CN103450175A - Conjugated dienes derivative and preparation method thereof and application as anti-cancer drug - Google Patents
Conjugated dienes derivative and preparation method thereof and application as anti-cancer drug Download PDFInfo
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- CN103450175A CN103450175A CN201310350441XA CN201310350441A CN103450175A CN 103450175 A CN103450175 A CN 103450175A CN 201310350441X A CN201310350441X A CN 201310350441XA CN 201310350441 A CN201310350441 A CN 201310350441A CN 103450175 A CN103450175 A CN 103450175A
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- 0 CC(N(CCCC1*)C1=C(C=O)[N+]([O-])=O)Cl Chemical compound CC(N(CCCC1*)C1=C(C=O)[N+]([O-])=O)Cl 0.000 description 3
- JWUXLALPRFRLRJ-NYWYOEKOSA-N CCN(CCN1)/C1=C(/C=C(/c1nc2ccccc2[s]1)\C#N)\[N+]([O-])=O Chemical compound CCN(CCN1)/C1=C(/C=C(/c1nc2ccccc2[s]1)\C#N)\[N+]([O-])=O JWUXLALPRFRLRJ-NYWYOEKOSA-N 0.000 description 1
- YPIFLXOVPCARGI-UHFFFAOYSA-N CCc1nc2ccccc2[o]1 Chemical compound CCc1nc2ccccc2[o]1 YPIFLXOVPCARGI-UHFFFAOYSA-N 0.000 description 1
- ZMZSYUSDGRJZNT-UHFFFAOYSA-N N#CCc1nc2ccccc2[s]1 Chemical compound N#CCc1nc2ccccc2[s]1 ZMZSYUSDGRJZNT-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D233/26—Radicals substituted by carbon atoms having three bonds to hetero atoms
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
- C07D413/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- 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
- C07D413/12—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 linked by a chain containing hetero atoms as chain links
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- 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
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
The invention discloses a conjugated dienes derivative and a preparation method and application of the conjugated dienes derivative as an anti-cancer drug. The structure of the conjugated dienes derivative is shown as formula I. Practice shows that a compound has obvious activity on inhibiting the growth of cancer cells; and the antitumor activity of some optimized compounds is obviously superior toprior to that of a contrast drug. The preparation of such compound is simple and easy to carry out; raw materials are easy to obtainily available; and the conjugated dienes derivative is a substance with antitumor activity and has a wide application prospect.
Description
Technical field
The invention belongs to the organic drug synthesis technical field, be specifically related to a kind of conjugated dienes derivative and preparation method thereof and purposes as cancer therapy drug.
Background technology
Antitumour drug refers to the medicine of anti-malignant tumor, claims again anticarcinogen.Malignant tumour is a kind of common disease and frequently-occurring disease of serious threat human health, and the mortality ratio shelter that the mankind cause because of malignant tumour has the second of mortality, becomes No. second " killer " being only second to cardiovascular disorder.At the beginning of 2013, up-to-date one edition " 2012 Chinese tumours registration annual report " of the issue of national tumour Register shows, the annual new cases of cancer of China approximately 3,120,000, and because the cancer mortality number surpasses 2,000,000, this means every 1 minute has 6 people to be diagnosed as cancer.The sternness of current national pathogenesis of cancer trend, incidence and mortality is lasting ascendant trend.Cancer has become serious threat human life safety and has affected one of significant problem of human life quality, and the problem caused therefrom also more and more becomes the burden of socio-economic development.
At present, the methods for the treatment of of tumour mainly contains operative treatment, radiotherapy and pharmacological agent (chemotherapy), but be still to a great extent, take pharmacological agent as main.Most common solid tumors still lack active drug as lung cancer, liver cancer, colorectal carcinoma and carcinoma of the pancreas etc., and many antitumor drugs produce resistance in process of clinical application, and therefore, the research and development of new type antineoplastic medicine are imperative.Along with social scientific-technical progress, the mankind are clear gradually to the cognition of cancer, the prevention of some cancer and method, technology and the theory of early diagnosis are also reached its maturity, but still can not cure cancer fully, can only very limitedly extend the survival time of cancer patient.The significantly increase of the long-term existence of Cancerous disease, the prolongation of the survival time of cancer patient, cancer new cases and the characteristics that cancer is difficult to cure will determine that human society will constantly increase the demand of cancer drug.Under this large situation, the research and development of cancer therapy drug will be one of popular research fields of pharmaceutical industry circle, continually develop optionally new type anticancer active medicine of high-efficiency low-toxicity, become when last significant research work.
The 1,3-butadiene derivative has biological activity widely usually, Bioorg.Med.Chem.Lett.2004 for example, 14,1483; Bioorg.Med.Chem.Lett.1998, put down in writing compound U0126(1 in 8,2839,4-diamino-2,3-dicyano-Isosorbide-5-Nitrae-bis-(adjacent amino-benzene sulfydryl) divinyl) be a kind of MAPKK inhibitor commonly used, the propagation of malignant cell is made a significant impact.The applicant, in process of scientific research, has found that series has the polysubstituted conjugated diolefine derivative of unsymmetrical structure, presents significant antitumour activity, has obvious application prospect.
Summary of the invention
The object of the present invention is to provide a kind of asymmetric conjugated dienes derivative and preparation method thereof and as the purposes of cancer therapy drug.
