CN1982313A - Camptothecin compound containing multiple organic hydroxy-acid group on 10-bit substituent, its production and composition - Google Patents
Camptothecin compound containing multiple organic hydroxy-acid group on 10-bit substituent, its production and composition Download PDFInfo
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Abstract
A camptothecin compound containing multiple organic carboxylic group on 10-bit substituting group, its production, medicinal composition and use as antineoplastic are disclosed. A1 and A2 express C1-C6 straight chain alkyl residue, C3-C20 branched chain alkyl residue or H. A1 and A2 can't be H simultaneously, A1 and A2 are connected into ring, B represents organic carboxylic or other carboxylic salt functional group, when A1 expresses H, A2 represents aromatic nucleus base residue, C5-C6 naphthene residue and 4-6heterocyclic residue, C3-C20 is branched chain alkyl residue, and A2-B is selected from C((CH2)a-CONH-C((CH2)a-COOH)a)a, a=1, 2 or 3.
Description
Technical field
The present invention relates to a kind of plant alkaloid as cytotoxic drug, especially a kind of camptothecine compounds, in particular, the present invention relates to contain on 10 bit substituents Comptothecin compounds of a plurality of organic hydroxy-acid groups, its preparation method, contain their pharmaceutical composition and as medicine, particularly as the application of antitumor drug.
Background technology
U.S. scientist Wall in 1966 etc. are separated to camptothecine first from the camplotheca acuminata of China after,, cause the interest that people are very big because of its unique chemical structure and notable antitumor activity.But camptothecine can not enter clinical study owing to poorly water-soluble.In the seventies, the Chinese scholar opens lactonic ring with sodium hydroxide, is prepared into water miscible sodium salt and carries out clinical study, serious bone marrow depression appears in the result, vomiting, diarrhoea and serious side effects such as hemorrhagic cystitis, and open loop form activity reduces greatly, and clinical study is stopped.1985, the results of study such as Hsiang of JohnHopkins university show, camptothecine is the specific inhibitor of DNA topoisomerase I, and topoisomerase I is a kind of ribozyme of cell, with the duplicating, transcribe, repair and recombinate relevant of DNA, all there is expression in its any stage in the cell cycle, and the content of topoisomerase I is than the content height in the normal cell in the known cancer cell, thereby this anti-tumor compounds has certain selectivity.And topoisomerase I occurs with suitable high density in propagation phase cell and stationary phase cell, and level is similar in the tumour cell of slowly propagation and fast breeding, show its to tumour of fast breeding and slowly growing tumors antitumour activity is all arranged.The gate is opened in this great revaluation that is found to be camptothecine.The medicine scholar has carried out structure of modification as target spot to camptothecine, has obtained a large amount of achievements.10-hydroxycamptothecine for example, from 1977 since China's listing, be widely used, all effective in cure to malignant tumours such as primary hepatocarcinoma, cancer of the stomach, incidence adenogenous epithelial cancer, leukemia, the rectum cancer, bladder cancer.Its structural formula is as follows:
In recent years, the bibliographical information of research camptothecine is a lot, and for example U.S. Pat 5,646,159 US4,604,463; US6,111,107; US6,350,756 etc.From camptothecine, use Manich and be reflected at 9 upward introducing amine methyl, have better water solubility and anti-tumor activity, wherein 10-hydroxyl 9-dimethylamino methyl camptothecine (Topotecan) was in listing in 1996, as ovarian cancer patient's second line treatment medicine, U.S. FDA was ratified its second line treatment medicine as small cell lung cancer (SCLC) again in 1999.Introduce the compound S N-38 that ethyl obtains on 7 of 10-hydroxycamptothecine, have good antineoplastic activity, its water-soluble prodrug Erie in listing in 1994, is used for the treatment of colorectal cancer for health (Irinotecan).In addition, also has domestic camptothecine compounds research report, the camptothecin derivative that replaces of Chinese patent 200310108532 disclosed 9-alkyl 10-hydroxyls for example, Chinese patent 200410052756 disclosed 10-alkoxy camptothecin derivatives etc.However, still need invention curative effect height, toxicity is low, the camptothecine compounds of good water solubility.
Summary of the invention:
The purpose of this invention is to provide the Comptothecin compounds that contains a plurality of organic hydroxy-acid groups on 10 bit substituents of a kind of general formula (I), it has good water-solubility, stronger tumor cytotoxic activity.
Another object of the present invention provides the preparation method who contains the Comptothecin compounds of a plurality of organic hydroxy-acid groups on 10 bit substituents of a kind of general formula (I).
One aspect of the present invention relates to pharmaceutical composition, and it comprises carrier commonly used in the compound of the general formula (I) as active ingredient and isomer and the pharmacy field.
What further aspect of the present invention related to is general formula (I) compound or the anticancer usage that contains their pharmaceutical composition.
According to the present invention, contain the Comptothecin compounds of a plurality of organic hydroxy-acid groups on 10 bit substituents shown in general formula (I):
It is characterized in that wherein A
1, A
2Expression independently of one another contains the C of replacement
1-C
6The straight chained alkyl residue, C
3-C
20Branched-chain alkyl residue or H, condition is that both can not be H simultaneously;
A
1, A
2Connect into ring, comprise the residue of aromatic nucleus, saturated, unsaturated heterocycle base;
Wherein B represents and A
1, A
2The functional group that contains 1 to 9 organic carboxyl acid or its carboxylate salt that connects, its carboxylate salt comprises an alkali metal salt or alkaline earth salts such as sodium, potassium, calcium;
Work as A
1During expression H, connect A
1B meaningless, A
2Expression contains the fragrant cyclic group residue of replacement, contains the C of replacement
5-C
6Cycloalkyl residues contains the N that is selected from of replacement, and the monatomic 4-6 unit heterocyclic residues of O or S contains the C of replacement
3-C
20The branched-chain alkyl residue, A
2-B is selected from-C{ (CH
2) a-CONH-C[(CH
2) a-COOH] a}a ,-C{ (CH
2) a-CONH-C[(CH
2) a-COO
-] a}a, wherein a=1,2 or 3.
According to the present invention, A wherein preferably
1, A
2Expression independently of one another contains the C of replacement
1-C
4The straight chained alkyl residue contains the C of replacement
3-C
10Branched-chain alkyl residue or H, condition is that both can not be H simultaneously;
Wherein B represents and A
1, A
2The functional group that contains 1 to 9 organic carboxyl acid or its carboxylate salt that connects, its carboxylate salt comprises an alkali metal salt or alkaline earth salts such as sodium, potassium, calcium;
Work as A
1During expression H, connect A
1B meaningless, A
2Expression contains the phenyl or the benzyl residue of replacement, contains the C of replacement
3-C
10The branched-chain alkyl residue, A
2-B is selected from-C{ (CH
2) a-CONH-C[(CH
2) a-COOH] a}a ,-C{ (CH
2) a-CONH-C[(CH
2) a-COO
-] a}a, a=1 wherein, 2 or 3.
The precursor structure that contains the Comptothecin compounds of a plurality of organic hydroxy-acid groups on 10 bit substituents of the present invention can be a 10-hydroxycamptothecine, also can be on the 10-hydroxycamptothecine structural formula, use technology well known in the art and contain substituent analogue on synthetic 7,9,11 or 20.
Contain the form that the Comptothecin compounds of a plurality of organic hydroxy-acid groups can isomer according to the present invention on 10 bit substituents and exist, and described usually " compound of the present invention " or " Comptothecin compounds that contains a plurality of organic hydroxy-acid groups on 10 bit substituents of the present invention " comprises the isomer of this compound.
Can there be the cis-trans-isomer of two keys in the Comptothecin compounds that contains a plurality of organic hydroxy-acid groups on 10 bit substituents of the present invention, asymmetric center has S configuration or R configuration, the present invention includes all possible steric isomer, and two or more mixture of isomers.If there is suitable/trans isomer, the present invention relates to the mixture of cis form and trans forms and these forms.Individual isomer can separate according to conventional methods or prepare by three-dimensional selection is synthetic if desired.
According to the Comptothecin compounds that contains a plurality of organic hydroxy-acid groups on 10 bit substituents of the present invention preferably from natural 10-hydroxycamptothecine compound, its optical isomer, or their carboxylate salt.Most preferably from natural 10-hydroxycamptothecine compound, or their carboxylate salt.
The preparation method who contains the Comptothecin compounds of a plurality of organic hydroxy-acid groups on 10 bit substituents of the present invention comprises the following steps:
At first preparation contains the amine acyl chlorides or the isocyanic acid compounds of two or more organic hydroxy-acid groups accordingly, the terminal of these compounds contains secondary amine group or primary amine group, with this compound and corresponding acylating reagent reaction that contains amido, under organic base catalytic, obtain containing the compound of amine acyl chlorides or isocyanate functional base; With 10-hydroxycamptothecine or its analogue and corresponding amine acyl chlorides or isocyanic acid compounds, prepare the carboxylicesters that contains the Comptothecin compounds of organic hydroxy-acid group on 10 bit substituents by condensation reaction again; Be that described carboxyester hydrolysis becomes the corresponding carboxylic acid compound at last; This carboxylic acid cpd and alkali reaction are made salt.It is characterized in that the building-up reactions step comprises following reagent, catalyzer and reaction conditions:
At first preparation contains the amine acyl chlorides or the isocyanic acid compounds of two or more organic hydroxy-acid groups accordingly, will contain the compound and corresponding acylating reagent reaction of amido, and acylating reagent is phosgene (COCI
2) or trichloromethylchloroformate (Cl
3COCO
2CCl
3), catalyzer is an organic bases, comprises triethylamine (Et
3N) or pyridine, solvent is ethanol or tetrahydrofuran (THF) (THF);
Again with 10-hydroxycamptothecine or its analogue with contain the amine acyl chlorides or the isocyanic acid compounds of two or more organic hydroxy-acid groups accordingly, prepare the corresponding carboxylic acid ester by condensation reaction, temperature of reaction is 0-60 ℃, and the solvent of reaction is an anhydrous organic solvent, comprises methylene dichloride (CH
2Cl
2), chloroform (CHCl
3), N, dinethylformamide (DMF) or tetrahydrofuran (THF) (THF), catalyst for reaction is an organic bases, comprises triethylamine (Et
3N) or pyridine;
Be that the carboxyester hydrolysis that contains the Comptothecin compounds of organic hydroxy-acid group on 10 bit substituents becomes the corresponding carboxylic acid compound at last, its substituting group terminal is the hydrolysis of tertiary butyl ester, reagent is selected formic acid for use, if the substituting group terminal is the carboxyester hydrolysis of methyl esters or ethyl ester, adopt the inorganic alkali of equivalent, comprise lithium hydroxide, potassium hydroxide or sodium hydroxide, the temperature of reaction is 0-60 ℃, preferred temperature 20-30 ℃, time is 1-24 hour, the hydrolysis reaction solvent is the caustic liquor solution or 1 of methyl alcohol, the caustic liquor solution of 4-dioxane.
The multi-carboxylic acid compounds who contains the Comptothecin compounds of organic hydroxy-acid group on these 10 bit substituents can make salt with general ordinary method and alkali reaction, and preferred alkali is sodium hydroxide, potassium hydroxide, yellow soda ash or sodium bicarbonate etc.
