Small molecule leptin receptor modulators

A solvate, tautomer technology, applied in the field of small molecule leptin receptor modulators, can solve problems such as reducing food intake

Inactive Publication Date: 2011-08-17
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This sequence was shown to reduce food intake when injected with ICV, whereas the sequence taken from the C-terminus showed no effect

Method used

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  • Small molecule leptin receptor modulators
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  • Small molecule leptin receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0234] 2-Piperazin-1-ylethyl {(1S)-1-(4-hydroxybenzyl)-2-[methyl(3-methylbutyl)amino]-2-oxoethyl}carbamate Dihydrochloride

[0235]

[0236] (S)-1-(carboxy)-2-(4-tert-butoxyphenyl)ethylcarbamate 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl ester (intermediate Enzyme 1; 415 mg, 0.84 mmol), N-methylisoamylamine (85 mg, 0.84 mmol) and DIPEA (0.40 mL, 2.30 mmol) were dissolved in DMF (10 mL), then cooled in an ice-water bath. PyBrOP (400 mg, 0.86 mmol) was added. The reaction mixture was stirred at 0 °C for 6 hours, then allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was suspended in 0.2M aqueous HCl (50 mL) and extracted with DCM (3 x 50 mL). The combined DCM extracts were dried (MgSO 4 ), concentrated in vacuo and purified by reverse phase chromatography to give (S)-1-(N-isopentyl-N-methylcarbamoyl)-2-(4-tert-butoxyhydroxyphenyl)ethylamino 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl formate (262 mg, 54%) a...

Embodiment 2

[0239] [(1S)-2-[Benzyl(methyl)amino]-1-(4-hydroxybenzyl)-2-oxoethyl]carbamate 2-piperazin-1-ylethyl ester dihydrochloride

[0240]

[0241] (S)-1-(carboxy)-2-(4-tert-butoxyphenyl)ethylcarbamate 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl ester (intermediate Body 1; 378 mg, 0.77 mmol), N-methylbenzylamine (95 mg, 0.75 mmol), PyBrOP (360 mg, 0.77 mmol) and DIPEA (0.40 mL, 2.30 mmol) were dissolved in DMF (10 mL) cooled with ice water . The reaction mixture was stirred overnight, then concentrated in vacuo. Suspend the residue in 6% NaHCO 3 in aqueous solution (50 mL) and extracted with DCM (3 x 50 mL). The combined DCM extracts were dried (MgSO 4) and concentrated in vacuo. Purification of the residue by normal phase chromatography (gradient elution with MeOH in DCM from 0% to 10%) followed by reverse phase chromatography afforded (S)-1-(N-benzyl-N-methylaminomethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-(4-tert-butoxyphenyl)ethylcarbamate (164 mg, 35%), y...

Embodiment 3

[0244] {(1S)-1-(4-Hydroxybenzyl)-2-[methyl(2-phenylethyl)amino]-2-oxoethyl}carbamic acid 2-piperazin-1-ylethyl ester di Hydrochloride

[0245]

[0246] (S)-1-(carboxy)-2-(4-tert-butoxyphenyl)ethylcarbamate 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl ester (intermediate Body 1; 404mg, 0.82mmol), N-methylphenethylamine (120mg, 0.89mmol), PyBrOP (390mg, 0.84mmol) and DIPEA (0.4mL, 2.3mmol) were dissolved in DMF (10mL )middle. The reaction mixture was stirred overnight then concentrated in vacuo. Suspend the residue in 6% NaHCO 3 in aqueous solution (50 mL) and extracted with DCM (3 x 50 mL). The combined DCM extracts were dried (MgSO 4 ) and concentrated in vacuo. Purification of the residue by reverse phase chromatography gave (S)-1-(N-methyl-N-phenethylcarbamoyl)-2-(4-tert-butoxyphenyl)ethylcarbamate 2-( 4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl ester (257 mg, 51%) as a yellow gum. All of this material (257 mg, 0.42 mmol) was dissolved in DCM (10 mL), treated wi...

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Abstract

The present invention relates to new compounds of formula (I), to pharmaceutical compositions comprising these compounds and to the use of these compounds as leptin receptor modulator mimetics in the preparation of medicaments against conditions associated with weight gain, type 2 diabetes and dyslipidemias.

Description

field of invention [0001] The present application relates to novel pyridine and piperazine derivatives, pharmaceutical compositions comprising these compounds and the use of these compounds as leptin receptor modulator mimetics for the preparation of medicaments for the treatment of weight gain, type 2 diabetes and Dyslipidemia-related disorders. Background technique [0002] Obesity is a growing epidemic in the industrialized world. Often, first-line treatment is to provide patients with dietary and lifestyle advice, such as reducing the fat content of their diet and increasing their physical activity. However, some patients may also require drug therapy to maintain the beneficial results from the dietary and lifestyle changes described above. [0003] Leptin is a hormone synthesized in adipocytes that is thought to act in the hypothalamus to reduce food intake and reduce body weight (see e.g. Bryson, J.M. (2000) Diabetes, Obesity and Metabolism 2:83- 89). [0004] It h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/30C07D405/12C07D413/12C07D295/088A61K31/495A61P3/04
CPCC07D413/12C07D213/30C07D405/12C07D295/088A61P1/16A61P3/00A61P3/04A61P3/06A61P3/10A61P9/00A61P9/10A61P9/12A61P13/12A61P15/08A61P17/00A61P17/02A61P25/02A61P27/02A61P29/00A61P37/00A61P37/02
Inventor I·辛普森M·希金博顿E·钱普曼A·V-A·霍根
Owner ASTRAZENECA AB
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