CN103450062B - Double-target point medicine compound for treating tumors as well as preparation method and application thereof - Google Patents
Double-target point medicine compound for treating tumors as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a double-target point medicine compound for treating tumors as well as a preparation method and an application thereof. The double-target point medicine compound has a structure shown in a general formula II and can be used for preparing medicines for treating chronic inflammations and tumors of liver cancers, pancreatic cancers, lung cancers, breast cancers, brain cancers, colon cancers and gastric cancers.
Description
The application is application number: the dividing an application of 201310028119.5, the applying date: 2013.1.25, title " Ras and HDAC double inhibitor and its production and use ".
Technical field
Pharmaceutical field of the present invention, be specifically related to can be used as hydroximic acid farnesyl thio-salicylic acid derivative and the pharmacy acceptable salt thereof of Ras and HDAC double inhibitor, their preparation method, the medicinal compositions that contains these derivatives and their medicinal use, relate in particular to prevention, delay or treat Ras or HDAC separately or both participate in the disease, the particularly application in the medicine of tumour that mediate simultaneously.
Background technology
Alltrans farnesyl thiosalicylic acid (is called for short: FTA, trade(brand)name: Salirasib) as the new Ras protein inhibitor based on farnesyl transferase, similar to farnesyl halfcystine on cells in vivo film, can competitive replace F-Ras and F-Ras mutain is combined with Galectins, inhibition causes downstream signal path Z(by Ras and comprises Raf and PI3K signal path) and the tumorigenic stimulator of mTOR(, it can rely on or open independently PI3K signal path), thereby inducing apoptosis of tumour cell, the growth of inhibition tumor cell.Research shows, FTA can suppress kinds of tumors (cerebral glioma, liver cancer, lung cancer, carcinoma of the pancreas, mammary cancer, colorectal carcinoma etc.) cell proliferation and migration (Cancer Chemother Pharmacol, 2008,61 (1): 89-96; Cancer Chemother Pharmacol, 2009,65 (2): 235-241; J Thorac Oncol, 2011,6 (8): 1435-1437).Though FTA is in II phase clinical study, because it cannot stop and reversion of malignant tumor development process forcefully, and clinical therapeutic efficacy is not high, and using dosage is large, conventionally needs clinically to have the antitumour drug combination therapy of cytotoxicity with other.Tracing it to its cause, may be separately the inhibition of Ras albumen target spot to be difficult to the blocking-up tumour cell malignant proliferation process that reaches desirable, and likely cause tumor drug resistance.
Farnesyl thiosalicylic acid (FTA, Salirasib)
The orderly regulation and control of genetic transcription are the prerequisites that body cell maintains normal function, if gene transcription regulation dysfunction, cell canceration may occur.Histon deacetylase (HDAC) (histone deacetylases; HDACs) and acetylation of histone enzyme (histone acetyltransferases; HATs) be the Liang Ge family that controls histone afterbody Acetylation Level in chromatin in eukaryotic cell; the lysine residue that core histones N-terminal afterbody comprises; HAT and HDAC acetylize and deacetylation substrate; the acetylize of the epsilon-amino of lysine residue and deacetylation, represent the main molecules epigenetic mechanism that controlling gene is expressed.In tumour cell, the overexpression of HDACs causes histone and DNA bonding force to strengthen, thereby causes karyomit(e) isomery, affects genetic transcription.Meanwhile, the HDACs of overexpression can suppress cell cycle supressor p21
cIP1or p27
kIP1expression, reduce the stability of tumor-inhibiting factor p53, and the expression of the hypoxia inducible factor in promotion tumour cell (Hypoxia induciblefactor-l, HIF-l) and vascular endothelial growth factor (vascular endothelial growth factor, VEGF).Research is found; HDACs inhibitor (HDACi) is by suppressing the enzymic activity of HDACs; hinder the deacetylation of histone; make chromosome structure lax; promote transcription factor and DNA combination, effectively inhibition tumor cell propagation, causes cell-cycle arrest; the differentiation of inducing tumor cell and apoptosis, the susceptibility of raising chemicotherapy.Therefore, HDACs becomes the novel targets of cancer therapy drug design, and it is effectively tactful that exploitation HDACs inhibitor (HDACi) is regarded as one of oncotherapy.
According to another clinical study, show, Ras inhibitor FTA can significantly block the growth of tumour cell cycle under the effect of hdac inhibitor valproic acid, inhibition Survivin(IAP) expression and Aurora A oncogene are transcribed, especially for having K-ras genic mutation type lung cancer and intestinal cancer, its curative effect is more clear and definite, and (Int.J.Cancer 2011,128,691 – 701); Ras inhibitor Sorafenib not only can obviously suppress Ras/Raf/MEK/ERK and PI3K/Akt path under hdac inhibitor Vorinostat synergy, can also suppress inhibitor of apoptosis protein expresses, collaborative cell killing effect changes by Bax configuration and to plastosome transposition, stimulate plastosome release cells pigment C, thereby promote apoptosis (Clin.Cancer Res.2008,14 (17): 5385 – 5399).Based on these research, we consider to introduce HDACs inhibitor structure fragment on Ras inhibitor FTA carboxyl, make it not only there is Ras and suppress active, and target HDACs treatment simultaneously, effectively inhibition tumor cell propagation, induces its differentiation and apoptosis, cause cell-cycle arrest, suppress Ras mutain and downstream Ras/Raf/MEK/ERK, PI3K/Akt signal path, thus obtain efficient, low toxicity, the Ras with synergistic effect and many target spots of HDACs antitumor drug.
For obtaining the compound more excellent than FTA anti-tumor activity, we have carried out the structural modification research of FTA.The invention discloses a class and there is the Ras of pharmaceutical use and hydroximic acid FTA derivative and the pharmacy acceptable salt thereof of HDAC dual restraining activities, have not yet to see any report to this compounds.
Summary of the invention
The object of the present invention is to provide the Ras of a kind of Ras of having and HDAC dual restraining activities and HDAC double inhibitor and its production and use.
Technical solution of the present invention is:
Ras and a HDAC double inhibitor, is characterized in that: the structure with following formula I:
In formula I :-NH-A-CO-is selected from and is configured as glycine residue, L-or D-type α-alanine residue, Beta-alanine residue, L-or D-type α-amino-isovaleric acid residue, L-or D-type leucine residue, L-or D-type Isoleucine residue, L-or D-type methionine residues, L-or D-type cysteine residues, L-or D-type phenylalanine residue, L-or D-type tyrosine residues, L-or D-type tryptophan residue, L-or D-type arginine residues, L-or D-type proline residue, L-or D-type histidine residues, or be selected from-NH (CH
2)
ncO-, n=3～7, or be selected from
m=0～5, R=H, methyl, ethyl, propyl group, butyl, amyl group, or be selected from
or be selected from
o=0～5, or be selected from
In the structure of described formula I-NH-A-CO-is selected from as follows:
-NH-A-CO-=-NHCH
2CO-；
Or-NH-A-CO-=-NH (CH
2)
2cO-;
Or-NH-A-CO-=-NH (CH
2)
3cO-;
Or-NH-A-CO-=-NH (CH
2)
4cO-;
Or-NH-A-CO-=-NH (CH
2)
5cO-;
Or-NH-A-CO-=
Or-NH-A-CO-=
Or-NH-A-CO-=
Or-NH-A-CO-=
Or-NH-A-CO-=
Or-NH-A-CO-=
Or-NH-A-CO-=
Or-NH-A-CO-=
Ras and a HDAC double inhibitor, is characterized in that: the structure with following general formula II:
In general formula II :-NH-A-CO-is selected from and is configured as glycine residue, L-or D-type α-alanine residue, Beta-alanine residue, L-or D-type α-amino-isovaleric acid residue, L-or D-type leucine residue, L-or D-type Isoleucine residue, L-or D-type methionine residues, L-or D-type cysteine residues, L-or D-type phenylalanine residue, L-or D-type tyrosine residues, L-or D-type tryptophan residue, L-or D-type arginine residues, L-or D-type proline residue, L-or D-type histidine residues, or be selected from-NH (CH
2)
ncO-, n=3～7, or be selected from
or be selected from
o=0～5, or be selected from
be selected from-O-of X, or be selected from-NH-, or be selected from-NCH
3-, m=1～8.
In the structure of described general formula II-NH-A-CO-, X and m be selected from following combination:
-NH-A-CO-=-NHCH
2CO-，X=NH，m=3；
Or-NH-A-CO-=
x=NH, m=2;
Or-NH-A-CO-=
x=NH, m=1;
Or-NH-A-CO-=-NHCH
2cO-, X=NH, m=1;
Or-NH-A-CO-=-NHCH
2cO-, X=NH, m=2;
A preparation method for Ras and HDAC double inhibitor, is characterized in that:
Described formula I preparation method comprises the following steps:
A. first FTA is prepared under sulfur oxychloride effect to FTA acyl chlorides (1);
B. again with H
2n-A-COOMe reacts and obtains compound (2) in the dichloromethane solution of triethylamine;
C. compound (2) reacts and makes formula I under the methanol solution of potassium hydroxide with oxammonium hydrochloride again;
Formula I reaction scheme is as follows:
Wherein, in formula I :-NH-A-CO-is selected from and is configured as-and NH-A-CO-is selected from and is configured as glycine residue, L-or D-type α-alanine residue, Beta-alanine residue, L-or D-type α-amino-isovaleric acid residue, L-or D-type leucine residue, L-or D-type Isoleucine residue, L-or D-type methionine residues, L-or D-type cysteine residues, L-or D-type phenylalanine residue, L-or D-type tyrosine residues, L-or D-type tryptophan residue, L-or D-type arginine residues, L-or D-type proline residue, L-or D-type histidine residues; Or be selected from-NH (CH
2)
ncO-, n=3～7; Or be selected from
m=0～5, R=H, methyl, ethyl, propyl group, butyl, amyl group; Or be selected from
or be selected from
o=0～5; Or be selected from
A preparation method for Ras and HDAC double inhibitor, is characterized in that:
Described general formula II preparation method comprises the following steps:
A. compound (2) is hydrolyzed and obtains compound (3) in containing the methanol solution of NaOH;
B. compound (3) is under condensing agent 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC) and DMAP (DMAP) effect, with HX (CH2) mCOOMe reacting generating compound (4);
C. final compound (4) reacts and makes general formula II with oxammonium hydrochloride under the methanol solution of potassium hydroxide;
General formula II reaction scheme is as follows:
Wherein, in general formula II :-NH-A-CO-is selected from and is configured as glycine residue, L-or D-type α-alanine residue, Beta-alanine residue, L-or D-type α-amino-isovaleric acid residue, L-or D-type leucine residue, L-or D-type Isoleucine residue, L-or D-type methionine residues, L-or D-type cysteine residues, L-or D-type phenylalanine residue, L-or D-type tyrosine residues, L-or D-type tryptophan residue, L-or D-type arginine residues, L-or D-type proline residue, L-or D-type histidine residues; Or be selected from-NH (CH
2)
ncO-, n=3～7; Or be selected from
or be selected from
o=0～5; Or be selected from
be selected from-O-of X, or be selected from-NH-, or be selected from-NCH
3-; M=1～8.
A pharmaceutical composition, is characterized in that: be the pharmaceutical composition that contains formula I or II compound.
The application in the tumour medicine of preparing treatment chronic inflammatory diseases and Hepatoma therapy, carcinoma of the pancreas, lung cancer, mammary cancer, the cancer of the brain, colorectal carcinoma, cancer of the stomach of a kind of Ras and HDAC double inhibitor.
The application in the tumour medicine of preparing treatment chronic inflammatory diseases and Hepatoma therapy, carcinoma of the pancreas, lung cancer, mammary cancer, the cancer of the brain, colorectal carcinoma, cancer of the stomach of a kind of Ras and HDAC double inhibitor.
