CN105777731B - The bridged piperazine derivatives and its preparation method and application of Han You oxadiazoles - Google Patents
The bridged piperazine derivatives and its preparation method and application of Han You oxadiazoles Download PDFInfo
- Publication number
- CN105777731B CN105777731B CN201610259548.7A CN201610259548A CN105777731B CN 105777731 B CN105777731 B CN 105777731B CN 201610259548 A CN201610259548 A CN 201610259548A CN 105777731 B CN105777731 B CN 105777731B
- Authority
- CN
- China
- Prior art keywords
- piperazine
- solid product
- oxadiazoles
- han
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention belongs to technical field of organic synthesis, and in particular to a kind of bridged piperazine derivatives and its preparation method and application of Han You oxadiazoles.The bridged piperazine derivatives of Han You oxadiazoles of the present invention, structural formula are as follows：
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of bridged piperazine derivatives of Han You oxadiazoles and its preparation
Method and purposes.
Background technology
In recent years, application of the piperazine compounds in organic synthesis and medicine has caused organise educational circles and pharmacy circle
Extensive concern.Piperazine ring is the hexa-member heterocycle for containing two nitrogen-atoms in molecule, is the ideal structure list of azotic heterocyclic compound
Member has the characteristics that the enthalpy of formation is high, thermal stability is good.The compound of the ring containing phenylpiperazine has efficient pharmacological activity mostly,
Some have been developed into clinical medicine.
From the point of view of currently available technology, oxadiazole and derivative have potential active anticancer, these compounds are non-selection
There is active anticancer to all cancer cells to property wide spectrum.Its derivative of You Yu oxadiazoles has apparent inhibition to make growth of cancer cells
With the foreground as very promising anticancer drug extremely merits attention.With piperazines He oxadiazole class drug research not
It is disconnected deeply, carried out on the basis of constantly understanding its pharmacological activity and mechanism of anticancer action effective structure of modification and modification and
MOLECULE DESIGN, it will have the piperazines drug of more and more efficient, low toxicity Han You oxadiazoles for clinic, promote the well-being of mankind.
Invention content
The object of the present invention is to provide a kind of piperazine derivatives to Han You oxadiazole of the cancer cell with obvious inhibiting effect
Object；Scientific and reasonable, simple and practicable preparation method and purposes that present invention simultaneously provides its.
The bridged piperazine derivatives of Han You oxadiazoles of the present invention, structural formula are as follows：
Wherein, R is Chloro-O-Phenyl, benzyl, o-methoxyphenyl, p-methoxyphenyl, p-fluorophenyl, pyridyl group, neighbour
Fluorophenyl, p-nitrophenyl, rubigan, 2,3- dichlorophenyls, 3,4- dichlorophenyls, m-methoxyphenyl, diphenyl methyl
Or one kind of m-trifluoromethylphenyl；
Structural formula is as follows：
The preparation method of the bridged piperazine derivatives of the Han You oxadiazoles, includes the following steps：
(1) 3,4-Dihydroxybenzoic acid, the concentrated sulfuric acid, methanol are subjected to back flow reaction, TLC detections obtain until raw material disappearance
To solid product；
(2) solid product, acetone, Bromofume, the potassium carbonate obtained step (1) carries out back flow reaction, obtains solid
Product；
(3) solid product, ethyl alcohol, the hydrazine hydrate obtained step (2) carries out back flow reaction, obtains solid product；
(4) solid product, ethyl alcohol, carbon disulfide, the potassium hydroxide obtained step (3) carries out back flow reaction, then steams
It is dry, add distillation water dissolution, filter, obtained filtrate its pH value of dilute hydrochloric acid tune to 4~5, solid product is precipitated to obtain in filtering；
(5) phenylpiperazine of the solid product, substituent group that obtain step (4), ethyl alcohol, formaldehyde through stirring at normal temperature, filtering,
Obtain the bridged piperazine derivatives of Han You oxadiazoles.
