Compound used as ALK (anaplastic lymphoma kinase) inhibitor and application thereof

A compound and solvate technology, applied in the field of medicine, can solve problems such as visual impairment, elevated liver transaminase levels, and large side effects

Pending Publication Date: 2018-10-23
TYK MEDICINES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, crizotinib will cause the following side effects: visual disturbance, gastrointestinal side effects, and 16% of patients had grade 3-4 elevated liver transaminase levels. In addition, ALK-positive patients were treated with crizotinib at the initial stage Acquired drug resistance inevitably occurs after the sensitive period. Studies have found that patients generally develop drug resistance after 1-2 years of treatment
At present, the second-generation ALK inhibitors, such as LDK378, alectinib and AP26113, have been found in early studies to improve the efficacy of treatment, but they all have the problem of large side effects

Method used

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  • Compound used as ALK (anaplastic lymphoma kinase) inhibitor and application thereof
  • Compound used as ALK (anaplastic lymphoma kinase) inhibitor and application thereof
  • Compound used as ALK (anaplastic lymphoma kinase) inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] The synthesis of compound c-1, reaction formula is as follows:

[0110]

[0111] 1) Synthesis of compound b3-1: Put compound b1-1 (0.5g, 3mmol) into a 100mL three-necked flask, add DMF (30mL), then add compound b2 (0.86g, 4.7mmol), anhydrous potassium carbonate ( 1.23g, 9.5mmol), stirred overnight at 60°C, TLC showed that the reaction was basically complete, cooled to room temperature, added 100mL of water, extracted with ethyl acetate, washed the organic phase with saturated brine, dried over anhydrous magnesium sulfate, concentrated through the column, and obtained 0.7g khaki solid, 1 H NMR (400MHz, DMSO): δ11.82(s, 1H), 8.45(m, 2H), 7.68(m, 2H), 7.27(m, 1H), 1.79(d, J=13.6Hz, 6H); MS m / z(ESI): 316[M+H] + .

[0112] 2) Synthesis of compound c-1: Dissolve compound a6 (150 mg, 0.5 mmol) in acetone / water (volume ratio 3:1, 8 mL in total), add compound b3-1 (200 mg, 0.6 mmol), 3 drops of concentrated hydrochloric acid , sealed, heated to 100°C, stirred overnight, c...

Embodiment 2

[0114] The synthesis of compound c-2, reaction formula is as follows:

[0115]

[0116] 1) Synthesis of compound b3-2: Put compound b1-2 (2g, 16.3mmol) into a 100mL three-necked flask, add DMF (70mL), then add compound b2 (4.65g, 25mmol), anhydrous potassium carbonate (7.16 g, 52mmol), stirred overnight at 60°C, TLC showed that the reaction was basically complete, cooled to room temperature, added 100mL of water, extracted with ethyl acetate, washed the organic phase with saturated brine, dried over anhydrous magnesium sulfate, concentrated through the column to obtain 1.5g yellow solid, 1 H NMR (400MHz, CDCl 3 ): δ8.51(d,J=8Hz,1H),8.18(s,1H),8.13(br,,1H),7.07(m,2H),6.95(d,J=8Hz 1H); MS m / z(ESI): 270[M+H] + .

[0117] 2) Synthesis of compound c-2: Dissolve compound a6 (150 mg, 0.5 mmol) in acetone / water (3:1, 8 mL), add compound b3-2 (190 mg, 0.6 mmol) and 3 drops of concentrated hydrochloric acid, seal and heat to 100°C, stirred overnight, cooled to room temperature,...

Embodiment 3

[0119] The synthesis of compound c-3, reaction formula is as follows:

[0120]

[0121] 1) Synthesis of compound b3-3: Put compound b1-3 (2g, 16.3mmol) into a 100mL three-necked flask, add DMF (70mL), then add compound b2 (4.65g, 25mmol), anhydrous potassium carbonate (7.16 g, 52mmol), stirred overnight at 60°C, TLC showed that the reaction was basically complete, cooled to room temperature, added 100mL of water, extracted with ethyl acetate, washed the organic phase with saturated brine, dried over anhydrous magnesium sulfate, concentrated through the column to obtain 1.5g yellow solid, 1 H NMR (400MHz, CDCl 3 ): δ8.19(s,1H),7.63(d,J=8.4Hz,2H),7.63(t,J=7.6Hz,2H),7.21(s,1H),7.17(t,J=7.2Hz ,2H); MS m / z (ESI): 240[M+H] + .

[0122] 2) Synthesis of compound c-3: Dissolve compound a6 (150 mg, 0.5 mmol) in acetone / water (3:1, 8 mL), add compound b3-3 (190 mg, 0.6 mmol) and 3 drops of concentrated hydrochloric acid, seal and heat to 100°C, stirred overnight, cooled to room t...

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Abstract

The invention discloses a compound shown in a formula I, and pharmaceutically acceptable salts, stereoisomers, solvates or predrugs. The symptoms are defined in claim requirements. The compound shownin the formula I has good inhibiting activity on ALK (anaplastic lymphoma kinase), and can be used for preparing medicines for adjusting the activity of the ALK activity or treating the ALK-related diseases, especially nonsmall-cell lung cancer drugs. (The formula I is shown in the attached figure.).

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to compounds used as ALK kinase inhibitors and their application in the preparation of drugs for regulating ALK kinase activity or treating ALK-related diseases, especially non-small cell lung cancer. Background technique [0002] Malignant tumors are one of the main killers of human health. For example, according to the statistics of the World Health Organization, at this stage, there are 12 million newly diagnosed lung cancer patients in the world every year, and 8 million people die from lung cancer every year. At present, human beings have made remarkable progress in the level of understanding and treatment of tumors, and some tumors can be effectively controlled. However, due to the complex mechanism of tumor formation, the growth of most malignant tumor cells has multiple pathways, resulting in strong vitality of cancer cells, and inhibiting one or part of the pathways cannot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D403/12C07D471/10C07F9/6558A61K31/506A61K31/635A61K31/5377A61K31/675A61K31/53A61P35/00A61P11/00
CPCA61P11/00A61P35/00C07D401/12C07D401/14C07D403/12C07D471/10C07F9/65583
Inventor 吴豫生职五斌王新吴世勇李敬亚郭瑞云郑茂林梁阿朋王国辉陈明涛马杰牛成山
Owner TYK MEDICINES INC
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