Specifically, the hydroximic acid FTA derivative shown in formula I is preferably from following compounds:
N-(2-(hydroxylamino)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (compound number: I
1, lower same)
N-(3-(hydroxylamino)-3-oxa-propyl group)-farnesyl thiosalicylic acid acid amides (I
2)
N-(4-(hydroxylamino)-4-oxa-butyl)-farnesyl thiosalicylic acid acid amides (I
3)
N-(5-(hydroxylamino)-5-oxa-amyl group)-farnesyl thiosalicylic acid acid amides (I
4)
N-(6-(hydroxylamino)-6-oxa-hexyl)-farnesyl thiosalicylic acid acid amides (I
5)
(S)-N-(1-(hydroxylamino)-1-oxa-propyl group-2-yl)-farnesyl thiosalicylic acid acid amides (I
6)
(S)-N-(1-(hydroxylamino)-3-methyl isophthalic acid-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (I
7)
(S)-N-(1-(hydroxylamino)-4-methylthio group-1-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (I
8)
(S)-N-(1-(hydroxylamino)-4-methyl isophthalic acid-oxa-amyl group-2-yl)-farnesyl thiosalicylic acid acid amides (I
9)
(S)-N-(1-(hydroxylamino)-3-methyl isophthalic acid-oxa-amyl group-2-yl)-farnesyl thiosalicylic acid acid amides (I
10)
(E)-N-(4-(3-(hydroxylamino)-3-oxa--1-propenyl) phenyl)-farnesyl thiosalicylic acid acid amides (I
11)
N-(4-(3-(hydroxylamino)-3-oxa-propyl group) phenyl)-farnesyl thiosalicylic acid acid amides (I
12)
N-(4-(hydroxylamino formyl radical) phenyl)-farnesyl thiosalicylic acid acid amides (I
13)
N-(4-(hydroxylamino formyl radical) benzyl)-farnesyl thiosalicylic acid acid amides (I
14)
Hydroximic acid FTA derivative shown in general formula II is preferably from following compounds:
N-(2-(4-(azanol)-4-oxa-butylamine base)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (II
1)
(S)-N-(1-(3-(azanol)-3-oxa-Propylamino)-1-oxa-propyl group-2-yl)-farnesyl thiosalicylic acid acid amides (II
2) (S)-N-(1-(2-(azanol)-2-oxa-ethylamino-)-3-methyl isophthalic acid-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (II
3)
N-(2-(2-(azanol)-2-oxa-ethylamino-)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (II
4)
N-(2-(3-(azanol)-3-oxa-Propylamino)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (II
5)
The structure of said structure formula I preferred compound code name and correspondence thereof is as shown in table 1
Table 1 formula I preferred compound code name and corresponding structure thereof
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
Described compound comprises all conformers, optically active isomer and the racemic modification of formula I, II compound, diastereomer and tautomer and steric isomer, and the mixture of above-mentioned form.
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 oral dosage form administration, as tablet, capsule, dispersible powder, granule etc.The various formulations of pharmaceutical composition of the present invention can be prepared according to the method for knowing in pharmaceutical field.In these medicinal preparationss, can contain for example activeconstituents of 0.05%～90% weight with carrier combinations, 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 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) blue colorimetry (MTT) antitumor activity in vitro of tetramethyl-nitrogen azoles
The pharmacological results shows: the compounds of this invention has restraining effect in various degree to human tumor cell's propagation, majority of compounds anti-tumor activity is all significantly better than lead compound FTA, and most antitumor activity of compound are slightly stronger or suitable than positive control drug SAHA.Through a series of tumour cell tests, find that these compounds are stronger to pancreatic cancer cell PANC-1, liver cancer cell SMMC-7721 and human glioma cell U251 effect, especially I in table 4
1-3, I
11-12and II
1-2compound under 25 μ mol/L concentration inhibiting rate all considerably beyond primer FTA.
Table 3 part of compounds of the present invention is to the inhibiting rate % of tumor cell proliferation (25 μ mol/L)
ND: do not detect.
(2) p-Raf in Ras downstream, p-Akt, p-ERK suppress active testing
Experimental result is found: chemical compounds I
1-I
14or compound ii 1-II 5 all suppresses active to Ras downstream p-Raf, p-Akt, p-ERK in varying degrees, retained that parent nucleus FTA is original suppresses active to Ras downstream signal path, wherein chemical compounds I
1-I
3, I
11-I
14, II
2under 6.125 μ M and 12.5 μ M concentration, can significantly suppress Akt, ERK, the phosphorylation of Raf molecule, points out novel hydroximic acid FTA derivative still to retain Ras downstream signal path is suppressed to active.
(3) HDACs is suppressed to active testing
Experimental result is found: chemical compounds I
1-I
14or compound ii
1-II
5all in varying degrees HDACs is suppressed to active, wherein chemical compounds I
1-I
3, I
6, I
11, I
14, II
2hDACs is suppressed to activity data in Table 4, chemical compounds I
1-I
3, I
11, I
14, II
2all demonstrate the inhibition slightly strong or more suitable than positive control drug SAHA active, point out novel hydroximic acid FTA derivative not only to have Ras downstream signal path is suppressed to active, and it is active to have HDACs inhibition, thereby obtain Ras and many target spots of HDACs antitumous effect with synergistic effect.
Table 4 part of compounds vitro enzyme of the present invention suppresses experimental result
Embodiment
In order further to illustrate the present invention, provide a series of embodiment below, these embodiment are illustrative completely, they are only used for the present invention to specifically describe, and not should be understood to limitation of the present invention.The present invention FTA used is laboratory preparation, content >98%.
Embodiment 1N-(2-(hydroxylamino)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (I
1) preparation
The preparation of farnesyl thiosalicylic acid acyl chlorides (1)
0.36g (1.00mmol) FTA is dissolved in to the anhydrous CH of 10mL
2cl
2in, add wherein 0.40mL (5.51mmol) sulfur oxychloride, stir 1 hour the concentrated yellow oil farnesyl thiosalicylic acid acyl chlorides (1) that to obtain at 55 ℃.
The preparation of N-(2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a)
0.09g (1.00mmol) glycine methyl ester and 0.2mL (1.50mmol) triethylamine are dissolved in to the anhydrous CH of 5mL
2cl
2in, under ice bath, drip and make 1 the anhydrous CH of 10mL above
2cl
2solution, the 1.5h of stirring at room reaction afterwards, reaction solution is used respectively 10mL water and saturated NaCl solution washing, CH
2cl
2with anhydrous sodium sulfate drying, filter, be spin-dried for to obtain 0.37g yellow oil, yield 86%.
N-(2-(hydroxylamino)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (I
1) preparation
The oxammonium hydrochloride of 1.74g (25mmol) is dissolved in 10mL methyl alcohol, the 10mL methanol solution that slowly adds 1.40g (25mmol) potassium hydroxide under ice bath, after stirring at room 1h, filter, under ice bath to the 5mL methanol solution that adds 0.21g (0.5mmol) compound (2a) in filtrate, after stirring at room 0.5h, add 0.06g (1.0mmol) potassium hydroxide, then continue after room temperature reaction 24h, concentrated, column chromatography obtains oily matter 0.16g, yield 69%.
1H?NMR(CDCl
3,300MHz):δ7.80(d,1H,J=7.8Hz,Ar-H),7.24(m,2H,Ar-H),7.12(m,1H,Ar-H),5.22(m,1H,SCH
2C
H),5.01(m,2H,2×CH
2C
H=CCH
3),4.56(m,2H,NHC
H 2),3.82(d,2H,J=7.2Hz,SC
H 2),2.10-1.76(m,8H,2×CHC
H 2C
H 2CH),1.69-1.56(m,12H,4×CH
3);ESI-MS(m/z):431[M+H]
+.
Embodiment 2N-(3-(hydroxylamino)-3-oxa-propyl group)-farnesyl thiosalicylic acid acid amides (I
2) preparation
The preparation of N-(3-(methoxyl group)-3-oxa-propyl group)-farnesyl thiosalicylic acid acid amides (2b)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in 3-alanine methyl esters alternative method, react with (1) and make yellow oil (2b), yield 85% again.
N-(3-(hydroxylamino)-3-oxa-propyl group)-farnesyl thiosalicylic acid acid amides (I
2) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 2b alternative method, then react with oxammonium hydrochloride and make oily matter (I
2), yield 73%.
1H?NMR(CDCl
3,300MHz):δ8.24(m,1H,NH),8.09(m,1H,NH),7.65(m,2H,ArH),7.37(m,2H,ArH),5.41(m,1H,SCH
2C
H),5.18(m,2H,2×CH
2C
H=CCH
3),3.76(d,2H,J=7.2Hz,SC
H 2),3.18(m,4H,2×CH
2),2.05-1.83(m,8H,2×CHC
H 2C
H 2CH),1.69-1.55(m,12H,4×CH
3);ESI-MS(m/z):445[M+H]
+.
Embodiment 3N-(4-(hydroxylamino)-4-oxa-butyl)-farnesyl thiosalicylic acid acid amides (I
3) preparation
The preparation of N-(4-(methoxyl group)-4-oxa-butyl)-farnesyl thiosalicylic acid acid amides (2c)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in 4-Aminobutanoicacid methyl esters alternative method, react with (1) and make yellow oil (2c), yield 83% again.
N-(4-(hydroxylamino)-4-oxa-butyl)-farnesyl thiosalicylic acid acid amides (I
3) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 2c alternative method, then react with oxammonium hydrochloride and make oily matter (I
3), yield 70%.
1H?NMR(CDCl
3,300MHz):δ7.98(d,1H,J=7.8Hz,Ar-H),7.60-7.57(m,2H,Ar-H),7.39(m,1H,Ar-H),5.46(m,1H,SCH
2C
H),5.20(m,2H,2×CH
2C
H=CCH
3),3.78(d,2H,J=7.2Hz,SC
H 2),3.52(m,2H,NHC
H 2),2.34(m,2H,C
H 2CONH),2.21(m,2H,NHCH
2C
H 2),2.00-1.87(m,8H,2×CHC
H 2C
H 2CH),1.68-1.57(m,12H,4×CH
3);ESI-MS(m/z):459[M+H]
+.
Embodiment 4N-(5-(hydroxylamino)-5-oxa-amyl group)-farnesyl thiosalicylic acid acid amides (I
4) preparation
The preparation of N-(5-(methoxyl group)-5-oxa-amyl group)-farnesyl thiosalicylic acid acid amides (2d)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in 5-aminovaleric acid methyl esters alternative method, react with (1) and make yellow oil (2d), yield 77% again.
N-(5-(hydroxylamino)-5-oxa-amyl group)-farnesyl thiosalicylic acid acid amides (I
4) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 2d alternative method, then react with oxammonium hydrochloride and make oily matter (I
4), yield 71%.
1H?NMR(CDCl
3,300MHz):δ7.88(d,1H,J=7.8Hz,Ar-H),7.67-7.58(m,2H,Ar-H),7.32(m,1H,Ar-H),5.34(m,1H,SCH
2C
H),5.28(m,2H,2×CH
2C
H=CCH
3),3.81(d,2H,J=7.2Hz,SC
H 2),3.40(m,2H,NHC
H 2),2.32(m,2H,C
H 2CONH),2.01-1.89(m,8H,2×CHC
H 2C
H 2CH),1.59-1.70(m,12H,4×CH
3),1.56(m,2H,NHCH
2C
H 2),1.53(m,2H,C
H 2CH
2CONH);ESI-MS(m/z):473[M+H]
+.
The preparation of embodiment 5N-(6-(hydroxylamino)-6-oxa-hexyl)-farnesyl thiosalicylic acid acid amides (I 5)
The preparation of N-(6-(methoxyl group)-6-oxa-hexyl)-farnesyl thiosalicylic acid acid amides (2e)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in 6-aminocaprolc acid methyl esters alternative method, react with (1) and make yellow oil (2e), yield 72% again.
N-(6-(hydroxylamino)-6-oxa-hexyl)-farnesyl thiosalicylic acid acid amides (I
5) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 2e alternative method, then react with oxammonium hydrochloride and make oily matter (I
5), yield 73%.
1H?NMR(CDCl
3,300MHz):δ8.11(d,1H,J=7.8Hz,Ar-H),7.60-7.58(m,2H,Ar-H),7.31(m,1H,Ar-H),5.90(m,1H,SCH
2C
H),5.15(m,2H,2×CH
2C
H=CCH
3),3.74(d,2H,J=7.2Hz,SC
H 2),3.54(m,2H,NHC
H 2),2.43(m,2H,C
H 2CONH),2.13-1.82(m,8H,2×CHC
H 2C
H 2CH),1.70-1.59(m,12H,4×CH
3),1.56(m,2H,NHCH
2C
H 2),1.32(m,2H,C
H 2CH
2CONH);ESI-MS(m/z):487[M+H]
+.
The preparation of embodiment 6 (S)-N-(1-(hydroxylamino)-1-oxa-propyl group-2-yl)-farnesyl thiosalicylic acid acid amides (I 6)
(S) preparation of-N-(1-(methoxyl group)-1-oxa-propyl group-2-yl)-farnesyl thiosalicylic acid acid amides (2f)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in L-α alanine methyl ester alternative method, react with (1) and make yellow oil (2f), yield 70% again.
(S)-N-(1-(hydroxylamino)-1-oxa-propyl group-2-yl)-farnesyl thiosalicylic acid acid amides (I
6) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 2f alternative method, then react with oxammonium hydrochloride and make oily matter (I
6), yield 65%.
1H?NMR(CDCl
3,300MHz):δ7.84(d,1H,J=7.8Hz,Ar-H),7.66-7.55(m,2H,Ar-H),7.35(m,1H,Ar-H),5.42(m,1H,SCH
2C
H),5.25(m,2H,2×CH
2C
H=CCH
3),4.71(m,1H,NHC
H),3.81(m,2H,SC
H 2),2.01-1.87(m,8H,2×CHC
H 2C
H 2CH),1.78-1.46(m,12H,4×CH=CC
H 3),1.48(m,3H,NHCHC
H 3);ESI-MS(m/z):445[M+H]
+.
Embodiment 7 (S)-N-(1-(hydroxylamino)-3-methyl isophthalic acid-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (I
7) preparation
(S) preparation of-N-(1-(methoxyl group)-3-methyl isophthalic acid-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (2g)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in Valine methyl esters alternative method, react with (1) and make yellow oil (2g), yield 65% again.
(S)-N-(1-(hydroxylamino)-3-methyl isophthalic acid-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (I
7) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 2g alternative method, then react with oxammonium hydrochloride and make oily matter (I
7), yield 68%.