For achieving the above object, the structure of conjugated dienes derivative of the present invention is shown in general formula I, and general formula I is:
In formula:
R
1be selected from one of following radicals:
In above-mentioned formula: R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
17, R
18, R
19, R
20, R
21, R
22, R
23, R
24, R
25, R
26be respectively methyl, ethyl, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, methoxyl group, hydroxyl, fluorine, chlorine, bromine, iodine, nitro, cyano group or hydrogen.
R
2and R
3independent separately is hydrogen, C
1-8alkyl, C
1-8alkoxyl group, benzyl, substituted benzyl, containing the C of unsaturated link(age)
2-8alkyl or C
3-8alkoxyl group, C
1-8alkyl-C
3-8alkoxyl group, C
3-8alkoxyl group-carbonyl, carbobenzoxy-(Cbz), containing the C of unsaturated link(age)
2-8alkyl-carbonyl, C
3-8cycloalkyl-carbonyl, benzoyl, heterocyclic radical-carbonyl, C
1-6haloalkyl, C
1-6a kind of in halogenated alkoxy, halogenated heterocyclic base-carbonyl; Perhaps, R
2and R
3common formation-CH
2-(CH
2)
n-CH
2-or-CH
2-YR-CH
2-, wherein, n be 0,1,2 or 3, Y be heteroatoms (being other atoms beyond de-carbon and hydrogen, as nitrogen, phosphorus or boron etc.), R is substituting group, R is hydrogen, C
1-8alkyl, C
2-8alkoxyl group, containing the C of unsaturated link(age)
2-8alkyl, C
1-8alkyl-C
3-8alkoxyl group, C
3-8alkoxyl group-carbonyl, carbobenzoxy-(Cbz), C
2-8thiazolinyl-carbonyl, C
2-8alkynyl-carbonyl, C
3-8cycloalkyl-carbonyl, benzoyl, heterocyclic radical-carbonyl, C
1-6haloalkyl, C
1-6a kind of in halogenated alkoxy, halogenated heterocyclic base-carbonyl;
R
4for hydrogen, C
1-8alkyl-carbonyl, C
3-8alkoxyl group-carbonyl, carbobenzoxy-(Cbz), C
2-8thiazolinyl-carbonyl, C
2-8alkynyl-carbonyl, C
3-8cycloalkyl-carbonyl, benzoyl, substituted benzoyl, cyanogen ethanoyl, heterocyclic radical-carbonyl, aryl amine-thiocarbonyl group, C
1-6haloalkyl, C
1-6a kind of in halogenated alkoxy, halogenated heterocyclic base-carbonyl, halogen aromatic amines base-thiocarbonyl group;
R
5a kind of in nitro, cyano group, trifluoromethyl, trifluoroacetyl group, alkoxy acyl, alkyl-formyl radical, trifyl;
R
6for hydrogen or halogen;
R
7for hydrogen, cyano group, nitro, halogen, trifluoromethyl, trifluoroacetyl group, C
1-10alkyl-formyl radical, C
1-10alkoxyl group-formyl radical;
R
8be selected from one of following radicals:
Above-mentioned R
8in group: R
27, R
28, R
29, R
30, R
31, R
32, R
33, R
34, R
35be respectively methyl, ethyl, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, methoxyl group, hydroxyl, fluorine, chlorine, bromine, iodine, nitro, cyano group or hydrogen; Z is O or S or NH.
Preferably, described R
1for: methyl, ethyl, propyl group,
in a kind of (in formula: R
13, R
14, R
15, R
16, R
21, R
23civilian described as defined above); R
2for: a kind of in methyl, ethyl, benzyl, substituted benzyl; R
3for: a kind of in methyl, ethyl, benzyl, substituted benzyl; Perhaps R
2with R
3common formation-CH
2cH
2-,-CH
2cH
2cH
2-,-CH
2oCH
2-,-CH
2nHCH
2-,-CH
2n (CH
3) CH
2-,-CH
2sCH
2-,-CH
2n(C
2h
5) CH
2-in a kind of; R
4for: a kind of in hydrogen, ethanoyl, carbobenzoxy-(Cbz), methoxycarbonyl, benzoyl, substituted benzoyl, acryl; R
5for: a kind of in cyano group, nitro, trifluoroacetyl group; R
6for: a kind of in hydrogen, chlorine, bromine; R
7for: a kind of in hydrogen, cyano group, nitro, trifluoromethyl, trifluoroacetyl group; R
8for: cyano group, nitro,
in a kind of (in formula: R
28, R
29, R
31, R
32, R
34, R
35civilian described as defined above).
Simultaneously, the invention provides the preparation method of above-mentioned conjugated dienes derivative, particularly, this preparation method's synthetic route is as follows:
Described reaction is carried out under organic solvent and catalyzer condition;
R in reaction formula
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8definition with above described.
In the preparation method of above-mentioned conjugated dienes derivative, preferred, described solvent is a kind of in ethanol, methyl alcohol, acetonitrile, tetrahydrofuran (THF), acetone, butanols; Described catalyzer is a kind of in sodium hydroxide, potassium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, triethylamine, piperidines, pyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium tert-butoxide.
In the preparation method of above-mentioned conjugated dienes derivative, further preferred, temperature of reaction is 20～80 ℃, and the reaction times is 0.5～48h, so controls reaction times and temperature, can effectively improve speed of reaction and reduce the generation of side reaction.