Wherein：
In step (1), 3,4-Dihydroxybenzoic acid, the concentrated sulfuric acid, methanol usage ratio be 1:0.1:5, wherein 3,4- bis-
Hydroxybenzoic acid is in terms of mmol, and the concentrated sulfuric acid, methanol are in terms of mL.
In step (2), solid product that step (1) obtains, acetone, Bromofume, potassium carbonate usage ratio be 1:20:
1:1.5, wherein solid product that step (1) obtains, Bromofume, potassium carbonate are in terms of mmol, and for acetone in terms of mL, reflux is anti-
It is 15h between seasonable.
In step (3), solid product that step (2) obtains, ethyl alcohol, hydrazine hydrate usage ratio be 0.1:2:0.5,
In, the solid product that step (2) obtains is in terms of mmol, and ethyl alcohol, hydrazine hydrate are in terms of mL, reflux time 15h.
In step (4), solid product that step (3) obtains, ethyl alcohol, carbon disulfide, potassium hydroxide usage ratio be 1:
20:1:1, wherein solid product that step (3) obtains, carbon disulfide, potassium hydroxide are in terms of mmol, and ethyl alcohol is in terms of mL, reflux
Reaction time is for 24 hours.
In step (5), the phenylpiperazine of solid product, substituent group that step (4) obtains, the usage ratio of ethyl alcohol, formaldehyde
It is 1:1:20:1.5, wherein the phenylpiperazine of solid product, phenylpiperazine or the substituent group that step (4) obtains, formaldehyde with
Mmol is counted, and ethyl alcohol is in terms of mL, stirring at normal temperature 12h.
In step (5), substituted phenylpiperazine is Chloro-O-Phenyl piperazine, benzyl piperazine, o-methoxyphenyl piperazine, right
Methoxyphenylpiperazderivatives, p-fluorophenyl piperazine, Pyridylpiperazine, o-fluorophenyl piperazine, p-nitrophenyl piperazine, rubigan piperazine
Piperazine, 2,3- dichlorophenylpiperazines, 3,4- dichlorophenylpiperazines, m-methoxyphenyl piperazine, diphenylmethyl piperazine or trifluoro
One kind in aminomethyl phenyl piperazine.
The bridged piperazine derivatives of Han You oxadiazoles of the present invention can be used in preparing anticancer drug.
Beneficial effects of the present invention are as follows：
The present invention will introduce phenylpiperazine ring with high anti-cancer activity oxadiazoles, and the piperazine for preparing Han You oxadiazoles spreads out
Biology.The bridged piperazine derivatives of Han You oxadiazoles have apparent inhibiting effect to growth of cancer cells, and raw materials used cheap, simple easy
, reaction step is few, and yield is high, is suitble to industrialized production, is used to prepare anticancer drug.
Specific implementation mode
The present invention is described further with reference to embodiments.
Embodiment 1
5- (2,3- dihydrobenzos [b] [1,4] dioxine -6- bases) -3- ((4- (4- methoxyphenyls) piperazine -1-
Base) methyl) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
Above compound preparation method is as follows：
(1) 3,4-Dihydroxybenzoic acid, the concentrated sulfuric acid, methanol are subjected to back flow reaction, TLC detections obtain until raw material disappearance
To solid product；
The usage ratio of 3,4- dihydroxy-benzoic acids, the concentrated sulfuric acid and methanol is 1:0.1:5, wherein 3,4- dihydroxy benzenes first
Acid is in terms of mmol, and the concentrated sulfuric acid, methanol are in terms of mL.
(2) solid product, acetone, Bromofume, the potassium carbonate obtained step (1) carries out back flow reaction, obtains solid
Product；
Solid product that step (1) obtains, acetone, Bromofume, potassium carbonate usage ratio be 1:20:1:1.5,
In, solid product that step (1) obtains, Bromofume, potassium carbonate are in terms of mmol, and in terms of mL, reflux time is acetone
15h。
(3) solid product, ethyl alcohol, the hydrazine hydrate obtained step (2) carries out back flow reaction, obtains solid product；
Solid product that step (2) obtains, ethyl alcohol, hydrazine hydrate usage ratio be 0.1:2:0.5, wherein step (2)
To solid product in terms of mmol, ethyl alcohol, hydrazine hydrate are in terms of mL, reflux time 15h.
