CN106220641A - Indole volution compound containing the blue hydrocarbon structure of more wound and preparation method and application - Google Patents
Indole volution compound containing the blue hydrocarbon structure of more wound and preparation method and application Download PDFInfo
- Publication number
- CN106220641A CN106220641A CN201610533171.XA CN201610533171A CN106220641A CN 106220641 A CN106220641 A CN 106220641A CN 201610533171 A CN201610533171 A CN 201610533171A CN 106220641 A CN106220641 A CN 106220641A
- Authority
- CN
- China
- Prior art keywords
- wound
- indole
- blue hydrocarbon
- compound containing
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to a kind of indole volution compound containing the blue hydrocarbon structure of more wound with tumors inhibition activity, there is following general structure:
Description
Technical field
The invention belongs to medicinal chemistry art, relate to hetero atom spiro-compound, be specifically related to a kind of containing the blue hydrocarbon of more wound
The indole Spirocyclic derivatives of structure, synthesize and apply.
Background technology
All containing spirane structure in many natural products, wherein hetero atom spiro-compound has antitumor, anxiety, resists
The biological activity widely such as bacterium, blood pressure lowering and analgesia, owing to the mechanism of action is unique, and is not likely to produce Drug resistance, for 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.).
Indole spiro-compound is the hetero atom spiro-compound that a class is important, universally present in many have physiology and
In the natural alkaloid of pharmacologically active, it has also become construction unit ((a) Pavlovska1, T.L. indispensable in many medicines；
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.).Research shows, indole volution compound is a kind of important in human body
The endogeneous activity factor, be present in a large number in nervous system, internal cell monoamine oxidase, MAO can be maintained normal water
Flat, thus it is effectively prevented generation ((a) Glover, the V. of the neurodegenerative disease such as Parkinson's disease, 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, this compounds also has good antitumor, resists
Biological activity ((a) Yu, the B. such as allergy, tuberculosis and antithrombotic；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 biological,
Medicine and other fields has very important status and application prospect widely.To the synthesis of this compounds with exploitation
Cause concern ((a) Zhu, the S.L. of chemist and medicine 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 blue hydrocarbon (Isosorbide-5-Nitrae-dimethyl-7-isopropyl, Guaiazulene) of wound is the effective ingredient of ocean Flos Chrysanthemi, has
The effect such as the strongest antipepsin, antiinflammatory, antiallergic, antioxidation and antiviral ((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 derivants all show good
Good biological activity ((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, at present in the urgent need to exploitation new there is specific bioactive molecule.Logical
Cross the structural modification to spiro-compound molecule, be the important channel obtaining bioactive compound, there is wide answering
Use prospect.
Summary of the invention
It is an object of the invention to provide a kind of indole volution containing the blue hydrocarbon structure of more wound with tumors inhibition activity
Compounds.
Another object of the present invention is to provide a kind of easy to operate, and raw material is easy to get, and productivity is high, and orchid is more created in good the containing of selectivity
The indole volution compound preparation method of hydrocarbon structure.
The present invention also provides for a kind of indole volution compound containing the blue hydrocarbon structure of more wound as in antitumor drug
Application.
For solving above-mentioned technical problem, the present invention is achieved in that
The indole Spirocyclic derivatives containing the blue hydrocarbon structure of more wound that the present invention provides, has a following general structure:
Wherein, R1For the one in H, alkyl, alkoxyl, hydroxyl, amino, halogen, nitro, cyano group or carboxylic acid and ester thereof；R2
For H, alkyl or aryl；X is cyano group or alkoxy carbonyl group.
The preparation method of the above-mentioned indole volution compound containing the blue hydrocarbon structure of more wound, can implement as follows:
(1) triethylamine is added to 1-cyanogen acetyl group in the solution of the heal blue hydrocarbon of wound, isatin and cyanoacetate and react；
(2) after completion of the reaction, by directly filtering or reactant liquor being concentrated to give crude product；
(3) by gained crude product by recrystallization, purpose product is obtained.
As a kind of preferred version, solution described in step of the present invention (1) is with ethanol or acetonitrile as solvent.
Further, the blue hydrocarbon of isatin of the present invention, 1-cyanogen acetyl group more wound, the mol ratio of cyanoacetate are followed successively by 1:
1～1.5:1～1.5.
Further, the present invention is in terms of molal weight, and the consumption of described triethylamine is the 5～50% of isatin.
The preparation method of the above-mentioned indole volution compound containing the blue hydrocarbon structure of more wound, also can implement as follows:
(1) triethylamine is added to 1-cyanogen acetyl group in the solution of the heal blue hydrocarbon of wound, isatin and Cyanoacetyl-Cyacetazid and react；
(2) after completion of the reaction, by directly filtering or reactant liquor being concentrated to give crude product；
(3) by gained crude product by recrystallization, purpose product is obtained.
As a kind of preferred version, the blue hydrocarbon of isatin of the present invention, 1-cyanogen acetyl group more wound, the mol ratio of Cyanoacetyl-Cyacetazid depend on
Secondary for 1:1～1.5:1～1.5.
The above-mentioned indole volution compound containing the blue hydrocarbon structure of more wound is as the application in antitumor drug.
The present invention ties up under triethylamine effect, with the blue hydrocarbon of 1-cyanogen acetyl group more wound, isatin and cyanoacetate (or the third two
Nitrile) it is reaction raw materials, by three component reaction one-step synthesis.
Composition principle is:
The blue hydrocarbon (1) of 1-cyanogen acetyl group described in above-mentioned building-up process more wound is the compound with following structure:
This compound refers to document (kingly way woods, Li Di, Cao Liang, organic chemistry, 2012,32,1741-1745.) method,
With the blue hydrocarbon of more wound as substrate, prepared by the acylation reaction of cyanoacetic acid and acetic anhydride:
It addition, the isatin described in above-mentioned building-up process is the compound with following structure:
Wherein, R1For the one in H, alkyl, alkoxyl, hydroxyl, halogen, nitro, cyano group, carboxylic acid and ester thereof etc.；R2For H,
Alkyl, aryl.
This compounds refer to document (Zhang Xiaofei, Liu Huaye, Gao Wentao, Bohai University's journal (natural science edition),
2009,30,212.) method, with aromatic amine as raw material, by Sandmeyer reaction preparation；1-replaces Isatine derivatives and refers 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, with isatin as raw material, is prepared by N-alkylated reaction:
It is a further object of the present invention to provide the indole Spirocyclic derivatives containing the blue hydrocarbon structure of more wound and prepare cancer therapy drug
In application.
The indole volution compound containing the blue hydrocarbon structure of more wound that the present invention provides, through human stomach cancer cell line (SGC-
7901) and human lung carcinoma cell line (H446) inhibitory activity measure show, gastric carcinoma cells and human lung carcinoma cell are had good by it
Good inhibitory action, has stronger development prospect, be expected to be further developed into into new tumor growth inhibitors, for
The medicine of cancer or the synthesis etc. of related drugs.
The present invention is easy to operate containing the synthetic method of the indole volution compound of the blue hydrocarbon structure of more wound, raw material is easy to get,
Productivity is high, selectivity is good, provides effective route of synthesis for synthesizing the multi-ring indole volution compound condensed.
The present invention will be described further with example below, but present disclosure is not limited by this embodiment.
Specific embodiment
Embodiment 1
2 '-amino-3 ', 5 '-dicyano-6 '-(3,8-dimethyl-5-isopropyl-1-base)-2-oxygen spiral shell (indoline-3,
4 '-pyrans) (A1) synthesis
In 50mL reaction bulb, triethylamine (20mg, 0.2mmol) is joined isatin (147mg, 1.0mmol), 1-cyanogen second
In ethanol (25mL) solution of the blue hydrocarbon (318mg, 1.2mmol) of acyl group more wound and Cyanoacetyl-Cyacetazid (79mg, 1.2mmol), heat back
Flow 5 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reactant mixture concentrating 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]+.
Elementary 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 group-6 '-(3,8-dimethyl-5-isopropyl-1-base)-2-oxygen spiral shell (indoline-3,4 '-pyrrole
Mutter)-3 '-Ethyl formate (A2) synthesis
In 50mL reaction bulb, triethylamine (20mg, 0.2mmol) is joined isatin (147mg, 1.0mmol), 1-cyanogen second
In ethanol (25mL) solution of the blue hydrocarbon (318mg, 1.2mmol) of acyl group more wound and ethyl cyanoacetate (135mg, 1.2mmol), add
Hot reflux 6 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reactant mixture concentrating under reduced pressure, ethanol 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]+.
Elementary 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 '-dicyano-6 '-(3,8-dimethyl-5-isopropyl-1-base)-1-methyl-2-oxygen spiral shell (Yin
Diindyl quinoline-3,4 '-pyrans) (A3) synthesis
In 50mL reaction bulb, triethylamine (30mg, 0.3mmol) is joined 1-methylisatin (161mg, 1.0mmol),
In ethanol (25mL) solution of the blue hydrocarbon (318mg, 1.2mmol) of 1-cyanogen acetyl group more wound and Cyanoacetyl-Cyacetazid (79mg, 1.2mmol),
It is heated to reflux 3 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reactant mixture concentrating 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]+.
Elementary 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 group-6 '-(3,8-dimethyl-5-isopropyl-1-base)-1-methyl-2-oxygen spiral shell (indoline-
3,4 '-pyrans)-3 '-Ethyl formate (A4) synthesis
In 50mL reaction bulb, triethylamine (30mg, 0.3mmol) is joined 1-methylisatin (161mg, 1.0mmol),
The ethanol (25mL) of the blue hydrocarbon (318mg, 1.2mmol) of 1-cyanogen acetyl group more wound and 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, reactant mixture is reduced pressure dense
Contracting, ethyl alcohol recrystallization obtains 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]+.
Elementary 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 group-6 '-(3,8-dimethyl-5-isopropyl-1-base)-1,5-dimethyl-2-oxygen spiral shell (Yin
Diindyl quinoline-3,4 '-pyrans)-3 '-Ethyl formate (A5) synthesis
In 50mL reaction bulb, triethylamine (30mg, 0.3mmol) is joined 1,5-dimethylisatin (175mg,
1.0mmol), the blue hydrocarbon (318mg, 1.2mmol) of 1-cyanogen acetyl group more wound and the ethanol of ethyl cyanoacetate (135mg, 1.2mmol)
(25mL), in solution, it is heated to reflux 3 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reactant mixture
Concentrating 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]+.
Elementary 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 '-dicyano-6 '-(3,8-dimethyl-5-isopropyl-1-base)-1-benzyl-2-oxygen spiral shell (Yin
Diindyl quinoline-3,4 '-pyrans) (A6) synthesis
In 50mL reaction bulb, triethylamine (40mg, 0.4mmol) is joined 1-benzyl isatin (237mg, 1.0mmol),
In ethanol (25mL) solution of the blue hydrocarbon (318mg, 1.2mmol) of 1-cyanogen acetyl group more wound and Cyanoacetyl-Cyacetazid (79mg, 1.2mmol),
It is heated to reflux 2 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reactant mixture concentrating under reduced pressure, ethanol
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]+.
Elementary 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 group-6 '-(3,8-dimethyl-5-isopropyl-1-base)-1-benzyl-2-oxygen spiral shell (indoline-
3,4 '-pyrans)-3 '-Ethyl formate (A7) synthesis
In 50mL reaction bulb, triethylamine (20mg, 0.2mmol) is joined 1-benzyl isatin (237mg, 1.0mmol),
The ethanol (25mL) of the blue hydrocarbon (318mg, 1.2mmol) of 1-cyanogen acetyl group more wound and 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, reactant mixture is reduced pressure dense
Contracting, recrystallisation from isopropanol obtains 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]+.
Elementary 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 '-dicyano-6 '-(3,8-dimethyl-5-isopropyl-1-base)-5-methoxyl group-2-oxygen spiral shell
(indoline-3,4 '-pyrans) (A7) synthesis
In 50mL reaction bulb, triethylamine (20mg, 0.2mmol) is joined 5-methoxyl group isatin (177mg,
1.0mmol), the blue hydrocarbon (318mg, 1.2mmol) of 1-cyanogen acetyl group more wound and the ethanol of Cyanoacetyl-Cyacetazid (79mg, 1.2mmol)
(25mL), in solution, it is heated to reflux 5 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reactant mixture
Concentrating 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]+.
Elementary 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 '-dicyano-6 '-(3,8-dimethyl-5-isopropyl-1-base)-1-methyl-5-chloro-2-oxygen
Spiral shell (indoline-3,4 '-pyrans) (A8) synthesis
In 50mL reaction bulb, triethylamine (50mg, 0.5mmol) is joined 1-methyl-5-chloro isatin (196mg,
1.0mmol), the blue hydrocarbon of 1-cyanogen acetyl group more wound (344mg, 1., 3mmol) and the acetonitrile of Cyanoacetyl-Cyacetazid (86mg, 1.3mmol)
(25mL), in solution, it is heated to reflux 5 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reactant mixture
Concentrating 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]+.
Elementary 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 '-dicyano-6 '-(3,8-dimethyl-5-isopropyl-1-base)-1-methyl-5-bromo-2-oxygen
Spiral shell (indoline-3,4 '-pyrans) (A9) synthesis
In 50mL reaction bulb, triethylamine (40mg, 0.4mmol) is joined 1-methyl-5-bromoisatin (240mg,
1.0mmol), the blue hydrocarbon (344mg, 1.3mmol) of 1-cyanogen acetyl group more wound and the acetonitrile of Cyanoacetyl-Cyacetazid (86mg, 1.3mmol)
(30mL), in solution, it is heated to reflux 7 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reactant mixture
Concentrating 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]+.
Elementary 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 '-dicyano-6 '-(3,8-dimethyl-5-isopropyl-1-base)-1-methyl-5-methoxyl group-
2-oxygen spiral shell (indoline-3,4 '-pyrans) (A10) synthesis
In 50mL reaction bulb, triethylamine (20mg, 0.2mmol) is joined 1-methyl-5-methoxyl group isatin (191mg,
1.0mmol), the blue hydrocarbon (318mg, 1.2mmol) of 1-cyanogen acetyl group more wound and the ethanol of Cyanoacetyl-Cyacetazid (79mg, 1.2mmol)
(25mL), in solution, it is heated to reflux 2 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reactant mixture
Concentrating 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]+.
Elementary 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-1-base)-1-methyl-5-methoxyl group-2-
Oxygen spiral shell (indoline-3,4 '-pyrans)-3 '-Ethyl formate (A12) synthesis
In 50mL reaction bulb, triethylamine (20mg, 0.2mmol) is joined 1-methyl-5-methoxyl group isatin (191mg,
1.0mmol), the blue hydrocarbon (318mg, 1.2mmol) of 1-cyanogen acetyl group more wound and the ethanol of Cyanoacetyl-Cyacetazid (79mg, 1.2mmol)
(25mL), in solution, it is heated to reflux 3 hours (with silica gel column chromatography plate (TLC) monitoring reaction).After completion of the reaction, by reactant mixture
Concentrating 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]+.
Elementary analysis (C33H33N3O5): measured value (theoretical value), C 71.93 (71.85), H 6.11 (6.03), N 7.71
(7.62).
Anti-tumor activity is tested
MTT (tetramethyl azo azoles salt) method is used to measure the indole Spirocyclic derivatives of the present invention suppression to growth of tumour cell
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 technique:
(1) preparation of sample: dissolved with 20 μ LDMSO by compound to be tested (1mg) respectively, takes solution after 2 μ L dissolve and uses
1000 μ L culture fluid dilution (this culture fluid is containing the DMEM culture medium that hyclone mass concentration is 10%) so that it is concentration is
100 μ g/mL, then with identical culture fluid serial dilution to concentration 1-10 μ g/mL.
(2) preparation of culture medium: preparation DMEM culture medium so that blue or green containing 800,000 units in every 1000mL DMEM culture medium
Mycin, 1.0g streptomycin and the inactivated fetal bovine serum of 10% mass.
(3) cultivation of cell: respectively by above-mentioned tumor cell inoculation in the culture medium that step (2) is prepared, in 37 DEG C,
5%CO2Cultivating in incubator, 3-5d passes on.
(4) sample inhibitory action to growth of tumour cell is measured
By cell human stomach cancer cell line (SGC-7901), human lung carcinoma cell line (NCI-H446), disappear with EDTA-pancreatin respectively
Change liquid digestion, and be diluted to 1 × 105/mL by culture medium, be added in 96 porocyte culture plates, every hole 100 μ L, put 37 DEG C, 5%
CO2Incubator is cultivated.Discard former culture medium after 24 hours, add the culture medium containing test sample, every hole 200 μ L, Mei Genong
Degree adds 3 holes, puts 37 DEG C, 5%CO2Incubator is cultivated, in cell culture well, after 72 hours, adds the MTT of 5mg/mL, every hole
10 μ L, put 37 DEG C and hatch 4 hours, add DMSO, every hole 150 μ L, by microplate reader colorimetric under 570nm wavelength.Respectively with equally
Condition with without sample, culture medium culturing containing same concentration DMSO above-mentioned cancer cell as comparison, calculate sample to swollen
Median lethal concentration (the IC of tumor cell growth50)。
After above-mentioned steps is measured, the IC of the compounds of this invention50As shown in the table:
Compound A1-A12Anti-tumor activity
As seen from the above table, the compound that the embodiment of the present invention provides shows good anti-gastric cancer and anti-lung cancer activity, its
Middle compound A5And A9Effect be better than clinic cancer therapy drug cisplatin.
In sum, the invention provides a class and there is the indole volution compound of active anticancer, find such simultaneously
Compound has excellent anti-gastric cancer and anti-lung cancer activity, thus the research and development for cancer therapy drug have expanded research substrate, for entering one
Step application provides possible, has huge clinical value and development prospect.
It is understood that above with respect to the specific descriptions of the present invention, be merely to illustrate the present invention and be not limited to this
Technical scheme described by inventive embodiments, it will be understood by those within the art that, still can carry out the present invention
Amendment or equivalent, to reach identical technique effect；As long as meet use needs, all protection scope of the present invention it
In.
Claims (10)
1. the indole volution compound containing the blue hydrocarbon structure of more wound, it is characterised in that there is following general structure:
Wherein, R1For the one in H, alkyl, alkoxyl, hydroxyl, halogen, nitro, cyano group or carboxylic acid and ester thereof；R2For H, alkyl
Or aryl；X is cyano group or alkoxy carbonyl group.
The most according to claim 1, the preparation method of the indole volution compound containing the blue hydrocarbon structure of more wound, its feature exists
In, implement as follows:
(1) triethylamine is added to 1-cyanogen acetyl group in the solution of the heal blue hydrocarbon of wound, isatin and cyanoacetate and react；
(2) after completion of the reaction, by directly filtering or reactant liquor being concentrated to give crude product；
(3) by gained crude product by recrystallization, purpose product is obtained.
The most according to claim 2, the preparation method of the indole volution compound containing the blue hydrocarbon structure of more wound, its feature exists
In: solution described in step (1) with ethanol or acetonitrile as solvent.
The most according to claim 3, the preparation method of the indole volution compound containing the blue hydrocarbon structure of more wound, its feature exists
In: the blue hydrocarbon of described isatin, 1-cyanogen acetyl group more wound, the mol ratio of cyanoacetate are followed successively by 1:1～1.5:1～1.5.
The most according to claim 4, the preparation method of the indole volution compound containing the blue hydrocarbon structure of more wound, its feature exists
In: in terms of molal weight, the consumption of described triethylamine is the 5～50% of isatin.
The most according to claim 1, the preparation method of the indole volution compound containing the blue hydrocarbon structure of more wound, its feature exists
In, implement as follows:
(1) triethylamine is added to 1-cyanogen acetyl group in the solution of the heal blue hydrocarbon of wound, isatin and Cyanoacetyl-Cyacetazid and react；
(2) after completion of the reaction, by directly filtering or reactant liquor being concentrated to give crude product；
(3) by gained crude product by recrystallization, purpose product is obtained.
The most according to claim 6, the preparation method of the indole volution compound containing the blue hydrocarbon structure of more wound, its feature exists
In: solution described in step (1) with ethanol or acetonitrile as solvent.
The most according to claim 7, the preparation method of the indole volution compound containing the blue hydrocarbon structure of more wound, its feature exists
In: the blue hydrocarbon of described isatin, 1-cyanogen acetyl group more wound, the mol ratio of Cyanoacetyl-Cyacetazid are followed successively by 1:1～1.5:1～1.5.
The most according to claim 8, the preparation method of the indole volution compound containing the blue hydrocarbon structure of more wound, its feature exists
In: in terms of molal weight, the consumption of described triethylamine is the 5～50% of isatin.
10. the indole volution compound creating blue hydrocarbon structure as claimed in claim 1 containing healing is as antitumor drug
In application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610533171.XA CN106220641B (en) | 2016-07-08 | 2016-07-08 | Containing the indoles volution compound 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 |
|---|---|---|---|
| CN201610533171.XA CN106220641B (en) | 2016-07-08 | 2016-07-08 | Containing the indoles volution compound and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106220641A true CN106220641A (en) | 2016-12-14 |
| CN106220641B CN106220641B (en) | 2019-01-04 |
Family
ID=57520314
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610533171.XA Expired - Fee Related CN106220641B (en) | 2016-07-08 | 2016-07-08 | Containing the indoles volution compound and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106220641B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749295A (en) * | 2017-01-11 | 2017-05-31 | 中国药科大学 | A kind of synthetic method of volution Oxoindole gamma-butyrolacton class compound |
| CN106748957A (en) * | 2016-11-14 | 2017-05-31 | 牡丹江师范学院 | Containing Benzazole compounds for more creating blue hydrocarbon Azulene structure and preparation method and application |
| CN107056784A (en) * | 2017-06-26 | 2017-08-18 | 苏州大学 | A kind of chiral double hydroxyindole spiro-compounds and its synthetic method |
| 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 |
| CN109400562A (en) * | 2018-12-19 | 2019-03-01 | 渤海大学 | It is a kind of containing derivative of kojic acid, the preparation method and applications of more creating blue hydrocarbon Azulene structure |
| CN109456263A (en) * | 2018-12-19 | 2019-03-12 | 渤海大学 | It is a kind of containing dipyridyl derivatives, the preparation method and applications of more creating blue hydrocarbon Azulene structure |
| CN113861095A (en) * | 2021-11-18 | 2021-12-31 | 南昌工程学院 | Method for preparing guaiazulene indole compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102267929A (en) * | 2011-06-20 | 2011-12-07 | 四川国康药业有限公司 | Preparation of novel N-amino acid substituted azulene sulfamide medicine and anti-gastric ulcer actions thereof |
| CN104003959A (en) * | 2014-06-11 | 2014-08-27 | 四川大学 | Guaiac orchid hydrocarbon azulene ramification and preparing method and application thereof |
| CN104974123A (en) * | 2015-07-13 | 2015-10-14 | 渤海大学 | Coumarin compound with antioxidant activity, and preparation method and application thereof |
-
2016
- 2016-07-08 CN CN201610533171.XA patent/CN106220641B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102267929A (en) * | 2011-06-20 | 2011-12-07 | 四川国康药业有限公司 | Preparation of novel N-amino acid substituted azulene sulfamide medicine and anti-gastric ulcer actions thereof |
| CN104003959A (en) * | 2014-06-11 | 2014-08-27 | 四川大学 | Guaiac orchid hydrocarbon azulene ramification and preparing method and application thereof |
| CN104974123A (en) * | 2015-07-13 | 2015-10-14 | 渤海大学 | Coumarin compound with antioxidant activity, and preparation method and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| 李帝: "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", 《渤海大学硕士学位论文》 * |
| 王道林，等: "1-(2-氨基-3,5-二氰基-4-芳基-4 H -吡喃-6-基)愈创兰烃薁的合成", 《有机化学》 * |
| 王道林，等: "1-(2-苯并呋喃酰基)愈创兰烃薁的合成", 《有机化学》 * |
| 王道林，等: "1-(香豆素-3-酰基)愈创兰烃薁的合成及其抗菌活性", 《有机化学》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106748957A (en) * | 2016-11-14 | 2017-05-31 | 牡丹江师范学院 | Containing Benzazole compounds for more creating blue hydrocarbon Azulene structure and preparation method and application |
| CN106748957B (en) * | 2016-11-14 | 2019-07-26 | 牡丹江师范学院 | Containing the Benzazole compounds and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure |
| CN106749295A (en) * | 2017-01-11 | 2017-05-31 | 中国药科大学 | A kind of synthetic method of volution Oxoindole gamma-butyrolacton class compound |
| CN107056784A (en) * | 2017-06-26 | 2017-08-18 | 苏州大学 | A kind of chiral double hydroxyindole spiro-compounds and its synthetic method |
| 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 |
| CN109400562A (en) * | 2018-12-19 | 2019-03-01 | 渤海大学 | It is a kind of containing derivative of kojic acid, the preparation method and applications of more creating blue hydrocarbon Azulene structure |
| CN109456263A (en) * | 2018-12-19 | 2019-03-12 | 渤海大学 | It is a kind of containing dipyridyl derivatives, the preparation method and applications of more creating blue hydrocarbon Azulene structure |
| CN109456263B (en) * | 2018-12-19 | 2021-10-12 | 渤海大学 | Bipyridine derivative containing guaiazulene structure, preparation method and application thereof |
| CN109400562B (en) * | 2018-12-19 | 2022-12-27 | 渤海大学 | Kojic acid derivative containing guaiazulene azulene 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106220641B (en) | 2019-01-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106220641B (en) | Containing the indoles volution compound and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure | |
| CN110483418B (en) | 3-substituted quinazolinone-2-formamide derivative and preparation method and application thereof | |
| CN109336866A (en) | A kind of polysubstituted pyridine cyclics preparation method and application | |
| JP7101781B2 (en) | Salt morphology as an Akt inhibitor and its crystalline morphology | |
| CN110330452A (en) | Nafoxidine alkanes compound or its pharmaceutically acceptable salt and its preparation method and application | |
| CN106674115A (en) | Licochalcone A dihydropyrazolamide compounds with antineoplastic activity and synthetic method thereof | |
| CN110437156B (en) | Paeonol dihydropyrimidinone derivative, preparation method and application thereof | |
| CN108864089B (en) | Indolopyridone drug molecule and preparation method and application thereof | |
| CN117551052A (en) | Oxadiazole derivative with anti-tumor activity and preparation method thereof | |
| CN106188075B (en) | Indoles volution compound and the preparation method and application thereof | |
| CN116496219A (en) | Six-membered and five-membered heterocyclic compound, and pharmaceutical composition and application thereof | |
| CN113527195B (en) | 5-aryl nicotinamide LSD1/HDAC double-target inhibitor, preparation method and application thereof | |
| CN113045567B (en) | Phosphatase recruitment chimera (PHORCs) compound based on protein phosphatase 5, preparation method and medical application thereof | |
| CN110078706B (en) | Imatinib derivative and preparation method and application thereof | |
| CN111606888B (en) | Pyrrole derivative and preparation method and application thereof | |
| CN110194741B (en) | 4-benzoyl piperazine-3-nitro-1, 8-naphthalimide derivative and preparation method and application thereof | |
| CN108358841B (en) | 4- ((2-substituted quinoline-4-yl) amino) benzoyl hydrazine derivatives, and preparation method and application thereof | |
| CN106632322B (en) | Pyrazole indolizine compounds and preparation method thereof and purposes | |
| CN114478509B (en) | Five-membered heterocycle substituted benzamide compound and preparation method and application thereof | |
| CN114436925B (en) | M-diphenol ether compound, preparation method and application thereof | |
| CN115368333B (en) | Ibuprofen-coumarin skeleton-containing compound and application thereof | |
| CN113563330B (en) | 3-position derivative of beta-carbopol as well as preparation method and application thereof | |
| CN102219745B (en) | 2-aryl substituted benzimidazole derivatives, as well as preparation method and application thereof | |
| CN111423413B (en) | Preparation and application of pyrazole derivative containing (3-methoxy-4-substituted pyridylmethoxy) phenyl unit | |
| CN111875605B (en) | Preparation and application of bisamide compound containing substituted pyrazole and beta-carboline units |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | 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 |
Granted publication date: 20190104 Termination date: 20190708 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |