CN100400497C - Compounds of class of styracin and cinepazid ester phenylpropionic acid, prepration method and application - Google Patents

Compounds of class of styracin and cinepazid ester phenylpropionic acid, prepration method and application Download PDF

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CN100400497C
CN100400497C CNB2004101028941A CN200410102894A CN100400497C CN 100400497 C CN100400497 C CN 100400497C CN B2004101028941 A CNB2004101028941 A CN B2004101028941A CN 200410102894 A CN200410102894 A CN 200410102894A CN 100400497 C CN100400497 C CN 100400497C
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compound
dimethoxy
ester
phenylallene
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CN1796363A (en
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赵昱
周长新
白骅
胡利红
邹宏斌
巫秀美
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Zhejiang Hisun Pharmaceutical Co Ltd
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Abstract

The present invention relates to a styracin compound which has cytotoxic activity and is disclosed in the formula (1) and an analogue thereof or a phenylpropyl phenylpropionate compound disclosed in the formula (2) and an analogue and medical salts or solvates thereof. The present invention also relates to a preparation method of the compounds and preparation midbody compounds thereof, the medical application of the compounds and a medical composition which contains the compounds. The compounds of the present invention have certain tumor cell growth inhibition activity, and can be used as antitumor medicines in anticipation.

Description

The purposes of styracin and phenylpropionic acid phenyl propyl compound and preparation method thereof and preparation medicine
Invention field
The present invention relates to organic chemistry, pharmaceutical chemistry and area of pharmacology, particularly, the present invention relates to styracin and phenylpropionic acid phenylpropyl alcohol ester and phenylpropionic acid propyl benzene ester compound and its key intermediate and their preparation method and they purposes as medicine.
Background of invention
At present, because the problems of bringing in the industrial development such as environmental pollution, the existent environment of people quality constantly descends, and the sickness rate of tumor disease and lethality rate also constantly rise.Yet the specifics of treatment tumor disease can not be satisfactory, and at present the selectivity of antitumor clinical used cytotoxic drug not high cause to Normocellular pernicious killing and wounding, limited the general applicability of such medicine.Therefore, seek and find that the high cytotoxicity antitumor drug of new selectivity is worldwide research focus.We also are devoted to the research of antitumor drug.TaiWan, China scholar Chen Jih-Jung in 2003 etc. separate from slender lobule wind rattan and obtain a new compound with phenylpropionic acid phenylpropyl alcohol ester structure, and it has been made cell toxicity test, discovery has certain cytotoxicity (Chen to mouse leukemia cell (P-388), J.J.Duh, C.Y.Huang, H.Y.and Chen, I.S. (2003) Helv.Chim.Acta.86,2058-2064.).Therefore the objective of the invention is to this compounds is synthesized and structure of modification, growth produces stronger inhibiting phenylpropionic acid phenylpropyl alcohol ester cpds and analogue thereof to tumor cell line in the hope of seeking.According to the whole world especially susceptibility of often swell the knurl spectrum of disease and the tumour cell of China, we have selected Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell (KB), human lung carcinoma cell (A549), the index that human cervical carcinoma cell (Hela) five strain tumour cells are estimated as cell in vitro cytotoxic activity pharmacology.
Goal of the invention
The object of the present invention is to provide a kind of compound, particularly, the invention provides a kind of the have styracin shown in the formula (1) and its analogue and pharmacologically acceptable salt or solvate with cytotoxic activity:
Figure C20041010289400061
Wherein:
Substituent R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'Can be identical or different, be independently selected from hydrogen respectively, sulfydryl, nitro, cyano group contains the alkyl of 1～8 carbon, the alkoxyl group that contains 1～8 carbon contains the alkylamino radical of 1～8 carbon, the unsaturated alkyl of 1～15 carbon, the unsaturated-oxyl of 1～15 carbon contains the alkoxyl group alkoxyl group of 1～8 carbon, replaces or unsubstituted aryl, replace or unsubstituted aryloxy, replace or unsubstituted aralkoxy, contain the acyloxy of 1～8 carbon, contain the alkoxyl group alkoxyl group of 1～8 carbon, its condition is a substituent R 6, R 7, R 8, R 6 ', R 7 'And R 8 'Can not be hydrogen simultaneously; Substituent X is selected from hydrogen (H) 2, hydroxyl (OH) 2, oxygen, sulphur; Radicals R is selected from oxygen, and nitrogen contains the alkylidene group of 1-8 carbon, contains the imido grpup of 1-8 carbon, contains the alkylene oxide group of 1-8 carbon, contains the alkylene sulfenyl of 1-8 carbon;
The substituting group that wherein is used to replace is selected from the alkyl that contains 1～8 carbon, contains the alkoxyl group of 1～8 carbon, halogen, and hydroxyl, amino, nitro, cyano group contains the alkylamino radical of 1～8 carbon or phenyl.
Another object of the present invention provided have cytotoxic activity as the formula (2) the phenylpropionic acid phenyl propyl compound and analogue with and pharmacologically acceptable salt or solvate:
Figure C20041010289400071
Substituent R wherein 6, R 7, R 8, R 6 ', R 7 'Or R 8 'And the definition of substituent X and radicals R and formula (1) is identical.
Another object of the present invention has provided the preparation method of formula (1), formula (2) compound.
Another purpose of the present invention has provided the purposes that is used to prepare control tumor disease medicine of formula (1) and formula (2) compound.
Another object of the present invention has provided a kind of pharmaceutical composition that is used for anti-tumor disease that contains formula (1), formula (2) compound.
Summary of the invention
The invention provides a kind of have the styracin compounds shown in the formula (1) and its analogue and pharmacologically acceptable salt or solvate:
Wherein:
Substituent R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'Can be identical or different, be independently selected from hydrogen respectively, sulfydryl, nitro, cyano group contains the alkyl of 1～8 carbon, the alkoxyl group that contains 1～8 carbon contains the alkylamino radical of 1～8 carbon, the unsaturated alkyl of 1～15 carbon, the unsaturated-oxyl of 1～15 carbon contains the alkoxyl group alkoxyl group of 1～8 carbon, replaces or unsubstituted aryl, replace or unsubstituted aryloxy, replace or unsubstituted aralkoxy, contain the acyloxy of 1～8 carbon, its condition is a substituent R 6, R 7, R 8, R 6 ', R 7 'And R 8 'Can not be hydrogen simultaneously; Substituent X is selected from hydrogen (H) 2, hydroxyl (OH) 2, oxygen, sulphur; Radicals R is selected from oxygen, and nitrogen contains the alkylidene group of 1-8 carbon, contains the alkylene amido of 1-8 carbon, contains the alkylene oxide group of 1-8 carbon, contains the alkylene sulfenyl of 1-8 carbon;
The substituting group that wherein is used to replace is selected from the alkyl that contains 1～8 carbon, contains the alkoxyl group of 1～8 carbon, halogen, and hydroxyl, amino, nitro, cyano group contains the alkylamino radical of 1～8 carbon or phenyl.
The preferred formula of the present invention (1) compound and pharmacologically acceptable salt thereof or solvate be, wherein:
Substituent X in formula (1) is an oxygen, when substituent R is oxygen, is the styracin compounds shown in the formula (I):
Figure C20041010289400081
Wherein:
Substituent R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'Can be identical or different, be independently selected from hydrogen respectively, sulfydryl, nitro, cyano group contains the alkyl of 1～8 carbon, the alkoxyl group that contains 1～8 carbon contains the alkylamino radical of 1～8 carbon, the unsaturated alkyl of 1～15 carbon, the unsaturated-oxyl of 1～15 carbon contains the alkoxyl group alkoxyl group of 1～8 carbon, replaces or unsubstituted aryl, replace or unsubstituted aryloxy, replace or unsubstituted aralkoxy, contain the acyloxy of 1～8 carbon, its condition is a substituent R 6, R 7, R 8, R 6 ', R 7 'And R 8 'Can not be hydrogen simultaneously;
The substituting group that wherein is used to replace is selected from the alkyl that contains 1～8 carbon, contains the alkoxyl group of 1～8 carbon, halogen, and hydroxyl, amino, nitro, cyano group contains the alkylamino radical of 1～8 carbon or phenyl;
The preferred formula of the present invention (I) compound and basic pharmacologically acceptable salt or solvate be, wherein:
R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'Can be identical or different, be independently selected from hydrogen respectively, nitro, the alkyl that contains 1～8 carbon contains the alkylamino radical of 1～8 carbon, contains the alkoxyl group of 1～8 carbon, the ethylenic unsaturation oxygen base that contains 1～15 carbon, replace or unsubstituted aralkoxy, contain the alkoxyl group alkoxyl group of 1～8 carbon, its condition is a substituent R 6, R 7, R 8, R 6 ', R 7 'And R 8 'Can not be hydrogen simultaneously;
The substituting group that wherein is used to replace is selected from the alkyl that contains 1～8 carbon, contains the alkoxyl group of 1～8 carbon, halogen, and hydroxyl, amino, nitro, cyano group contains the alkylamino radical of 1～8 carbon or phenyl.
