CN102702052B - Novel diamine-containing farnesyl thiosalicylic acid derivative and preparation method and medicinal application thereof - Google Patents

Novel diamine-containing farnesyl thiosalicylic acid derivative and preparation method and medicinal application thereof Download PDF

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CN102702052B
CN102702052B CN2012102016946A CN201210201694A CN102702052B CN 102702052 B CN102702052 B CN 102702052B CN 2012102016946 A CN2012102016946 A CN 2012102016946A CN 201210201694 A CN201210201694 A CN 201210201694A CN 102702052 B CN102702052 B CN 102702052B
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CN102702052A (en
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凌勇
杨宇民
王新杨
肖幼安
郭益冰
钟梦菊
甘东汇
丰楠楠
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Fujian Jin Hua Technology Co., Ltd.
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Nantong University
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Abstract

The invention provides a novel diamine-containing farnesyl thiosalicylic acid derivative and pharmaceutically acceptable salt thereof, a preparation method for the derivative and the salt, a medicinal composition containing the derivative, and medicinal application of the derivative, the salt and the composition, particularly application to preparation of anti-tumor medicines and neuroprotection medicines.

Description

The novel farnesyl thio-salicylic acid derivative, its preparation method and the medicinal use thereof that contain Diamines
Technical field
The present invention relates to biomedicine field; be specifically related to novel farnesyl thio-salicylic acid derivative and pharmacy acceptable salt thereof that a class contains Diamines; their preparation method; the medicinal compositions that contains these derivatives and their medicinal use, the particularly application in preparing antitumor drug and nerve protection medicine.
Background technology
Alltrans farnesyl thiosalicylic acid (is called for short: FTA, trade(brand)name: Salirasib) be first Ras protein inhibitor based on farnesyl, can competitive replace F-Ras and the F-Ras mutain is combined with Galectins, inhibition causes downstream signal path (comprising Raf and P13K signal path) and mTOR (tumorigenic stimulator by Ras, it can rely on or open independently the P13K signal path), thereby the promotion apoptosis of tumor cells, the growth of inhibition tumor cell.Research shows, the IC of FTA to breast cancer cell MCF-7 and MBA-MD-231 50in 75 μ M left and right; To brain glioblastoma cell U87 (IC 50=50 μ M), carcinoma of the pancreas Panc-1 (IC 50=35 μ M), lung cell A549 (IC 50=40 μ M), H23 (IC50=75 μ M), HTB58 (IC 50=50 μ M) restraining effect is all arranged.FTA(oral administration, dosage 40mg/kg) to the inhibitory rate to 54.6% of nude mice Panc-1 transplanted tumor.Pharmacokinetic shows, under above-mentioned dosage, the transformation period of FTA in the rat body is 141.6min(Zundelevich A, Elad-Sfadia G, Haklai R, et al.Mol Cancer Ther, 2007,6 (6): 1765-1773; Goldberg L, Haklai R, Bauer V. et al.J Med Chem, 2009,52 (1): 197-205).Because FTA has anti-tumor activity and less toxic side effect preferably, now entered clinical II phase research, treatment lung cancer and carcinoma of the pancreas (Riely GJ, Johnson ML, Medina C, et al.J Thorac Oncol, 2011,6 (8): 1435-1437; Bustinza-Linares E, Kurzrock R, Tsimberidou AM, et al.Future Oncol, 2010,6 (6): 885-891).Yet, though FTA is in the clinical study of II phase, because it can't stop and reversion of malignant tumor development process forcefully, and clinical therapeutic efficacy is not high, using dosage is large, usually needs clinically to have the antitumour drug combination therapy of cytotoxicity with other.According to another bibliographical information, Ras inhibitor FTA also has neuroprotective (Marciano D, Shohami E, Kloog Y, et al.J Neurotrauma, 2007,24 (8): 1378-86 of long-acting closed injury of brain; Shohami E, Yatsiv I, Alexandrovich A, Haklai R, et al.J Cereb Blood Flow Metab, 2003,23 (6): 728-38).
Farnesyl thiosalicylic acid (FTA, Salirasib)
For this reason; we are according to life science and information science latest Progress; Advanced Idea and the means of the design of application new drug are modified, are transformed the FTA structure; introduce other pharmacophoric group; for obtaining than FTA anti-tumor activity or the stronger compound of brain injury neuroprotective; the invention discloses the novel FTA derivative of Diamines and pharmacy acceptable salt thereof that a class has pharmaceutical use, have not yet to see any report to this compounds.
Summary of the invention
The present invention discloses new diamine class FTA derivative and pharmacy acceptable salt, its preparation method and the medicinal use thereof that a class has anti-tumor activity first.Compound disclosed by the invention is new diamine class FTA derivative and the pharmacy acceptable salt thereof shown in general formula I, II and III:
Figure BDA00001781840500021
In formula I: n=1 ~ 9;
R 1represent H, CH 3(CH 3) CH, CH 3(CH 3) CHCH 2, Cyclohexyl, Cyclopentyl or X (CH 2) m, wherein
M=0 ~ 9, X=H, OH, NH2, Cl, F, CN, COOH, Ph or PhCH 2;
R 2represent H, CH 3(CH 3) CH, CH 3(CH 3) CHCH 2, Cyclohexyl, Cyclopentyl or Y (CH 2) p, wherein,
P=0 ~ 9, Y=H, OH, NH2, Cl, F, CN, COOH, Ph or PhCH 2;
Perhaps,
Figure BDA00001781840500022
representative
Figure BDA00001781840500023
Figure BDA00001781840500024
In the general formula II: m=0 ~ 9; X=CH, N; N=0 ~ 3; O=0 ~ 3;
R represents CH 3(CH 3) CH, CH 3(CH 3) CHCH 2, Cyclohexyl, Cyclopentyl or Y (CH 2) p, wherein, p=0 ~ 9, Y=H, OH, NH 2, Cl, F, CN, COOH, Ph or PhCH 2.
In the general formula III: n=1 ~ 9;
R representative-X (CH 2) ny, wherein X=O, NH or CH 2, n=0 ~ 8, Y=H, OH, NH2, CN, COOH, COOMe, Cl, F, OCH 3, OCH 2cH 3, NHCH 3or NHCH 2cH 3;
Perhaps, R represents Ph, 2-OHPh, 2-SHPh, 2-S-farnesyl-Ph, 2-OAcPh, 2-SAcPh, 3-OHPh, 4-OHPh, 3,4-OHPh, 3,5-OHPh, 3,4,5-OHPh, 3-OMePh, 4-OMePh, 3,4-OMePh, 3,5-OMePh, 3,4,5-OMePh, perhaps
Figure BDA00001781840500033
r wherein 3=H, OH or OCH 3, R 4=H, OH or OCH 3;
Perhaps, RCO represents L-or D-type L-Ala, L-or D-type phenylalanine, L-or D-type methionine(Met), L-or D-type leucine, L-or D-type Isoleucine, L-or D-type Methionin, L-or D-type proline(Pro), L-or D-type glutamine or L-or D-type l-asparagine.
Specifically, the Diamines FTA derivative shown in general formula I is preferably from following compounds:
N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (compound number: I 1, lower same)
N-(3-aminopropyl) farnesyl thiosalicylic acid acid amides (I 2)
N-(4-ammonia butyl) farnesyl thiosalicylic acid acid amides (I 3)
N-(5-ammonia amyl group) farnesyl thiosalicylic acid acid amides (I 4)
N-(6-ammonia hexyl) farnesyl thiosalicylic acid acid amides (I 5)
N-(3-dimethylamino-propyl) farnesyl thiosalicylic acid acid amides (I 6)
N-(3-diethylin propyl group) farnesyl thiosalicylic acid acid amides (I 7)
N-(3-dipropyl aminopropyl) farnesyl thiosalicylic acid acid amides (I 8)
N-(4-dimethylamino butyl) farnesyl thiosalicylic acid acid amides (I 9)
N-(4-diethylin butyl) farnesyl thiosalicylic acid acid amides (I 10)
N-(3-piperidyl propyl group) farnesyl thiosalicylic acid acid amides (I 11)
N-(3-pyrryl propyl group) farnesyl thiosalicylic acid acid amides (I 12)
N-(3-(4-methylpiperazine-1-yl) propyl group) farnesyl thiosalicylic acid acid amides (I 13)
N-(4-piperidyl butyl) farnesyl thiosalicylic acid acid amides (I 14)
N-(4-pyrryl butyl) farnesyl thiosalicylic acid acid amides (I 15)
N-(morpholinyl propyl group) farnesyl thiosalicylic acid acid amides (I 16)
N-(3-(N, N-dihydroxy ethyl)-aminopropyl) farnesyl thiosalicylic acid acid amides (I 17)
N-(2-(N-hydroxyethyl)-amino-ethyl) farnesyl thiosalicylic acid acid amides (I 18)
Diamines FTA derivative shown in the general formula II is preferably from following compounds:
N-(2-(1-benzyl piepridine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 1)
N-(2-(1-benzyl piepridine-4-yl) methyl) farnesyl thiosalicylic acid acid amides (II 2)
N-(2-(1-ethyl piperidine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 3)
N-(2-(1-benzyl diethylenediamine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 4)
N-(2-(1-ethyl piperazidine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 5)
Diamines FTA derivative shown in the general formula III is preferably from following compounds:
N-(2-(Aspirin amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 1)
N-(3-(Aspirin amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 2)
N-(4-(Aspirin amide group) butyl) farnesyl thiosalicylic acid acid amides (III 3)
N-(5-(Aspirin amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 4)
N-(6-(Aspirin amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 5)
N-(2-(3-(3-methoxyl group-4-acetoxyl group phenyl)-2-allyl acid amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 6)
N-(3-(3-(3-methoxyl group-4-acetoxyl group phenyl)-2-allyl acid amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 7)
N-(4-(3-(3-methoxyl group-4-acetoxyl group phenyl)-2-allyl acid amide group) butyl) farnesyl thiosalicylic acid acid amides (III 8)
N-(5-(3-(3-methoxyl group-4-acetoxyl group phenyl)-2-allyl acid amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 9)
N-(6-(3-(3-methoxyl group-4-acetoxyl group phenyl)-2-allyl acid amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 10)
N-(2-(3,4,5-trimethoxybenzoic acid amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 11)
N-(3-(3,4,5-trimethoxybenzoic acid amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 12)
N-(4-(3,4,5-trimethoxybenzoic acid amide group) butyl) farnesyl thiosalicylic acid acid amides (III 13)
N-(5-(3,4,5-trimethoxybenzoic acid amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 14)
N-(6-(3,4,5-trimethoxybenzoic acid amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 15)
N-(2-(2 hydroxybenzoic acid amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 16)
N-(3-(2 hydroxybenzoic acid amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 17)
N-(4-(2 hydroxybenzoic acid amide group) butyl) farnesyl thiosalicylic acid acid amides (III 18)
N-(5-(2 hydroxybenzoic acid amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 19)
N-(6-(2 hydroxybenzoic acid amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 20)
N-(2-(3-(3-methoxyl group-4-hydroxy phenyl)-2-allyl acid amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 21)
N-(3-(3-(3-methoxyl group-4-hydroxy phenyl)-2-allyl acid amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 22)
N-(4-(3-(3-methoxyl group-4-hydroxy phenyl)-2-allyl acid amide group) butyl) farnesyl thiosalicylic acid acid amides (III 23)
N-(5-(3-(3-methoxyl group-4-hydroxy phenyl)-2-allyl acid amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 24)
N-(6-(3-(3-methoxyl group-4-hydroxy phenyl)-2-allyl acid amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 25)
N-(2-(Gallic Acid amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 26)
N-(3-(Gallic Acid amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 27)
N-(4-(Gallic Acid amide group) butyl) farnesyl thiosalicylic acid acid amides (III 28)
N-(5-(Gallic Acid amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 29)
N-(6-(Gallic Acid amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 30)
N-(3-farnesyl thiosalicylic acid amidopropyl) farnesyl thiosalicylic acid acid amides (III 31)
N-(4-farnesyl thiosalicylic acid amide group butyl) farnesyl thiosalicylic acid acid amides (III 32)
N-(5-farnesyl thiosalicylic acid amide group amyl group) farnesyl thiosalicylic acid acid amides (III 33)
The structure of said structure formula I preferred compound code name and correspondence thereof is as shown in table 1
Table 1 general formula I preferred compound code name and corresponding structure thereof
Figure BDA00001781840500051
Figure BDA00001781840500061
The structure of said structure general formula II preferred compound code name and correspondence thereof is as shown in table 2
Table 2 general formula II preferred compound code name and corresponding structure thereof
Figure BDA00001781840500062
The structure of said structure general formula III preferred compound code name and correspondence thereof is as shown in table 3
Table 3 general formula III preferred compound code name and corresponding structure thereof
Figure BDA00001781840500063
Figure BDA00001781840500071
Another object of the present invention is to provide the preparation method of formula I of the present invention, II and the described compound of III.
The preparation of the derivative of FTA shown in formula I, its synthetic route is as follows:
Step comprises:
By FTA, under the effect of sulfur oxychloride or oxalyl chloride, preparation FTA acyl chlorides, by FTA acyl chlorides and NH 2(CH 2) ncH 2nR 1r 2in the dichloromethane solution of triethylamine or salt of wormwood or sodium carbonate, reaction obtains compound of Formula I;
Perhaps, FTA and NH 2(CH 2) ncH 2nR 1r 2under condensing agent and DMAP (DMAP) effect, condensation makes compound of Formula I.
Wherein, n=1 ~ 9;
R 1represent H, CH 3(CH 3) CH, CH 3(CH 3) CHCH 2, Cyclohexyl, Cyclopentyl or X (CH 2) m, m=0 ~ 9 wherein, X=H, OH, NH 2, Cl, F, CN, COOH, Ph or PhCH 2;
R 2represent H, CH 3(CH 3) CH, CH 3(CH 3) CHCH 2, Cyclohexyl, Cyclopentyl or Y (CH 2) p, wherein, p=0 ~ 9, Y=H, OH, NH2, Cl, F, CN, COOH, Ph or PhCH 2;
Perhaps,
Figure BDA00001781840500081
representative
Figure BDA00001781840500082
Figure BDA00001781840500083
In the preparation method of above-mentioned compound of Formula I, condensing agent used is selected from 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), N, N-DIC (DIC), Vinyl chloroformate or methyl esters, solvent is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), ethyl acetate, methyl acetate, 1, one or more in 2-ethylene dichloride, benzene, toluene, dioxane or DMF.
