CN107722035A - A kind of qinghaosu bridged piperazine derivatives and its preparation method and the application in medicines resistant to liver cancer is prepared - Google Patents
A kind of qinghaosu bridged piperazine derivatives and its preparation method and the application in medicines resistant to liver cancer is prepared Download PDFInfo
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Abstract
The invention discloses a kind of qinghaosu bridged piperazine derivatives and preparation method thereof and application of this analog derivative in medicines resistant to liver cancer is prepared.This method prepares qinghaosu bridged piperazine derivatives using triethylamine as acid binding agent, by " one kettle way ", and reaction condition is gentle, easy to operate, and yield is preferable.In addition, made derivative has obvious In-vitro Inhibitory Effect to the cells of human liver cancer SMMC 7721, it is suitable with the inhibition of a line anti-liver cancer and anti-clinical chemotherapy agent vincristine.Application of the present invention for qinghaosu bridged piperazine derivatives in medicines resistant to liver cancer is prepared provides feasible strategy.
Description
Technical field
The present invention relates to a kind of qinghaosu-bridged piperazine derivatives and its preparation method and the application in medicines resistant to liver cancer is prepared.
Background technology
Qinghaosu has good antimalarial active, but its antitumor activity is less.Though qinghaosu and its derivative
So clinically using for many years, but still suffer from oil-soluble and water solubility is bad, heat endurance is poor, easily by wet, hot and reproducibility thing
The influence of matter and decompose, the shortcomings of clinical recurrence rate is high, is restricted its application.Therefore, by the method for chemical improvement, if
A series of new artemisinin derivative is counted and prepared, and investigates its antitumor activity, is a significant job.
Piperazine by way of forming multiple hydrogen bonds or ionic bond, can improve the bioactivity of medicine, can also adjust
The dissolubility and acid-base balance of medicine, promote the pharmacokinetics of medicine, have obvious effect in anti-tumor aspect.Therefore, often
It is incorporated into as a kind of synergist groups in drug molecule.
Dithiocarbamates compound is a kind of important sulfur-containing compound with unique texture and property, is being closed
Occupy important position into medicine.It has extensive bioactivity, as antibacterial, antiviral, anti-oxidant and treatment are chronic
Alcoholism and heavy metal poisoning etc..In recent years, increasing research finds that dithiocarbamates compound has
Preferable tumor prevention and antitumor activity, cause the research interest of domestic and foreign scholars.
Method of the invention by " treating different things alike ", using piperazine as attachment, under mild conditions, by two thio first of amino
Acrylate structure is introduced into qinghaosu molecule, qinghaosu-bridged piperazine derivatives of preparation, and human liver cancer cell (SMMC-7721) is grown
There is obvious inhibitory action, therefore qinghaosu-bridged piperazine derivatives are very worth as the prospect of very promising medicines resistant to liver cancer
Concern.
The content of the invention
In view of above-mentioned, it is an object of the invention to provide a kind of qinghaosu-bridged piperazine derivatives.Such derivative preparation method
Simply, resisting liver cancer activity is high.
Another object of the present invention is to provide the preparation method of a kind of qinghaosu-bridged piperazine derivatives.
It is also an object of the present invention to provide application of a kind of qinghaosu-bridged piperazine derivatives in terms of anti-liver cancer and anti-.
The purpose of the present invention is to be achieved through the following technical solutions：
(1) one kind qinghaosu-bridged piperazine derivatives, it is characterized in that it has below formula：
R is in formula：
(2) preparation method of qinghaosus-bridged piperazine derivatives：
The carbon disulfide that qinghaosu-piperazine and dosage are four times of amounts of qinghaosu-piperazine is dissolved in acetonitrile, then adds dosage
For the triethylamine of ten times of amounts of qinghaosu-piperazine, after 10min is stirred at room temperature, addition dosage is the halo of qinghaosu-piperazine doubling dose
Thing acetonitrile solution, 60 DEG C are gradually increased to, react 4~12h, TLC tracking, phosphomolybdic acid colour developing, after reaction terminates, solvent, silicon is evaporated off
Plastic column chromatography isolates and purifies (PE:EA=16:1~6:1) qinghaosu-bridged piperazine derivatives, are obtained.