Further preferred formula (I) compound of the present invention and pharmacologically acceptable salt thereof or solvate be, wherein:
R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'Can be identical or different, be independently selected from hydrogen respectively, nitro contains the alkoxyl group of 1～8 carbon, contains the ethylenic unsaturation oxygen base of 1～15 carbon, replaces or unsubstituted aralkoxy, contains the alkoxyl group alkoxyl group of 1～8 carbon, and its condition is a substituent R 6, R 7, R 8, R 6 ', R 7 'And R 8 'Can not be hydrogen simultaneously;
The substituting group that wherein is used to replace is selected from the alkyl that contains 1～8 carbon, contains the alkoxyl group of 1～8 carbon, halogen, hydroxyl, amino, nitro.
The preferred formula of the present invention (I) compound comprises:
I-a. (E)-7-methoxyl group-cinnamic acid-(E)-(7 '-methoxyl group) phenylallene ester;
I-b. (E)-(6,7, the 8-trimethoxy) cinnamic acid-(E)-(7 '-methoxyl group) the phenylallene ester;
I-c. (E)-(7-nitro) cinnamic acid-(E)-(6 ', 7 '-dimethoxy) the phenylallene ester;
I-d. (E)-(6,7, the 8-trimethoxy) cinnamic acid-(E)-(6 ', 7 ', 8 '-trimethoxy) the phenylallene ester;
I-e. (E)-(7-methoxyl group) cinnamic acid-(E)-(6 ', 7 '-dimethoxy) the phenylallene ester;
I-f. (E)-(6, the 7-dimethoxy) cinnamic acid-(E)-(6 ', 7 '-dimethoxy) the phenylallene ester;
I-g. (E)-(6,7, the 8-trimethoxy) cinnamic acid-(E)-(6 ', 7 '-dimethoxy) the phenylallene ester;
I-h. (E)-(7-methoxymethoxy) cinnamic acid-(E)-(6 ', 7 '-the dimethoxy methoxyl group) the phenylallene ester;
I-i. (E)-(7-methoxymethoxy) cinnamic acid-(E)-(7 '-methoxymethoxy) the phenylallene ester;
I-j. (E)-(7-hydroxyl) cinnamic acid-(E)-(7 '-methoxyl group) the phenylallene ester;
I-k. (E)-(7-methoxymethoxy) cinnamic acid-(E)-the phenylallene ester;
I-l. (E)-(6,7-dimethoxy methoxyl group) cinnamic acid-(E)-the phenylallene ester;
I-m. (E)-(6,7-dimethoxy methoxyl group) cinnamic acid-(E)-(7 '-methoxymethoxy)-the phenylallene ester;
I-n. (E)-(7-methoxymethoxy) cinnamic acid-(E)-(7 '-methoxyl group) the phenylallene ester;
I-o. (E)-(6,8-dimethoxy-7-O-(3 ", 4 " dichloro) benzyl)-cinnamic acid-(E)-(6 ', 8 '-dimethoxy-7 '-O-(3 " ', 4 " '-dichloro) benzyl)-the phenylallene ester;
I-p. (E)-(6,8-dimethoxy-7-O-(4 " bromine) benzyl)-cinnamic acid-(E)-(6 ', 8 '-dimethoxy-7 '-O-(4 " '-bromine) benzyl)-the phenylallene ester;
I-q. (E)-(6,8-dimethoxy-7-O-(3 " bromine) benzyl)-cinnamic acid-(E)-(6 ', 8 '-dimethoxy-7 '-O-(3 " '-bromine) benzyl)-the phenylallene ester;
I-r. (E)-(6,8-dimethoxy-7-O-(2 " fluorine, 4 " bromine) benzyl)-cinnamic acid-(E)-(6 ', 8 '-dimethoxy-7 '-O-(2 " '-fluorine, 4 " '-bromine) benzyl)-the phenylallene ester;
I-s. (E)-(6,8-dimethoxy-7-O-geranyl)-cinnamic acid-(E)-(6 ', 8 '-dimethoxy-7 '-the O-geranyl)-the phenylallene ester;
The invention provides a kind of have the phenylpropionic acid phenyl propyl compound shown in the formula (2) and its analogue and pharmacologically acceptable salt or solvate:
Figure C20041010289400101
Wherein:
Substituent R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'Can be identical or different, be independently selected from hydrogen respectively, sulfydryl, nitro, cyano group contains the alkyl of 1～8 carbon, the alkoxyl group that contains 1～8 carbon contains the alkylamino radical of 1～8 carbon, the unsaturated alkyl of 1～15 carbon, the unsaturated-oxyl of 1～15 carbon contains the alkoxyl group alkoxyl group of 1～8 carbon, replaces or unsubstituted aryl, replace or unsubstituted aryloxy, replace or unsubstituted aralkoxy, contain the acyloxy of 1～8 carbon, its condition is a substituent R 6, R 7, R 8, R 6 ', R 7 'And R 8 'Can not be hydrogen simultaneously; Substituent X can be hydrogen (H) 2, hydroxyl (OH) 2, oxygen, sulphur; Radicals R can be an oxygen, and nitrogen contains the alkylidene group of 1-8 carbon, contains the alkylene amido of 1-8 carbon, contains the alkylene oxide group of 1-8 carbon, contains the alkylene sulfenyl of 1-8 carbon;
The substituting group that wherein is used to replace can be the alkyl that contains 1～8 carbon, contains the alkoxyl group of 1～8 carbon, halogen, and hydroxyl, amino, nitro, cyano group contains the alkylamino radical of 1～8 carbon or phenyl;
The preferred formula of the present invention (2) compound and pharmacologically acceptable salt thereof or solvate are: the substituent X in formula (2) is an oxygen, when substituent R is oxygen, is the phenylpropionic acid phenyl propyl compound shown in the formula (II):
Wherein:
Substituent R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'Can be identical or different, be independently selected from hydrogen respectively, sulfydryl, nitro, cyano group contains the alkyl of 1～8 carbon, the alkoxyl group that contains 1～8 carbon contains the alkylamino radical of 1～8 carbon, the unsaturated alkyl of 1～15 carbon, the unsaturated-oxyl of 1～15 carbon contains the alkoxyl group alkoxyl group of 1～8 carbon, replaces or unsubstituted aryl, replace or unsubstituted aryloxy, replace or unsubstituted alkoxyl group, contain the acyloxy of 1～8 carbon, its condition is a substituent R 6, R 7, R 8, R 6 ', R 7 'And R 8 'Can not be hydrogen simultaneously;
The substituting group that wherein is used to replace is selected from the alkyl that contains 1～8 carbon, contains the alkoxyl group of 1～8 carbon, halogen, and hydroxyl, amino, nitro, cyano group contains the alkylamino radical of 1～8 carbon or phenyl;
The preferred formula of the present invention (II) compound and pharmacologically acceptable salt or dissolved matter, wherein:
R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'Can be identical or different, be independently selected from hydrogen respectively, nitro, the alkyl that contains 1～8 carbon contains the alkylamino radical of 1～8 carbon, contains the alkoxyl group of 1～8 carbon, the ethylenic unsaturation oxygen base that contains 1～15 carbon, replace or unsubstituted aralkoxy, contain the alkoxyl group alkoxyl group of 1～8 carbon, its condition is a substituent R 6, R 7, R 8, R 6 ', R 7 'And R 8 'Can not be hydrogen simultaneously;
The substituting group that wherein is used to replace is selected from the alkyl that contains 1～8 carbon, contains the alkoxyl group of 1～8 carbon, halogen, and hydroxyl, amino, nitro, cyano group contains the alkylamino radical of 1～8 carbon or phenyl.