Preparation method's synthetic route of FTA derivative shown in the general formula II is as follows:
Wherein, m=0 ~ 9; X=CH, N; N=0 ~ 3, o=0 ~ 3;
R represents CH 3(CH 3) CH, CH 3(CH 3) CHCH 2, Cyclohexyl, Cyclopentyl or Y (CH 2) p, wherein, p=0 ~ 9, Y=H, OH, NH 2, Cl, F, CN, COOH, Ph or PhCH 2;
Step comprises:
(1) compound 2 reacts and obtains compound 4 with R-Br or R-Cl under the effect of salt of wormwood or triethylamine;
(2) compound 4 reacts with methylsulfonyl chloride and obtains compound 5;
(3) compound 5 reacts with excessive ammonia and obtains compound 6;
(4) compound 6 reacts and obtains general formula II compound under condensing agent and DMAP effect with FTA, or compound 6 and FTA acyl chlorides, and under the effect of acid binding agent triethylamine or salt of wormwood, reaction obtains general formula II compound.
In above-mentioned general formula II compounds process for production thereof step (4), condensing agent is selected from 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), N, N-DIC (DIC), Vinyl chloroformate or methyl esters, solvent is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), ethyl acetate, methyl acetate, 1, one or more in 2-ethylene dichloride, benzene, toluene, dioxane or DMF.
The preparation synthetic route of FTA derivative shown in the general formula III is as follows:
Figure BDA00001781840500091
Wherein, n=1 ~ 9;
R representative-X (CH 2) ny, wherein X=O, NH or CH 2, n=0 ~ 8, Y=H, OH, NH 2, CN, COOH, COOMe, Cl, F, OCH 3, OCH 2cH 3, NHCH 3or NHCH 2cH 3;
Perhaps represent Ph, 2-OHPh, 2-SHPh, 2-S-farnesyl-Ph, 2-OAcPh, 2-SAcPh, 3-OHPh, 4-OHPh, 3,4-OHPh, 3,5-OHPh, 3,4,5-OHPh, 3-OMePh, 4-OMePh, 3,4-OMePh, 3,5-OMePh, 3,4,5-OMePh, perhaps
Figure BDA00001781840500093
r wherein 3=H, OH or OCH 3, R 4=H, OH or OCH 3;
Perhaps, RCO represents L-or D-type L-Ala, L-or D-type phenylalanine, L-or D-type methionine(Met), L-or D-type leucine, L-or D-type Isoleucine, L-or D-type Methionin, L-or D-type proline(Pro), L-or D-type glutamine or L-or D-type l-asparagine;
Step comprises:
(1) by compound 7 and NH 2(CH 2) ncH 2nH 2under the effect of condensing agent, reaction obtains compound 9, or compound 7 and sulfur oxychloride or oxalyl chloride reaction are obtained to corresponding acyl chlorides directly and NH 2(CH 2) ncH 2nH 2under the effect of acid binding agent triethylamine or salt of wormwood, reaction obtains compound 9;
(2) compound 9 reacts and obtains general formula III compound under condensing agent and DMAP effect with FTA, or compound 9 and FTA acyl chlorides, and under the effect of acid binding agent triethylamine or salt of wormwood, reaction prepares general formula III compound.
Above-mentioned preparation method's step (1) and (2) middle condensing agent for preparing general formula III compound is selected from 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), N, N-DIC (DIC), Vinyl chloroformate or methyl esters.
The organic solvent that above-mentioned reaction adopts is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), ethyl acetate, ethyl formate, methyl acetate, 1, one or more mixture of 2-ethylene dichloride, benzene, toluene, dioxane, DMF, preferentially adopt anhydrous methylene chloride or anhydrous tetrahydro furan or DMF.
A further object of the present invention is to provide general formula I of the present invention, II, the application of III compound in preparing the medicine for treating tumor thing.
Further purpose of the present invention is to provide a kind of pharmaceutical composition of general formula I of the present invention, II, III compound or its medically acceptable salt and pharmaceutically acceptable carrier or auxiliary material containing effective dosage.
A further object of the present invention is to provide general formula I of the present invention, II, the application of III compound in preparing antitumor drug and nerve protection medicine; especially Hepatoma therapy; carcinoma of the pancreas; lung cancer; mammary cancer; the cancer of the brain, the application in the application in the tumour medicines such as colorectal carcinoma and cancer of the stomach and brain injury nerve protection medicine.
Due to general formula I of the present invention, II, III compound, according to life science and information science latest Progress, Advanced Idea and the means of the design of application new drug are modified, are transformed the FTA structure, introduce that other pharmacophoric group obtains, it has the structure similar with FTA, can infer that from chemical structure and space structure formula I of the present invention, II and III compound have the pharmacological action of FTA.
The compounds of this invention can be made preparation for administration separately or with one or more pharmaceutically acceptable carrier combinations.For example, solvent, thinner etc., can use the oral dosage form administration, but as tablet, capsule dispersed powders, granule etc.The various formulations of pharmaceutical composition of the present invention can be prepared according to the method for knowing in pharmaceutical field.Can contain for example activeconstituents of 0.05% ~ 90% weight with carrier combinations in these medicinal preparationss, the more common approximately activeconstituents of weight between 15% ~ 60%.The compounds of this invention dosage can be 0.005 ~ 5000mg/kg/ days, also can exceed this dosage range according to the different using dosages of disease severity or formulation.
The compounds of this invention can with other antitumor drugs for example alkylating agent (as endoxan or cis-platinum), antimetabolite (as 5 FU 5 fluorouracil or hydroxyurea), topoisomerase enzyme inhibitor (as camptothecine), mitotic inhibitor (as taxol or vinealeucoblastine(VLB)), DNA intercalating agent (as Zorubicin) combined utilization, in addition can also with the radiotherapy combined utilization.These other antitumor drugs or radiotherapy can or give at different time with the compounds of this invention while.Thereby these combination therapys can produce synergy contributes to improve result for the treatment of.
The part pharmacological tests of the compounds of this invention is as follows:
1, adopt mtt assay to measure research to the Cytostatic to tumor cell rate of the compounds of this invention
Through a series of tumour cell tests, find that these general formula Is of the present invention, II, III compound are stronger to pancreatic cancer cell PANC-1 and human glioma cell U251 effect, wherein the cytoactive of most of the compounds of this invention is stronger than lead compound FTA, especially in table 4, all I and II compound inhibiting rate under 25 μ mol/L concentration all is greater than 90%, all considerably beyond primer FTA;
In human liver cancer cell Hep3B, human lung cancer cell A549 and human breast cancer cell MDA-MB-231, majority of compounds activity of the present invention is all over parent compound FTA, and in table 4, all I, II and compound III 16, III 18, III 21 inhibiting rate under 25 μ mol/L concentration is the 3-4 times of left and right of parent compound FTA;
The pharmacological results shows, the compounds of this invention has restraining effect in various degree to the propagation of human tumor cells, and the majority of compounds anti-tumor activity all significantly is better than FTA.
2, adopt flow cytometer to be detected apoptosis rate, selecting active compound I7 is representative, found that I7 has stronger cytotoxicity at 12.5 μ mol/L in to PANC-1, apoptosis rate can reach 63%, and the LO2 cell is not had to obvious restraining effect, this results suggest I7 is the apoptosis of inducing tumor cell optionally, less to normal cell injury, thereby realizes the effect of specific killing tumour cell.
3, Western blot detection of active preferably Diamines FTA derivative I 7 result that affects of carcinoma of the pancreas PANC-1 cell Bcl-2, Bax and Caspase3 protein expression is shown, the mode that Compound I 7 suppresses cell proliferation is relevant to cell death inducing, the mechanism of action of its inducing apoptosis of tumour cell is mainly that the Bax protein expression increases by impelling, Bcl-2 down-regulated expression and activate Caspase 3 vigor and activate apoptosis pathway, produces short apoptosis effect.
Above-mentioned experimental result is preferred compound I in formula I of the present invention, II and III compound 1-I 18, II 1-II 5, III 1-III 33the pharmacological results, the pharmacological effect that the present invention is met to other compounds of formula I, II and III structure also has directive significance, because formula I of the present invention, II and III compound have the chemical structure similar with FTA and space structure, thereby there is same or analogous pharmacological effect effect, through above-mentioned preferred compound I 1-I 18, II 1-II 5, III 1-III 33the checking of pharmacological evaluation, illustrate that formula I, II and III compound have anti-tumor activity.
Embodiment
In order further to illustrate the present invention, below provide a series of embodiment, these embodiment are illustrative fully, they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.The present invention FTA used is the laboratory self-control, content > 98%.
The preparation of embodiment 1 farnesyl thiosalicylic acid acyl chlorides
0.54g (1.50mmol) FTA is dissolved in to the anhydrous CH of 10mL 2cl 2in, add wherein 0.60mL (8.27mmol) sulfur oxychloride, stir 1 hour the concentrated yellow oil farnesyl thiosalicylic acid acyl chlorides that to obtain under 55 ℃.
The preparation of embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I1)
0.30g (5mmol) 1，2-diaminoethane and 0.20mL (1.50mmol) triethylamine are dissolved in to the anhydrous CH of 5mL 2cl 2in, slowly drip wherein the anhydrous CH of 10mL of 0.38g (1.0mmol) farnesyl thiosalicylic acid acyl chlorides under ice bath 2cl 2solution, the 1.5h of stirring at room reaction afterwards, concentrated solvent, steam except the residue quadrol, and column chromatography obtains the 0.28g yellow oil, yield 70.5%.
1H NMR(CDCl 3,300MHz):8.00(m,1H,Ar-H),7.78(m,1H,Ar-H),7.38(m,2H,Ar-H),5.23(m，1H，SCH 2C H)，5.08(m，2H，2×CH 2C H=CCH 3)，3.56(d，2H，J＝9.0Hz，SCH 2)，2.99-3.05(m，4H,2×NCH 2),1.99(m,8H,2×CHC H 2C H 2CH),1.53-1.68(m,12H,4×CH 3);ESI-MS(m/z):401[M+H] +。
Embodiment 3N-(3-aminopropyl) farnesyl thiosalicylic acid acid amides (I 2) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, make faint yellow oily matter N-(3-aminopropyl) farnesyl thiosalicylic acid acid amides (I by the 1，2-diaminoethane in 1,3-propylene diamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction 2), yield 70.1%.
1H NMR(CDCl 3,300MHz):7.93(m,2H,Ar-H),7.32(m,2H,Ar-H),5.21(m,1H,SCH 2C H),5.12(m,2H,2×CH 2C H=CCH 3),3.51(d,2H,J＝9.0Hz,SCH 2),3.05(m,4H,2×NC H 2),1.90-1.99(m,8H,2×CHC H 2C H 2CH),1.54-1.69(m,14H,4×CH 3,CH 2C H 2CH 2);ESI-MS(m/z):415[M+H] +。
Embodiment 4N-(4-ammonia butyl) farnesyl thiosalicylic acid acid amides (I 3) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, the 1，2-diaminoethane in the Putriscine alternative method and farnesyl thiosalicylic acid acyl chloride reaction make yellow oil N-(4-ammonia butyl) farnesyl thiosalicylic acid acid amides (I 3), yield 70.3%.
1H NMR(CDCl 3,300MHz):7.96(m,2H,Ar-H),7.38(m,2H,Ar-H),5.22(m,1H,SCH 2C H)，5.12(m，2H，2×CH 2C H=CCH 3)，3.51(d，2H，J＝9.0Hz，SCH 2)，3.05(m，4H，2×NCH 2)，1.87-1.98(m,8H,2×CHC H 2C H 2CH),1.52-1.78(m,16H,4×CH 3,CH 2C H 2C H 2CH 2);ESI-MS(m/z):429[M+H] +。
Embodiment 5N-(5-ammonia amyl group) farnesyl thiosalicylic acid acid amides (I 4) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, make yellow oil N-(5-ammonia amyl group) farnesyl thiosalicylic acid acid amides (I by the 1，2-diaminoethane in 1,5-pentamethylene diamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction 4), yield 73.1%.
1H NMR(CDCl 3，300MHz):8.01(m，2H，Ar-H)，7.32(m，2H，Ar-H)，5.32(m，1H，SCH 2C H)，5.10(m,2H,2×CH 2C H=CCH 3),3.52(d,2H,J＝9.0Hz,SCH 2),3.06(m,4H,2×NCH 2),1.97-2.02(m,8H,2×CHC H 2C H 2CH),1.52-1.78(m,16H,4×CH 3,2×NCH 2C H 2),1.33(m,2H,NCH 2CH 2C H 2);ESI-MS(m/z):443[M+H] +。
Embodiment 6N-(6-ammonia hexyl) farnesyl thiosalicylic acid acid amides (I 5) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, make orange-yellow oily thing N-(6-ammonia hexyl) farnesyl thiosalicylic acid acid amides (I by the 1，2-diaminoethane in 1,6-hexanediamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction 5), yield 84.5%.
1H NMR(CDCl 3,300MHz):δ7.37(m,3H,Ar-H),7.23(m,1H,Ar-H),5.23(m,1H,SCH 2C H)，5.09(m，2H，2×CH 2C H=CCH 3)，3.53(d，2H，J＝9.0 Hz，SCH 2)，3.15(m，4H，2×NCH 2)，1.95-2.05(m,8H,2×CHC H 2C H 2CH),1.55-1.77(m,16H,4×CH3,2×NCH 2C H 2),1.31-1.34(m,4H,2×NCH 2CH 2C H 2);ESI-MS(m/z):457[M+H] +。
Embodiment 7N-(3-dimethylamino-propyl) farnesyl thiosalicylic acid acid amides (I 6) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, by N, N-dimethyl-1, the 1，2-diaminoethane in 3-propylene diamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction make brown oil, yield 81.2%.
1H NMR(CDCl 3,300MHz):7.98(m,2H,Ar-H),7.31(m,2H,Ar-H),5.33(m,1H,SCH 2C H),5.14(m,2H,2×CH 2C H=CCH 3),3.38(d,2H,J＝9.0Hz,SCH 2),3.05(m,2H,NCH 2),2.47(m,2H,NCH 2),2.24(s,6H,CH 3NCH 3),1.90-1.99(m,8H,2×CHC H 2C H 2CH),1.54-1.69(m,14H,4×CH 3,CH 2C H 2C H 2);ESI-MS(m/z):443[M+H] +。
Embodiment 8N-(3-diethylin propyl group) farnesyl thiosalicylic acid acid amides (I 7) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, by N, N-diethyl-1, the 1，2-diaminoethane in 3-propylene diamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction make faint yellow oily matter N-(3-diethylin propyl group) farnesyl thiosalicylic acid acid amides (I 7), yield 81.2%.
1H NMR(CDCl 3,300MHz):8.08(m,1H,Ar-H),7.89(m,1H,Ar-H),7.30(m,2H,Ar-H),5.23(m，1H，SCH 2C H)，5.06(m，2H，2×CH 2C H=CCH 3)，3.48-3.42(m，4H，SCH 2，NCH 2)，2.42(m，6H，3×NCH 2),1.90-1.99(m,8H,2×CHC H 2C H 2CH),1.54-1.69(m,14H,4×CH 3,CH 2C H 2CH 2),0.90(m，6H，2×CH 2C H 3);ESI-MS(m/z):471[M+H] +。
Embodiment 9N-(3-dipropyl aminopropyl) farnesyl thiosalicylic acid acid amides (I 8) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, 1，2-diaminoethane and farnesyl thiosalicylic acid acyl chloride reaction in the amino propylamine alternative method of 3-dipropyl make faint yellow oily matter, yield 76.8%.
1H NMR(CDCl 3,300MHz):8.02(m,1H,Ar-H),7.72(m,1H,Ar-H),7.31(m,2H,Ar-H),5.20(m,1H,SCH 2C H),5.04(m,2H,2×CH 2C H=CCH 3),3.50-3.44(m,4H,SCH 2,NHCH 2),2.46-2.40(m,6H,3×NCH 2),1.94-2.00(m,8H,2×CHC H 2C H 2CH),1.46-1.72(m,18H,4×CH=CC H 3,CH 2C H 2CH 2,2×C H 2CH 3),0.89(m,6H,2×CH 2C H 3);ESI-MS(m/z):499[M+H] +。
Embodiment 10N-(4-dimethylamino butyl) farnesyl thiosalicylic acid acid amides (I 9) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, the 1，2-diaminoethane in 4-dimethylamino butylamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction make faint yellow oily matter N-(4-dimethylamino butyl) farnesyl thiosalicylic acid acid amides (I 9), yield 78.0%.
1H NMR(CDCl 3,300MHz)：8.04(m,1H,Ar-H),7.76(m,1H,Ar-H),7.30(m,2H,Ar-H),5.24(m，1H，SCH 2C H)，5.03(m，2H，2×CH 2C H=CCH 3)，3.54-3.33(m，4H，SCH 2，NCH 2)，2.47(m，2H,CH 2N),2.24(s,6H,2×NCH 3),1.94-2.00(m,8H,2×CHC H 2C H 2CH),1.53-1.74(m,16H,4×CH=CC H 3,CH 2C H 2C H 2CH 2);ESI-MS (m/z):457[M+H] +。
Embodiment 11N-(4-diethylin butyl) farnesyl thiosalicylic acid acid amides (I 10) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, the 1，2-diaminoethane in 3-diethylin butylamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction make yellow oil N-(4-diethylin butyl) farnesyl thiosalicylic acid acid amides (I 10), yield 71.4%.
1H NMR (CDCl 3,300MHz):7.99(m,2H,Ar-H),7.27(m,2H,Ar-H),5.32(m,1H,SCH 2C H),5.03(m,2H,2×CH 2C H=CCH 3),3.55(d,2H,J＝9.0Hz,SCH 2),3.32(m,2H,NHC H 2),2.42(m,6H,3×CH 2N),1.90-2.02(m,8H,2×CHC H 2C H 2CH),1.54-1.76(m,16H,4×CH=CC H 3,CH 2C H 2C H 2CH 2),0.93(m,6H,2×CH 2C H 3);ESI-MS(m/z):485[M+H] +。
Embodiment 12N-(3-piperidyl propyl group) farnesyl thiosalicylic acid acid amides (I 11) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, the 1，2-diaminoethane in 3-piperidyl propylamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction make faint yellow oily matter N-(3-piperidyl propyl group) farnesyl thiosalicylic acid acid amides (I 11), yield 66.8%.
1HNMR(CDCl 3，300MHz):8.03(m，2H，Ar-H)，7.32(m，2H，Ar-H)，5.33(m，1H，SCH 2C H)，5.09(m,2H,2×CH 2C H=CCH 3),3.46-3.30(m,4H,SCH 2,NCH 2),2.47(m,6H,3×NCH 2),1.90-2.02(m,8H,2×CHC H 2C H 2CH),1.44-1.76(m,20H,4×CH 3,4×CH 2);ESI-MS (m/z):483[M+H] +。
Embodiment 13N-(3-pyrryl propyl group) farnesyl thiosalicylic acid acid amides (I 12) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, the 1，2-diaminoethane in 3-pyrryl propylamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction make faint yellow oily matter N-(3-pyrryl propyl group) farnesyl thiosalicylic acid acid amides (I 12), yield 69.4%.
1H NMR(CDCl 3,300MHz):8.01(m,2H,Ar-H),7.36(m,2H,Ar-H),5.38(m,1H,SCH 2C H)，5.12(m，2H，2×CH 2C H=CCH 3)，3.48-3.34(m，4H，SCH 2，NCH 2)，2.52-2.40(m，6H，3×NCH 2),1.93-2.02(m,8H,2×CHC H 2C H 2CH),1.45-1.74(m,18H,4×CH 3,3×CH 2);ESI-MS(m/z):469[M+H] +。
Embodiment 14N-(3-(4-methylpiperazine-1-yl) propyl group) farnesyl thiosalicylic acid acid amides (I 13) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, 1，2-diaminoethane in 3-(4-methylpiperazine-1-yl) propylamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction make faint yellow oily matter N-(3-(4-methylpiperazine-1-yl) propyl group) farnesyl thiosalicylic acid acid amides (I 13), yield 66.8%.
1H NMR(CDCl 3,300MHz):8.01(m,1H,Ar-H),7.56(m,1H,Ar-H),7.36(m,2H,Ar-H),5.32(m，1H，SCH 2C H)，5.01(m，2H，2×CH 2C H=CCH 3)，3.52-3.40(m，4H，SCH 2，CONCH 2)，2.57(3H,s,NCH 3),2.49-2.36(m,10H,5×NCH 2),1.89-2.01(m,8H,2×CHC H 2C H 2CH),1.50-1.74(m,14H,4×CH 3,C H 2C H 2CH 2);ESI-MS (m/z):484[M+H] +。
Embodiment 15N-(4-piperidyl butyl) farnesyl thiosalicylic acid acid amides (I 14) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, the 1，2-diaminoethane in 4-piperidyl butylamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction make faint yellow oily matter N-(4-piperidyl butyl) farnesyl thiosalicylic acid acid amides (I 14), yield 69.1%.
1H NMR(CDCl 3,300MHz):8.01(m,2H,Ar-H),7.30(m,2H,Ar-H),5.38(m,1H,SCH 2C H),5.12(m,2H,2×CH 2C H=CCH 3),3.49-3.33(m,4H,SCH 2,NCH 2),3.52-2.39(m,6H,3×CH 2N),1.90-2.04(m,8H,2×CHC H 2C H 2CH),1.46-1.75(m,22H,4×CH 3,5×CH 2);ESI-MS(m/z):497[M+H] +;
Embodiment 16N-(4-pyrryl butyl) farnesyl thiosalicylic acid acid amides (I 15) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, the 1，2-diaminoethane in 4-pyrryl butylamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction make faint yellow oily matter N-(4-pyrryl butyl) farnesyl thiosalicylic acid acid amides (I 15), yield 70.7%.
1H NMR(CDCl 3,300MHz):
Figure BDA00001781840500151
8.03(m,2H,Ar-H),7.36(m,2H,Ar-H),5.32(m,1H,SCH 2C H),5.11(m,2H,2×CH 2C H=CCH 3),3.46-3.31(m,4H,SCH 2,NCH 2),2.56-2.41(m,6H,3×CH 2N),1.91-2.03(m,8H,2×CHC H 2C H 2CH),1.52-1.74(m,20H,4×CH 3,4×CH 2);ESI-MS(m/z):483[M+H] +。
Embodiment 17N-(morpholinyl propyl group) farnesyl thiosalicylic acid acid amides (I 16) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, the 1，2-diaminoethane in morpholinyl propylamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction make yellow oil N-(morpholinyl propyl group) farnesyl thiosalicylic acid acid amides (I 16), yield 69.8%.
1H NMR(CDCl 3,300MHz):
Figure BDA00001781840500152
7.96(m,1H,Ar-H),7.52(m,1H,Ar-H),7.31(m,2H,Ar-H),5.30(m,1H,SCH 2C H),5.02(m,2H,2×CH 2C H=CCH 3),3.78(m,4H,CH 2OCH 2),3.50-3.26(m,4H,SCH 2,CONCH 2),2.49-2.33(m,6H,3×CH 2N),1.92-2.01(m,8H,2×CHC H 2C H 2CH),1.52-1.77(m,14H,4×CH 3,CH 2C H 2CH 2);ESI-MS (m/z):485[M+H] +。
Embodiment 18N-(3-(N, N-dihydroxy ethyl)-aminopropyl) farnesyl thiosalicylic acid acid amides (I 17) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, by 3-(N, the N-dihydroxy ethyl) 1，2-diaminoethane in-amino propylamine alternative method and farnesyl thiosalicylic acid acyl chloride reaction make faint yellow oily matter N-(3-(N, N-dihydroxy ethyl)-aminopropyl) farnesyl thiosalicylic acid acid amides (I 17), yield 73.4%.
1H NMR(CDCl 3,300MHz):7.91(m,1H,Ar-H),7.50(m,1H,Ar-H),7.35(m,2H,Ar-H),5.41(m，1H，SCH 2C H)，5.12(m，2H，2×CH 2C H=CCH 3)，3.66(m，2H，2×OH)，3.51-3.30(m，8H，SCH 2，CONCH 2,2×C H 2OH),2.69-2.53(m,6H,3×NCH 2),1.92-2.01(m,8H,2×CHC H 2C H 2CH),1.52-1.77(m,14H,4×CH 3,CH 2C H 2CH 2);ESI-MS(m/z):503[M+H] +。
Embodiment 19N-(2-(N-hydroxyethyl)-amino-ethyl) farnesyl thiosalicylic acid acid amides (I 18) preparation
With reference to embodiment 2N-(2-aminoethyl) farnesyl thiosalicylic acid acid amides (I 1) the preparation method, 1，2-diaminoethane in 2-(N-hydroxyethyl)-aminoethyl alternative method and farnesyl thiosalicylic acid acyl chloride reaction make faint yellow oily matter N-(2-(N-hydroxyethyl)-amino-ethyl) farnesyl thiosalicylic acid acid amides (I 18), yield 73.4%.
1H NMR(CDCl 3,300MHz):δ7.37(m,3H,Ar-H),7.26(m,1H,Ar-H),5.23(m,1H,SCH 2C H),5.08(m,2H,2×CH 2C H=CCH 3),3.56(d,2H,J＝9.0Hz,SCH 2),3.10-3.31(m,4H,CONCH 2,C H 2OH),2.51(m,4H,CH 2NCH 2),1.99(m,8H,2×CHC H 2C H 2CH),1.60-1.79(m,12H,4×CH=CC H 3);ESI-MS(m/z):445[M+H] +。
Embodiment 20N-(2-(1-benzyl piepridine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 1) preparation
(1) preparation of 2-(1-benzyl piepridine-4-yl) ethanol (4a)
0.13g (1.00mmol) 4-hydroxyethyl piperidine and 0.17g (1.00mmol) bromobenzyl are dissolved in to 20mLCH 2cl 2, add wherein 0.21g (1.51mmol) K 2cO 3at room temperature stir 10h, steaming desolventizes, and 30mL acetic acid ethyl dissolution residual solid, wash with 50mL, use again ethyl acetate (50mL * 2) aqueous layer extracted, merge organic phase, drying, filter, become a cadre and obtain 0.18g oily matter 2-(1-benzyl piepridine-4-yl) ethanol (4a), yield 82.2%;
(2) preparation of 2-(1-benzyl piepridine-4-yl) ethyl methane sulfonate (5a)
0.22g (1.00mmol) compound 4a is dissolved in to the anhydrous CH of 10mL 2cl 2, slowly drip wherein the anhydrous CH of 5mL of 0.14g (1.22mmol) MsCl under ice bath 2cl 2solution, dropwise rear stirring at room 1.5h, steaming desolventizes, and 30mL acetic acid ethyl dissolution residual solid, wash with 50mL, use again ethyl acetate (50mL * 2) aqueous layer extracted, merge organic phase, drying, filter, become a cadre and obtain 0.23g oily matter 2-(1-benzyl piepridine-4-yl) ethyl methane sulfonate (5a), yield 77.4%;
(3) preparation of 2-(1-benzyl piepridine-4-yl) ethamine (6a)
0.2g (0.67mmol) compound 5a is added in 10mL ammoniacal liquor, stirring at room 24h, reaction solution directly concentrated becoming a cadre obtains 0.15g oily matter 2-(1-benzyl piepridine-4-yl) ethamine (6a), yield 75.3%;
(4) N-(2-(1-benzyl piepridine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 1) preparation
0.22g (1.0mmol) compound 6a and 0.15g (1.5mmol) triethylamine are dissolved in to the anhydrous CH of 15mL 2cl 2, slowly drip wherein the anhydrous CH of 5mL of 0.38g (1.01mmol) farnesyl thiosalicylic acid acyl chlorides under ice bath 2cl 2solution, then stirring at room 1.5h, steaming desolventizes and remains triethylamine, and 50mL acetic acid ethyl dissolution residual solid, wash with 50mL, use again ethyl acetate (50mL * 2) aqueous layer extracted, merge organic phase, drying, filter, become a cadre, column chromatography obtains 0.38g oily matter N-(2-(1-benzyl piepridine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 1), yield 68.1%.
1H NMR(CDCl 3,300MHz):8.00(m,1H,Ar-H),7.78(m,1H,Ar-H),7.38(m,2H,Ar-H),7.27(m,2H,Ar-H),6.94(m,2H,Ar-H),6.78(m,1H,Ar-H),5.24(m,1H,SCH 2C H),5.02(m,2H,2×CH 2C H=CCH 3),3.68(s,2H,NCH 2),3.56(d,2H,J＝9.0Hz,SCH 2),3.32-3.45(m,2H,NCH 2),3.01-2.99(m,4H,CH 2NCH 2),1.99-2.01(m,8H,2×CHC H 2C H 2CH),1.53-1.68(m,19H,4×CH=CC H 3,CH,3×NCH 2C H 2);ESI-MS(m/z):559[M+H] +。
Embodiment 21N-(2-(1-benzyl piepridine-4-yl) methyl) farnesyl thiosalicylic acid acid amides (II 2) preparation
(1) preparation of 2-(1-benzyl piepridine-4-yl) methyl alcohol (4b)
With reference to the preparation method of embodiment 20 steps (1) compound 4a, the 4-hydroxyethyl piperidine in 4-hydroxymethyl piperidine alternative method and bromobenzyl reaction make oily matter 2-(1-benzyl piepridine-4-yl) methyl alcohol (4b), yield 70.2%;
(2) preparation of 2-(1-benzyl piepridine-4-yl) methyl mesylate (5b)
With reference to the preparation method of embodiment 20 steps (2) compound 5a, the compound 4a in compound 4b alternative method and MsCl reaction make oily matter 2-(1-benzyl piepridine-4-yl) methyl mesylate (5b), yield 67.6%;
(3) preparation of 2-(1-benzyl piepridine-4-yl) methylamine (6b)
With reference to the preparation method of embodiment 20 steps (3) compound 6a, the compound 5a in compound 5b alternative method makes oily matter 2-(1-benzyl piepridine-4-yl) methylamine (6b), yield 81.2% under the ammoniacal liquor effect;
(4) N-(2-(1-benzyl piepridine-4-yl) methyl) farnesyl thiosalicylic acid acid amides (II 2) preparation
With reference to embodiment 20 steps (4) compound ii 1the preparation method, the compound 6a in compound 6b alternative method and farnesyl thiosalicylic acid acyl chloride reaction make oily matter N-(2-(1-benzyl piepridine-4-yl) methyl) farnesyl thiosalicylic acid acid amides (II 2), yield 71.3%.
1H NMR(CDCl 3,300MHz):8.01(m,1H,Ar-H),7.72(m,1H,Ar-H),7.38(m,2H,Ar-H),7.26(m，2H，Ar-H)，6.97(m，2H，Ar-H)，6.72(m，1H，Ar-H)，5.22(m，1H，SCH 2C H)，5.02(m，2H，2×CH 2C H=CCH 3),3.68(s,2H,NCH 2),3.57(d,2H,J＝9.0Hz,SCH 2),3.32(m,2H,NCH 2),3.02-2.99(m,4H,CH 2NCH 2),1.99-2.01(m,8H,2×CHC H 2C H 2CH),1.53-1.68(m,17H,4×CH=CC H 3,CH,2×NCH 2C H 2);ESI-MS(m/z):545[M+H] +。
Embodiment 22N-(2-(1-ethyl piperidine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 3) preparation
(1) preparation of 2-(1-ethyl piperidine-4-yl) ethanol (4c)
Preparation method with reference to embodiment 20 steps (1) compound 4a, 4-hydroxyethyl piperidine in 4-hydroxyethyl piperidine alternative method, bromobenzyl reaction in the bromic ether alternative method makes oily matter 2-(1-ethyl piperidine-4-yl) ethanol (4c), yield 71.2%;
(2) preparation of 2-(1-ethyl piperidine-4-yl) ethyl methane sulfonate (5c)
With reference to the preparation method of embodiment 20 steps (2) compound 5a, the compound 4a in compound 4c alternative method and MsCl reaction make oily matter 2-(1-ethyl piperidine-4-yl) ethyl methane sulfonate (5c), yield 72.1%;
(3) preparation of 2-(1-ethyl piperidine-4-yl) ethamine (6c)
With reference to the preparation method of embodiment 20 steps (3) compound 6a, the compound 5a in compound 5c alternative method makes oily matter 2-(1-ethyl piperidine-4-yl) ethamine (6c), yield 87.1% under the ammoniacal liquor effect;
(4) N-(2-(1-ethyl piperidine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 3)
With reference to embodiment 20 steps (4) compound ii 1the preparation method, the compound 6a in compound 6c alternative method and farnesyl thiosalicylic acid acyl chloride reaction make oily matter N-(2-(1-ethyl piperidine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 3), yield 73.4%;
1H NMR(CDCl 3,300MHz):8.00(m,1H,Ar-H),7.68(m,1H,Ar-H),7.40(m,2H,Ar-H),5.32(m,1H,SCH 2C H),5.11(m,2H,2×CH 2C H=CCH 3),3.59(d,2H,J＝9.0Hz,SCH 2),3.42(m,2H,NCH 2),3.00-2.69(m,4H,3×NCH 2),1.99-2.01(m,8H,2×CHC H 2C H 2CH),1.50-1.68(m,19H,4×CH=CC H 3，CH，3×NCH 2C H 2)，1.01(m，3H，CH 3);ESI-MS(m/z):497[M+H] +。
Embodiment 23N-(2-(1-benzyl diethylenediamine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 4)
(1) preparation of 2-(1-benzyl diethylenediamine-4-yl) ethanol (4d)
With reference to the preparation method of embodiment 20 steps (1) compound 4a, the 4-hydroxyethyl piperidine in the hydroxyethyl piperazine alternative method and bromobenzyl reaction make oily matter 2-(1-benzyl diethylenediamine-4-yl) ethanol (4d, yield 65.3%;
(2) preparation of 2-(1-benzyl diethylenediamine-4-yl) ethyl methane sulfonate (5d)
With reference to the preparation method of embodiment 20 steps (2) compound 5a, the 4a in compound 4d alternative method and MsCl reaction make oily matter 2-(1-benzyl diethylenediamine-4-yl) ethyl methane sulfonate (5d), yield 82.1%;
(3) preparation of 2-(1-benzyl diethylenediamine-4-yl) ethamine (6d)
With reference to the preparation method of embodiment 20 steps (3) compound 6a, the 5a in compound 5d alternative method makes oily matter 2-(1-benzyl diethylenediamine-4-yl) ethamine (6d), yield 82.7% under the ammoniacal liquor effect;
(4) N-(2-(1-benzyl diethylenediamine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 4) preparation
With reference to embodiment 20 steps (4) compound ii 1the preparation method, the 6a in compound 6d alternative method and farnesyl thiosalicylic acid acyl chloride reaction make oily matter N-(2-(1-benzyl diethylenediamine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 4), yield 68.4%.
1H NMR(CDCl 3,300MHz):8.01(m,1H,Ar-H),7.72(m,1H,Ar-H),7.39(m,2H,Ar-H),7.26(m，2H，Ar-H)，6.97(m，2H，Ar-H)，6.72(m，1H，Ar-H)，5.31(m，1H，SCH 2C H)，5.01(m，2H，2×CH 2C H=CCH 3),3.67(s,2H,NCH 2),3.57(d,2H,J＝9.0Hz,SCH 2),3.32(m,2H,NCH 2),2.67-2.39(m,10H,5×NCH 2),1.98-2.03(m,8H,2×CHC H 2C H 2CH),1.53-1.69(m,12H,4×CH 3)；ESI-MS(m/z):560[M+H] +。
Embodiment 24N-(2-(1-ethyl piperazidine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 5)
(1) preparation of 2-(1-ethyl piperazidine-4-yl) ethanol (4e)
With reference to the preparation method of embodiment 20 steps (1) 4a, the 4-hydroxyethyl piperidine in the hydroxyethyl piperazine alternative method, the bromobenzyl reaction in the bromic ether alternative method makes oily matter 2-(1-ethyl piperazidine-4-yl) ethanol (4e), yield 65.3%;
(2) preparation of 2-(1-ethyl piperazidine-4-yl) ethyl methane sulfonate (5e)
With reference to the preparation method of embodiment 20 steps (2) 5a, the 4a in compound 4e alternative method and MsCl reaction make oily matter 2-(1-ethyl piperazidine-4-yl) ethyl methane sulfonate (5e), yield 82.1%;
(3) preparation of 2-(1-ethyl piperazidine-4-yl) ethamine (6e)
With reference to the preparation method of embodiment 20 steps (3) 6a, the 5a in compound 5e alternative method makes oily matter 2-(1-ethyl piperazidine-4-yl) ethamine (6e), yield 82.7% under the ammoniacal liquor effect;
(4) N-(2-(1-ethyl piperazidine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 5) preparation
With reference to embodiment 20 steps (4) compound ii 1the preparation method, the 6a in compound 6e alternative method and farnesyl thiosalicylic acid acyl chloride reaction make oily matter N-(2-(1-ethyl piperazidine-4-yl) ethyl) farnesyl thiosalicylic acid acid amides (II 5), yield 79.3%.
1H NMR(CDCl 3,300MHz):8.00(m,1H,Ar-H),7.76(m,1H,Ar-H),7.40(m,2H,Ar-H),7.26(m，2H，Ar-H)，6.96(m，2H，Ar-H)，6.70(m，1H，Ar-H)，5.28(m，1H，SCH 2C H)，5.10(m，2H，2×CH 2C H=CCH 3),3.58(d,2H,J＝9.0Hz,SCH 2),3.45(m,2H,NCH 2),2.67-2.39(m,12H,6×NCH 2),1.99-2.00(m,8H,2×CHC H 2C H 2CH),1.53-1.68(m,12H,4×CH=CC H 3),1.03(m,3H,CH 3);ESI-MS(m/z):498[M+H] +。
Embodiment 25N-(2-(Aspirin amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 1) preparation
(1) preparation of N-(2-amino-ethyl)-Aspirin acid amides (9a)
1.5g (25.00mmol) 1，2-diaminoethane and 0.76g (7.52mmol) triethylamine are dissolved in to the anhydrous CH of 30mL 2cl 2, slowly drip wherein the anhydrous CH of 20mL of 1g (5.05mmol) acetylsalicylic acid acyl chlorides under 0-5 ℃ 2cl 2solution, drip complete stirring at room 1.5h, and steaming desolventizes, triethylamine and excessive 1，2-diaminoethane, and column chromatography obtains 0.90g yellow oil N-(2-amino-ethyl)-Aspirin acid amides (9a), yield 81.1%;
(2) N-(2-(Aspirin amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 1) preparation
0.12g (0.54mmol) compound 9a and 0.071g (0.70mmol) triethylamine are dissolved in the 5mL dry DMF, drip the anhydrous CH of 10mL of 0.18g (0.48mmol) farnesyl thiosalicylic acid acyl chlorides under ice bath 2cl 2solution, drip complete stirring at room 2h, steams and desolventize and remain triethylamine, and column chromatography obtains 0.19g yellow oil N-(2-(Aspirin amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 1), yield 70.4%.
1H NMR(CDCl 3,300MHz):8.01(s,1H,Ar-H),7.75(d,1H,J＝6.0Hz,Ar-H),7.39(m,4H,Ar-H)，7.27(m，2H，Ar-H)，6.86(m，1H，NH)，5.76(m，1H，NH)，5.21(m，1H，SCH 2C H)，5.13(m，2H,2×CH 2C H=CCH 3),3.71(m,2H,2×NCH 2),3.51(d,2H,J＝9.0Hz,SCH 2),2.62(s,3H,COCH 3),1.95-2.05(m,8H,2×CHC H 2C H 2CH),1.51-1.77(m,12H,4×CH=CC H 3)；ESI-MS (m/z):547[M+H] +。
Embodiment 26N-(3-(Aspirin amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 2) preparation
(1) preparation of N-(3-aminopropyl)-Aspirin acid amides (9b)
Preparation method with reference to embodiment 25 steps (1) compound 9a, by 1,1，2-diaminoethane in 3-propylene diamine alternative method and acetylsalicylic acid acyl chloride reaction make faint yellow oily matter N-(3-aminopropyl)-Aspirin acid amides (9b), yield 77.2%;
(2) N-(3-(Aspirin amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 2) preparation
With reference to embodiment 25 steps (2) compound III 1the preparation method, the 9a in compound 9b alternative method and farnesyl thiosalicylic acid acyl chloride reaction make yellow transparent oily matter N-(3-(Aspirin amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 2), yield 67.4%.
1H NMR(CDCl 3,300MHz):8.01(s,1H,Ar-H),7.66(d,1H,J＝6.0Hz,Ar-H),7.31(m,4H,Ar-H)，7.22(m，2H，Ar-H)，6.96(m，1H，NH)，5.86(m，1H，NH)，5.22(m，1H，SCH 2C H)，5.01(m，2H,2×CH 2C H=CCH 3),3.54(d,2H,J＝9.0Hz,SCH 2),3.40-3.30(m,2H,2×NCH 2),2.78(s,3H,COCH 3),1.93-2.03(m,10H,2×CHC H 2C H 2CH,CH 2C H 2CH 2),1.51-1.77(m,12H,4×CH=CC H 3);ESI-MS(m/z):561[M+H] +。
Embodiment 27N-(4-(Aspirin amide group) butyl) farnesyl thiosalicylic acid acid amides (III 3) preparation
(1) preparation of N-(4-aminobutyl)-Aspirin acid amides (9c)
Preparation method with reference to embodiment 25 steps (1) compound 9a, by 1,1，2-diaminoethane in 4-butanediamine alternative method and acetylsalicylic acid acyl chloride reaction make faint yellow oily matter N-(4-aminobutyl)-Aspirin acid amides (9c), yield 79.0%;
(2) N-(4-(Aspirin amide group) butyl) farnesyl thiosalicylic acid acid amides (III 3) preparation
With reference to embodiment 25 steps (1) compound III 1the preparation method, the 9a in compound 9c alternative method and farnesyl thiosalicylic acid acyl chloride reaction make yellow transparent oily matter N-(4-(Aspirin amide group) butyl) farnesyl thiosalicylic acid acid amides (III 3), yield 73.2%.
1H NMR(CDCl 3,300MHz):8.06(s,1H,Ar-H),7.71(d,1H,J＝6.0Hz,Ar-H),7.42(m,2H,Ar-H),7.30(m,2H,Ar-H),7.22(m,2H,Ar-H),6.82(m,1H,NH),5.61(m,1H,NH),5.22(m,1H,SCH 2C H)，5.03(m，2H，2×CH 2C H=CCH 3)，3.50(d，2H，J＝9.0 Hz，SCH 2)，3.35(m，2H，2×NCH 2)，2.82(s,3H,COCH 3),1.92-2.01(m,10H,2×CHC H 2C H 2CH),1.51-1.77(m,16H,4×CH=CC H 3,2×CH 2);ESI-MS(m/z):575[M+H] +。
Embodiment 28N-(5-(Aspirin amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 4) preparation
(1) preparation of N-(the amino amyl group of 5-)-Aspirin acid amides (9d)
Preparation method with reference to embodiment 25 steps (1) compound 9a, by 1,1，2-diaminoethane in 5-pentamethylene diamine alternative method and acetylsalicylic acid acyl chloride reaction make faint yellow oily matter N-(the amino amyl group of 5-)-Aspirin acid amides (9d), yield 75.7%;
(2) N-(5-(Aspirin amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 4) preparation
With reference to embodiment 25 steps (2) compound III 1the preparation method, the 9a in compound 9d alternative method and farnesyl thiosalicylic acid acyl chloride reaction make yellow transparent oily matter N-(5-(Aspirin amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 4), yield 68.3%.
1H NMR(CDCl 3,300MHz):8.02(s,1H,Ar-H),7.62(d,1H,J＝6.0Hz,Ar-H),7.43(m,2H,Ar-H),7.32(m,2H,Ar-H),7.21(m,2H,Ar-H),6.82(m,1H,NH),5.69(m,1H,NH),5.20(m,1H,SCH 2C H)，5.04(m，2H，2×CH 2C H=CCH 3)，3.53(d，2H，J＝9.0 Hz，SCH 2)，3.42(m，2H，2×NCH 2)，2.75(s,3H,COCH 3),1.87-2.02(m,8H,2×CHC H 2C H 2CH),1.52-1.74(m,16H,4×CH=CC H 3,2×CH 2),1.40(m,2H,CH 2);ESI-MS(m/z):589[M+H] +。
Embodiment 29N-(6-(Aspirin amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 5) preparation
(1) preparation of N-(the amino hexyl of 6-)-Aspirin acid amides (9e)
Preparation method with reference to embodiment 25 steps (1) compound 9a, by 1,1，2-diaminoethane in 6-hexanediamine alternative method and acetylsalicylic acid acyl chloride reaction make yellow oil N-(the amino hexyl of 6-)-Aspirin acid amides (9e), yield 83.4%;
(2) N-(6-(Aspirin amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 5) preparation
With reference to embodiment 25 steps (2) compound III 1the preparation method, the 9a in compound 9d alternative method and farnesyl thiosalicylic acid acyl chloride reaction make yellow transparent oily matter N-(6-(Aspirin amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 5), yield 68.3%.
1H NMR(CDCl 3,300MHz):8.02(s,1H,Ar-H),7.65(d,1H,J＝6.0Hz,Ar-H),7.39(m,2H,Ar-H),7.33(m,2H,Ar-H),7.26(m,2H,Ar-H),6.86(m,1H,NH),5.76(m,1H,NH),5.26(m,1H,SCH 2C H)，5.10(m，2H，2×CH 2C H=CCH 3)，3.52(d，2H，J＝9.0 Hz，SCH 2)，3.48(m，2H，NCH 2)，3.25(m,2H,NCH 2),2.88(s,3H,COCH 3),1.97-2.03(m,8H,2×CHC H 2C H 2CH),1.50-1.75(m,16H,4×CH=CC H 3,2×NCH 2C H 2),1.41(m,4H,CH 2CH 2);ESI-MS (m/z):603[M+H] +。
Embodiment 30N-(2-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) ethyl) farnesyl thiosalicylic acid acid amides (III 6) preparation
(1) preparation of N-(2-amino-ethyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides (9k)
Preparation method with reference to embodiment 25 steps (1) compound 9a, acetylsalicylic acid acyl chlorides and 1 in 3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid acyl chlorides alternative method, 2-quadrol and reaction make glassy yellow solid N-(2-amino-ethyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides (9k), yield 83.6%;
(2) N-(2-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) ethyl) farnesyl thiosalicylic acid acid amides (III 6) preparation
With reference to the preparation method of embodiment 25 steps (2) compound III 1, the 9a in compound 9k alternative method and farnesyl thiosalicylic acid acyl chlorides make yellow oil N-(2-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) ethyl) farnesyl thiosalicylic acid acid amides (III 6), yield 70.2%.
1H NMR(CDCl 3,300MHz):8.00(s,1H,Ar-H),7.58-7.67(m,2H,Ar-H),7.55(d,1H,NH),7.33(m，2H，Ar-H)，7.01(m，2H，Ar-H)，6.86-6.83(m，1H，J＝9Hz，COCH=C H)，6.25-6.20(d，1H，J＝15Hz,COC H=CH),5.80(m,1H,NH),5.27(m,1H,SCH 2C H),5.01(m,2H,2×CH 2C H=CCH 3),3.85(s,3H,OCH 3),3.42-3.56(m,6H,SCH 2,2×NCH 2),2.88(s,3H,COCH 3),1.97-2.02(m,8H,2×CHC H 2C H 2CH)，1.50-1.71(m，12H，4×CH=CC H 3);ESI-MS(m/z):619[M+H] +。
Embodiment 31N-(3-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) propyl group) farnesyl thiosalicylic acid acid amides (III 7) preparation
(1) preparation of N-(3-aminopropyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides (9l)
Preparation method with reference to embodiment 25 steps (1) compound 9a, by 1, in 3-propylene diamine and 3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid acyl chlorides alternative method 1,2-quadrol and acetylsalicylic acid acyl chloride reaction make glassy yellow solid N-(3-aminopropyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides (9l), yield 86.1%;
(2) N-(3-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) propyl group) farnesyl thiosalicylic acid acid amides (III 7) preparation
With reference to embodiment 25 steps (2) compound III 1the preparation method, the 9a in compound 9l alternative method and farnesyl thiosalicylic acid acyl chloride reaction make yellow oil N-(3-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) propyl group) farnesyl thiosalicylic acid acid amides (III 7), yield 64.8%.
1H NMR(CDCl 3,300MHz):8.02(s,1H,Ar-H),7.51-7.67(m,2H,Ar-H,NH),7.32(m,2H,Ar-H),7.11(m,2H,Ar-H),6.96-6.93(m,1H,J＝9Hz,COCH=C H),6.26-6.21(d,1H,J＝15Hz,COC H=CH),5.86(m,1H,NH),5.23(m,1H,SCH 2C H),5.02(m,2H,2×CH 2C H=CCH 3),3.83(s,3H,OCH 3),3.45-3.52(m,6H,SCH 2,2×NCH 2),2.82(s,3H,COCH 3),1.90-2.02(m,10H,2×CHC H 2C H 2CH,CH 2),1.50-1.71(m,12H,4×CH=CC H 3);ESI-MS(m/z):633[M+H] +。
Embodiment 32N-(4-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) butyl) farnesyl thiosalicylic acid acid amides (III 8) preparation
(1) preparation of N-(4-aminobutyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides (9m)
Preparation method with reference to embodiment 25 steps (1) compound 9a, by 1, in 4-butanediamine and 3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid acyl chlorides alternative method 1,2-quadrol and acetylsalicylic acid acyl chloride reaction make yellow oil N-(4-aminobutyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides (9m), yield 77.3%;
(2) N-(4-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) butyl) farnesyl thiosalicylic acid acid amides (III 8) preparation
With reference to embodiment 25 steps (2) compound III 1the preparation method, the 9a in compound 9m alternative method and farnesyl thiosalicylic acid acyl chloride reaction make glassy yellow oily matter N-(4-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) butyl) farnesyl thiosalicylic acid acid amides (III 8), yield 70.2%.
1H NMR(CDCl 3,300MHz):8.01(s,1H,Ar-H),7.48-7.63(m,2H,Ar-H,NH),7.30(m,2H,Ar-H)，7.12(m，2H，Ar-H)，6.96-6.93(m，1H，J＝9Hz，COCH=C H)，6.23-6.18(d，1H，J＝15Hz，COC H=CH),5.83(m,1H,NH),5.22(m,1H,SCH 2C H),5.05(m,2H,2×CH 2C H=CCH 3),3.82(s,3H,OCH 3),3.50-3.41(m,6H,SCH 2,2×NCH 2),2.80(s,3H,COCH 3),1.90-2.02(m,8H,2×CHC H 2C H 2CH),1.50-1.75(m,16H,4×CH=CCH3,CH 2C H 2C H 2CH 2);ESI-MS(m/z):647[M+H] +。
Embodiment 33N-(5-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) amyl group) farnesyl thiosalicylic acid acid amides (III 9) preparation
(1) preparation of N-(the amino amyl group of 5-)-3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides (9n)
Preparation method with reference to embodiment 25 steps (1) compound 9a, by 1, in 5-pentamethylene diamine and 3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid acyl chlorides alternative method 1,2-quadrol and acetylsalicylic acid acyl chloride reaction make yellow oil N-(the amino amyl group of 5-)-3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides (9n), yield 80.3%;
(2) N-(5-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) amyl group) farnesyl thiosalicylic acid acid amides (III 9) preparation
With reference to embodiment 25 steps (2) compound III 1the preparation method, the 9a in compound 9n alternative method and farnesyl thiosalicylic acid acyl chloride reaction make faint yellow oily matter N-(5-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) amyl group) farnesyl thiosalicylic acid acid amides (III 9), yield 65.6%.
1H NMR(CDCl 3,300MHz):8.02(s,1H,Ar-H),7.53-7.70(m,2H,Ar-H,NH),7.35(m,2H,Ar-H)，7.11(m，2H，Ar-H)，6.94-6.91(m，1H，J＝9Hz，COCH=C H)，6.25-6.20(d，1H，J＝15Hz，COC H=CH),5.80(m,1H,NH),5.31(m,1H,SCH 2C H),5.11(m,2H,2×CH 2C H=CCH 3),3.73(s,3H,OCH 3),3.52-3.40(m,6H,SCH 2,2×NCH 2),2.83(s,3H,COCH 3),1.94-2.00(m,8H,2×CHC H 2C H 2CH),1.50-1.75(m,16H,4×CH=CC H 3,2×CH 2),1.41(m,2H,CH 2);ESI-MS(m/z):647[M+H] +。
Embodiment 33N-(6-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) hexyl) farnesyl thiosalicylic acid acid amides (III 10) preparation
(1) preparation of N-(the amino hexyl of 6-)-3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides (9o)
Preparation method with reference to embodiment 25 steps (1) compound 9a, by 1, in 6-hexanediamine and 3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid acyl chlorides alternative method 1,2-quadrol and acetylsalicylic acid acyl chloride reaction make yellow oil N-(the amino hexyl of 6-)-3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides (9o), yield 80.3%;
(2) N-(6-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) hexyl) farnesyl thiosalicylic acid acid amides (III 10) preparation
With reference to embodiment 25 steps (2) compound III 1the preparation method, the 9a in compound 9o alternative method and farnesyl thiosalicylic acid acyl chloride reaction make faint yellow oily matter N-(6-(3-(3-methoxyl group-4-acetoxyl group phenyl) acrylic acid amides base) hexyl) farnesyl thiosalicylic acid acid amides (III 10), yield 63.8%.
1H NMR(CDCl 3,300MHz):8.01(s,1H,Ar-H),7.59-7.68(m,2H,Ar-H),7.55(m,1H,NH),7.39(m，2H，Ar-H)，7.02(m，2H，Ar-H)，6.87-6.84(d，1H，J＝9Hz，COCH=C H)，6.26-6.21(d，1H，J＝15Hz,COC H=CH),5.87(m,1H,NH),5.26(m,1H,SCH 2C H),5.08(m,2H,2×CH 2C H=CCH 3),3.90(s,3H,OCH 3),3.46-3.61(m,6H,SCH 2,2×NCH 2),2.88(s,3H,COCH 3),1.97-2.02(m,8H,2×CHC H 2C H 2CH),1.50-1.71(m,16H,4×CH=CC H 3,2×NCH 2C H 2),1.43(m,4H,CH 2CH 2);ESI-MS(m/z):675[M+H] +。
Embodiment 35N-(2-(3,4,5-trimethoxybenzoic acid amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 11) preparation
(1) N-(2-amino-ethyl)-3,4, the preparation of 5-trimethoxybenzoic acid acid amides (9f)
Preparation method with reference to embodiment 25 steps (1) compound 9a, by 3,4, acetylsalicylic acid acyl chlorides and 1 in 5-trimethoxybenzoic acid acyl chlorides alternative method, the 2-reacting ethylenediamine makes white solid N-(2-amino-ethyl)-3,4,5-trimethoxybenzoic acid acid amides (9f), yield 76.6%;
(2) N-(2-(3,4,5-trimethoxybenzoic acid amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 11) preparation with reference to embodiment 25 steps (2) compound III 1the preparation method, the 9a in compound 9f alternative method and farnesyl thiosalicylic acid acyl chloride reaction make yellow oil N-(2-(3,4,5-trimethoxybenzoic acid amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 11), yield 70.4%.
1H NMR(CDCl 3,300MHz):δ7.81(m,1H,Ar-H),7.46(m,1H,Ar-H),7.32(m,1H,Ar-H),7.23(m,1H,Ar-H),7.12(m,2H,Ar-H),5.29-5.20(t,1H,J=15Hz,SCH 2C H),5.10(m,2H,2×CH 2C H=CCH 3),3.83(m,9H,3×OC H 3),3.71-3.45(m,6H,SC H 2,2×NC H 2),2.01-1.98(m,8H,2×CHC H 2C H 2CH),1.70-1.63(m,12H,4×CH=CC H 3),;ESI-MS(m/z):595[M+H] +。
Embodiment 35N-(3-(3,4,5-trimethoxybenzoic acid amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 12) preparation
(1) N-(3-aminopropyl)-3,4, the preparation of 5-trimethoxybenzoic acid acid amides (9g)
Preparation method with reference to embodiment 25 steps (1) compound 9a, by 1,3-propylene diamine and 3,4,1，2-diaminoethane in 5-trimethoxybenzoic acid acyl chlorides alternative method and acetylsalicylic acid acyl chloride reaction make white solid N-(3-aminopropyl)-3,4,5-trimethoxybenzoic acid acid amides (9g), yield 79.2%;
(2) N-(3-(3,4,5-trimethoxybenzoic acid amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 12) preparation
With reference to embodiment 25 steps (2) compound III 1the preparation method, the 9a in compound 9g alternative method and farnesyl thiosalicylic acid acyl chloride reaction make transparent oily matter N-(3-(3,4,5-trimethoxybenzoic acid amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 12), yield 67.2%.
