CN100465175C - 7-bit substituted comptothecine kind compound and pharmaceutical use thereof - Google Patents
7-bit substituted comptothecine kind compound and pharmaceutical use thereof Download PDFInfo
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- CN100465175C CN100465175C CNB2005101109036A CN200510110903A CN100465175C CN 100465175 C CN100465175 C CN 100465175C CN B2005101109036 A CNB2005101109036 A CN B2005101109036A CN 200510110903 A CN200510110903 A CN 200510110903A CN 100465175 C CN100465175 C CN 100465175C
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Abstract
The invention relates to 7-place substituting high camptothecin class compound and the application that belongs to chemical technology field. It includes racemic mixture and enantiomer. It has the function of restraining topoismerase and has anti-tumor activity, antifungal activity, and antivirus activity.
Description
Technical field
The present invention relates to medical technical field, is a kind of new high camptothecine compounds with anti-tumor activity and as the purposes of medicine.
Background technology
Camptothecine (camptothecin is a kind of natural alkaloid that obtains that extracts from camplotheca acuminata CPT), has condensed five rings rigid structure, and is as follows:
Camptothecine is most important topoisomerase I inhibitor, and the various human tumor cell line is shown anti-tumor activity.For many years structure is imitated research and has been obtained large quantities of derivatives that exploitation is worth that have, wherein irinotecan (Irinotecan, CPT-11) and topotecan (Topotecan TPT) is successively gone on the market by the FDA approval.
The hexa-atomic lactonic ring E of camptothecine encircles the carboxylate form that facile hydrolysis open loop in vivo becomes non-activity, and its activity in vivo is significantly reduced, and has caused its tangible toxicity.Thereby for improving camptothecine compounds stability enhanced activity in vivo, the investigator changes into prodrug with 20-position hydroxy ester at first, thereby can effectively stop the formation of intramolecular hydrogen bond to suppress the lactonic ring hydrolysis like this.People such as Olivier Lavergne have proposed the brand-new camptothecin analogues with seven yuan of beta-hydroxy lactonic rings of a class at WO97/00876, claim again high camptothecine (homocamptothecin, hCPT).Show the enhanced anti-tumor activity, and had metabolic stability enhanced advantage.The David Bom of Pittsburgh university has proposed the high camptothecine that 7-position silylation replaces at WO00/61146, has more strengthened the ester dissolubility, and is water-soluble different for improving with other, can see through hemato encephalic barrier like this.In addition, Zhang Wannian etc. provide the method for a kind of difference and above two the brand-new high camptothecine of preparation at CN1557814A, and have synthesized the high camptothecin derivative that 7-position chloromethyl replaces.Yet being still, the water-soluble and high toxicity of medicine needs the constantly problem of solution.
Summary of the invention
Be to solve the deficiencies in the prior art, the 7-position that the invention provides new anti-tumor activity replaces high Comptothecin compounds, comprise racemic modification, enantiomeric forms with and any mixture or its pharmaceutical salts of these forms, structure such as general formula (I):
Wherein:
R
1: expression-C (R
6)=N-R
7Group, wherein R
7Expression phenyl or [N=X] heterocyclic radical, and have one or more following substituted radicals at least: hydrogen, hydroxyl, halogen, low alkyl group, lower alkoxy, phenyl, cyano group, nitro ,-NR
8R
9
Or R
1Expression (CH
2)
mOCO (CH
2)
kR
10, R
10Expression hydrogen, low alkyl group, low-grade halogenated alkyl, replacement or unsubstituted [N=X] heterocyclic radical, rudimentary aralkyl, wherein substituting group be hydroxyl, halogen, low alkyl group, lower alkoxy, phenyl, cyano group, nitro ,-NR
8R
9
R
2, R
3, R
4Represent following groups independently: hydrogen, halogen, low alkyl group, OR
11, nitro, amino, perhaps R
2And R
3Form 3 or 4 yuan chain together, or R
3And R
4Form 3 or 4 yuan chain together, wherein the unit of this chain is selected from CH
2, O, as methylene-dioxy or ethylenedioxy;
R
5The expression low alkyl group, preferable methyl, ethyl, propyl group, preferred especially ethyl;
R
6Expression hydrogen, low alkyl group, lower alkoxy, the cycloalkyl that contains 3 to 10 carbon atoms, rudimentary aralkyl;
R
8And R
9Represent hydrogen or low alkyl group independently;
R
11Expression hydrogen or low alkyl group;
[N=X] represents 4 to 7 yuan of heterocyclic radicals, and X represents to constitute the needed chain of heterocyclic radical and is selected from CH, CH
2, O, S, N or NR
12
R
12Expression hydrogen or low alkyl group;
M, k represent the integer between the 0-6 respectively;
So-called low alkyl group is for containing 1 to 6 carbon atom straight chain or branched-chain alkyl, as methyl, ethyl, sec.-propyl etc. among the present invention; Lower alkoxy is for containing 1 to 6 carbon atom straight chain or branched alkoxy; Low-grade halogenated alkyl is to contain the low alkyl group that 1 to 3 halogen atom replaces; Rudimentary aralkyl is the low alkyl group that is connected with aryl.Halogen refers to fluorine, chlorine, bromine, iodine.
