CN103450175B - Conjugated dienes derivative and preparation method thereof and the purposes as cancer therapy drug - Google Patents

Conjugated dienes derivative and preparation method thereof and the purposes as cancer therapy drug Download PDF

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CN103450175B
CN103450175B CN201310350441.XA CN201310350441A CN103450175B CN 103450175 B CN103450175 B CN 103450175B CN 201310350441 A CN201310350441 A CN 201310350441A CN 103450175 B CN103450175 B CN 103450175B
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conjugated dienes
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nitro
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CN103450175A (en
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柯少勇
杨自文
石丽桥
刘曼莉
王开梅
梁英
江爱兵
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Aynor Cutting (wuhan) Biotechnology Co Ltd
Hubei Biopesticide Engineering Research Center
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Hubei Biopesticide Engineering Research Center
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    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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
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Abstract

The invention discloses a kind of conjugated dienes derivative and preparation method thereof and the purposes as cancer therapy drug.The structure of this conjugated dienes derivative is for shown in general formula I:

Description

Conjugated dienes derivative and preparation method thereof and the purposes as cancer therapy drug
Technical field
The invention belongs to organic drug synthesis technical field, be specifically related to a kind of conjugated dienes derivative and preparation method thereof and the purposes as cancer therapy drug.
Background technology
Antitumour drug refers to the medicine of anti-malignant tumor, also known as 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 tumour registration annual report " that national tumour Register issues shows, the annual new cancer cases about 3,120,000 of China, because number of cancer deaths is more than 2,000,000, this means within every 1 minute, have 6 people to be diagnosed as cancer.Current Nattonal Cancer incidence trend is severe, and incidence and mortality is in continuing ascendant trend.Cancer has become one of serious threat human life safety and the significant problem affecting 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 is still based on pharmacological agent to a great extent.Most common solid tumors such as lung cancer, liver cancer, colorectal carcinoma and carcinoma of the pancreas etc. still lack active drug, 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 the scientific-technical progress of society, the mankind are clear gradually to the cognition of cancer, the method of the prevention of some cancer and early diagnosis, technology and theory are also reached its maturity, but still can not cure cancer completely, very limitedly can only extend the survival time of cancer patient.Decision human society will constantly increase the demand of cancer drug by the feature that significantly increase and the cancer of the long-term existence of Cancerous disease, the showed prolonged survival of cancer patient, cancer new cases are difficult to cure.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 high-efficiency low-toxicity optionally new type anticancer active medicine, become when the significant research work of last item.
1,3-butadiene derivative has biological activity widely usually, such as Bioorg.Med.Chem.Lett.2004, and 14,1483; Bioorg.Med.Chem.Lett.1998,8, describe compound U0126 (1 in 2839,4-diamino-2,3-dicyano-Isosorbide-5-Nitrae-bis-(adjacent amino-benzene sulfydryl) divinyl) be a kind of conventional MAPKK inhibitor, the propagation of malignant cell is made a significant impact.Applicant, in process of scientific research, has found that series has the polysubstituted conjugated diolefine derivative of unsymmetrical structure, has presented significant antitumour activity, have 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 the purposes as cancer therapy drug.
For achieving the above object, the structure of conjugated dienes derivative of the present invention is for 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 3respective is independently hydrogen, C 1-8alkyl, C 1-8alkoxyl group, benzyl, substituted benzyl, C containing unsaturated link(age) 2-8alkyl or C 3-8alkoxyl group, C 1-8alkyl-C 3-8alkoxyl group, C 3-8alkoxy-carbonyl, carbobenzoxy-(Cbz), C containing unsaturated link(age) 2-8alkyl-carbonyl, C 3-8cycloalkyl-carbonyl, benzoyl, heterocyclic radical-carbonyl, C 1-6haloalkyl, C 1-6one in halogenated alkoxy, halogenated heterocyclic base-carbonyl; Or, 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 (other atoms namely beyond de-carbon and hydrogen, as nitrogen, phosphorus or boron etc.), R is substituting group, and R is hydrogen, C 1-8alkyl, C 2-8alkoxyl group, C containing unsaturated link(age) 2-8alkyl, C 1-8alkyl-C 3-8alkoxyl group, C 3-8alkoxy-carbonyl, carbobenzoxy-(Cbz), C 2-8thiazolinyl-carbonyl, C 2-8alkynyl-carbonyl, C 3-8cycloalkyl-carbonyl, benzoyl, heterocyclic radical-carbonyl, C 1-6haloalkyl, C 1-6one in halogenated alkoxy, halogenated heterocyclic base-carbonyl;
R 4for hydrogen, C 1-8alkyl-carbonyl, C 3-8alkoxy-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 1-6one in halogenated alkoxy, halogenated heterocyclic base-carbonyl, halogen aromatic amines base-thiocarbonyl group;
R 5for the one 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 one (in formula: R 13, R 14, R 15, R 16, R 21, R 23definition as described above); R 2for: the one in methyl, ethyl, benzyl, substituted benzyl; R 3for: the one in methyl, ethyl, benzyl, substituted benzyl; Or 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 one; R 4for: the one in hydrogen, ethanoyl, carbobenzoxy-(Cbz), methoxycarbonyl, benzoyl, substituted benzoyl, acryl; R 5for: the one in cyano group, nitro, trifluoroacetyl group; R 6for: the one in hydrogen, chlorine, bromine; R 7for: the one in hydrogen, cyano group, nitro, trifluoromethyl, trifluoroacetyl group; R 8for: cyano group, nitro, in one (in formula: R 28, R 29, R 31, R 32, R 34, R 35definition as described above).
Meanwhile, the invention provides the preparation method of above-mentioned conjugated dienes derivative, particularly, the synthetic route of this preparation method is as follows:
Described reaction is carried out under organic solvent and catalysts conditions;
R in reaction formula 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8definition with mentioned above.
In the preparation method of above-mentioned conjugated dienes derivative, preferably, described solvent is the one in ethanol, methyl alcohol, acetonitrile, tetrahydrofuran (THF), acetone, butanols; Described catalyzer is the one 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 preferably, temperature of reaction is 20 ~ 80 DEG C, and the reaction times is 0.5 ~ 48h, so controls reaction times and temperature, effectively can improve speed of reaction and reduce the generation of side reaction.
Preparation method of the present invention adopts polysubstituted fragrance and heterocyclic aldehydes M and contains active methylene compound (i.e. R 7-CH 2-R 8) carry out Knoevenagel condensation reaction, conjugated dienes derivative I can be obtained.Polysubstituted fragrance wherein and heterocyclic aldehydes M can adopt the methodology of organic synthesis of method described in patent WO2004058714A1 or other routines to prepare.
Present invention also offers the conjugated dienes derivative with said structure general formula I and prepare the application of cancer therapy drug.Conjugated dienes derivative provided by the present invention and pharmacy acceptable salt thereof are (such as: general inorganic hydrochlorate, example hydrochloric acid salt, vitriol, phosphoric acid salt and organic acid salt, as mesylate, fluoroform sulphonate, acetate, trifluoroacetate, benzoate etc.), to human hepatocarcinoma cells 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; Human Gastric carcinoma's cell BCG-823, SGC-7901, HS-746T, MGC-803; Human nasopharynx's cancer cells KB, CNE-2, SUNE-1; Human ovarian cancer cell 3AO, SKOV3, TYK; Human prostate cancer PC-3,22RV1; Human cervix cancer cells Hela, RhoC, VAV2; Human skin melanoma cell A375; People's epidermal carcinoma cell A431; Human glioma cells C6 etc. have significant inhibit activities; And to monkey-kidney cells MARC145, Madin-Darby canine kidney(cell line) MDCK and mankind's normal liver cell strain HL-7702 etc., there is more weak inhibit activities.In practical application, conjugated dienes derivative of the present invention and pharmacy acceptable salt thereof are prepared into various practical medicament, as the medicine of granule, tablet, pill, capsule, injection, suspension agent or emulsion by ordinary method.
The present invention passes through design and synthesis and the screening active ingredients research of system, based on conjugated dienes structural matrix, construct 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 is obviously 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, conjugated dienes derivative of the present invention and preparation method thereof and the purposes as cancer therapy drug are described in further detail.
Embodiment 1
One in the structure particular compound as listed in Table 1 of partly conjugated diene derivative of the present invention:
Table 1: the representative compound structure list of general formula I
Embodiment 2
Be numbered compound 2-(benzo [d] thiazol-2-yl)-4-(1-(phenyl) tetrahydroglyoxaline-2-the subunit)-4-nitro but-2-ene nitrile of I-6 in embodiment 1, its preparation method is:
With N-phenylethylenediamine for starting raw material, with reference to the method disclosed in patent WO2004058714A1, pass through successively and 1,1-bis-thiomethyl-2-nitroethylene generation substitution reaction, then prepare intermediate 2-(1-(phenyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde (M-1) with the condensation reaction of DMF dimethylacetal, basic hydrolysis.Then taking M-1 and 2-(1-(phenyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.12g (0.5mmol) is dissolved in 10mL dehydrated alcohol, under room temperature condition, add the potassium hydroxide of 2-cyanogen methylbenzothiazole (i.e. compd A) 0.096g (0.55mmol) and catalytic amount successively, the first stirring at room temperature of reaction mixture 30 minutes, then slowly 40-45 DEG C is heated to, insulation reaction, TLC monitoring is to reacting completely.Decompression remove portion solvent, after cooling, 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 DEG C; MS (ESI) m/z389.9 (M+H) +, calcd.forC 20h 15n 5o 2sm/z=389.1.
Embodiment 3
Be numbered compound 2-(benzo [d] oxazole-2-base)-4-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-the subunit)-4-nitro but-2-ene nitrile of I-37 in embodiment 1, its preparation method is:
Take CCMP as starting raw material, pass through with the substitution reaction of quadrol, with 1 successively, the substitution reaction of 1-bis-thiomethyl-2-nitroethylene, then prepare intermediate 2-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde (M-2) with the condensation reaction of DMF dimethylacetal, basic hydrolysis.Then weighing M-2 and 2-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g (0.5mmol) is dissolved in 10mL dehydrated alcohol, under room temperature condition, add 2-cyanogen Jia base benzoxazole (compd B) 0.087g (0.55mmol) successively, and the piperidines of catalytic amount, the first stirring at room temperature of reaction mixture 30 minutes, then 40 DEG C are slowly heated to, insulation reaction, TLC monitoring is to reacting completely.Decompression remove portion solvent, after cooling, 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 DEG C; 1hNMR (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.forC 20h 15clN 6o 3m/z=422.1.
Embodiment 4
Be numbered compound 2-(6-chloropyridine-3-base)-4-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-the subunit)-4-nitro but-2-ene nitrile of I-38 in embodiment 1, its preparation method is:
Weighing M-2 and 2-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g (0.5mmol) is dissolved in 10mL dehydrated alcohol, under room temperature condition, add 2-(6-chloropyridine-3-base) acetonitrile (Compound C) 0.084g (0.55mmol) successively, and the sodium hydroxide of catalytic amount, the first stirring at room temperature of reaction mixture 20 minutes, then slowly 35-40 DEG C is heated to, insulation reaction, TLC monitoring is to reacting completely.Decompression remove portion solvent, after cooling, 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 DEG C; MS (ESI) m/z417.0 (M+H) +, calcd.forC 18h 14cl 2n 6o 2m/z=416.1.
Embodiment 5
Be numbered compound 2-(4-nitrophenyl)-4-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-the subunit)-4-nitro but-2-ene nitrile of I-40 in embodiment 1, its preparation method is:
Weighing M-2 and 2-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g (0.5mmol) is dissolved in 15mL dehydrated alcohol, then under room temperature condition, add 4-nitrobenzene ethane nitrile (Compound D) 0.089g (0.55mmol) successively, and the potassium hydroxide of catalytic amount, the first stirring at room temperature of reaction mixture 30 minutes, then 45 DEG C are slowly heated to, insulation reaction, TLC monitoring is to reacting completely.Decompression remove portion solvent, after cooling, 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 DEG C; MS (ESI) m/z426.9 (M+H) +, calcd.forC 19h 15clN 6o 4m/z=426.1.
Embodiment 6
Be numbered compound 2-(benzo [d] thiazol-2-yl)-4-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-the subunit)-4-nitro but-2-ene nitrile of I-36 in embodiment 1, its preparation method is:
Taking M-2 and 2-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g (0.5mmol) is dissolved in 10mL dehydrated alcohol, then under room temperature condition, add 2-cyanogen methylbenzothiazole (compd A) 0.096g (0.55mmol), add basic catalyst again, the first stirring at room temperature of reaction mixture 40 minutes, then be slowly heated to 50 DEG C, insulation reaction, TLC monitoring is to reacting completely.Decompression remove portion solvent, after cooling, 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 DEG C; 1hNMR (400MHz, 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.forC 20h 15clN 6o 2sm/z=438.1.
Embodiment 7
Be numbered compound 2-(benzo [d] thiazol-2-yl)-4-(1-(benzyl) tetrahydroglyoxaline-2-the subunit)-4-nitro but-2-ene nitrile of I-16 in embodiment 1, its preparation method is:
Take Benzyl Chloride as starting raw material, pass through with the substitution reaction of quadrol, with 1 successively, the substitution reaction of 1-bis-thiomethyl-2-nitroethylene, then prepare intermediate 2-(1-(benzyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde (M-3) with the condensation reaction of DMF dimethylacetal, basic hydrolysis.Then taking M-3 and 2-(1-(benzyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.124g (0.5mmol) is dissolved in 10mL dehydrated alcohol, add 2-cyanogen methylbenzothiazole (compd A) 0.096g (0.55mmol) successively, add the potassium hydroxide of catalytic amount again, the first stirring at room temperature 1h of reaction mixture, then 40 DEG C are slowly heated to, insulation reaction, TLC monitoring is to reacting completely.Decompression remove portion solvent, after cooling, 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 DEG C; 1hNMR (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.forC 21h 17n 5o 2sm/z=403.1.
Embodiment 8
Be numbered compound 2-(benzo [d] thiazol-2-yl)-4-(1-(ethyl) tetrahydroglyoxaline-2-the subunit)-4-nitro but-2-ene nitrile of I-27 in embodiment 1, its preparation method is:
Take NEED as starting raw material, pass through successively and 1,1-bis-thiomethyl-2-nitroethylene generation substitution reaction, then prepare intermediate 2-(1-(ethyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde (M-4) with the condensation reaction of DMF dimethylacetal, basic hydrolysis.Then taking M-4 and 2-(1-(ethyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.093g (0.5mmol) is dissolved in 8mL dehydrated alcohol, add the piperidines of 2-cyanogen methylbenzothiazole (compd A) 0.096g (0.55mmol) and catalytic amount successively, stirring at room temperature, TLC monitoring is to reacting completely.Decompression remove portion solvent, after cooling, 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 DEG C; MS (ESI) m/z342.2 (M+H) +, calcd.forC 16h 15n 5o 2sm/z=341.1.
Embodiment 9
Be numbered compound 2-(2-(1-((2-diuril azoles-5-base) methyl) tetrahydroglyoxaline-2-the subunit)-2-nitro ethylidene) propane dinitrile of I-48 in embodiment 1, its preparation method is:
With 2-chloro-5-chloromethyl thiazole for starting raw material, pass through with the substitution reaction of quadrol, with 1 successively, the substitution reaction of 1-bis-thiomethyl-2-nitroethylene, then prepare intermediate 2-(1-((2-diuril azoles-5-base) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde (M-5) with the condensation reaction of DMF dimethylacetal, basic hydrolysis.Then taking M-5 and 2-(1-((2-diuril azoles-5-base) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.15g (0.5mmol) is dissolved in 10mL dehydrated alcohol, under room temperature condition, add the sodium hydroxide of propane dinitrile 0.036g (0.55mmol) and catalytic amount successively, the first stirring at room temperature of reaction mixture is after 30 minutes, then 40 DEG C are slowly heated to, insulation reaction, TLC monitoring is to reacting completely.Decompression remove portion solvent, after cooling, 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 DEG C; 1hNMR (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.forC 12h 9clN 6o 2sm/z=336.0.
Embodiment 10
Be numbered compound 2-(benzo [d] thiazol-2-yl)-4-(1-((2-diuril azoles-5-base) methyl) tetrahydroglyoxaline-2-the subunit)-4-nitro but-2-ene nitrile of I-52 in embodiment 1, its preparation method is:
Weighing M-5 and 2-(1-((2-diuril azoles-5-base) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.15g (0.5mmol) is dissolved in 15mL dehydrated alcohol, then the piperidines of 2-cyanogen methylbenzothiazole (compd A) 0.096g (0.55mmol) and catalytic amount is added successively, stir under room temperature condition, TLC monitoring is to reacting completely.Decompression remove portion solvent, after cooling, 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 DEG C; 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.forC 18h 13clN 6o 2s 2m/z=444.0.
Embodiment 11
Be numbered compound 2-(2-diuril azoles-5-base)-4-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-the subunit)-4-nitro but-2-ene nitrile of I-39 in embodiment 1, its preparation method is:
Taking M-2 and 2-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g (0.5mmol) is dissolved in 10mL anhydrous methanol, add the sodium hydroxide of 2-(2-diuril azoles-5-base) acetonitrile (compound F 17-hydroxy-corticosterone) 0.087g (0.55mmol) and catalytic amount successively, stirring at room temperature, TLC monitoring is 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 DEG C; MS (ESI) m/z422.8 (M+H) +, calcd.forC 16h 12cl 2n 6o 2sm/z=422.0.
Embodiment 12
Be numbered compound 4-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-subunit)-2-(1H-indoles-3-the formyl radical)-4-nitro but-2-ene nitrile of I-41 in embodiment 1, its preparation method is:
Taking M-2 and 2-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g (0.5mmol) is dissolved in 15mL dehydrated alcohol; add the potassium hydroxide of 3-cyanogen acetylindole (compound G) 0.092g (0.55mmol) and catalytic amount successively; stirring at room temperature, TLC monitoring is to reacting completely.Decompression remove portion solvent, after cooling, 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 DEG C; 1hNMR (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.forC 22h 17clN 6o 3m/z=448.1.
Embodiment 13
Compound 2-(benzo [d] thiazol-2-yl)-5-(((6-chloropyridine-3-base) methyl) (ethyl) is amino)-5-(the methylamino-)-4-nitro-2 of I-64 is numbered in embodiment 1,4-pentadiene nitrile, its preparation method is:
Take CCMP as starting raw material, pass through with the substitution reaction of ethamine, with 1 successively, the substitution reaction of 1-bis-thiomethyl-2-nitroethylene, with the substitution reaction of methylamine, prepare intermediate 3-(((6-chloropyridine-3-base) methyl) (ethyl) is amino)-3-(methylamino-)-2-nitro propenal (M-6) with the condensation reaction of DMF dimethylacetal, basic hydrolysis.Then weighing M-6 and 3-(((6-chloropyridine-3-base) methyl) (ethyl) is amino)-3-(methylamino-)-2-nitro propenal 0.15g (0.5mmol) is dissolved in 10mL methyl alcohol, add the potassium hydroxide of 2-cyanogen methylbenzothiazole (compd A) 0.096g (0.55mmol) and catalytic amount successively, stirring at room temperature, TLC monitoring is 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 DEG C; MS (ESI) m/z454.9 (M+H) +, calcd.forC 21h 19clN 6o 2sm/z=454.1.
Embodiment 14
Be numbered compound 2-(5-chlorobenzene is [d] thiazol-2-yl also)-4-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-the subunit)-4-nitro but-2-ene nitrile of I-47 in embodiment 1, its preparation method is:
Taking M-2 and 2-(1-((6-chloropyridine-3-base) methyl) tetrahydroglyoxaline-2-subunit)-2-nitro acetaldehyde 0.14g (0.5mmol) is dissolved in 15mL methyl alcohol, add the potassium hydroxide of 2-(5-chloro benzothiazole-2-base) acetonitrile (compound H) 0.12g (0.55mmol) and catalytic amount successively, stirring at room temperature, TLC monitoring is to reacting completely.Decompression remove portion solvent, after cooling, 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 DEG C; 1hNMR (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.forC 20h 14cl 2n 6o 2sm/z=472.0.
The preparation of other compound in embodiment 15 table 1
The preparation of other compound in embodiment 1, with reference to basic synthetic method described in embodiment 2 ~ 14, and the constitutional features of compound described in associative list 1 selects different conventional industrial chemicals, other compound that just can be listed in preparation table.
The Anticancer Activity in vitro evaluation of embodiment 16 compound
For examination cancer cells: human hepatocarcinoma cells's strain HepG2, Huh-7; Mankind mastopathy cell's strain MCF-7; Human Lung Cancer cell line A549, H1975; Human Gastric carcinoma's cell strain BCG-823; Human cervix cancer cells's 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: RPMIMedium1640 cell culture medium, 10% calf serum and 0.01%L-glutamine are mixed with nutrient solution.Cultured cells strain is placed in 37 DEG C, 5%CO 2under saturated humidity, cellar culture goes down to posterity, and experiment is all with the cell being in logarithmic phase.
Anticancer Activity in vitro evaluates (mtt assay): with 0.25% trypsinase, cell dissociation is made single-cell suspension liquid, be inoculated in 96 orifice plates, 37 DEG C, 5%CO by every hole 6000-7000 cell 2spend the night, add the sample of different concns, respectively using single celled nutrient solution and without pharmaceutically-active cell as blank and negative control, with cancer therapy drug 5 FU 5 fluorouracil and U0126 for positive control, often group establishes 8 multiple holes, continues to cultivate 48h and obtains 72h.Every hole adds MTT (5mg/mL) 20 μ l and continues to cultivate 4h, and abandon supernatant liquor, every hole adds 150 μ lDMSO, hatches 10min for 37 DEG C, and microplate reader detects the light absorption value (A at 570nm wavelength place 570).Calculate average inhibition as follows:
Inhibiting rate=(A negative control– A laboratory sample)/(A negative control– A blank) × 100%
Partial test result is as shown in table 2 below, and result shows, the polysubstituted asymmetric conjugated dienes derivative of preparation shows obvious restraining effect to for examination cancer cells, compared with contrast medicament 5 FU 5 fluorouracil and U0126, and superior activity.Therefore, the compounds of this invention can be widely used in cancer therapy drug field, has significant researching value and application prospect.
The antitumour activity of table 2 part of compounds
In table 2: aiC 50<40 μM is designated as +++, IC 5040 ~ 100 μMs are designated as ++, IC 50>100 μM be 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 anti-cancer activity in vivo evaluation of embodiment 17 compound
For examination animal: BALB/C type male nude mouse, body weight is about 18-22g.
Tumor cell line: human liver cancer cell (HepG-2).
Test method: by be cultured to logarithmic phase HepG-2 cell dissociation, counting after be diluted to 5 × 10 6/ mL.Aseptically, be only inoculated in nude mice flank by 0.2mL/ subcutaneous, observe every day and measure tumor size.14d after injection, nude mice by subcutaneous forms macroscopic tumour, when diameter of tumor>=6mm calculates volume as follows: Volume=Length × Width 2/ 2, gross tumor volume reaches 100mm 3time start administration of dividing into groups.By nude mice random packet, and blank group (10%DMAC+10%CremophorELinPBS) and 5-Fu control group (20mg/kg) are set simultaneously, every day intraperitoneal injection 1 time, continuous 7 days, calculate and often organize 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 results from vivo experiments shows, the polysubstituted conjugated dienes derivative of preparation serves certain restraining effect to for examination cancer cells, 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; Compared with contrast medicament 5 FU 5 fluorouracil (5-FU), 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 are prepared into various practical medicament by ordinary method, as the medicine of granule, tablet, pill, capsule, injection, suspension agent or emulsion, be widely used in the Prevention and Curation field of cancer.

Claims (5)

1. a conjugated dienes derivative, is characterized in that: its general structure is:
In formula:
R 1be selected from one of following radicals:
R 2and R 3common formation-CH 2cH 2-;
R 4for hydrogen; R 5for nitro; R 6for hydrogen; R 7for cyano group;
R 8be selected from one of following radicals:
2. a preparation method for conjugated dienes derivative according to claim 1, is characterized in that: its Reactive Synthesis route is as follows:
Described reaction is carried out under organic solvent and catalysts conditions, wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8definition as described in the appended claim 1, described catalyzer is the one 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.
3. the preparation method of conjugated dienes derivative according to claim 2, is characterized in that: described solvent is the one in ethanol, methyl alcohol, acetonitrile, tetrahydrofuran (THF), acetone, butanols.
4. the preparation method of the conjugated dienes derivative according to Claims 2 or 3, is characterized in that: temperature of reaction is 20 ~ 80 DEG C, and the reaction times is 0.5 ~ 48h.
5. conjugated dienes derivative is preparing the application in cancer therapy drug as claimed in claim 1.
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