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

AI Technical Summary

Problems solved by technology

[0011] The possibility of 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

[0160] Materials and methods

[0161] Unless otherwise specified, in SiO 2 (40-63 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-MeCN 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% MeCN; 4.25-4.4min: ramp up to 100% MeCN; 4.4-4.9min: keep at 100% MeCN; 4.9-6.0min: return to 100% H 2 O. Using an electrospray ion source in positive (ES + ) or negative (ES - ) mass spectra were acquired in ion mode.

[0162] 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 in 1.5 minutes with UV detection at 215-350 nm. Gradient information: 0-0.8min: 98% MeCN 2% NH 4 HCO 3 to 98% NH 4 HCO 3 2% MeCN; 0.8-1.2min: keep at 98% NH 4 HCO 3 2% MeCN. Using an...

Embodiment 1

[0491]Example 1: 1-[(3S,4S)-4-amino-1-(5-{(R)-3-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]butyl Oxy}pyrimidin-2-yl)pyrrolidin-3-yl]piperidin-2-one

[0492]

[0493] (R)-5-Chloro-2-{4-[1-methyl-3-(2-chloropyrimidin-5-yloxy)-propyl]piperidin-1-yl}pyrimidine (Preparation 4, 160 mg, 0.42 mmol), tert-butyl [(3S,4S)-4-(2-oxopiperidin-1-yl)pyrrolidin-3-yl]carbamate (Preparation 41, 148 mg, 0.53 mmol) and DBU (160 mg, 1.05 mmol) in DMSO (2 mL) was heated to 100° C. for 16 hours. The mixture was diluted with water, then the organics were extracted into DCM (×3) and dried (MgSO 4 ). The solvent was removed in vacuo followed by purification by column chromatography (IH:IPA, 100:0, 85:15) to give [(3S,4S)-1-(5-{(R)-3-[1-(5-chloro tert-butyl carbamate : RT=4.67min; m / z (ES + )=629.3[M+H] + . The residue was dissolved in DCM (5 mL), then TFA (1 mL) was added before the mixture was stirred for 20 min. with saturated Na 2 CO 3 The solution was quenched and the organics were extr...

Embodiment 2

[0494] Example 2: 1-[(3S,4S)-4-amino-1-(5-{(R)-3-[1-(3-isopropyl-[1,2,4]oxadiazole- 5-yl)piperidin-4-yl]butoxy}pyridin-2-yl)pyrrolidin-3-yl]piperidin-2-one p-toluenesulfonate

[0495]

[0496] To (R)-2-bromo-5-{3-[1-(3-isopropyl-[1,2,4]-oxadiazol-5-yl)piperidin-4-yl]butoxy } To a solution of pyridine (preparation 5, 200 mg, 0.47 mmol) in dioxane (5 mL) was added [(3S,4S)-4-(2-oxopiperidin-1-yl)pyrrolidin-3-yl] tert-butyl carbamate (Preparation 41, 160 mg, 0.56 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo-[3.3.3]deca Monoalkane (16.2 mg, 0.05 mmol), potassium tert-butoxide (159 mg, 1.65 mmol) and tris(dibenzylideneacetone)dipalladium (43 mg, 0.05 mmol). Argon was bubbled through the mixture for 30 minutes, then heated at 120° C. for 60 minutes in a microwave reactor. The mixture was diluted with DCM, followed by saturated NaHCO 3 solution, washed with brine, and dried (MgSO 4 ). The solvent was removed in vacuo and the residue was purified by column chroma...

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Abstract

The present invention is directed to therapeutic compounds of the following formula (I) 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 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 triglycer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/506A61P3/10
CPCC07D403/12A61P3/00A61P3/04A61P3/06A61P3/08A61P43/00A61P7/00A61P9/12A61P3/10C07D401/14C07D413/14A61K31/506
Inventor O·巴尔巴T·B·杜普雷P·T·弗里M·C·T·弗雷R·P·吉瓦拉特南T·M·克鲁尔K·L·斯科菲尔德D·史密斯T·斯塔罗斯科A·J·W·斯图尔特D·F·斯通豪斯S·A·斯温D·M·威索尔
Owner PROSIDION LIMITED
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