Qinghaosu-bridged piperazine derivatives reaction is represented by the chemical formula as follows：
Advantages of the present invention and caused beneficial effect are：
1. the present invention is using triethylamine as acid binding agent, under the conditions of " treating different things alike ", by multi-component cascade reaction, efficiently
Rate prepares such qinghaosu-piperazine, and the reaction condition is gentle, and experimental implementation is simple and feasible, it is not necessary in the anhydrous and oxygen-free bar of harshness
Carried out under part, no metal reagent is environmentally friendly, and atom utilization is high.
2. qinghaosu-bridged piperazine derivatives of the present invention have obvious inhibitory action to human hepatocarcinoma BEL-7402 growth,
Therefore qinghaosu-bridged piperazine derivatives of the present invention can apply to prepare medicines resistant to liver cancer.
Embodiment
The present invention is further described by following examples, but the scope of the present invention is not appointed by these embodiments
What is limited.
Embodiment one：The preparation of qinghaosu-piperazine-aminodithioformic acid benzyl ester (compound 1)
At room temperature, (1.2mmol, 0.42g) qinghaosu piperazine, (4.8mmol, 0.36g) are sequentially added into round-bottomed flask
Carbon disulfide, 20mL acetonitriles and (12mmol, 1mL) triethylamine, stirring 10 minutes after, add 5mL dissolved with (2.5mmol,
0.43g) the acetonitrile solution of bromobenzyl, 60 DEG C are gradually heated to, react 12h, after TLC tracking reactions terminate, solvent is evaporated off, through silica gel
Column chromatography [eluant, eluent：V (petroleum ether)：V (ethyl acetate)=16:1] target compound is purified to obtain.White solid, yield
72.6%, m.p.130.4-130.8 DEG C, 1H NMR(400MHz,CDCl3)δ:7.37
(t, J=12.6Hz, 2H), 7.32-7.26 (m, 3H), 5.29 (d, J=10.7Hz, 1H), 4.56 (s, 2H), 4.35 (s, 2H),
4.07 (d, J=9.8Hz, 1H), 3.89 (s, 2H), 3.07 (s, 2H), 2.79 (s, 2H), 2.58 (s, 1H), 2.34 (td, J=
13.8,3.5Hz, 1H), 2.00 (d, J=14.4Hz, 1H), 1.94-1.81 (m, 1H), 1.78-1.65 (m, 2H), 1.55 (d, J
=12.8Hz, 2H), 1.49-1.15 (m, 5H), 1.03 (dd, J=18.0,7.7Hz, 2H), 0.95 (d, J=6.1Hz, 3H),
0.83 (d, J=6.5Hz, 3H)；13C NMR(101MHz,CDCl3)δ:196.01,135.90,129.36,128.54,127.44,
103.98,91.54,90.35,80.19,77.20,51.63,46.92,45.70,42.07,37.35,36.25,34.20,
28.50,25.97,24.70,21.57,20.25,13.46；IR(KBr)ν/cm-1:2981,2941,2866,1600,1491,
1447,1378,1310,1217,1161,1101,1039,999,955,926,880,842,743,712,611,550,486；
HRMS m/z:calcd for C27H38N2NaO4S2 541.2168,found 541.2170[M+Na]+.
Embodiment two：The preparation of qinghaosu-piperazine-aminodithioformic acid-(2- methyl) benzyl ester (compound 2)
Preparation method substitutes bromobenzyl with adjacent methyl bromobenzyl, obtains target compound, faint yellow solid, yield with embodiment one
55.6%, m.p.87.4-88.4 DEG C, 1H NMR(400MHz,CDCl3)δ:7.34(d,J
=7.1Hz, 1H), 7.16 (tt, J=6.2,3.7Hz, 3H), 5.27 (s, 1H), 4.51 (s, 2H), 4.35 (s, 2H), 4.06 (d,
J=10.2Hz, 1H), 3.89 (s, 2H), 3.06 (s, 2H), 2.78 (s, 2H), 2.57 (dqd, J=11.2,7.3,4.7Hz,
1H), 2.44-2.27 (m, 4H), 1.99 (ddd, J=14.6,5.0,2.9Hz, 1H), 1.86 (ddt, J=13.6,6.7,
3.4Hz, 1H), 1.70 (dp, J=10.6,3.4Hz, 2H), 1.60-1.38 (m, 5H), 1.38-1.16 (m, 4H), 1.08-0.91
(m, 3H), 0.82 (d, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ:196.11,137.36,133.17,130.40,
130.38,127.85,126.13,103.92,91.49,90.29,80.14,51.58,50.16,46.87,45.65,40.67,
37.29,36.20,34.15,28.45,25.93,24.65,21.52,20.22,19.28,13.42；IR(KBr)ν/cm-1:
2924,2870,1462,1422,1376,1310,1275,1230,1209,1130,1101,1040,1020,982,879,734,
550,510；HRMS m/z:calcd for C28H41N2O4S2 533.2429,found 533.2514[M+H]+.