1H?NMR(CDCl
3,300MHz):δ8.02(d,1H,J=7.8Hz,Ar-H),7.78-7.40(m,2H,Ar-H),7.23(m,1H,Ar-H),5.44(m,1H,SCH
2C
H),5.04(m,2H,2×CH
2C
H=CCH
3),4.53(m,1H,NHC
H),3.80(d,2H,J=7.2Hz,SC
H 2),2.03-1.78(m,9H,2×CHC
H 2C
H 2CH,NHCHC
H),1.71-1.60(m,12H,4×CH=CC
H 3),0.94(m,6H,CH(C
H 3)
2);ESI-MS(m/z):473[M+H]
+.
Embodiment 8 (S)-N-(1-(hydroxylamino)-4-methylthio group-1-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (I
8) preparation
(S) preparation of-N-(1-(methoxyl group)-4-methylthio group-1-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (2h)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in METHIONINE methyl esters alternative method, react with (1) and make yellow oil (2h), yield 69% again.
(S)-N-(1-(hydroxylamino)-4-methylthio group-1-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (I
8) preparation
With reference to the preparation method of I 1 in embodiment 1, the 2a in 2h alternative method, then react with oxammonium hydrochloride and make oily matter (I
8), yield 72%.
1H?NMR(CDCl
3,300MHz):δ7.95(d,1H,J=7.6Hz,Ar-H),7.70-7.54(m,2H,Ar-H),7.14(m,1H,Ar-H),5.60(m,1H,SCH
2C
H),5.32(m,2H,2×CH
2C
H=CCH
3),4.81(m,1H,NHC
H),3.91(m,2H,SC
H 2CH=CCH
3),2.46(t,2H,J=7.6Hz,C
H 2SCH
3),2.13(s,3H,SCH
3),2.08-1.80(m,10H,CHC
H 2,2×CHC
H 2C
H 2CH),1.70-1.40(m,12H,4×CH=CC
H 3);ESI-MS(m/z):505[M+H]
+.
Embodiment 9 (S)-N-(1-(hydroxylamino)-4-methyl isophthalic acid-oxa-amyl group-2-yl)-farnesyl thiosalicylic acid acid amides (I
9) preparation
(S) preparation of-N-(1-(methoxyl group)-4-methyl isophthalic acid-oxa-amyl group-2-yl)-farnesyl thiosalicylic acid acid amides (2i)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in L-Leu methyl esters alternative method, react with (1) and make yellow oil (2i), yield 66% again.
(S)-N-(1-(hydroxylamino)-4-methyl isophthalic acid-oxa-amyl group-2-yl)-farnesyl thiosalicylic acid acid amides (I
9) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 2i alternative method, then react with oxammonium hydrochloride and make oily matter (I
9), yield 71%.
1H?NMR(CDCl
3,300MHz):δ8.05(d,1H,J=7.8Hz,Ar-H),7.82-7.52(m,2H,Ar-H),7.48(m,1H,Ar-H),5.39(m,1H,SCH
2C
H),5.13(m,2H,2×CH
2C
H=CCH
3),4.26(m,1H,NHC
H),3.95(d,2H,J=7.2Hz,SC
H 2),,2.21-1.80(m,10H,2×CHC
H 2C
H 2CH,NHCHC
H 2),1.68-1.44(m,12H,4×CH=CC
H 3),1.31(m,2H,C
H 2CH
3),0.84(t,3H,J=7.4Hz,CH
2C
H 3);ESI-MS(m/z):487[M+H]
+.
Embodiment 10 (S)-N-(1-(hydroxylamino)-3-methyl isophthalic acid-oxa-amyl group-2-yl)-farnesyl thiosalicylic acid acid amides (I
10) preparation
(S) preparation of-N-(1-(methoxyl group)-3-methyl isophthalic acid-oxa-amyl group-2-yl)-farnesyl thiosalicylic acid acid amides (2j)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in ILE methyl esters alternative method, react with (1) and make yellow oil (2j), yield 69% again.
(S)-N-(1-(hydroxylamino)-3-methyl isophthalic acid-oxa-amyl group-2-yl)-farnesyl thiosalicylic acid acid amides (I
10) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 2j alternative method, then react with oxammonium hydrochloride and make oily matter (I
10), yield 70%.
1H?NMR(CDCl
3,300MHz):δ7.87(d,1H,J=7.8Hz,Ar-H),7.53-7.43(m,2H,Ar-H),7.31(m,1H,Ar-H),5.33(m,1H,SCH
2C
H),5.10(m,2H,2×CH
2C
H=CCH
3),4.78(m,1H,NHC
H),3.65(d,2H,J=7.2Hz,SC
H 2),2.66(m,1H,NHCHC
H),2.05-1.72(m,8H,2×CHC
H 2C
H 2CH),1.63-1.41(m,12H,4×CH=CC
H 3),1.03(m,6H,C
H 3CHC
H 3);ESI-MS(m/z):487[M+H]
+.
Embodiment 11 (E)-N-(4-(3-(hydroxylamino)-3-oxa-propyl group-1-thiazolinyl) phenyl)-farnesyl thiosalicylic acid acid amides (I
11) preparation
(E) preparation of-N-(4-(3-(methoxyl group)-3-oxa-propyl group-1-thiazolinyl) phenyl)-farnesyl thiosalicylic acid acid amides (2k)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in p-aminophenyl methyl acrylate alternative method, react with (1) and make yellow oil (2k), yield 72% again.
(E)-N-(4-(3-(hydroxylamino)-3-oxa-propyl group-1-thiazolinyl) phenyl)-farnesyl thiosalicylic acid acid amides (I
11) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 2k alternative method, then react with oxammonium hydrochloride and make oily matter (I
11), yield 72%.
1H?NMR(CDCl
3,300MHz):7.90(m,1H,ArH),7.72(m,2H,ArH),7.55(m,2H,ArH,ArCH),7.40(m,2H,ArH),7.30(m,1H,ArH),5.23(m,1H,SCH
2C
H),5.04(m,2H,2×CH
2C
H=CCH
3),3.50(d,2H,J=7.2Hz,SCH
2),1.97-2.04(m,8H,CH
2),1.55-1.69(m,12H,CH
3);ESI-MS(m/z):519[M+H]
+.
Embodiment 12N-(4-(3-(hydroxylamino)-3-oxa-propyl group) phenyl)-farnesyl thiosalicylic acid acid amides (I
12) preparation
The preparation of N-(4-(3-(methoxyl group)-3-oxa-propyl group) phenyl)-farnesyl thiosalicylic acid acid amides (2l)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in p-aminophenyl methyl propionate alternative method, react with (1) and make yellow oil (2l), yield 66% again.
N-(4-(3-(hydroxylamino)-3-oxa-propyl group) phenyl)-farnesyl thiosalicylic acid acid amides (I
12) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 2l alternative method, then react with oxammonium hydrochloride and make oily matter (I
12), yield 68%.
1H?NMR(CDCl
3,300MHz):7.92(m,1H,ArH),7.75(m,2H,ArH),7.51(m,2H,ArH),7.44(m,2H,ArH),7.36(m,1H,ArH),5.26(m,1H,SCH
2C
H),5.06(m,2H,2×CH
2C
H=CCH
3),3.50(d,2H,J=7.2Hz,SCH
2),2.93(m,2H,ArCH
2),2.74(m,2H,CH
2CO),2.00(m,8H,CH
2),1.54(m,12H,CH
3);ESI-MS(m/z):521[M+H]
+.
Embodiment 13N-(4-(hydroxyl amido formacyl) phenyl)-farnesyl thiosalicylic acid acid amides (I
13) preparation
The preparation of N-(4-(methoxy methyl acyl group) phenyl)-farnesyl thiosalicylic acid acid amides (2m)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in methyl p-aminobenzoate alternative method, react with (1) and make yellow oil (2m), yield 69% again.
N-(4-(hydroxyl amido formacyl) phenyl)-farnesyl thiosalicylic acid acid amides (I
13) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 2m alternative method, then react with oxammonium hydrochloride and make oily matter (I
13), yield 73%.
1H?NMR(CDCl
3,300MHz):8.13(m,1H,Ar-H),7.97(d,1H,J=7.8Hz,Ar-H),7.78(m,2H,Ar-H),7.27-7.40(m,4H,Ar-H),5.24(m,1H,SCH
2C
H),5.09(m,2H,2×CH
2C
H=CCH
3),3.58(d,2H,J=7.2Hz,SCH
2),1.99-2.05(m,8H,4×CH
2),1.45-1.68(m,12H,4×CH
3);ESI-MS(m/z):493[M+H]
+.
Embodiment 14N-(4-(hydroxyl amido formacyl) benzyl)-farnesyl thiosalicylic acid acid amides (I
14) preparation
The preparation of N-(4-(methoxy methyl acyl group) benzyl)-farnesyl thiosalicylic acid acid amides (2n)
Preparation method with reference to N-in embodiment 1 (2-(methoxyl group)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (2a), glycine methyl ester in paraaminomethyl benzoic acid methyl esters alternative method, react with (1) and make yellow oil (2n), yield 65% again.
N-(4-(hydroxyl amido formacyl) benzyl)-farnesyl thiosalicylic acid acid amides (I
14) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 2n alternative method, then react with oxammonium hydrochloride and make oily matter (I
14), yield 67%.
1H?NMR(CDCl
3,300MHz):7.95(m,1H,ArH),7.78(m,2H,ArH),7.53(m,2H,ArH,ArCH),7.41(m,2H,ArH),7.28(m,1H,ArH),5.26(m,1H,SCH
2C
H),5.05(m,2H,2×CH
2C
H=CCH
3),4.39(s,2H,ArCH
2),3.53(d,2H,J=7.2Hz,SCH
2),1.97-2.02(m,8H,CH
2),1.51-1.67(m,12H,CH
3);ESI-MS(m/z):507[M+H]
+.
The preparation of embodiment 15N-(2-(4-(azanol)-4-oxa-butylamine base)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (II 1)
The preparation of N-(2-(hydroxyl)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (3a)
0.43g (1.00mmol) 2a is dissolved in 10mL MeOH, add wherein the 2mL1M NaOH aqueous solution, stir 1.5h at 60 ℃, steam except the methyl alcohol in reaction solution, drip wherein again 2M hydrochloric acid soln and regulate pH to 3-4, after use ethyl acetate (3 * 50mL) extraction, merge organic layer, by 50mL saturated common salt washing for organic layer, anhydrous sodium sulfate drying, filter, be spin-dried for and obtain oily matter 0.36g, yield 87%.
The preparation of N-(2-(4-methoxyl group-4-oxa-butylamine base)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (4a)
0.42g (1.01mmol) 3a and 0.12g (1.00mmol) 4-Aminobutanoicacid methyl esters are dissolved in to the anhydrous CH of 10mL
2cl
2in, add wherein 0.02g (0.16mmol) DMAP, after under ice bath, slowly drip the anhydrous CH of 5mL of 0.20g (1.04mmol) EDC
2cl
2solution, room temperature reaction 24h, uses respectively 20mL1M hydrochloric acid soln by reaction solution, the washing of 20mL saturated common salt, anhydrous sodium sulfate drying organic layer, filters, and becomes a cadre and obtains oily matter, yield 65%.
N-(2-(4-(azanol)-4-oxa-butylamine base)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (II
1) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 4a alternative method, then react with oxammonium hydrochloride and make oily matter (II
1), yield 68%.
H?NMR(CDCl
3,300MHz):δ7.98(d,1H,J=7.8Hz,Ar-H),7.75-7.46(m,2H,Ar-H),7.31(m,1H,Ar-H),5.40(m,1H,SCH
2C
H),5.09(m,2H,2×CH
2C
H=CCH
3),4.48(m,2H,NHC
H 2CONH),3.77(d,2H,J=7.2Hz,SCH
2),3.20(m,2H,NHC
H 2),2.33(t,2H,J=7.6Hz,CH
2CO),1.92-1.74(m,10H,2×CHC
H 2C
H 2CH,NHCH
2C
H 2),1.57-1.46(m,12H,4×CH
3);ESI-MS(m/z):516[M+H]
+.
Embodiment 16 (S)-N-(1-(3-(azanol)-3-oxa-Propylamino)-1-oxa-propyl group-2-yl)-farnesyl thiosalicylic acid acid amides (II
2) preparation
(S) preparation of-N-(1-(hydroxyl)-1-oxa-propyl group-2-yl)-farnesyl thiosalicylic acid acid amides (3b)
With reference to the preparation method of N-in embodiment 11 (2-(hydroxyl)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (3a), by the 2a in 2f alternative method, hydrolysis obtains oily matter (3b), yield 80%.
(S) preparation of-N-(1-(3-(methoxyl group)-3-oxa-Propylamino)-1-oxa-propyl group-2-yl)-farnesyl thiosalicylic acid acid amides (4b)
Preparation method with reference to N-in embodiment 11 (2-(4-methoxyl group-4-oxa-butylamine base)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (4a), by 3a and 4-Aminobutanoicacid methyl esters in 3b and 3-alanine methyl esters alternative method, condensation reaction obtains oily matter (4b), yield 66%.
(S)-N-(1-(3-(azanol)-3-oxa-Propylamino)-1-oxa-propyl group-2-yl)-farnesyl thiosalicylic acid acid amides (II
2) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 4b alternative method, then react with oxammonium hydrochloride and make oily matter (II
2), yield 68%.
H?NMR(CDCl
3,300MHz):δ7.83(d,1H,J=7.8Hz,Ar-H),7.60-7.51(m,2H,Ar-H),7.40(m,1H,Ar-H),5.63(m,1H,SCH
2C
H),5.16(m,2H,2×CH
2C
H=CCH
3),4.71(m,1H,NHC
HCH
3),3.62(d,2H,J=7.2Hz,SCH
2),2.28(m,2H,NHC
H 2),2.23(t,2H,J=7.6Hz,CH
2CO),1.97-1.74(m,8H,2×CHC
H 2C
H 2CH),1.64-1.41(m,15H,4×CH=CC
H 3,NHCHC
H 3);ESI-MS(m/z):516[M+H]
+.
Embodiment 17 (S)-N-(1-(2-(azanol)-2-oxa-ethylamino-)-3-methyl isophthalic acid-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (II
3) preparation
(S) preparation of-N-(1-(hydroxyl)-3-methyl isophthalic acid-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (3c)
With reference to the preparation method of N-in embodiment 11 (2-(hydroxyl)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (3a), by the 2a in 2g alternative method, hydrolysis obtains oily matter (3c), yield 77%.
(S) preparation of-N-(1-(2-(methoxyl group)-2-oxa-ethylamino-)-3-methyl isophthalic acid-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (4c)
Preparation method with reference to N-in embodiment 11 (2-(4-methoxyl group-4-oxa-butylamine base)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (4a), by the 3a in 3c and glycine methyl ester alternative method and 4-Aminobutanoicacid methyl esters, condensation reaction obtains oily matter (4c), yield 61%.
(S)-N-(1-(2-(azanol)-2-oxa-ethylamino-)-3-methyl isophthalic acid-oxa-butyl-2-yl)-farnesyl thiosalicylic acid acid amides (II
3) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 4c alternative method, then react with oxammonium hydrochloride and make oily matter (II
3), yield 72%.
H?NMR(CDCl
3,300MHz):δ8.14(d,1H,J=7.8Hz,Ar-H),7.60-7.56(m,2H,Ar-H),7.36(m,1H,Ar-H),5.47(m,1H,SCH
2C
H),5.17(m,2H,2×CH
2C
H=CCH
3),4.68(m,1H,NHC
H),4.42(m,2H,NHC
H 2CONH),3.72(d,2H,J=7.2Hz,SC
H 2),2.13-1.84(m,9H,2×CHC
H 2C
H 2CH,NHCHC
H),1.66-1.49(m,12H,4×CH=CC
H 3),1.02(m,6H,CH
2(C
H 3)
2);ESI-MS(m/z):530[M+H]
+.
Embodiment 18N-(2-(2-(azanol base)-2-oxa-ethylamino-)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (II
4) preparation
The preparation of N-(2-(2-(methoxyl group)-2-oxa-ethylamino-)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (4d)
Preparation method with reference to N-in embodiment 11 (2-(4-methoxyl group-4-oxa-butylamine base)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (4a), by the 3a in 3a and glycine methyl ester alternative method and 4-Aminobutanoicacid methyl esters, condensation reaction obtains oily matter (4d), yield 56%.
N-(2-(2-(azanol base)-2-oxa-ethylamino-)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (II
4) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 4d alternative method, then react with oxammonium hydrochloride and make oily matter (II
4), yield 73%.
H?NMR(CDCl
3,300MHz):δ7.90(d,1H,J=7.8Hz,Ar-H),7.60-7.53(m,2H,Ar-H),7.36(m,1H,Ar-H),5.43(m,1H,SCH
2C
H),5.22(m,2H,2×CH
2C
H=CCH
3),4.66(m,1H,NHC
H 2),3.77(d,2H,J=7.2Hz,SC
H 2),2.03-1.81(m,8H,2×CHC
H 2C
H 2CH),1.66-1.43(m,12H,4×CH=CC
H 3);ESI-MS(m/z):488[M+H]
+.
Embodiment 19N-(2-(3-(azanol base)-3-oxa-Propylamino)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (II
5) preparation
The preparation of N-(2-(3-(methoxyl group)-3-oxa-Propylamino)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (4e)
Preparation method with reference to N-in embodiment 11 (2-(4-methoxyl group-4-oxa-butylamine base)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (4a), by 3a and 4-Aminobutanoicacid methyl esters in 3a and 3-alanine methyl esters alternative method, condensation reaction obtains oily matter (4e), yield 59%.
N-(2-(3-(azanol base)-3-oxa-Propylamino)-2-oxa-ethyl)-farnesyl thiosalicylic acid acid amides (II
5) preparation
With reference to I in embodiment 1
1preparation method, the 2a in 4e alternative method, then react with oxammonium hydrochloride and make oily matter (II
5), yield 71%.
H?NMR(CDCl
3,300MHz):8.01(d,1H,J=7.6Hz,Ar-H),7.70-7.39(m,4H,Ar-H),7.30-7.25(m,3H,Ar-H),5.68(m,1H,SCH
2C
H),5.27(m,2H,2×CH
2C
H=CCH
3),4.73(m,1H,NHC
H 2),3.79(d,2H,J=7.4Hz,SC
H 2),3.54(m,2H,NHC
H 2),2.59(t,2H,J=7.6Hz,C
H 2CONH),2.04-1.78(m,8H,2×CHC
H 2C
H 2CH),1.68-1.50(m,12H,4×CH=CC
H 3);ESI-MS(m/z):502[M+H]
+.
Embodiment 20
Blue colorimetry (MTT) antitumor activity in vitro of tetramethyl-nitrogen azoles
Adopt the tetramethyl-nitrogen blue colorimetry of azoles (MTT) to evaluate the antiproliferative activity of the compounds of this invention to 8 kinds of human cancer cell strains.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 and SAHA as positive control drug.SAHA is widely used antitumor drug clinically at present, and its action target is exactly HDAC, therefore selects it as positive control drug.
Human cancer cell strain: liver cancer cell SMMC-7721, pancreatic cancer cell PANC-1, lung carcinoma cell H460, breast cancer cell MCF-7, brain cancer cell U251, ovarian cancer cell SKOV-3, transitional cell bladder carcinoma cell line EJ, stomach cancer cell SGC-7901.
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
14or compound ii
1-II
5(compound dilutes with PBS after dissolving with DMSO, and test-compound concentration is respectively 6.25 * 10
-6, 1.25 * 10
-5, 2.5 * 10
-5, 5 * 10
-5mol/L), every hole 20 μ L, cultivate 48 hours.MTT is added in 96 orifice plates, and every hole 20 μ L, react in incubator 4 hours.Suck supernatant liquor, add DMSO, every hole 150 μ L, jolting 5min on dull and stereotyped shaking table.With enzyme-linked immunosorbent assay instrument, at wavelength, be the optical density that 570nm place measures every hole, calculate cell inhibitory rate.Experimental result is as shown in table 3.
Cell inhibitory rate=(negative control group OD Zhi – tested material group OD value)/negative control group OD value * 100%.
Embodiment 21
The p-Raf in Ras downstream, p-Akt, p-ERK suppress active testing
Adopt Western blotting to detect test-compound I
1-I
14or compound ii
1-II
5p-Raf, the p-Akt in the Ras downstream of tumour cell PANC-1, p-ERK are suppressed to active testing.Get in exponential phase of growth cell in good condition make every milliliter containing 1.5 * 10
5the suspension of individual cell, is inoculated on 96 orifice plates, puts constant temperature CO
2in incubator, cultivate 24h.Change liquid, add 6.25 μ M, 12.5 μ M test-compounds, negative control adds equivalent PBS, continues to cultivate 8h.Trysinization, PBS cleans twice.Sample is resuspended in PBS, abandons supernatant, and cell is placed in 2mL EP pipe and adds protein cleavage liquid, 200 μ L/ pipes, repeatedly after piping and druming in ice bath reaction 30min, in centrifuging and taking supernatant liquor 2mL EP pipe, adopting SDS-PAGE(gum concentration is 12%) separated and transfer on nitrocellulose membrane.Film is put in 5% the skim-milk confining liquid of now joining, sealing finishes with a small amount of Blot wash, remaining milk powder rinsing is clean, and primary antibodie is diluted to working concentration with TBST, 500 μ L/ bars, and room temperature shaking table reacts 1h, can put thereafter 4 ℃ and spend the night.After reaction finishes, cut off valve bag, discarded antibody, is placed in ware by each film and cleans 4 times with TBST.With two of TBST dilution peroxidase mark, resist to working fluid concentration 500 μ L/ bars.By front method envelope and shaking table reaction, after reaction finishes, abandon two and resist, with TBST, clean 4 times.PIERCE luminescent solution A liquid+B liquid equal-volume mixes and pours in the valve bag making, and after reaction 5min, film is transferred to exposure image in BIO-RAD gel imaging instrument magazine.
Embodiment 22
HDACs is suppressed to active testing
Adopt ELISA enzyme linked immunological test compounds active to the inhibition of HDAC in vitro.EpiQuik
tMhADC Activity/Inhibition Assay Kit is purchased from Epigentek company, test-compound is configured to respectively to the solution of 1nM, 10nM and tri-concentration of 100nM, get respectively 10 μ L HDACs damping fluids and 5 μ LHela nucleus extraction things are jointly hatched after 5min at 37 ℃, add 25 μ L HDAC fluorogenic substrates, at 37 ℃, hatch 45min, then in reacting hole, add 25 μ L HDAC Assay developer termination reactions, and hatch 20min at 37 ℃, use microplate reader to go out to survey absorbancy at 405nm.Compound under each concentration of each compound is tested in triplicate.
Hela nucleus extraction thing working method: get containing the nutrient solution of 10% calf serum and cultivate Hela cell strain, with the lower cell of pipettor piping and druming, centrifugal collection supernatant, leaves cell precipitation standby.Every 20 μ L cell precipitations (approximately 2 * 10
6cell) add 200 μ L interpolation phenylmethylsulfonyl fluoride (PMSF) cell protein extract reagent, high speed vortex makes cell suspend completely and scatter, ice bath 5-10min, adds suppressor proteins extraction agent 10 μ L, after high speed vortex at 4 ℃ high speed centrifugation 5min.Absorb remaining supernatant completely, then add 50 μ L interpolation the Nuclear extract of PMSF extract reagent, repeat, after high speed vortex and centrifugal removal supernatant, can extract the Hela Nuclear extract obtaining.
Data analysing method: a. calculates the average signal value of each sample; B. the signal value of each concentration of specimens deducts average background signal value; C. calculate the inhibiting rate of each sample.100% active hole count value is deducted respectively after each testing compound different concns corresponding aperture numerical value, divided by 100% active hole count value, be multiplied by 100 inhibiting rates that obtain respectively each test-compound different concns.Inhibiting rate=(100% active hole count value-testing compound corresponding aperture numerical value)/100% active hole count value * 100.The IC of test-compound
50in Excel, with concentration and corresponding inhibiting rate, through nonlinear regression and fitting, obtain.
Claims (1)
1. a preparation method who treats two target drug compounds of tumour, is characterized in that: described medical compounds has the structure of following general formula II:
In general formula II :-NH-A-CO-is selected from and is configured as glycine residue, L-or D-type α-alanine residue, Beta-alanine residue, L-or D-type α-amino-isovaleric acid residue, L-or D-type leucine residue, L-or D-type Isoleucine residue, L-or D-type methionine residues, L-or D-type cysteine residues, L-or D-type phenylalanine residue, L-or D-type tyrosine residues, L-or D-type tryptophan residue, L-or D-type arginine residues, L-or D-type proline residue, L-or D-type histidine residues, or be selected from-NH (CH
2)
ncO-, n=3～7, or be selected from
or be selected from
o=0～5, or be selected from
be selected from-O-of X, or be selected from-NH-, or be selected from-NCH
3-, m=1～8,
Described general formula II preparation method comprises the following steps:
A. compound (2) is hydrolyzed and obtains compound (3) in containing the methanol solution of NaOH;
B. compound (3) is under condensing agent 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC) and DMAP (DMAP) effect, with HX (CH
2)
mcOOMe reacting generating compound (4);
C. final compound (4) reacts and makes general formula II with oxammonium hydrochloride under the methanol solution of potassium hydroxide;
General formula II reaction scheme is as follows:
Wherein, in general formula II :-NH-A-CO-is selected from and is configured as glycine residue, L-or D-type α-alanine residue, Beta-alanine residue, L-or D-type α-amino-isovaleric acid residue, L-or D-type leucine residue, L-or D-type Isoleucine residue, L-or D-type methionine residues, L-or D-type cysteine residues, L-or D-type phenylalanine residue, L-or D-type tyrosine residues, L-or D-type tryptophan residue, L-or D-type arginine residues, L-or D-type proline residue, L-or D-type histidine residues; Or be selected from-NH (CH
2)
ncO-, n=3～7; Or be selected from
or be selected from
o=0～5; Or be selected from
be selected from-O-of X, or be selected from-NH-, or be selected from-NCH
3-; M=1～8.
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