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Novel deuterated urea compounds

A technology for compounds and compositions, applied in the field of medicine, which can solve the problems of variable, unpredictable results, and reduced metabolic clearance, etc.

Active Publication Date: 2021-11-19
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The effect of deuterium substitution on metabolic rate has been reported on some drugs (for example, see Blake, MI et al., JPharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res, 1985, 14:1-40 ; Kushner, DJ et al., Can J Physiol Pharmacol, 1999, 79-88; Fisher, MB et al., Curr Opin Drug Discov Devel, 2006, 9: 101-09), outcome is variable and unpredictable
For some compounds, deuteration causes decreased metabolic clearance in vivo

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Example 1. Preparation of 1-((S)-2-(two (methyl-d 3 )amino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(thiophen-3-yl)propane-2-yl)urea (compound (S)-1)

[0138]

[0139] step 1)

[0140] To the reaction flask was added (s)-2-amino-3-(4-hydroxyphenyl)propanamide (3.00 g, 16.65 mmol), acetonitrile (35 ml), and then 20% d 2 - formaldehyde heavy aqueous solution (27ml, 166.50mmol), stirring at room temperature; at the same time, add sodium borodeuteride (4.06g, 96.99mmol) and acetonitrile (5ml) to another reaction flask, add deuterium dropwise to the reaction at 0°C Acetic acid (20ml, 290.97mmol); the obtained d 1 - Sodium triacetoxy borodeuteride suspension was added in portions to the previous reaction mixture. After TLC monitors that the reaction is complete, add saturated aqueous sodium bicarbonate solution to the reaction to quench the reaction, then extract with isopropanol:ethyl acetate=1:3 (30ml*4) to obtain the organic phase, add anhydrous magnesium sulfate to dry,...

Embodiment 2

[0151] Example 2. Preparation of 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl-1,1-d 2 )-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea (compound (S)-2)

[0152]

[0153] step 1)

[0154] Add compound I-1 (1.00g, 4.80mmol) and anhydrous tetrahydrofuran (10ml) to the reaction flask, and stir at 0°C for 30 minutes under nitrogen protection; add 1.0M BD3-THF (28.90ml, 28.90mmol), heated to reflux overnight after the dropwise addition. After the completion of the reaction was monitored by TLC, methanol was slowly added at low temperature to quench the reaction. The reaction solution was spin-dried, and then methanol was added for rotary evaporation (10ml*3), then concentrated hydrochloric acid (1.0ml, 12mmol) was added, and ethanol was strip-evaporated (10ml*3). Acetone (10ml) was added into the reaction flask, and a solid precipitated out. Compound II-3 (0.674 g) was obtained by suction filtration and drying under reduced pressure at 45°C.

[0155] 1 H-NMR (500M, DMSO-d ...

Embodiment 3

[0161] Example 3. Preparation of 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl-3,5-d 2 )Propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea (compound (S)-3)

[0162]

[0163] step 1)

[0164] Add trifluoroacetic anhydride (1.5 g, 7.41 mmol) to a microwave reaction flask, and slowly add heavy water (15 ml) dropwise therein under an ice-water bath; add compound II-1 (0.8, 2.99 mmol) to the above reaction solution. Under microwave conditions, 160°C, 150Power, react for two hours. After the reaction, the heavy aqueous solution was removed by rotary evaporation, and the same amount of trifluoroacetic anhydride and heavy water as before were added, and exchanged again under the same reaction conditions. After the reaction was completed, the solvent was removed by rotary evaporation, acetone was added to make a slurry, and finally compound II-4 (0.654 g) was obtained by drying under reduced pressure.

[0165] 1 H-NMR (500M, DMSO-d 6 ): δ=11.10(br, 1H), 9.45(br, 1H), 8.51(br, 2H), ...

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Abstract

A novel deuterated urea compound, specifically relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition containing these compounds. Also disclosed are the use of these compounds and pharmaceutical compositions comprising these compounds in the manufacture of a medicament for the treatment of pain.

Description

[0001] Cross References to Related Applications [0002] This application claims the rights and interests of the Chinese invention patent application No. 201710024735.1 submitted to the State Intellectual Property Office of the People's Republic of China on January 13, 2017, the entire content of which is hereby incorporated herein by reference. technical field [0003] The application belongs to the field of medicine, in particular, the application relates to novel deuterated urea compounds, their preparation methods and pharmaceutical compositions containing these compounds. The present application also relates to the use of these compounds and pharmaceutical compositions containing these compounds in the preparation of medicines for treating pain. Background technique [0004] Opioids are alkaloids extracted from opium (poppy) and their derivatives in vivo and in vitro. They interact with central specific receptors to relieve pain and produce a sense of well-being. These...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/54A61K31/17A61K31/381A61P25/04
CPCA61K31/17A61K31/381A61P25/04C07D233/54
Inventor 张寅生任景高勇
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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