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Compounds for the treatment of metabolic disorders

A compound, a technique of stereochemistry, applied in the field of therapeutic compounds for metabolic diseases

Inactive Publication Date: 2012-02-08
PROSIDION LIMITED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The possibility of using a combination of a GPR119 agonist and a DPP-IV inhibitor has been suggested, 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 two 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

[0169] Materials and methods

[0170] Unless otherwise specified, in SiO 2 (40-60 mesh) for column chromatography. LCMS data were acquired as follows: Atlantis 3 μC 18 Chromatography 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: 0.0-0.3min 100%H 2 O; 0.3-4.25min: Ramp up to 10% H 2 O-90%CH 3 CN; 4.25-4.4min: ramp up to 100% CH 3 CN; 4.4-4.9min: keep at 100% CH 3 CN; 4.9-6.0min: back to 100%H 2 O. Using an electrospray ion source in positive (ES + ) or negative (ES - ) mass spectra were acquired in ion mode.

[0171] LCMS data (method 2) were acquired as follows: a Chromolith SpeedROD column (4.6 x 50.0 monolithic, flow = 3.0 mL / min) was washed with 0.1% TFA in H 2 O-CH 3 CN solution was eluted for 3 minutes and detected by UV at 220 nm. Gradient information: 0-2min 99%H 2 O 1% MeCN to 100% MeCN; 2-3min: keep at 100% CH 3 CN. Using an electros...

Embodiment 1

[0453] Example 1: (S)-4-(5-{4-[2-amino-3-(3,3-difluoropyrrolidin-1-yl)-3-oxopropyl]-3-fluorobenzene Base}pyridin-2-yloxy)piperidine-1-carboxylate isopropyl ester

[0454]

[0455] Under argon, (S)-4-(5-{4-[2-tert-butoxycarbonylamino-3-(3,3-difluoropyrrolidin-1-yl)-3-oxopropyl A solution of isopropyl ]-3-fluorophenyl}pyridin-2-yloxy)piperidine-1-carboxylate (Preparation 38, 280 mg, 0.44 mmol) in DCM (5 mL) was cooled to 0 °C. TFA (1 mL) was added and the reaction was stirred at 0 °C for 2 hours. Another portion of TFA (0.5 mL) was added and stirring was continued for 1 hour. React with saturated NaHCO 3 The solution was quenched and the organics were extracted into DCM. The organic phase was washed with brine, dried (MgSO 4 ) and the solvent was removed in vacuo. Purified by column chromatography (SiO 2 , DCM:MeOH, 98:2, 97:3, 95:5, 90:10, 80:20) gave the title compound: RT=3.18min; m / z (ES + )=535.3[M+H] + .

[0456] Using a procedure similar to that outlined in E...

Embodiment 17

[0460] Example 17: (S)-4-(5-{4-[2-amino-3-((S)-3-fluoropyrrolidin-1-yl)-3-oxopropyl]-3-fluoro Phenyl}pyridin-2-yloxy)piperidine-1-carboxylate isopropyl hydrochloride

[0461]

[0462] Under argon, (S)-4-(5-{4-[2-tert-butoxycarbonylamino-3-((S)-3-fluoropyrrolidin-1-yl)-3-oxopropane A solution of isopropyl]-3-fluorophenyl}pyridin-2-yloxy)piperidine-1-carboxylate (Preparation 39, 230 mg, 0.37 mmol) in DCM (4 mL) was cooled to 0 °C. TFA (1 mL) was added and the reaction was stirred for 16 hours. The mixture was diluted with DCM and saturated Na 2 CO 3 solution to adjust the pH. Pass the organic phase through a separatory funnel and remove the solvent in vacuo. Purified by column chromatography (SiO 2 , DCM:MeOH, 100:0, 95:5, 93:7) afforded the title compound as its free base. The product was taken up in 4M HCl in dioxane and stirred at room temperature for 15 minutes. The solvent was removed in vacuo to afford the title compound. RT=2.81min; m / z (ES + )=517.4[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 (I).

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 the needs of the individual patient, but there is a continuing need for new antidiabetic drugs, especially those that are better tolerated and have fewer adverse effects. [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 t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D403/14C07D413/14A61K31/4523A61K31/397A61P3/00
CPCC07D213/64C07D401/12C07D401/14C07D403/14C07D413/14A61P25/00A61P27/02A61P27/16A61P3/00A61P3/04A61P3/06A61P3/08A61P43/00A61P9/10A61P9/12A61P3/10A61K31/4523
Inventor O·巴尔巴P·T·弗里M·C·T·弗雷W·加切尔R·P·吉瓦拉特南T·M·克鲁尔M·J·普罗克特C·P·萨姆布鲁克-斯密斯K·L·斯科菲尔德D·史密斯A·J·W·斯图尔特D·F·斯通豪斯S·A·斯温
Owner PROSIDION LIMITED
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