New pyridine derivatives as leptin receptor modulator mimetics

A technology of solvate and pyridine carbamate, applied in anti-inflammatory agents, drug combinations, non-central analgesics, etc., can solve the problems of reducing food intake and having no effect

Inactive Publication Date: 2011-08-03
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 at the C-terminus showed no effect

Method used

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  • New pyridine derivatives as leptin receptor modulator mimetics
  • New pyridine derivatives as leptin receptor modulator mimetics
  • New pyridine derivatives as leptin receptor modulator mimetics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0196] Pyridin-4-ylmethyl Dimethylcarbamate Hydrochloride

[0197]

[0198] To a solution of 4-nitrophenyl(pyridin-4-yl)methyl carbonate (Intermediate 1; 274 mg, 1.00 mmol) in DMF (5 mL) was added DIPEA (182 μL, 1.05 mmol), dimethylamine (2M solution , in THF, 525 μL, 1.05 mmol) and DMAP (30 mg, catalytic). 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 / DCM from 0% to 5%). The residue was dissolved in MeOH (1.0 mL) and washed with 2M HCl in Et 2 O (0.50 mL, 1.0 mmol) solution treatment and vacuum drying afforded (pyridin-4-yl)methyl dimethylcarbamate hydrochloride (133 mg, 61%) as a white solid.

[0199] Analytical HPLC: purity 99.8% (system A, R T =2.85min); Analytical LCMS: purity 100% (system C, R T =3.43min), ES + : 180.8[MH] + ; HRMS: C 9 h 12 N 2 o 2 Calculated value: 180.0899, measured value: 180.0900.

Embodiment 2

[0201] [(2S)-Tetrahydrofuran-2-ylmethyl]pyridin-4-ylmethyl carbamate hydrochloride

[0202]

[0203] To a solution of 4-nitrophenyl(pyridin-4-yl)methyl carbonate (Intermediate 1; 274 mg, 1.00 mmol) in DMF (5 mL) was added DIPEA (182 μL, 1.05 mmol), (S)-(tetrahydrofuran -2-yl)methylamine (108 μL, 1.05 mmol) and 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 / DCM from 0% to 5%). The residue was dissolved in MeOH (1.0 mL) and washed with 2M HCl in Et 2 O (0.50 mL, 1.0 mmol) solution treatment and vacuum drying afforded [(2S)-tetrahydrofuran-2-ylmethyl]pyridin-4-ylmethyl carbamate hydrochloride (110 mg, 41%) as an off-white solid .

[0204] Analytical HPLC: 100% purity (system A, R T =3.07min); Analytical LCMS: purity 99% (system C, R T =3.56min), ES + : 236.8[MH] + ; HRMS: C 12 h 16 N 2 o 3 Calculated value:...

Embodiment 3

[0206] (2-Hydroxyethyl)pyridin-4-ylmethyl carbamate hydrochloride

[0207]

[0208] To a solution of 4-nitrophenyl(pyridin-4-yl)methyl carbonate (Intermediate 1; 274 mg, 1.00 mmol) in DMF (10 mL) was added DMAP (122 mg, 1.0 mmol) and ethanolamine (62 mg, 1.0 mmol) ). The reaction mixture was stirred for 48 hours, then concentrated in vacuo. The residue was purified by normal phase chromatography (eluting with EtOAc), followed by ion exchange chromatography (10 g Strata-SCX, eluting with MeOH, followed by 1% NH 3 / MeOH elution). The residue was dissolved in MeOH (1.0 mL) and washed with 2M HCl in Et 2 O (0.50 mL, 1.0 mmol) was treated with solution and dried in vacuo to give pyridin-4-ylmethyl (2-hydroxyethyl)carbamate hydrochloride (24 mg, 10%) as a white powder.

[0209] Analytical HPLC: 100% purity (system B, R T =5.48min); Analytical LCMS: purity 100% (system E, R T =4.24min), ES + : 196.9[MH] + ; HRMS: C 9 h 12 N 2 o 3 Calculated value: 196.0848, measured va...

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PUM

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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 II 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 leptin receptor modulator mimetics in the preparation of diseases associated with weight gain, type II diabetes and dyslipidemias Uses in medicine. Background technique [0002] The prevalence of obesity is increasing in industrialized societies. Typically, first-line treatment is to provide the patient 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 effects of the dietary and lifestyle changes described above. [0003] Leptin is a hormone synthesized in adipocytes that is believed to act in the hypothalamus to reduce food intake and body weight (see, eg, Bryson, J.M. (2000) Diabetes, Obesity and Metabolism 2:83-89). [0004] The ratio of leptin ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/44A61K31/4409A61K31/443A61K31/4439C07D213/30C07D405/12C07D413/12A61P3/00
CPCC07D405/12C07D413/12C07D213/30A61P1/16A61P3/00A61P3/04A61P3/06A61P3/10A61P5/02A61P5/48A61P5/50A61P7/00A61P9/10A61P9/12A61P9/14A61P13/12A61P15/00A61P15/08A61P17/00A61P17/02A61P25/00A61P25/02A61P27/02A61P29/00A61P37/00A61P37/04A61P43/00
Inventor M·希金博顿I·辛普森J·霍顿C·泰扎克A·V-A·霍根
Owner ASTRAZENECA AB
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