(4) solid product, ethyl alcohol, carbon disulfide, the potassium hydroxide obtained step (3) carries out back flow reaction, then steams
It is dry, add distillation water dissolution, filter, obtained filtrate its pH value of dilute hydrochloric acid tune to 4~5, solid product is precipitated to obtain in filtering；
Solid product that step (3) obtains, ethyl alcohol, carbon disulfide, potassium hydroxide usage ratio be 1:20:1:1,
In, solid product that step (3) obtains, carbon disulfide, potassium hydroxide are in terms of mmol, and in terms of mL, reflux time is ethyl alcohol
24h。
(5) solid product that obtains step (4), p-methoxyphenyl piperazine, ethyl alcohol, formaldehyde are through stirring at normal temperature 12h, mistake
Filter, obtains the bridged piperazine derivatives of Han You oxadiazoles；
Solid product that step (4) obtains, p-methoxyphenyl piperazine, ethyl alcohol, formaldehyde usage ratio be 1:1:20:
1.5, wherein solid product that step (4) obtains, p-methoxyphenyl piperazine, formaldehyde are in terms of mmol, and ethyl alcohol is in terms of mL.
White powder, yield 80%, Mp:147.2-148.1℃.1H NMR(400MHz,CDCl3):3.077-3.134
(m, 8H), 3.808-3.825 (m, 3H), 4.345-4.385 (m, 4H), 5.166 (s, 2H), 6.863-6.886 (d, J=
9.2Hz, 2H), 6.920-6.943 (d, J=9.2Hz, 2H), 6.992-7.013 (d, J=8.4Hz, 1H), 7.471-7.498
(m,2H)。
Embodiment 2
5- (2,3- dihydrobenzos [b] [1,4] dioxine -6- bases) -3- ((4- (4- nitrobenzophenones) piperazine -1-
Base) methyl) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with p-nitrophenyl piperazine, obtains target compound.
Yellow powder, yield 85%, Mp:202.6-202.7℃.1H NMR(400MHz,CDCl3):3.035-3.061
(m, 4H), 3.487-3.513 (m, 4H), 4.352-4.380 (m, 4H), 5.165 (s, 2H), 6.832-6.856 (d, J=
9.6Hz, 2H), 6.988-7.008 (d, J=8.0Hz, 1H), 7.454-7.480 (m, 2H), 8.139-8.162 (d, J=
9.2Hz,2H)。
Embodiment 3
5- (2,3- dihydrobenzos [b] [1,4] dioxine -6- bases) -3- ((4- (2- methoxyphenyls) piperazine -1-
Base) methyl) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with o-methoxyphenyl piperazine, obtains target chemical combination
Object.
White powder, yield 80%, Mp:181.0-181.7℃.1H NMR(400MHz,CDCl3):3.120(s,
8H), 3.877 (s, 3H), 4.348-4.388 (m, 4H), 5.181 (s, 2H), 6.879-6.899 (d, J=8.0Hz, 1H),
6.942-7.071(m,4H),7.468-7.494(m,2H)。
Embodiment 4
3- (4- (2- chlorphenyls) piperazine -1- bases) methyl) -5- (2,3- dihydrobenzos [b] [1,4] dioxine -6-
Base) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with Chloro-O-Phenyl piperazine, obtains target compound.
White powder, yield 75%, Mp:179.1-179.6℃.1H NMR(400MHz,CDCl3):3.105-3.117
(d, J=4.4Hz, 8H), 4.347-4.387 (m, 4H), 5.168 (s, 2H), 6.998-7.036 (m, 2H), 7.076-7.099
(m,1H),7.243-7.385(m,1H),7.372-7.395(m,1H),7.487-7.518(m,2H)。
Embodiment 5
5- (2,3- dihydrobenzos [b] [1,4] dioxine -6- bases) -3- ((4- (pyridine -2- bases) piperazine -1- bases)
Methyl) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with Pyridylpiperazine, obtains target compound.
