1,2,4-triazole compound

一种化合物、三氮唑的技术，应用在医药领域，能够解决代谢清除率降低等问题

Inactive Publication Date: 2020-08-11
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For some compounds, deuteration causes decreased metabolic clearance in vivo

Method used

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  • 1,2,4-triazole compound
  • 1,2,4-triazole compound
  • 1,2,4-triazole compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Example 1 5-(4-cyclopropyl-1H-imidazolyl-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazole-3- Base-5-d)pyridin-2-yl-3,4-d 2 ) - Preparation of 2-fluoro-4-methylbenzamide (compound T-1).

[0106]

[0107] Concrete synthetic steps are as follows:

[0108]

[0109] Step 1 Synthesis of compound 2.

[0110] Add compound 1 (5.0g, 32.86mmol) and methanol (60mL) to a 100mL single-necked flask equipped with magnetic stirring in turn, stir to dissolve, and slowly add hydrazine hydrate (3.29g, 65.72mmol) dropwise. The liquid was heated under reflux for 3 hours, then cooled to room temperature, a large amount of white solid was precipitated, filtered, the filter cake was washed with cold methanol, and dried to obtain 3.5 g of the white solid, with a yield of 70%. LC-MS(APCI):m / z=153.2(M+1) + . 1 H NMR (DMSO-d 6 ,300MHz)(δ / ppm):9.14(s,1H),7.51(t,J=5.7Hz,1H),7.11(d,J=5.7Hz,1H),6.61(d,J=6.0Hz,1H ),6.08(s,2H),4.48(s,2H).

[0111] Step 2 Synthesis of compound 3.

[0112] Add com...

Embodiment 2

[0125] Example 2 5-(4-cyclopropyl-1H-imidazolyl-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazole-3- yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide-6-d (compound T-2).

[0126]

[0127] Concrete synthetic steps are as follows:

[0128]

[0129] Step 1 Synthesis of Compound 12.

[0130] Add compound 6 (2.0g, 9.8mmol) and heavy water (10mL) to a 20mL microwave tube equipped with magnetic stirring, and slowly add a heavy aqueous solution of DCl (0.817mL, 9.8mmol, 12M) under stirring. Lower the temperature to 160°C and react for 1.5 hours. Cool to room temperature, saturated NaHCO 3 Adjust the pH to 10, extract with dichloromethane (20mLx3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 1.59g of a brown solid, with a yield of 79.1%. LC-MS(APCI):m / z=205.1(M+1) + . 1 H NMR (DMSO-d 6 ,300MHz)(δ / ppm):6.93(d,J=7.2Hz,1H),4.94(s,2H),1.99(s,3H).

[0131] Step 2 Synthesis of compound 13.

[0132] Add compound 12 (1.59g, 7.75mmol) an...

Embodiment 3

[0141] Example 3 5-(4-cyclopropyl-1H-imidazolyl-1-yl)-N-(6-(4-(prop-2-yl-1,1,1,3,3,3-d 6 )- Preparation of 4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound T-3).

[0142]

[0143] Concrete synthetic steps are as follows:

[0144]

[0145] Step 1 Synthesis of Compound 18.

[0146] Ammonium acetate (6.32 g, 78 mmol) and MeOD (50 mL) were added to a 50 mL one-necked flask equipped with magnetic stirring, N 2 The temperature was raised to reflux under atmosphere for 3 hours. Concentrate to dryness under reduced pressure, then add MeOD (10mL), add acetone-d under stirring 6 (1.0g, 15.6mmol) and NaBH 3 CN (980mg, 15.6mmol), N 2 The reaction was stirred overnight at room temperature under atmosphere. Add water (10mL) to quench the reaction, adjust the pH to 2 with 6M hydrochloric acid, extract with ethyl acetate (20mLx2), adjust the pH to 12 with 6M NaOH in the aqueous phase, extract with dichloromethane (20mLx3), combine the organic phases, an...

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Abstract

The invention relates to 1,2,4-triazole compound represented by a formula (I), and pharmaceutically acceptable salts thereof. The compound has apoptosis signaling kinase 1 (ASK1) inhibitor activity and is thus useful in the treatment of ASK1-mediated disorders, including chronic liver diseases, cardiovascular diseases, metabolic disorders, respiratory disorders, gastrointestinal disorders and neurodegenerative diseases. The invention further provides a pharmaceutical composition containing the compound and application of the pharmaceutical composition.

Description

[0001] This application is a divisional application of an invention patent application with an application date of September 30, 2018, an application number of 201811159093.7, and an invention title of "a 1,2,4-triazole compound". technical field [0002] The invention belongs to the technical field of medicine, and in particular relates to a 1,2,4-triazole compound, a composition containing the compound and its application. In particular, the present invention relates to certain deuterium-substituted 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-[6-(4-isopropyl- 4H-1,2,4,-triazol-3-yl)-2-pyridine]-benzamide, these deuterium-substituted compounds are used in the treatment of ASK1-mediated diseases, and have better pharmacokinetic properties . Background technique [0003] Many current drugs suffer from poor absorption, distribution, metabolism and / or excretion (ADME) properties, which prevent their wider use or limit their use to certain indications. Poor ADME pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07B59/00A61K31/4439A61P3/10A61P13/12A61P11/00A61P1/16A61P37/00A61P35/00A61P37/06A61P19/08A61P29/00A61P9/12
CPCA61P1/16A61P3/10A61P9/12A61P11/00A61P13/12A61P19/08A61P29/00A61P35/00A61P37/00A61P37/06C07B59/002C07B2200/05C07D401/14A61K31/4164A61K31/4436A61K31/4439A61K45/06A61P3/00A61P19/00A61P31/12C07B59/00C07D233/56C07D401/04
Inventor 王义汉李焕银
Owner SHENZHEN TARGETRX INC
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