CN106748957B - Containing the Benzazole compounds and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure - Google Patents
Containing the Benzazole compounds and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure Download PDFInfo
- Publication number
- CN106748957B CN106748957B CN201611025968.5A CN201611025968A CN106748957B CN 106748957 B CN106748957 B CN 106748957B CN 201611025968 A CN201611025968 A CN 201611025968A CN 106748957 B CN106748957 B CN 106748957B
- Authority
- CN
- China
- Prior art keywords
- dimethyl
- azulene
- tetrahydro
- ketone
- indoles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Abstract
The Benzazole compounds for the blue hydrocarbon Azulene structure containing more wound with tumors inhibition activity that the present invention relates to a kind of, have the following structure general formula:
Description
Technical field
The invention belongs to field of medicinal chemistry, are related to Benzazole compounds, and in particular to one kind contains the blue hydrocarbon Azulene structure of more wound
Benzazole compounds and the preparation method and application thereof.
Background technique
Indole derivatives have the natural productions of important physiology and pharmacological activity in many universally present in nature
All contain indole structure unit in object, is widely used in the fields such as food, pesticide, dyestuff, medicine, feed and pharmaceutical synthesis
((a)Schreiber,S.L.；Science,2000,287,1964；(b)Wess,G.；Urmann,M.；Sickenberger,
B.Angew.Chem.Int.Ed.Engl.,2001,40,3341；(c)Abdel,A.S.；J.Pestic.Sci.,2010,35,
431.), there is very important status and very extensive application prospect in biology, medicine and other fields.To such compound
Synthesis has caused the concern of chemist and drug scholar with exploitation, and application prospect is very wide.
Especially many alkaloids containing indole structure are because of its distinctive anti-inflammatory, antiemetic, decompression, antidepression, the inclined head for the treatment of
Pain and anti-tumor activity and have received widespread attention, thus spread out by the method for organic synthesis acquisition indoles with similar structure
Biology has become a hot topic of research.
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.)。
It is efficiently, easy to operate in addition, continuous possessed by multi-component reaction, the advantages that reaction yield is high, in recent years by
The most attention and extensive concern of academia are arrived.Multi-component reaction, which can be constructed fast and effeciently, largely has structural complexity
With multifarious compound therefrom to find the drug presoma with important physiology and pharmacological activity, thus have become
Indispensable important tool (Zhu, J.-P. in organic chemistry and pharmaceutical chemists hand；Bienayme,H.Ed.II
Multicomponent Reactions.2005,WILEY,Weinheim.)。
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 benzazolyl compounds molecule is crossed, is an important channel for obtaining bioactive compound, there is wide answer
Use prospect.
Summary of the invention
The indoles 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
Close object.
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 Benzazole compounds preparation method of hydrocarbon Azulene structure.
The present invention also provides a kind of Benzazole compounds of blue hydrocarbon Azulene structure containing more wound as answering in anti-tumor drug
With.
In order to solve the above technical problems, the present invention is implemented as follows:
The indole derivatives of the blue hydrocarbon Azulene structure provided by the invention containing more wound, have the following structure
General formula:
Wherein, R1For H, alkyl, aryl；R2For H, alkyl.
The above-mentioned preparation method containing the Benzazole compounds for more creating blue hydrocarbon Azulene structure, can implement as follows:
(1) triethylene diamine is added to 1- chloracetyl in the solution be cured and create blue hydrocarbon Azulene, amine and hydroresorcinol into
Row reaction；
(2) after completion of the reaction, by the way that crude product is obtained by filtration；
(3) by gained crude product by recrystallizing to get purpose product.
As a preferred embodiment, solution takes water as a solvent in step (1) of the present invention.
Further, 1- chloracetyl of the present invention more creates blue hydrocarbon Azulene, amine and 1, and the molar ratio of hydroresorcinol is successively
For 1:1~1.5:1~1.5.
Further, for the present invention in terms of molal weight, the dosage of the triethylene diamine is that 1- chloracetyl more creates blue hydrocarbon
The 1~50% of Azulene.
Methylamine, ethamine, n-propylamine, cyclohexylamine, aniline, P-nethoxyaniline, parachloroanilinum may be selected in amine of the present invention
Or para-fluoroaniline.
The Benzazole compounds of the above-mentioned blue hydrocarbon Azulene structure containing more wound are as the application in anti-tumor drug.
The present invention ties up under triethylene diamine effect, and blue hydrocarbon Azulene, amine and 1 are more created with 1- chloracetyl, and hydroresorcinol 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- chloracetyl described in above-mentioned synthesis process, which more creates blue hydrocarbon Azulene:
The compound can refer to document (kingly way woods, Han Shan, Gu Zheng, Xu Jiao, organic chemistry, 2008,28,1641-1645.)
Method is made using more creating blue hydrocarbon Azulene as substrate by the acylation reaction of chloracetyl chloride:
It is a further object of the present invention to provide the indole derivatives of the blue hydrocarbon Azulene structure containing more wound in preparing anticancer drug
Using.
It is provided by the invention containing the Benzazole compounds for more creating blue hydrocarbon Azulene structure, through human stomach cancer cell line (SGC-7901) and
The inhibitory activity measurement of human lung carcinoma cell line (H446) shows that it has good inhibition to gastric carcinoma cells and human lung carcinoma cell
Effect has stronger development and application prospect, is expected to be further developed into as new tumor growth inhibitors, controlling for cancer
Treat drug or the synthesis of related drugs etc..
Synthetic method of the present invention containing the Benzazole compounds for more creating blue hydrocarbon Azulene structure, the reaction process take water as a solvent,
Obtain product by multicomponent, single step reaction, avoid the separation of intermediate and the bring wasting of resources, embody Atom economy,
The validity of combined coefficient.Easy to operate, raw material is easy to get, and provides effective conjunction to synthesize polycyclic condensed Benzazole compounds
At approach.
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
1,6,6- trimethyl -2- (3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -4H- indoles -4-
Ketone) (A1) synthesis
In 50mL reaction flask, triethylene diamine (34mg, 0.3mmol) is added to 1- chloracetyl and more creates blue hydrocarbon Azulene
(275mg, 1.0mmol), methylamine (30% aqueous solution) (155mg, 1.5mmol) and 5, dimethyl -1 5-, hydroresorcinol
In water (30mL) solution of (168mg, 1.2mmol), it is heated to reflux 6 hours (with silica gel column chromatography plate (TLC) monitoring reaction).Reaction
After, reaction mixture is cooled to room temperature, the solid product of precipitation is collected, with ethyl alcohol recrystallization, yield 76%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 0.88 (s, 6H), 1.46 (d, J=6.6Hz, 6H), 1.80 (s, 2H), 2.15
(s,2H),2.62(s,3H),3.05(s,3H),3.20-3.25(m,1H),3.29(s,3H),6.64(s,1H),7.28-7.30
(m,2H),7.78(s,1H),8.26(s,1H)。
IR (KBr) ν: 1667 (C=O) cm-1。
MS(ESI)m/z:375[M+H]+。
Elemental analysis (C26H31NO): measured value (theoretical value), C 83.67 (83.60), H 8.46 (8.37), N 3.82
(3.75)。
Embodiment 2
1- ethyl -2- (3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -6,6- dimethyl -4H- Yin
Diindyl -4- ketone) (A2) synthesis
In 50mL reaction flask, triethylene diamine (45mg, 0.4mmol) is added to 1- chloracetyl and more creates blue hydrocarbon Azulene
(275mg, 1.0mmol), ethamine (50% aqueous solution) (117mg, 1.3mmol) and 5, dimethyl -1 5-, hydroresorcinol
In water (20mL) solution of (140mg, 1.0mmol), it is heated to reflux 6 hours (with silica gel column chromatography plate (TLC) monitoring reaction).Reaction
After, reaction mixture is cooled to room temperature, the solid product of precipitation is collected, with ethyl alcohol recrystallization, yield 80%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 0.93 (s, 6H), 1.45 (d, J=6.6Hz, 6H), 1.55 (t, J=7.5Hz,
3H), 1.87 (s, 2H), 2.21 (s, 2H), 2.60 (s, 3H), 3.09 (s, 3H), 3.20-3.24 (m, 1H), 3.76 (q, J=
7.5Hz,2H),6.61(s,1H),7.26-7.29(m,2H),7.76(s,1H),8.27(s,1H)。
IR (KBr) ν: 1669 (C=O) cm-1。
MS(ESI)m/z:389[M+H]+。
Elemental analysis (C27H33NO): measured value (theoretical value), C 83.75 (83.68), H 8.64 (8.58), N 3.69
(3.61)。
Embodiment 3
1- ethyl -2- (3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -4H- indoles -4- ketone) (A3)
Synthesis
In 50mL reaction flask, triethylene diamine (45mg, 0.4mmol) is added to 1- chloracetyl and more creates blue hydrocarbon Azulene
(275mg, 1.0mmol), ethamine (50% aqueous solution) (108mg, 1.2mmol) and 1, hydroresorcinol (134mg, 1.2mmol)
Water (20mL) solution in, be heated to reflux 7 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, reaction is mixed
It closes object to be cooled to room temperature, the solid product of precipitation is collected, with ethyl alcohol recrystallization, yield 75%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.49 (d, J=6.6Hz, 6H), 1.48 (t, J=7.5Hz, 3H), 1.91 (d, J
=7.2Hz, 2H), 2.03-2.09 (m, 2H), 2.32 (d, J=6.6Hz, 2H), 2.62 (s, 3H), 3.11 (s, 3H), 3.19-
3.21 (m, 1H), 3.67 (q, J=7.5Hz, 2H), 6.65 (s, 1H), 7.28-7.31 (m, 2H), 7.79 (s, 1H), 8.32 (s,
1H)。
IR (KBr) ν: 1660 (C=O) cm-1。
MS(ESI)m/z:361[M+H]+。
Elemental analysis (C27H33NO): measured value (theoretical value), C 83.59 (83.52), H 8.22 (8.13), N 3.97
(3.90)。
Embodiment 4
1- propyl -2- (3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -6,6- dimethyl -4H- Yin
Diindyl -4- ketone) (A4) synthesis
In 50mL reaction flask, triethylene diamine (34mg, 0.3mmol) is added to 1- chloracetyl and more creates blue hydrocarbon Azulene
(275mg, 1.0mmol), n-propylamine (71mg, 1.2mmol) and 5, dimethyl -1 5-, hydroresorcinol (168mg, 1.2mmol)
Water (20mL) solution in, be heated to reflux 4 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, reaction is mixed
It closes object to be cooled to room temperature, the solid product of precipitation is collected, with ethyl alcohol recrystallization, yield 83%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 0.92 (t, J=7.5Hz, 3H), 1.16 (s, 6H), 1.48 (d, J=6.6Hz,
6H),1.61-1.65(m,2H),1.81(s,2H),2.25(s,2H),2.63(s,3H),3.16(s,3H),3.23-3.26(m,
1H), 3.44 (t, J=7.5Hz, 2H), 6.61 (s, 1H), 7.24-7.26 (m, 2H), 7.73 (s, 1H), 8.26 (s, 1H).
IR (KBr) ν: 1672 (C=O) cm-1。
MS(ESI)m/z:389[M+H]+。
Elemental analysis (C28H35NO): measured value (theoretical value), C 83.81 (83.74), H 8.43 (8.78), N 3.56
(3.49)。
Embodiment 5
1- cyclohexyl -2- (3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -6,6- dimethyl -4H- Yin
Diindyl -4- ketone) (A5) synthesis
In 50mL reaction flask, triethylene diamine (56mg, 0.5mmol) is added to 1- chloracetyl and more creates blue hydrocarbon Azulene
(275mg, 1.0mmol), cyclohexylamine (100mg, 1.0mmol) and 5, dimethyl -1 5-, hydroresorcinol (168mg, 1.2mmol)
Water (30mL) solution in, be heated to reflux 7 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, reaction is mixed
It closes object to be cooled to room temperature, the solid product of precipitation is collected, with ethyl alcohol recrystallization, yield 84%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 0.98-1.02 (m, 1H), 1.17 (s, 6H), 1.9 (d, J=6.6Hz, 6H),
1.46-1.51(m,4H),1.67-1.69(m,4H),1.80(s,2H),2.23(s,2H),2.62(s,3H),3.05(s,3H),
3.25-3.28(m,1H),3.52-3.54(m,1H),6.64(s,1H),7.22-7.25(m,2H),7.79(s,1H),8.36(s,
1H)。
IR (KBr) ν: 1678 (C=O) cm-1。
MS(ESI)m/z:441[M+H]+。
Elemental analysis (C31H39NO): measured value (theoretical value), C 84.38 (84.31), H 8.99 (8.90), N 3.24
(3.17)。
Embodiment 6
1- phenyl -2- (3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -6,6- dimethyl -4H- Yin
Diindyl -4- ketone) (A6) synthesis
In 50mL reaction flask, triethylene diamine (45mg, 0.4mmol) is added to 1- chloracetyl and more creates blue hydrocarbon Azulene
(275mg, 1.0mmol), aniline (103mg, 1.1mmol) and 5, dimethyl -1 5-, hydroresorcinol (168mg, 1.2mmol)
In water (40mL) solution, it is heated to reflux 5 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, reaction is mixed
Object is cooled to room temperature, and collects the solid product of precipitation, with ethyl alcohol recrystallization, yield 73%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.10 (s, 6H), 1.47 (d, J=6.6Hz, 6H), 1.73 (s, 2H), 2.31
(s,2H),2.64(s,3H),3.14(s,3H),3.23-3.27(m,1H),6.58(s,1H),7.21-7.36(m,7H),7.78
(s,1H),8.35(s,1H)。
IR (KBr) ν: 1672 (C=O) cm-1。
MS(ESI)m/z:437[M+H]+。
Elemental analysis (C31H33NO): measured value (theoretical value), C 85.54 (85.48), H 7.71 (7.64), N 3.29
(3.22)。
Embodiment 7
1- (4- methoxyphenyl) -2- (3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -6,6- diformazan
Base -4H- indoles -4- ketone) (A7) synthesis
In 50mL reaction flask, triethylene diamine (34mg, 0.3mmol) is added to 1- chloracetyl and more creates blue hydrocarbon Azulene
(275mg, 1.0mmol), P-nethoxyaniline (123mg, 1.0mmol) and 5, dimethyl -1 5-, hydroresorcinol (168mg,
In water (30mL) solution 1.2mmol), it is heated to reflux 5 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction,
Reaction mixture is cooled to room temperature, the solid product of precipitation is collected, with ethyl alcohol recrystallization, yield 85%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.14 (s, 6H), 1.48 (d, J=6.6Hz, 6H), 1.70 (s, 2H), 2.35
(s,2H),2.64(s,3H),3.06(s,3H),3.23-3.26(m,1H),3.69(s,3H),6.61(s,1H),7.23-7.34
(m, 4H), 7.42 (d, J=8.4Hz, 2H), 7.78 (s, 1H), 8.24 (s, 1H).
IR (KBr) ν: 1679 (C=O) cm-1。
MS(ESI)m/z:467[M+H]+。
Elemental analysis (C32H35NO): measured value (theoretical value), C 82.66 (82.54), H 7.65 (7.58), N 3.08
(3.01)。
Embodiment 8
1- (4- methoxyphenyl) -2- (3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -4H- indoles -
4- ketone) (A8) synthesis
In 50mL reaction flask, triethylene diamine (34mg, 0.3mmol) is added to 1- chloracetyl and more creates blue hydrocarbon Azulene
(275mg, 1.0mmol), P-nethoxyaniline (123mg, 1.0mmol) and 1, the water of hydroresorcinol (134mg, 1.2mmol)
In (40mL) solution, it is heated to reflux 6 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reaction mixture
It is cooled to room temperature, collects the solid product of precipitation, with ethyl alcohol recrystallization, yield 82%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.47 (d, J=6.6Hz, 6H), 1.76 (d, J=7.2Hz, 2H), 2.24-
2.28 (m, 2H), 2.46 (d, J=7.8Hz, 2H), 2.63 (s, 3H), 3.11 (s, 3H), 3.23-3.26 (m, 1H), 3.73 (s,
3H), 6.61 (s, 1H), 7.20-7.32 (m, 4H), 7.46 (d, J=8.4Hz, 2H), 7.79 (s, 1H), 8.34 (s, 1H).
IR (KBr) ν: 1683 (C=O) cm-1。
MS(ESI)m/z:439[M+H]+。
Elemental analysis (C30H31NO): measured value (theoretical value), C 82.66 (82.35), H 7.65 (7.14), N 3.08
(3.20)。
Embodiment 9
1- (4- chlorphenyl) -2- (3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -6,6- dimethyl -
4H- indoles -4- ketone) (A9) synthesis
In 50mL reaction flask, triethylene diamine (56mg, 0.5mmol) is added to 1- chloracetyl and more creates blue hydrocarbon Azulene
(275mg, 1.0mmol), parachloroanilinum (141mg, 1.1mmol) and 5, dimethyl -1 5-, hydroresorcinol (168mg,
In water (30mL) solution 1.2mmol), it is heated to reflux 5 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction,
Reaction mixture is cooled to room temperature, the solid product of precipitation is collected, with ethyl alcohol recrystallization, yield 78%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.10 (s, 6H), 1.40 (d, J=6.6Hz, 6H), 1.64 (s, 2H), 2.46
(s,2H),2.58(s,3H),3.08(s,3H),3.22-3.26(m,1H),6.61(s,1H),7.29-7.32(m,2H),7.38
(d, J=8.8Hz, 2H), 7.56 (d, J=8.8Hz, 2H), 7.79 (s, 1H), 8.35 (s, 1H).
IR (KBr) ν: 1684 (C=O) cm-1。
MS(ESI)m/z:471[M+H]+。
Elemental analysis (C31H32ClNO): measured value (theoretical value), C 79.31 (79.21), H 6.95 (6.86), N 3.05
(2.98)。
Embodiment 10
1- (4- fluorophenyl) -2- (3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -6,6- dimethyl -
4H- indoles -4- ketone) (A10) synthesis
In 50mL reaction flask, triethylene diamine (34mg, 0.3mmol) is added to 1- chloracetyl and more creates blue hydrocarbon Azulene
(275mg, 1.0mmol), para-fluoroaniline (133mg, 1.2mmol) and 5, dimethyl -1 5-, hydroresorcinol (168mg,
In water (40mL) solution 1.2mmol), it is heated to reflux 5 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction,
Reaction mixture is cooled to room temperature, the solid product of precipitation is collected, with ethyl alcohol recrystallization, yield 81%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.12 (s, 6H), 1.42 (d, J=6.6Hz, 6H), 1.71 (s, 2H), 2.49
(s,2H),2.65(s,3H),3.13(s,3H),3.23-3.27(m,1H),6.65(s,1H),7.26-7.30(m,2H),7.34
(d, J=9.2Hz, 2H), 7.63 (d, J=9.2Hz, 2H), 7.79 (s, 1H), 8.34 (s, 1H).
IR (KBr) ν: 1680 (C=O) cm-1。
MS(ESI)m/z:455[M+H]+。
Elemental analysis (C31H32FNO): measured value (theoretical value), C 82.17 (82.09), H 7.20 (7.11), N 3.17
(3.09)。
Embodiment 11
1- (4- chlorphenyl) -2- (3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -4H- indoles -4-
Ketone) (A11) synthesis
In 50mL reaction flask, triethylene diamine (45mg, 0.4mmol) is added to 1- chloracetyl and more creates blue hydrocarbon Azulene
(275mg, 1.0mmol), parachloroanilinum (128mg, 1.0mmol) and 1, the water of hydroresorcinol (134mg, 1.2mmol)
In (30mL) solution, it is heated to reflux 8 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reaction mixture
It is cooled to room temperature, collects the solid product of precipitation, with ethyl alcohol recrystallization, yield 76%.
Structural analysis is as follows:
1H NMR(400MHz,CDCl3) δ: 1.38 (d, J=6.6Hz, 6H), 1.79 (d, J=7.2Hz, 2H), 2.28-
2.31 (m, 2H), 2.50 (d, J=7.2Hz, 2H), 2.56 (s, 3H), 3.04 (s, 3H), 3.20-3.25 (m, 1H), 6.63 (s,
1H), 7.31-7.35 (m, 2H), 7.41 (d, J=8.8Hz, 2H), 7.59 (d, J=8.8Hz, 2H), 7.82 (s, 1H), 8.39
(s,1H)。
IR (KBr) ν: 1688 (C=O) cm-1。
MS(ESI)m/z:443[M+H]+。
Elemental analysis (C29H28ClNO): measured value (theoretical value), C 78.89 (78.80), H 6.46 (6.39), N 3.24
(3.17)。
Anti-tumor activity test
Indole derivatives of the present invention are measured to the inhibiting effect of growth of tumour cell using MTT (tetramethyl azo azoles salt) method
It is evaluated, subject cell uses human stomach cancer cell line (SGC-7901) and human lung carcinoma cell line
(NCI-H446), anticancer drug cis-platinum 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-A11Anti-tumor activity
By test result as it can be seen that compound provided in an embodiment of the present invention shows good anti-gastric cancer and anti-lung cancer is living
Property, wherein compound A8Effect use anticancer drug cis-platinum close to clinical.
In conclusion the present invention provides a kind of Benzazole compounds with anticancer activity, while finding such chemical combination
Object 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, further to answer
It is possible with providing, there is huge clinical value and development and application prospect.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (3)
1. a kind of containing the Benzazole compounds for more creating blue hydrocarbon Azulene structure, which is characterized in that be selected from 1,6,6- trimethyl -2-(3,8-
Dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -4H- indoles -4- ketone), 1- ethyl -2-(3,8- dimethyl -5- it is different
Propyl Azulene -1- base) -1,5,6,7- tetrahydro -6,6- dimethyl -4H- indoles -4- ketone), 1- ethyl -2-(3,8- dimethyl -5- it is different
Propyl Azulene -1- base) -1,5,6,7- tetrahydro -4H- indoles -4- ketone), 1- propyl -2-(3,8- dimethyl -5- isopropyl Azulene -1-
Base) -1,5,6,7- tetrahydro -6,6- dimethyl -4H- indoles -4- ketone), 1- cyclohexyl -2-(3,8- dimethyl -5- isopropyl Azulene -
1- yl) -1,5,6,7- tetrahydro -6,6- dimethyl -4H- indoles -4- ketone), 1- phenyl -2-(3,8- dimethyl -5- isopropyl Azulene -
1- yl) -1,5,6,7- tetrahydro -6,6- dimethyl -4H- indoles -4- ketone), 1-(4- methoxyphenyl) -2-(3,8- dimethyl -5-
Isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -6,6- dimethyl -4H- indoles -4- ketone), 1-(4- methoxyphenyl) -2-(3,8-
Dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -4H- indoles -4- ketone), 1-(4- chlorphenyl) -2-(3,8- diformazan
Base -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -6,6- dimethyl -4H- indoles -4- ketone), 1-(4- fluorophenyl) -2-(3,
8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -6,6- dimethyl -4H- indoles -4- ketone) or 1-(4- chlorobenzene
Base) -2-(3,8- dimethyl -5- isopropyl Azulene -1- base) -1,5,6,7- tetrahydro -4H- indoles -4- ketone).
2. the preparation method according to claim 1 containing the Benzazole compounds for more creating blue hydrocarbon Azulene structure, which is characterized in that press
Following steps are implemented:
(1) triethylene diamine is added to 1- chloracetyl to be cured and creates blue hydrocarbon Azulene, corresponding amine and corresponding hydroresorcinol
It is reacted in aqueous solution；The 1- chloracetyl is cured mole for creating blue hydrocarbon Azulene, corresponding amine and corresponding hydroresorcinol
Than being followed successively by 1:1~1.5:1~1.5；In terms of molal weight, the dosage of the triethylene diamine is that 1- chloracetyl more creates blue hydrocarbon
The 1~50% of Azulene；
(2) after completion of the reaction, by the way that crude product is obtained by filtration；
(3) by gained crude product by recrystallizing to get purpose product.
3. a kind of as described in claim 1 containing more creating the Benzazole compounds of blue hydrocarbon Azulene structure answering in the preparation of antitumor drugs
With.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611025968.5A CN106748957B (en) | 2016-11-14 | 2016-11-14 | Containing the Benzazole compounds and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611025968.5A CN106748957B (en) | 2016-11-14 | 2016-11-14 | Containing the Benzazole compounds and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106748957A CN106748957A (en) | 2017-05-31 |
| CN106748957B true CN106748957B (en) | 2019-07-26 |
Family
ID=58971490
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611025968.5A Expired - Fee Related CN106748957B (en) | 2016-11-14 | 2016-11-14 | Containing the Benzazole compounds and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106748957B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456263B (en) * | 2018-12-19 | 2021-10-12 | 渤海大学 | Bipyridine derivative containing guaiazulene structure, preparation method and application thereof |
| CN113861095A (en) * | 2021-11-18 | 2021-12-31 | 南昌工程学院 | Method for preparing guaiazulene indole compound |
| CN114957081B (en) * | 2022-05-27 | 2024-04-05 | 中国科学院上海有机化学研究所 | Azulene compounds, intermediates, preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106220641A (en) * | 2016-07-08 | 2016-12-14 | 渤海大学 | Indole volution compound containing the blue hydrocarbon structure of more wound and preparation method and application |
-
2016
- 2016-11-14 CN CN201611025968.5A patent/CN106748957B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106220641A (en) * | 2016-07-08 | 2016-12-14 | 渤海大学 | Indole volution compound containing the blue hydrocarbon structure of more wound and preparation method and application |
Non-Patent Citations (5)
| Title |
|---|
| 3-(2-苯并呋喃酰基)薁-1-羧酸甲酯的有效合成;王道林，等;《有机化学》;20071231;第27卷(第11期);1404-1408 |
| A facile one-pot synthesis of novel 1-substituted 2-(8-hydroxyquinolin-5-yl)-1,5,6,7-tetrahydro-6,6-dimethyl- 4H-indol-4-one derivatives;Shawkat Abdel-Mohsen，等;《ARKIVOC 》;20160607(第iv期);184-192 |
| Synthesis and cytotoxic evaluation of new (4,5,6,7-tetrahydro-indol-1-yl)-3-R-propionic acids and propionic acid ethyl esters generated by molecular mimicry;Roberto Martinez，等;《Bioorganic & Medicinal Chemistry》;20061213;第15卷;3912-3918 |
| 基于愈创蓝烃薁的新型薁类衍生物合成方法研究;于家懿;《渤海大学硕士学位论文》;20130915;2、46 |
| 基于氰乙酰基愈创蓝烃薁的新型薁类衍生物合成方法研究;李帝;《渤海大学硕士学位论文》;20121015;第6、58-61页 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106748957A (en) | 2017-05-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101580477B (en) | Dehydroabietylamine derivatives and application thereof in bactericidal and antineoplastic medicaments | |
| CN106748957B (en) | Containing the Benzazole compounds and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure | |
| CN106220641B (en) | Containing the indoles volution compound and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure | |
| CN105712932B (en) | A kind of preparation and application of the pyrazoles oxime ether compound of -3- of methyl containing 1- aryl -4- chlorine pyrrazole structure | |
| CN107266348B (en) | Preparation, structure and the purposes of 4-acetylbiphenyl hydrazone -3- indolecarboxaldehyde Schiff base | |
| CN104812761B (en) | Double B-carboline alkaloid compounds, its preparation method and its pharmaceutical composition and purposes | |
| CN106632043A (en) | Licochalcone A pyrazoline derivatives with antitumor activity and synthesis method thereof | |
| CN108299398B (en) | Carbazole-containing quinazoline derivative with anti-tumor activity and pharmaceutical application thereof | |
| CN106674129A (en) | Licochalcone A dihydro-amino miazines compound with antitumor activity and synthetic method of licochalcone A dihydro-amino miazines compound | |
| CN110330452A (en) | Nafoxidine alkanes compound or its pharmaceutically acceptable salt and its preparation method and application | |
| CN105968064B (en) | Two tolyl tetrazine diformamide compounds of one kind and preparation and application | |
| CN102382164B (en) | Toad lactam compound as well as preparation method and application thereof | |
| CN107573318A (en) | A kind of new gossypol Schiff bases derivative and its synthetic method for having antitumor activity | |
| CN107698648B (en) | Naphthylimide derivative containing cholesterol and synthesis and application thereof | |
| CN110437156A (en) | Paeonol dihydro-pyrimidin ketones derivant and its preparation method and application | |
| CN109796471A (en) | Indolone spirocyclopropane spiral shell-thiazolone or spiral shell-terahydro thiazolone derivative and its preparation method and application | |
| CN108864089B (en) | Indolopyridone drug molecule and preparation method and application thereof | |
| CN101823990A (en) | Amino-acid ester dithiocarbamic acid ester compound as well as preparation method and application thereof | |
| CN104926804B (en) | One kind has compound, the preparation method and use of antitumor action | |
| CN108148080B (en) | Organic golden (III) complex of metal and its synthetic method and application | |
| CN113444095A (en) | Triazine substituted imidazole compound and preparation method and application thereof | |
| CN103044326A (en) | 5-bromo oxoisoaporphine, and synthesis method and application thereof | |
| CN111196791B (en) | Chiral gamma-butyrolactone derivative and synthesis method and application thereof | |
| US20210106702A1 (en) | Neutron beam dynamic therapy | |
| CN113461700B (en) | Application of oxygen-promoted dearomatization reaction in construction of spiro-dienone skeleton |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190726 Termination date: 20201114 |