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Amido substituted indolonaphthalenone derivatives and medicinal uses thereof

A substituent and unsubstituted technology, which is applied in the field of amido-substituted indoxaphthalenone derivatives and their medical applications, can solve the problems of Crizotinib bioavailability to be improved, Crizotinib drug resistance, etc.

Inactive Publication Date: 2014-12-03
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, existing clinical studies have shown that resistance to Crizotinib has emerged, and the bioavailability of Crizotinib in the body needs to be improved
At present, there is no single inhibitor targeting ALK on the market. Alectinib (also known as CH5424802), which is in the second phase of clinical trials, is a selective ALK inhibitor. Its unique four-ring structure has attracted widespread attention (Bioorganic & Medicinal Chemistry 20 (2012) 1271 –1280; J. Med. Chem. 2011, 54, 6286–6294)

Method used

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  • Amido substituted indolonaphthalenone derivatives and medicinal uses thereof
  • Amido substituted indolonaphthalenone derivatives and medicinal uses thereof
  • Amido substituted indolonaphthalenone derivatives and medicinal uses thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0037] Preparation of Example 1 Compound S1

[0038]

[0039] For the synthesis of compound 1-1, refer to CN102459172.

[0040] Synthesis of compound 1-2:

[0041] Dissolve compound 1-1 in ethanol, add 0.2eq cuprous iodide (CuI) and 0.2eq iron triacetylacetonate (Fe(acac) 3 ) After the addition, prepare an aqueous solution of sodium hydroxide and ammonia, dissolve 2eq of sodium hydroxide in 10eq of aqueous ammonia, add the aqueous solution of sodium hydroxide to the reaction solution, and seal the tube at 90°C for 48 hours. After the reaction was completed, the reaction solution was filtered, extracted with chloroform and water, the organic phase was mixed with silica gel and loaded on the column, CHCl 3 :MeOH:NH 3 .H 2 O=100:1:1~100:20:1 (volume ratio) to obtain compound 1-2.

[0042] 1 H NMR (300MHz, CDCl 3 )δ10.19(s,1H),8.51(d,J=8.1Hz,1H),8.14(s,1H),7.67(s,1H),7.50(dd,J=8.2,1.4Hz,1H), 6.81 (s, 1H), 4.15 (s, 2H), 2.55 (q, J=7.4Hz, 3H), 1.80 (s, 6H), 1.37–1.25 (m, ...

preparation Embodiment 2

[0046] Preparation of Example 2 Compound S2

[0047]

[0048] Synthesis of compound S2:

[0049] Compound S2 was synthesized the same as compound S1 except that compound 2-(4-piperidinyl)-2-propanol was used instead of 4-(4-piperidinyl)morpholine.

[0050] 1 H NMR (300MHz, CDCl 3 +MeOD)δ8.30(dd,J=8.2,0.7Hz,1H),8.04(s,1H),7.97(s,1H),7.65(dd,J=1.4,0.7Hz,1H),7.38(dd ,J=8.2,1.4Hz,1H),4.06(d,J=13.1Hz,2H),2.79(t,J=11.8Hz,2H),2.57(q,J=7.5Hz,2H),1.76(d ,J=11.6Hz,2H),1.63(s,6H),1.22(m,5H),1.06(s,6H).

preparation Embodiment 3

[0051] Preparation of Example 3 Compound S3

[0052]

[0053] Synthesis of compound S3:

[0054] Instead of 4-(4-piperidine Except for base) morpholine, the synthesis of compound S3 is the same as that of compound S1.

[0055] 1 H NMR (300MHz, CDCl 3 +MeOD)δ8.36(d,J=8.2Hz,1H),8.16(s,1H),7.73(s,1H),7.72(s,1H),7.42(dd,J=8.2,1.4Hz,1H ),4.99(s,2H),4.23(t,J=5.2Hz,2H),4.02(t,J=5.3Hz,2H),2.65(q,J=7.5Hz,2H),1.68(s,6H ),1.23(t,J=7.5Hz,3H).

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Abstract

The invention relates to amido substituted indolonaphthalenone derivatives and medicinal uses thereof, and concretely relates to compounds with tyrosine kinase ALK selective inhibition activity, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, preparation methods of the compounds and the salts or solvates, a medicinal composition containing the compounds, uses of the above compounds in the preparation of medicines for preventing or treating biological anaplastic lymphoma kinase related abnormal cell proliferation, form change and / or hyperkinesias associated diseases, uses in the preparation of medicines for treating or preventing angiogenesis or cancerometastasis related diseases, and especially uses in the preparation of medicines for treating or preventing the growth and transfer of tumors.

Description

technical field [0001] The present invention relates to the field of synthesis of pharmaceutical compounds, in particular to a class of compounds with selective inhibitory activity on tyrosine kinases and their pharmaceutically acceptable salts or pharmaceutically acceptable solvates, and their preparation methods, including the compounds pharmaceutical composition, and the use of these compounds in the preparation of drugs for the prevention or treatment of diseases associated with progressive lymphoma enzymes in vivo, accompanied by abnormal cell proliferation, morphological changes, and hyperkinesia, and in the preparation of drugs for Use in medicines for preventing or treating diseases related to angiogenesis or cancer metastasis, especially in the preparation of medicines for preventing or treating tumor growth and metastasis. Background technique [0002] Aplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that belongs to the insulin receptor superfamily. It...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D487/04C07D403/12A61K31/5377A61K31/454A61K31/4985A61K31/407A61K31/403A61P35/00A61P35/04
CPCC07D401/12C07D403/12C07D487/04
Inventor 张翱耿美玉丁健宋子兰艾菁李晓刚彭霞
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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