White powder, yield 86%, Mp:171.6-172.4℃.1H NMR(400MHz,CDCl3):3.003-3.028
(m,4H),3.635(s,4H),4.335-4.376(m,4H),5.167(s,2H),6.646-6.695(m,2H),6.981-
7.002 (d, J=8.4Hz, 1H), 7.454-7.534 (m, 3H), 8.203-8.218 (m, 1H).
Embodiment 6
5- (2,3- dihydrobenzos [b] [1,4] dioxine -6- bases) -3- ((4- (4- fluorophenyls) piperazine -1- bases)
Methyl) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with p-fluorophenyl piperazine, obtains target compound.
White powder, yield 85%, Mp:152.9-153.1℃.1H NMR(400MHz,CDCl3):3.056-3.080
(m,4H),3.152-3.176(m,4H),4.344-4.385(m,4H),5.164(s,2H),6.885-6.919(m,2H),
6.975-7.027(m,3H),7.469-7.496(m,2H)。
Embodiment 7
5- (2,3- dihydrobenzos [b] [1,4] dioxine -6- bases) -3- ((4- (2- fluorophenyls) piperazine -1- bases)
Methyl) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with o-fluorophenyl piperazine, obtains target compound.
White powder, yield 80%, Mp:147.8-148.9℃.1H NMR(400MHz,CDCl3):3.086-3.109
(m, 4H), 3.147-3.160 (d, J=9.2Hz, 4H), 4.359-4.386 (m, 4H), 5.169 (s, 2H), 6.994-7.015
(m, 3H), 7.082-7.102 (d, J=8.0Hz, 2H), 7.476-7.502 (m, 2H).
Embodiment 8
3- ((4- (4- chlorphenyls) piperazine -1- bases) methyl) -5- (2,3- dihydrobenzos [b] [1,4] dioxines -
6- yls) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with rubigan piperazine, obtains target compound.
White powder, yield 85%, Mp:149.2-150.7℃.1H NMR(400MHz,CDCl3):2.444(s,
4H),2.898-2.922(m,4H),4.357-4.396(m,4H),5.090(s,2H),7.012-7.032(m,1H),7.354-
7.380(m,4H),7.490-7.523(m,2H)。
Embodiment 9
3- ((4- benzhydryl piperazidine -1- bases) methyl) -5- (2,3- dihydrobenzos [b] [1,4] dioxine -6-
Base) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with diphenylmethyl piperazine, obtains target compound.
White powder, yield 78%, Mp:160.4-161.0℃.1H NMR(400MHz,CDCl3):2.468(s,
3H),2.747(s,1H),2.916(s,3H),3.261(s,1H),4.358-4.371(m,4H),5.093(s,2H),5.592-
5.606 (m, 1H), 6.998-7.044 (m, 2H), 7.199-7.216 (m, 2H), 7.269 (s, 1H), 7.410-7.429 (d, J=
7.6Hz, 4H), 7.471 (s, 1H), 7.491-7.516 (d, J=10.0Hz, 3H).
Embodiment 10
5- (2,3- dihydrobenzos [b] [1,4] dioxine -6- bases) -3- ((4- (3- (trifluoromethyl) phenyl) piperazines
Piperazine -1- bases) methyl) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with m-trifluoromethyl phenylpiperazine, obtains target chemical combination
Object.
White powder, yield 83%, Mp:132.4-132.8℃.1H NMR(400MHz,CDCl3):3.061-3.086
(m,4H),3.282-3.306(m,4H),4.343-4.383(m,4H),5.170(s,2H),6.993-7.132(m,5H),
7.471-7.503(m,2H)。
Embodiment 11
3- ((4- (2,3- dichlorophenyls) piperazine -1- bases) methyl) -5- (2,3- dihydrobenzos [b] [1,4] dioxa hexamethylenes
Alkene -6- bases) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with 2,3- dichlorophenylpiperazines, obtains target chemical combination
Object.