It (is R with containing active methylene compound that preparation method of the present invention adopts polysubstituted fragrance and heterocyclic aldehydes M
7-CH
2-R
8) carry out the Knoevenagel condensation reaction, can obtain the conjugated dienes derivative I.Polysubstituted fragrance wherein and heterocyclic aldehydes M can adopt the described method of patent WO2004058714A1 or the preparation of other conventional methodology of organic synthesis.
The present invention also provides the conjugated dienes derivative with said structure general formula I preparing the application of cancer therapy drug.Conjugated dienes derivative provided by the present invention and pharmacy acceptable salt thereof are (for example: conventional inorganic acid salt, example hydrochloric acid salt, vitriol, phosphoric acid salt and organic acid salt, as mesylate, fluoroform sulphonate, acetate, trifluoroacetate, benzoate etc.), to human liver cancer cell HepG2, Huh-7, SMMC-7721, MHCC97, BEL-7402, PLC/PRF/5, Hep3B, HCC-9204, PG5; Human Lung Cancer cell A549, H1299, PC-9, MSTO-211H, H1975, NCIH446, NCIH460; Mankind mastopathy cell MCF-7, T47D, 1590, Bcap-37, MDA-MB-453, ZR-75-30; Mankind's stomach cancer cell BCG-823, SGC-7901, HS-746T, MGC-803; Human NPC cell KB, CNE-2, SUNE-1; Human ovarian cancer cell 3AO, SKOV3, TYK; Human prostate cancer PC-3,22RV1; Human hela cell Hela, RhoC, VAV2; Human skin melanoma cell A375; People's epidermal carcinoma cell A431; It is active that human glioma cells C6 etc. have significant inhibition; And monkey-kidney cells MARC145, Madin-Darby canine kidney(cell line) MDCK and mankind's normal liver cell strain HL-7702 etc. had to weak inhibition activity.In practical application, conjugated dienes derivative of the present invention and pharmacy acceptable salt thereof can be prepared into various practical medicaments by ordinary method, as the medicine of granule, tablet, pill, capsule, injection, suspension agent or emulsion.
The present invention is synthetic and screening active ingredients research by the design of system, take conjugated dienes structure parent as basis, built the polysubstituted asymmetric conjugated dienes compounds of a class, described compound has obvious growth inhibitory activity to tumor cell, and the anti-tumor activity of part preferred compound obviously is better than control drug.And the preparation process of this compounds is simple, and raw material is easy to get, it is a kind of anti-tumor active substance with broad prospect of application.
Embodiment
Below in conjunction with specific embodiment, to conjugated dienes derivative of the present invention and preparation method thereof with as the purposes of cancer therapy drug, be described in further detail.
Embodiment 1
The structure of partly conjugated diene derivative of the present invention is a kind of in particular compound as listed in Table 1:
Table 1: the representative compound structure list of general formula I
Embodiment 2
Be numbered the compound 2-(benzo [d] thiazol-2-yl) of I-6-4-(1-(phenyl) tetrahydroglyoxaline-2-subunit)-4-nitro but-2-ene nitrile in embodiment 1, its preparation method is:
Take the N-phenylethylenediamine as starting raw material, with reference to the disclosed method of patent WO2004058714A1, pass through successively and 1,1-bis-thiomethyls-2-nitroethylene generation substitution reaction, then with the condensation reaction of DMF dimethylacetal, basic hydrolysis, prepare intermediate 2-(1-(phenyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde (M-1).Then taking M-1 is 2-(1-(phenyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.12g(0.5mmol) be dissolved in the 10mL dehydrated alcohol, under room temperature condition, add successively 2-cyanogen methylbenzothiazole (being compd A) 0.096g(0.55mmol) and the potassium hydroxide of catalytic amount, the first stirring at room of reaction mixture 30 minutes, then slowly be heated to 40-45 ℃, insulation reaction, TLC monitors to reacting completely.Decompression remove portion solvent, cooling after, suction filtration obtains target compound I-6, yellow powder 0.14g, mass yield 72%.This compound basic physical and chemical is as follows: Mp>250 ℃; MS (ESI) m/z389.9 (M+H)
+, calcd.for C
20h
15n
5o
2s m/z=389.1.
Embodiment 3
Be numbered the compound 2-(benzo [d] oxazole-2-yl) of I-37-4-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-4-nitro but-2-ene nitrile in embodiment 1, its preparation method is:
Take CCMP as starting raw material, pass through successively with the substitution reaction of quadrol, with 1, the substitution reaction of 1-bis-thiomethyls-2-nitroethylene, then with the condensation reaction of DMF dimethylacetal, basic hydrolysis, prepare intermediate 2-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde (M-2).Then weighing M-2 is 2-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g(0.5mmol) be dissolved in the 10mL dehydrated alcohol, under room temperature condition, add successively 2-cyanogen Jia base benzoxazole (compd B) 0.087g(0.55mmol), and the piperidines of catalytic amount, the first stirring at room of reaction mixture 30 minutes, then slowly be heated to 40 ℃, insulation reaction, TLC monitors to reacting completely.Decompression remove portion solvent, cooling after, suction filtration obtains target compound I-37, yellow powder 0.14g, mass yield 66%.The concrete physico-chemical property of this compound is as follows: Mp>250 ℃;
1h NMR (400MHz, DMSO-d
6, TMS), δ (ppm): 9.50 (s, 1H), 8.57 (s; 1H), 8.48 (s, 1H), 7.95 (d, J=8Hz; 1H), 7.78 (d, J=8Hz, 2H), 7.56 (d; J=8Hz, 1H), 7.41 (t, J=7.2Hz, 2H); (4.83 s, 2H), 4.16 (t, J=8Hz; 2H), 3.97 (t, J=8Hz, 2H); MS (ESI) m/z422.9 (M+H)
+, calcd.for C
20h
15clN
6o
3m/z=422.1.
Embodiment 4
Be numbered the compound 2-(6-chloropyridine-3-yl) of I-38-4-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-4-nitro but-2-ene nitrile in embodiment 1, its preparation method is:
Weighing M-2 is 2-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g(0.5mmol) be dissolved in the 10mL dehydrated alcohol, under room temperature condition, add successively 2-(6-chloropyridine-3-yl) acetonitrile (Compound C) 0.084g(0.55mmol), and the sodium hydroxide of catalytic amount, the first stirring at room of reaction mixture 20 minutes, then slowly be heated to 35-40 ℃, insulation reaction, TLC monitors to reacting completely.Decompression remove portion solvent, cooling after, suction filtration obtains target compound I-38, glassy yellow powder 0.15g, mass yield 72%.This compound basic physical and chemical is as follows: Mp>250 ℃; MS (ESI) m/z417.0 (M+H)
+, calcd.for C
18h
14cl
2n
6o
2m/z=416.1.
Embodiment 5
Be numbered the compound 2-(4-nitrophenyl) of I-40-4-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-4-nitro but-2-ene nitrile in embodiment 1, its preparation method is:
Weighing M-2 is 2-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g(0.5mmol) be dissolved in the 15mL dehydrated alcohol, then under room temperature condition, add successively 4-nitrobenzene ethane nitrile (Compound D) 0.089g(0.55mmol), and the potassium hydroxide of catalytic amount, the first stirring at room of reaction mixture 30 minutes, then slowly be heated to 45 ℃, insulation reaction, TLC monitors to reacting completely.Decompression remove portion solvent, cooling after, suction filtration obtains target compound I-40, khaki color powder 0.14g, mass yield 66%.This compound basic physical and chemical is as follows: Mp141-142 ℃; MS (ESI) m/z426.9 (M+H)
+, calcd.for C
19h
15clN
6o
4m/z=426.1.
Embodiment 6
Be numbered the compound 2-(benzo [d] thiazol-2-yl) of I-36-4-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-4-nitro but-2-ene nitrile in embodiment 1, its preparation method is:
Taking M-2 is 2-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g(0.5mmol) be dissolved in the 10mL dehydrated alcohol, then under room temperature condition, add 2-cyanogen methylbenzothiazole (compd A) 0.096g(0.55mmol), add again basic catalyst, the first stirring at room of reaction mixture 40 minutes, then slowly be heated to 50 ℃, insulation reaction, TLC monitors to reacting completely.Decompression remove portion solvent, cooling after, suction filtration obtains target compound I-36, yellow powder 0.15g, mass yield 68%.The concrete physico-chemical property of this compound is as follows: Mp207-209 ℃;
1h NMR (400 MHz, CDCl
3, TMS), δ (ppm): 10.26 (s, 1H), 8.41 (s, 1H); (8.37 s, 1H), 8.01 (d, J=8Hz, 1H); (7.88 d, J=8Hz, 1H), 7.83 (d, J=8Hz; 1H), 7.49 (t, J=8Hz, 1H), 7.41 (d; J=8Hz, 2H), 4.85 (s, 2H), 4.32 (t; J=8Hz, 2H), 3.90 (t, J=8Hz, 2H); MS (ESI) m/z439.6 (M+H)
+, calcd.for C
20h
15clN
6o
2s m/z=438.1.
Embodiment 7
Be numbered the compound 2-(benzo [d] thiazol-2-yl) of I-16-4-(1-(benzyl) tetrahydroglyoxaline-2-subunit)-4-nitro but-2-ene nitrile in embodiment 1, its preparation method is:
Take Benzyl Chloride as starting raw material, pass through successively with the substitution reaction of quadrol, with 1, the substitution reaction of 1-bis-thiomethyls-2-nitroethylene, then with the condensation reaction of DMF dimethylacetal, basic hydrolysis, prepare intermediate 2-(1-(benzyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde (M-3).Then taking M-3 is 2-(1-(benzyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.124g(0.5mmol) be dissolved in the 10mL dehydrated alcohol, add successively 2-cyanogen methylbenzothiazole (compd A) 0.096g(0.55mmol), the potassium hydroxide that adds again catalytic amount, the first stirring at room 1h of reaction mixture, then slowly be heated to 40 ℃, insulation reaction, TLC monitors to reacting completely.Decompression remove portion solvent, cooling after, suction filtration obtains target compound I-16, glassy yellow powder 0.14g, mass yield 69%.The concrete physico-chemical property of this compound is as follows: Mp192-193 ℃;
1h NMR (400MHz, DMSO-d
6, TMS), δ (ppm): 9.89 (s, 1H), 8.22 (s, 1H), 8.10-7.95 (m, 2H), 7.53-7.33 (m, 7H), 4.82 (s, 2H), 4.14 (t, J=8Hz, 2H), 3.96 (t, J=8Hz, 2H); MS (ESI) m/z404.7 (M+H)
+, calcd.for C
21h
17n
5o
2s m/z=403.1.
Embodiment 8
Be numbered the compound 2-(benzo [d] thiazol-2-yl) of I-27-4-(1-(ethyl) tetrahydroglyoxaline-2-subunit)-4-nitro but-2-ene nitrile in embodiment 1, its preparation method is:
Take NEED as starting raw material, pass through successively and 1,1-bis-thiomethyls-2-nitroethylene generation substitution reaction, then with the condensation reaction of DMF dimethylacetal, basic hydrolysis, prepare intermediate 2-(1-(ethyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde (M-4).Then taking M-4 is 2-(1-(ethyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.093g(0.5mmol) be dissolved in the 8mL dehydrated alcohol, add successively 2-cyanogen methylbenzothiazole (compd A) 0.096g(0.55mmol) and the piperidines of catalytic amount, stirring at room, TLC monitors to reacting completely.Decompression remove portion solvent, cooling after, suction filtration obtains target compound I-27, khaki color powder 0.13g, mass yield 76%.This compound basic physical and chemical is as follows: Mp>250 ℃; MS (ESI) m/z342.2 (M+H)
+, calcd.forC
16h
15n
5o
2s m/z=341.1.
Embodiment 9
Be numbered compound 2-(2-(1-((2-diuril azoles-5-yl) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro ethylidene) propane dinitrile of I-48 in embodiment 1, its preparation method is:
Take the 2-chloro-5-chloromethyl thiazole as starting raw material, pass through successively with the substitution reaction of quadrol, with 1, the substitution reaction of 1-bis-thiomethyls-2-nitroethylene, then with the condensation reaction of DMF dimethylacetal, basic hydrolysis, prepare intermediate 2-(1-((2-diuril azoles-5-yl) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde (M-5).Then taking M-5 is 2-(1-((2-diuril azoles-5-yl) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.15g(0.5mmol) be dissolved in the 10mL dehydrated alcohol, under room temperature condition, add successively propane dinitrile 0.036g(0.55mmol) and the sodium hydroxide of catalytic amount, the first stirring at room of reaction mixture is after 30 minutes, then slowly be heated to 40 ℃, insulation reaction, TLC monitors to reacting completely.Decompression remove portion solvent, cooling after, suction filtration obtains target compound I-48, pale yellow powder 0.12g, mass yield 71%.The concrete physico-chemical property of this compound is as follows: Mp170-172 ℃;
1h NMR (400MHz, CDCl
3, TMS), δ (ppm): 8.21 (s, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 4.92 (s, 2H), 4.21 (t, J=10Hz, 2H), 3.97 (t, J=10Hz, 2H); MS (ESI) m/z337.8 (M+H)
+, calcd.for C
12h
9clN
6o
2s m/z=336.0.
Embodiment 10
Be numbered the compound 2-(benzo [d] thiazol-2-yl) of I-52-4-(1-((2-diuril azoles-5-yl) methyl) tetrahydroglyoxaline-2-subunit)-4-nitro but-2-ene nitrile in embodiment 1, its preparation method is:
Weighing M-5 is 2-(1-((2-diuril azoles-5-yl) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.15g(0.5mmol) be dissolved in the 15mL dehydrated alcohol, then add successively 2-cyanogen methylbenzothiazole (compd A) 0.096g(0.55mmol) and the piperidines of catalytic amount, under room temperature condition, stir, TLC monitors to reacting completely.Decompression remove portion solvent, cooling after, suction filtration obtains target compound I-52, pale yellow powder 0.16g, mass yield 72%.This compound basic physical and chemical is as follows: Mp>250 ℃;
1hNMR (400MHz, DMSO-d
6, TMS), δ (ppm): 9.94 (s, 1H), 8.25 (s, 1H), 8.11-8.01 (m; 2H), 7.80 (s, 1H), 7.58-7.43 (m, 2H), 4.92 (s, 2H); (4.11 t, J=8Hz, 2H), 3.96 (t, J=8Hz, 2H); MS (ESI) m/z445.0 (M+H)
+, calcd.for C
18h
13clN
6o
2s
2m/z=444.0.
Embodiment 11
Be numbered the compound 2-(2-diuril azoles-5-yl) of I-39-4-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-4-nitro but-2-ene nitrile in embodiment 1, its preparation method is:
Taking M-2 is 2-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g(0.5mmol) be dissolved in the 10mL anhydrous methanol, add successively 2-(2-diuril azoles-5-yl) acetonitrile (compound F 17-hydroxy-corticosterone) 0.087g(0.55mmol) and the sodium hydroxide of catalytic amount, stirring at room, TLC monitors to reacting completely.Removal of solvent under reduced pressure, crude product obtains target compound I-39 through column chromatographic isolation and purification, yellow powder 0.13g, mass yield 61%.This compound basic physical and chemical is as follows: Mp>250 ℃; MS (ESI) m/z422.8 (M+H)
+, calcd.for C
16h
12cl
2n
6o
2s m/z=422.0.
Embodiment 12
Be numbered the compound 4-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit) of I-41-2-(1H-indoles-3-formyl radical)-4-nitro but-2-ene nitrile in embodiment 1, its preparation method is:
Taking M-2 is 2-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g(0.5mmol) be dissolved in the 15mL dehydrated alcohol; add successively 3-cyanogen ethanoyl indoles (compound G) 0.092g(0.55mmol) and the potassium hydroxide of catalytic amount; stirring at room, TLC monitors to reacting completely.Decompression remove portion solvent, cooling after, suction filtration obtains target compound I-41, glassy yellow powder 0.17g, mass yield 76%.The concrete physico-chemical property of this compound is as follows: Mp246-248 ℃;
1h NMR (400MHz, DMSO-d
6, TMS), δ (ppm): 12.07 (s, 1H), 8.93 (s, 1H); (8.49 s, 1H), 8.19 (s, 1H), 8.11 (d; J=8Hz, 1H), 8.01 (s, 1H), 7.95 (d; J=8Hz, 1H), 7.55 (dd, J=8Hz, 2H); (7.28-7.19 m, 2H), 4.83 (s, 2H), 4.10 (t; J=8Hz, 2H), 3.94 (t, J=8Hz, 2H); MS (ESI) m/z448.9 (M+H)
+, calcd.for C
22h
17clN
6o
3m/z=448.1.
Embodiment 13
Be numbered the compound 2-(benzo [d] thiazol-2-yl) of I-64-5-(((6-chloropyridine-3-yl) methyl) (ethyl) amino)-5-(methylamino-)-4-nitro-2 in embodiment 1,4-pentadiene nitrile, its preparation method is:
Take CCMP as starting raw material, pass through successively with the substitution reaction of ethamine, with 1, the substitution reaction of 1-bis-thiomethyls-2-nitroethylene, with the substitution reaction of methylamine, with the condensation reaction of DMF dimethylacetal, basic hydrolysis, prepare intermediate 3-(((6-chloropyridine-3-yl) methyl) (ethyl) amino)-3-(methylamino-)-2-nitro propenal (M-6).Then weighing M-6 is 3-(((6-chloropyridine-3-yl) methyl) (ethyl) amino)-3-(methylamino-)-2-nitro propenal 0.15g(0.5mmol) be dissolved in 10mL methyl alcohol, add successively 2-cyanogen methylbenzothiazole (compd A) 0.096g(0.55mmol) and the potassium hydroxide of catalytic amount, stirring at room, TLC monitors to reacting completely.Removal of solvent under reduced pressure, crude product obtains target compound I-64 through column chromatographic isolation and purification, khaki color powder 0.13g, mass yield 57%.This compound basic physical and chemical is as follows: Mp102-103 ℃; MS (ESI) m/z454.9 (M+H)
+, calcd.for C
21h
19clN
6o
2s m/z=454.1.
Embodiment 14
Be numbered the compound 2-(the 5-chlorobenzene is [d] thiazol-2-yl also) of I-47-4-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-4-nitro but-2-ene nitrile in embodiment 1, its preparation method is:
Taking M-2 is 2-(1-((6-chloropyridine-3-yl) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g(0.5mmol) be dissolved in 15mL methyl alcohol, add successively 2-(5-chloro benzothiazole-2-yl) acetonitrile (compound H) 0.12g(0.55mmol) and the potassium hydroxide of catalytic amount, stirring at room, TLC monitors to reacting completely.Decompression remove portion solvent, cooling after, suction filtration obtains target compound I-47, yellow powder 0.17g, mass yield 72%.The concrete physico-chemical property of this compound is as follows: Mp>250 ℃;
1h NMR (400MHz, DMSO-d
6, TMS), δ (ppm): 9.84 (s, 1H), 8.96 (s; 1H), 8.47 (s, 1H), 8.25 (s; 1H), 8.14-8.04 (m, 2H), 7.94 (s; 1H), 7.56-7.38 (m, 2H), 4.83 (d; J=4Hz, 2H), 4.14 (t, J=8Hz; 2H), 4.01 (t, J=8Hz, 2H); MS (ESI) m/z472.9 (M+H)
+, calcd.for C
20h
14cl
2n
6o
2s m/z=472.0.
The preparation of other compound in embodiment 15 tables 1
The preparation of other compound in embodiment 1, with reference to the described basic synthetic method of embodiment 2～14, and the constitutional features of compound described in associative list 1 selects different conventional industrial chemicals, but just other listed compound in preparation table.
The Anticancer Activity in vitro evaluation of embodiment 16 compounds
For trying cancer cells: human liver cancer Cell Line HepG2, Huh-7; Mankind mastopathy cell's strain MCF-7; Human Lung Cancer cell line A549, H1975; Mankind's stomach cancer cell line BCG-823; Human hela cell strain Hela; Human skin melanoma cell strain A375; People's epidermal carcinoma cell strain A431; Glioma cell line C6; Monkey kidney cell line MARC145; Madin-Darby canine kidney(cell line) strain MDCK; Mankind's normal liver cell strain HL-7702 etc.
Cell cultures: RPMI Medium1640 cell culture medium, 10% calf serum and 0.01%L-glutamine are mixed with nutrient solution.The cultured cells strain is placed in 37 ℃, 5%CO
2under saturated humidity, cellar culture goes down to posterity, and the cell in logarithmic phase is all used in experiment.
