Azetidine derivatives as g-protein coupled receptor (GPR119) agonists

A technology of heterocyclic group and alkyl group, which is applied in the direction of drug combination, medical preparations containing active ingredients, metabolic diseases, etc., and can solve problems such as insufficient treatment of dyslipidemia

Inactive Publication Date: 2009-06-24
PROSIDION LIMITED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Drugs targeting the pathophysiology associated with insulin-dependent type 1 diabetes and non-insulin-dependent type 2 diabetes have many potential side effects and do not adequately address dyslipidemia and hyperglycemia in a high proportion of patients

Method used

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  • Azetidine derivatives as g-protein coupled receptor (GPR119) agonists
  • Azetidine derivatives as g-protein coupled receptor (GPR119) agonists
  • Azetidine derivatives as g-protein coupled receptor (GPR119) agonists

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preparation example Construction

[0107] Further details on the preparation of compounds of formula (I) are found in the Examples.

[0108] Compounds of formula (I) can be prepared individually or as a compound library comprising at least 2, eg 5-1000 compounds of formula (I), more preferably 10-100 compounds of formula (I). Compound libraries can be prepared by combinatorial "split and mix" methods or multiple parallel syntheses using solution or solid phase chemistry using methods known to those skilled in the art.

[0109] In the synthesis of compounds of formula (I), labile functional groups such as hydroxyl, carboxyl and amino groups in intermediate compounds may be protected. Protecting groups may be removed at any step in the synthesis of compounds of formula (I), or present on the final compound of formula (I). An extensive discussion of the methods by which various labile functional groups can be protected and the methods for cleaving the resulting protected derivatives can be found, for example, in ...

Embodiment

[0157] LCMS protocol:

[0158] Waters Xterra MS C18, 5 μm (4.6 x 50 mm, flow rate 1.5 mL / min), in 12 min with 0.1% (v / v) ammonium in H 2 O-MeCN gradient elution with UV detection at 215 and 254 nm. Gradient information: 0.0-8.0min: from 95% H 2 O-5% MeCN up to 5% H 2 O-95% MeCN; 8.0-9.9min: keep at 5% H 2 O-95% MeCN; 9.9-10.0min: back to 95% H 2 O-5% MeCN; 10.0-12.0min: keep at 95% H 2 O-5% MeCN. Using positive ion (ESI + ) or anion (ESI - ) mode electrospray ionization source to obtain mass spectra.

[0159] Preparative LCMS protocol:

[0160] The gradient used for mass spectrometry-guided HPLC purification was as follows: Waters Xterra MSC18, 5 μm (19 x 50 mm, flow rate 25 mL / min) in 10 min with 0.1% (vol / vol) ammonium in H 2 O-MeCN gradient elution with UV detection at 215 and 254 nm. 0.0-0.50min: keep at 95%H 2 O-5% MeCN; 0.5-7.5min: from 95% H 2 O-5% MeCN up to 5% H 2 O-95% MeCN; 7.5-8.4min: keep at 5% H 2 O-95% MeCN; 8.4-8.5min: back to 95% H 2 O-5% MeCN;...

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Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof, are agonists of GPR119 and are useful for the treatment of diabetes and as peripheral regulators of satiety, e.g. for the treatment of obesity and metabolic syndrome.

Description

Background of the invention [0001] The present invention relates to G protein coupled receptor (GPCR) agonists. In particular, the invention relates to GPR119 agonists, which are useful in the treatment of obesity (eg as satiety regulators), metabolic syndrome and diabetes. [0002] Obesity is characterized by excess adipose tissue mass relative to body size. Clinically, body fat mass is measured by body mass index (BMI; weight (kg) / height (m) 2 ) or waist circumference. An individual is considered obese when their BMI is greater than 30 and there are established medical consequences of being overweight. It has been medically accepted for some time that weight gain, especially from abdominal body fat, is associated with diabetes, high blood pressure, heart disease, and many other health complications such as arthritis, stroke, gallbladder disease, muscle and respiratory Disease, back pain and even an increased risk of some cancers. [0003] Pharmacological approaches to t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/04C07D401/12C07D401/14C07D405/14A61K31/435A61K31/495A61P3/00
CPCC07D401/14C07D401/12C07D405/14C07D205/04A61P3/00A61P3/04A61P3/06A61P3/10A61P9/12A61P43/00A61K31/435
Inventor M·C·T·法伊夫W·加特赖尔C·M·拉沙米熊
Owner PROSIDION LIMITED
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