White powder, yield 85%, Mp:148.5-149.9℃.1H NMR(400MHz,CDCl3):3.102(s,
4H),3.438-3.489(m,4H),4.344-4.385(m,4H),5.164(s,1H),5.590-5.611(m,1H),7.003-
7.044(m,2H),7.185-7.240(m,2H),7.491-7.519(m,2H)。
Embodiment 12
5- (2,3- dihydrobenzos [b] [1,4] dioxine -6- bases) -3- ((4- (3- methoxyphenyls) piperazine -1-
Base) methyl) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with m-methoxyphenyl piperazine, obtains target chemical combination
Object.
White powder, yield 80%, Mp:155.4-155.8℃.1H NMR(400MHz,CDCl3):3.046-3.070
(m,4H),3.232-3.257(m,4H),3.813-3.845(m,3H),4.342-4.382(m,4H),5.161(s,2H),
6.458-6.491(m,2H),6.556-6.576(m,1H),6.990-7.011(m,1H),7.184-7.225(m,1H),
7.468-7.500(m,2H)。
Embodiment 13
3- ((4- (3,4- dichlorophenyls) piperazine -1- bases) methyl) -5- (2,3- dihydrobenzos [b] [1,4] dioxa hexamethylenes
Alkene -6- bases) -1,3,4- oxadiazoles -2 (3H)-thioketones preparation.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with 3,4- dichlorophenylpiperazines, obtains target chemical combination
Object.
White powder, yield 85%, Mp:159.2-159.9℃.1H NMR(400MHz,CDCl3):3.031-3.056
(m,2H),3.212-3.237(m,2H),3.431(s,2H),3.520-3.534(m,2H),4.343-4.384(m,4H),
5.154 (s, 1H), 5.590-5.611 (m, 1H), 6.773 (s, 1H), 6.971-7.041 (m, 2H), 7.373-7.395 (d, J=
8.8Hz,1H),7.466-7.493(m,2H)。
Embodiment 14
3-(4- benzyl diethylenediamine-1- bases) methyl)-5- (2,3- dihydrobenzos [b] [1,4] dioxine-6- bases)-1,
The preparation of 3,4- oxadiazoles -2 (3H)-thioketones.
The preparation method is the same as that of Example 1.P-methoxyphenyl piperazine is replaced with benzyl piperazine, obtains target compound.
White powder, yield 85%, Mp:97.8-98.2℃.1H NMR(400MHz,CDCl3):2.544(s,4H),
2.967(s,4H),3.578-3.588(m,2H),4.341-4.382(m,4H),5.093(s,2H),6.984-7.044(m,
1H),7.349(s,3H),7.380-7.393(m,2H),7.451-7.482(m,2H)。
Embodiment 15
Following Anticancer Activities are carried out to the product that embodiment 1-14 is obtained：
1, experiment material
1.1 cell strain
Human liver cancer cell (human hepatocellular liver carcinoma cell line)；HepG2
Human cervical carcinoma cell (human cervical cancer cells)；HELA
Human colon cancer cell (human colon cancer cells)；SW1116
Gastric carcinoma cells (human gastric cancer cells)；BGC823
1.2 reagent
1640 culture mediums of RPMI (GIBCO), newborn bovine serum (Hangzhou Chinese holly biological engineering material), trypsase
(Sigma), MTT (Sigma), injection streptomysin (the auspicious positive pharmacy in Shandong, 1,000,000 units of 1g /), benzylpenicillin sodium for injection
(Shandong Shandong medicine, 800,000 units /).Other common chemical reagent are that domestic analysis is pure.
2, experimental method
The preparation of 2.1 culture mediums
One liter of one bag of 1640 culture mediums of RPMI (Gibcio USA) plus water, add 2g sodium bicarbonates, 100,000 units of Penicillin
With 100mg streptomysins, pH value is adjusted to 7.4, with 0.22mm degerming membrane filtration degermings.90mL culture mediums add the newborn ox blood of inactivation
Clear 10mL is complete culture solution.Trypsase is made into 0.25% solution with D-hanks buffer solutions, 4 DEG C of preservations after filtration sterilization
It is spare.
