New compounds v

A technology of compounds and hydrates, applied in the fields of drug combination, organic chemistry, digestive system, etc., can solve problems such as reducing food intake

Inactive Publication Date: 2011-11-16
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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  • New compounds v
  • New compounds v
  • New compounds v

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0247] Pyridin-4-ylmethyl morpholine-4-carboxylate hydrochloride

[0248]

[0249] To a solution of Intermediate 1 (274 mg, 1.00 mmol) in DMF (5 mL) was added DIPEA (0.35 mL, 2.00 mmol) and morpholine (91.8 μL, 1.05 mmol) followed by DMAP (30 mg, catalytic amount). The reaction mixture was stirred overnight at room temperature, then concentrated in vacuo. The residue was purified by normal phase chromatography (gradient elution with MeOH in DCM from 0% to 5%). The obtained residue was dissolved in MeOH (1.0 mL), and added to Et 2 2M HCl in O (0.50 mL, 1.00 mmol). The solution was stirred for 10 minutes and concentrated in vacuo to give pyridin-4-ylmethyl morpholine-4-carboxylate hydrochloride (187 mg, 72%) as a white solid.

[0250] Analytical HPLC: 100% purity (system B, R T =2.84min); Analytical LCMS: 100% purity (system D, R T =3.44min), ES + : 222.9[MH] + ;C 11 h 14 N 2 o 3 HRMS calculated value: 222.1004, found value 222.1008.

Embodiment 2

[0252] (3R)-3-Hydroxypyrrolidine-1-carboxylic acid pyridin-4-ylmethyl ester

[0253]

[0254] (R)-3-Hydroxypyrrolidine (87 mg, 1 mmol), Intermediate 1 (274 mg, 1.0 mmol), DIPEA (354 μL, 2.0 mmol) and DMAP (10 mg, catalytic amount) were dissolved in DMF (5 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The crude product was purified by normal phase chromatography (gradient elution with methanol in DCM from 0% to 5%) followed by preparative HPLC (gradient elution with acetonitrile in water from 5% to 95%) to give a colorless oil (3R)-3-Hydroxypyrrolidine-1-carboxylic acid pyridin-4-ylmethyl ester (65 mg, 29%).

[0255] Analytical HPLC: 100% purity (system B, R T =2.63min); Analytical LCMS: 100% purity (system D, R T =3.21min), ES + : 222.8[MH] + .

Embodiment 3

[0257] (2R,6S)-2,6-Dimethylmorpholine-4-carboxylic acid pyridin-4-ylmethyl ester hydrochloride

[0258]

[0259] To a solution of Intermediate 1 (1.02 g, 3.72 mmol) in DMF (6 mL) was added DIPEA (0.8 mL, 4.6 mmol), DMAP (10 mg, catalytic amount) and cis-2,6-dimethylmorpholine (0.5 mL, 4.1 mmol). The reaction mixture was stirred at room temperature for 7 days, then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with 1M Na 2 CO 3 aqueous solution (4x50mL), dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by normal phase chromatography (gradient eluting with methanol in DCM from 0% to 5%) to give a white solid. Dissolve the solid in Et 2 O and added excess Et 2 2M HCl in O. The resulting precipitate was collected by filtration and washed with Et 2 O washed and dried in vacuo to give (2R,6S)-2,6-dimethylmorpholine-4-carboxylic acid pyridin-4-ylmethyl ester hydrochloride (782 mg, 73%) as a white powder.

[0260] Analytic...

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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 derivatives, pharmaceutical compositions comprising these compounds and the use of these compounds as mimetics of leptin receptor modulators for the manufacture of medicaments targeting disease. 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 has been demonstrated that obese individuals have a reduced proportion of circu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4439A61K31/4545A61K31/496A61K31/5377C07D213/30C07D213/40C07D401/12C07D413/12A61P3/00
CPCC07D413/12C07D213/30C07D401/12C07D213/40A61P1/16A61P13/12A61P15/00A61P15/08A61P17/00A61P17/02A61P25/02A61P27/02A61P29/00A61P3/00A61P3/02A61P3/04A61P35/00A61P3/06A61P37/04A61P43/00A61P5/02A61P5/50A61P7/00A61P9/00A61P9/10A61P9/12A61P9/14A61P3/10
Inventor M·希金博顿I·辛普森J·霍顿C·泰扎克A·V-A·霍根E·钱普曼
Owner ASTRAZENECA AB
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