Contain an asymmetric c atom in the beta-hydroxy lactonic ring of The compounds of this invention, two kinds of configurations of R and S are arranged.Its racemic modification can be by splitting method [as the method for Olivier Lavergne etc.: J.Med.Chem.41:5410 (1998)] obtain optically pure enantiomorph.In addition, the carbon-to-nitrogen double bon during the 7-position replaces has cis-trans-isomer.The present invention includes these enantiomorph configurations and their various combinations, and racemic compound.
The present invention also provides the preparation method of such high camptothecine compounds.Synthetic route is as follows:
Can preparation formula (I) compound with the method that describes below and give an example for preferred compound of the present invention.
Initial three ring key intermediate 9-ethyl-9-hydroxyls-2,3,4,8-tetrahydrochysene-5H-6-oxa--3a-nitrogen heterocyclic indenes in heptan-1,4,7-triketone (VI) can obtain with reference to patent CN1557814A, but the different adjacent 2-aminooxyethanol acetal reference literature method that replaces [J.Org.Chem.44:578 (1979) such as Sugasawa; J.Am.Chem.Soc.100:484 such as Sugasawa (1978)] obtain.The Frielander condensation reaction of then they being carried out classics can obtain having the high camptothecin derivative of different substituents on the A ring.Be example with high camptothecine below, describe concrete synthesis step in detail:
1, for formula (I) compound, R
2, R
3, R
4When all being hydrogen, what three ring key intermediates (VI) and adjacent 2-aminooxyethanol acetal were carried out that the Frielander condensation reaction obtains is high camptothecine, usually adopt polarity or non-polar solvent such as benzene, toluene, ethanol, acetate etc., non-polar solvents such as preferred benzene, toluene.The used catalyzer of Frielander condensation is an an acidic catalyst, comprises organic acid and mineral acid, preferably organic acid such as tosic acid, acetate, formic acid etc., especially preferably tosic acid.
2, high camptothecine is obtained the 7-methylol with methyl alcohol and suitable oxidation system reaction under acidic conditions and replace high camptothecine (III).Acid herein is mineral acid, comprises the sulfuric acid of hydrochloric acid, different solubility etc., and the sulfuric acid of preferred different solubility is as 96%, 90%, 80%, 75% sulfuric acid, preferred especially 75% sulfuric acid.Oxidation system comprises the combination of reductive agent (as ferrous sulfate, iron protoxide etc.) and oxygenant (as hydrogen peroxide, Peracetic Acid etc.), preferably sulfuric acid is ferrous/and the hydrogen peroxide system.
3, the 7-methylol being replaced high camptothecine (III) just can obtain the 7-aldehyde radical with the oxidation of cationoid oxygenant and replace high camptothecine (II).The cationoid oxygenant here comprises sulfuric acid, acetate, phosphorus oxychloride, sulfur oxychloride etc., and solvent comprises water, dioxane, pyridine, N, and dinethylformamide (N, N-dimethylformamide, DMF) or do not have etc.Preferred cationoid oxygenant is an acetate, and solvent does not preferably adopt other solvents.
In addition, acid and 7-methylol being replaced high camptothecine (III) reacts in the presence of acidic conditions or condensing agent and can obtain ester compound.Acidic conditions is meant mineral acid, comprise hydrochloric acid, sulfuric acid, phosphoric acid etc., preferably sulfuric acid, condensing agent refers to various ester class condensing agents, comprise dicyclohexyl carbodiimide (dicyclohexylcarbodiimide, DCC), N, N '-di-isopropyl carbodiimide (N, N '-Diisopropylcarbodiimide, DIPC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, EDCI) etc., preferred DCC.Solvent select for use polarity or non-polar solvent such as methylene dichloride, benzene, methyl-sulphoxide (dimethylsulfoxide, DMSO) etc., preferred methylene dichloride.
4, the 7-aldehyde radical replaces high camptothecine (II) and amine and reacts under acidic catalyst and can obtain imine compound, the acid here comprises organic acid and mineral acid, as: acetate, tosic acid, sulfuric acid, Ytterbiumtriflate hydrate (ytterbium trifluoromethanesu lfonate hydrate, Yb (OTf)
3) etc., preferred Yb (OTf)
3Solvent is selected polarity or non-polar solvent such as methylene dichloride, benzene, DMSO etc., preferred methylene dichloride for use.
Will be clear that and work as R
2, R
3, R
4When respectively replacement being arranged, adopting uses the same method also can obtain similar compounds, as: R
3When being methoxyl group, at first obtain the high camptothecine of 10-methoxyl group; R
3, R
4Be 10, the high camptothecine of 11-difluoro when all having F to replace; R
3, R
4Become ethylenedioxy, promptly get 10, the high camptothecine of 11-ethylenedioxy.Just can get corresponding 7-imines and 7-ester derivative by above-mentioned route then.
Some compound of the present invention can be according to the form of ordinary method preparation position pharmaceutical salts.Comprise its organic acid salt and inorganic acid salt: mineral acid includes, but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, bisphosphate, Hydrogen bromide, nitric acid etc., and organic acid includes, but is not limited to acetate, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment, oxalic acid etc.
Formula of the present invention (I) compound has the effect that suppresses topoisomerase, and has anti-tumor activity.Prior art hints that compound of the present invention has antiviral activity [Chiang.J.Li etc., The Journal ofBiological Chemistry, 269:7051 (1994)] and anti-mycotic activity [Fostel J. etc., FEMSMicrobiology Letters, 138:105 (1996)], therefore compound of the present invention can be used for preparing the corresponding treatment medicine.
Compound of the present invention has anti-tumor activity, they can be used for treating tumour, comprise the cancer that positions such as esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, uterine endometrium, ovary, prostate gland, testis, bladder, kidney, liver, pancreas, bone, reticular tissue, skin, eye, brain and central nervous system take place, and thyroid carcinoma, leukemia, king's evil, lymphoma and myelomatosis etc. suddenly.
Compound of the present invention can also be used for the treatment of virus infection and fungi infestation.
The pharmacologically active of The compounds of this invention makes it can be used to prepare antitumor, antimycotic and antiviral, so the present invention also comprises with these compounds and pharmaceutical salts thereof the pharmaceutical composition as activeconstituents.This pharmaceutical composition can be solid form or liquid form.
The present invention also comprises any mixture or the purposes of its pharmaceutical salts aspect the following medicine of preparation of formula (I) compound and racemic modification, enantiomeric forms and these forms: medicine, the antitumor drug, antifungal drug and the antiviral aspect that suppress topoisomerase.
Embodiment
Below in conjunction with embodiment the present invention is described in detail, but the following example should not regarded limitation of the scope of the invention as.
Synthesizing of embodiment 1 high camptothecine
With 1.00g 9-ethyl-9-hydroxyl-2,3,8,9-tetrahydrochysene-5H-6-oxa--3a-azepine-ring indenes in heptan-1,4,7-triketone and 0.80g o-Aminobenzaldehyde Glycol Acetal in 800mL toluene, reflux water-dividing, after 30 minutes, add the 0.10g tosic acid, continue backflow 1h, cooled and filtered, with acetone and methanol wash, get the high camptothecine of 0.98g yellow solid (70.4%).
1HNMR(DMSO)，δ:0.87(t，3H)，1.86(q，2H)，3.06(d，1H)，3.49(d，1H)，5.28(s，2H)，5.39(d，1H)，5.53(d，1H)，6.03(s，1H)，7.42(s，1H)，7.72(t，1H)，7.87(t，1H)，8.15(q，2H)，8.69(s，1H)。
Synthesizing of the high camptothecine of embodiment 2 7-methylols
To the sulfuric acid of the high camptothecine dropping of the 0.98g that is suspended in 30mL methyl alcohol and 25mL water 25mL 75%, add the FeSO of 0.80g then
4.7H
2O.Be cooled to 0 ℃ with frozen water, Dropwise 5 mL 30% H
2O
2, continue to be stirred to room temperature reaction 14h.With separating out solid after the dilution of 200mL water, filter, with hot DMF washing, filtrate is boiled off solvent, (the eluent: CH of purifying on silica gel chromatographic column
2Cl
2/ CH
3OH 100:4), get the high camptothecine of 0.61g yellow solid 7-methylol (64.7%).
1HNMR(DMSO)，δ:0.88(t，3H)，1.87(q，2H)，3.06(d，1H)，3.47(d，1H)，5.27(d，2H)，5.41(s，2H)，5.40(d，1H)，5.53(d，1H)，5.80(t，1H)，6.03(s，1H)，7.40(s，1H)，7.71(t，1H)，7.86(t，1H)，8.16(d，1H)，8.20(d，1H)。
Synthesizing of the high camptothecine of embodiment 3 7-aldehyde radicals
The high camptothecine of 0.61g 7-methylol is heated to back flow reaction 6h in 200mL acetate, boils off solvent, (the eluent: CH of purifying on silica gel chromatographic column
2Cl
2/ CH
3OH 100:4), get the high camptothecine of 0.32g yellow solid 7-aldehyde radical (52.7%).
1HNMR(DMSO)，δ:0.87(t，3H)，1.88(q，2H)，3.07(d，1H)，3.49(d，1H)，5.42(d，1H)，5.52(s，2H)，5.55(d，1H)，6.06(s，1H)，7.46(s，1H)，7.92(t，1H)，7.98(t，1H)，8.31(d，1H)，9.04(d，1H)，11.10(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 4 7-(4-aminomethyl phenyl) methylene
With the high camptothecine of 50mg7-aldehyde radical, 10mg Yb (OTf)
3, 70mg para-totuidine and 15mL methylene dichloride stirring at room 10h boil off solvent, (the eluent: CH of purifying on silica gel chromatographic column after the filtration
2Cl
2/ CH
3OH 100:2), get the amino high camptothecine (26.0%) of 16mg yellow solid 7-(4-aminomethyl phenyl) methylene
1HNMR(DMSO)，δ:0.87(t，3H)，1.87(q，2H)，2.40(s，3H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.55(d，1H)，5.59(s，2H)，6.05(s，1H)，7.36(d，2H)，7.46(s，1H)，7.53(d，2H)，7.84(t，1H)，7.94(t，1H)，8.26(d，1H)，9.00(d，1H)，9.72(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 5 7-(2-aminomethyl phenyl) methylene
According to the method for embodiment 4, replace para-totuidine with Ortho Toluidine, obtain the amino high camptothecine (24.4%) of 15mg yellow solid 7-(2-aminomethyl phenyl) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，2.50(s，3H)，3.08(d，1H)，348(d，1H)，542(d，1H)，5.54(d，1H)，5.59(s，2H)，6.05(s，1H)，7.29(t，1H)，7.35(t，1H)，7.38(d，1H)，746(s，1H)，7.50(d，1H)，7.83(t，1H)，7.95(t，1H)，8.26(d，1H)，8.99(d，1H)，9.66(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 6 7-(3-aminomethyl phenyl) methylene
According to the method for embodiment 4, replace para-totuidine with meta-aminotoluene, obtain the amino high camptothecine (24.4%) of 15mg yellow solid 7-(3-aminomethyl phenyl) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，2.44(s，3H)，3.09(d，1H)，348(d，1H)，5.42(d，1H)，5.55(d，1H)，5.60(s，2H)，6.04(s，1H)，7.22(t，1H)，7.39(d，1H)，7.41(s，1H)，743(d，1H)，7.46(s，1H)，7.84(t，1H)，7.96(t，1H)，8.27(d，1H)，9.00(d，1H)，9.71(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 7 7-(2-hydroxy phenyl) methylene
According to the method for embodiment 4, replace para-totuidine with o-aminophenol, obtain the amino high camptothecine (16.2%) of 10mg yellow solid 7-(2-hydroxy phenyl) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.55(d，1H)，5.67(s，2H)，6.05(s，1H)，6.95(t，1H)，6.96(d，1H)，7.01(d，1H)，7.20(t，1H)，7.46(s，1H)，7.47(s，1H)，7.83(t，1H)，7.96(t，1H)，8.27(d，1H)，8.93(d，1H)，9.49(s，1H)，9.66(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 8 7-(2-bromophenyl) methylene
According to the method for embodiment 4, replace para-totuidine with o-bromoaniline, obtain the amino high camptothecine (18.6%) of 13mg yellow solid 7-(2-bromophenyl) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.54(d，1H)，5.70(s，2H)，6.05(s，1H)，7.33(t，1H)，7.47(s，1H)，7.57(t，1H)，7.72(d，1H)，7.84(d，1H)，7.86(t，1H)，7.96(t，1H)，8.28(d，1H)，9.02(d，1H)，9.74(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 9 7-(4-bromophenyl) methylene
According to the method for embodiment 4, replace para-totuidine with para-bromoaniline, obtain the amino high camptothecine (20.1%) of 14mg yellow solid 7-(2-bromophenyl) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.55(d，1H)，5.58(s，2H)，6.05(s，1H)，7.46(s，1H)，7.56(d，2H)，7.74(d，2H)，7.84(t，1H)，7.95(t，1H)，8.27(d，1H)，8.99(d，1H)，9.72(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 10 7-(3, the 5-3,5-dimethylphenyl) methylene
According to the method for embodiment 4, with 3, the 5-dimethyl replaces para-totuidine, obtains the amino high camptothecine (23.7%) of 15mg yellow solid 7-(3, the 5-3,5-dimethylphenyl) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.89(q，2H)，2.39(s，6H)，2.92(d，1H)，3.08(d，1H)，5.42(d，1H)，5.56(d，1H)，5.58(s，2H)，6.07(s，1H)，7.04(s，1H)，7.32(s，2H)，7.46(s，1H)，7.84(t，1H)，7.96(t，1H)，8.27(d，1H)，8.99(d，1H)，9.69(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 11 7-(2-p-methoxy-phenyl) methylene
According to the method for embodiment 4, replace para-totuidine with Ortho Anisidine, obtain the amino high camptothecine (25.2%) of 16mg yellow solid 7-(2-p-methoxy-phenyl) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，3.09(d，1H)，3.48(d，1H)，3.92(s，3H)，5.42(d，1H)，5.55(d，1H)，5.57(s，2H)，6.04(s，1H)，7.09(t，1H)，7.19(d，1H)，7.35(t，1H)，7.46(s，1H)，7.47(d，1H)，7.83(t，1H)，7.95(t，1H)，8.26(d，1H)，8.94(d，1H)，9.67(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 12 7-(3-chloro-phenyl-) methylene
According to the method for embodiment 4, replace para-totuidine with m-chloro aniline, obtain the amino high camptothecine (23.4%) of 15mg yellow solid 7-(3-chloro-phenyl-) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.55(d，1H)，5.59(s，2H)，6.05(s，1H)，7.43(d，1H)，7.46(s，1H)，7.52(d，1H)，7.57(t，1H)，7.71(s，1H)，7.83(t，1H)，7.95(t，1H)，8.27(d，1H)，9.02(d，1H)，9.73(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 13 7-(2-chloro-phenyl-) methylene
According to the method for embodiment 4, replace para-totuidine with m-chloro aniline, obtain the amino high camptothecine (23.4%) of 15mg yellow solid 7-(2-chloro-phenyl-) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.55(d，1H)，5.64(s，2H)，6.05(s，1H)，7.41(t，1H)，7.46(s，1H)，7.52(t，1H)，7.67(d，1H)，7.75(d，1H)，7.85(t，1H)，7.95(t，1H)，8.28(d，1H)，9.03(d，1H)，9.75(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 14 7-(4-chloro-phenyl-) methylene
According to the method for embodiment 4, replace para-totuidine with p-Chlorobenzoic acid amide, obtain the amino high camptothecine (23.4%) of 15mg yellow solid 7-(4-chloro-phenyl-) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，3.09(d，1H)，3.48(d，1H)，5.42(d，1H)，5.47(s，2H)，5.52(d，1H)，6.05(s，1H，OH)，7.44(s，1H)，7.59(d，2H)，7.61(d，2H)，7.81(t，1H)，7.93(t，1H)，8.23(d，1H)，8.95(d，1H)，9.68(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 15 7-(2,4 dichloro benzene base) methylene
According to the method for embodiment 4, replace para-totuidine with 2,4 dichloro aniline, obtain the amino high camptothecine (26.3%) of 18mg yellow solid 7-(2,4 dichloro benzene base) methylene.
1HNMR(DMSO)，δ:0.88(t，3H)，1.87(q，2H)，3.08(d，1H)，3.46(d，1H)，5.42(d，1H)，5.54(d，1H)，5.62(s，2H)，6.06(s，1H)，7.46(s，1H)，7:62(d，1H)，7.82(s，1H)，7.84(d，1H)，7.86(t，1H)，7.96(t，1H)，8.28(d，1H)，9.02(d，1H)，9.76(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 16 7-(2, the 4-3,5-dimethylphenyl) methylene
According to the method for embodiment 4, with 2, the 4-xylidine replaces para-totuidine, obtains the amino high camptothecine (25.3%) of 16mg yellow solid 7-(2, the 4-3,5-dimethylphenyl) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.54(d，1H)，5.57(s，2H)，6.06(s，1H)，7.16(d，1H)，7.20(s，1H)，7.45(s，1H)，7.49(d，1H)，7.82(t，1H)，7.94(t，1H)，8.25(d，1H)，8.99(d，1H)，9.69(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 17 7-(2, the 5-dichlorophenyl) methylene
According to the method for embodiment 4, with 2, the 5-dichlorphenamide bulk powder replaces para-totuidine, obtains the amino high camptothecine (24.8%) of 17mg yellow solid 7-(2, the 5-dichlorophenyl) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.54(d，1H)，5.63(s，2H)，6.06(s，1H)，7.46(s，1H)，748(d，1H)，7.69(d，1H)，7.86(t，1H)，7.95(t，1H)，7.97(s，1H)，8.29(d，1H)，9.06(d，1H)，9.78(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 18 7-(3, the 4-dichlorophenyl) methylene
According to the method for embodiment 4, with 3, the 4-dichlorphenamide bulk powder replaces para-totuidine, obtains the amino high camptothecine (24.8%) of 17mg yellow solid 7-(3, the 4-dichlorophenyl) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.54(d，1H)，5.60(s，2H)，6.07(s，1H)，7.47(s，1H)，7.58(d，1H)，7.80(d，1H)，7.85(t，1H)，7.95(s，1H)，7.96(t，1H)，8.28(d，1H)，9.01(d，1H)，9.75(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 19 7-(3-chloro-4-aminomethyl phenyl) methylene
According to the method for embodiment 4, replace para-totuidine with 3-chloro-4-monomethylaniline, obtain the amino high camptothecine (19.7%) of 13mg yellow solid 7-(3-chloro-4-aminomethyl phenyl) methylene.
1HNMR(DMSO)，δ:0.88(t，3H)，1.88(q，2H)，2.36(s，3H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.55(d，1H)，5.58(s，2H)，6.06(s，1H)，7.46(s，1H)，7.50(d，1H)，7.52(d，1H)，7.75(s，1H)，7.84(t，1H)，7.95(t，1H)，8.26(d，1H)，9.02(d，1H)，9.74(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 20 7-phenyl methylenes
According to the method for embodiment 4, replace para-totuidine with aniline, obtain the amino high camptothecine (23.5%) of 14mg yellow solid 7-phenyl methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.55(d，1H)，5.60(s，2H)，6.05(s，1H)，7.41(t，2H)，7.46(s，1H)，7.54(d，2H)，7.59(m，1H)，7.84(t，1H)，7.96(t，1H)，8.27(d，1H)，9.01(d，1H)，9.72(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 21 7-(4-acetylphenyl) methylene
According to the method for embodiment 4, replace para-totuidine with para-aminoacetophenone, obtain the amino high camptothecine (15.4%) of 10mg yellow solid 7-(4-acetylphenyl) methylene.
1HNMR(DMSO)，δ:0.87(t，3H)，1.88(q，2H)，2.65(s，3H)，3.08(d，1H)，3.48(d，1H)，542(d，1H)，5.55(d，1H)，5.61(s，2H)，6.06(s，1H)，746(s，1H)，7.65(d，2H)，7.86(t，1H)，7.91(t，1H)，8.13(d，2H)，8.30(d，1H)，9.02(d，1H)，9.74(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 22 7-(4-tert-butyl-phenyl) methylene
According to the method for embodiment 4, replace para-totuidine with tertiary butyl aniline, obtain the amino high camptothecine (18.0%) of 12mg yellow solid 7-(4-tert-butyl-phenyl) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.35(s，9H)，1.88(q，2H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.55(d，1H)，5.59(s，2H)，6.05(s，1H)，7.46(s，1H)，7.54(d，2H)，7.56(d，2H)，7.83(t，1H)，7.95(t，1H)，8.27(d，IH)，9.00(d，1H)，9.71(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 23 7-(3-chloro-4-fluorophenyl) methylene
According to the method for embodiment 4, replace para-totuidine with 3-chloro-4-fluoroaniline, obtain the amino high camptothecine (22.6%) of 15mg yellow solid 7-(3-chloro-4-fluorophenyl) methylene.
1HNMR(DMSO)，δ:0.89(t，3H)，1.88(q，2H)，3.09(d，1H)，3.48(d，1H)，5.42(d，1H)，5.55(d，1H)，5.57(s，2H)，6.05(s，1H)，7.45(s，1H)，7.58(d，1H)，7.61(d，1H)，7.84(t，1H)，7.94(t，1H)，7.95(s，1H)，8.26(d，1H)，9.01(d，1H)，9.74(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 24 7-(4-cyano-phenyl) methylene
According to the method for embodiment 4, replace para-totuidine with the p-aminophenyl nitrile, obtain the amino high camptothecine (15.9%) of 10mg yellow solid 7-(4-cyano-phenyl) methylene.
1HNMR(DMSO)，δ:0.88(t，3H)，1.88(q，2H)，3.08(d，1H)，3.48(d，1H)，5.42(d，1H)，5.55(d，1H)，5.59(s，2H)，6.06(s，1H)，7.47(s，1H)，7.68(d，2H)，7.85(t，1H)，7.97(t，1H)，8.02(d，2H)，8.28(d，1H)，8.98(d，1H)，9.71(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 25 7-(3, the 4-3,5-dimethylphenyl) methylene
According to the method for embodiment 4, with 3, the 4-xylidine replaces para-totuidine, obtains the amino high camptothecine (25.3%) of 16mg yellow solid 7-(3, the 4-3,5-dimethylphenyl) methylene.
1HNMR(DMSO)，δ:0.88(t，3H)，1.88(q，2H)，2.31(s，3H)，2.34(s，3H)，3.09(d，1H)，3.48(d，1H)，5.42(d，1H)，5.55(d，1H)，5.58(s，2H)，6.05(s，1H)，7.30(d，1H)，7.36(d，1H)，7.43(s，1H)，7.46(s，1H)，7.83(t，1H)，7.95(t，1H)，8.26(d，1H)，9.00(d，1H)，9.72(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 26 7-(3, the 4-difluorophenyl) methylene
According to the method for embodiment 4, with 3, the 4-difluoroaniline replaces para-totuidine, obtains the amino high camptothecine (17.1%) of 11mg yellow solid 7-(3, the 4-difluorophenyl) methylene.
1HNMR(DMSO)，δ:0.88(t，3H)，1.88(q，2H)，3.09(d，1H)，3.48(d，1H)，5.42(d，1H)，5.55(d，1H)，5.58(s，2H)，6.06(s，1H)，7.46(s，1H)，7.47(s，1H)，7.62(d，1H)，7.83(d，1H)，7.85(t，1H)，7.96(t，1H)，8.28(d，1H)，9.01(d，1H)，9.73(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 27 7-(3-fluorophenyl) methylene
According to the method for embodiment 4, replace para-totuidine with m-fluoroaniline, obtain the amino high camptothecine (14.5%) of 9mg yellow solid 7-(3-fluorophenyl) methylene.
1HNMR(DMSO)，δ:0.87(t，3H)，1.87(q，2H)，3.07(d，1H)，3.47(d，1H)，5.42(d，1H)，5.52(s，2H)，5.55(d，1H)，6.05(s，1H)，7.25(d，1H)，7.46(s，1H)，7.49(d，1H)，7.53(t，1H)，7.89(s，1H)，7.91(t，1H)，7.98(t，1H)，8.30(d，1H)，9.03(d，1H)，9.73(s，1H)。
Synthesizing of the amino high camptothecine of embodiment 28 7-(3, the 5-dichlorophenyl) methylene
According to the method for embodiment 4, with 3, the 5-dichloro-obtains the amino high camptothecine (30.7%) of 21mg yellow solid 7-(3, the 5-dichlorophenyl) methylene for para-totuidine.
1HNMR(DMSO)，δ:0.89(t，3H)，1.89(q，2H)，2.39(s，6H)，2.92(d，1H)，3.08(d，1H)，5.42(d，1H)，5.56(d，1H)，5.59(s，2H)，6.06(s，1H)，746(s，1H)，7.63(s，1H)，7.68(s，2H)，7.84(t，1H)，7.96(t，1H)，8.27(d，1H)，9.01(d，1H)，9.74(s，1H)。
Synthesizing of the high camptothecine of embodiment 29 7-benzoyl oxygen methyl
With the high camptothecine of 39mg 7-methylol, 21mg DCC, 12mg 4-lutidine, 14mg phenylformic acid and 15mL methylene dichloride stirring at room 10h boil off solvent, (the eluent: CH of purifying on silica gel chromatographic column
2Cl
2/ CH
3OH 100:2), get the 11mg faint yellow solid 7-benzoyl high camptothecine of oxygen methyl (22.2%)
1HNMR (DMSO), δ: 0.87 (t, 3H), 1.87 (q, 2H), 3.06 (d, 1H), 3.48 (d, 1H), 5.40 (d, 1H), 5.50 (s, 2H), 5.53 (d, 1H), 6.03 (s, 2H), 6.04 (s, 1H), 7.43 (s, 1H), 7.53 (t, 2H), 7.67 (t, 1H), 7.81 (t, 1H), 7.92 (t, 1H), 8.01 (t, 2H), 8.22 (d, 1H), 8.44 (d, 1H).
Synthesizing of the high camptothecine of embodiment 30 7-acetyl-o-methyls
According to the method for embodiment 29, replace phenylformic acid with acetate, get the high camptothecine of 10mg faint yellow solid 7-acetyl-o-methyl (23.0%)
1HNMR(DMSO)，δ:0.87(t，3H)，1.87(q，2H)，2.10(s，3H)，3.06(d，1H)，3.48(d，1H)，5.40(d，1H)，5.42(s，2H)，5.53(d，1H)，5.75(s，2H)，6.04(s，1H)，7.42(s，1H)，7.78(t，1H)，7.90(t，1H)，8.20(d，1H)，8.29(d，1H)。
Synthesizing of the high camptothecine of embodiment 31 7-phenylacetyl oxygen methyl
According to the method for embodiment 29, replace phenylformic acid with toluylic acid, get the 13mg faint yellow solid 7-phenylacetyl high camptothecine of oxygen methyl (25.5%)
1HNMR(DMSO)，δ:0.87(t，3H)，2.03(q，2H)，3.19(d，1H)，3.48(d，1H)，3.76(s，2H)，5.33(d，1H)，5.36(s，2H)，5.45(d，1H)，5.69(s，2H)，5.72(s，1H)，7.26-7.30(m，5H)，7.52(s，1H)，7.56(t，1H)，7.73(t，1H)，7.95(d，1H)，8.06(d，1H)。
Synthesizing of the high camptothecine of embodiment 32 7-phenylpropyl alcohol acyl-oxygen methyl
According to the method for embodiment 29, replace phenylformic acid with phenylpropionic acid, get the 9mg faint yellow solid 7-phenylpropyl alcohol high camptothecine of acyl-oxygen methyl (17.2%)
1HNMR(DMSO)，δ:0.88(t，3H)，2.05(q，2H)，2.95(t，2H)，3.13(d，1H)，3.50(d，1H)，5.38(d，1H)，5.51(s，2H)，5.59(d，1H)，5.68(s，2H)，5.79(s，1H)，7.05-7.26(m，5H)，7.56(s，1H)，7.67(t，1H)，7.73(t，1H)，8.06(d，1H)，8.34(d，1H)。
Synthesizing of the high camptothecine of embodiment 33 7-Chinese cassia tree acyl-oxygen methyl
According to the method for embodiment 29, replace phenylformic acid with styracin, get the 10mg faint yellow solid 7-Chinese cassia tree high camptothecine of acyl-oxygen methyl (19.2%)
1HNMR(DMSO)，δ:0.87(t，3H)，2.05(q，2H)，3.23(d，1H)，3.60(d，1H)，5.34(d，1H)，5.52(s，2H)，5.58(d，1H)，5.70(s，2H)，5.86(s，1H)，6.52(d，1H)，7.05-7.26(m，5H)，7.35(d，1H)，7.41(s，1H)，7.57(t，1H)，7.63(t，1H)，7.90(d，1H)，8.11(d，1H)。
Synthesizing of the high camptothecine of embodiment 34 7-benzene oxygen acetyl-o-methyls
According to the method for embodiment 29, replace phenylformic acid with phenoxy acetic acid, get the 12mg faint yellow solid 7-benzene high camptothecine of oxygen acetyl-o-methyl (22.2%)
1HNMR(DMSO)，δ:0.88(t，3H)，2.05(q，2H)，2.35(t，2H)，3.60(d，1H)，3.93(d，1H)，4.16(t，2H)，5.35(d，1H)，5.50(s，2H)，5.60(d，1H)，5.71(s，2H)，5.82(s，1H)，7.04-7.26(m，5H)，7.35(s，1H)，7.59(t，1H)，7.83(t，1H)，8.09(d，1H)，8.32(d，1H)。
The anti-tumor activity test of The compounds of this invention
Compound of the present invention has been carried out the tumor cell proliferation inhibition test, and test method adopts conventional mtt assay.
Cell strain is selected A549 (human lung carcinoma cell), LOVO (people's colon-cancer cell), MCF-7 (human breast cancer cell) for use.Nutrient solution is that DMEM+15% NBS+ is two anti-.
Sample liquid preparation: after DMSO (Merck) dissolving, adding PBS (-) is made into solution or the uniform suspension of 100 μ g/mL, use PBS (-) dilution of DMSO then, ultimate density is respectively 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL, 0.001 μ g/mL, 0.0001 μ g/mL.
The antitumor drug topotecan of listing is made into reference substance solution with same condition.
It is 3 * 10 that the every hole of 96 orifice plates adds concentration
4The cell suspension 100 μ L of individual/mL, promptly 3000 cells/well are put 37 ℃, 5% CO
2In the incubator.After 24 hours, add sample liquid and reference substance liquid respectively, 10 μ L/ holes, 37 ℃ act on 72 hours.Every hole adds MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-phenylbenzene tetrazolium father-in-law bromide) the solution 20 μ L of 5mg/mL, act on and add lysate DMSO after 4 hours, put in the incubator in 100 μ L/ holes, and the full-automatic microplate reader of inferior daily MK-2 is surveyed 570nm OD value.Calculation of half inhibitory concentration IC
50
Test-results sees Table 1, and wherein, sample is meant the high camptothecine compounds for preparing among the corresponding embodiment.
Table 1 test compounds is to the half-inhibition concentration IC of tumour cell
50(unit: μ g/mL)
Above experimental result shows that compound of the present invention has good antineoplastic activity, and a plurality of compounds are higher than the marketed drug topotecan, so The compounds of this invention and its esters can be used to prepare antitumor drug.
Claims (6)
1. any mixture of 7-substituted homocamptothecins compounds, its racemic modification, enantiomeric forms or its these forms of general formula (I) expression, or its pharmaceutical salts:
It is characterized in that:
R
1: expression-C (R
6)=N-R
7Group, wherein R
7The expression phenyl and has one or more following substituted radicals at least: hydrogen, hydroxyl, halogen, low alkyl group, lower alkoxy, phenyl, cyano group, nitro ,-NR
8R
9
R
2, R
3, R
4Represent following groups independently: hydrogen, halogen, low alkyl group, OR
11, nitro, amino, perhaps R
2And R
3Form 3 or 4 yuan chain together, or R
3And R
4Form 3 or 4 yuan chain together, wherein the unit of this chain is selected from CH
2, O;
R
5The expression low alkyl group;
R
6Expression hydrogen, low alkyl group, lower alkoxy, the cycloalkyl that contains 3 to 10 carbon atoms, rudimentary aralkyl;
R
8And R
9Represent hydrogen or low alkyl group independently;
R
11Expression hydrogen or low alkyl group;
So-called low alkyl group is for containing 1 to 6 carbon atom straight chain or branched-chain alkyl; Lower alkoxy is for containing 1 to 6 carbon atom straight chain or branched alkoxy; Low-grade halogenated alkyl is to contain the low alkyl group that 1 to 3 halogen atom replaces; Rudimentary aralkyl is the low alkyl group that is connected with aryl.
2. any mixture of the arbitrary compound in the claim 1, its racemic modification form, enantiomeric forms or its these forms or its pharmaceutical salts application in preparation topoisomerase enzyme inhibitor, antitumor drug, antifungal drug or antiviral.
3. by the described compound of claim 1, it is characterized in that R
5Be ethyl.
4. by claim 1 or the described compound of claim 3, it is characterized in that described compound is selected from:
The amino high camptothecine of-7-(4-aminomethyl phenyl) methylene
The amino high camptothecine of-7-(2-aminomethyl phenyl) methylene
The amino high camptothecine of-7-(3-aminomethyl phenyl) methylene
The amino high camptothecine of-7-(2-hydroxy phenyl) methylene
The amino high camptothecine of-7-(2-bromophenyl) methylene
The amino high camptothecine of-7-(4-bromophenyl) methylene
The amino high camptothecine of-7-(3, the 5-3,5-dimethylphenyl) methylene
The amino high camptothecine of-7-(2-p-methoxy-phenyl) methylene
The amino high camptothecine of-7-(3-chloro-phenyl-) methylene
The amino high camptothecine of-7-(2-chloro-phenyl-) methylene
The amino high camptothecine of-7-(4-chloro-phenyl-) methylene
The amino high camptothecine of-7-(2,4 dichloro benzene base) methylene
The amino high camptothecine of-7-(2, the 4-3,5-dimethylphenyl) methylene
The amino high camptothecine of-7-(2, the 5-dichlorophenyl) methylene
The amino high camptothecine of-7-(3, the 4-dichlorophenyl) methylene
The amino high camptothecine of-7-(3-chloro-4-aminomethyl phenyl) methylene
The amino high camptothecine of-7-phenyl methylene
The amino high camptothecine of-7-(4-acetylphenyl) methylene
The amino high camptothecine of-7-(4-tert-butyl-phenyl) methylene
The amino high camptothecine of-7-(3-chloro-4-fluorophenyl) methylene
The amino high camptothecine of-7-(4-cyano-phenyl) methylene
The amino high camptothecine of-7-(3, the 4-3,5-dimethylphenyl) methylene
The amino high camptothecine of-7-(3, the 4-difluorophenyl) methylene
The amino high camptothecine of-7-(3-fluorophenyl) methylene
The amino high camptothecine of-7-(3, the 5-dichlorophenyl) methylene.
5. the midbody compound II for preparing the described 7-substituted homocamptothecins compounds of claim 1
Wherein:
R
2, R
3, R
4Represent following groups independently: hydrogen, halogen, low alkyl group, OR
11, nitro, amino, perhaps R
2And R
3Form 3 or 4 yuan chain together, or R
3And R
4Form 3 or 4 yuan chain together, wherein the unit of this chain is selected from CH
2, O;
R
5The expression low alkyl group;
So-called low alkyl group is for containing 1 to 6 carbon atom straight chain or branched-chain alkyl.
6. by the described compound of claim 5, it is characterized in that R
5Be ethyl.
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