Deuterated Defactinib compounds and application thereof

A technology for compounds and uses, applied in organic chemistry, drug combinations, organic chemistry methods, etc., can solve problems such as unpredictable deuterium effects, and achieve the effects of improved metabolic stability and pharmacokinetic properties and excellent application prospects.

Active Publication Date: 2019-11-15
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, suitable sites for deuteration of drugs are not obvious, and deuteration effects are also unpredictable

Method used

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  • Deuterated Defactinib compounds and application thereof
  • Deuterated Defactinib compounds and application thereof
  • Deuterated Defactinib compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1, N-(trideuteromethyl)-4-((4-(((3-(N-methylmethylsulfonyl)pyrazin-2-yl)methyl)amino)-5- Synthesis of (trifluoromethyl)pyrimidin-2-yl)amino)benzamide (Compound 1)

[0042]

[0043] (1) Compound tert-butyl (4-((tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)((3-(N-methylmethylsulfonyl)pyrazin-2-yl)methyl )amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)(methyl)carbamate

[0044]

[0045] N-methyl-4-((4-(((3-(N-methylmethylsulfonyl)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidine-2 -yl)amino)benzamide (200.0mg, 0.39mmol; compound 1-1, purchased from Chengdu Henghui Chemical Technology Co., Ltd.), DMAP (1.3g, 10.57mmol) was added to 10mL of dichloromethane, and then drop (Boc) 2 O (1.7 g, 7.83 mmol). The system was refluxed in an oil bath at 45°C for 24 hours. The next day, cool to room temperature, add dichloromethane and HCl (0.1M) solution, extract, leave to stand and separate layers, the organic phase is washed with saturated brine, drie...

Embodiment 2

[0053] Example 2, N-methyl-4-((4-(((3-(N-deuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoro Synthesis of Methyl)pyrimidin-2-yl)amino)benzamide (Compound 2)

[0054]

[0055] (1) Synthesis of compound N-deuteromethylmethanesulfonamide

[0056]

[0057] Weighed methanesulfonyl chloride (3.0g, 26.19mmol) into a 100mL single-neck round bottom flask, and added dichloromethane (30mL) into it, and stirred at room temperature to dissolve and clarify. Subsequently, the system was transferred to an ice-water bath to continue cooling and stirring. After 15 minutes, triethylamine (6.1 g, 60.24 mmol) was slowly added to the system. After the addition was complete, the system continued to insulate and stir for 10 minutes. Then, deuterated methylamine hydrochloride (2.0 g, 28.81 mmol) was slowly added in batches to the system. After completion, the ice bath was removed, and the system was allowed to return to room temperature and react overnight with stirring. ...

Embodiment 3

[0078] Example 3, N-(trideuteromethyl)-4-((4-(((3-(N-deuteromethylmethanesulfonamido)pyrazin-2-yl)methyl)amino)- Synthesis of 5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (Compound 3)

[0079]

[0080] (1) Synthesis of compound tert-butyl (4-(deuteromethylcarbamoyl) phenyl) carbamate

[0081]

[0082] Weigh 4-((tert-butoxycarbonyl)amino)benzoic acid (1.1 g, 4.64 mmol) into a 100 mL single-neck round bottom flask, add 20 mL of DMF to it, and stir at room temperature. Subsequently, EDCI (1.3 g, 6.96 mmol), TEA (1.2 g, 11.6 mmol), deuterated methylamine hydrochloride (327.2 mg, 4.64 mmol), and DMAP (28 mg, 0.23 mmol) were successively added to the system. After completion, the system was stirred and reacted overnight at room temperature. The next day, after monitoring the consumption of raw materials, ethyl acetate (30mL) and water (20mL) were added to the system, stirred vigorously, and after standing to separate layers, the aqueous phase was back-extracted with eth...

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Abstract

The invention discloses compounds or optical isomers, pharmaceutically acceptable salts, hydrates or solvates of the compounds. The compounds are represented by a formula (I), wherein R<1> to R<18> are each independently selected from hydrogen and deuterium, and not all hydrogen. The compounds, the salts, the hydrates or the solvates of the compounds provided by the invention can be used as a FAKinhibitor and used for preparing an anticancer drug, and compared with undeuterated control compound Defactinib, the compounds provided by the invention have significantly-improved metabolism stability and pharmacokinetic performance, and have excellent application prospects.

Description

technical field [0001] The present invention relates to deuterated Defactinib compounds and uses thereof. Background technique [0002] Defactinib (VS-6063), developed by Verastem, is a selective and orally effective FAK inhibitor with a structural formula of Clinical trials are currently underway. [0003] Deuterated drugs refer to the replacement of part of the hydrogen atoms in the drug molecule with deuterium. Since the shape and volume of deuterium in drug molecules are very close to hydrogen, deuterated drugs will retain the in vitro biological activity and selectivity of the original drug. Since the C-D bond is more stable than the C-H bond, the C-D bond is less likely to be broken during the metabolic reaction of the deuterated drug, and its half-life may be prolonged. [0004] However, due to the complex metabolic process of biological systems, the pharmacokinetic properties of drugs in vivo are affected by many factors and show corresponding complexity. Compar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61P35/00A61K31/506
CPCC07D403/12A61P35/00C07B2200/05A61K31/506
Inventor 杜武李宇温坤李兴海陈元伟
Owner HINOVA PHARM INC
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