Embodiment three：The preparation of qinghaosu-piperazine-aminodithioformic acid-(4- methyl) benzyl ester (compound 3)
Preparation method substitutes bromobenzyl with 4- methyl bromobenzyl, obtains target compound with embodiment one.White solid, yield
50.3%, m.p.135.9-136.9 DEG C, 1H NMR(400MHz,CDCl3)
δ:7.27 (d, J=7.5Hz, 2H), 7.12 (d, J=7.8Hz, 2H), 5.27 (s, 1H), 4.52 (s, 2H), 4.35 (s, 2H),
4.06 (d, J=10.3Hz, 1H), 3.91 (s, 2H), 3.05 (s, 2H), 2.78 (s, 2H), 2.57 (ddd, J=10.9,7.2,
4.3Hz, 1H), 2.35-2.29 (m, 4H), 2.00 (ddd, J=14.4,4.9,3.0Hz, 1H), 1.86 (ddt, J=13.6,
6.8,3.6Hz, 1H), 1.70 (ddd, J=13.0,7.3,3.5Hz, 2H), 1.59 (s, 2H), 1.55 (dt, J=13.8,
4.4Hz, 1H), 1.49-1.40 (m, 1H), 1.38 (s, 2H), 1.32 (td, J=13.4,3.6Hz, 1H), 1.22 (td, J=
11.3,6.5Hz, 1H), 1.00 (dd, J=12.1,3.7Hz, 1H), 0.94 (d, J=6.2Hz, 3H), 0.82 (d, J=7.1Hz,
3H)；13C NMR(101MHz,CDCl3)δ:196.19,137.20,132.67,129.28,129.26,104.00,91.55,
90.36,80.20,77.20,51.65,46.93,45.72,41.91,37.36,36.26,34.21,28.52,25.97,
24.71,21.59,21.13,20.26,13.46；IR(KBr)ν/cm-1:2924,2869,2846,1512,1456,1416,
1376,1278,1230,1135,1055,980,879,825,741,487；HRMS m/z:calcd for
C28H40NaN2O4S2555.2429,found 555.2338[M+Na]+.
Example IV：The preparation of qinghaosu-piperazine-aminodithioformic acid-(2- chlorine) benzyl ester (compound 4)
Preparation method substitutes bromobenzyl, heating response 4h obtains target compound, and pink colour is solid with embodiment one with adjacent chlorobenzyl chloride
Body, yield 50.6%, m.p.90.3-91 DEG C, 1H NMR(400MHz,CDCl3)δ:
7.56 (dd, J=5.8,3.6Hz, 1H), 7.37 (dd, J=5.7,3.6Hz, 1H), 7.21 (dd, J=5.9,3.5Hz, 2H),
5.27 (s, 1H), 4.72 (s, 2H), 4.35 (s, 2H), 4.06 (d, J=10.2Hz, 1H), 3.91 (s, 2H), 3.50 (s, 1H),
3.06 (s, 2H), 2.78 (s, 2H), 2.57 (ddd, J=10.9,7.2,4.4Hz, 1H), 2.34 (td, J=13.9,3.9Hz,
1H), 2.03-1.96 (m, 1H), 1.91-1.82 (m, 1H), 1.71 (ddd, J=12.4,7.3,3.5Hz, 2H), 1.56 (s,
2H), 1.48-1.41 (m, 1H), 1.38 (s, 3H), 0.94 (d, J=6.2Hz, 3H), 0.82 (d, J=7.1Hz, 3H)；13C NMR
(101MHz,CDCl3)δ:195.76,134.45,134.18,131.48,129.46,128.89,126.87,104.01,
91.52,90.32,80.21,77.20,51.58,50.55,45.66,39.42,37.30,36.19,34.13,28.48,
25.86,24.63,21.53,20.18,13.40；IR(KBr)ν/cm-1:3096,3023,1885,1472,1404,1275,
1231,1208,1185,1130,1053,983,926,879,826,743,550；HRMS m/z:calcd for C27H37Cl
NaN2O4S2575.1776,found 575.1778[M+Na]+.
Embodiment five：The preparation of qinghaosu-piperazine-aminodithioformic acid-(4- chlorine) benzyl ester (compound 5)
Preparation method, to substitute bromobenzyl to chlorine bromobenzyl, obtains target compound, white solid, yield with embodiment one
71.5%, m.p.111.3-112.2 DEG C, 1H NMR(400MHz,CDCl3)δ:
7.35-7.30 (m, 2H), 7.28 (d, J=2.3Hz, 2H), 5.27 (s, 1H), 4.54 (s, 2H), 4.34 (s, 2H), 4.07 (d, J
=10.2Hz, 1H), 3.97-3.83 (m, 2H), 3.49 (d, J=5.0Hz, 1H), 3.06 (s, 2H), 2.78 (s, 2H), 2.57
(ddd, J=11.0,7.1,4.3Hz, 1H), 2.34 (td, J=13.9,3.9Hz, 1H), 2.00 (dt, J=14.6,3.8Hz,
1H), 1.90-1.82 (m, 1H), 1.71 (ddd, J=12.5,7.4,3.5Hz, 2H), 1.58-1.42 (m, 3H), 1.38 (s,
4H), 1.04-0.97 (m, 1H), 0.95 (d, J=6.2Hz, 3H), 0.82 (d, J=7.1Hz, 3H)；13C NMR(101MHz,
CDCl3)δ:195.48,134.85,133.20,130.67,128.64,104.00,91.56,90.35,80.20,77.20,
51.63,50.90,45.70,41.02,37.36,36.25,34.19,28.51,25.98,24.69,21.58,20.26,
13.46；IR(KBr)ν/cm-1:2926,2865,1738,1488,1424,1378,1305,1276,1159,1104,1052,
978,926,879；HRMS m/z:calcd for C27H37ClNaN2O4S2 575.1780,found 575.1782[M+Na]+.
Embodiment six：The preparation of qinghaosu-piperazine-aminodithioformic acid-(4- bromines) benzyl ester (compound 6)
Preparation method, to substitute bromobenzyl to bromine benzyl chloride, obtains target compound, white solid, yield with embodiment one
55.7%, m.p.136.9-138 DEG C, 1H NMR(400MHz,CDCl3)δ:7.45–
7.40 (m, 2H), 7.30-7.24 (m, 4H), 5.27 (s, 1H), 4.53 (s, 2H), 4.34 (s, 2H), 4.06 (d, J=10.3Hz,
1H), 3.90 (d, J=27.5Hz, 2H), 3.06 (s, 2H), 2.78 (s, 2H), 2.57 (ddd, J=10.7,7.2,4.3Hz,
1H), 2.38-2.29 (m, 1H), 2.00 (ddd, J=14.5,4.9,2.9Hz, 1H), 1.86 (ddt, J=10.1,7.0,
3.4Hz, 1H), 1.75-1.66 (m, 1H), 1.59-1.46 (m, 2H), 1.38 (s, 3H), 1.30 (dd, J=13.7,3.7Hz,
1H), 1.22 (td, J=11.2,6.5Hz, 1H), 1.07-0.98 (m, 1H), 0.95 (d, J=6.2Hz, 3H), 0.82 (d, J=
7.2Hz,3H)；13C NMR(101MHz,CDCl3)δ:195.44,135.42,131.59,131.01,121.32,104.00,
91.56,90.35,80.20,77.20,51.64,46.94,45.71,41.04,37.36,36.25,34.20,28.51,
25.98,24.70,21.58,20.25,13.46；IR(KBr)ν/cm-1:2925,2865,1476,1425,1378,1305,
1276,1229,1158,1042,1020,979,931,879,826,609；HRMS m/z:calcd for
C27H38BrN2O4S2597.1378,found 597.1465[M+H]+.
Embodiment seven：The preparation of qinghaosu-piperazine-aminodithioformic acid-(4- cyano group) benzyl ester (compound 7)
Preparation method substitutes bromobenzyl, heating response 4h, through silica gel column chromatography [eluant, eluent with embodiment one to cyano-benzyl bromide：
V (petroleum ether)：V (ethyl acetate)=12：1] purify and obtain faint yellow solid, yield 65.8%, m.p.146.7-147.3 DEG C, 1H NMR(400MHz,CDCl3)δ:7.62–7.57(m,2H),7.52–7.48(m,
2H), 5.27 (s, 1H), 4.65 (s, 2H), 4.34 (s, 2H), 4.07 (d, J=10.3Hz, 1H), 3.91 (d, J=29.7Hz,
2H), 3.07 (s, 2H), 2.79 (s, 2H), 2.57 (ddd, J=10.9,7.3,4.4Hz, 1H), 2.34 (ddd, J=14.5,
13.3,4.0Hz, 1H), 2.05-1.96 (m, 1H), 1.86 (ddt, J=13.6,6.7,3.6Hz, 1H), 1.75-1.67 (m,
2H), 1.57 (d, J=1.9Hz, 1H), 1.55-1.46 (m, 1H), 1.38 (s, 4H), 1.34-1.27 (m, 1H), 1.27-1.19
(m, 1H), 1.02 (td, J=13.1,12.2,4.0Hz, 1H), 0.95 (d, J=6.2Hz, 3H), 0.82 (d, J=7.2Hz,
3H)；13C NMR(101MHz,CDCl3)δ:194.67,142.62,132.19,129.98,118.78,111.03,104.01,
91.56,90.34,80.20,77.20,51.62,50.87,45.69,40.78,37.35,36.23,34.18,28.50,
25.97,24.68,21.57,20.24,13.45；IR(KBr)ν/cm-1:3140,2937,2864,2229,1736,1606,
1477,1378,1305,1276,1158,1051,980,926,880,543cm-1；HRMS m/z:calcd for
C28H37NaN3O4S2 566.2116,found 566.2118[M+Na]+.
Embodiment eight：The preparation of qinghaosu-piperazine-aminodithioformic acid-(4- nitros) benzyl ester (compound 8)
Preparation method substitutes bromobenzyl with 4- nitros bromobenzyl, obtains target compound, yellow solid, yield with embodiment one
67.6%, m.p.82.2-82.9 DEG C, 1H NMR(400MHz,CDCl3)δ:8.19–8.13
(m, 2H), 7.59-7.54 (m, 2H), 5.27 (s, 1H), 4.69 (s, 2H), 4.34 (s, 2H), 4.07 (d, J=10.3Hz, 1H),
3.92 (d, J=31.3Hz, 2H), 3.07 (s, 2H), 2.80 (s, 2H), 2.57 (ddd, J=10.9,7.2,4.3Hz, 1H),
2.39-2.29 (m, 1H), 2.00 (dt, J=14.4,4.1Hz, 1H), 1.90-1.82 (m, 1H), 1.71 (ddd, J=12.7,
7.6,3.6Hz,2H),1.59–1.46(m,2H),1.42(s,1H),1.38(s,3H),1.34–1.18(m,2H),1.07–0.92
(m,4H),0.90–0.78(m,3H)；13C NMR(101MHz,CDCl3)δ:196.96,194.68,142.62,132.20,
129.98,111.04,104.02,103.98,91.56,90.34,80.21,77.20,51.63,50.88,45.69,40.79,
37.35,37.16,36.26,34.20,31.16,28.51,28.32,25.97,24.69,22.28,21.58,20.25,
13.96,13.46；IR(KBr)ν/cm-1:3316,3047,2924,2870,2011,1754,1599,1453,1345,1275,
1159,1041,983,879,724cm-1；HRMS m/z:calcd for C27H37N3NaO6S2 586.2016,
found586.2018[M+Na]+.
Embodiment nine：The preparation of qinghaosu-piperazine-aminodithioformic acid -2- menaphthyls ester (compound 9)
Preparation method replaces bromobenzyl, through silica gel column chromatography [eluant, eluent with embodiment one with 2- bromomethyls naphthalene：V (oil
Ether)：V (ethyl acetate)=12:1] purify and obtain white solid, yield 60.3%, m.p.143.8-144.0 DEG C, 1H NMR(400MHz,CDCl3)δ:7.86–7.77(m,5H),7.51–7.42(m,
3H), 5.27 (s, 1H), 4.74 (s, 2H), 4.37 (s, 2H), 4.07 (d, J=10.2Hz, 1H), 3.93 (s, 2H), 3.07 (s,
2H), 2.79 (s, 2H), 2.57 (tt, J=11.2,6.9Hz, 1H), 2.38-2.29 (m, 1H), 1.99 (dd, J=14.4,
4.2Hz, 1H), 1.86 (ddd, J=13.6,6.6,3.4Hz, 1H), 1.71 (ddd, J=12.7,7.6,3.6Hz, 2H), 1.58
(s, 3H), 1.40 (d, J=16.5Hz, 4H), 1.34-1.18 (m, 1H), 1.07-0.90 (m, 3H), 0.90-0.78 (m, 3H)；13C NMR(101MHz,CDCl3)δ:195.88,133.41,133.26,132.64,128.27,128.11,127.70,
127.59,127.27,126.11,125.87,103.96,91.52,90.33,80.17,77.20,51.61,46.91,45.68,
42.28,40.07,37.32,36.23,34.17,28.49,26.85,25.95,24.67,21.55,20.23,13.44；IR
(KBr)ν/cm-1:2924,2870,1599,1508,1422,1376,1309,1275,1231,1159,1130,1020,982,
879,755,474；HRMS m/z:calcd for C31H40NaN2O4S2 591.2429,found 591.2342[M+Na]+.
Embodiment ten：The preparation of qinghaosu-piperazine-aminodithioformic acid amyl group ester (compound 10)
Preparation method substitutes bromobenzyl with chloropentane, heating response 10h, obtains target compound, pale yellow colored solid with embodiment one
Body, yield 58.0%, m.p.135.8-136.2 DEG C of 1H NMR(400MHz,CDCl3)
δ:5.25 (s, 1H), 4.32 (s, 2H), 4.05 (d, J=10.2Hz, 1H), 4.00-3.82 (m, 2H), 3.27 (t, J=7.4Hz,
2H), 3.04 (dt, J=11.8,5.2Hz, 2H), 2.76 (p, J=4.9Hz, 2H), 2.56 (ddt, J=10.1,7.1,3.6Hz,
1H), 2.32 (td, J=13.9,3.9Hz, 1H), 1.98 (ddd, J=14.5,5.0,3.0Hz, 1H), 1.84 (ddt, J=
13.6,6.8,3.5Hz, 2H), 1.69 (ddt, J=14.8,10.2,5.4Hz, 5H), 1.53 (dt, J=13.6,4.3Hz, 1H),
1.47-1.26 (m, 8H), 1.21 (td, J=11.2,6.4Hz, 1H), 1.07-0.96 (m, 1H), 0.96-0.85 (m, 6H),
0.81 (d, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ:196.89,103.92,91.51,90.29,80.16,
51.60,50.11,46.87,45.68,37.31,37.11,36.22,34.17,31.12,28.48,28.28,25.93,
24.66,22.24,21.55,20.23,13.93,13.44；IR(KBr)ν/cm-1:3232,3079,2937,1755,1423,
1388,1277,1233,1160,1131,1022,999,932,881cm-1；HRMS m/z:calcd for C25H42N2NaO4S2
521.2477,found 521.2479[M+Na]+.
Embodiment 11：The preparation of qinghaosu-piperazine-aminodithioformic acid stearyl (compound 11)
Preparation method substitutes bromobenzyl with 1- chlorine octadecane, obtains target compound, yellow, waxy solid, production with embodiment one
Rate 49.3%, 1H NMR(400MHz,CDCl3)δ:5.25(s,1H),4.32(s,2H),
4.05 (d, J=10.2Hz, 1H), 3.27 (t, J=7.5Hz, 2H), 3.04 (dt, J=11.0,4.9Hz, 2H), 2.76 (dt, J
=11.3,4.8Hz, 2H), 2.56 (ddd, J=11.2,7.2,4.2Hz, 1H), 2.32 (td, J=13.9,3.9Hz, 1H),
1.98 (ddd, J=14.5,4.9,2.9Hz, 1H), 1.84 (ddt, J=13.5,6.7,3.5Hz, 1H), 1.74-1.63 (m,
4H), 1.53 (dt, J=13.9,4.4Hz, 1H), 1.30 (d, J=49.8Hz, 39H), 1.01 (td, J=13.1,12.3,
4.0Hz, 1H), 0.93 (d, J=6.2Hz, 3H), 0.89-0.77 (m, 6H)；13C NMR(101MHz,CDCl3)δ:196.84,
103.87,91.47,90.27,80.12,51.58,46.87,45.66,37.28,37.12,36.20,34.16,31.84,
29.62,29.60,29.58,29.53,29.44,29.29,29.15,28.97,28.56,28.45,25.90,24.64,
22.61,21.52,20.20,14.07,13.41；IR(KBr)ν/cm-1:2923,2852,1466,1421,1376,1310,
1275,1231,1130,1055,983,880,834,721,551；HRMS m/z:calcd for C38H69N2O4S2
681.4621,found681.4713[M+H]+.
Embodiment 12：The preparation of qinghaosu-piperazine-aminodithioformic acid-(benzyloxy acyl group) methyl esters (compound 12)
Preparation method substitutes bromobenzyl, through silica gel column chromatography [eluant, eluent with embodiment one with benzyl acetate bromide：V (oil
Ether)：V (ethyl acetate)=6:1] purify and obtain orange/yellow solid, yield 35%, m.p.82.3-83.3 DEG C, 1H NMR(400MHz,CDCl3)δ:7.40–7.36(m,4H),7.33
(dddd, J=11.4,4.9,2.9,1.8Hz, 1H), 5.28 (s, 1H), 5.19 (s, 2H), 4.31 (s, 2H), 4.21 (s, 2H),
4.07 (d, J=10.2Hz, 1H), 3.95 (d, J=32.2Hz, 2H), 3.08 (dt, J=11.3,5.0Hz, 2H), 2.80 (dt, J
=11.5,5.2Hz, 2H), 2.63-2.53 (m, 1H), 2.34 (ddd, J=14.5,13.3,3.9Hz, 1H), 2.05-1.96 (m,
1H), 1.87 (ddd, J=13.6,6.6,3.4Hz, 1H), 1.71 (ddt, J=11.2,6.5,3.5Hz, 2H), 1.60 (s, 1H),
1.55 (dt, J=13.6,4.3Hz, 1H), 1.49-1.41 (m, 1H), 1.38 (s, 3H), 1.35-1.18 (m, 2H), 1.07-
0.98 (m, 1H), 0.95 (d, J=6.2Hz, 3H), 0.83 (d, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ:
194.32,168.57,135.47,128.52,128.30,128.29,104.01,91.54,90.36,80.20,67.46,
51.64,46.91,45.71,38.91,37.36,36.26,34.21,28.53,26.88,25.97,24.71,21.59,
20.26,13.46；IR(KBr)ν/cm-1:2925,2871,1738,1425,1376,1275,1235,1040,980,925,878,
741,697,550；HRMS m/z:calcd for C29H40NaN2O6S2 599.2328,found 599.2246[M+Na]+.
Embodiment 13：The external anti-human liver cancer SMMC-7721 cytoactive researchs of qinghaosu-bridged piperazine derivatives
Using MTT (tetrazolium-based colorimetric assay), qinghaosu-bridged piperazine derivatives (compound 1~12), measure are chosen
Its inhibiting rate to human hepatocarcinoma BEL-7402, calculate IC50It is worth (μM).Concrete operation step is as follows：
1st, cell recovery
Cell culture medium：1640+10%FBS+1% (Penicillin-Streptomycin Solution)
(1) SMMC7721 cells are taken out from liquid nitrogen respectively, be quickly put into 37 DEG C of water-baths, jog cryopreservation tube makes jelly
Liquid storage dissolves；
(2) cell is transferred to respectively in the centrifuge tube containing 5mL culture mediums after dissolving, cell, room temperature is collected by centrifugation
1000rpm centrifuges 5min, abandons supernatant；
(3) with the complete medium suspension cell containing 10% hyclone, it is inoculated into culture dish, gently piping and druming mixes,
37 DEG C, 5%CO2, cultivate under the conditions of saturated humidity.
2nd, passage
When the density of cell reaches 80%, cell is passed on：
(1) culture medium is discarded, is washed one time with PBS；
(2) add the trypsin digestion and cells of 1-2mL 0.25%, micro- Microscopic observation, digest 30-60s, it can be seen that cell
It is separated from each other and is rounded, be i.e. digestion is completed；
(3) pancreatin is quickly discarded, adds complete medium, cell is blown and beaten, single cell suspension is made, by 1:3 ratio passes
Generation, 37 DEG C, 5%CO2, expand culture under the conditions of saturated humidity.
3rd, cell processing and MTT detections
(1) take in exponential phase, the good SMMC7721 cells of growth conditions, it is close to adjust cell with 1640 culture mediums
Spend to 1 × 104Individual/mL, 96 orifice plates are accessed, per the μ L cell suspensions of hole 100, while set blank group, 37 DEG C of overnight incubations are (in cell
The 100 sterile PBS of μ L are added in the holes around of hole)；
(2) after cell attachment well-grown 24h, old nutrient solution is absorbed, various concentrations are added into each culture hole
The test liquid of compound 1~12.5 parallel repeating holes are set per concentration, while set isometric dimethyl sulfoxide (DMSO) (DMSO) solvent
With the blank control wells without pharmaceutical culture medium, in 37 DEG C, 5%CO2Incubator in continue to cultivate.
After cultivating 24h, 48h, 72h respectively, abandoning supernatant, add 10 μ L (2mg/mL in PBS) MTT per hole, continue to train
After supporting 4h, culture supernatant in hole is suctioned out, 150 μ L dimethyl sulfoxide (DMSO)s are added per hole, vibration 10min dissolves bluish violet crystal
After fully, the absorbance (OD values) per hole sample is determined with ELIASA at wavelength 568nm, removes peak and minimum,
Take the average value of surplus value.
The calculating of inhibiting rate：The inhibiting rate of cell growth calculates according to the following formula：
Inhibiting rate (%)=[1- (test sample OD values-blank OD values)/(negative control OD value-blank OD values)] ×
100%
The inhibiting rate of 1 qinghaosu of table-bridged piperazine derivatives, 1~12 pair of human hepatocarcinoma BEL-7402
The suppression IC of 2 qinghaosus of table-bridged piperazine derivatives, 1~12 pair of human hepatocarcinoma BEL-740250It is worth (μM)
[a] Zhao Chenyang, Qiu Rong, Zheng Rong beam Lanzhou University journal (from section's version), 2000,36 (4), (Changchun is new by 66-68.
Alkali:IC50=63.2 ± 1.8 μ g/mL=0.074 ± 0.002 μM)；[b]J.J.Lu,L.H.Meng,Y.J.Cai,et
al.Cancer.Biol.Ther.2008,7,1017-1023.
Claims (3)
1. a kind of qinghaosu-bridged piperazine derivatives, it is characterized in that it has below formula：
R is in formula：
2. the preparation method of a kind of qinghaosu-bridged piperazine derivatives as claimed in claim 1：It is characterized in that by qinghaosu-piperazine
It is that four times of carbon disulfide measured of qinghaosu-piperazine are dissolved in acetonitrile with dosage, it is ten times of amounts of qinghaosu-piperazine then to add dosage
Triethylamine, after 10min is stirred at room temperature, addition dosage is the halides acetonitrile solution of qinghaosu-piperazine doubling dose, is gradually increased to 60
DEG C, 4~12h is reacted, TLC tracking, phosphomolybdic acid colour developing, after reaction terminates, solvent, silica gel column chromatography separating purification (PE is evaporated off:EA
=16:1~6:1) qinghaosu-bridged piperazine derivatives, are obtained.
3. application of a kind of qinghaosu-bridged piperazine derivatives in medicines resistant to liver cancer is prepared.
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