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Compounds for the treatment of metabolic disorders

A compound, haloalkyl technology, applied in the field of therapeutic compounds for metabolic diseases

Inactive Publication Date: 2012-03-28
PROSIDION LIMITED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The possibility of combining a GPR119 agonist and a DPP-IV inhibitor has been proposed, however this requires the administration of two separate formulation products or a co-formulation of the two active ingredients to the patient, with the inherent problem of achieving both. Compatibility of active ingredients in terms of physicochemical, pharmacokinetic and pharmacodynamic properties

Method used

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  • Compounds for the treatment of metabolic disorders
  • Compounds for the treatment of metabolic disorders
  • Compounds for the treatment of metabolic disorders

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0166] Materials and methods

[0167] Unless otherwise specified, in SiO 2 (40-63 mesh) for column chromatography. LCMS data were acquired as follows: Atlantis 3 μC 18 Column (3.0 × 20.0mm, flow rate = 0.85mL / min) with 0.1% HCO 2 H of H 2 O-CH 3 CN solution was eluted for 6 minutes and detected by UV at 220 nm. Gradient information: 0.0-0.3 minutes 100% H 2 O; 0.3-4.25 minutes: ramp up to 10% H 2 O-90% MeCN; 4.25-4.4 minutes: ramp up to 100% MeCN; 4.4-4.9 minutes: hold at 100% MeCN; 4.9-6.0 minutes: return to 100% H 2 O. Mass spectra were acquired using an electrospray ionization source in positive (ES+) or negative (ES-) mode.

[0168] LCMS-method 2 data acquisition is as follows: Xbridge C18 column (2.1 × 50mm, 2.5μM, flow rate 0.8mL / min) with MeCN-10mM NH 4 HCO 3 The solution was eluted for 1.5 minutes and detected by UV at 215-350 nm. Gradient information: 0-0.8 minutes: 98% MeCN 2% NH 4 HCO 3 to 98% NH 4 HCO 3 2% MeCN; 0.8-1.2 minutes: keep at 98% NH 4 H...

preparation example 1

[0174] Preparation 1: tert-butyl 4-[5-(6-chloropyridin-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylate

[0175]

[0176] To a solution of 6-chloronicotinic acid (500 mg, 3.17 mmol) in THF (25 mL) was added EDCI (0.74 g, 3.89 mmol) followed by HOBt (583 mg, 3.81 mmol) and the reaction was stirred at room temperature for 10 minutes. tert-Butyl 4-(N-hydroxyamidinomethoxy)piperidine-1-carboxylate (866 mg, 3.17 mmol) was added and the reaction was stirred at room temperature for 16 hours before the solvent was removed in vacuo. The resulting residue was partitioned between EtOAc (100 mL) and water (50 mL). The organic phase was separated and washed with saturated NaHCO 3 solution, then brine and dried (MgSO 4 ), and the solvent was removed in vacuo. The residue was dissolved in toluene and the reaction was heated to 110 °C for 16 hours. The solvent was removed in vacuo and purified by column chromatography (IH:EtOAc, 70:30) to give the title compound: RT = 3.97 m...

preparation example 2

[0177] Preparation 2: tert-butyl 4-[5-(2-chloropyrimidin-5-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylate

[0178]

[0179] To a solution of 2-chloropyrimidine-5-carboxylic acid (100 mg, 0.63 mmol) in THF (10 mL) was added 1,3-diisopropylcarbodiimide (99 μL, 0.63 mmol) and the reaction was stirred at room temperature for 10 minute. tert-butyl 4-(N-hydroxyamidinomethoxy)piperidine-1-carboxylate (172 mg, 0.63 mmol) was added, and the mixture was stirred at room temperature for 72 hours. The reaction solvent was removed in vacuo, and the resulting residue was redissolved in EtOAc (100 mL). The organic mixture was washed with water, then brine and dried (MgSO 4 ), and the solvent was removed in vacuo. The residue was dissolved in toluene and heated to 80°C for 16 hours. The solvent was removed in vacuo and purified by column chromatography (IH:EtOAc, 60:40) to give the title compound: RT = 3.77 min, m / z (ES + )=396.1[M+H] + .

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Abstract

The present invention is directed to therapeutic compounds which have activity as agonists of GPR119 and are useful for the treatment of metabolic disorders including type II diabetes.

Description

technical field [0001] The present invention relates to therapeutic compounds useful in the treatment of metabolic diseases including type II diabetes. In particular, the present invention relates to compounds having activity as GPR119 agonists. Background technique [0002] Drugs targeting the pathophysiology associated with non-insulin-dependent type II diabetes have many potential side effects and are underutilized for dyslipidemia and hyperglycemia in a high proportion of patients. Treatment typically uses diet, exercise, hypoglycemic agents, and insulin to focus on individual patient needs, but there is a continuing need for new antidiabetic drugs, especially those that have fewer adverse effects and are better tolerated . [0003] Likewise, metabolic syndrome (syndrome X) puts humans at high risk for coronary artery disease and is characterized by a set of risk factors including central obesity (excess fat tissue in the abdomen), glucose intolerance , high triglycer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61K31/4245A61P3/10
CPCC07D413/14A61P3/00A61P3/04A61P3/06A61P3/08A61P43/00A61P9/12A61P3/10A61K31/4427A61K31/4245
Inventor O·巴尔巴S·H·戴维斯M·C·T·法伊夫R·P·吉瓦拉丹K·L·斯科菲尔德T·斯塔罗斯科A·J·W·斯图尔特S·A·斯温D·M·维瑟尔
Owner PROSIDION LIMITED
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