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Pyrazolo [1,5-A]pyrimidines as inhibitors of stearoyl-coA desaturase

A solvate and alkyl technology, which can be used in medical preparations containing active ingredients, metabolic diseases, cardiovascular system diseases, etc., and can solve problems that have not been shown.

Inactive Publication Date: 2010-08-11
INOVACIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it has not been shown that this compound can modulate the activity of SCD

Method used

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  • Pyrazolo [1,5-A]pyrimidines as inhibitors of stearoyl-coA desaturase
  • Pyrazolo [1,5-A]pyrimidines as inhibitors of stearoyl-coA desaturase
  • Pyrazolo [1,5-A]pyrimidines as inhibitors of stearoyl-coA desaturase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0416] [2-({[6-(3,4-dichlorobenzyl)pyrazolo[1,5-α]pyrimidin-3-yl]carbonyl}-amino)ethyl]carbamate tert-butyl

[0417]

[0418]A solution of 6-(3,4-dichlorobenzyl)pyrazolo[1,5-α]pyrimidine-3-carboxylic acid (Intermediate 8, 45 mg, 0.15 mmol) in DMF (6 mL) was treated with (2-amino Ethyl) tert-butyl carbamate (27 mg, 0.17 mmol) was treated followed by TBTU (57 mg, 0.18 mmol) and triethylamine (18 mg, 0.18 mmol). The mixture was stirred overnight at room temperature, and by preparative HPLC (XTerra C18, 50 mM NH 4 HCO 3 pH 10-CH 3 CN) to obtain the title compound (60 mg, 86%) as a brown solid. Part of the product (5 mg) was prepared by HPLC (ACE C8, 0.1% TFA-CH 3 CN) was repurified to give the title compound (0.2 mg) as a white solid. Calculated value C of MS(ESI+) 21 h 23 Cl 2 N 5 o 3 463.1178, found 463.1177.

Embodiment 2

[0420] 6-(3,4-Dichlorobenzyl)-N-{2-[(pyrazin-2-ylcarbonyl)amino]ethyl}pyrazolo[1,5-α]-pyrimidine-3-carboxamide

[0421]

[0422] [2-({[6-(3,4-dichlorobenzyl)pyrazolo[1,5-α]pyrimidin-3-yl]carbonyl}amino)-ethyl]carbamate tert-butyl ester ( Example 1, 60 mg, 0.13 mmol)) was dissolved in a mixture of DCM / TFA (4 mL, 50:50) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give 2-({[6-(3,4-dichlorobenzyl)pyrazolo[1,5-(3]pyrimidin-3-yl]carbonyl}-amino)ethylammonium ( ethanaminium) trifluoroacetate (45 mg, 95%). Crude trifluoroacetate (15 mg, 0.040 mmol) was dissolved in DMF (2 mL), and 2-pyrazinecarboxylic acid (6.5 mg, 0.050 mmol) Treatment followed by TBTU (17mg, 0.054mmol) and triethylamine (5.4mg, 0.054mmol). The mixture was stirred at room temperature for 3 hours before applying preparative HPLC (ACE C8, 0.1% TFA-CH 3 CN) to obtain the title compound (0.9 mg, 5%) as a white solid. Calculated value C of MS(ESI+) 21 h 17 Cl 2 N 7 o ...

Embodiment 3

[0428] 6-(3,4-Dichlorobenzyl)-N-[2-(methylsulfinyl)ethyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide

[0429]

[0430] 6-(3,4-Dichlorobenzyl)-N-[2-(methylthio)ethyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide (Intermediate 15, 4mg, 0.01 mmol) was dissolved in phenol (0.5 mL) and treated with 30% (w / w) hydrogen peroxide (0.6 μL, 0.02 mmol) for 1 min at room temperature. The reaction mixture was prepared by HPLC (XTerra C18, 50mM NH 4 HCO 3 pH 10-CH 3 CN) to give the title compound (1 mg) as a white solid. Calculated value C of MS(ESI+) 17 h 16 Cl 2 N 4 o 2 S 410.0371, found 410.0366.

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Abstract

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, which are useful as inhibitors of human stearoyl-CoA desaturase (SCD). The invention further relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the treatment or prevention ofmedical conditions in which the modulation of SCD activity is beneficial, such as cardiovascular diseases, obesity, non-insulin-dependentdiabetes mellitus, hypertension, metabolic syndrome, neurological diseases, immunedisorders, cancer and various skin diseases.

Description

technical field [0001] The present invention relates to compounds of formula (I) for use as inhibitors of human stearoyl-CoA desaturase (SCD) activity. The present invention further relates to the use of compounds of formula (I) for the treatment of medical conditions in which modulation of SCD activity is beneficial, such as cardiovascular disease, obesity, non-insulin-dependent diabetes mellitus, hypertension, metabolic Syndrome, neuropathy, immune disorders, cancer and various skin diseases. Background technique [0002] Regulation of cell membrane lipid composition can maintain membrane fluidity. A key enzyme involved in this process is the microsomal stearoyl-CoA desaturase (SCD; Δ9-desaturase; EC 1.14.99.5), which is the limiting factor for the synthesis of monounsaturated fatty acids from saturated fatty acids by cells. Tachyzymes [see eg review in Ntambi (1999) J. Lipid Res. 40, 1549]. The major products of SCD are oleoyl-CoA and palmitoleoyl-CoA, which are formed...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P9/12
CPCC07D487/04A61P17/00A61P17/02A61P17/04A61P17/06A61P25/00A61P3/10A61P35/00A61P3/04A61P37/02A61P43/00A61P9/00A61P9/12
Inventor U·布雷姆伯格A·林登T·伦德巴克J·尼尔森M·威克M·伯格纳P·布兰特K·哈默R·林戈姆
Owner INOVACIA
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