The building-up reactions of preparation The compounds of this invention generally is to carry out under normal temperature or room temperature (10-30 ℃) condition.Its building-up reactions general formula is as follows: (Base represents pyridine or triethylamine in the formula)
According to embodiment of the present invention, the Comptothecin compounds that contains a plurality of organic hydroxy-acid groups on described the present invention's 10 bit substituents also comprises hydrate, carboxylicesters or the prodrug of acceptable salt, salt on its pharmacodynamics.
Therefore the present invention also relates to and containing as the The compounds of this invention of activeconstituents and the pharmaceutical composition of conventional medicine vehicle or assistant agent.Usually pharmaceutical composition of the present invention contains the The compounds of this invention of 0.1-95 weight %.
The pharmaceutical composition of The compounds of this invention can be according to method preparation well known in the art.When being used for this purpose, if desired, The compounds of this invention and one or more solids or liquid medicine vehicle and/or assistant agent can be combined, make and can be used as suitable administration form or the dosage form that people's medicine or veterinary drug use.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.
The compounds of this invention or the route of administration that contains its pharmaceutical composition can be drug administration by injection, comprise intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection therapy etc., in addition, also comprise the thoracic cavity drug administration by injection, the perfusion administration in bladder, abdominal cavity etc. and through artery to the insertion administration at positions such as brain, liver, kidney, four limbs, intestines etc.
Form of administration can be liquid dosage form, solid dosage.As liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations, for example tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, suppository or lyophilized injectable powder etc.
The compounds of this invention can be made ordinary preparation, also can be sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For example, can be extensive use of various carrier well known in the art for the unit form of administration is made tablet.Example about carrier is, for example thinner and absorption agent are as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, lime carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent such as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol etc.; Tackiness agent such as starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, carboxymethyl cellulose, methylcellulose gum, lac, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent is as dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, lime carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, for example sucrose, glyceryl stearate, theobroma oil, hydrogenated vegetable wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, Liquid Paraffin, polyoxyethylene glycol etc.Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For example, can be extensive use of various carrier well known in the art for pill is made in the administration unit.Example about carrier is, for example thinner and absorption agent are as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talcum powder etc.; Tackiness agent is as gum arabic, tragacanth gum, gelatin, ethanol, honey, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.
For example for capsule is made in the administration unit, the The compounds of this invention of effective constituent is mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatin or soft capsule.Also the The compounds of this invention of effective constituent can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into, or make injection and use.
For example the The compounds of this invention of effective constituent is made injection preparation, as solution, suspensoid solution, emulsion, lyophilized injectable powder etc., this preparation can be moisture or non-water, can contain acceptable carrier on a kind of and/or multiple pharmacodynamics,, as thinner, tackiness agent, lubricant, sanitas, tensio-active agent or dispersion agent.Can be selected from water, ethanol, polyoxyethylene glycol, 1 as thinner, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, polyoxyethylene sorbitol fatty acid ester etc.In addition, ooze injection liquid, can in injection preparation, add proper amount of sodium chloride, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH regulator agent etc. in order to prepare etc.These auxiliary materials are that this area is commonly used.In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives, sweeting agent or other material.
The dosage of The compounds of this invention pharmaceutical composition depends on many factors, for example to prevent or treat the character and the severity of disease, the sex of patient or animal, age, body weight, personality and individual reaction, route of administration, administration number of times etc., therefore therapeutic dose of the present invention can have large-scale variation.The using dosage of pharmaceutical cpd of the present invention is well known to a person skilled in the art.Can be according to the actual drug quantity that is contained in the preparation last in the The compounds of this invention composition, in addition suitable adjustment to reach the requirement of its treatment significant quantity, is finished prevention of the present invention or therapeutic purpose.The suitable dose scope of the every day of The compounds of this invention is from 0.1-1000mg/m
2Especially 1-100mg/m
2Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations, the dosage regimen that this is subject to administration doctor's clinical experience and comprises utilization chemotherapy, radiotherapy means.
Screen compound performance good antineoplastic activity of the present invention from anti tumor activity in vitro.Can be used as antitumor drug and be used for animal, be preferred for Mammals, particularly the people.
Embodiment
The following examples are used for further specifying the present invention, but do not limit the present invention in any way.
Synthesizing of two acetic acid of embodiment 1:10-(carboxylic acid amides) hydroxycamptothecine-N-and disodium salt thereof:
The structural formula of the two acetic acid of 10-(carboxylic acid amides) hydroxycamptothecine N-is as follows:
The synthetic route of the two acetic acid of 10-(carboxylic acid amides) hydroxycamptothecine-N-is as follows:
Benzylamine diacetic acid tert-butyl ester BnN (CH
2CO
2-tBu)
2Synthetic:
With benzylamine (8.4ml, 0.077mol) and salt of wormwood (21.5g 0.156mol) is dissolved in the 120ml ethanol, and (30.0g 0.158mol) is added dropwise in the benzylamine solution with the monobromo-acetic acid tert-butyl ester under the room temperature.Reaction solution is at room temperature stirred, observe, till the reactant benzylamine disappears with silica gel thin-layer (TLC) chromatography.Remove ethanol under the vacuum, with oily matter water and ethyl acetate (EtOAc) extraction.Anhydrous sodium sulfate drying is used in ester layer water and saturated brine washing again.Remove the EtOAc solvent under the vacuum, its residue obtains BnN (CH with purification by silica gel column chromatography
2CO
2-tBu)
2(17.9g), be colorless oil, yield is 69.2%, Low Resolution Mass Spectra LRMS:M+1=336.4.
Amido diacetic acid tert-butyl ester HN (CH
2CO
2-tBu)
2Synthetic:
With BnN (CH
2CO
2-tBu)
2(28.0g 83.5mmol) is dissolved in the 200ml methyl alcohol, at N
2Protection add down palladium carbon (Pd/C) (8.74g) and ammonium formiate (26.5g, 420mmol).With this mixing liquid reflux 12 hours, remove by filter Pd/C, again the methanol solvate of filtrate to be removed, its residual solids obtains solid NH (CH with purification by silica gel column chromatography (oil mystery Pet/EtOAc 2: 1)
2CO
2-tBu)
2(15.45g, 75.1%), Low Resolution Mass Spectra LRMS:M+1=246.4.
Amine acyl chlorides diacetic acid tert-butyl ester ClCON (CH
2CO
2-tBu)
2Synthetic:
With above intermediate NH (CH
2CO
2-tBu)
2(12.87g, 52.46mmol), Et
3N (10.42mL) is dissolved among the 50mL THF.Under the ice-water bath, its adding is dissolved with Cl
3COCO
2CCl
3(5.70g is among THF 19.24mmol) (250mL).This mixed solution is at room temperature stirred 3h.Remove the THF solvent under the vacuum, obtain crude product.This crude product is suspended among the EtOAc, and solids removed by filtration is removed the EtOAc solvent of filtrate again, and its residual solids obtains colorless solid ClCON (CH with purification by silica gel column chromatography (Pet/EtOAc 10: 1)
2CO
2-tBu)
2(11g, 68.1%) .RF:0.31over 10:1Pet/EtOAc, Low Resolution Mass Spectra LRMS:M+1=330.3.
10-(t-BuO
2CCH
2)
2NCO
2Synthesizing of-camptothecine:
With 10-hydroxycamptothecine (0.311g, 0.856mmol) and ClCON (CH
2CO
2-tBu)
2(1.712mmol) be dissolved in the 21mL pyridine, stirred 12 hours under the room temperature.Remove pyridine solvent under the vacuum.Use CHCl
3(100mL) extraction, the NaHCO with 7%
3Solution 100ml and saturated brine washing CHCl
3Layer is used anhydrous sodium sulfate drying.With purification by silica gel column chromatography (CHCl
3/ EtOAc1: 1) obtain yellow solid 10-(t-BuO
2CCH
2)
2NCO
2-camptothecine 0.51g, yield 93.8%.RF:0.49 (CHCl
3: EA: EtOH 1: 1: 0.1). Low Resolution Mass Spectra LRMS:M+1=636.7.
Synthesizing of the two acetic acid of 10-(carboxylic acid amides) hydroxycamptothecine-N-:
With 10-(t-BuO
2CCH
2)
2NCO
2(0.44g 0.6922mmol) is dissolved in the 8.0mL formic acid-camptothecine, stirs 12 hours under the room temperature.Remove formic acid solvent under the vacuum, obtain yellow solid.With EtOAc and CHCl
3Washing obtains the two acetic acid 0.31g of yellow solid 10-(carboxylic acid amides) hydroxycamptothecine-N-, yield 85.6%.Proton nmr spectra
1HNMR (DMSO-d6): δ
0.89 (3H, t, J=7.2Hz), 1.87 (2H, m), 4.12 (2H, s), 4.28 (2H, s), 5.30 (2H, s), 5.43 (2H, s), 6.54 (1H, s), 7.34 (1H, s), 7.58 (1H, dd, J
1=9.2Hz, J
2=2.8Hz), 7.88 (1H, d, J=2.8Hz), 8.20 (1H, d, J=9.2Hz), 8.70 (1H, s), 12.99 (2H, s), Low Resolution Mass Spectra LRMS:M+1=524.3.
Synthesizing of the two acetic acid disodiums of 10-(carboxylic acid amides) hydroxycamptothecine-N-:
With 10-(t-BuO
2CCH
2)
2NCO
2-camptothecine (0.340g, 0.6499mmol) be dissolved among the 1.0mLDMF, quantitatively add the 52.0mg aqueous sodium hydroxide solution then, remove the DMF solvent under the vacuum freezedrying, obtain faint yellow solid, obtain the two acetic acid disodium salt 0.340g of water-soluble solid 10-(carboxylic acid amides) hydroxycamptothecine-N-, yield 92.3%, LRMS:M-2Na+1=524.3 with the EtOAc washing.
Synthesizing of two propionic acid of embodiment 2:10-(carboxylic acid amides) hydroxycamptothecine-N-and disodium salt thereof:
The two propionic acid structural formulas of 10-(carboxylic acid amides) hydroxycamptothecine-N-are as follows:
Synthetic route is referring to embodiment 1, and synthetic method is similar.
The two propionic acid tert-butyl ester BnN (CH of benzylamine
2CH
2CO
2-tBu)
2Synthetic:
With benzylamine (5.46mL, 0.05mol) and salt of wormwood (21.5g 0.156mol) is dissolved in the 100ml ethanol, and (15.38mL 0.105mol) is added dropwise in the benzylamine solution with the bromo acid tert-butyl ester under the room temperature.With reaction solution reflux 48 hours, observe with the TLC chromatography, till the reactant benzylamine disappears.Remove alcohol solvent under the vacuum, with oily matter water and ethyl acetate extraction.Anhydrous sodium sulfate drying is used in ester layer water and saturated brine washing again.Remove the EtOAc solvent under the vacuum, its residue obtains BnN (CH with purification by silica gel column chromatography
2CH
2CO
2-tBu)
2(14g), be colorless oil, (Pet/AcOEt5: 1), yield is 77% to RF:0.74, Low Resolution Mass Spectra LRMS:M+1=364.1.
The two propionic acid tert-butyl ester NH (CH of amido
2CH
2CO
2-tBu)
2Synthetic:
At N
2Down, with BnN (CH
2CH
2CO
2-tBu)
2(1.09g 3.0mmol) is dissolved in the 20ml methyl alcohol, at N
2Adding Pd/C (0.32g) and ammonium formiate under the protection (0.946g, 15mmol).With this mixing liquid reflux 12 hours, solids removed by filtration Pd/C removed the methanol solvate of filtrate again, and its residual solids obtains solid HN (CH with purification by silica gel column chromatography (Pet/EtOAc 2: 1)
2CH
2CO
2-tBu)
2(0.61g, 74.4%), RF:0.29 (Pet/EtOAc 1: 1), Low Resolution Mass Spectra LRMS:M+1=274.0
The two propionic acid tert-butyl ester ClCON (CH of amine acyl chlorides
2CH
2CO
2-tBu)
2Synthetic:
Under the ice-water bath, with NH (CH
2CH
2CO
2-tBu)
20.16g, 0.5395mmol), Et
3(0.29mL 2.10mmol) is dissolved among the 10mLTHF N.Its adding is dissolved with Cl
3COCO
2CCl
3(0.16g is among THF 0.5395mmol) (10ml).This mixed solution was at room temperature stirred 3 hours.Remove the THF solvent under the vacuum, obtain ClCON (CH
2CH
2CO
2-tBu)
2Crude product.Directly carry out next step reaction.
10-(t-BuO
2C CH
2CH
2)
2NCO
2Synthesizing of-camptothecine:
With 10-hydroxycamptothecine (0.311g, 0.856mmol) and ClCON (CH
2CH
2CO
2Bu-t)
2(1.712mmol) be dissolved in the 20mL pyridine, stirred 12 hours under the room temperature.Remove pyridine solvent under the vacuum.Use CHCl
3(100mLX2) extraction, the NaHCO with 7%
3Solution and saturated brine washing CHCl
3Layer is used anhydrous sodium sulfate drying.Remove CHCl under the vacuum
3Get solid crude product behind the solvent, with purification by silica gel column chromatography (CHCl
3/ EtOAc1: 1) obtain yellow solid 10-(t-BuO
2CCH
2CH
2)
2NCO
2-camptothecine 0.51g, yield 93.8%.RF:0.49 (CHCl
3: EA: EtOH 1: 1: 0.1), Low Resolution Mass Spectra LRMS:M+1=662.7.
Synthesizing of the two propionic acid of 10-(carboxylic acid amides) hydroxycamptothecine N-:
With 10-(t-BuO
2C CH
2CH
2)
2NCO
2(0.4g 0.60mmol) is dissolved in the 8.0mL formic acid-camptothecine, stirs 12 hours under the room temperature.Remove formic acid solvent under the vacuum, obtain yellow solid.With EtOAc and ether wash the two propionic acid 0.216g of yellow solid 10-(carboxylic acid amides) hydroxycamptothecine-N-, yield 65.0%.Low Resolution Mass Spectra LRMS:M+1=552.3. proton nmr spectra
1HNMR (DMSO-d
6) δ: 0.89 (3H, t, J=7.2Hz), 1.87 (2H, m), 4.12 (2H, s), 2.57 (2H, t, J=6.8 Hz), 2.67 (2H, t, J=6.8Hz), 3.55 (2H, t, J=6.8Hz), 3.71 (2H, t, J=6.8Hz), 5.30 (2H, s), 5.43 (2H, s), 6.53 (1H, s), 7.68 (1H, dd, J
1=9.2Hz, J
2=2.8Hz), 7.91 (1H, d, J=2.8Hz), 8.18 (1H, d, J=9.6Hz), 8.32 (1H, s), 8.65 (1H, s).
Synthesizing of the two propionic acid disodium salts of 10-(carboxylic acid amides) hydroxycamptothecine-N-:
With 10-(t-BuO
2C CH
2CH
2)
2NCO
2(0.212g 0.3844mmol) is dissolved among the 1.0mL DMF-camptothecine, quantitatively adds the 30mg aqueous sodium hydroxide solution then.Remove the DMF solvent under the vacuum freezedrying, obtain faint yellow solid, obtain the two propionic acid disodium salt 0.21g of water-soluble solid 10-(carboxylic acid amides) hydroxycamptothecine N-, yield 92%, Low Resolution Mass Spectra LRMS:M+1=596.5 with the EtOAc washing.
Embodiment 3:10-[N-(4,4 '-dipropionic acid) butyric acid) carboxylic acid amides] hydroxycamptothecine synthetic:
10-[N-(4,4 '-dipropionic acid) butyric acid) carboxylic acid amides]-the hydroxycamptothecine structural formula is as follows:
The tricarboxylic acid tert-butyl ester derivative intermediate of routine reaction formula obtains by the following method down.With Nitromethane 99Min. and tertiary butyl acrylate, obtain nitrotrimethylolmethane carboxylic acid tert-butyl ester derivative by the MICHEAL addition.This compound 50g (0.11mol) is placed the round-bottomed flask of 1000ml, add the 400ml dehydrated alcohol and make its dissolving, add the Raney Ni (0.26mol) for preparing by the 30g alumel then.The normal temperature and pressure H-H reaction.The complete after-filtration of reactant reaction is removed Raney Ni, and rotation pressure reducing and steaming alcohol solvent obtains the 46.6g white solid, amido tricarboxylic acid tert-butyl ester derivative compound [1, the two tert.-butoxy acyl groups of 5--3-[(2-tert.-butoxy acyl group) ethyl] the 3-aminopentane].Productive rate 100%.Rf=0.806 (ethyl acetate); Mp:60～62 ℃.LRMS:M+1=416.1; M+ sodium=438.3.
The amine acyl chlorides preparation method of describing with embodiment 1 obtains following isocyanic acid tricarboxylic acid tert-butyl ester derivative (MW=441), does not have the crude product of purifying to be used for the coupled reaction (reaction formula Phosgen is a phosgene) of next step and 10-hydroxycamptothecine.
With above isocyanic acid tricarboxylic acid tert-butyl ester derivative (1.5g, 3.2mmol) and 10-hydroxycamptothecine (0.364g 1.0mmol), places pyridine (81mL).Stirring at room 24 hours.Remove pyridine solvent under the decompression.Enriched material CH
2Cl
2(200mL), use NaHCO again with the water extraction
3(7%, 100mL), use anhydrous Na with the full salt washing organic phase of closing
2SO
4Dry organic layer.Rotation pressure reducing and steaming CH
2Cl
2Solvent obtains crude product.Silica gel column chromatography (CHCl
3/ EtOAc1: obtain light yellow solid 10-hydroxycamptothecine tricarboxylic acid tert-butyl ester derivative (0.51g, 60%) RF:0.3 (CHCl 1)
3: EA: EtOH 1: 1: 0.1).
Above 10-hydroxycamptothecine tricarboxylic acid tert-butyl ester derivative (0.51g) is dissolved in the formic acid (10mL), stirring at room 12 hours, formic acid solvent is removed in the rotation decompression, obtains yellow solid.This solid recrystallization in acetonitrile is got 10-[N-(4,4 '-dipropionic acid) butyric acid) carboxylic acid amides]-hydroxycamptothecine (0.3g), Low Resolution Mass Spectra (LRMS) M-1=636.
Synthesizing of embodiment 4:10-(carboxylic acid amides) hydroxycamptothecine-N-nine carboxylic acids:
10-(carboxylic acid amides) hydroxycamptothecine-N-nine carboxylic acid structure formulas are as follows:
The preparation of substituting group part:
With among the embodiment 3 [1; the two tert.-butoxy acyl groups of 5--3-[(2-tert.-butoxy acyl group) ethyl] the 3-aminopentane] 50g (0.12mol) and compound three replacement propionic acid Nitromethane 99Min. 10g (0.036mol) (seeing last figure); place the round-bottomed flask of a 1000ml; add 350mLDMF; after treating compound dissolution, add I-hydroxybenzotriazole (HOBt) 17.9g (0.13mol) again.Get 1 then, 3-dicyclohexylcarbodiimide (DCC) 27.3g (0.13mol) places the beaker of a 100ml, add 50mLDMF and make its dissolving, it is added dropwise in the reaction flask, stirring at room reaction 48h, solids removed by filtration adds 400mL EtOAc in reaction solution, (100 * 4mL) wash water, the anhydrous sodium sulfate drying organic layer.The decompression rotation boils off DMF and EtOAc equal solvent, and the gained residue is used column chromatography nitro-compound (II) the white solid 36g that obtains reaction formula (last figure), and productive rate is 67.5%.Rf=0.375 (EtOAc: hexane=1: 2); 151～153 ℃ of Mp; Low Resolution Mass Spectra LRMS:M+1 1470.4M+ water=1487.4.
Above compound (II) 28g (0.019mol) places the round-bottomed flask of a 1000ml, adds the 400mL dehydrated alcohol, adds the RaneyNi (0.26mol) that is prepared by the 30g alumel again.Hydrogenation under the normal temperature and pressure.The after-filtration that reacts completely is removed Raney Ni, and alcohol solvent is removed in the rotation decompression, obtains white solid compound (III) 27g.Productive rate 100%.Rf＝0.51(D∶M＝10∶1)；Mp＝180～181℃；LRMS：M+1 1440.3。The amine acyl chlorides preparation method of describing with embodiment 1 obtains isocyanic acid nine carboxylic acid tert-butyl ester derivatives (IV), and the crude product that is not further purified (IV) the Low Resolution Mass Spectra LRMS:M+1-1726 that obtains is directly used in the coupled reaction of next step and 10-hydroxycamptothecine.
With above isocyanic acid nine carboxylic acid tert-butyl ester derivatives (IV) (15g) and 10-hydroxycamptothecine (0.364g 1.0mmol), places pyridine (150mL).Stirring at room 74 hours.Remove pyridine solvent under the decompression.Enriched material CH
2Cl
2(500mL), use NaHCO again with the water extraction
37%, 100mL), use the anhydrous sodium sulfate drying organic layer with saturated salt washing organic phase.CH is removed in the rotation decompression
2Cl
2Solvent obtains crude product, with this crude product through silica gel column chromatography (CHCl
3/ EtOAc1: obtain white solid 10-hydroxycamptothecine nine carboxylic acid tert-butyl ester derivatives (0.7g) 1).
Above 10-hydroxycamptothecine nine carboxylic acid tert-butyl ester derivatives (0.7g) are dissolved in formic acid (10mL), stirring at room 74 hours, formic acid solvent is removed in the rotation decompression, obtains 10-(carboxylic acid amides) hydroxycamptothecine-N-nine carboxylic acid products (0.1g), Low Resolution Mass Spectra (LRMS) M-1=1324.
Dioctyl phthalate is synthetic between embodiment 5:10-(carboxylic acid amides) hydroxycamptothecine-N-5-benzene: the dioctyl phthalate structural formula is as follows between 10-(carboxylic acid amides) hydroxycamptothecine-N-5-benzene:
Synthetic method:
Under condition of ice bath, with Cl
3COCO
2CCl
3(0.15g, 0.5mmol) and triethylamine (0.3mL) place the round-bottomed flask that contains 10mL THF, slowly add 1,3-(5-amido) phthalic acid (0.135g, 1.5mmol).Reaction liquid is under agitation through being raised to room temperature in 2 hours.The THF solvent is removed in rotation decompression, and the crude product isocyanic acid compound (0.2g) that obtains is directly used in the reaction of next step and 10-hydroxycamptothecine.
Above isocyanic acid (0.2g) is dissolved in DMF (5mL) to be dissolved in 10-hydroxycamptothecine (0.15g) among the DMF (10mL) again.Under 0 ℃ the former is being added among the latter stirring at room 74 hours. remove the DMF solvent under the decompression. enriched material CH
2Cl
2(50mL) with the water extraction, water and saturated salt washing organic phase is used the anhydrous sodium sulfate drying organic layer again.CH is removed in the rotation decompression
2Cl
2Solvent obtains dioctyl phthalate tert-butyl ester derivative between crude product 10-(carboxylic acid amides) hydroxycamptothecine-N-5-benzene.With this crude product through silica gel column chromatography (CHCl
3/ EtOAc 1: 1) obtains the dioctyl phthalate tert-butyl ester (0.07g) between white solid 10-(carboxylic acid amides) hydroxycamptothecine-N-5-benzene behind the purifying, Low Resolution Mass Spectra (LRMS) M+1=684.
The dioctyl phthalate tert-butyl ester (0.07g) between above 10-(carboxylic acid amides) hydroxycamptothecine-N-5-benzene is dissolved in the formic acid (10mL), stirring at room 24 hours, formic acid solvent is removed in the rotation decompression, solid is carried out recrystallization obtain dioctyl phthalate (0.02g) between 10-(carboxylic acid amides) hydroxycamptothecine-N-5-benzene in ether, Low Resolution Mass Spectra (LRMS) M-1=570.
Pharmacological evaluation:
Specimen preparation: 10-hydroxycamptothecine (HCPT) adds several dimethyl sulfoxide (DMSO) (DMSO) must supply test agent with dissolved in distilled water then, and other samples are used for experiment with dissolved in distilled water.
Experimental technique: six kinds of human body tumour cells (SGC-7901, BEL-7404, BEL-7402, Bcap-37, HL-60 and K562), a kind of mouse tumour cell P388 is suspended in respectively in RPMI-1640 (Gibco) substratum, provide with 10% bovine serum,, contain 5%CO 37 ℃ of temperature
2Air ambient is cultivated down.Every kind of tumour cell concentration is (1-5) * 10
8/ L, the embodiment compound and the tumour cell effect 3-5d of the 10-hydroxycamptothecine of different concns and confession examination; HL-60 effect 12h; P388 effect 48h.Adopt MTT and the trypan blue row method of dying to measure.The vitro cytotoxicity measuring the results are shown in Table 1:
Table 1.10-hydroxycamptothecine and embodiment compound compare different tumour cell effects:
| Tumour cell | HCPT | IC 50/mmol.L -1(logit method) | Embodiment 5 | |
| Embodiment 1 | Embodiment 2 | |||
| Disodium salt | Disodium salt | |||
| BEL-7404 BEL-7402 SGC-7901 Bcap-37 HL-60 K562 P338 | 0.20 0.05 5.80 0.45 0.78 0.08 0.24 | 0.16 0.07 4.90 0.30 0.42 0.04 0.18 | 0.20 0.03 5.20 0.70 0.82 0.10 0.22 | 1.15 0.10 6.20 1.11 1.84 0.04 0.61 |
BEL-7402 and BEL-7404: people's malignancy hepatic tumor cell strain; SGC-7901: human stomach cancer cell line; Bcap-37: human breast cancer cell strain; HL-60 and K562: human leukemia JEG-3; P338: murine leukemia JEG-3.
Experimental result shows: embodiment 1,2, and 5 three compounds all present the cytotoxicity that is similar to 10-hydroxycamptothecine.The effect of the inhibition tumour cell of embodiment 1 compound is best, also is better than 10-hydroxycamptothecine.
Claims (7)
1, the Comptothecin compounds that contains a plurality of organic hydroxy-acid groups on a kind of 10 bit substituents shown in general formula (I):
It is characterized in that wherein A
1, A
2Expression independently of one another contains the C of replacement
1-C
6The straight chained alkyl residue, C
3-C
20Branched-chain alkyl residue or H, condition is that both can not be H simultaneously,
A
1, A
2Connect into ring, comprise the residue of aromatic nucleus, saturated, unsaturated heterocycle base,
Wherein B represents and A
1, A
2The functional group that contains 1 to 9 organic carboxyl acid or its carboxylate salt that connects,
Work as A
1During expression H, connect A
1B meaningless, A
2Expression contains the residue of the fragrant cyclic group of replacement, contains the C of replacement
5-C
6Cycloalkyl residues contains the N that is selected from of replacement, and the monatomic 4-6 unit heterocyclic residues of O or S contains the C of replacement
3-C
20The branched-chain alkyl residue, A
2-B is selected from-C{ (CH
2) a-CONH-C[(CH
2) a-COOH] a}a ,-C{ (CH
2) a-CONH-C[(CH
2) a-COO-] a}a, wherein a=1,2 or 3.
2, contain the Comptothecin compounds of a plurality of organic hydroxy-acid groups on 10 bit substituents according to claim 1, it is characterized in that wherein A
1, A
2Expression independently of one another contains the C of replacement
1-C
4The straight chained alkyl residue contains the C of replacement
3-C
10Branched-chain alkyl residue or H, condition is that both can not be H simultaneously,
Wherein B represents and A
1, A
2The functional group that contains 1 to 9 organic carboxyl acid or its carboxylate salt that connects,
Work as A
1During expression H, connect A
1B meaningless, A
2Expression contains the phenyl or the benzyl residue of replacement, contains the C of replacement
3-C
10The branched-chain alkyl residue, A
2-B is selected from-C{ (CH
2) a-CONH-C[(CH
2) a-COOH] a}a ,-C{ (CH
2) a-CONH-C[(CH
2) a-COO
-] a}a, a=1 wherein, 2 or 3.
3, the Comptothecin compounds that contains a plurality of organic hydroxy-acid groups on 10 bit substituents according to claim 1 and 2 is characterized in that described compound is selected from natural 10-hydroxycamptothecine compound, its optical isomer, or their carboxylate salt.
4; prepare the method that contains the Comptothecin compounds of a plurality of organic hydroxy-acid groups on 10 bit substituents as claimed in claim 1 or 2; at first preparation contains the amine acyl chlorides or the isocyanic acid compounds of two or more organic hydroxy-acid groups accordingly; the terminal of these compounds contains secondary amine group or primary amine group; this is contained the compound and corresponding acylating reagent reaction of amido; under organic base catalytic, obtain containing the compound of amine acyl chlorides or isocyanate functional base; again with 10-hydroxycamptothecine or its analogue and corresponding amine acyl chlorides or isocyanic acid compounds; prepare the carboxylicesters that contains the Comptothecin compounds of organic hydroxy-acid group on 10 bit substituents by condensation reaction; be that described carboxyester hydrolysis becomes the corresponding carboxylic acid compound at last; this carboxylic acid cpd and alkali reaction are made salt; it is characterized in that comprising in the building-up reactions step following reagent, catalyzer and reaction conditions:
At first preparation contains the amine acyl chlorides or the isocyanic acid compounds of two or more organic hydroxy-acid groups accordingly; the compound and corresponding acylating reagent reaction that will contain amido; acylating reagent is phosgene or trichloromethylchloroformate; catalyzer is an organic bases; comprise triethylamine or pyridine; solvent is tetrahydrofuran (THF) or ethanol
Again with 10-hydroxycamptothecine or its analogue with contain the amine acyl chlorides or the isocyanic acid compounds of two or more organic hydroxy-acid groups accordingly, prepare the corresponding carboxylic acid ester by condensation reaction, setting-up point is 0-60 ℃, the solvent of reaction is an anhydrous organic solvent, comprise methylene dichloride, chloroform, N, dinethylformamide or tetrahydrofuran (THF), catalyst for reaction is an organic bases, comprise triethylamine or pyridine
Be that the carboxyester hydrolysis that contains the Comptothecin compounds of organic hydroxy-acid group on 10 bit substituents becomes the corresponding carboxylic acid compound at last, its substituting group terminal is the hydrolysis of tertiary butyl ester, reagent is selected formic acid for use, if the substituting group terminal is the carboxyester hydrolysis of methyl esters or ethyl ester, adopt the inorganic alkali of equivalent, comprise lithium hydroxide, potassium hydroxide or sodium hydroxide, temperature of reaction is 0-60 ℃, time is 1-24 hour, and the hydrolysis reaction solvent is the caustic liquor solution or 1 of methyl alcohol, the caustic liquor solution of 4-dioxane.
5, the Comptothecin compounds that contains a plurality of organic hydroxy-acid groups on 10 bit substituents according to claim 1 and 2 is characterized in that described compound comprises hydrate, carboxylicesters or the prodrug of acceptable salt, salt on its pharmacodynamics.
6, a kind of pharmaceutical composition is characterized in that containing the Comptothecin compounds and the pharmaceutically acceptable carrier that contain a plurality of organic hydroxy-acid groups on the claim 1 of significant quantity or 2 described 10 bit substituents.
7, pharmaceutical composition according to claim 5 is characterized in that described composition can be tablet, capsule, injection, sustained release preparation, controlled release preparation and various particulate delivery system.
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|---|---|---|---|
| CN2005100479746A CN1982313B (en) | 2005-12-13 | 2005-12-13 | Camptothecin compound containing multiple organic hydroxy-acid group on 10-bit substituent, its production and composition |
| PCT/CN2006/003318 WO2007068188A1 (en) | 2005-12-13 | 2006-12-07 | Camptothecin compounds with a substituent located in 10-position comprising multi-carboxyl groups, their preparation processes and their pharmaceutical compositions |
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|---|---|---|---|
| CN2005100479746A CN1982313B (en) | 2005-12-13 | 2005-12-13 | Camptothecin compound containing multiple organic hydroxy-acid group on 10-bit substituent, its production and composition |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848840A (en) * | 2012-12-03 | 2014-06-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Camptothecin derivatives and medical application thereof |
| CN103864810A (en) * | 2012-12-07 | 2014-06-18 | 天津科技大学 | Preparation method of novel 10-hydroxycamptothecine 10-position derivatives and application in antitumor drugs |
| CN104262352A (en) * | 2014-09-01 | 2015-01-07 | 中国人民解放军军事医学科学院毒物药物研究所 | Camptothecin derivatives and medical application thereof |
| WO2023150899A1 (en) * | 2022-02-08 | 2023-08-17 | Canwell Biotech Limited | Conjugates of chemotherapy agents and tissue-binding small molecules, compositions and methods thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6019790A (en) * | 1983-07-14 | 1985-01-31 | Yakult Honsha Co Ltd | Novel camptothecin derivative |
| US5646159A (en) * | 1994-07-20 | 1997-07-08 | Research Triangle Institute | Water-soluble esters of camptothecin compounds |
-
2005
- 2005-12-13 CN CN2005100479746A patent/CN1982313B/en active Active
-
2006
- 2006-12-07 WO PCT/CN2006/003318 patent/WO2007068188A1/en active Application Filing
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848840A (en) * | 2012-12-03 | 2014-06-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Camptothecin derivatives and medical application thereof |
| CN103864810A (en) * | 2012-12-07 | 2014-06-18 | 天津科技大学 | Preparation method of novel 10-hydroxycamptothecine 10-position derivatives and application in antitumor drugs |
| CN104262352A (en) * | 2014-09-01 | 2015-01-07 | 中国人民解放军军事医学科学院毒物药物研究所 | Camptothecin derivatives and medical application thereof |
| CN104262352B (en) * | 2014-09-01 | 2018-06-15 | 中国人民解放军军事医学科学院毒物药物研究所 | Camptothecin derivative and its medical usage |
| WO2023150899A1 (en) * | 2022-02-08 | 2023-08-17 | Canwell Biotech Limited | Conjugates of chemotherapy agents and tissue-binding small molecules, compositions and methods thereof |
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| WO2007068188A1 (en) | 2007-06-21 |
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