CN1955183A - 20-bit esterified camptothecine derivate, its preparation method and drug composite and use - Google Patents

20-bit esterified camptothecine derivate, its preparation method and drug composite and use Download PDF

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CN1955183A
CN1955183A CN 200510116740 CN200510116740A CN1955183A CN 1955183 A CN1955183 A CN 1955183A CN 200510116740 CN200510116740 CN 200510116740 CN 200510116740 A CN200510116740 A CN 200510116740A CN 1955183 A CN1955183 A CN 1955183A
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amino
low alkyl
alkyl group
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CN1955183B (en
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温显道
刘红岩
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Institute of Materia Medica of CAMS
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Abstract

This invention discloses a new camptothecin derivate of 20-position esterification, its preparation, containing their medicine combination, and its usage of using it as medicine, especially as antitumor drug.

Description

Camptothecin derivative, its method for making and its pharmaceutical composition and purposes that 20-is bit esterified
Technical field
The present invention relates to the bit esterified camptothecin derivative of new 20-, its preparation method contains their pharmaceutical composition, and as medicine, especially as the purposes of antitumor drug.
Background technology
(Camptothecin is to separate a kind of alkaloid that obtains from Hong paulownia section drought lotus plant camptotheca acuminata (Camptotheca acuminata) CPT) to camptothecine.Experimental results show that camptothecine has antitumour activity to many solid tumors, it mainly acts on DNA topoisomerase I (Topo I, a kind of in many cancer cells the enzyme of high expression level), is the specific inhibitor of the most classical Topo I.At present Topo I becomes one of the most popular target spot of design new type anticancer medicine.National cancer institute (NCI) medicine mechanism analysis computer network system has been classified Topo I inhibitor as one of six big series antineoplastic medicaments of primary study.Except that the U.S. and Japan, France, Germany, Italy and Korea S are also in the research work of carrying out camptothecin derivative.
In view of the serious toxicity (bone marrow depression, hemorrhagic cystitis and diarrhoea) of camptothecine has limited its application in cancer therapy.Natural camptothecine is insoluble in water, and is fat-soluble also very poor.In order to increase the water-soluble of camptothecine, the anti-tumor activity of camptothecine sodium salt had once been estimated in the clinical trial of the seventies, and insufficient is that its sodium-salt form produces serious toxicity to human body, and antitumour activity is low, and it is clinical therefore to have interrupted the II phase.The discovery of the eighties topology isomerase I causes the interest .1989 of oncologist to camptothecine again, discovers that the semi-synthetic derivative of camptothecine has outstanding anti-tumor activity to the bare mouse different species transplantation tumor.Studies show that, CPT by with reversible combination of Topo I-DNA binary cleavable mixture (cleavable complex), form CPT-DNA-Topo I ternary complex, thereby stablized the cleavable mixture, form " roadblock ", cause replication fork (replication fork) not go on, thereby cause death of neoplastic cells.Yet the anti-tumor activity of camptothecine in human body is but very low, and this is because camptothecine exists the balance between the carboxylate form of the lactone form of closing and open loop in vivo, and the open loop form depends on pH value and animal species.Particularly human serum albumin (HSA) preferentially combines with the open loop form of camptothecine, forms stabilized complex, makes balance to the displacement of open loop form, makes the lactone content that has anti-tumor activity in proper too low.
Contain four six-rings and a five-ring in the molecule of camptothecine, the E ring is an Alpha-hydroxy lactone and a chiral centre (20S configuration) is arranged.Also there is an intramolecular hydrogen bond (Fig. 1) in the camptothecin molecule, makes that the activity of E cyclocarbonyl is very high, under the attack of nucleophilic reagent, be easy to open loop.Structure activity study shows: concerning anti-tumor activity, the hydroxy-lactone ring E of camptothecine is the constitutional features of most critical, evidence is in nude mice, the camptothecine activity of closing lactone form is far superior to the camptothecine sodium salt of open loop form, so camptothecine lactonic ring stability in vivo is the important factor that influences anti-tumor activity.We think that the serious toxicity (mouse maximum tolerated dose MTD 12mg/kg) of camptothecine mainly is because the open loop form and the HSA of camptothecine combine closely after in medicine enters human body, make camptothecine balance in vivo from closing lactone form to the displacement of open loop form, the very fast open loop of camptothecine (transformation period is less than half an hour).Research also finds, the A of camptothecine, the substituting group on the B ring particularly 7, and the two replacements of 10-can disturb that open loop form and HSA's combine increase lactonic ring stability in vivo.The 20-hydroxyalkyl acrylate of bibliographical information camptothecine and aryloxyacetic acid ester prodrugs can reduce toxicity in addition, increase the stability of lactone, thereby improve the anti-tumor activity of camptothecine.
Two at present external camptothecine soluble derivative Erie compare determined curative effect with topotecan (Topotecan) with the parent compound camptothecine for health (Irinotecan), and antitumor spectra is wide, clinically widespread use.Other has a plurality of derivatives such as 9-nitrocamptothecin, DX-8951f, and GG-211, Bay38-3441, BN80915 and CKD-602 are carrying out the II/III clinical study.And domestic camptothecine only arranged, and 10-hydroxycamptothecine, Erie is for health and topotecan listing.Because camptothecine and 10-hydroxycamptothecine are not modified natural products, toxicity is bigger, and anti-tumor activity is low, has limited them in Clinical Application; Moreover these medicines of patient's life-time service easily produce resistance, press for the antitumor drug of seeking high-efficiency low-toxicity.
The compounds of this invention also has cytotoxic activity except that cancer cells is had the cytotoxic activity to the resistance cancer cells; Little to normal cytotoxicity, and big to cytotoxicity.
Summary of the invention
In order to overcome the deficiencies in the prior art, the object of the present invention is to provide a kind of new bit esterified camptothecin derivative and isomer thereof of 20-;
Another object of the present invention is to provide a kind of new 20-the preparation method of bit esterified camptothecin derivative;
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.
Another object of the present invention is to provide the application of bit esterified camptothecin derivative of a kind of new 20-and composition thereof as antitumor drug.
First aspect of the present invention relates to the compound shown in general formula (I).
Figure A20051011674000081
In this general formula
R 1Be selected from: hydrogen, halogen, low alkyl group, lower alkoxy, junior alkyl halides, hydroxyl, RCOO, cyano group, aldehyde radical, nitro, amino, carboxyl, lower alkoxycarbonyl, rudimentary alcoxyl carbonyl amino, lower alkyl aminomethyl, (4-methyl isophthalic acid-piperazinyl) methyl, the lower trialkyl silylation, alkane carbonyl oxygen methyl, benzene methoxyl methyl, benzene first carbonyl oxygen methyl, rudimentary alkoxyl-methyl, CH 2NR 5R 6(R 5And R 6Be respectively hydrogen, the 1-6 carbon atom alkyl, the aryl substituted alkyl, hydroxyl replaces low alkyl group, the amino low alkyl group that replaces, single or two substituted-amino low alkyl groups, ring is amino);
R 2Be selected from: hydrogen, halogen, low alkyl group, lower alkoxy, hydroxyl, RCOO, cyano group, aldehyde radical, nitro, amino, RCONH, junior alkyl halides, carboxyl, lower alkoxycarbonyl, rudimentary alcoxyl carbonyl amino, CH 2NR 7R 8(R 7And R 8Be respectively hydrogen, the 1-6 carbon atom alkyl, the aryl substituted alkyl, hydroxyl replaces low alkyl group, the amino low alkyl group that replaces, single or two substituted-amino low alkyl groups, ring is amino), CH 2R 9(R 9Be lower alkoxy, cyano group), NR 10R 11(R 10, R 11Be respectively low alkyl group, aryl, dialkylamino alkyl, amino low alkyl group, hydroxyl low-grade alkyl);
R 3Be selected from: hydrogen, halogen, low alkyl group, lower alkoxy, amino lower alkoxy, hydroxyl, the RCOO of replacing, cyano group, aldehyde radical, nitro, amino, junior alkyl halides, carboxyl, lower alkoxycarbonyl, rudimentary alcoxyl carbo methoxy group, rudimentary alcoxyl carbonyl amino, the amino low alkyl group that replaces, hydroxyl replaces low alkyl group, [4-(piperidino)-piperidino] carbonyl oxygen base;
R 4Be selected from: hydrogen, halogen, low alkyl group, lower alkoxy, RCOO, cyano group, aldehyde radical, nitro, amino, junior alkyl halides, carboxyl, lower alkoxycarbonyl, rudimentary alcoxyl carbonyl amino;
Or R 1And R 2Cheng Huan, or R 2And R 3Cheng Huan, R 3And R 4Cheng Huan;
It is characterized in that:
R is: the 1-pyrimidyl (I) of a.1-pyrimidyl or replacement;
Figure A20051011674000091
R 5Be: hydrogen, halogen, low alkyl group.
B. benzene sulfydryl or substituted benzene sulfydryl (II);
Figure A20051011674000092
R 6Be: hydrogen, halogen, nitro, amino, low alkyl group, lower alkoxy, cyano group, the list of aldehyde radical replaces or intersects polysubstituted.
C. pyridine sulfydryl or substituted pyridines sulfydryl (III);
Figure A20051011674000093
R 7Be: hydrogen, halogen, nitro, amino, low alkyl group, lower alkoxy, cyano group, the list of aldehyde radical replaces or intersects polysubstituted, nitrogen-atoms again aromatic ring 2,3,4,5,6.
D. pyrimidine sulfydryl or substituted pyrimidines sulfydryl (IV);
R 8Be: hydrogen, halogen, nitro, amino, low alkyl group, lower alkoxy, cyano group, the list of aldehyde radical replaces or intersects polysubstituted, and the sulfydryl position can be at 2,4 or 5.
E. aryl or substituted aryl (V);
R 9Be: hydrogen, halogen, nitro, amino, low alkyl group, lower alkoxy, cyano group, aldehyde radical, the list of aryl replaces or intersects polysubstituted.
F. array structure (VI) under being:
R 10Be: hydrogen, halogen, nitro, amino, low alkyl group, lower alkoxy, cyano group, the list of aldehyde radical replaces or intersects polysubstituted.
According to the present invention, the compound of preferred general formula (I) is including but not limited to the compound shown in general formula (Ia):
Figure A20051011674000102
Wherein, R as defined above.
According to the present invention, the compound of preferred general formula (I) is including but not limited to the compound shown in general formula (Ib):
Figure A20051011674000103
R 11Be: hydrogen, low alkyl group, lower alkylcarbonyl.
Wherein, R as defined above.
According to the present invention, the compound of preferred general formula (I) is including but not limited to the compound shown in general formula (Ic):
Wherein, R as defined above.
In the present invention, term " halogen " is meant fluorine, chlorine, bromine, iodine.Term " low alkyl group " " lower alkyl " is the alkyl of the straight or branched of 1-6 carbon atom.
According to the present invention, the form that The compounds of this invention can isomer exists, and described usually " The compounds of this invention " comprises the isomer of this compound.
Can there be the cis-trans-isomer of two keys in The compounds of this invention, and 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, single if desired foreign body object can separate according to conventional methods or prepare by three-dimensional selection is synthetic.
According to embodiment of the present invention, described The compounds of this invention also comprises hydrate, ester or the prodrug of acceptable salt, salt on its pharmacodynamics.
Another aspect of the present invention relates to the preparation method of The compounds of this invention.
Figure A20051011674000112
The compound of invention is to prepare by reacting camptothecine or its analogue and corresponding carboxylic acid or carboxylic acid halides.Camptothecin analogues is that in camptothecine 7,9,10,11 have various substituent compounds, and it is synthetic that their preparation can be consulted literature method.Provide the title of part document below.
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Preferred acid be selected from 2-(ethyl thioglycollic acid of pyridine-4-), 2-(thymus pyrimidine-1-) acetate, 2-[(4-methylpyrimidine)-2-] ethyl thioglycollic acid, 3,4,5-trimethoxy toluylic acid, 3-(4-benzoyl bromide) propionic acid, 4-chlorobenzene ethyl thioglycollic acid.The mol ratio of acid and camptothecine is 1-5: 1; Preferred 1.5-3.5: 1; More preferably 2-3: 1.
Condensation reaction takes place under the condition that suitable condensing agent, catalyzer exist.Preferred condensation reagent is to comprise 1,3 dicyclohexylcarbodiimide (DCC), two pyridine carbonic ethers (2-DPC), 1-(3-dimethylamine propyl)-3-ethyl carbimide hydrochloride (EDCI), 1,3-di-isopropyl carbimide (DIPC), 4-pyrrolidyl pyridine.1-[(3-dimethylamino most preferably) propyl group]-3-ethyl carbimide hydrochloride (EDCI), the 1-[(3-dimethylamino) propyl group]-mol ratio of 3-ethyl carbimide hydrochloride and camptothecine is 2-6: 1; Preferred 2.5-5.5: 1; More preferably 3.5-4.5: 1.
Preferred catalyzer is a tertiary amine.Preferred tertiary amine is selected from 4-Dimethylamino pyridine (DMAP), 4-pyrrolidyl pyridine.4-Dimethylamino pyridine (DMAP) most preferably, the mol ratio of (0.71,0.95) 4-Dimethylamino pyridine and camptothecine is 0.5-1.5: 1; Preferred 0.75-0.95: 1.
Be reflected under the The suitable solvent and carry out, preferred solvent is anhydrous non-protonic solvent, more preferably haloalkane, DMF, tetrahydrofuran (THF) (THF), N, dinethylformamide (DMF) etc.Methylene dichloride most preferably.
Be reflected at-carry out under the 20-60 ℃, preferred temperature of reaction is between 0 ℃-60 ℃, and preferred temperature is 20 ℃-30 ℃, and most preferred temperature is a room temperature.
Reaction times is 2-48 hour, preferably 6-36 hour, and most preferably 10-24 hour.
With this neighborhood technician known method washing, dry, concentrated, separate with silica gel column chromatography, eluent is chloroform and methanol mixture.
Further aspect of the present invention also relates to and containing as the The compounds of this invention of active ingredient 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 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.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection therapy 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 are tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder etc. for example.
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 and tackiness agent are as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, for example 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, Tristearoylglycerol, theobroma oil, hydrogenation 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, whiteruss, 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, Gelucire, kaolin, talcum powder etc.; Tackiness agent is as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, 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 effective constituent The compounds of this invention is mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also the effective constituent The compounds of this invention 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 compounds of this invention is made injection preparation, as solution, suspensoid solution, emulsion, lyophilized injectable powder, this preparation can be moisture or non-water, can contain acceptable carrier, thinner, tackiness agent, lubricant, sanitas, tensio-active agent or dispersion agent on a kind of and/or multiple pharmacodynamics.Can be selected from water, ethanol, polyoxyethylene glycol, 1 as thinner, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, Polyoxyethylene Sorbitol Fatty Acid Esters 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.
Another aspect of the present invention also relates to the purposes of The compounds of this invention and pharmaceutical composition.The dosage of The compounds of this invention and 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.In general, the using dosage of Chinese materia medica composition 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 1-1000mg/m 2, 10-100mg/m especially 2Above-mentioned dosage can the single dose form or be divided into several, two, three or four these dosage regimens that are subject to administration doctor's clinical experience and comprise utilization chemotherapy, radiotherapy means of dosage form administration for example.
The invention compound by suitable medication such as oral, parenterai administration such as IP, IV treats animal tumor.Tumour comprises leukemia and solid tumor such as colon, ovary, mammary gland, prostate gland, lung, kidney and melanoma.The dosage range of administration depends on route of administration, age, body weight, body surface area and patient's treatment situation.Concerning the people, body surface area is determined by height and body weight.The suitable dose scope of the compound of invention is from 1-1000mg/m 2, 10-100mg/m especially 2
Abbreviation
EDCI (1-3-dimethylamine propyl)-3-ethyl carbimide hydrochloride;
DCC:1,3-dicyclohexyl carbimide;
DIPC:1,3-di-isopropyl carbimide;
The DMAP:4-dimethylamino pyridine;
THF: tetrahydrofuran (THF);
DMF:N, dinethylformamide.
Embodiment
The following examples are used for further specifying the present invention, but this and do not mean that any limitation of the invention.
Embodiment 1.
Camptothecine-20-O-2-(ethyl thioglycollic acid ester of pyridine-4-)
In the dry round-bottomed flask of the 25mL that has induction stirring, add 30mg (0.0861mmol) camptothecine, 30mg (0.172mmol) 2-(pyridine-4-) ethyl thioglycollic acid, 66mg (0.344mmol) 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI), 10mg (0.0819mmol) 4-Dimethylamino pyridine (DMAP) and 5mL anhydrous methylene chloride, reaction mixture was stirring at room 10 hours, reaction solution with the dilution of 50mL chloroform, is used 50mL water, the saturated NaHCO of 50mL then successively 3Solution and the water washing of 50mL saturated common salt add anhydrous MgSO 4Drying removes by filter MgSO 4After, the pressure reducing and steaming solvent, residue with silica gel column chromatography separate (eluent: chloroform-methanol 100: 1), obtain the 26mg white solid, yield: 60%, mp:207-210 ℃, 1H NMR (400MHZ, CDCl 3): δ 8.41 (s, 1H, Ar-H), 8.24 (m, 3H, Ar-H), 7.97 (d, J=8.0Hz, 1H, Ar-H), 7.88 (t, J=7.2Hz, 1H, Ar-H), 7.70 (t, J=7.2Hz, 1H, Ar-H), 7.35 (d, J=5.6Hz, 2H, Ar-H), 7.17 (s, 1H, Ar-H), 5.70 (d, J=17.2Hz, 1H, H17), 5.41 (d, J=17.2Hz, 1H, H17), 5.27 (s, 2H, H5), 3.97 (s, 2H, SCH 2), 2.28 (dm, 2H, 19-CH 2), 0.98 (t, J=7.6Hz, 3H, 18-CH 3).
Embodiment 2.
Camptothecine-20-O-2-(acetic ester of thymus pyrimidine-1-)
In the dry round-bottomed flask of the 25mL that has induction stirring, add 40mg (0.106mmol) camptothecine, 60mg (0.326mmol) 2-(thymus pyrimidine-1-) acetate, 80mg (0.424mmol) 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI), 10mg (0.0819mmol) 4-Dimethylamino pyridine (DMAP) and 5mL anhydrous methylene chloride, reaction mixture was stirring at room 24 hours, reaction solution with the dilution of 50mL chloroform, is used 50mL water, the saturated NaHCO of 50mL then successively 3Solution and the water washing of 50mL saturated common salt add anhydrous MgSO 4Drying removes by filter MgSO 4After, the pressure reducing and steaming solvent, residue with silica gel column chromatography separate (eluent: chloroform-methanol 100: 1), obtain the 14mg yellow solid, yield: 24%, mp:206-208 ℃, 1H NMR (400MH Z, CDCl 3): δ 8.50 (s, 1H, Ar-H), 8.44 (d, J=8.0Hz, 1H, Ar-H), 8.00 (d, J=8.0Hz, 1H, Ar-H), 7.91 (t, J=7.6Hz, 1H, Ar-H), 7.74 (t, J=7.6Hz, 1H, Ar-H), 7.58 (s, 1H, Ar-H), 7.14 (s, 1H, Ar-H), 5.67 (d, J=17.6Hz, 1H, H17), 5.42 (d, J=17.6Hz, 1H, H17), 5.32 (s, 2H, H5), 4.89 (d, J=17.6Hz, 1H, NCH 2COO), 4.59 (d, J=17.6Hz, 1H, NCH 2COO), 2.28 (dm, 2H, 19-CH 2), 1.01 (t, J=7.6Hz, 3H, 18-CH 3).
Embodiment 3.
Camptothecine-20-O-2-[(4-methylpyrimidine)-and 2-] the ethyl thioglycollic acid ester
Figure A20051011674000172
In the dry round-bottomed flask of the 25mL that has induction stirring, add 40mg (0.115mmol) camptothecine, 52mg (0.282mmol) 2-[(4-methylpyrimidine)-2-] ethyl thioglycollic acid, 90mg (0.469mmol) 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI), 10mg (0.0819mmol) 4-Dimethylamino pyridine (DMAP) and 5mL anhydrous methylene chloride, reaction mixture was stirring at room 12 hours, reaction solution with the dilution of 50mL chloroform, is used 50mL water, the saturated NaHCO of 50mL then successively 3Solution and the water washing of 50mL saturated common salt add anhydrous MgSO 4Drying removes by filter MgSO 4After, the pressure reducing and steaming solvent, residue with silica gel column chromatography separate (eluent: chloroform-methanol 100: 1), obtain the 50mg yellow solid, yield: 85%, mp:231-233 ℃, 1H NMR (400MH Z, CDCl 3): δ 8.40 (s, 1H, Ar-H), 8.21 (d, J=8.0Hz, 1H, Ar-H), 7.97 (d, J=8.0Hz, 1H, Ar-H), 7.86 (t, J=7.6Hz, 1H, Ar-H), 7.69 (t, J=7.6Hz, 1H, Ar-H), 7.25 (s, 1H, Ar-H), 6.60 (s, 1H, Ar-H), 5.62 (d, J=17.2Hz, 1H, H17), 5.43 (d, J=17.2Hz, 1H, H17), 5.27 (s, 2H, H5), 4.12 (d, J=16.8Hz, 1H, SCH 2), 4.08 (d, J=16.8Hz, 1H, SCH 2), 2.34 (m, 3H NCCH 3), 2.22 (dm, 2H, 19-CH 2), 0.95 (t, J=7.6Hz, 3H, 18-CH 3).
Embodiment 4.
Camptothecine-20-O-3,4,5-trimethoxy phenylacetate
In the dry round-bottomed flask of the 25mL that has induction stirring, add 40mg (0.115mmol) camptothecine, 65mg (0.282mmol) 3,4,5-trimethoxy toluylic acid, 90mg (0.469mmol) 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI), 10mg (0.0819mmol) 4-Dimethylamino pyridine (DMAP) and 5mL anhydrous methylene chloride, reaction mixture was stirring at room 12 hours, reaction solution with the dilution of 50mL chloroform, is used 50mL water, the saturated NaHCO of 50mL then successively 3Solution and the water washing of 50mL saturated common salt add anhydrous MgSO 4Drying removes by filter MgSO 4After, the pressure reducing and steaming solvent, residue with silica gel column chromatography separate (eluent: chloroform-methanol 100: 1), obtain the 52mg yellow solid, yield: 82%, mp:216-219 ℃, 1H NMR (400MHZ, CDCl 3): δ 8.39 (s, 1H, Ar-H), 8.25 (d, J=8.0Hz, 1H, Ar-H), 7.93 (d, J=8.0Hz, 1H, Ar-H), 7.85 (t, J=7.2Hz, 1H, Ar-H), 7.68 (t, J=7.2Hz, 1H, Ar-H), 7.14 (s, 1H, Ar-H), 6.52 (s, 2H, Ar-H), 5.65 (d, J=17.2Hz, 1H, H17), 5.42 (d, J=17.2Hz, 1H, H17), 5.27 (s, 2H, H5), 3.77 (m, 9H, OCH 3), 2.29 (dm, 2H, 19-CH 2), 0.98 (t, J=7.6Hz, 3H, 18-CH 3).
Embodiment 5.
Camptothecine-20-O-3-(4-benzoyl bromide) propionic ester
Figure A20051011674000191
In the dry round-bottomed flask of the 25mL that has induction stirring, add 30mg (0.0861mmol) camptothecine, 44mg (0.190mmol) 3-(4-benzoyl bromide) propionic acid, 60mg (0.313mmol) 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI), 10mg (0.0819mmol) 4-Dimethylamino pyridine (DMAP) and 5mL anhydrous methylene chloride; reaction mixture was stirring at room 12 hours; reaction solution with the dilution of 50mL chloroform, is used 50mL water, the saturated NaHCO of 50mL then successively 3Solution and the water washing of 50mL saturated common salt add anhydrous MgSO 4Drying removes by filter MgSO 4After, the pressure reducing and steaming solvent, residue with silica gel column chromatography separate (eluent: chloroform-methanol 100: 1), obtain the 44mg yellow solid, yield: 87%, mp:215-218 ℃, IR (KBr) ν 3485,2939,2821,1743,1662,1616,1500,1238,1157,760,723,592cm -1 1H NMR (600MHZ, CD 3Cl 3): δ 8.40 (s, 1H, Ar-H), 8.28 (d, J=8.4Hz, 1H, Ar-H), 7.95 (d, J=8.4Hz, 1H, Ar-H), 7.81 (t, J=7.2Hz, 1H, Ar-H), 7.79 (d, J=7.8Hz, 2H, Ar-H), 7.69 (t, J=7.2Hz, 1H, Ar-H), 7.48 (d, J=7.8Hz, 2H, Ar-H), 7.41 (s, 1H, Ar-H), 5.67 (d, J=16.8Hz, 1H, H17), 5.41 (d, J=16.8Hz, 1H, H17), 5.29 (d, J=10.8Hz, 2H, H5), 3.25 (m, 2H, ArCOCH 2), 3.03 (m, 2H, ArCOCCH 2), 2.18 (dm, 2H, 19-CH 2), 1.01 (t, J=7.2Hz, 3H, 18-CH 3).
Embodiment 6
Camptothecine-20-O-4-chlorobenzene ethyl thioglycollic acid ester
In the dry round-bottomed flask of the 25mL that has induction stirring, add 30mg (0.0861mmol) camptothecine, 30mg (0.148mmol) 4-chlorobenzene ethyl thioglycollic acid, 60mg (0.313mmol) 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride (EDCI), 10mg (0.0819mmol) 4-Dimethylamino pyridine (DMAP) and 3mL anhydrous methylene chloride, reaction mixture was stirring at room 12 hours, reaction solution with the dilution of 50mL chloroform, is used 50mL water, the saturated NaHCO of 50mL then successively 3Solution and the water washing of 50mL saturated common salt add anhydrous MgSO 4Drying removes by filter MgSO 4After, the pressure reducing and steaming solvent, residue with silica gel column chromatography separate (eluent: chloroform-methanol 100: 1), obtain the 23mg yellow solid, yield: 50%, mp:182-184 ℃, 1H NMR (600MHZ, CD 3Cl 3): δ 8.40 (s, 1H, Ar-H), 8.24 (d, J=8.4Hz, 1H, Ar-H), 7.96 (d, J=8.4Hz, 1H, Ar-H), 7.86 (t, J=7.2Hz, 1H, Ar-H), 7.69 (t, J=7.2Hz, 1H, Ar-H), 7.39 (d, J=8.4Hz, 2H, Ar-H), 7.22 (s, 1H, Ar-H), 7.10 (d, J=8.4Hz, 2H, Ar-H), 5.65 (d, J=16.8Hz, 1H, H17), 5.41 (d, J=16.8Hz, 1H, H17), 5.26 (s, 2H, H5), 3.78 (d, J=15.0Hz, 1H, SCH 2), 3.73 (d, J=15.0Hz, 1H, SCH 2), 2.23 (dm, 2H, 19-CH 2), 0.94 (t, J=7.2Hz, 3H, 18-CH 3).
Pharmacological evaluation
Experimental example 1.MTT legal person cancer cells fragmentation test
Medicine and reagent: DMSO analytical pure; RPMI1640 is the GIBCO product; Calf serum is the animal doctor of a Beijing Military Area Command centre of prevention and cure product.
Instrument: BIORAD550 type microplate reader.
Mtt assay is measured: collect well-grown tumour cell, be mixed with 1 * 10 with the RPMI1640 substratum that contains 10% calf serum -4/ mL cell suspension is inoculated in 96 well culture plates, and every empty 100 μ L (containing 1000 tumour cells) put 37 ℃, 5%CO 2Cultivate dosing after 24 hours in the incubator, blank and solvent control are established in experiment, and given the test agent is established 4 concentration, and 3 parallel holes of every concentration are put 37 ℃, 5%CO 2Cultivated 4 days in the incubator.Discard nutrient solution, every hole adds MTT solution (0.4mg/mL, RPMI1640 preparation) 100 μ L, hatches 4 hours for 37 ℃.Abandoning supernatant, every hole add MTT solution 150 μ L, and dissolved particles behind the gentle agitation, is detecting wavelength 540nm with 550 type microplate reader, and reference wavelength 450nm measures the OD value down.
The result calculates: can obtain dose response curve with the different concns of medicine and the inhibiting rate mapping of pair cell, therefrom obtain half-inhibition concentration (IC 50).
Derivative of the present invention the results are shown in Table 1. to the anti-tumor activity of human tumor cell line
The anti tumor activity in vitro of table 1 camptothecin derivative
Compound IC 50/μmol·L-1
KB KB/VCR A549 HCT-8 Bel7402 A2780
Topotecan CPT 1 embodiment 12 embodiment 23 embodiment 34 embodiment 45 embodiment 56 embodiment 6 0.007 0.003 0.006 0.005 0.033 0.014 0.042 0.049 0.100 0.031 0.511 0.080 0.924 0.500 0.357 0.204 0.078 0.009 0.076 0.009 0.245 0.086 0.306 0.313 0.022 0.003 0.008 0.005 0.551 0.010 0.087 0.055 0.078 0.007 0.050 0.008 0.100 0.153 0.090 0.087 0.032 0.006 0.044 0.007 0.0815 0.063 0.093 0.072
KB: human oral cancer cells; KB/VCR: people's resistance cancer cell of oral cavity; A549: human lung adenocarcinoma cell; A2780: Proliferation of Human Ovarian Cell; HCT-8: human colon cancer cell; Bel7402: human liver cancer cell.

Claims (12)

1, the compound shown in general formula (I)
In this general formula
R 1Be selected from: hydrogen, halogen, low alkyl group, lower alkoxy, junior alkyl halides, hydroxyl, RCOO, cyano group, aldehyde radical, nitro, amino, carboxyl, lower alkoxycarbonyl, rudimentary alcoxyl carbonyl amino, lower alkyl aminomethyl, (4-methyl isophthalic acid-piperazinyl) methyl, the lower trialkyl silylation, alkane carbonyl oxygen methyl, benzene methoxyl methyl, benzene first carbonyl oxygen methyl, rudimentary alkoxyl-methyl, CH 2NR 5R 6(R 5And R 6Be respectively hydrogen, the 1-6 carbon atom alkyl, the aryl substituted alkyl, hydroxyl replaces low alkyl group, the amino low alkyl group that replaces, single or two substituted-amino low alkyl groups, ring is amino);
R 2Be selected from: hydrogen, halogen, low alkyl group, lower alkoxy, hydroxyl, RCOO, cyano group, aldehyde radical, nitro, amino, RCONH, junior alkyl halides, carboxyl, lower alkoxycarbonyl, rudimentary alcoxyl carbonyl amino, CH 2NR 7R 8(R 7And R 8Be respectively hydrogen, the 1-6 carbon atom alkyl, the aryl substituted alkyl, hydroxyl replaces low alkyl group, the amino low alkyl group that replaces, single or two substituted-amino low alkyl groups, ring is amino), CH 2R 9(R 9Be lower alkoxy, cyano group), NR 10R 11(R 10, R 11Be respectively low alkyl group, aryl, dialkylamino alkyl, amino low alkyl group, hydroxyl low-grade alkyl);
R 3Be selected from: hydrogen, halogen, low alkyl group, lower alkoxy, amino lower alkoxy, hydroxyl, the RCOO of replacing, cyano group, aldehyde radical, nitro, amino, junior alkyl halides, carboxyl, lower alkoxycarbonyl, rudimentary alcoxyl carbo methoxy group, rudimentary alcoxyl carbonyl amino, the amino low alkyl group that replaces, hydroxyl replaces low alkyl group, [4-(piperidino)-piperidino] carbonyl oxygen base;
R 4Be selected from: hydrogen, halogen, low alkyl group, lower alkoxy, RCOO, cyano group, aldehyde radical, nitro, amino, junior alkyl halides, carboxyl, lower alkoxycarbonyl, rudimentary alcoxyl carbonyl amino;
Or R 1And R 2Cheng Huan, or R 2And R 3Cheng Huan, R 3And R 4Cheng Huan;
It is characterized in that:
R is selected from: the 1-pyrimidyl (I) of a.1-pyrimidyl or replacement;
Figure A2005101167400003C1
R 5Be: hydrogen, halogen, low alkyl group;
B. benzene sulfydryl or substituted benzene sulfydryl (II);
R 6Be: hydrogen, halogen, nitro, amino, low alkyl group, lower alkoxy, cyano group, the list of aldehyde radical replaces or intersects polysubstituted;
C. pyridine sulfydryl or substituted pyridines sulfydryl (III);
Figure A2005101167400003C3
R 7Be: hydrogen, halogen, nitro, amino, low alkyl group, lower alkoxy, cyano group, the list of aldehyde radical replaces or intersects polysubstituted, nitrogen-atoms again aromatic ring 2,3,4,5,6;
D. pyrimidine sulfydryl or substituted pyrimidines sulfydryl (IV);
Figure A2005101167400003C4
R 8Be: hydrogen, halogen, nitro, amino, low alkyl group, lower alkoxy, cyano group, the list of aldehyde radical replaces or intersects polysubstituted, and the sulfydryl position can be at 2,4 or 5;
E. aryl or substituted aryl (V);
Figure A2005101167400003C5
R 9Be: hydrogen, halogen, nitro, amino, low alkyl group, lower alkoxy, cyano group, aldehyde radical, the list of aryl replaces or intersects polysubstituted;
F. array structure (VI) under being:
Figure A2005101167400004C1
R 10Be: hydrogen, halogen, nitro, amino, low alkyl group, lower alkoxy, cyano group, the list of aldehyde radical replaces or intersects polysubstituted.
2, compound according to claim 1 is characterized in that, this compound comprises the compound shown in the following general formula (Ia):
Figure A2005101167400004C2
Wherein, R such as claim 1 definition.
3, compound according to claim 1 is characterized in that, this compound comprises the compound shown in the following general formula (Ib):
R 11Be: hydrogen, low alkyl group, lower alkylcarbonyl;
Wherein, R such as claim 1 definition.
4, compound according to claim 1 is characterized in that, this compound comprises the compound shown in the following general formula (Ic):
Figure A2005101167400005C1
Wherein, R such as claim 1 definition.
According to the described compound of claim 1-4, it is characterized in that 5, this compound comprises hydrate, ester or the prodrug of acceptable salt, salt on its pharmacodynamics.
6, preparation is characterized in that as the method for arbitrary described compound of claim 1-4, camptothecine or its analogue and corresponding carboxylic acid condensation reaction, preparation corresponding compounds.
According to the preparation method of claim 6, it is characterized in that 7, the used condensation reagent of described condensation reaction comprises the 1-[(3-dimethylamino) propyl group]-3-ethyl carbimide hydrochloride.
According to the preparation method of claim 6, it is characterized in that 8, the used catalyzer of described condensation reaction comprises 4-Dimethylamino pyridine (DMAP).
According to the preparation method of claim 6, it is characterized in that 9, the used organic solvent of described condensation reaction is a methylene dichloride.
10, a kind of pharmaceutical composition is characterized in that, contain effective dose as the described arbitrary compound of claim 1-4, and acceptable carrier on the pharmacodynamics.
According to the pharmaceutical composition of claim 10, it is characterized in that 11, described pharmaceutical composition can be tablet, capsule, pill, injection, sustained release preparation, controlled release preparation and various particulate delivery system.
12, as the application of the arbitrary compound of claim 1-4 in the preparation antitumor drug.
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