The preparation of 2.2 liquids
Sample 1.0mg accurately is weighed, is added in the 1.5mL centrifuge tubes of sterilizing, DMSO 1mL are added, are made into 1mg/mL
Stoste, -40 DEG C of freezen protectives.After melting before use respective concentration application is diluted to appropriate D-hanks.
2.3 cell culture and passage
The equal adhere-wall culture of cell is in the Tissue Culture Flask of complete culture solution containing 10mL, in 37 DEG C, 5%CO2, under saturated humidity
Culture.Cell is washed twice after covering with bottom of bottle with sterilizing D-hanks liquid, is added 0.25% trypsin digestion and cell 2min, is outwelled pancreas
After adding full nutrient solution 30mL, cell is dispelled with pipette after jog cell can be completely fallen off for protease, is sub-packed in 3 newly
Tissue Culture Flask in, continue to cultivate.
2.4 active anticancers are tested
One bottle of cell for just growing up to intact monolayer is taken, cell is collected after trypsin digestion, is blown and beaten uniformly with pipette,
Two drop cell suspension trypan blues (Trypan Blue) are taken to dye, (dead cell number must not for living cell counting number under microscope
More than 5%), cell number is adjusted to 1 × 10 with complete culture solution4A cell/mL.It is added per hole in 96 porocyte culture plates
100 μ L cell suspensions, CO is placed in by culture plate2It is cultivated in incubator for 24 hours, in 11 μ L of every Kong Zhongjia containing difference after taking-up culture plate
The solution of concentration sample so that drug final concentration is respectively 100,50,25,12.5,6.25 and 3.125 μ g/mL, Mei Genong
Degree sets 3 parallel holes, separately sets 6 hole cells and makees normal control hole and positive cis-platinum control wells.Culture plate is in microwell plate after adding medicine
Mixing is vibrated on oscillator, is placed in CO2Continue culture in incubator for 24 hours.Culture plate is taken out, is added 25 μ L 5mg/mL's per hole
MTT liquid vibrates mixing, continues to cultivate 4h.10min is cultivated after being added per 100 μ L DMSO of hole.Microplate reader measures each hole light absorption
(OD values) measures wavelength 490nm.The inhibition of four kinds of cell Proliferations of drug pair is calculated by CalcuSyn softwares according to each hole OD values
Rate, i.e. IC50Value, experimental result are shown in Table 1.
1 drug inhibiting tumor cell proliferation experiment of table
aParallel laboratory test three times, experimental result are averaged, and error is between 5%-10%.
Claims (9)
1. a kind of bridged piperazine derivatives of Han You oxadiazoles, it is characterised in that its structural formula is as follows：
Wherein, R is one kind in following group：
2. a kind of preparation method of the bridged piperazine derivatives of Han You oxadiazoles described in claim 1, it is characterised in that including following
Step：
（1）3,4-Dihydroxybenzoic acid, the concentrated sulfuric acid, methanol are subjected to back flow reaction, TLC detections disappear up to raw material, consolidate
Body product；
（2）By step（1）Obtained solid product, acetone, Bromofume, potassium carbonate carries out back flow reaction, obtains solid product；
（3）By step（2）Obtained solid product, ethyl alcohol, hydrazine hydrate carries out back flow reaction, obtains solid product；
（4）By step（3）Obtained solid product, ethyl alcohol, carbon disulfide, potassium hydroxide carries out back flow reaction, is then evaporated, adds
Water dissolution, filtering are distilled, obtained filtrate its pH value of dilute hydrochloric acid tune to 4~5 filters, solid product is precipitated to obtain；
（5）By step（4）Obtained solid product, the piperazine of R substitutions, ethyl alcohol, formaldehyde are contained through stirring at normal temperature, filtering
The bridged piperazine derivatives of oxadiazole；Wherein, R is the group described in claim 1.
3. the preparation method of the bridged piperazine derivatives of Han You oxadiazoles according to claim 2, it is characterised in that：Step（1）
In, 3,4-Dihydroxybenzoic acid, the concentrated sulfuric acid, methanol usage ratio be 1:0.1:5, wherein 3,4-Dihydroxybenzoic acid with
Mmol is counted, and the concentrated sulfuric acid, methanol are in terms of mL.
4. the preparation method of the bridged piperazine derivatives of Han You oxadiazoles according to claim 2, it is characterised in that：Step（2）
In, step（1）Obtained solid product, acetone, Bromofume, potassium carbonate usage ratio be 1:20:1:1.5, wherein step
（1）Obtained solid product, Bromofume, potassium carbonate are in terms of mmol, and acetone is in terms of mL, reflux time 15h.
5. the preparation method of the bridged piperazine derivatives of Han You oxadiazoles according to claim 2, it is characterised in that：Step（3）
In, step（2）Obtained solid product, ethyl alcohol, hydrazine hydrate usage ratio be 0.1:2:0.5, wherein step（2）It obtains
Solid product is in terms of mmol, and ethyl alcohol, hydrazine hydrate are in terms of mL, reflux time 15h.
6. the preparation method of the bridged piperazine derivatives of Han You oxadiazoles according to claim 2, it is characterised in that：Step（4）
In, step（3）Obtained solid product, ethyl alcohol, carbon disulfide, potassium hydroxide usage ratio be 1:20:1:1, wherein step
（3）Obtained solid product, carbon disulfide, potassium hydroxide are in terms of mmol, and for ethyl alcohol in terms of mL, reflux time is for 24 hours.
7. the preparation method of the bridged piperazine derivatives of Han You oxadiazoles according to claim 2, it is characterised in that：Step（5）
In, step（4）Obtained solid product, the piperazine of R substitutions, ethyl alcohol, formaldehyde usage ratio be 1:1:20:1.5, wherein step
Suddenly（4）Obtained solid product, the piperazine of R substitutions, formaldehyde are in terms of mmol, and ethyl alcohol is in terms of mL, stirring at normal temperature 12h.
8. the preparation method of the bridged piperazine derivatives of Han You oxadiazoles according to claim 2, it is characterised in that：Step（5）
In, the piperazines of R substitutions is Chloro-O-Phenyl piperazine, benzyl piperazine, o-methoxyphenyl piperazine, p-methoxyphenyl piperazine, right
Fluorophenyl piperazine, Pyridylpiperazine, o-fluorophenyl piperazine, p-nitrophenyl piperazine, rubigan piperazine, 2,3- dichlorophenyl piperazines
One in piperazine, 3,4- dichlorophenylpiperazines, m-methoxyphenyl piperazine, diphenylmethyl piperazine or m-trifluoromethyl phenylpiperazine
Kind.
