Fused polycyclic indoline compound and preparation method thereof as well as pharmaceutical composition and application

A polycyclic indoline compound technology, applied in the field of fused polycyclic indoline compounds, can solve the problems of long synthesis steps, cumbersome operations, and inability to apply industrial production

Active Publication Date: 2017-07-18
SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is to overcome the technical problems such as low reaction yield, long synthesis steps, narrow scope of applicable substituents, cumbersome operation and inabili

Method used

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  • Fused polycyclic indoline compound and preparation method thereof as well as pharmaceutical composition and application
  • Fused polycyclic indoline compound and preparation method thereof as well as pharmaceutical composition and application
  • Fused polycyclic indoline compound and preparation method thereof as well as pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Enamine 14a (0.3mmol), indium trichloride (3.3mg), Molecular sieves (200 mg), and 2 mL of dichloromethane were added to the reaction tube, and then dimethyl methylene malonate (R 9 =H, 0.9 mmol) in 2 mL of dichloromethane, reacted at room temperature for 5 hours to obtain product 1a, 134.9 mg, yield 90%, 95 / 5dr. 1 H NMR (400MHz, CDCl 3 )δ7.66(d,J=8.0Hz,2H),7.39–7.35(m,3H),7.13(td,J=8.0,1.2Hz,1H),6.73(td,J=7.2,0.8Hz,1H ),6.51(d,J=8.0Hz,1H),4.28(d,J=1.2Hz,1H),3.70–3.63(m,7H),3.34(t,J=10.0Hz,1H),3.13–3.09 (m,1H),2.82(s,3H),2.46(s,3H),2.20–2.11(m,2H),1.89–1.85(m,2H),1.79–1.75(m,1H),1.69–1.61 (m,1H).

[0113]

Embodiment 2

[0115] Enamine 14b (0.3mmol), ferric chloride (3.3mg), Molecular sieves (200 mg), and 2 mL of dichloromethane were added to the reaction tube, and then dimethyl methylene malonate (R 9 =H, 0.9 mmol) in 2 mL of dichloromethane, reacted at room temperature for 6 hours to obtain product 1b, 135.5 mg, yield 88%, >95 / 5dr. 1 H NMR (400MHz, CDCl 3 )δ7.68(d, J=8.0Hz, 2H), 7.37(d, J=8.0Hz, 2H), 7.16(s, 1H), 6.95(d, J=8.0Hz, 1H), 6.47(d, J=8.4Hz, 1H), 4.23(d, J=1.2Hz, 1H), 3.71–3.65(m, 7H), 3.37(t, J=10.4Hz, 1H), 3.15–3.11(m, 1H), 2.80(s,3H),2.47(s,3H),2.26–2.10(m,5H),1.89–1.84(m,2H),1.79–1.74(m,1H),1.70–1.59(m,1H).

[0116]

Embodiment 3

[0118] Enamine 14c (0.3mmol), indium trichloride (3.3mg), Molecular sieves (100 mg), and 2 mL of dichloromethane were added to the reaction tube, and then dimethyl methylene malonate (R 9 =H, 0.9 mmol) in 2 mL of dichloromethane, reacted at room temperature for 3 hours to obtain product 1c, 110.4 mg, yield 57%, >95 / 5dr. 1 H NMR (400MHz, CDCl 3 )δ7.67(d, J=8.4Hz, 2H), 7.36(d, J=8.4Hz, 2H), 7.29(s, 1H), 7.15(d, J=8.0Hz, 1H), 6.51(d, J=8.0Hz, 1H), 4.65(s, 2H), 4.27(s, 1H), 3.71–3.63(m, 7H), 3.35(t, J=10.4Hz, 1H), 3.13–3.09(m, 1H) ),2.81(s,3H),2.47(s,3H),2.24–2.10(m,2H),1.91–1.82(m,2H),1.79–1.74(m,1H),1.66–1.58(m,1H ),0.95(s,9H),0.12(d,J=2.0Hz,6H).

[0119]

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Abstract

The invention discloses a fused polycyclic indoline compound and a preparation method thereof as well as a pharmaceutical composition and application. The compound provided by the invention has an obvious inhibiting effect on tumor cells Kyse-450, MDA-MB-231 and SKGT-4 and has remarkable bioactivity for plasmodium falciparum dd2 having drug resistance for chloroquine; meanwhile, the preparation method disclosed by the invention has the advantages of high reaction yield, short synthesis steps, wide range of suitable substituent group and simple operation, and is expected to realize an industrial application prospect. (The formula is shown in the description).

Description

technical field [0001] The invention relates to a condensed polycyclic indoline compound, its preparation method, pharmaceutical composition and application. Background technique [0002] As we all know, polycyclic indoline structures widely exist in natural or non-natural active molecules, and have more and more important uses in many aspects such as pesticides and medicines ((a) J.Cassayre, L.P.Molleyres, P.Maienfisch , F. Cederbaum, U.S. Patent No. 8309567, 2012; (b) K.J.Barakat, K.Cheng, W.W.S.Chan, B.S.Butler, T.M.Jacks, K.D.Schleim, D.F.Hora Jr, G.J.Hickey, R.G.Smith, A.A.Patchett, R.P.Nargund , Bioorg.Med.Chem.Lett.1998,8,1431-1436; (c) B. Lippa, G. Pan, M. Corbett, C. Li, G. S. Kauffman, J. Pandit, S. Robinson, L. Wei , E. Kozina, E.S. Marr, G. Borzillo, E. Knauth, E.G. Barbacci-Tobin, P. Vincent, M. Troutman, D. Baker, F. Rajamohan, S. Kakar, T. Clark, J. Morris, Bioorg 2008, 18, 3359-3363; (d) W. Palatnick; R. Meatherall; D. Sitar; M. Tenenbein Clin. Toxicol. 199...

Claims

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Application Information

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IPC IPC(8): C07D487/10C07D491/22A61K31/403A61K31/407A61P35/00A61P33/06
CPCC07D487/10C07D491/22Y02A50/30Y02P20/55
Inventor 唐勇朱俊程雨晶王丽佳
Owner SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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