1H NMR(CDCl 3,300MHz):δ7.81(m,1H,Ar-H),7.57(m,1H,Ar-H),7.31(m,1H,Ar-H),7,22(m，1H，Ar-H)，7.15(m，2H，Ar-H)，5.30-5.20(t，1H，J=15Hz，SCH 2C H)，5.07(m，2H，2×CH 2C H=CCH 3)，3.88(m，9H，3×OC H 3)，3.74-3.40(m，6H，SC H 2，2×NC H 2)，2.01-1.98(m，8H，2×CHC H 2C H 2CH)，1.70-1.57(m，14H，4×CH=CC H 3，CH 2C H 2CH 2)，;ESI-MS(m/z):609[M+H] +。
Embodiment 37N-(4-(3,4,5-trimethoxybenzoic acid amide group) butyl) farnesyl thiosalicylic acid acid amides (III 13) preparation
(1) N-(4-aminobutyl)-3,4, the preparation of 5-trimethoxybenzoic acid acid amides (9h)
With reference to the preparation method of embodiment 25 steps (1) compound 9a, by 1，2-diaminoethane and acetylsalicylic acid acyl chloride reaction in Putriscine and 3,4,5-trimethoxybenzoic acid acyl chlorides alternative method, make white solid, yield 82.5%.
(2) N-(4-(3,4,5-trimethoxybenzoic acid amide group) butyl) farnesyl thiosalicylic acid acid amides (III 13) preparation with reference to embodiment 25 steps (2) compound III 1the preparation method, the 9a in compound 9h alternative method and farnesyl thiosalicylic acid acyl chloride reaction make transparent oily matter N-(4-(3,4,5-trimethoxybenzoic acid amide group) butyl) farnesyl thiosalicylic acid acid amides (III 13), yield 65.9%.
1H NMR(CDCl 3,300MHz):δ7.73(m,1H,Ar-H),7.52(m,1H,Ar-H),7.38(m,1H,Ar-H),7.21(m，1H，Ar-H)，7.10(m，2H，Ar-H)，5.23(t，1H，J＝15Hz，SCH 2C H)，5.02(m，2H，2×CH 2C H=CCH 3),3.81(m,9H,3×OC H 3),3.72-3.41(m,6H,SC H 2,2×NC H 2),2.00-1.96(m,8H,2×CHC H 2C H 2CH),1.72-1.54(m,16H,4×CH=CC H 3,CH2CH 2C H 2CH 2),;ESI-MS(m/z):623[M+H] +。
Embodiment 38N-(5-(3,4,5-trimethoxybenzoic acid amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 14) preparation
(1) N-(the amino amyl group of 5-)-3,4, the preparation of 5-trimethoxybenzoic acid acid amides (9i)
Preparation method with reference to embodiment 25 steps (1) compound 9a, by 1,5-pentamethylene diamine and 3,4,1，2-diaminoethane in 5-trimethoxybenzoic acid acyl chlorides alternative method and acetylsalicylic acid acyl chloride reaction make white solid N-(the amino amyl group of 5-)-3,4,5-trimethoxybenzoic acid acid amides (9i), yield 80.3%;
(2) N-(5-(3,4,5-trimethoxybenzoic acid amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 14) preparation with reference to embodiment 25 steps (2) compound III 1the preparation method, the 9a in compound 9i alternative method and farnesyl thiosalicylic acid acyl chloride reaction make transparent oily matter N-(5-(3,4,5-trimethoxybenzoic acid amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 14), yield 67.6%.
1H NMR(CDCl 3,300MHz):δ7.74(m,1H,Ar-H),7.55(m,1H,Ar-H),7.37(m,1H,Ar-H),7.20(m,1H,Ar-H),7.12(m,2H,Ar-H),5.32(t,1H,J＝15Hz,SCH 2C H),5.07(m,2H,2×CH 2C H=CCH 3),3.70(m,9H,3×OC H 3),3.72-3.41(m,6H,SC H 2,2×NC H 2),2.00-1.96(m,8H,2×CHC H 2C H 2CH),1.73-1.52(m,16H,4×CH=CC H 3,2×CH 2),1.32(m,2H,CH 2);ESI-MS(m/z):637[M+H] +。
Embodiment 39N-(6-(3,4,5-trimethoxybenzoic acid amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 15) preparation
(1) N-(the amino hexyl of 6-)-3,4, the preparation of 5-trimethoxybenzoic acid acid amides (9j)
With reference to the preparation method of embodiment 25 steps (1) compound 9a, by 1，2-diaminoethane and acetylsalicylic acid acyl chloride reaction in 1,6-hexanediamine and 3,4,5-trimethoxybenzoic acid acyl chlorides alternative method, make white solid, yield 84.6%;
(2) N-(6-(3,4,5-trimethoxybenzoic acid amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 15) preparation
With reference to embodiment 25 steps (2) compound III 1the preparation method, the 9a in compound 9j alternative method and farnesyl thiosalicylic acid acyl chloride reaction make transparent oily matter N-(6-(3,4,5-trimethoxybenzoic acid amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 15), yield 71.6%.
1H NMR(CDCl 3,300MHz):δ7.62(m,1H,Ar-H),7.36(m,1H,Ar-H),7.31(m,1H,Ar-H),7.28(m，1H，Ar-H)，7.11(m，2H，Ar-H)，5.28-5.23(t，1H，J＝15Hz，SCH 2C H)，5.11-5.06(m，2H，2×CH 2C H=CCH 3),3.87(m,9H,3×OC H 3),3.55-3.45(m,6H,SC H 2,2×NC H 2),2.02-1.99(m,8H,2×CHC H 2C H 2CH),1.70-1.63(m,12H,4×CH=CCH 3),1.54(m,8H,C H 2C H 2C H 2C H 2);ESI-MS(m/z):651[M+H] +。
Embodiment 40N-(2-(2 hydroxybenzoic acid amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 16) preparation
By 0.5g (0.89mmol) compound III 1be dissolved in 10mL methyl alcohol, the aqueous solution that adds wherein the NaOH of 1mL 1mol/L, 60 ℃ of lower stirring reaction 2h, steam except methyl alcohol 1N salt acid for adjusting pH to 6, ethyl acetate (50mL * 3) extraction, merge organic phase, drying, filter, concentrated 0.38g oily matter N-(2-(2 hydroxybenzoic acid amide group) ethyl) the farnesyl thiosalicylic acid acid amides (III that obtains 16), yield 82.1%.
1H NMR(CDCl 3,300MHz):8.19(m,1H,Ar-H),7.62(m,2H,Ar-H),7.25(m,3H,Ar-H),6.56(m，2H，Ar-H)，5.26(m，1H，SCH 2C H)，5.08(m，2H，2×CH 2C H=CCH 3)，3.55(m，6H，SCH 2，2×NCH 2),2.01(m,8H,2×CHC H 2C H 2CH),1.70(m,12H,4×CH 3);ESI-MS(m/z):521[M+H] +。
Embodiment 41N-(3-(2 hydroxybenzoic acid amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 17) preparation
With reference to embodiment 40 compound III 16the preparation method, by the compound III 2compound III 1 in alternative method is hydrolyzed and obtains oily matter N-(3-(2 hydroxybenzoic acid amide group) propyl group) farnesyl thiosalicylic acid acid amides (III under the effect of the NaOH of 1mol/L 17), yield 80.7%.
1H NMR(CDCl 3,300MHz):8.00(s,1H,Ar-H),7.62(d,1H,J＝6.0Hz,Ar-H),7.31(m,4H,Ar-H),7.20(m,2H,Ar-H),6.95(m,1H,NH),5.82(m,1H,NH),5.36(s,1H,OH)5.25(m,1H,SCH 2C H),5.02(m,2H,2×CH 2C H=CCH 3),3.51(d,2H,J＝9.0Hz,SCH 2),3.42-3.30(m,2H,2×NCH 2),1.97-2.02(m,10H,2×CHC H 2C H 2CH,CH 2C H 2CH 2),1.50-1.75(m,12H,4×CH 3);ESI-MS(m/z):535[M+H] +。
Embodiment 42N-(4-(2 hydroxybenzoic acid amide group) butyl) farnesyl thiosalicylic acid acid amides (III 18) preparation
With reference to the preparation method of embodiment 40 compound III 16, by the compound III 3compound III in alternative method 1under the NaOH of 1mol/L effect, hydrolysis obtains oily matter N-(4-(2 hydroxybenzoic acid amide group) butyl) farnesyl thiosalicylic acid acid amides (III 18), yield 78.3%.
1H NMR(CDCl 3,300MHz):δ7.68(m,2H,Ar-H),7.40(m,2H,Ar-H),7.34(m,2H,Ar-H),6.91(m，1H，Ar-H)，5.28-5.24(t，1H，J=15Hz，SCH 2C H)，5.11-5.06(t，2H，J＝15Hz，2×CH 2C H=CCH 3),3.49(m,6H,SC H 2,2×CONC H 2),2.02-1.98(m,8H,2×CHCH 2CH 2CH),1.71-1.68(m,12H,4×CH=CCH 3),1.60-154(m,4H,2×NCH 2C H 2);ESI-MS (m/z):549[M+H] +。
Embodiment 43N-(5-(2 hydroxybenzoic acid amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 19) preparation
With reference to embodiment 40 compound III 16the preparation method, by the compound III 4compound III in alternative method 1under the NaOH of 1mol/L effect, hydrolysis obtains oily matter N-(5-(2 hydroxybenzoic acid amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 19), yield 82.3%.
1H NMR(CDCl 3,300MHz):8.00(s,1H,Ar-H),7.61(d,1H,J＝6.0Hz,Ar-H),7.43(m,2H,Ar-H),7.30(m,2H,Ar-H),7.20(m,2H,Ar-H),6.81(m,1H,NH),5.69(m,1H,NH),5.38(m,1H,OH)，5.23(m，1H，SCH 2C H)，5.04(m，2H，2×CH 2C H=CCH 3)，3.53(d，2H，J＝9.0Hz，SCH 2)，3.40(m,2H,2×NCH 2),1.87-2.02(m,8H,2×CHC H 2C H 2CH),1.52-1.74(m,16H,4×CH=CC H 3,2×CH 2),1.39(m,2H,CH 2);ESI-MS(m/z):563[M+H] +。
Embodiment 44N-(6-(2 hydroxybenzoic acid amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 20) preparation
With reference to embodiment 40 compound III 16the preparation method, by the compound III 5compound III in alternative method 1under the NaOH of 1mol/L effect, hydrolysis obtains oily matter N-(6-(2 hydroxybenzoic acid amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 20), yield 77.2%.
1H NMR(CDCl 3,300MHz):8.05(s,1H,Ar-H),7.65(d,1H,J＝6.0Hz,Ar-H),7.36(m,2H,Ar-H),7.35(m,2H,Ar-H),7.26(m,2H,Ar-H),6.83(m,1H,NH),5.72(m,1H,NH),5.32(m,1H,OH)，5.21(m，1H，SCH 2C H)，5.11(m，2H，2×CH 2C H=CCH 3)，3.56(d，2H，J＝9.0 Hz，SCH 2)，3.48(m,2H,NCH 2),3.25(m,2H,NCH 2),1.97-2.01(m,8H,2×CHC H 2C H 2CH),1.52-1.76(m,16H,4×CH=CC H 3,2×NCH 2C H 2),1.36(m,4H,CH 2CH 2);ESI-MS (m/z):577[M+H] +。
Embodiment 45N-(2-(3-(3-methoxyl group-4-hydroxy phenyl) acrylic acid amides base) ethyl) farnesyl thiosalicylic acid acid amides (III 21) preparation
With reference to embodiment 40 compound III 16the preparation method, by the compound III 11compound III in alternative method 1under the effect of the NaOH of 1mol/L, hydrolysis obtains oily matter N-(2-(3-(3-methoxyl group-4-hydroxy phenyl) acrylic acid amides base) ethyl) farnesyl thiosalicylic acid acid amides (III 21), yield 83.6%.
1H NMR(CDCl 3,300MHz):δ7.64(m,2H,Ar-H),7.40(m,2H,Ar-H),7.06(m,2H,Ar-H),6.91(m，1H，Ar-H)，6.91-6.88(d，1H，J＝9.0 Hz，COCH=C H)，6.39-6.34(d，1H，J＝15.0Hz，COC H=CH),5.27(m,1H,SCH 2C H),5.08(m,2H,2×CH 2CH＝CCH 3),3.93(m,3H,OCH 3),3.58-3.55(m,6H,SC H 2,NC H 2C H 2N),2.01(m,8H,2×CHC H 2C H 2CH),1.68(m,12H,4×CH=CC H 3);ESI-MS (m/z):577[M+H] +。
Embodiment 46N-(3-(3-(3-methoxyl group-4-hydroxy phenyl) acrylic acid amides base) propyl group) farnesyl thiosalicylic acid acid amides (III 22) preparation
With reference to embodiment 40 compound III 16the preparation method, by the compound III 12compound III in alternative method 1under the effect of 1mol/LNaOH, hydrolysis obtains oily matter N-(3-(3-(3-methoxyl group-4-hydroxy phenyl) acrylic acid amides base) propyl group) farnesyl thiosalicylic acid acid amides (III 22), yield 86.1%.
1H NMR(CDCl 3,300MHz):δ7.63(m,1H,Ar-H),7.52(m,1H,Ar-H),7.38(m,2H,Ar-H),7.06(m，3H，Ar-H)，6.91-6.88(d，1H，J＝9.0Hz，COCH=C H)，6.38-6.33(d，1H，J＝15.0Hz，COC H=CH),5.27(m,1H,SCH 2CH),5.07(m,2H,2×CH 2CH＝CCH 3),3.39(s,3H,OC H 3),3.57-3.52(m，6H，SCH 2，2×NC H 2)，2.02-1.97(m，8H，2×CHC H 2C H 2CH)，1.55-1.67(m，14H，4×CH=CC H 3,NCH 2C H 2);ESI-MS(m/z):591[M+H] +。
Embodiment 47N-(4-(3-(3-methoxyl group-4-hydroxy phenyl) acrylic acid amides base) butyl) farnesyl thiosalicylic acid acid amides (III 23) preparation
With reference to embodiment 40 compound III 16the preparation method, by the compound III 13compound III in alternative method 1under the effect of 1mol/LNaOH, hydrolysis obtains oily matter N-(4-(3-(3-methoxyl group-4-hydroxy phenyl) acrylic acid amides base) butyl) farnesyl thiosalicylic acid acid amides (III 23), yield 73.8%.
1H NMR(CDCl 3,300MHz):8.00(s,1H,Ar-H),7.46-7.65(m,2H,Ar-H,NH),7.32(m,2H,Ar-H)，7.12(m，2H，Ar-H)，6.96-6.93(m，1H，J＝9Hz，COCH=C H)，6.23-6.18(d,1H,J＝15Hz，COC H=CH),5.89(m,1H,NH),5.20(m,1H,SCH 2C H),5.01(m,2H,2×CH 2C H=CCH 3),3.82(s,3H,OCH 3),3.53-3.41(m,6H,SCH 2,2×NCH 2),1.90-2.01(m,8H,2×CHC H 2C H 2CH),1.50-1.76(m，16H，4×CH=CCH 3，CH 2C H 2C H 2CH 2);ESI-MS(m/z):605[M+H] +。
Embodiment 48N-(5-(3-(3-methoxyl group-4-hydroxy phenyl) acrylic acid amides base) amyl group) farnesyl thiosalicylic acid acid amides (III 24) preparation
With reference to embodiment 40 compound III 16the preparation method, by the compound III 14compound III in alternative method 1under the effect of 1mol/LNaOH, hydrolysis obtains oily matter N-(5-(3-(3-methoxyl group-4-hydroxy phenyl) acrylic acid amides base) amyl group) farnesyl thiosalicylic acid acid amides (III 24), yield 82.3%.
1H NMR(CDCl 3,300MHz):8.01(s,1H,Ar-H),7.57-7.70(m,2H,Ar-H,NH),7.32(m,2H,Ar-H)，7.02(m，2H，Ar-H)，6.99-6.96(m，1H，J＝9Hz，COCH=C H)，6.26-6.21(d，1H，J＝15Hz，COC H=CH),5.93(m,1H,NH),5.24(m,1H,SCH 2C H),5.18(m,2H,2×CH 2C H=CCH 3),3.73(s,3H,OCH 3),3.52-3.40(m,6H,SCH 2,2×NCH 2),1.97-2.00(m,8H,2×CHC H 2C H 2CH),1.52-1.70(m,16H,4×CH=CC H 3,2×CH 2),1.40(m,2H,CH 2);ESI-MS (m/z):619[M+H] +。
Embodiment 49N-(6-(3-(3-methoxyl group-4-hydroxy phenyl) acrylic acid amides base) hexyl) farnesyl thiosalicylic acid acid amides (III 25) preparation
With reference to embodiment 40 compound III 16the preparation method, by the compound III 15compound III in alternative method 1under the effect of 1mol/LNaOH, hydrolysis obtains oily matter N-(6-(3-(3-methoxyl group-4-hydroxy phenyl) acrylic acid amides base) hexyl) farnesyl thiosalicylic acid acid amides (III 25), yield 83.6%.
1H NMR(CDCl 3,300MHz):8.01(s,1H,Ar-H),7.59-7.68(m,2H,Ar-H),7.87(m,1H,NH),7.32(m，2H，Ar-H)，7.03(m，2H，Ar-H)，6.87-6.84(d，1H，J＝9Hz，COCH=C H)，6.26-6.21(d，1H，J＝15Hz,COC H=CH),5.87(m,1H,NH),5.26(m,1H,SCH 2C H),5.08(m,2H,2×CH 2C H=CCH 3),3.92(s,3H,OCH 3),3.46-3.60(m,6H,SCH 2,2×NCH 2),1.99-2.01(m,8H,2×CHC H 2C H 2CH),1.54-1.73(m,16H,4×CH=CC H 3,2×NCH 2C H 2),1.43(m,4H,CH 2CH 2);ESI-MS(m/z):633[M+H] +。
Embodiment 50N-(2-(Gallic Acid amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 26) preparation
By the compound III 110.65g (1.1mmol) be dissolved in the 15mL methylene dichloride, drip the boron tribromide dichloromethane solution that 10mL concentration is 1M, during continuation reaction 3h falls back, with dry concentrated after dichloromethane extraction, column chromatography for separation, obtain faint yellow waxy solid N-(2-(Gallic Acid amide group) ethyl) farnesyl thiosalicylic acid acid amides (III 26), yield 51.2%.
1H NMR(CDCl 3,300MHz):δ7.80(m,1H,Ar-H),7.46(m,1H,Ar-H),7.32(m,1H,Ar-H),7.23(m,1H，Ar-H)，7.12(m，2H，Ar-H)，5.38(m，3H，3×OH)，5.29-5.20(t，1H，J＝15Hz，SCH 2C H)，5.10(m，2H,2×CH 2C H=CCH 3),3.71-3.45(m,6H,SC H 2,2×NC H 2),2.01-1.98(m,8H,2×CHC H 2C H 2CH),1.70-1.63(m,12H,4×CH=CC H 3),;ESI-MS(m/z):553[M+H] +。
Embodiment 51N-(3-(Gallic Acid amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 27) preparation
With reference to embodiment 50 compound III 26the preparation method, by the compound III 12compound III in replacement method 11dichloromethane solution reaction with the 1M boron tribromide, make faint yellow waxy solid N-(3-(Gallic Acid amide group) propyl group) farnesyl thiosalicylic acid acid amides (III 27), yield 47.4%.
1H NMR(CDCl 3,300MHz):δ7.80(m,1H,Ar-H),7.61(m,1H,Ar-H),7.33(m,1H,Ar-H),7.22(m,1H,Ar-H),7.19(m,2H,Ar-H),5.35(m,3H,3×OH),5.31-5.20(t，1H,J＝15Hz,SCH 2C H),5.02(m，2H，2×CH 2C H=CCH 3)，3.74-3.40(m，6H，SC H 2，2×NC H 2)，2.00-1.91(m，8H，2×CHC H 2C H 2CH),1.77-1.56(m,14H,4×CH=CC H 3,CH 2C H 2CH 2),;ESI-MS(m/z):567[M+H] +。
Embodiment 52N-(4-(Gallic Acid amide group) butyl) farnesyl thiosalicylic acid acid amides (III 28) preparation
With reference to embodiment 50 compound III 26the preparation method, by the compound III 13compound III in replacement method 11dichloromethane solution reaction with the 1M boron tribromide, make faint yellow waxy solid N-(4-(Gallic Acid amide group) butyl) farnesyl thiosalicylic acid acid amides (III 28), yield 45.8%.
1H NMR(CDCl 3,300MHz):δ7.74(m,1H,Ar-H),7.51(m,1H,Ar-H),7.38(m,1H,Ar-H),7.21(m,1H,Ar-H),7.10(m,2H,Ar-H),5.35(m,3H,3×OH),5.20(t,1H,J＝15Hz,SCH 2C H),5.00(m,2H,2×CH 2C H=CCH 3),3.73-3.41(m,6H,SC H 2,2×NC H 2),2.02-1.98(m,8H,2×CHC H 2C H 2CH),1.74-1.52(m,16H,4×CH=CC H 3,2×NCH 2C H 2),;ESI-MS(m/z):581[M+H] +。
Embodiment 53N-(5-(Gallic Acid amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 29) preparation
With reference to embodiment 50 compound III 26the preparation method, by the compound III 14compound III in replacement method 11dichloromethane solution reaction with the 1M boron tribromide, make faint yellow waxy solid N-(5-(Gallic Acid amide group) amyl group) farnesyl thiosalicylic acid acid amides (III 29), yield 43.6%.
1H NMR(CDCl 3,300MHz):δ7.87(m,1H,Ar-H),7.55(m,1H,Ar-H),7.37(m,1H,Ar-H),7.21(m，1H，Ar-H)，7.12(m，2H，Ar-H)，5.39(m，3H，3×OH)，5.21(t，1H，J＝15Hz，SCH 2C H)，5.07(m,2H,2×CH 2C H=CCH 3),3.72-3.42(m,6H,SC H 2,2×NC H 2),2.03-1.96(m,8H,2×CHC H 2C H 2CH),1.73-1.50(m,16H,4×CH=CC H 3,2×NCH 2C H 2),1.32(m,2H,CH 2);ESI-MS(m/z):595[M+H] +。
Embodiment 54N-(6-(Gallic Acid amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 30) preparation
With reference to embodiment 50 compound III 26the preparation method, by the compound III 15compound III in replacement method 11dichloromethane solution reaction with the 1M boron tribromide, make faint yellow waxy solid N-(6-(Gallic Acid amide group) hexyl) farnesyl thiosalicylic acid acid amides (III 30), yield 44.1%.
1H NMR(CDCl 3,300MHz):δ7.68(m,1H,Ar-H),7.38(m,1H,Ar-H),7.31(m,1H,Ar-H),7.22(m，1H，Ar-H)，7.07(m，2H，Ar-H)，5.35(m，3H，3×OH)，5.28-5.23(t，1H，J＝15Hz，SCH 2C H)，5.11-5.06(m,2H,2×CH 2C H=CCH 3),3.55-3.45(m,6H,SC H 2,2×NC H 2),2.02-1.99(m,8H,2×CHC H 2C H 2CH),1.56-1.67(m,16H,4×CH 3,2×NCH 2C H 2),1.52-1.44(m,4H,CH 2CH 2);ESI-MS(m/z):609[M+H] +。
Embodiment 55N-(3-farnesyl thiosalicylic acid amidopropyl) farnesyl thiosalicylic acid acid amides (III 31) preparation
1,3-propylene diamine and triethylamine are dissolved in to anhydrous CH 2cl 2, the anhydrous CH of dripping method Thessaloniki thiosalicylic acid acyl chlorides under ice bath 2cl 2solution, drip complete stirring at room 1h, and steaming desolventizes, triethylamine, and column chromatography obtains off-white color oily matter N-(3-farnesyl thiosalicylic acid amidopropyl) farnesyl thiosalicylic acid acid amides (III 31), yield 63.2%.
1H NMR(CDCl 3,300MHz):δ7.72(m,2H,Ar-H),7.40(m,4H,Ar-H),6.81(m,2H,Ar-H),5.29(m,2H,2×SCH 2C H),5.09(m,4H,4×CH 2C H=CCH 3),3.49-3.53(m,8H,2×SC H 2,2×CONHC H 2),2.02-1.90(m,18H,4×CHC H 2C H 2CH,CH 2C H 2CH 2),1.54-1.73(m,24H,8×CH=CC H 3),;ESI-MS (m/z):755[M+H] +。
Embodiment 56N-(4-farnesyl thiosalicylic acid amide group butyl) farnesyl thiosalicylic acid acid amides (III 32) preparation
With reference to embodiment 55 compound III 31the preparation method, in the Putriscine replacement method 1,3-propylene diamine and farnesyl thiosalicylic acid acyl chloride reaction make colorless oil N-(4-farnesyl thiosalicylic acid amide group butyl) farnesyl thiosalicylic acid acid amides (III 32), yield 67.8%.
1H NMR(CDCl 3,300MHz):δ7.72(m,2H,Ar-H),7.40(m,4H,Ar-H),6.81(m,2H,Ar-H),5.29(m，2H，2×SCH 2C H)，5.09(m，4H，4×CH 2C H=CCH 3)，3.49-3.53(m，8H，2×SC H 2，2×CONHC H 2),2.02(m,16H,4×CHC H 2C H 2CH),1.50-1.71(m,24H,8×CH=CC H 3),1.23(m,4H,2×NHCH 2C H 2);ESI-MS(m/z):769[M+H] +。
Embodiment 57N-(5-farnesyl thiosalicylic acid amide group amyl group) farnesyl thiosalicylic acid acid amides (III 33) preparation
With reference to embodiment 55 compound III 31the preparation method, by 1 in 1,5-pentamethylene diamine replacement method, 3-propylene diamine and farnesyl thiosalicylic acid acyl chloride reaction make colorless oil N-(5-farnesyl thiosalicylic acid amide group amyl group) farnesyl thiosalicylic acid acid amides (III 33), yield 54.2%.
1H NMR(CDCl 3,300MHz):δ7.65(m,2H,Ar-H),7.35(m,4H,Ar-H),6.88(m,2H,Ar-H),5.28(m，2H，2×SCH 2C H)，5.09(m，4H，4×CH 2C H=CCH 3)，3.48-3.53(m，8H，2×SC H 2，2×CONHC H 2),2.01(m,16H,4×CHC H 2C H 2CH),1.53-1.70(m,24H,8×CH=CC H 3),1.26(m,4H,2×NHCH 2C H 2),0.89(m,2H,NHCH 2CH 2C H 2);ESI-MS(m/z):783[M+H] +。
Blue colorimetry (MTT) antitumor activity in vitro of embodiment 58 tetramethyl-nitrogen azoles
The antiproliferative activity of the compounds of this invention to 6 kinds of human cancer cell strains that adopted routinely MTT to estimate.Mtt assay has been widely used in the responsive mensuration of large-scale screening anti-tumor medicine, cell toxicity test and tumour radiotherapy etc.Select FTA as positive control drug.
Human cancer cell strain: liver cancer cell Hep 3B, lung cell A549, pancreatic cancer cell PANC-1, breast cancer cell MDA-MB-231, brain cancer cell U251, colon cancer cell HCT116.
Experimental technique is as follows: get in one bottle, cell in good condition exponential phase of growth, add 0.25% tryptic digestion, attached cell is come off, make every milliliter containing 2 * 10 4~ 4 * 10 4the suspension of individual cell.Obtained cell suspension is inoculated on 96 orifice plates, and every hole 180 μ L, put constant temperature CO 2in incubator, cultivate 24 hours.Change liquid, add test-compound I 1-I 18, compound ii 1-II 5or compound III 1-III 33(compound dilutes with PBS after dissolving with DMSO, and test-compound concentration is respectively 1 * 10 -7, 1 * 10 -6, 5 * 10 -5mol/L), every hole 20 μ L, cultivate 48 hours.MTT is added in 96 orifice plates, every hole 20 μ L, in incubator, reaction is 4 hours.Suck supernatant liquor, add DMSO, every hole 150 μ L, on dull and stereotyped shaking table, jolting is 5 minutes.Be the optical density that the 570nm place measures every hole with enzyme-linked immunosorbent assay instrument at wavelength, calculate cell inhibitory rate.Experimental result is as shown in table 4.
Cell inhibitory rate=(negative control group OD Zhi – tested material group OD value)/negative control group OD value * 100%.