Anticancer Activity in vitro is estimated (mtt assay): with 0.25% trypsinase, by cell dissociation and make single-cell suspension liquid, be inoculated in 96 orifice plates by every hole 6000-7000 cell, 37 ℃, 5%CO
2spend the night, add the sample of different concns, using respectively single celled nutrient solution and without pharmaceutically-active cell as blank and negative control, with cancer therapy drug 5 FU 5 fluorouracil and the positive contrast of U0126, establish 8 multiple holes for every group, continue to cultivate 48h and obtain 72h.Every hole adds MTT(5mg/mL) 20 μ l continuation cultivation 4h, abandon supernatant liquor, every hole adds 150 μ l DMSO, hatches 10min for 37 ℃, and microplate reader detects the light absorption value (A at 570nm wavelength place
570).Calculate as follows average inhibiting rate:
Inhibiting rate=(A
negative control– A
laboratory sample)/(A
negative control– A
blank) * 100%
The partial test result is as shown in table 2 below, and result shows, the polysubstituted asymmetric conjugated dienes derivative of preparation, to for the examination cancer cells, showing obvious restraining effect, is compared superior activity with contrasting medicament 5 FU 5 fluorouracil and U0126.Therefore, the compounds of this invention can be widely used in the cancer therapy drug field, and significant researching value and application prospect are arranged.
The antitumour activity of table 2 part of compounds
In table 2:
aiC
50<40 μ M are designated as +++, IC
5040～100 μ M are designated as ++, IC
50100 μ M are designated as+.
babbreviation: HepG-2 – human liver cancer cell; BCG-823 – gastric carcinoma cells; MCF-7 – human breast cancer cell; Hela – human cervical carcinoma cell; C6 – human glioma cells; A549 – human lung carcinoma cell; MARC145 – monkey-kidney cells; HL-7702 – Human normal hepatocyte; MDCK – Madin-Darby canine kidney(cell line).
c– does not detect.
du0126, positive control.
e5-Fluorouracil, positive control.
The vivo antitumor activity rating of embodiment 17 compounds
For trying animal: BALB/C type male nude mouse, the about 18-22g of body weight.
Tumor cell line: human liver cancer cell (HepG-2).
Test method: will be cultured to logarithmic phase the HepG-2 cell dissociation, the counting after be diluted to 5 * 10
6/ mL.Under aseptic condition, only be inoculated in the nude mice flank by 0.2mL/ subcutaneous, observe and measure tumor size every day.14d after injection, nude mice by subcutaneous forms macroscopic tumour, as diameter of tumor>=6mm volume calculated: Volume=Length * Width as follows
2/ 2, gross tumor volume reaches 100mm
3the time start the administration of dividing into groups.By the nude mice random packet, and blank group (10%DMAC+10%Cremophor EL in PBS) and 5-Fu control group (20mg/kg) be set simultaneously, every day, intraperitoneal injection was 1 time, continuous 7 days, calculate every group of mean tumour volume, nude mice mean body weight and inhibition rate of tumor growth (TGI), TGI%=100 * [1-(experimental group mean tumour volume
final-experimental group mean tumour volume
initial)/(blank group mean tumour volume
final-blank group mean tumour volume
initial)].
Preliminary in vivo test result shows, the polysubstituted conjugated dienes derivative of preparation is to for the examination cancer cells, having played certain restraining effect, and administration is after 7 days, Compound I-16 treatment group mean tumour volume 162mm
3, 5-FU treatment group mean tumour volume 353mm
3, blank group mean tumour volume 298mm
3; With contrasting medicament 5 FU 5 fluorouracil (5-FU), compare, Compound I-16 superior activity, and the TGI value of this compound reaches 49.81%.
Therefore, conjugated dienes derivative of the present invention and pharmacy acceptable salt thereof can be prepared into various practical medicaments by ordinary method, as the medicine of granule, tablet, pill, capsule, injection, suspension agent or emulsion, be widely used in prevention and the treatment field of cancer.
Claims (7)
1. a conjugated dienes derivative, it is characterized in that: its general structure is:
In formula:
R
1be selected from one of following radicals:
Above-mentioned R
1in group: R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
17, R
18, R
19, R
20, R
21, R
22, R
23, R
24, R
25, R
26be respectively a kind of in methyl, ethyl, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, methoxyl group, hydroxyl, fluorine, chlorine, bromine, iodine, nitro, cyano group or hydrogen;
R
2and R
3independently be respectively separately hydrogen, C
1-8alkyl, C
1-8alkoxyl group, benzyl, substituted benzyl, containing the C of unsaturated link(age)
2-8alkyl or C
3-8alkoxyl group, C
1-8alkyl-C
3-8alkoxyl group, C
3-8alkoxyl group-carbonyl, carbobenzoxy-(Cbz), containing the C of unsaturated link(age)
2-8alkyl-carbonyl, C
3-8cycloalkyl-carbonyl, benzoyl, heterocyclic radical-carbonyl, C
1-6haloalkyl, C
1-6a kind of in halogenated alkoxy, halogenated heterocyclic base-carbonyl;
Perhaps, R
2and R
3common formation-CH
2-(CH
2)
n-CH
2-or-CH
2-YR-CH
2-, wherein, n be 0,1,2 or 3, Y be heteroatoms, R is hydrogen, C
1-8alkyl, C
2-8alkoxyl group, containing the C of unsaturated link(age)
2-8alkyl, C
1-8alkyl-C
3-8alkoxyl group, C
3-8alkoxyl group-carbonyl, carbobenzoxy-(Cbz), C
2-8thiazolinyl-carbonyl, C
2-8alkynyl-carbonyl, C
3-8cycloalkyl-carbonyl, benzoyl, heterocyclic radical-carbonyl, C
1-6haloalkyl, C
1-6a kind of in halogenated alkoxy, halogenated heterocyclic base-carbonyl;
R
4for hydrogen, C
1-8alkyl-carbonyl, C
3-8alkoxyl group-carbonyl, carbobenzoxy-(Cbz), C
2-8thiazolinyl-carbonyl, C
2-8alkynyl-carbonyl, C
3-8cycloalkyl-carbonyl, benzoyl, substituted benzoyl, cyanogen ethanoyl, heterocyclic radical-carbonyl, aryl amine-thiocarbonyl group, C
1-6haloalkyl, C
1-6a kind of in halogenated alkoxy, halogenated heterocyclic base-carbonyl, halogen aromatic amines base-thiocarbonyl group;
R
5a kind of in nitro, cyano group, trifluoromethyl, trifluoroacetyl group, alkoxy acyl, alkyl-formyl radical, trifyl;
R
6for hydrogen or halogen;
R
7for hydrogen, cyano group, nitro, halogen, trifluoromethyl, trifluoroacetyl group, C
1-10alkyl-formyl radical, C
1-10a kind of in alkoxyl group-formyl radical;
R
8be selected from one of following radicals:
Above-mentioned R
8in group: R
27, R
28, R
29, R
30, R
31, R
32, R
33, R
34, R
35be respectively methyl, ethyl, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, methoxyl group, hydroxyl, fluorine, chlorine, bromine, iodine, nitro, cyano group or hydrogen; Z is S or O or NH.
2. conjugated dienes derivative according to claim 1, is characterized in that: described R
1for: methyl, ethyl, propyl group,
in a kind of; R
2for: a kind of in methyl, ethyl, benzyl, substituted benzyl, R
3for: a kind of or R in methyl, ethyl, benzyl, substituted benzyl
2with R
3common formation-CH
2cH
2-,-CH
2cH
2cH
2-,-CH
2oCH
2-,-CH
2nHCH
2-,-CH
2n (CH
3) CH
2-,-CH
2sCH
2-,-CH
2n(C
2h
5) CH
2-in a kind of; R
4for: a kind of in hydrogen, ethanoyl, carbobenzoxy-(Cbz), methoxycarbonyl, benzoyl, substituted benzoyl, acryl; R
5for: a kind of in cyano group, nitro, trifluoroacetyl group; R
6for: a kind of in hydrogen, chlorine, bromine; R
7for: a kind of in hydrogen, cyano group, nitro, trifluoromethyl, trifluoroacetyl group; R
8for: cyano group, nitro,
in a kind of.
3. the preparation method of a conjugated dienes derivative claimed in claim 1, it is characterized in that: its reaction synthetic route is as follows:
Described reaction is carried out under organic solvent and catalyzer condition, wherein R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8definition described in claim 1.
4. the preparation method of conjugated dienes derivative according to claim 3 is characterized in that: described solvent is a kind of in ethanol, methyl alcohol, acetonitrile, tetrahydrofuran (THF), acetone, butanols.
5. the preparation method of conjugated dienes derivative according to claim 3 is characterized in that: described catalyzer is a kind of in sodium hydroxide, potassium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, triethylamine, piperidines, pyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium tert-butoxide.
6. according to the preparation method of claim 3,4 or 5 described conjugated dienes derivatives, it is characterized in that: temperature of reaction is 20～80 ℃, and the reaction times is 0.5～48h.
7. the application of conjugated dienes derivative in preparing cancer therapy drug as claimed in claim 1.
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| CN106966986A (en) * | 2017-04-13 | 2017-07-21 | 云南大学 | N benzyls heterocyclic nitro ketene semiamine analog derivative and synthetic method and antitumor application thereof |
| CN110256404A (en) * | 2019-04-30 | 2019-09-20 | 华东理工大学 | Bifunctional vinyl compound, its preparation and purposes with insecticidal activity |
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| WO2003040129A1 (en) * | 2001-11-05 | 2003-05-15 | Bayer Cropscience Aktiengesellschaft | Halogenated nitrobutadienes for controlling animal pests |
| WO2004058714A1 (en) * | 2002-12-20 | 2004-07-15 | Dow Agrosciences Llc | Compounds useful as pesticides |
| CN102690258A (en) * | 2012-05-29 | 2012-09-26 | 湖北省生物农药工程研究中心 | Nitrogenous heterocyclic-imide derivative and preparation method and purpose thereof |
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| WO2003040129A1 (en) * | 2001-11-05 | 2003-05-15 | Bayer Cropscience Aktiengesellschaft | Halogenated nitrobutadienes for controlling animal pests |
| WO2004058714A1 (en) * | 2002-12-20 | 2004-07-15 | Dow Agrosciences Llc | Compounds useful as pesticides |
| CN102690258A (en) * | 2012-05-29 | 2012-09-26 | 湖北省生物农药工程研究中心 | Nitrogenous heterocyclic-imide derivative and preparation method and purpose thereof |
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| CN106966986A (en) * | 2017-04-13 | 2017-07-21 | 云南大学 | N benzyls heterocyclic nitro ketene semiamine analog derivative and synthetic method and antitumor application thereof |
| CN106966986B (en) * | 2017-04-13 | 2019-10-11 | 云南大学 | N- benzyl heterocyclic nitro ketene semiamine analog derivative and synthetic method and antitumor application thereof |
| CN110256404A (en) * | 2019-04-30 | 2019-09-20 | 华东理工大学 | Bifunctional vinyl compound, its preparation and purposes with insecticidal activity |
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