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Heterocyclyl-substituted indoxaphthalenone derivatives and their medical use

A technology of uses and organisms, applied in the fields of drug combination, anti-tumor drugs, organic chemistry, etc., can solve the problems of Crizotinib bioavailability to be improved, Crizotinib resistance and other issues

Inactive Publication Date: 2018-01-05
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 ALK-targeting inhibitor on the market. Alectinib (also known as CH5424802), which is in the second phase of clinical trials, is a selective ALK inhibitor. Its unique tetracyclic structure has attracted widespread attention.

Method used

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  • Heterocyclyl-substituted indoxaphthalenone derivatives and their medical use
  • Heterocyclyl-substituted indoxaphthalenone derivatives and their medical use
  • Heterocyclyl-substituted indoxaphthalenone derivatives and their medical use

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0038] Preparation of Example 1 Compound S1

[0039]

[0040] For the synthesis of compound 1-1, refer to CN102459172.

[0041] The synthesis of compound 1-2 refers to J.Med.Chem.2011, 54, 6342-6363.

[0042] Synthesis of Compound S1:

[0043] Dissolve compound 1-1 and 1.3eq compound 1-2 in dry 1,4-dioxane, add 0.2eq tetraphenylphosphine palladium and a few drops of 2M sodium carbonate solution under nitrogen protection, and heat at 120°C in microwave 1h, after the reaction was complete, the insoluble matter was filtered off, and the filtrate was directly mixed with silica gel and put on the column, and the chloroform [CHCl 3 ]: Methanol [MeOH]=100:1~30:1 (volume ratio) to obtain compound S1.

[0044] 1 H NMR (300MHz, CDCl 3 +MeOD)δ8.33(dd,J=8.2,0.7Hz,1H),8.23(d,J=8.2Hz,1H),7.80(d,J=2.6Hz,2H),7.68(s,1H), 7.63(s,1H),7.47(dd,J=8.2,1.6Hz,1H),7.40(dd,J=8.2,1.4Hz,1H),4.32(m,1H),4.03(d,J=11.5Hz ,2H), 3.55–3.41(m,2H), 2.10–1.98(m,4H), 1.73(s,6H).

preparation Embodiment 2

[0045] Preparation of Example 2 Compound S2

[0046]

[0047] For the synthesis of compound 2-1, refer to CN102459172.

[0048] Synthesis of Compound S1:

[0049] The synthesis of compound S2 was the same as that of compound S1 except that compound 1-1 was replaced by compound 2-1.

[0050] 1 H NMR (300MHz, CDCl 3 +MeOD)δ8.29(d,J=8.1Hz,1H),8.11(s,1H),7.64(s,1H),7.53(s,2H),7.39(s,1H),7.35(d,J =8.1Hz,1H),4.29(m,1H),3.99(d,J=11.2Hz,2H),3.46(d,J=10.2Hz,2H),2.66(d,J=7.3Hz,2H), 2.02(s,4H), 1.65(s,6H), 1.17–1.07(m,3H).

preparation Embodiment 3

[0051] Preparation of Example 3 Compound S3

[0052]

[0053] Synthetic references of compound 3-1 J. Med. Chem. 2011, 54, 6342–6363.

[0054] Synthesis of compound 3-2:

[0055] The synthesis of compound S3 was the same as that of compound S2 except that compound 3-1 was used instead of compound 1-2.

[0056] Synthesis of compound S3:

[0057] Dissolve compound 3-2 in dichloromethane, add trifluoroacetic acid, and stir at room temperature. After the reaction was complete, the reaction solution was distilled off under reduced pressure, then ethyl acetate and saturated sodium bicarbonate were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and spin-dried to obtain compound S3.

[0058] 1 H NMR (300MHz, CDCl 3 +MeOD)δ8.42(d,J=10.2Hz,1H),8.24(s,1H),7.72(s,1H),7.61(d,J=6.8Hz,2H),7.54–7.43(m,2H ),4.27(s,1H),3.26(s,2H),2.84–2.68(m,4H),2.20(d,J=10.7Hz,2H),2.06–1.89(m,2H),1.75(s, 6H), 1.21 (m, 3H).

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Abstract

The invention relates to a heterocyclic radical-substituted indolonaphthalenone derivative and its uses in medicines. Concretely, the invention relates to a compound having tyrosine kinase a n a p l a s t i c l y m p h o m a k i n a s e (ALK) selective inhibition activity and its pharmaceutically acceptable salt or solvate, a preparation method of the compound and its pharmaceutically acceptable salt or solvate, and uses of the compound and its pharmaceutically acceptable salt or solvate in preparation of drugs for preventing or treating biological in-vivo ALK-related diseases with abnormal cell proliferation, morphologic change and / or motion function hyperfunction, in preparation of drugs for preventing or treating angiogenesis or cancerometastasis-related diseases and especially in preparation of drugs for treating or preventing tumor growth and transfer.

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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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/14C07D401/14C07D403/04C07D403/14A61K31/4155A61K31/454A61P35/00A61P35/04
CPCC07D401/14C07D403/04C07D403/14C07D405/14
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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