CN106220641B - Containing the indoles volution compound and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure - Google Patents
Containing the indoles volution compound and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
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Abstract
The indoles volution compound for the blue hydrocarbon Azulene structure containing more wound with tumors inhibition activity that the present invention relates to a kind of, has the following structure general formula:
Description
Technical field
The invention belongs to field of medicinal chemistry, are related to hetero atom spiro-compound, and in particular to one kind contains the blue hydrocarbon Azulene of more wound
Indoles Spirocyclic derivatives, synthesis and its application of structure.
Background technique
All contain spirane structure in many natural products, wherein hetero atom spiro-compound has antitumor, antianxiety, resists
The extensive bioactivity such as bacterium, decompression and analgesia due to mechanism of action uniqueness, and is not likely to produce drug resistance, is clinical medicine
Research and development open frontier ((a) Onishhi, T.；Sebahar,P.R.；Williams,R.M.Org.Lett.2003,17,
3135；(b)Cremer,N.S.；Hamamouch,N.C.J.Am.Chem.Soc.2005,127,10130；(c)Zhou,B.；
Yang,Y.X.；Shi,J.J.；Luo,Z.；Li,y.C.J.Org.Chem.2013,78,2897.).
Indoles spiro-compound is a kind of important hetero atom spiro-compound, universally present in many have physiology and
In the natural alkaloid of pharmacological activity, it has also become indispensable structural unit ((a) Pavlovska1, T.L. in many drugs；
Redkin,R.G.；Lipson,V.V.；Atamanuk,D.V.Mol Divers,2016,20,299；(b)Shngh,G.S.；
Desta,Z.Y.Chem.Rev.2012,112,6104.).Studies have shown that indoles volution compound is a kind of important in human body
The endogeneous activity factor, be largely present in nervous system, intracorporal cell monoamine oxidase can be maintained into normal water
It is flat, to be effectively prevented generation ((a) Glover, V. of the neurodegenerative disorders such as parkinsonism, convulsions, epilepsy；
Halket,J.；Watkins,P.J.J.Neurochem.1988,51,656；(b)Finberg,J.P.；Wang,J.；
Goldstein,D.S.J.Neurochem.1995,65,1213.).Meanwhile such compound also have well it is antitumor, anti-
The bioactivity such as allergy, treating tuberculosis and antithrombotic ((a) Yu, B.；Yu,D.Q.；Liu,H.M.Eur.J.Med.Chem.2015,
97,673；(b)Cui,C.B.；Kakeya,H.；Osada, H.Tetrahedron, 1996,52,12651.), thus biology,
Medicine and other fields have very important status and very extensive application prospect.Synthesis and exploitation to such compound are
Cause concern ((a) Zhu, S.L. of chemist and drug scholar；Jia,S.J.；Zhang,Y.Tetrahedron,2007,63,
9365；(b)Chen,X.；Wei,Q.；Luo,S.；Xiao,H.；Gong,L.J.Am.Chem.Soc.2009,131,13819；(c)
Tsubouchi,H.；Sasaki,H.；Itotani,M.；Haraguchi,Y.；Miyamura,S.；Matsumoto,M.；
Hashizume,H.；Tomishige,T.；Kawasaki,K.；Sumida,T.；Hasegawa,T.；Tanaka,K.；
Takemura,I.WO 2005042542,2005；(d)Shi,Y.；Lin,A.J.；Mao,H.B.；Mao,Z.J.；Li,W.P.；
Hu,H.W.；Zhu,C.J.；Cheng,Y.X.Chem.Eur.J.2013,19,1914；(e)Zhang,J.；Gao,H.；Sun,J.；
Yan,C.G.Eur.J.Org.Chem.2014,5598.)。
More the effective component that blue hydrocarbon Azulene (Isosorbide-5-Nitrae-dimethyl -7- isopropyl Azulene, Guaiazulene) is foreign chrysanthemum is created, is had
Very strong antipepsin, anti-inflammatory, antiallergy, it is anti-oxidant and antiviral the effects of ((a) Jung, F.Pharmazie, 1951,6,
192；(b)Kouichi,N.；Tomio,N.；Hiroyuki,Y.；Shogo,I.；Yoshiaki,
K.Eur.J.Pharm.Biopharm.2003,56,347；(c)Kourounakis,A.P.；Rekka,E.A.；
Kourounakis,P.N.J.Pharm.Pharmacol.1997,49,938；(d)Flori,J.；Teti,G.；Gotti,R.；
Mazzotti,G.；Falconi,M.Toxicol.in Vitro.2011,25,64.).Its many derivatives all show good
Good bioactivity ((a) Kurokawa, S.Chem.Lett.1981,1569；(b)Kurokawa,
S.Bull.Chem.Soc.Jpn.1983,56,2311；(c)Franchi,E.；Ingrosso,G.；Marchetti,F.；
Pinzino,C.Tetrahedron,2003,59,5003.)。
In pharmaceutical synthesis, medicine and other fields, there is an urgent need to develop the new bioactive molecules with specificity at present.It is logical
The structural modification to spiro-compound molecule is crossed, is an important channel for obtaining bioactive compound, there is wide answer
Use prospect.
Summary of the invention
The indoles loop coil for the blue hydrocarbon Azulene structure containing more wound with tumors inhibition activity that the purpose of the present invention is to provide a kind of
Class compound.
Another object of the present invention is to provide a kind of easy to operate, and raw material is easy to get, and yield is high, good blue containing more creating of selectivity
The indoles volution compound preparation method of hydrocarbon Azulene structure.
The present invention also provides a kind of indoles volution compounds of blue hydrocarbon Azulene structure containing more wound in as anti-tumor drug
Application.
In order to solve the above technical problems, the present invention is implemented as follows:
The indoles Spirocyclic derivatives of the blue hydrocarbon Azulene structure provided by the invention containing more wound, have the following structure general formula:
Wherein, R1For H, alkyl, alkoxy, hydroxyl, amino, halogen, nitro, cyano or one of carboxylic acid and its ester；R2
For H, alkyl or aryl；X is cyano or alkoxy carbonyl group.
The above-mentioned preparation method containing the indoles volution compound for more creating blue hydrocarbon Azulene structure, can implement as follows:
(1) triethylamine is added to 1- cyanogen acetyl group in the solution be cured and create blue hydrocarbon Azulene, isatin and cyanoacetate and is reacted；
(2) after completion of the reaction, by directly filtering or reaction solution being concentrated to get crude product；
(3) by gained crude product by recrystallizing to get purpose product.
As a preferred embodiment, solution described in step (1) of the present invention is using ethyl alcohol or acetonitrile as solvent.
Further, isatin of the present invention, 1- cyanogen acetyl group are cured the blue hydrocarbon Azulene of wound, the molar ratio of cyanoacetate is followed successively by 1:
1~1.5:1~1.5.
Further, for the present invention in terms of molal weight, the dosage of the triethylamine is the 5~50% of isatin.
The above-mentioned preparation method containing the indoles volution compound for more creating blue hydrocarbon Azulene structure, can also implement as follows:
(1) triethylamine is added to 1- cyanogen acetyl group in the solution be cured and create blue hydrocarbon Azulene, isatin and malononitrile and is reacted；
(2) after completion of the reaction, by directly filtering or reaction solution being concentrated to get crude product；
(3) by gained crude product by recrystallizing to get purpose product.
As a preferred embodiment, isatin of the present invention, 1- cyanogen acetyl group be cured create blue hydrocarbon Azulene, malononitrile molar ratio according to
Secondary is 1:1~1.5:1~1.5.
The indoles volution compound of the above-mentioned blue hydrocarbon Azulene structure containing more wound is as the application in anti-tumor drug.
The present invention ties up under triethylamine effect, and blue hydrocarbon Azulene, isatin and cyanoacetate (or the third two are more created with 1- cyanogen acetyl group
Nitrile) it is reaction raw materials, pass through three component reaction one-step synthesis.
Composition principle are as follows:
It is the compound having the following structure that 1- cyanogen acetyl group described in above-mentioned synthesis process, which more creates blue hydrocarbon Azulene (1):
The compound can refer to document (kingly way woods, Li Di, Cao Liang, organic chemistry, 2012,32,1741-1745.) method,
More to create blue hydrocarbon Azulene as substrate, it is made by the acylation reaction of cyanoacetic acid and acetic anhydride:
In addition, isatin described in above-mentioned synthesis process is the compound having the following structure:
Wherein, R1For one of H, alkyl, alkoxy, hydroxyl, halogen, nitro, cyano, carboxylic acid and its ester etc.；R2For H,
Alkyl, aryl.
Such compound can refer to document (Zhang Xiaofei, Liu Huaye, Gao Wentao, Bohai University's journal (natural science edition),
2009,30,212.) method is reacted by Sandmeyer and is prepared using aromatic amine as raw material；1- replaces Isatine derivatives can refer to
Document ((a) Clay, C.M.；Abdallah,H.M.；Jordan,C.；Knisley,K.；Ketcha D.M.Arkivoc,2012,
vi,317；(b)Azizian,J.；Fallah-Bagher-Shaidaei,H.；Kafayati,H.Synth.Commun.2003,
33,789.) method is made using isatin as raw material by N- alkylated reaction:
It is a further object of the present invention to provide preparing anticancer drug containing the indoles Spirocyclic derivatives for more creating blue hydrocarbon Azulene structure
In application.
The indoles volution compound of the blue hydrocarbon Azulene structure provided by the invention containing more wound, through human stomach cancer cell line (SGC-
7901) and the inhibitory activity of human lung carcinoma cell line (H446) measurement shows it to gastric carcinoma cells and human lung carcinoma cell with good
Good inhibiting effect has stronger development and application prospect, is expected to be further developed into as new tumor growth inhibitors, is used for
The synthesis etc. of the therapeutic agent or related drugs of cancer.
Synthetic method of the present invention containing the indoles volution compound for more creating blue hydrocarbon Azulene structure is easy to operate, raw material is easy to get,
Yield is high, selectivity is good, provides effective route of synthesis to synthesize polycyclic condensed indoles volution compound.
The present invention will be described further with following example, but the contents of the present invention are not limited by this embodiment.
Specific embodiment
Embodiment 1
2 '-amino -3 ', 5 '-dicyanos -6 '-(3,8- dimethyl -5- isopropyl Azulene -1- base) -2- oxygen spiral shell (indoline -3,
4 '-pyrans) (A1) synthesis
In 50mL reaction flask, triethylamine (20mg, 0.2mmol) is added to isatin (147mg, 1.0mmol), 1- cyanogen second
Acyl group is cured in ethyl alcohol (25mL) solution for creating blue hydrocarbon Azulene (318mg, 1.2mmol) and malononitrile (79mg, 1.2mmol), is heated back
Stream 5 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, reaction mixture is concentrated under reduced pressure, ethyl alcohol recrystallization
Obtain blue solid, yield 82%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.46 (d, J=6.6Hz, 6H), 2.62 (s, 3H), 3.05 (s, 3H), 3.20-
3.25(m,1H),7.13-7.21(m,4H),7.28-7.30(m,2H),7.62(s,2H),7.78(s,1H),8.26(s,1H),
11.64(brs,1H).
IR (KBr) ν: 3428 (NH), 3341 (NH), 2237 (CN), 2243 (CN), 1718 (C=O) cm-1.
MS(ESI)m/z:461[M+H]+.
Elemental analysis (C29H24N4O2): measured value (theoretical value), C 75.72 (75.63), H 5.34 (5.25), N 12.25
(12.17).
Embodiment 2
2 '-amino -5 '-cyano -6 '-(3,8- dimethyl -5- isopropyl Azulene -1- base) -2- oxygen spiral shell (3,4 '-pyrrole of indoline -
Mutter) -3 '-Ethyl formate (A2) synthesis
In 50mL reaction flask, triethylamine (20mg, 0.2mmol) is added to isatin (147mg, 1.0mmol), 1- cyanogen second
Acyl group is cured in ethyl alcohol (25mL) solution for creating blue hydrocarbon Azulene (318mg, 1.2mmol) and ethyl cyanoacetate (135mg, 1.2mmol), is added
Heat reflux 6 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, reaction mixture is concentrated under reduced pressure, ethyl alcohol weight
Crystallization obtains blue solid, yield 85%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 0.73 (t, J=7.2Hz, 3H), 1.44 (d, J=6.6Hz, 6H), 2.62 (s,
3H), 3.07 (s, 3H), 3.20-3.24 (m, 1H), 3.68 (q, J=7.2Hz, 2H), 7.16-7.25 (m, 4H), 7.26-7.29
(m,2H),7.69(s,2H),7.79(s,1H),8.31(s,1H),11.69(brs,1H).
IR (KBr) ν: 3422 (NH), 3349 (NH), 2235 (CN), 1694 (C=O), 1715 (C=O) cm-1.
MS(ESI)m/z:509[M+H]+.
Elemental analysis (C31H29N3O4): measured value (theoretical value), C 73.46 (73.35), H 5.84 (5.76), N 8.37
(8.28).
Embodiment 3
2 '-amino -3 ', 5 '-dicyanos -6 '-(3,8- dimethyl -5- isopropyl Azulene -1- base) -1- methyl -2- oxygen spiral shell (Yin
Diindyl quinoline -3,4 '-pyrans) (A3) synthesis
In 50mL reaction flask, triethylamine (30mg, 0.3mmol) is added to 1- methylisatin (161mg, 1.0mmol),
1- cyanogen acetyl group is cured in ethyl alcohol (25mL) solution for creating blue hydrocarbon Azulene (318mg, 1.2mmol) and malononitrile (79mg, 1.2mmol),
It is heated to reflux 3 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, reaction mixture is concentrated under reduced pressure, isopropyl
Alcohol is recrystallized to give blue solid, yield 84%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.45 (d, J=6.6Hz, 6H), 2.61 (s, 3H), 3.03 (s, 3H), 3.18
(s,3H),3.20-3.24(m,1H),7.10-7.23(m,4H),7.24-7.29(m,2H),7.60(s,2H),7.74(s,1H),
8.32(s,1H).
IR (KBr) ν: 3423 (NH), 2232 (CN), 2246 (CN), 1723 (C=O) cm-1.
MS(ESI)m/z:476[M+H]+.
Elemental analysis (C30H26N4O2): measured value (theoretical value), C 76.01 (75.93), H 5.61 (5.52), N 11.89
(11.81).
Embodiment 4
2 '-amino -5 '-cyano -6 '-(3,8- dimethyl -5- isopropyl Azulene -1- base) -1- methyl -2- oxygen spiral shell (indoline -
3,4 '-pyrans) -3 '-Ethyl formate (A4) synthesis
In 50mL reaction flask, triethylamine (30mg, 0.3mmol) is added to 1- methylisatin (161mg, 1.0mmol),
1- cyanogen acetyl group is cured the blue hydrocarbon Azulene (318mg, 1.2mmol) of wound and the ethyl alcohol (25mL) of ethyl cyanoacetate (135mg, 1.2mmol) is molten
In liquid, it is heated to reflux 4 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, reaction mixture is depressurized dense
Contracting, ethyl alcohol recrystallization obtain blue solid, yield 80%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 0.79 (t, J=7.2Hz, 3H), 1.41 (d, J=6.6Hz, 6H), 2.62 (s,
3H), 3.10 (s, 3H), 3.23 (s, 3H), 3.21-3.26 (m, 1H), 3.62 (q, J=7.2Hz, 2H), 7.19-7.27 (m,
4H),7.29-7.32(m,2H),7.74(s,2H),7.83(s,1H),8.34(s,1H).
IR (KBr) ν: 3424 (NH), 2232 (CN), 1696 (C=O), 1726 (C=O) cm-1.
MS(ESI)m/z:522[M+H]+.
Elemental analysis (C32H31N3O4): measured value (theoretical value), C 73.75 (73.68), H 6.07 (5.99), N 8.17
(8.06).
Embodiment 5
2 '-amino -5 '-cyano -6 '-(3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5- dimethyl -2- oxygen spiral shell (Yin
Diindyl quinoline -3,4 '-pyrans) -3 '-Ethyl formate (A5) synthesis
In 50mL reaction flask, by triethylamine (30mg, 0.3mmol) be added to 1,5- dimethylisatin (175mg,
1.0mmol), 1- cyanogen acetyl group is cured the ethyl alcohol for creating blue hydrocarbon Azulene (318mg, 1.2mmol) and ethyl cyanoacetate (135mg, 1.2mmol)
In (25mL) solution, it is heated to reflux 3 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reaction mixture
It is concentrated under reduced pressure, ethyl alcohol recrystallization obtains blue solid, yield 86%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 0.83 (t, J=7.2Hz, 3H), 1.43 (d, J=6.6Hz, 6H), 2.64 (s,
3H), 3.01 (s, 3H), 3.12 (s, 3H), 3.20-3.23 (m, 1H), 3.24 (s, 3H), 3.65 (q, J=7.2Hz, 2H),
7.11-7.20(m,3H),7.25-7.30(m,2H),7.62(s,2H),7.76(s,1H),8.37(s,1H).
IR (KBr) ν: 3415 (NH), 2230 (CN), 1705 (C=O), 1734 (C=O) cm-1.
MS(ESI)m/z:536[M+H]+.
Elemental analysis (C33H33N3O4): measured value (theoretical value), C 74.08 (74.00), H 6.9 (6.21), N 7.95
(7.84).
Embodiment 6
2 '-amino -3 ', 5 '-dicyanos -6 '-(3,8- dimethyl -5- isopropyl Azulene -1- base) -1- benzyl -2- oxygen spiral shell (Yin
Diindyl quinoline -3,4 '-pyrans) (A6) synthesis
In 50mL reaction flask, triethylamine (40mg, 0.4mmol) is added to 1- benzyl isatin (237mg, 1.0mmol),
1- cyanogen acetyl group is cured in ethyl alcohol (25mL) solution for creating blue hydrocarbon Azulene (318mg, 1.2mmol) and malononitrile (79mg, 1.2mmol),
It is heated to reflux 2 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, reaction mixture is concentrated under reduced pressure, ethyl alcohol
It is recrystallized to give blue solid, yield 87%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.40 (d, J=6.6Hz, 6H), 3.05 (s, 3H), 3.14 (s, 3H), 3.20-
3.25(m,1H),3.27(s,2H),7.26-7.35(m,9H),7.64(s,2H),7.76(s,1H),8.41(s,1H).
IR (KBr) ν: 3431 (NH), 2230 (CN), 2243 (CN), 1718 (C=O) cm-1.
MS(ESI)m/z:551[M+H]+.
Elemental analysis (C36H30N4O2): measured value (theoretical value), C 78.60 (78.52), H 5.57 (5.49), N 10.25
(10.17).
Embodiment 7
2 '-amino -5 '-cyano -6 '-(3,8- dimethyl -5- isopropyl Azulene -1- base) -1- benzyl -2- oxygen spiral shell (indoline -
3,4 '-pyrans) -3 '-Ethyl formate (A7) synthesis
In 50mL reaction flask, triethylamine (20mg, 0.2mmol) is added to 1- benzyl isatin (237mg, 1.0mmol),
1- cyanogen acetyl group is cured the blue hydrocarbon Azulene (318mg, 1.2mmol) of wound and the ethyl alcohol (25mL) of ethyl cyanoacetate (135mg, 1.2mmol) is molten
In liquid, it is heated to reflux 3 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, reaction mixture is depressurized dense
Contracting, recrystallisation from isopropanol obtain blue solid, yield 87%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 0.77 (t, J=7.2Hz, 3H), 1.43 (d, J=6.6Hz, 6H), 3.05 (s,
3H), 3.10 (s, 3H), 3.20-3.26 (m, 1H), 3.34 (s, 2H), 3.71 (q, J=7.2Hz, 2H), 7.13-7.25 (m,
9H),7.28-7.37(m,2H),7.67(s,2H),7.79(s,1H),8.45(s,1H).
IR (KBr) ν: 3439 (NH), 2235 (CN), 1718 (C=O), 1734 (C=O) cm-1.
MS(ESI)m/z:599[M+H]+.
Elemental analysis (C38H35N3O4): measured value (theoretical value), C 76.45 (76.36), H 5.97 (5.90), N 10.78
(10.71).
Embodiment 8
2 '-amino -3 ', 5 '-dicyanos -6 '-(3,8- dimethyl -5- isopropyl Azulene -1- base) -5- methoxyl group -2- oxygen spiral shell
(indoline -3,4 '-pyrans) (A7) synthesis
In 50mL reaction flask, by triethylamine (20mg, 0.2mmol) be added to 5- methoxyl group isatin (177mg,
1.0mmol), 1- cyanogen acetyl group is cured the ethyl alcohol for creating blue hydrocarbon Azulene (318mg, 1.2mmol) and malononitrile (79mg, 1.2mmol)
In (25mL) solution, it is heated to reflux 5 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reaction mixture
It is concentrated under reduced pressure, ethyl alcohol recrystallization obtains blue solid, yield 85%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.42 (d, J=6.6Hz, 6H), 3.05 (s, 3H), 3.12 (s, 3H), 3.20-
3.25(m,1H),3.94(s,3H),7.15-7.26(m,3H),7.21-7.25(m,2H),7.58(s,2H),7.76(s,1H),
8.30(s,1H),11.74(brs,1H).
IR (KBr) ν: 3423 (NH), 3235 (NH), 2236 (CN), 2249 (CN), 1728 (C=O) cm-1.
MS(ESI)m/z:492[M+H]+.
Elemental analysis (C30H26N4O3): measured value (theoretical value), C 73.53 (73.45), H 5.46 (5.34), N 11.53
(11.42).
Embodiment 9
2 '-amino -3 ', 5 '-dicyanos -6 '-(3,8- dimethyl -5- isopropyl Azulene -1- base) -1- methyl-5-chloro -2- oxygen
Spiral shell (indoline -3,4 '-pyrans) (A8) synthesis
In 50mL reaction flask, by triethylamine (50mg, 0.5mmol) be added to 1- methyl-5-chloro isatin (196mg,
1.0mmol), 1- cyanogen acetyl group is cured the acetonitrile for creating blue hydrocarbon Azulene (344mg, 1., 3mmol) and malononitrile (86mg, 1.3mmol)
In (25mL) solution, it is heated to reflux 5 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reaction mixture
It is concentrated under reduced pressure, Recrystallisation from acetic acid obtains blue solid, yield 81%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.43 (d, J=6.6Hz, 6H), 2.62 (s, 3H), 3.11 (s, 3H), 3.20-
3.25(m,1H),3.39(s,3H),7.24(s,1H),7.30-7.34(m,2H),7.38-7.40(m,2H),7.77(s,2H),
7.84(s,1H),8.39(s,1H).
IR (KBr) ν: 3431 (NH), 2230 (CN), 2246 (CN), 1732 (C=O) cm-1.
MS(ESI)m/z:510[M+H]+.
Elemental analysis (C30H25ClN4O2): measured value (theoretical value), C 70.84 (70.79), H 5.03 (4.95), N
11.08(11.01).
Embodiment 10
2 '-amino -3 ', 5 '-dicyanos -6 '-(3,8- dimethyl -5- isopropyl Azulene -1- base) bromo- 2- oxygen of -1- methyl -5-
Spiral shell (indoline -3,4 '-pyrans) (A9) synthesis
In 50mL reaction flask, by triethylamine (40mg, 0.4mmol) be added to 1- methyl -5-bromoisatin (240mg,
1.0mmol), 1- cyanogen acetyl group is cured the acetonitrile for creating blue hydrocarbon Azulene (344mg, 1.3mmol) and malononitrile (86mg, 1.3mmol)
In (30mL) solution, it is heated to reflux 7 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reaction mixture
It is concentrated under reduced pressure, Recrystallisation from acetic acid obtains blue solid, yield 80%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.43 (d, J=6.6Hz, 6H), 2.64 (s, 3H), 3.10 (s, 3H), 3.18-
3.23(m,1H),3.31(s,3H),7.32(s,1H),7.35-7.37(m,2H),7.47-7.50(m,2H),7.74(s,2H),
7.89(s,1H),8.48(s,1H).
IR (KBr) ν: 3416 (NH), 2233 (CN), 2248 (CN), 1737 (C=O) cm-1.
MS(ESI)m/z:554[M+H]+.
Elemental analysis (C30H25BrN4O2): measured value (theoretical value), C 65.18 (65.10), H 4.63 (4.55), N
10.19(10.12).
Embodiment 11
2 '-amino -3 ', 5 '-dicyanos -6 '-(3,8- dimethyl -5- isopropyl Azulene -1- base) -1- methyl -5- methoxyl group -
2- oxygen spiral shell (indoline -3,4 '-pyrans) (A10) synthesis
In 50mL reaction flask, by triethylamine (20mg, 0.2mmol) be added to 1- methyl -5- methoxyl group isatin (191mg,
1.0mmol), 1- cyanogen acetyl group is cured the ethyl alcohol for creating blue hydrocarbon Azulene (318mg, 1.2mmol) and malononitrile (79mg, 1.2mmol)
In (25mL) solution, it is heated to reflux 2 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reaction mixture
It is concentrated under reduced pressure, ethyl alcohol recrystallization obtains blue solid, yield 83%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.48 (d, J=6.6Hz, 6H), 2.64 (s, 3H), 3.05 (s, 3H), 3.20-
3.24(m,1H),3.38(s,3H),3.98(s,3H),7.11-7.20(m,3H),7.21-7.26(m,2H),7.67(s,2H),
7.72(s,1H),8.36(s,1H).
IR (KBr) ν: 3420 (NH), 2231 (CN), 2246 (CN), 1725 (C=O) cm-1.
MS(ESI)m/z:506[M+H]+.
Elemental analysis (C31H28N4O3): measured value (theoretical value), C 73.87 (73.79), H 5.68 (5.59), N 11.17
(11.10).
Embodiment 12
2 '-amino -5 '-dicyano -6 '-(3,8- dimethyl -5- isopropyl Azulene -1- base) -1- methyl -5- methoxyl group -2-
- 3 '-Ethyl formate (A of oxygen spiral shell (indoline -3,4 '-pyrans)12) synthesis
In 50mL reaction flask, by triethylamine (20mg, 0.2mmol) be added to 1- methyl -5- methoxyl group isatin (191mg,
1.0mmol), 1- cyanogen acetyl group is cured the ethyl alcohol for creating blue hydrocarbon Azulene (318mg, 1.2mmol) and malononitrile (79mg, 1.2mmol)
In (25mL) solution, it is heated to reflux 3 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reaction mixture
It is concentrated under reduced pressure, recrystallisation from isopropanol obtains blue solid, yield 84%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 0.83 (t, J=7.2Hz, 3H), 1.43 (d, J=6.6Hz, 6H), 2.60 (s,
3H), 3.02 (s, 3H), 3.21-3.24 (m, 1H), 3.34 (s, 3H), 3.64 (q, J=7.2Hz, 2H), 4.03 (s, 3H),
7.14-7.20(m,3H),7.21-7.25(m,2H),7.62(s,2H),7.74(s,1H),8.39(s,1H).
IR (KBr) ν: 3428 (NH), 2234 (CN), 1698 (C=O), 1726 (C=O) cm-1.
MS(ESI)m/z:553[M+H]+.
Elemental analysis (C33H33N3O5): measured value (theoretical value), C 71.93 (71.85), H 6.11 (6.03), N 7.71
(7.62).
Anti-tumor activity test
Inhibition of the indoles Spirocyclic derivatives of the present invention to growth of tumour cell is measured using MTT (tetramethyl azo azoles salt) method
Effect is evaluated, and subject cell uses human stomach cancer cell line (SGC-7901) and human lung carcinoma cell line (NCI-H446), anticancer
Drugs Cisplatin is as positive reference substance.
Active testing material
Experimental method:
(1) preparation of sample: respectively dissolving 20 μ LDMSO of compound to be tested (1mg), and solution is used after taking 2 μ L to dissolve
1000 μ L culture solutions dilute (culture solution is the DMEM culture medium that mass concentration containing fetal calf serum is 10%), make its concentration
100 μ g/mL, then with identical culture solution serial dilution to using concentration 1-10 μ g/mL.
(2) preparation of culture medium: preparing DMEM culture medium, so that green containing 800,000 units in every 1000mL DMEM culture medium
The inactivated fetal bovine serum of mycin, 1.0g streptomysin and 10% mass.
(3) culture of cell: respectively by above-mentioned tumor cell inoculation in the culture medium that step (2) is prepared, in 37 DEG C,
5%CO2It is cultivated in incubator, 3-5d passage.
(4) inhibiting effect of the measurement sample to growth of tumour cell
By cell human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (NCI-H446), disappeared respectively with EDTA- pancreatin
Change liquid digestion, and be diluted to 1 × 105/mL with culture medium, is added in 96 porocyte culture plates, every 100 μ L of hole sets 37 DEG C, 5%
CO2It is cultivated in incubator.Former culture medium is discarded after 24 hours, and the culture medium containing test sample, every hole 200 μ L, Mei Genong is added
Degree plus 3 holes, set 37 DEG C, 5%CO2It is cultivated in incubator, the MTT of 5mg/mL, every hole is added after 72 hours in cell culture well
10 μ L, set 37 DEG C be incubated for 4 hours, be added DMSO, every 150 μ L of hole, with microplate reader under 570nm wavelength colorimetric.Respectively with same
Condition uses the above-mentioned cancer cell of the culture medium culture without sample, containing same concentration DMSO as control, calculates sample to swollen
Half lethal concentration (the IC of tumor cell growth50)。
After above-mentioned steps measure, the IC of the compounds of this invention50It is as shown in the table:
Compound A1-A12Anti-tumor activity
As seen from the above table, compound provided in an embodiment of the present invention shows good anti-gastric cancer and anti-lung cancer activity,
Middle compound A5And A9Effect use anticancer drug cis-platinum better than clinical.
In conclusion the present invention provides a kind of indoles volution compounds with anticancer activity, while finding such
Compound has excellent anti-gastric cancer and anti-lung cancer activity, so that research substrate has been expanded in the research and development for anticancer drug, it is into one
Step application offer is possible, has huge clinical value and development and application prospect.
It is understood that being merely to illustrate the present invention above with respect to specific descriptions of the invention and being not limited to this
Technical solution described in inventive embodiments, those skilled in the art should understand that, still the present invention can be carried out
Modification or equivalent replacement, to reach identical technical effect；As long as meet use needs, all protection scope of the present invention it
It is interior.
Claims (4)
1. a kind of containing the indoles volution compound for more creating blue hydrocarbon Azulene structure, which is characterized in that have the following structure general formula:
Wherein, R1For-H ,-CH3、-OCH3, Cl or Br；R2For-H ,-CH3Or-Bn；X is-CN or-COOEt.
2. the preparation method according to claim 1 containing the indoles volution compound for more creating blue hydrocarbon Azulene structure, feature exist
In implementation as follows:
(1) triethylamine is added to 1- cyanogen acetyl group in the solution be cured and create blue hydrocarbon Azulene, isatin and cyanoacetate and is reacted；It is described
Solution is using ethyl alcohol or acetonitrile as solvent；The isatin, 1- cyanogen acetyl group are cured the blue hydrocarbon Azulene of wound, the molar ratio of cyanoacetate is followed successively by 1:
1~1.5:1~1.5；In terms of molal weight, the dosage of the triethylamine is the 5~50% of isatin；
(2) after completion of the reaction, by directly filtering or reaction solution being concentrated to get crude product；
(3) by gained crude product by recrystallizing to get purpose product.
3. the preparation method according to claim 1 containing the indoles volution compound for more creating blue hydrocarbon Azulene structure, feature exist
In implementation as follows:
(1) triethylamine is added to 1- cyanogen acetyl group in the solution be cured and create blue hydrocarbon Azulene, isatin and malononitrile and is reacted；It is described molten
Liquid is using ethyl alcohol or acetonitrile as solvent；The isatin, 1- cyanogen acetyl group be cured create blue hydrocarbon Azulene, the molar ratio of malononitrile be followed successively by 1:1~
1.5:1~1.5；In terms of molal weight, the dosage of the triethylamine is the 5~50% of isatin；
(2) after completion of the reaction, by directly filtering or reaction solution being concentrated to get crude product；
(3) by gained crude product by recrystallizing to get purpose product.
4. a kind of indoles volution compound of the blue hydrocarbon Azulene structure containing more wound as described in claim 1 is in the preparation of antitumor drugs
Application.
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| CN108250080A (en) * | 2018-03-20 | 2018-07-06 | 黑龙江中医药大学 | Containing azulene structure triaryl methane compounds, preparation method and its as the application in anti-oxidizing activities or antitumor drug |
| CN109400562B (en) * | 2018-12-19 | 2022-12-27 | 渤海大学 | Kojic acid derivative containing guaiazulene azulene structure, preparation method and application thereof |
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