The inhibiting rate % (25 μ mol/L) of table 4 the compounds of this invention to Partial tumors cell proliferation
Compounds Hep 3B A549 U251 PANC-1 MDA-MB-231 HCT116
FTA 23.50 38.35 31.12 43.72 26.14 27.36
I 1 71.54 77.94 95.63 93.75 77.47 80.35
I 2 88.73 86.36 96.24 98.21 85.23 89.18
I 3 86.26 88.17 98.43 99.47 87.21 85.35
I 4 88.31 80.78 97.39 95.75 83.27 88.92
I 5 81.91 82.22 96.06 92.96 81.58 84.82
I 6 87.63 90.97 98.15 94.70 82.40 81.76
I 7 87.59 92.11 98.91 99.59 88.69 89.35
I 8 88.18 94.24 95.12 96.08 86.87 91.54
I 9 92.06 90.25 97.94 96.72 92.55 91.73
I 10 91.22 86.75 93.27 97.18 92.82 93.68
I 11 94.77 88.83 92.31 98.92 88.44 ND
I 12 95.66 92.56 95.33 93.06 92.56 90.32
I 13 90.18 91.36 90.73 96.61 85.61 96.53
I 14 84.33 87.31 93.78 96.11 88.23 ND
I 15 86.81 85.77 94.80 93.95 84.62 ND
I 16 88.38 86.17 92.11 96.76 86.72 ND
Ⅱ 1 92.70 91.55 92.77 96.98 90.36 88.22
Ⅱ 2 87.99 83.16 88.77 95.02 91.46 90.56
Ⅱ 3 89.53 84.94 81.3 NA 89.78 87.55
Ⅱ 4 88.64 87.38 88.48 94.11 90.22 ND
Ⅱ 5 89.43 85.29 96.26 95.36 88.96 ND
Ⅲ 2 1.63 6.25 3.56 2.38 8.45 7.34
Ⅲ 3 31.06 35.45 44.83 53.81 32.71 37.86
Ⅲ 9 3.54 5.72 3.28 1.93 4.64 4.44
Ⅲ 12 59.11 68.79 68.87 73.33 62.56 ND
Ⅲ 16 90.23 88.33 94.47 98.81 93.57 92.98
Ⅲ 18 92.85 88.32 98.93 99.83 92.70 88.35
Ⅲ 21 88.54 89.55 97.17 91.42 87.09 93.54
Ⅲ 22 94.21 91.68 94.37 96.56 92.14 85.69
Ⅲ 23 93.36 93.87 95.82 97.02 93.24 83.87
Ⅲ 31 48.86 57.05 69.85 56.09 63.98 ND
ND: do not detect.
Embodiment 59 flow cytometers detect apoptosis rate
Select pancreas cancer cell strain PANC-1, and, in the logarithmic phase state, add Digestive system (0.125% trypsinase+0.01%EDTA) digestion, count 2 ~ 2.5 * 10 5individual/ml, make cell suspension, is inoculated in culture plate, puts constant temperature CO 2in incubator, cultivate 24 hours.Use the DMEM culture medium culturing of 2% serum instead, add the tested medical compounds I of different concns 1-I 18, compound ii 1-II 5or compound III 1-III 33, continue to cultivate 48 hours.Collecting cell, attached cell is with not collecting containing the trysinization of EDTA, and the centrifugal 5min of 1000r/min, with cold PBS washed cell secondary (the centrifugal 5min of 1000rpm), after counting, adds approximately 1 * 10 5individual cell is centrifugal in test tube, removes supernatant.Suspension cell is in the Binding Buffer of 500 μ L.After adding 5 μ L AnnexinV-FITC to mix, add 5 μ L Propidium Iodide, mix, lucifuge reaction 5～15min.In 1 hour, carry out observation and the detection of flow cytometer.Excitation wavelength Ex=488nm; Emission wavelength Em=530nm.Every group 3 pipe.Without the negative contrast of the cell of drug treating.Apoptotic cell is AnnexinV +and AnnexinV +pI +, and PI +cell be non-viable non-apoptotic cell, non-transfect cell is damaging cells not.The apoptotic cell calculated in 200 cells is test index.The apoptosis rate of actual apoptosis rate=medicine apoptosis rate/negative control group.
Experimental result is found Compound I 1-I 18, compound ii 1-II 5or compound III 1-III 33cytotoxicity is in various degree all arranged, wherein, Compound I 7have stronger cytotoxicity at 12.5 μ mol/L in to PANC-1, apoptosis rate can reach 63%, and the LO2 cell is not had to obvious restraining effect, this results suggest Compound I 7optionally the apoptosis of inducing tumor cell, less to normal cell injury, thereby realize the effect of specific killing tumour cell.
The impact of Diamines FTA derivative on carcinoma of the pancreas PANC-1 cell Bcl-2, Bax and Caspase3 protein expression preferably of embodiment 60Western blot detection of active
A. cell is processed: getting the cell in the PANC-1 of logarithmic phase, is 10 with after 0.25% tryptic digestion, adjusting cell density 6/ ml is inoculated in 6 well culture plates, and every hole 1.0ml adds the tested medicine I of different concns 1-I 18, compound ii 1-II 5or compound III 1-III 33, continue to cultivate 48 hours.
B. total protein extracts and determination of protein concentration: add cell protein lysate and proteinase inhibitor to extract total protein.Below all in ice bath, carry out.4 ℃ of centrifugal 12000g, 15min, sucking-off supernatant (cell pyrolysis liquid).
The c.BCA method is measured total protein concentration.
D.SDS-PAGE and Western blot analyze: use respectively Bcl-2, Bax and Caspase3 primary antibodie and two to resist.
E. carry out gray scale scanning, PDQuest7.2.0 software analysis result.Using β-actin as internal reference, and identical experiment repeats 3 times.
Experimental result is found, Compound I under 6.125 μ M and 12.5 μ M concentration 1-I 18, compound ii 1-II 5or compound III 1-III 33the mode that suppresses cell proliferation is all relevant to inducing apoptosis of tumour cell in varying degrees, wherein Compound I 7the mechanism of action of its inducing apoptosis of tumour cell is mainly that the Bax protein expression increases by impelling, Bcl-2 down-regulated expression and activate Caspase 3 vigor and activate apoptosis pathway, produces short apoptosis effect.

Claims (10)

1. a Diamines alltrans farnesyl thio-salicylic acid derivative and pharmacy acceptable salt thereof have the structure of following general formula I:
Figure FDA0000392820340000011
In general formula I: n=1～9;
R 1represent H, CH 3(CH 3) CH, CH 3(CH 3) CHCH 2perhaps X (CH 2) m, m=0～9 wherein, X=H;
R 2represent H, CH 3(CH 3) CH, CH 3(CH 3) CHCH 2perhaps Y (CH 2) p, wherein, p=0～9, Y=H;
Perhaps,
Figure FDA0000392820340000012
representative
Figure FDA0000392820340000014
2. compound as claimed in claim 1 or its pharmacy acceptable salt, it is characterized in that n in the structure of described general formula I,
Figure FDA0000392820340000015
be selected from following combination:
n=1，
Figure FDA0000392820340000016
Perhaps n=2,
Figure FDA0000392820340000017
Perhaps n=3,
Figure FDA0000392820340000018
Perhaps n=4,
Figure FDA0000392820340000019
Perhaps n=5,
Perhaps n=2,
Perhaps n=2,
Perhaps n=2,
Perhaps n=3,
Figure FDA00003928203400000114
Perhaps n=3,
Figure FDA00003928203400000115
Perhaps n=2,
Figure FDA00003928203400000116
Perhaps n=2,
Perhaps n=2,
Figure FDA0000392820340000022
Perhaps n=3,
Figure FDA0000392820340000023
Perhaps n=3,
Perhaps n=2,
Figure FDA0000392820340000025
3. a Diamines alltrans farnesyl thio-salicylic acid derivative and pharmacy acceptable salt thereof have the structure of following general formula I:
Figure FDA0000392820340000026
In general formula I: n=2,
Figure FDA0000392820340000027
Perhaps n=1,
Figure FDA0000392820340000028
4. a Diamines alltrans farnesyl thio-salicylic acid derivative and pharmacy acceptable salt thereof have the structure of following general formula I I:
Figure FDA0000392820340000029
In general formula I I: m=0～9; X=CH, N; N=0～3; O=0～3;
R represents CH 3(CH 3) CH, CH 3(CH 3) CHCH 2, or Y (CH 2) p, wherein, p=0～9, Y=H, Ph or PhCH 2.
5. compound as claimed in claim 4 or its pharmacy acceptable salt is characterized in that m, n, o, X and the R in the structure of described general formula I I is selected from following combination:
m=1，n=2， o =2，X=CH，R=PhCH 2；
Perhaps, m=0, n=2, o=2, X=CH, R=PhCH 2;
Perhaps, m=1, n=2, o=2, X=CH, R=CH 3cH 2;
Perhaps, m=1, n=2, o=2, X=N, R=PhCH 2;
Perhaps, m=1, n=2, o=2, X=N, R=CH 3cH 2.
6. a Diamines alltrans farnesyl thio-salicylic acid derivative and pharmacy acceptable salt thereof have the structure of following general formula I II:
Figure FDA0000392820340000031
In general formula III: n=1～9;
R represents Ph, 2-OHPh, 2-SHPh, 2-S-farnesyl-Ph, 2-OAcPh, 2-SAcPh, 3-OHPh, 4-OHPh, 3,4-OHPh, 3,5-OHPh, 3-OMePh, 4-OMePh, 3,4-OMePh, 3,5-OMePh, 3,4,5-OMePh or
Figure FDA0000392820340000032
r wherein 3=OCH 3, R 4=OH.
7. compound as claimed in claim 6 or its pharmacy acceptable salt is characterized in that n and the R in the structure of described general formula III is selected from following combination:
N=3,4 or 5, R=2-OAcPh;
Perhaps n=1-5, R=3,4,5-OMePh;
Perhaps n=1-5, R=2-OHPh;
Perhaps n=1-5,
Figure FDA0000392820340000033
Perhaps n=2-4, R=2-S-farnesyl-Ph.
8. the preparation method of one of claim 1-7 described Diamines alltrans farnesyl thio-salicylic acid derivative and pharmacy acceptable salt thereof,
(1), the compound of Formula I synthetic route is as follows:
Figure FDA0000392820340000041
Wherein, in general formula I: n=1～9;
R 1represent H, CH 3(CH 3) CH, CH 3(CH 3) CHCH 2perhaps X (CH 2) m, m=0～9 wherein, X=H;
R 2represent H, CH 3(CH 3) CH, CH 3(CH 3) CHCH 2perhaps Y (CH 2) p, wherein, p=0～9, Y=H;
Perhaps,
Figure FDA0000392820340000042
representative
Figure FDA0000392820340000043
Figure FDA0000392820340000044
Perhaps, n=2,
Figure FDA0000392820340000045
perhaps n=1,
Step comprises:
By alltrans farnesyl thiosalicylic acid, under the effect of chloride reagent, described chloride reagent is sulfur oxychloride or oxalyl chloride, prepares alltrans farnesyl thiosalicylic acid acyl chlorides, by alltrans farnesyl thiosalicylic acid acyl chlorides and NH 2(CH 2) ncH 2nR 1r 2in the dichloromethane solution of triethylamine or salt of wormwood or sodium carbonate, reaction obtains compound of Formula I;
Perhaps, alltrans farnesyl thiosalicylic acid and NH 2(CH 2) ncH 2nR 1r 2under condensing agent and DMAP effect, condensation makes compound of Formula I;
General formula I preparation method as described above, it is characterized in that described condensing agent is selected from 1,3-dicyclohexylcarbodiimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N, N-DIC, Vinyl chloroformate or methyl esters, solvent is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), ethyl acetate, methyl acetate, 1, one or more in 2-ethylene dichloride, benzene, toluene, dioxane or dimethyl formamide;
(2), general formula I I compou nd synthesis route is as follows:
Wherein, in general formula I I: m=0～9; X=CH, N; N=0～3; O=0～3; R represents CH 3(CH 3) CH, CH 3(CH 3) CHCH 2, or Y (CH 2) p, wherein, p=0～9, Y=H, Ph or PhCH 2;
Step comprises:
1) compound 2 reacts and obtains compound 4 with R-Br under the effect of salt of wormwood;
2) compound 4 reacts with methylsulfonyl chloride and obtains compound 5;
3) compound 5 reacts with excessive ammonia and obtains compound 6;
4) compound 6 reacts and obtains general formula I I compound with alltrans farnesyl thiosalicylic acid under condensing agent and DMAP effect, perhaps compound 6 and alltrans farnesyl thiosalicylic acid acyl chlorides react and obtain general formula I I compound under the effect of acid binding agent triethylamine or salt of wormwood;
General formula I I preparation method as described above; it is characterized in that step 4) described condensing agent is selected from 1; 3-dicyclohexylcarbodiimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N; N-DIC or Vinyl chloroformate or methyl esters; solvent is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), ethyl acetate, methyl acetate, 1, one or more in 2-ethylene dichloride, benzene, toluene, dioxane or dimethyl formamide;
(3), the general formula III synthetic route is as follows:
In general formula III: n=1～9;
R represents Ph, 2-OHPh, 2-SHPh, 2-S-farnesyl-Ph, 2-OAcPh, 2-SAcPh, 3-OHPh, 4-OHPh, 3,4-OHPh, 3,5-OHPh, 3-OMePh, 4-OMePh, 3,4-OMePh, 3,5-OMePh, 3,4,5-OMePh or
Figure FDA0000392820340000061
r wherein 3=OCH 3, R 4=OH;
Step comprises:
1) by compound 7 and NH 2(CH 2) ncH 2nH 2under the effect of condensing agent, reaction obtains compound 9, or by compound 7 and chloride reagent reaction, described chloride reagent is sulfur oxychloride or oxalyl chloride, obtains corresponding acyl chlorides directly and NH 2(CH 2) ncH 2nH 2under the effect of acid binding agent triethylamine or salt of wormwood, reaction obtains compound 9;
2) compound 9 reacts and obtains compound of formula III under condensing agent and DMAP effect with alltrans farnesyl thiosalicylic acid, perhaps compound 9 and alltrans farnesyl thiosalicylic acid acyl chlorides react the preparation compound of formula III under the effect of acid binding agent triethylamine or salt of wormwood;
Compound of formula III preparation method as described above, it is characterized in that step 1) and 2) described condensing agent is selected from 1,3-dicyclohexylcarbodiimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N, N-DIC, Vinyl chloroformate or methyl esters, solvent is selected from methylene dichloride, chloroform, tetrahydrofuran (THF), ethyl acetate, methyl acetate, 1, one or more in 2-ethylene dichloride, benzene, toluene, dioxane or dimethyl formamide.
9. a pharmaceutical composition, the pharmaceutical composition that contains the described general formula I of claim 1-7 any one, II or III compound or its medically acceptable salt and pharmaceutically acceptable auxiliary material.
10. described general formula I, II or III compound or its medically acceptable salt of claim 1-7 any one is preparing Hepatoma therapy, carcinoma of the pancreas, lung cancer, mammary cancer, the cancer of the brain, the application in colorectal carcinoma and cancer of the stomach tumour medicine.
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