A 1,2,4-triazole compound

A compound and composition technology, applied in the field of medicine, can solve problems such as reduced metabolic clearance rate

Active Publication Date: 2020-07-24
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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  • A 1,2,4-triazole compound
  • A 1,2,4-triazole compound
  • A 1,2,4-triazole compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] 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).

[0105]

[0106] Concrete synthetic steps are as follows:

[0107]

[0108] Step 1 Synthesis of compound 2.

[0109] 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).

[0110] Step 2 Synthesis of compound 3.

[0111] Add com...

Embodiment 2

[0124] 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).

[0125]

[0126] Concrete synthetic steps are as follows:

[0127]

[0128] Step 1 Synthesis of compound 12.

[0129] 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).

[0130] Step 2 Synthesis of compound 13.

[0131] Add compound 12 (1.59g, 7.75mmol) ...

Embodiment 3

[0140] 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).

[0141]

[0142] Concrete synthetic steps are as follows:

[0143]

[0144] Step 1 Synthesis of Compound 18.

[0145] 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 aqueous solution in the aqueous phase, extract with dichloromethane (20 mLx3), combine the ...

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Abstract

A 1,2,4-triazole compound shown in formula (I) and pharmaceutically acceptable salts thereof. The compound has the activity of an apoptosis signal-regulating kinase 1 ("ASK1") inhibitor; thus, the compound can be used for treating ASK1 mediated diseases including chronic liver disease, cardiovascular disease, metabolic disturbance, respiratory system disorder, gastrointestinal disorder, and neurodegenerative diseases. A pharmaceutical composition comprising the compound of formula (I) and uses thereof.

Description

technical field [0001] 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 [0002] 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 properties are also an important reason for the failure of drug candidates in clinical trials. One such problem is rapid metabolism, which causes many drugs that would otherwise be highly effective in disease treatment to be cleared fr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14A61K31/4439A61K45/06A61P3/10A61P13/12A61P1/16A61P9/12A61P29/00A61P37/00A61P35/00A61P19/00A61P3/00C07B59/00
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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