Further preferred formula (II) compound of the present invention and pharmacologically acceptable salt thereof or solvate are carried, wherein:
R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'Can be identical or different, be independently selected from hydrogen respectively, nitro contains the alkoxyl group of 1～8 carbon, contains the ethylenic unsaturation oxygen base of 1～15 carbon, replaces or unsubstituted aralkoxy, contains the alkoxyl group alkoxyl group of 1～8 carbon, and its condition is a substituent R 6, R 7, R 8, R 6 ', R 7 'And R 8 'Can not be hydrogen simultaneously;
The substituting group that wherein is used to replace is selected from the alkyl that contains 1～8 carbon, contains the alkoxyl group of 1～8 carbon, halogen, hydroxyl, amino, nitro.
The preferred formula of the present invention (II) compound comprises:
II-a.7-methoxyl group-phenylpropionic acid-7 '-methoxyl group-phenylpropyl alcohol ester;
II-b.6,7,8-trimethoxy-phenylpropionic acid-7 '-methoxyl group-phenylpropyl alcohol ester;
II-c.7-amino-phenylpropionic acid-6 ', 7 '-dimethoxy-phenylpropyl alcohol ester;
II-d.6,7-dimethoxy-phenylpropionic acid-6 ', 7 ' dimethoxy-phenylpropyl alcohol ester;
II-e.7-methoxyl group-phenylpropionic acid-6 ', 7 '-dimethoxy-phenylpropyl alcohol ester;
II-f.7-methyl-phenylpropionic acid-7 '-methyl-phenylpropyl alcohol ester;
II-g.6,7,8-trimethoxy-phenylpropionic acid-6 ', 7 '-dimethoxy-phenylpropyl alcohol ester;
II-h.7-methoxymethoxy-phenylpropionic acid-6 ', 7 '-dimethoxy methoxyl group-phenylpropyl alcohol ester;
II-i.6,7-dimethoxy methoxyl group-phenylpropionic acid-7 '-methoxymethoxy-phenylpropyl alcohol ester;
II-j.7-methoxymethoxy-phenylpropionic acid-7 '-methoxymethoxy-phenylpropyl alcohol ester;
II-k.7-methoxymethoxy-phenylpropionic acid phenylpropyl alcohol ester;
II-l.6,7-dimethoxy methoxyl group-phenylpropionic acid phenylpropyl alcohol ester;
II-m.7-methoxymethoxy-phenylpropionic acid-7 '-methoxyl group-phenylpropyl alcohol ester;
II-n.7-hydroxyl-phenylpropionic acid-7 '-methoxyl group-phenylpropyl alcohol ester;
The invention provides a kind of as the formula (3) formula (1) and the key intermediate benzyl ethylene compound of formula (2) compound and analogue thereof with and pharmacologically acceptable salt or solvate:
Figure C20041010289400121
Substituent R wherein 6, R 7, R 8, the definition of substituent X is identical with formula (1); Substituent R is selected from hydrogen, sulfydryl, and amido, hydroxyl contains the alkyl of 1-8 carbon, contains the alkylamino radical of 1-8 carbon, contains the alkoxyl group of 1-8 carbon, contains the alkylthio of 1-8 carbon;
The preferred formula of the present invention (3) compound and basic pharmacologically acceptable salt or solvate be, wherein:
R 6, R 7, R 8, can be identical or different, be independently selected from hydrogen respectively, hydroxyl, nitro contains the alkyl of 1～8 carbon, contains the alkylamino radical of 1～8 carbon, contains 1～8 carbon and alkoxyl group, the ethylenic unsaturation oxygen base that contains 1～15 carbon replaces or unsubstituted aralkoxy, contains the alkoxyl group alkoxyl group of 1～8 carbon; Substituent X is selected from hydrogen (H) 2, oxygen, sulphur; Radicals R is selected from hydrogen, sulfydryl, and amido, hydroxyl contains the alkoxyl group of 1～8 carbon;
The substituting group that wherein is used to replace is selected from the alkyl that contains 1～8 carbon, contains the alkoxyl group of 1～8 carbon, halogen, hydroxyl, amino, nitro.
Further preferred formula (3) compound of the present invention and pharmacologically acceptable salt thereof or solvate be, wherein:
R 6, R 7, R 8Can be identical or different, be independently selected from hydrogen respectively, hydroxyl, nitro contains the alkoxyl group of 1～8 carbon, contains the ethylenic unsaturation oxygen base of 1～15 carbon, replaces or unsubstituted aralkoxy, contains the alkoxyl group alkoxyl group of 1～8 carbon; Substituent X is hydrogen (H) 2, oxygen; Radicals R is a hydroxyl, contains the alkoxyl group of 1～8 carbon;
The substituting group that wherein is used to replace is selected from the alkyl that contains 1～8 carbon, contains the alkoxyl group of 1～8 carbon, halogen, hydroxyl, amino, nitro.
The further embodiment of the present invention is:
Substituent X in formula (3) compound is an oxygen, and substituent R is oxyethyl group (CH 3CH 2O) time, as the formula (4), be formula I-1 compound:
Figure C20041010289400122
Substituent R wherein 6, R 7, R 8Definition identical with formula (3).
Formula I-1 compound of the present invention comprises:
I-1-a. (E)-7-anisole ethyl propionate;
I-1-b. (E)-6,7-dimethoxy methoxyl group-phenylpropionic acid ethyl ester;
I-1-c. (E)-6,8-dimethoxy-7-O-(4 '-bromobenzyl)-the phenylpropionic acid ethyl ester;
I-1-d. (E)-7-oil of mirbane ethyl propionate;
I-1-e. (E)-7-methoxymethoxy phenylpropionic acid ethyl ester;
I-1-f. (E)-6,8-dimethoxy-7-O-(2 '-fluorine, 4 '-bromobenzyl)-the phenylpropionic acid ethyl ester;
I-1-g. (E)-6,7-dimethoxy-phenylpropionic acid ethyl ester;
I-1-h. ethyl cinnamate;
I-1-i. (E)-6,8-dimethoxy-7-O-(3 '-bromobenzyl)-the phenylpropionic acid ethyl ester;
I-1-i. (E)-6,7,8-trimethoxy-phenylpropionic acid ethyl ester;
I-1-k. (E)-7-methyl-phenylpropionic acid ethyl ester;
I-1-l. (E)-6,8-dimethoxy-7-O-(3 ', 4 '-dichloro benzyl)-the phenylpropionic acid ethyl ester;
I-1-m. (E)-6,8-dimethoxy-7-O-geranyl-phenylpropionic acid ethyl ester;
Substituent X in formula (3) compound is an oxygen, when substituent R is hydroxyl (OH), as the formula (5), is formula I-2 compound:
Figure C20041010289400131
Substituent R wherein 6, R 7, R 8Definition identical with formula (3).
Formula I-2 compound of the present invention comprises:
I-2-a. (E)-7-anisole vinylformic acid;
I-2-b. (E)-7-nitropropiol;
I-2-c. (E)-6,8-dimethoxy-7-O-(2 '-fluorine, 4 '-bromobenzyl)-cinnamic acid;
I-2-d. (E)-6,7-dimethoxy-cinnamic acid;
I-2-e. (E)-6,8-dimethoxy-7-O-(4 '-bromobenzyl)-cinnamic acid;
I-2-f. (E)-6,8-dimethoxy-7-O-(3 '-bromobenzyl)-cinnamic acid;
I-2-g. (E)-6,7,8-trimethoxy-cinnamic acid;
I-2-h. (E)-6,7-dimethoxy anisole vinylformic acid;
I-2-i. (E)-7-methyl-cinnamic acid;
I-2-j. (E)-7-methoxymethoxy cinnamic acid;
I-2-k. (E)-6,8-dimethoxy-7-O-(3 ', 4 '-dichloro benzyl)-cinnamic acid;
I-2-l. styracin;
I-2-m. (E)-6,8-dimethoxy-7-O-geranyl-cinnamic acid;
Substituent X in formula (3) compound is hydrogen (H 2), when substituent R is hydroxyl (OH), as the formula (6), be formula I-3 compound:
Figure C20041010289400141
Substituent R wherein 6, R 7, R 8Definition identical with formula (3).
Formula I-3 compound of the present invention comprises:
I-3-a. (E)-7-anisole propylene-1-alcohol;
I-3-b. (E)-6,7-dimethoxy anisole propylene-1-alcohol;
I-3-c. (E)-6,8-dimethoxy-7-O-(4 '-bromobenzyl)-phenylallene-1-alcohol;
I-3-d. (E)-6,7,8-trimethoxy-phenylallene-1-alcohol;
I-3-e. (E)-7-methoxymethoxy phenylallene-1-alcohol;
I-3-f. (E)-6,8-dimethoxy-7-O-(3 ', 4 '-dichloro benzyl)-phenylallene-1-alcohol;
I-3-g. (E)-6,7-dimethoxy-phenylallene-1-alcohol;
I-3-h. (E)-6,8-dimethoxy-7-O-(2 '-fluorine, 4 '-bromobenzyl)-phenylallene-1-alcohol;
I-3-i. (E)-6,8-dimethoxy-7-O-(3 '-bromobenzyl)-phenylallene-1-alcohol;
I-3-j. (E)-7-methyl-phenylallene-1-alcohol;
I-3-k. (E)-6,8-dimethoxy-7-O-geranyl-phenylallene-1-alcohol;
Another object of the present invention provides a kind of method by intermediate formula (3) compound formula (1), formula (2) compound.This synthesis route feature (with the substituent X is oxygen, and substituent R is that oxygen is the example explanation) is:
With the benzaldehyde compound that replaces by obtaining formula I-1 compound with triphenyl ethoxycarbonyl methyne phosphine alkane experience breath (wittig) prepared in reaction of loving and respect one's elder brother Wei; Obtain formula I-2 compound by formula I-1 compound through basic hydrolysis; Formula I-1 compound is by lithium aluminium hydride (LiAlH 4) reduction obtains the I-3 compound; Formula (1) compound can be by formula I-2 compound and formula I-3 compound at N, N-dicyclohexylcarbodiimide (DCC) and 4-Dimethylamino pyridine (DMAP) prepare formula I compound by esterification under existing, perhaps by formula I-2 compound and formula I-3 compound 1,1 '-dicarbapentaborane imidazoles (CDI), 1,8-diazabicyclo [5,4,0] 11 alkane-7-alkene (DBU) obtains by esterification under existing.Formula (2) compound can be made by palladium carbon (Pd-C) catalytic hydrogenation reaction by formula (1) compound.Preferred formula (1) compound, formula (2) compound, the concrete preparation process of formula (3) compound is as follows:
Figure C20041010289400151
Wherein, when the substituent R of formula I compound and formula II compound 6, R 7, R 8, R 6 ', R 7 'Or R 8 'In contain the alkylamino radical of 1～8 carbon; saturated or the unsaturated alkyl that contains 1～15 carbon; replace or unsubstituted aryl; replace or unsubstituted aralkyl; the acyl group that contains 1～8 carbon; when containing the alkoxyalkyl of 1～8 carbon, the phenyl aldehyde that reaction requires initial feed promptly to replace needs by this unsubstituted benzaldehyde compound by getting with this substituent related raw material prepared in reaction of generation.With substituent R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'In to contain aralkyl oxy be example explanation, work as substituent R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'In contain aralkyl oxy promptly by the benzaldehyde compound of correspondence position hydroxyl and halo aralkyl prepared in reaction and get, with substituent R 6, R 8, R 6 ', R 8 'Be methoxyl group, R 7, R 7 'For the formula I compound to bromo-benzyloxy-is the preparation of example explanation raw material substituted benzaldehyde, specific as follows shown in:
Wherein, when the substituent R of formula I compound and formula II compound 6, R 7, R 8, R 6 ', R 7 'Or R 8 'During hydroxyl; make after the phenyl aldehyde that reaction requires initial feed promptly to replace need be protected by methoxymethyl chlorine (MOMCl) by the benzaldehyde compound of hydroxyl, all need through making after 10% hydrochloric acid (10%HCl) hydrolysis with up-to-date style I compound and formula II compound.Concrete preparation process is with substituent R 6, R 8, R 6 ', R 8 'Hydrogen, R 7, R 7 'For the formula I compound of hydroxyl and formula II compound are that example illustrates this class reaction, specific as follows shown in:
I: raw material hydroxyl protection
Figure C20041010289400162
Ii: hydrolysis deprotection
Figure C20041010289400163
Formula of the present invention (1) compound, formula (2) compound and formula (3) compound or basic pharmacologically acceptable salt and solvate thereof can combine with spoke material or carrier pharmaceutically commonly used, have the active pharmaceutical composition that can be used for anti-curing oncoma of growth of tumour cell inhibition thereby prepare.Above-mentioned various kinds of drug composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Formula of the present invention (1) compound, formula (2) compound and formula (3) compound or pharmaceutically acceptable salt thereof and solvate thereof can with antitumor drug that has now gone on the market such as platinum medicine cis-platinum (DDP), camptothecine irinotecan (Irinatecan, CPT-11), the vinca alkaloids medicine loses carbon vincaleucoblastine (Vinorebine, the NVB nvelbine), deoxidation born of the same parents former times class medicine gemcitabine (Gemcitabine, Gemzar, strong selecting), etoposide (Etoposide), taxol (Paclitaxel) etc. is united use, prepare and have tumor growth and suppress active cytotoxicity composition, can be used for treating tumor disease.Such pharmaceutical grade compound can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Further specify the present invention below by embodiment.Embodiment has provided synthetic and the dependency structure appraising datum and the part activity data of representative compounds.Mandatory declaration, following embodiment is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1: the preparation of Compound I-i ((E)-(7-methoxymethoxy) phenylpropionic acid-(E)-(7 '-methoxymethoxy) phenylallene ester)
Figure C20041010289400171
This example relates to the general synthetic method of formula (1) compound with cytotoxic activity.Be specifically related to the synthetic of compound (E)-(7-methoxymethoxy) phenylpropionic acid-(E)-(7 '-methoxymethoxy) phenylallene ester.Will be to methoxy methoxy base styracin (292mg, 1.4mmol), N, N-dicyclohexylcarbodiimide (318mg, 15mmol), (34mg 0.28mmol) is dissolved in the methylene dichloride 4-Dimethylamino pyridine, at room temperature stirs 10 minutes, white opacity appears, (300mg, dichloromethane solution 15mmol) at room temperature stirred 24 hours to methoxy methoxy base styryl carbinol in adding.Diatomite filtration, filtrate concentrates, and crude product column chromatography for separation (n-hexane/ethyl acetate=8: 1, crude product/silica gel=1: 50) obtains white solid 468mg, and productive rate is 87.0%.
Compound I-i:Rf (n-hexane/ethyl acetate: 4/1): 0.6; 1HNMR (400MHz, CDCl 3): δ 3.48 (6H, s), 4.84 (2H, d, J=6.4Hz), 5.21 (4H, s), 6.25 (1H, dt, J=16.0,6.4Hz), 6.37 (1H, d, J=16.0Hz), 6.66 (1H, d, J=16.0Hz), 7.00～7.49 (8, m), 7.68 (1H, d, J=16.0Hz).
Method according to embodiment 1 prepares following table one illustrated embodiment 2-19 compound:
Figure C20041010289400172
Table one
Figure C20041010289400181
List the physicochemical data of each compound in the table one below:
Compound I-a:
White solid, fusing point: 63～64 ℃, Rf (n-hexane/ethyl acetate: 3/1): 0.71; 1HNMR (400MHz, CDCl 3): δ 3.84 (6H, s), 4.84 (2H, d, J=6.4Hz), 6.26 (1H, dt, J=16.0,6.4Hz), 6.35 (1H, d, J=16.0Hz), 6.66 (1H, d, J=16.0Hz), 6.83～7.50 (8H, m), 7.69 (1H, d, J=16.0Hz).
Compound I-b:
White solid, fusing point: 62～63 ℃, Rf (n-hexane/ethyl acetate: 3/1): 0.21; 1HNMR (400MHz, CDCl 3): δ 3.78 (3H, s), 3.88 (6H, s), 3.90 (3H, s), 4.85 (2H, d, J=6.4Hz), 6.24 (1H, dt, J=16.0,6.4Hz), 6.36 (1H, d, J=16.0Hz), 6.66 (1H, d, J=16.0Hz), 6.76～7.37 (6H, m), 7.64 (1H, d, J=16.0Hz).
Compound I-c:
Yellow solid, fusing point: 89～90 ℃, Rf (n-hexane/ethyl acetate: 3/1): 0.26; 1HNMR (400MHz, CDCl 3): δ 3.89 (3H, s), 3.91 (3H, s), 4.88 (2H, d, J=6.8Hz), 6.24 (1H, dt, J=16.0,6.8Hz), 6.58 (1H, d, J=16.0Hz), 6.82 (1H, d, J=16.0Hz) 6.95～7.18 (7H, m), 7.75 (1H, d, J=16.0Hz).
Compound I-d:
White solid, fusing point: 60～62 ℃, Rf (n-hexane/ethyl acetate: 3/1): 0.27; 1HNMR (400MHz, CDCl 3): δ 3.83 (3H, s), 3.86 (3H, s), 3.87 (3H, s), 3.88 (3H, s), 3.89 (3H, s), 3.90 (3H, s), 4.87 (2H, d, J=6.4Hz), 6.30 (1H, dt, J=16.0,6.4Hz), 6.40 (1H, d, J=16.0Hz), 6.64 (2H, s), 6.64 (1H, d, J=16.0Hz), 6.77 (2H, s), 7.66 (1H, d, J=16.0Hz).
Compound I-e:
White solid, fusing point: 66～67 ℃, Rf (n-hexane/ethyl acetate: 3/1): 0.22; 1HNMR (400MHz, CDCl 3): δ 3.84 (3H, s), 3.89 (3H, s), 3.91 (3H, s), 4.85 (2H, d, J=6.8Hz), 6.24 (1H, dt, J=16.0,6.8Hz), 6.36 (1H, d, J=16.0Hz), 6.65 (1H, d, J=16.0Hz), 6.80～7.49 (7H, m), 7.69 (1H, d, J=16.0Hz).
Compound I-f:
White crystal, fusing point: 78～79 ℃, Rf (n-hexane/ethyl acetate: 3/1): 0.21; 1HNMR (400MHZ, CDCl 3): δ 3.91 (6H, s), 3.92 (6H, s), 4.86 (2H, d, J=6.4Hz), 6.23 (1H, dt, J=16.0,6.4Hz), 6.36 (1H, d, J=16.0Hz), 6.66 (1H, d, J=16.0Hz), 6.84～7.13 (6H, m), 7.68 (1H, d, J=16.0Hz).
Compound I-g:
White solid, fusing point: 77～78 ℃, Rf (n-hexane/ethyl acetate: 3/1): 0.27; 1HNMR (400MHz, CDCl 3): δ 3.85 (3H, s), 3.86 (6H, s), 3.88 (6H, s), 4.86 (2H, d, J=6.4Hz), 6.25 (1H, dt, J=16.0,6.4Hz), 6.40 (1H, d, J=16.0Hz), 6.66 (1H, d, J=16.0Hz), 6.76～6.97 (5H, m), 7.65 (1H, d, J=16.0Hz).
Compound I-h:
White solid, fusing point: 65～66 ℃, Rf (n-hexane/ethyl acetate: 4/1): 0.38; 1HNMR (400MHz, CDCl 3): δ 3.48 (3H, s), 3.52 (3H, s), 3.53 (3H, s), 4.84 (2H, d, J=6.4Hz), 5.21 (2H, s), 5.24 (2H, s), 5.26 (2H, s), 6.25 (1H, dt, J=16.0,6.4Hz), 6.37 (1H, d, J=16.0Hz), 6.63 (1, d, J=16.0Hz), 7.00～7.50 (7H, m), 7.69 (1H, d, J=16.0Hz).
Compound I-i:
White crystal, fusing point: 30～31 ℃, Rf (n-hexane/ethyl acetate: 4/1): 0.60; 1HNMR (400MHZ, CDCl 3): δ 3.48 (6H, s), 4.84 (2H, d, J=6.4Hz), 5.21 (4H, s), 6.25 (1H, dt, J=16.0,6.4Hz), 6.37 (1H, d, J=16.0Hz), 6.66 (1H, d, J=16.0Hz), 7.00～7.48 (8H, m), 7.68 (1H, d, J=16.0Hz).
Compound I-j:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.18; 1HNMR (400MHz, CDCl 3): δ 3.93 (3H, s), 4.87 (2H, d, J=6.8Hz), 5.90 (1H, s), 6.36 (1H, dt, J=16.0,6.8Hz), 6.37 (1H, d, J=16.0Hz), 6.71 (1H, d, J=16.0Hz), 6.94～7.43 (8H, m), 7.67 (1H, d, J=16.0Hz).
Compound I-k:
White solid, fusing point: 52～53 ℃, Rf (n-hexane/ethyl acetate: 3/1): 0.54; 1HNMR (400MHz, CDCl 3): δ 3.49 (3H, s), 4.88 (2H, d, J=6.4Hz), 5.22 (2H, s) 6.36 (1H, dt, J=16.0,6.4Hz), 636 (1H, d, J=16.0Hz0,6.72 (1H, d, J=16.0Hz), 7.04～7.51 (9H, m), 7.70 (1H, d, J=16.0Hz).
Compound I-l:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.53; 1HNMR (400MHz, CDCl 3): δ 3.52 (3H, s), 3.53 (3H, s), 4.87 (2H, d, J=6.8Hz), 5.26 (2H, s), 5.27 (2H, s), 6.36 (1H, dt, J=16.0,6.8Hz), 6.37 (1H, d, J=16.0Hz), 6.72 (1H, d, J=16.0Hz), 6.85～7.62 (8H, m), 7.66 (1H, d, J=16.0Hz).
Compound I-m:
White crystal, fusing point: 32～33 ℃, Rf (n-hexane/ethyl acetate: 4/1): 0.32; 1HNMR (400MHz, CDCl 3): δ 3.48 (3H, s), 3.52 (3H, s), 3.53 (3H, s), 4.84 (2H, d, J=6.4Hz), 5.18 (2H, s), 5.26 (2H, s), 5.27 (2H, s), 6.25 (1H, dt, J=16.0,6.4Hz), 6.37 (1H, d, J=16.0Hz), 6.66 (1H, d, J=16.0Hz), 6.99～7.38 (7H, m), 7.65 (1H, d, J=16.0Hz).
Compound I-n:
White solid, fusing point: 49～50 ℃, Rf (n-hexane/ethyl acetate: 3/1): 0.20; 1HNMR (400MHz, CDCl 3): δ 3.48 (3H, s), 3.82 (3H, s), 4.84 (2H, d, J=6.8Hz), 5.21 (2H, s), 6.24 (1H, dt, J=16.0,6.8Hz), 6.36 (1H, d, J=16.0Hz), 6.66 (1H, d, J=16.0Hz), 6.83～7.49 (8H, m), 7.68 (1H, d, J=16.0Hz).
Compound I-o:
White solid, fusing point: 101～104 ℃, Rf (n-hexane/ethyl acetate: 3/1): 0.33; 1HNMR (400MHz, CDCl 3): δ 3.83 (3H, s), 3.84 (3H, s), 3.86 (3H, s), 3.87 (3H, s), 4.87 (2H, d, J=6.4Hz), 4.97 (2H, s), 5.00 (2H, s), 6.28 (1H, dt, J=16.0,6.8Hz), 6.40 (1H, d, J=16.0Hz), 6.63 (1H, d, J=16.0Hz), 6.63 (2H, s), 6.65 (1H, d, J=16Hz), 6.75 (2H, s), 7.26～7.30 (2H, m), 7.39～7.42 (2H, m), 7.65 (2H, s).
Compound I-p:
White solid, fusing point: 88～91 ℃, Rf (n-hexane/ethyl acetate: 3/1): 0.31; 1HNMR (400MHz, CDCl 3): δ 3.81 (3H, s), 3.82 (3H, s), 3.83 (3H, s), 3.85 (3H, s), 4.87 (2H, d, J=6.8Hz), 4.97 (2H, s), 5.00 (2H, s), 6.29 (1H, dt, J=16.0,6.8Hz), 6.39 (1H, d, J=16.0Hz), 6.60 (1H, d, J=16.0Hz), 6.62 (2H, s), 6.74 (2H, s), 7.35 (4H, d, J=6.8Hz), 7.47 (4H, d, J=6.8Hz) 7.64 (1H, d, J=16.0Hz).
Compound I-q:
White is gluey, Rf (n-hexane/ethyl acetate: 3/1): 0.32; 1HNMR (400MHz, CDCl 3): δ 3.83 (3H, s), 3.84 (3H, s), 3.87 (3H, s), 3.89 (3H, s), 4.87 (2H, d, J=6.4Hz), 4.97 (2H, s), 5.01 (2H, s), 6.26 (1H, dt, J=16.0,6.4Hz), 6.39 (1H, d, J=16.0Hz), 6.61 (1H, d, J=16.0Hz), 6.61 (2H, s), 6.75 (2H, s), 7.20 (2H, m), 7.37 (2H, d, J=8.0Hz), 7.42 (2H, d, J=8.0Hz), 7.64 (1H, d, J=16.0Hz), 7.71 (2H, s).
Compound I-r:
White solid, fusing point: 75～78 ℃, Rf (n-hexane/ethyl acetate: 3/1): 0.38; 1HNMR (400MHz, CDCl 3): δ 3.81 (3H, s), 3.82 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 4.87 (2H, d, J=6.4Hz), 5.05 (2H, s), 5.08 (2H, s), 6.25 (1H, dt, J=16.0,6.4Hz), 6.40 (1H, d, J=16.0Hz), 6.61 (2H, s), 6.63 (1H, d, J=16.0Hz), 6.74 (2H, s), 7.20～7.29 (4H, m), 7.48 (2H, d, J=8.0Hz), 7.46 (1H, d, J=16.0Hz).
Compound I-s:
Weak yellow liquid, Rf (n-hexane/ethyl acetate: 3/1): 0.58; 1HNMR (400MHz, CDCl 3): δ 1.59 (6H, s), 1.67 (12H, s), 2.04 (8H, m), 3.84 (3H, s), 3.85 (3H, s), 3.87 (3H, s), 3.88 (3H, s), 4.54 (4H, m), 4.87 (2H, d, J=6.4Hz), 5.07 (2H, m), 5.56 (2H, m), 6.28 (1H, dt, J=16.0,6.4Hz), 6.40 (1H, d, J=16.0Hz), 6.60 (2H, s), 6.63 (1H, d, J=16.0Hz), 6.75 (2H, s), 7.65 (1H, d, J=16.0Hz).
Embodiment 20: the preparation of Compound I I-j (4-methoxymethoxy-phenylpropionic acid-4-methoxymethoxy-phenylpropyl alcohol ester)
This example relates to the general synthetic method of formula (2) compound with cytotoxic activity.Be specifically related to compound 7,7 '-dimethoxy anisole propionic acid propyl benzene ester synthetic.(50mg, ethyl acetate 0.13mmol) (8mL) solution add and are equipped with in the three-necked bottle of 5mg 10% palladium carbon, import hydrogen, and room temperature reaction spends the night with compound (E)-(7-methoxymethoxy) phenylpropionic acid-(E)-(7 '-methoxymethoxy) phenylallene ester.Diatomite filtration, filtrate concentrates, and column chromatography (n-hexane/ethyl acetate=4: 1, crude product/silica gel=1: 50) separation obtains colourless oil droplet 48mg, and productive rate reaches 95.2%.
Compound I I-j: colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.67;
1HNMR(400MHz，CDCl 3)：δ1.90(2H，m)，2.53(2H，t，J＝8.0Hz)，2.64(2H，t，J＝8.0Hz)，2.91(2H，t，J＝8.0Hz)，3.47(3H，s)，3.48(3H，s)，4.12(2H，t，J＝6.8Hz)，5.15(2H，s)，5.16(2H，s)，6.95～7.15(8H，m)。
Method according to embodiment 20 prepares following table two illustrated embodiment 21-33 compounds:
Table 2
Figure C20041010289400222
Compound I I-a:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1) 0.71: 1HNMR (400MHz, CDCl 3): δ 1.91 (2H, m), 2.58 (2H, t, J=8.0Hz), 2.60 (2H, t, J=8.0Hz), 2.90 (2H, t, J=8.0Hz), 3.78 (6H, s), 4.07 (2H, t, J=6.4Hz), 6.82～7.14 (8H, m).
Compound I I-b:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.23; 1HNMR (400MHz, CDCl 3): δ 1.91 (2H, m), 2.61 (2H, t, J=8.0Hz), 2.63 (2H, t, J=8.0Hz), 2.90 (2H, t, J=8.0Hz), 3.78 (3H, s), 3.81 (3H, s), 3.84 (6H, s), 4.09 (2H, t, J=6.4Hz), 6.42～7.73 (6H, m).
Compound I I-c:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.13; 1HNMR (400MHz, CDCl 3): δ 1.91 (2H, m), 2.58 (2H, t, J=8.0Hz), 2.63 (2H, t, J=8.0Hz), 2.85 (2H, t, J=8.0Hz), 3.86 (3H, s), 3.87 (3H, s), 4.10 (2H, t, J=6.4Hz), 5.30 (2H, s), 6.43～7.02 (7H, m).
Compound I I-d:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.26; 1HNMR (400MHz, CDCl 3): δ 1.92 (2H, m), 2.61(2H, t, J=8.4Hz), 2.63 (2H, t, J=8.4Hz), 2.91 (2H, t, J=8.4Hz), 3.85 (3H, s), 3.86 (3H, s), 3.87 (6H, s), 4.10 (2H, t, J=6.4Hz), 6.70 (2H, s), 6.68～6.80 (6H, m).
Compound I I-e:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.25; 1HNMR (400MHz, CDCl 3): δ 1.91 (2H, m), 2.59 (2H, t, J=8.4Hz), 2.62 (2H, t, J=8.4Hz), 2.90 (2H, t, J=8.4Hz), 3.78 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 4.09 (2H, t, J=6.4Hz), 6.68～7.14 (7H, m).
Compound I I-f:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.26; 1HNMR (400MHz, CDCl 3): δ 1.92 (2H, m), 2.33 (3H, s), 2.34 (3H, s), 2.63 (2H, t, J=8.0Hz), 2.70 (2H, t, J=8.0Hz), 2.93 (2H, t, J=8.0Hz), 4.09 (2H, t, J=6.4Hz), 7.05～7.12 (8H, m).
Compound I I-g:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.28; 1HNMR (400MHz, CDCl 3): δ 1.91 (2H, m), 2.61 (2H, t, J=8.0Hz), 2.66 (2H, t, J=8.0Hz), 2.90 (2H, t, J=8.0Hz), 3.81 (3H, s), 3.84 (3H, s), 3.86 (6H, s), 3.87 (3H, s), 4.10 (2H, t, J=6.4Hz), 6.43～7.80 (5H, m).
Compound I I-h:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.39; 1HNMR (400MHz, CDCl 3): δ 1.91 (2H, m), 2.57 (2H, t, J=8.0Hz), 2.68 (2H, t, J=8.0Hz), 2.92 (2H, t, J=8.0Hz), 3.46 (3H, s), 3.52 (3H, s), 3.63 (3H, s), 4.09 (2H, t, J=6.8Hz), 5.14 (2H, s), 5.23 (2H, s), 6.73～7.14 (7H, m).
Compound I I-i:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.35; 1HNMR (400MHz, CDCl 3): δ 1.91 (2H, m), 2.61 (2H, t, J=8.0Hz), 2.63 (2H, t, J=8.0Hz), 2.89 (2H, t, J=8.0Hz), 3.48 (3H, s), 3.51 (3H, s), 3.52 (3H, s), 4.08 (2H, t, J=6.8Hz), 5.16 (2H, s), 5.20 (2H, s), 5.23 (2H, s), 6.79～7.27 (7H, m).
Compound I I-k:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.55; 1HNMR (400MHz, CDCl 3): δ 1.94 (2H, m), 2.61 (2H, t, J=8.0Hz), 2.65 (2H, t, J=8.0Hz), 2.91 (2H, t, J=8.0Hz), 3.47 (3H, s), 4.11 (2H, t, J=6.8Hz), 5.15 (2H, s), 6.95～7.31 (9H, m).
Compound I I-l:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.54; 1HN (400MHz, CDCl 3): δ 1.91 (2H, m), 2.61 (2H, t, J=8.0Hz), 2.66 (2H, t, J=8.0Hz) 2.89 (2H, t, J=8.0Hz), 3.51 (3H, s), 3.52 (3H, s), 4.12 (2H, t, J=6.8Hz), 5.20 (2H, s), 5.23 (2H, s), 6.80～7.31 (8H, m).
Compound I I-m:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.22; 1HNMR (400MHz, CDCl 3): δ 1.90 (2H, m), 2.59 (2H, t, J=8.0Hz), 2.61 (2H, t, J=8.0Hz), 2.91 (2H, t, J=8.0Hz), 3.29 (3H, s), 3.79 (3H, s), 4.08 (2H, t, J=6.0Hz), 5.15 (2H, s), 6.83～7.15 (8H, m).
Compound I I-n:
Colourless oil droplet, Rf (n-hexane/ethyl acetate: 3/1): 0.18; 1HNMR (400MHz, CDCl 3): δ 1.92 (2H, m), 2.58 (2H, t, J=8.0Hz), 2.64 (2H, t, J=8.0Hz), 2.88 (2H, t, J=8.0Hz), 3.79 (3H, s), 4.07 (2H, t, J=6.0Hz), 5.38 (1H, brs), 6.74～7.26 (8H, m).
In order to understand essence of the present invention better, respectively with the inhibiting The pharmacological results of compound, its new purposes in pharmacy field is described below to five kinds of tumor cell line growths.
Embodiment 34:Compound I-l is to the cytotoxic activity of KB cell
KB (oral epithelium cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay.Cell is through after 24 hours hatch, and the dimethyl sulfoxide solution of the Compound I that will newly join-1 joins in the hole respectively, makes that the compound ultimate density is 100 μ g/mL in the hole.After 72 hours, the phosphate buffered saline buffer that adds 10 μ L MTT (5mg/mL), continue 37 ℃ of cultivations after 4 hours again, removed a unconverted MTT in centrifugal 5 minutes, add 200 μ l methyl-sulphoxides in every hole, with the MTT crystal Jia Za (formazan) of dissolving and reducing, formed formazan microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample with respect to reference substance.
Compound I-l when concentration is 100 μ g/mL to the KB cell inhibitory rate is: 66.21%
Experiment conclusion: this experiment shows that this type of has the compound of cinnamic acid allyl phenyl ester knot, and the growth of KB cell is had certain restraining effect, might develop into the new medicine with antitumor action.
According to the method for embodiment 34, we have tested the pharmacologically active of The compounds of this invention to the KB cell, and concrete data see Table three.
Table three
The compound code name II-e II-m
Inhibiting rate during 100 μ g/mL 30.10％ 42.36％
Embodiment 35Compound I-3-f is to the cytotoxic activity of PC-3 cell
PC-3 (prostate cancer) cell F-12 culture medium culturing contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 34.
Compound I-3-f when concentration is 100 μ g/mL to PC-3 cell inhibiting rate is: 70.12%
Experiment conclusion: this experiment shows that this type of has the compound of phenylallene structure, and the growth of PC-3 cell is had certain restraining effect, might develop into the new medicine with antitumor action.
According to the method for embodiment 35, we have tested the pharmacologically active of The compounds of this invention to the PC-3 cell, and concrete data see Table four.
Table four
The compound code name II-e II-m I-l
Inhibiting rate during 100 μ g/L 23.71％ 30.69％ 47.79％
Embodiment 36:Compound I I-g is to the cytokine cytotoxic activity of CNE cell
CNE (nasopharyngeal carcinoma) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.With every hole 5 * 10 3The concentration of cell joins in 96 orifice plates, contains 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 34.
Compound I I-g when concentration is 100 μ g/mL to CNE cell inhibiting rate is: 48.75%
Experiment conclusion: this experiment shows that this type of has the compound of phenylpropionic acid propyl benzene ester structure, and the growth of CNE cell is had certain restraining effect, might develop into the new medicine with antitumor action.
According to the method for embodiment 36, we have tested the pharmacologically active of The compounds of this invention to the CNE cell, and concrete data see Table five.
Table five
The compound code name I-k II-d
Inhibiting rate during 100 μ g/mL 7.51％ 40.26％
Embodiment 37:Compound I-g is to the cytotoxic activity of A549 cell
A549 (people's lung cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with the training of RPMI 1640 substratum in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 34.
Compound I-g when concentration is 100 μ g/mL to A549 cell inhibiting rate is: 74.40%
Experiment conclusion: this experiment shows that this type of has the compound of cinnamic acid allyl phenyl ester junction structure, and the growth of A549 cell is had certain restraining effect, might develop into the new medicine with antitumor action.
According to the method for embodiment 37, we have tested the pharmacologically active of The compounds of this invention to the A549 cell, and concrete data see Table six.
Table six
The compound code name I-n II-g
Inhibiting rate during 100 μ g/mL 22.57％ 11.53％
Embodiment 38: Compound I-n is to the cytotoxic activity of Hela cell
Hela (human cervical carcinoma) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 34.
Compound I-n when concentration is 100 μ g/mL to Hela cell inhibiting rate is: 64.28%
Experiment conclusion: this experiment shows that this type of has the compound of phenylpropionic acid propyl benzene ester structure, and the growth of Hela cell is had certain restraining effect, might develop into the new medicine with antitumor action.
According to the method for embodiment 38, we have tested the pharmacologically active of The compounds of this invention to the Hela cell, and concrete data see Table seven.
Table seven
The compound code name II-m II-d I-k
Inhibiting rate during 100 μ g/mL 29.85％ 36.68％ 39.33％
In order to understand essence of the present invention better, the various pharmaceutical dosage forms of using this compounds below respectively are the preparation method of tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment and ointment for example, and its new application in pharmacy field is described.
Embodiment 39: tablet
With the compound that contains compound in claim 1, claim 2 and the claim 3 (is example with Compound I I-m) 2000mg, according to adding auxiliary material 8000mg behind the general pressed disc method mixing of pharmaceutics, be pressed into 100, every heavy 100mg.
Embodiment 40:Capsule
With the compound that contains compound in claim 1, claim 2 and the claim 3 (is example with Compound I-k) 2000mg, according to the requirement of pharmaceutics capsule with the 8000mg auxiliary materials and mixing after, the Capsules of packing into, the heavy 100mg of each capsule.
Embodiment 41:Injection
With the compound that contains compound in claim 1, claim 2 and the claim 3 (is example with Compound I I-n) 2000mg, according to the conventional dose method, carry out charcoal absorption, behind 0.65 μ filtering with microporous membrane, insert nitrogen pot and make hydro-acupuncture preparation.Every canned 2ml of injection, canned 1000 bottles altogether.
Embodiment 42:Aerosol
With the compound that contains compound in claim 1, claim 2 and the claim 3 (is example with Compound I I-e) 2000mg, after the dissolving of an amount of propylene glycol, add distilled water and other auxiliary materials after, the settled solution of making 200ml is promptly.
Embodiment 43:Suppository
With the compound that contains compound in claim 1, claim 2 and the claim 3 (is example with Compound I-3-f) 2000mg, it porphyrize adding glycerine is an amount of, grind well the back and add the glycogelatin that has melted, grind evenly, impouring has been coated with in the model of lubricant, makes 20 of Compound I-3-f bolt.
Embodiment 44:Film
With the compound that contains compound in claim 1, claim 2 and the claim 3 (is example with Compound I-g) 2000mg, polyvinyl alcohol, medicinal glycerin, water etc. are stirred the dissolving of expansion post-heating, 80 eye mesh screens filter, again Compound I I-1 is joined stirring and dissolving in the filtrate, 200 of the machine-processed films of filming.
Embodiment 45:Pill
With the compound that contains compound in claim 1, claim 2 and the claim 3 (is example with Compound I I-e) 2000mg, behind matrix 700mg heat fused mixings such as gelatin, splash in the cryogenic liquid paraffin, make dripping pill 100 balls altogether.
Embodiment 46:Externally-applied liniment
With with containing compound (is example with the Compound I I-m) 2g of compound in claim 1, claim 2 and the claim 3, according to the conventional dose method, with auxiliary material 0.5g mixed grinding such as emulsifying agent, adding distil water is made to 50ml again.
Embodiment 47:Ointment
With the compound that contains compound in claim 1, claim 2 and the claim 3 (is example with Compound I-o) 2000mg, grind well promptly with oleaginous base 198g such as Vaseline behind the porphyrize.

Claims (8)

1. the styracin analog derivative with cytotoxic activity or its pharmacologically acceptable salt or the solvate shown in the formula (I):
Figure C2004101028940002C1
Wherein:
Substituent R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'Can be identical or different, be independently selected from hydrogen respectively, nitro, the alkoxyl group of 1～8 carbon, the unsaturated-oxyl of 1～15 carbon, the alkoxyl group alkoxyl group of 1～8 carbon, the aralkoxy of replacement, the substituting group that wherein is used to replace is selected from halogen; R 6, R 7, R 8, R 6 ', R 7 'And R 8 'Can not be hydrogen simultaneously.
2. according to formula (I) compound of claim 1, it is characterized in that described compound is to be selected from following compounds:
I-a. (E)-7-methoxyl group-cinnamic acid-(E)-(7 '-methoxyl group) phenylallene ester;
I-b. (E)-(6,7, the 8-trimethoxy) cinnamic acid-(E)-(7 '-methoxyl group) the phenylallene ester;
I-c. (E)-(7-nitro) cinnamic acid-(E)-(6 ', 7 '-dimethoxy) the phenylallene ester;
I-d. (E)-(6,7, the 8-trimethoxy) cinnamic acid-(E)-(6 ', 7 ', 8 '-trimethoxy) the phenylallene ester;
I-e. (E)-(7-methoxyl group) cinnamic acid-(E)-(6 ', 7 '-dimethoxy) the phenylallene ester;
I-f. (E)-(6, the 7-dimethoxy) cinnamic acid-(E)-(6 ', 7 '-dimethoxy) the phenylallene ester;
I-g. (E)-(6,7, the 8-trimethoxy) cinnamic acid-(E)-(6 ', 7 '-dimethoxy) the phenylallene ester;
I-h. (E)-(7-methoxymethoxy) cinnamic acid-(E)-(6 ', 7 '-the dimethoxy methoxyl group) the phenylallene ester;
I-i. (E)-(7-methoxymethoxy) cinnamic acid-(E)-(7 '-methoxymethoxy) the phenylallene ester;
I-i. (E)-(7-hydroxyl) cinnamic acid-(E)-(7 '-methoxyl group) the phenylallene ester;
I-k. (E)-(7-methoxymethoxy) cinnamic acid-(E)-the phenylallene ester;
I-1. (E)-(6,7-dimethoxy methoxyl group) cinnamic acid-(E)-the phenylallene ester;
I-m.E)-(6,7-dimethoxy methoxyl group) cinnamic acid-(E)-(7 '-methoxymethoxy)-phenylallene ester;
I-n. (E)-(7-methoxymethoxy) cinnamic acid-(E)-(7 '-methoxyl group) the phenylallene ester;
I-o. (E)-(6,8-dimethoxy-7-O-(3 ", 4 " dichloro) benzyl)-cinnamic acid-(E)-(6 ', 8 '-dimethoxy-7 '-O-(3 " ', 4 " '-dichloro) benzyl)-the phenylallene ester;
I-p. (E)-(6,8-dimethoxy-7-O-(4 " bromine) benzyl)-cinnamic acid-(E)-(6 ', 8 '-dimethoxy-7 '-O-(4 " '-bromine) benzyl)-the phenylallene ester;
I-q. (E)-(6,8-dimethoxy-7-O-(3 " bromine) benzyl)-cinnamic acid-(E)-(6 ', 8 '-dimethoxy-7 '-O-(3 " '-bromine) benzyl)-the phenylallene ester;
I-r. (E)-(6,8-dimethoxy-7-O-(2 " fluorine, 4 " bromine) benzyl)-cinnamic acid-(E)-(6 ', 8 '-dimethoxy-7 '-O-(2 " '-fluorine, 4 " '-bromine) benzyl)-the phenylallene ester;
I-s. (E)-(6,8-dimethoxy-7-O-geranyl)-cinnamic acid-(E)-(6 ', 8 '-dimethoxy-7 '-the O-geranyl)-the phenylallene ester.
3. one kind has the phenylpropionic acid phenyl propyl derivative with cytotoxic activity or its pharmacologically acceptable salt or the solvate shown in the formula (II):
Figure C2004101028940003C1
Wherein:
Substituent R 6, R 7, R 8, R 6 ', R 7 'Or R 8 'Can be identical or different, be selected from hydrogen respectively, the alkoxyl group of 1～8 carbon, the alkoxyl group alkoxyl group of 1～8 carbon; Substituent R 6, R 7, R 8, R 6 ', R 7 'And R 8 'Can not be hydrogen simultaneously; Work as substituent R 6, R 7, R 6 ', R 7 'When being methoxyl group, R 8, R 8 'Can not be hydrogen simultaneously.
4. according to formula (II) compound of claim 3, it is characterized in that described compound is to be selected from following compounds:
II-a.7-methoxyl group-phenylpropionic acid-7 '-methoxyl group-phenylpropyl alcohol ester;
II-b.6,7,8-trimethoxy-phenylpropionic acid-7 '-methoxyl group-phenylpropyl alcohol ester;
II-c.7-amino-phenylpropionic acid-6 ', 7 '-dimethoxy-phenylpropyl alcohol ester;
II-d.6,7-dimethoxy-phenylpropionic acid-6 ', 7 '-dimethoxy-phenylpropyl alcohol ester;
II-e.7-methoxyl group-phenylpropionic acid-6 ', 7 '-dimethoxy-phenylpropyl alcohol ester;
II-f.7-methyl-phenylpropionic acid-7 '-methyl-phenylpropyl alcohol ester;
II-g.6,7,8-trimethoxy-phenylpropionic acid-6 ', 7 '-dimethoxy-phenylpropyl alcohol ester;
II-h.7-methoxymethoxy-phenylpropionic acid-6 ', 7 '-dimethoxy methoxyl group-phenylpropyl alcohol ester;
II-i.6,7-dimethoxy methoxyl group-phenylpropionic acid-7 '-methoxymethoxy-phenylpropyl alcohol ester;
II-j.7-methoxymethoxy-phenylpropionic acid-7 '-methoxymethoxy-phenylpropyl alcohol ester;
II-k.7-methoxymethoxy-phenylpropionic acid phenylpropyl alcohol ester;
II-1.6,7-dimethoxy methoxyl group-phenylpropionic acid phenylpropyl alcohol ester;
II-m.7-methoxymethoxy-phenylpropionic acid-7 '-methoxyl group-phenylpropyl alcohol ester;
II-n.7-hydroxyl-phenylpropionic acid-7 '-methoxyl group-phenylpropyl alcohol ester.
5. according to the preparation method of claim 1 Chinese style I compound, comprise with formula I-2 compound and formula I-3 compound that at N N-dicyclohexyl carbonyl diimine and 4-Dimethylamino pyridine exist down and prepare formula I compound by esterification:
Figure C2004101028940004C1
Or
With formula I-2 compound and formula I-3 compound 1,1 '-dicarbapentaborane imidazoles, 1,8-diazabicyclo [5,4,0] 11 alkane-7-alkene exists down and gets formula I compound by esterification:
Substituent R wherein 6, R 7, R 8, R 6 ', R 7 ', R 8 'Definition identical with claim 1.
6. according to the preparation method of claim 3 Chinese style II compound, comprise formula I compound is prepared formula II compound by palladium carbon catalytic hydrogenation reaction:
Figure C2004101028940004C3
Substituent R wherein 6, R 7, R 8, R 6 ', R 7 ', R 8 'Definition identical with claim 3.
7. be used to prepare the purposes of control tumor disease medicine according to the compound of one of claim 1-4 or their pharmacologically acceptable salt or their solvate.
8. pharmaceutical composition that is used to prevent and treat tumor disease, it contains compound or their pharmacologically acceptable salt or their solvate and the pharmaceutically acceptable auxiliaries according to one of claim 1-4 as activeconstituents for the treatment of significant quantity.
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