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Trifluoro methyl substituted quinoline or quinoxaline compound and preparation method thereof, and pharmaceutical composition containing the compound and purpose thereof

A compound, quinoxaline technology, applied in drug combination, organic chemistry, antineoplastic drugs, etc., can solve the problems of carcinogenicity, nitro functional group mutagenesis, poor solubility, etc.

Inactive Publication Date: 2015-01-07
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

[0009] The inventors found in previous work that a series of analogs 2 were obtained by removing the 4-position nitrogen atom in compound 1, which also showed better c-Met kinase inhibitory activity, but the preparation of such compounds was relatively difficult and their solubility was also low. Poor and limited use due to mutagenic and carcinogenic nitro functional groups

Method used

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  • Trifluoro methyl substituted quinoline or quinoxaline compound and preparation method thereof, and pharmaceutical composition containing the compound and purpose thereof
  • Trifluoro methyl substituted quinoline or quinoxaline compound and preparation method thereof, and pharmaceutical composition containing the compound and purpose thereof
  • Trifluoro methyl substituted quinoline or quinoxaline compound and preparation method thereof, and pharmaceutical composition containing the compound and purpose thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0064] Preparation of Example 1 Compound IA-1

[0065] 1.1 Synthesis of Intermediate 13

[0066]

[0067] Compound synthesis, reagents and conditions: i) potassium nitrate, concentrated sulfuric acid; ii) ammonium sulfide, ethanol, reflux; iii) a sodium nitrite, hydrobromic acid; b cuprous bromide, hydrobromic acid, reflux; iv) a N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide, reflux; b sodium periodate, N,N-dimethylformamide / water; v) iron powder, chlorine ammonium chloride, ethanol / water; vi)12, sodium hydroxide, ethanol, reflux.

[0068] 1.1.1 Synthesis of Compound 7

[0069] 4-Methyltrifluorotoluene (9.3 g, 58 mmol) was added into a round bottom flask containing 120 mL of concentrated sulfuric acid, and potassium nitrate (14.6 g, 145 mmol) was added with stirring and stirred at room temperature for 16 hours. The reaction solution was poured into ice water (300 mL). The aqueous phase was extracted three times with ethyl acetate, the organic phase was wa...

preparation Embodiment 2

[0092] Preparation of Example 2 Compound IA-2

[0093]

[0094] 2.1 Synthesis of intermediate 18

[0095] Intermediate 18 was synthesized in the same way as Intermediate 17 except that furan-2-boronic acid was used instead of phenylboronic acid.

[0096]

[0097] 1 H-NMR (300MHz, CDCl 3 ): δ8.10(d, J=9.9Hz, 1H), 7.65(s, 1H), 7.56(d, J=9.9Hz, 1H), 7.23(d, J=3.0Hz, 1H), 6.62(s , 1H), 5.45(s, 1H), 4.95(d, J=3.0Hz, 2H), 1.45(s, 9H).

[0098]

[0099] 1 H-NMR (300MHz, CDCl 3 ): δ8.18(d, J=9.6Hz, 1H), 7.65(d, J=1.2Hz, 1H), 7.56(d, J=9.6Hz, 1H), 7.20(d, J=5.2Hz, 1H ), 6.62(m, 1H), 4.44(s, 2H).

[0100] 2.2 Preparation of compound IA-2

[0101] Compound IA-2 was synthesized in the same manner as Compound IA-1 except that Intermediate 18 was used instead of Intermediate 17.

[0102] 1 H NMR (300MHz, CDCl 3 )δ8.74(d, J=2.7Hz, 1H), 8.09(d, J=8.4Hz, 1H), 7.68(s, 2H), 7.57(d, J=8.1Hz, 1H), 7.35(d, J=2.1Hz, 1H), 7.25(s, 1H), 6.95(s, 1H), 6.65(dd, J=3.6, 1.5Hz, 1H), 5.94...

preparation Embodiment 3

[0103] Preparation of Example 3 Compound IA-3

[0104]

[0105] 3.1 Synthesis of intermediate 19

[0106] Intermediate 19 was synthesized in the same way as Intermediate 17 except that thiophene-2-boronic acid was used instead of phenylboronic acid.

[0107]

[0108] 1 H-NMR (300MHz, CDCl 3 ): δ8.08(d, J=9.6Hz, 1H), 7.70(d, J=4.8Hz, 1H), 7.54(m, 2H), 7.17(m, 1H), 5.49(s, 1H), 4.95 (d, J=5.1Hz, 2H), 1.46(s, 9H).

[0109]

[0110] 1 H-NMR (300MHz, CDCl 3 ): δ8.08(d, J=9.6Hz, 1H), 7.68(m, 1H), 7.54(m, 1H), 7.50(d, J=9.6Hz, 1H), 7.17(m, 1H), 4.45 (s, 2H).

[0111] 3.2 Preparation of compound IA-3

[0112] Compound IA-3 was synthesized in the same manner as Compound IA-1, except that Intermediate 19 was used instead of Intermediate 17.

[0113] 1 H NMR (300MHz, CDCl3) δ8.77(d, J=2.7Hz, 1H), 8.11(d, J=9.6Hz, 1H), 7.72(d, J=3.9Hz, 2H), 7.58(d, J =5.4Hz, 1H), 7.40(d, J=9.6Hz, 1H), 7.35(d, J=2.7Hz, 1H), 7.20(dd, J=4.8, 3.9Hz, 1H), 6.96(s, 1H ), 5.74(t, J=6.3Hz, 1H)...

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Abstract

The invention relates to a quinoline or quinoxaline compound shown as a following general formula I, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a preparation method thereof. The invention further relates to pharmaceutical composition containing the compound and / or pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof, and application of the pharmaceutical composition containing the compound and / or pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof to preparation of medicaments for preventing or treating diseases related to abnormal propagation, morphology and of cells and hyperkinesia that are related to hepatocyte growth factor receptor (HGFR) in organism, and diseases related to angiogenesis or cancerometastasis, and especially medicaments for preventing or treating tumour growth and cancerometastasis.

Description

technical field [0001] The present invention relates to a class of trifluoromethyl-substituted quinoline or quinoxaline compounds with c-Met inhibitory activity and pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, and a preparation method thereof, comprising the Pharmaceutical compositions of compounds and / or their pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates, and these compounds and / or their pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates Drugs are used in the preparation of drugs for the prevention or treatment of diseases related to abnormal cell proliferation, morphological changes and hyperkinesia related to hepatocyte growth factor receptor (HGFR) in vivo, as well as diseases related to angiogenesis or cancer metastasis , especially for use in medicines for treating or preventing tumor growth and metastasis. Background technique [0002] Hepatocyte growth factor (hepatocyt...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/5025A61P35/04
Inventor 张翱耿美玉艾菁王元相彭霞
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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