9. a kind of purposes of the bridged piperazine derivatives of Han You oxadiazoles described in claim 1, it is characterised in that：Han You oxadiazoles
Bridged piperazine derivatives are used to prepare anticancer drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610259548.7A CN105777731B (en) | 2016-04-22 | 2016-04-22 | The bridged piperazine derivatives and its preparation method and application of Han You oxadiazoles |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610259548.7A CN105777731B (en) | 2016-04-22 | 2016-04-22 | The bridged piperazine derivatives and its preparation method and application of Han You oxadiazoles |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105777731A CN105777731A (en) | 2016-07-20 |
| CN105777731B true CN105777731B (en) | 2018-10-16 |
Family
ID=56399392
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610259548.7A Expired - Fee Related CN105777731B (en) | 2016-04-22 | 2016-04-22 | The bridged piperazine derivatives and its preparation method and application of Han You oxadiazoles |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105777731B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108341807B (en) * | 2018-02-08 | 2020-07-28 | 平顶山学院 | Piperazine amide compound containing benzodioxane skeleton and preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690261B (en) * | 2011-03-25 | 2015-02-25 | 南京大学 | Preparation method of 1,4-benzodioxan-containing 1,3,4-oxadiazole derivatives and use of the 1,4-benzdioxan-containing 1,3,4-oxadiazole derivatives in anti-cancer drugs |
| CN104230915B (en) * | 2014-08-29 | 2016-08-17 | 南京大学 | Phenylpiperazine derivatives containing thiazolidinedione and preparation method thereof and purposes |
-
2016
- 2016-04-22 CN CN201610259548.7A patent/CN105777731B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN105777731A (en) | 2016-07-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104530021A (en) | Compounds and preparation method thereof, application of compounds in preparing antineoplastic drugs and antineoplastic drugs prepared from compounds | |
| CN104558093A (en) | C21 steroid saponin aglycone derivative as well as preparation method and application thereof in preparing anti-tumor drugs | |
| CN103664785A (en) | Synthesis of novel dihydro-pyrazole sulfonamide derivative and application of novel dihydro-pyrazole sulfonamide derivative in anti-cancer drug | |
| CN104230905A (en) | Synthesis of dihydropyrazol sulfonamide derivatives containing benzodioxane skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs | |
| CN105777731B (en) | The bridged piperazine derivatives and its preparation method and application of Han You oxadiazoles | |
| CN104230889A (en) | Ciprofloxacin derivatives and preparation method and use of ciprofloxacin derivatives | |
| CN104230915B (en) | Phenylpiperazine derivatives containing thiazolidinedione and preparation method thereof and purposes | |
| CN104230904A (en) | Synthesis of dihydropyrazol sulfonamide derivatives containing naphthalene ring skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs | |
| CN103804303B (en) | Epidermal growth factor receptor (EGFR) small-molecule inhibitor pyrimidine derivative as well as preparation method and use thereof | |
| CN106565755B (en) | Using 1- pyridine -6- methoxy-p-carbolines as copper nitrate (II) chelate and its synthetic method of ligand and application | |
| CN108558986A (en) | Enoxolone analog derivative containing piperazine structure and preparation method thereof and purposes | |
| CN106045896B (en) | isatin hydrazide derivative and preparation method thereof | |
| CN107382944B (en) | Coumarin gossypol derivatives with anti-tumor activity and synthesis method thereof | |
| CN103819408B (en) | Nitro imidazole derivatives and its production and use | |
| CN104829534A (en) | Preparation method of dihydro-pyrazole morpholine derivatives containing naphthalene nucleus frameworks and application of dihydro-pyrazole morpholine derivatives to preparation of antitumor drugs | |
| CN112225733B (en) | Preparation method of 1,3, 4-thiadiazole pyridine-2-ketone derivative and application of derivative as anti-cancer drug | |
| CN103319431B (en) | 2-mercaptoacetophenone-containing 1, 3, 4-oxadiazole derivative, its preparation method and antitumor activity | |
| CN102786432B (en) | Acetaminophen ester derivative, preparation process and use thereof | |
| CN101161645B (en) | Urea derivatives as well as preparation method and uses thereof | |
| CN104861026A (en) | Furan skeleton included 2H-pyrazole hydroxamic acid C21 steroid saponin aglycone derivative and preparation method and application thereof | |
| CN103804322A (en) | Phenylpiperazine derivatives as well as preparation method and applications thereof | |
| CN104804066A (en) | Novel anti-cancer compound, preparation method for anti-cancer compound and application of anti-cancer compound to preparation of anti-cancer drugs | |
| CN107446001B (en) | Using 1- pyridine -6- methoxy-p-carboline as nickel chloride (II) chelate and its synthetic method of ligand and application | |
| CN105646490B (en) | The cyclohexadione compounds of indoles [1,2 a] pyrimidine [4,5 b] quinoline 7,13, preparation method and its medicinal usage | |
| CN102807508B (en) | Acetaminophen ketone derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181016 Termination date: 20210422 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |