSO and inosine (Inosine 9 β-D-ribose xanthoglobulin) 268mg (1m mol), be heated to 50 ℃, stir 12h, follow the tracks of reaction by TLC, in reaction solution, add entry after reacting completely, separate out yellow solid product, filter, the gained solid concentrates with chloroform and methyl alcohol mixed liquor dissolving, go up the silica gel chromatographic column separation then and obtain faint yellow compound 10-O-propyl group-inosine camptothecine powder, 100.6mg, m.p.＞250 ℃, molecular weight: 672.22; Yield 68.90%.Structural formula is as follows:
Embodiment 7:
The preparation of 10-O-(3-imidazolyl-1) propyl group camptothecine
(1) synthetic method of 10-O-(3-bromine) propyl group camptothecine is identical with embodiment 1 (1)
(2) 10-O-(3-imidazolyl-1) propyl group camptothecine is synthetic
In the 25mL round-bottomed flask, add compound 10-O-(3-bromine) propyl group camptothecine 145.5mg (0.3mmol), 1.5mL DMSO and imidazoles 68mg (1m mol), be heated to 40 ℃, stir 24h, follow the tracks of reaction by TLC, in reaction solution, add entry after reacting completely, separate out pale brown look solid product, filter, solid concentrates with chloroform and methyl alcohol mixed liquor dissolving, go up the silica gel chromatographic column separation then and obtain compound 10-O-(3-imidazolyl-1) propyl group camptothecine alkali pale yellow powder, 29.3mg m.p.194 ℃, molecular weight is: 472.5 yields 20.1%.Structural formula is as follows:
Embodiment 8:
10-O-(3-hydroxyl) propyl group camptothecine
(1) synthetic method of 10-O-(3-bromine) propyl group camptothecine is identical with embodiment 1 (1)
(2) 10-O-(3-hydroxypropyl-1) camptothecine is synthetic
In the 25mL round-bottomed flask, add compound 10-O-(3-bromine) propyl group camptothecine 121.25mg (0.25mmol), 1.5mL DMSO, stir and add urethanum 222.7mg (2.5mmol) down, 60 ℃ of heating, stir 72h, follow the tracks of reaction by TLC, with in the reaction solution impouring water, separate out solid after reacting completely, filter, the gained solids is with 1: 1 trichloromethane and dissolve with methanol, through silica gel column chromatography separating purification, with trichloromethane-methyl alcohol (100: 3) wash-out, getting compound 10-O-(3-hydroxyl) propyl group camptothecine. this compound is a pale yellow powder, 78.25mg m.p.206-208 ℃, molecular weight is: 422.15 yields 68.21%.Structural formula is as follows:
Embodiment 9:
10-O-(3-amido) propyl group camptothecine
(1) synthetic method of 10-O-(3-bromine) propyl group camptothecine is identical with embodiment 1 (1)
(2) 10-O-(3-amido) propyl group camptothecine is synthetic
In the 25mL round-bottomed flask, add compound 10-O-(3-bromine) propyl group camptothecine 145.5mg (0.3mmol), 1.5mL DMSO, stir and add ammoniacal liquor 0.051mL (0.75mmol) down, 60 ℃ of heat, stir 10h, follow the tracks of reaction by TLC, with in the reaction solution impouring water, separate out solid after reacting completely, filter, the gained solids is with 1: 1 trichloromethane and dissolve with methanol, through silica gel column chromatography separating purification, with trichloromethane-methyl alcohol (10: 1) wash-out, getting compound 10-O-(3-amido) propyl group camptothecine. compound is a pale yellow powder, 77.6mg, m.p.140-142 ℃, molecular weight: 421.16; Yield 58.22%.Structural formula is as follows:
Embodiment 10:
10-O-(2-pyridinium salt-1) ethyl-camptothecin
(1) 10-O-(2-bromine) ethyl-camptothecin is synthetic
Add 10-hydroxycamptothecine 182.18mg (0.5mmol) in the 25mL round-bottomed flask, 1.5mL DMSO and 345.94mg (2.5mmol) Anhydrous potassium carbonate after the stirring and dissolving, adds 1,2-dibromopropane 0.86mL (10.01mmol), N
2Be heated to 60 ℃ under the protection; stir 72h; follow the tracks of reaction by TLC; with in the reaction solution impouring water, separate out solid after reacting completely, filter; gained solid volume fraction is 8: 2 trichloromethane and a dissolve with methanol; through silica gel column chromatography separating purification, (100: 1-100: 3) gradient elution obtains compound 10-O-(2-bromine) ethyl-camptothecin with trichloromethane-methyl alcohol.This compound molecular weight is: 470.05, and structural formula is as follows:
(2) 10-O-(2-pyridinium salt-1) ethyl-camptothecin is synthetic
In the 25mL round-bottomed flask, add compound 10-O-(2-bromine) camptothecine 94.03mg (0.2mmol), 1.5mL DMSO and excess pyridine, be heated to 50 ℃, stir 12h, follow the tracks of reaction by TLC, product unfolded Rf value in methyl alcohol is zero, in reaction solution, add trichloromethane after reacting completely, separate out yellow solid product, filter, use the trichloromethane thorough washing, 60 ℃ of vacuum-dryings get product 10-O-(2-pyridinium salt-1) ethyl-camptothecin.This compound is a pale yellow powder, 86.76mg, and m.p.＞300 ℃, molecular weight is: 470.17; Yield 92.3%; Structural formula is as follows:
Embodiment 11:
10-O (2-(3-hydroxyl) pyridinium salt-1) ethyl-camptothecin
(1) synthetic method of 10-O-(2-bromine) ethyl-camptothecin is identical with embodiment 10 (1)
(2) 10-O (2-(3-hydroxyl) pyridinium salt-1) ethyl-camptothecin is synthetic
In the 25mL round-bottomed flask, add compound 10-O-(3-bromine) ethyl-camptothecin 94.03mg (0.2mmol), 1.5mL DMSO and excessive 3-phenolic hydroxyl group pyridine, be heated to 50 ℃ of reactants dissolved, stir 12h, follow the tracks of reaction by TLC, product unfolded Rf value in methyl alcohol is zero, back an amount of trichloromethane of adding in reaction solution reacts completely, separate out yellow solid product, filter, with the trichloromethane and the methyl alcohol mixed liquor thorough washing of suitable proportion, 60 ℃ of vacuum-dryings get product 10-O (2-(3-hydroxyl) pyridinium salt-1) ethyl-camptothecin.Compound is a pale yellow powder, 78.14mg, and m.p.208 ℃, molecular weight is: 486.17; Yield 80.4%; Structural formula is as follows:
Embodiment 12:
The preparation of 10-O-(2-imidazolyl-1) ethyl-camptothecin
(1) synthetic method of 10-O-(2-bromine) ethyl-camptothecin is identical with embodiment 10 (1)
(2) 10-O-(2-imidazolyl-1) ethyl-camptothecin is synthetic
In the 25mL round-bottomed flask, add compound 10-O-(2-bromine) ethyl-camptothecin 141.05mg (0.3mmol), 1.5mL DMSO and imidazoles 68mg (1m mol), be heated to 40 ℃, stir 24h, follow the tracks of reaction by TLC, in reaction solution, add entry after reacting completely, separate out pale brown look solid product, filter, solid concentrates with chloroform and methyl alcohol mixed liquor dissolving, go up the silica gel chromatographic column separation then and obtain compound 10-O-(2-imidazolyl-1) ethyl-camptothecin alkali pale yellow powder, 60.93mg, m.p.＞198 ℃, molecular weight is: 458.5 yields 43.2%.Structural formula is as follows:
Embodiment 13:
9-nitro-10-O-[3-pyridinium salt-1] the propyl group camptothecine
(1) 9-nitro-10-O-(3-bromine) propyl group camptothecine is synthetic
In the 25ml there-necked flask, add 9-nitro-10-hydroxycamptothecine, 204.5mg (0.5mmol), 2mlDMSO and 207.0mg (1.5mmol) Anhydrous potassium carbonate after the stirring and dissolving, adds 1,3-dibromopropane, N
2Be heated to 60 ℃ under the protection;, stir 9h, follow the tracks of reaction by TLC; after reacting completely with in the reaction solution impouring water; separate out solid, filter, get solid 0.1995g; with volume fraction 9: 1 trichloromethane and dissolve with methanol; through silica gel column chromatography separating purification, use trichloromethane-methyl alcohol=500: 1-300: 1 gradient elution gets pale yellow powder 222.9mg.M.p.240-242 ℃; Molecular weight 530.1; Yield 84.1%.Structural formula is as follows:
(2) 9-nitro-10-O-(3-pyridinium salt-1) propyl group camptothecine is synthetic
In the 25ml there-necked flask, add 9-nitro-10-O-(3-bromine) propyl group camptothecine, 106mg (0.2mmol), 1.5mlDMSO and excessive pyridine are heated to 60 ℃,, stir 15h, follow the tracks of reaction by TLC, product is unfolded R in methyl alcohol
fValue is zero, and the back that reacts completely adds an amount of trichloromethane in reaction solution, separate out yellow solid, filters, and uses the trichloromethane thorough washing, and 60 ℃ of vacuum-dryings obtain brown product 99.7mg.M.p.240-242 ℃; Yield 94.3%; Molecular weight 529.1; Structural formula is as follows:
Embodiment 14:
9-nitro-10-O-[3-(3-methylol) pyridinium salt-1] the propyl group camptothecine
(1) synthetic method of 9-nitro-10-O-(3-bromine) propyl group camptothecine is identical with embodiment 13 (1)
(2) 9-nitro-10-O-[3-(3-methylol base) pyridinium salt-1] propyl group camptothecine synthetic
In the 25ml there-necked flask, add 9-nitro-10-O-(3-bromine) propyl group camptothecine, 106mg (0.2mmol), 1.5mlDMSO and excessive 3-pyridone are heated to 60 ℃,, stir 15h, follow the tracks of reaction by TLC, product is unfolded R in methyl alcohol
fValue is zero, and the back that reacts completely adds an amount of trichloromethane in reaction solution, separate out yellow solid, filters, and uses the trichloromethane thorough washing, and 60 ℃ of vacuum-dryings obtain brown product 106.7mg.M.p.208-210 ℃; Yield 95.4%; Molecular weight 559.1; Structural formula is as follows:
Embodiment 15:
Camptothecine-20 (S)-O-[2-(3-hydroxyl) pyridinium salt-1] acetic ester
(1) camptothecine-20 (S)-O-2-chloracetate is synthetic
In the 25ml there-necked flask, add camptothecine 120mg (0.34mmol), 2-Mono Chloro Acetic Acid 94.5mg (1mmol), the 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 240mg (1.26mmol), 4-Dimethylamino pyridine (DMAP) 18mg (0.17mmol), anhydrous methylene chloride 5ml, stirred 2 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 and the water washing of 50ml saturated common salt, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure gets pale yellow powder 139.45mg.M.p; Yield 96.5%; Molecular weight 424.83; Structural formula is as follows:
(2) camptothecine-20 (S)-O-[2-(3-hydroxyl) pyridinium salt-1] acetic ester synthetic
Add camptothecine-20 (S)-O-2-chloracetate 85mg (0.2mmol) in the 25ml there-necked flask, 1mlDMSO and excessive 3-pyridone are heated to 45 ℃, stir 6 hours, follow the tracks of reaction by TLC, and product is unfolded R in methyl alcohol
fValue is zero.Add an amount of trichloromethane, anhydrous diethyl ether after reacting completely in reaction solution, separate out solid, filter, use the trichloromethane thorough washing, 60 ℃ of vacuum-dryings get pale yellow powder 77.5mg.M.p; Yield 74.5%; Molecular weight 519.93; Structural formula is as follows
Embodiment 16:
Camptothecine-20 (S)-O-[2-(3-fluorine) pyridinium salt-1] acetic ester
(1) synthetic method of camptothecine-20 (S)-O-2-chloracetate is identical with embodiment 15 (1).
(2) camptothecine-20 (S)-O-[2-(3-fluorine) pyridinium salt-1] acetic ester synthetic
Add camptothecine-20 (S)-O-2-chloracetate 85mg (0.2mmol) in the 25ml there-necked flask, 1mlDMSO and excessive 3-fluorine pyridine are heated to 50 ℃, stir 24 hours, follow the tracks of reaction by TLC, and product is unfolded R in methyl alcohol
fValue is zero.Add an amount of trichloromethane, anhydrous diethyl ether after reacting completely in reaction solution, separate out solid, filter, use the trichloromethane thorough washing, 60 ℃ of vacuum-dryings get pale yellow powder 58.56mg.M.p; Yield 56.10%; Molecular weight 521.92; Structural formula is as follows
Embodiment 17:
Camptothecine-20 (S)-O-[2-pyridinium salt-1] acetic ester
(1) synthetic method of camptothecine-20 (S)-O-2-chloracetate is identical with embodiment 15 (1).
(2) camptothecine-20 (S)-O-[2-pyridinium salt-1] acetic ester synthetic
Add camptothecine-20 (S)-O-2-chloracetate 85mg (0.2mmol) in the 25ml there-necked flask, 1mlDMSO and excessive pyridine are heated to 50 ℃, stir 6 hours, follow the tracks of reaction by TLC, and product unfolded Rf value in methyl alcohol is zero.Add an amount of trichloromethane, anhydrous diethyl ether after reacting completely in reaction solution, separate out solid, filter, use the trichloromethane thorough washing, 60 ℃ of vacuum-dryings get pale brown toner end 78.24mg.M.p; Yield 77.63%; Molecular weight 503.93; Structural formula is as follows
Embodiment 18:
Camptothecine-20 (S)-O-(2-pyrazolyl-1) acetic ester
(1) synthetic method of camptothecine-20 (S)-O-2-chloracetate is identical with embodiment 15 (1).
(2) camptothecine-20 (S)-O-[2-pyrazolyl-1] acetic ester synthetic
In the 25ml there-necked flask, add camptothecine-20 (S)-O-2-chloracetate 85mg (0.2mmol), 1mlDMSO and excessive pyrazoles are heated to 45 ℃, stir 72 hours, follow the tracks of reaction by TLC, in reaction solution, add chloroform, anhydrous diethyl ether after reacting completely, separate out the faint yellow solid product, filter, solid dissolves with chloroform and methyl alcohol mixed liquor, concentrate, go up the silica gel chromatographic column separation then and obtain compound camptothecine-20 (S)-O-[2-pyrazolyl-1] acetic ester, pale yellow powder 30.5mg.M.p; Yield 33.41%; Molecular weight 456.37; Structural formula is as follows
Embodiment 19:
Camptothecine-20 (S)-O-(2-imidazolyl-1) acetic ester
(1) synthetic method of camptothecine-20 (S)-O-2-chloracetate is identical with embodiment 15 (1).
(2) camptothecine-20 (S)-O-(2-imidazolyl-1) acetic ester is synthetic
In the 25ml there-necked flask, add camptothecine-20 (S)-O-2-chloracetate 85mg (0.2mmol), 1mlDMSO and excessive imidazoles, be heated to 45 ℃, stirred 6 hours, follow the tracks of reaction by TLC, in reaction solution, add chloroform, anhydrous diethyl ether after reacting completely, separate out the faint yellow solid product, filter, with anhydrous diethyl ether and washing with acetone, get compound camptothecine-20 (S)-O-[2-imidazolyl-1] acetic ester, faint yellow 75.05mg.M.p; Yield 82.23%; Molecular weight 456.37; Structural formula is as follows
Embodiment 20:
Camptothecine-20 (S)-O-(2-purine radicals) acetic ester
(1) synthetic method of camptothecine-20 (S)-O-2-chloracetate is identical with embodiment 15 (1).
(2) camptothecine-20 (S)-O-(2-purine radicals) acetic ester is synthetic
In the 25ml there-necked flask, add camptothecine-20 (S)-O-2-chloracetate 85mg (0.2mmol), 1mlDMSO and excessive purine, and add the 50mg anhydrous K
2CO
3Be heated to 45 ℃, stirred 8 hours, and followed the tracks of reaction by TLC, the back that reacts completely adds entry in reaction solution, separate out the faint yellow solid product, filter, solid concentrates with chloroform and methyl alcohol mixed liquor dissolving, go up the silica gel chromatographic column separation then and obtain compound camptothecine-20 (S)-O-(2-purine radicals) acetic ester, pale yellow powder 35.21mg.M.p; Yield 33.62%; Molecular weight 523.52; Structural formula is as follows
Embodiment 21:
Camptothecine-20 (S)-O-[2-(3-hydroxyl) pyridinium salt-1] propionic ester
(1) camptothecine-20 (S)-O-2-chloropropionic acid ester is synthetic
In the 25ml there-necked flask, add camptothecine 120mg (0.34mmol), 2-chloropropionic acid 108.52mg (1mmol), the 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI) 240mg (1.26mmol), 4-Dimethylamino pyridine (DMAP) 18mg (0.17mmol), anhydrous methylene chloride 5ml, stirred 2 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 and the water washing of 50ml saturated common salt, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure gets pale yellow powder 146.41mg.M.p; Yield 98.12%; Molecular weight 438.86; Structural formula is as follows:
(2) camptothecine-20 (S)-O-[2-(3-hydroxyl) pyridinium salt-1] propionic ester
Add camptothecine-20 (S)-O-2-chloropropionic acid ester 87.8mg (0.2mmol) in the 25ml there-necked flask, 1mlDMSO and excessive 3-pyridone are heated to 45 ℃, stir 6 hours, follow the tracks of reaction by TLC, and product is unfolded R in methyl alcohol
fValue is zero.Add an amount of trichloromethane, anhydrous diethyl ether after reacting completely in reaction solution, separate out solid, filter, use the trichloromethane thorough washing, 60 ℃ of vacuum-dryings get pale yellow powder 67.27mg.M.p; Yield 63.11%; Molecular weight 533.95; Structural formula is as follows
Embodiment 22:
Camptothecine-20 (S)-O-[2-(3-carboxyl) pyridinium salt-1] propionic ester
(1) synthetic method of camptothecine-20 (S)-O-2-chloropropionic acid ester is identical with embodiment 21 (1).
(2) camptothecine-20 (S)-O-[2-(3-carboxyl) pyridinium salt-1] propionic ester synthetic
Add camptothecine-20 (S)-O-2-chloropropionic acid ester 87.8mg (0.2mmol) in the 25ml there-necked flask, 1mlDMSO and excessive 3-carboxyl pyridine are heated to 50 ℃, stir 8 hours, follow the tracks of reaction by TLC, and product is unfolded R in methyl alcohol
fValue is zero.Add an amount of trichloromethane, anhydrous diethyl ether after reacting completely in reaction solution, separate out solid, filter, use the trichloromethane thorough washing, 60 ℃ of vacuum-dryings get pale brown toner end 54.3mg.M.p; Yield 48.31%; Molecular weight 561.96; Structural formula is as follows
Embodiment 23:
Camptothecine-20 (S)-O-[2-(3-methyl) pyridinium salt-1] propionic ester
(1) synthetic method of camptothecine-20 (S)-O-2-chloropropionic acid ester is identical with embodiment 21 (1).
(2) camptothecine-20 (S)-O-[2-(3-methyl) pyridinium salt-1] propionic ester synthetic
Add camptothecine-20 (S)-O-2-chloropropionic acid ester 87.8mg (0.2mmol) in the 25ml there-necked flask, 1mlDMSO and excessive 3-picoline are heated to 50 ℃, stir 8 hours, follow the tracks of reaction by TLC, and product is unfolded R in methyl alcohol
fValue is zero.Add an amount of trichloromethane, anhydrous diethyl ether after reacting completely in reaction solution, separate out solid, filter, use the trichloromethane thorough washing, 60 ℃ of vacuum-dryings get pale brown toner end 43.23mg.M.p; Yield 40.63%; Molecular weight 531.99; Structural formula is as follows
Embodiment 24:
Camptothecine-20 (S)-O-[2-pyridazine salt-1] propionic ester
(1) synthetic method of camptothecine-20 (S)-O-2-chloropropionic acid ester is identical with embodiment 21 (1).
(2) camptothecine-20 (S)-O-[2-pyridazine salt-1] propionic ester synthetic
Add camptothecine-20 (S)-O-2-chloropropionic acid ester 87.8mg (0.2mmol) in the 25ml there-necked flask, 1mlDMSO and excessive pyridazine are heated to 50 ℃, stir 12 hours, follow the tracks of reaction by TLC, and product is unfolded R in methyl alcohol
fValue is zero.Add an amount of trichloromethane, anhydrous diethyl ether after reacting completely in reaction solution, separate out solid, filter, use the trichloromethane thorough washing, 60 ℃ of vacuum-dryings get brown-black powder 32.38mg.M.p; Yield 31.20%; Molecular weight 518.95; Structural formula is as follows
Embodiment 25:
Camptothecine-20 (S)-O-(2-imidazolyl-1) propionic ester
(1) synthetic method of camptothecine-20 (S)-O-2-chloropropionic acid ester is identical with embodiment 21 (1).
(2) camptothecine-20 (S)-O-(2-imidazolyl-1) propionic ester is synthetic
Add camptothecine-20 (S)-O-2-chloropropionic acid ester 87.8mg (0.2mmol) in the 25ml there-necked flask, 1mlDMSO and excessive imidazoles are heated to 45 ℃, stirred 12 hours, follow the tracks of reaction by TLC, the back that reacts completely adds chloroform, anhydrous diethyl ether in reaction solution, separate out the faint yellow solid product, filter, solid concentrates with chloroform and methyl alcohol mixed liquor dissolving, goes up silica gel chromatographic column then and separates, get compound camptothecine-20 (S)-O-(2-imidazolyl-1) propionic ester, faint yellow 21.75mg.M.p; Yield 23.11%; Molecular weight 470.49; Structural formula is as follows
Embodiment 26:
Camptothecine-20 (S)-O-(2-purine radicals) propionic ester
(1) synthetic method of camptothecine-20 (S)-O-2-chloropropionic acid ester is identical with embodiment 21 (1).
(2) camptothecine-20 (S)-O-(2-purine radicals) propionic ester is synthetic
In the 25ml there-necked flask, add camptothecine-20 (S)-O-2-chloropropionic acid ester 87.8mg (0.2mmol), 1m1DMSO and excessive purine, and add the 50mg anhydrous K
2CO
3Be heated to 45 ℃, stirred 8 hours, and followed the tracks of reaction by TLC, the back that reacts completely adds entry in reaction solution, separate out the faint yellow solid product, filter, solid concentrates with chloroform and methyl alcohol mixed liquor dissolving, go up the silica gel chromatographic column separation then and obtain compound camptothecine-20 (S)-O-(2-purine radicals) propionic ester, pale yellow powder 45.21mg.M.p; Yield 42.05%; Structural formula is as follows, molecular weight 537.57.
Claims (10)
1. described camptothecin derivative is represented with following general formula (I), (II), (III):
Wherein
R
1Be hydrogen, ethyl;
R
2Be hydrogen, nitro;
R
3Be hydroxyl, amino, aminated compounds, contain one or more five yuan or hexa-atomic nitrogen-containing heterocycle compound and derivatives thereof;
R
4Be hydrogen, hydroxyl;
N can be 2,3,4.
2. camptothecin derivative according to claim 1, wherein R
1Be hydrogen; Ethyl.
3. camptothecin derivative according to claim 1, wherein R
2Be hydrogen, nitro.
4. camptothecin derivative according to claim 1, wherein R
1Be hydrogen, hydroxyl.
5. camptothecin derivative according to claim 1, wherein R
3Be
-NH
2
-OH
-NH(CH
2)mOH
m＝1，2，3，4，5
-NHCH
2COOC
2H
5
Deng five yuan or hexa-atomic nitrogen-containing heterocycle compound and spread out thing and hydroxyl, amino, aminated compounds.
6. water soluble camptothecin derivatives according to claim 1, n are 2,3,4 alkyl chain, and structure is-CH
2CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH
2CH
2-.
7. the preparation method 1 of the described water soluble camptothecin derivatives of claim 1,
It is characterized in that the camptothecin derivative shown in the formula (IV)
Wherein
R
1Definition with claim 2;
R
2Definition with claim 3;
R
4Definition with claim 4;
React with the haloalkane shown in the formula V or with the halogenated carboxylic acid shown in the formula (VI)
BrCH
2CH
2Br，BrCH
2CH
2CH
2Br，BrCH
2CH
2CH
2CH
2Br；
(V)
BrCH
2CH
2Cl，BrCH
2CH
2CH
2Cl，BrCH
2CH
2CH
2CH
2Cl；
ClCH
2COOH，CH
3ClCH
2COOH；
(VI)
BrCH
2COOH，CH
3BrCH
2COOH；
With production (VII) or (VII), the camptothecin derivative shown in (IX)
Wherein
R
1Definition with claim 2;
R
2Definition with claim 3;
R
4Definition with claim 4;
N is 2,3,4;
R
5Be Br, Cl;
R in camptothecin derivative VII, VII, IX and the claim 5 then
3Pairing nitrogen heterocyclic ring and derivative thereof, and all Ammonia derivatives reactions generate the described water soluble camptothecin derivatives of claim 1.
8. the preparation method 2 of the described water soluble camptothecin derivatives of claim 1;
It is characterized in that R in the claim 5
2Pairing nitrogen heterocyclic ring and derivative thereof, and all Ammonia derivatives and formula V shown in haloalkane or react with the halogenated carboxylic acid shown in the formula (VI)
BrCH
2CH
2Br，BrCH
2CH
2CH
2Br，BrCH
2CH
2CH
2CH
2Br；
(V)
BrCH
2CH
2Cl，BrCH
2CH
2CH
2Cl，BrCH
2CH
2CH
2CH
2Cl；
ClCH
2COOH，CH
3ClCH
2COOH；
(VI)
BrCH
2COOH，CH
3BrCH
2COOH；
Compound shown in difference production (X) or formula (XI), (XII)
Wherein
R
5Be Br, Cl;
N is 2,3,4;
R
3Definition with claim 5;
Then the compound of formula (X) or formula (XI), (XII) respectively with the camptothecin derivative reaction shown in (IV) of formula, generate the described water soluble camptothecin derivatives of claim 1.
Wherein
R
1Definition with claim 2;
R
2Definition with claim 3;
R
4Definition with claim 4;
9. contain just like the purposes of the compound described in the claim 1 to 6 in the preparation antitumor drug.
10. contain antitumor drug just like compound described in the claim 1 to 6.
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ID=40245410
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101967173A (en) * | 2010-09-15 | 2011-02-09 | 东北林业大学 | Novel camptothecin derivative coupled with cholic acid at position 10 |
| CN102649795A (en) * | 2011-06-23 | 2012-08-29 | 东北林业大学 | 10-methoxyl camptothecin derivative, preparation method and application |
| JP2017516807A (en) * | 2014-06-03 | 2017-06-22 | インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ | Rapamycin derivatives and methods for their preparation, pharmaceutical compositions and uses |
| CN108484623A (en) * | 2018-05-17 | 2018-09-04 | 浙江工业大学 | camptothecin derivative and preparation method and application thereof |
| CN116496287A (en) * | 2023-04-26 | 2023-07-28 | 东北林业大学 | New production process of camptothecine and hydroxycamptothecin in camptotheca acuminata seeds |
-
2008
- 2008-06-16 CN CNA2008100647425A patent/CN101343276A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101967173A (en) * | 2010-09-15 | 2011-02-09 | 东北林业大学 | Novel camptothecin derivative coupled with cholic acid at position 10 |
| CN102649795A (en) * | 2011-06-23 | 2012-08-29 | 东北林业大学 | 10-methoxyl camptothecin derivative, preparation method and application |
| CN102649795B (en) * | 2011-06-23 | 2014-08-06 | 东北林业大学 | 10-methoxyl camptothecin derivative, preparation method and application |
| JP2017516807A (en) * | 2014-06-03 | 2017-06-22 | インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ | Rapamycin derivatives and methods for their preparation, pharmaceutical compositions and uses |
| CN108484623A (en) * | 2018-05-17 | 2018-09-04 | 浙江工业大学 | camptothecin derivative and preparation method and application thereof |
| CN116496287A (en) * | 2023-04-26 | 2023-07-28 | 东北林业大学 | New production process of camptothecine and hydroxycamptothecin in camptotheca acuminata seeds |
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