Heterocyclic Gpcr agonists

A heterocyclic group, heteroaromatic ring technology, applied in the field of treatment of obesity and metabolic syndrome, GPR119 agonist, can solve problems such as insufficient treatment of dyslipidemia

Inactive Publication Date: 2009-06-17
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 diab

Method used

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  • Heterocyclic Gpcr agonists
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  • Heterocyclic Gpcr agonists

Examples

Experimental program
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preparation example Construction

[0122] Further details on the preparation of compounds of formula (I) are found in the Examples.

[0123] 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.

[0124] 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 1

[0221] Example 1: 4-{2-[3-(3-fluoro-4-methylthiophenyl)-[1,2,4]oxadiazol-5-yl]-1-methylethyl}piper tert-butyl pyridine-1-carboxylate

[0222]

[0223] A stirred solution of 3-fluoro-N-hydroxy-4-methylthiobenzamidine (200 mg, 1 mmol) in anhydrous THF (10 mL) was treated with sodium hydride (33.3 mg, 832 μmol). After 40 min, a solution of tert-butyl 4-(2-ethoxycarbonyl-1-methylethyl)piperidine-1-carboxylate (249 mg, 832 μmol) in anhydrous (3 mL) THF was added, and the mixture was heated under reflux for 18 h. The solvent was removed and the residue was purified by column chromatography (IH-EtOAc 4:1) to afford the title oxadiazole: δ H (CDCl 3 )0.99(d, 3H), 1.22-1.31(m, 2H), 1.39-1.45(m, 1H), 1.47(s, 9H), 1.68(br d, 2H), 2.08(m, 1H), 2.53( s, 3H), 2.66(m, 2H), 2.80(dd, 1H), 3.00(dd, 1H), 4.18(m, 2H), 7.31(t, 1H), 7.74(dd, 1H), 7.84(dd , 1H).

Embodiment 2

[0224] Example 2: 4-{2-[3-(3-fluoro-4-methylthiophenyl)-[1,2,4]oxadiazol-5-yl]propyl}piperidine-1-carboxy tert-butyl acid

[0225]

[0226] Using a method similar to that in Example 1, 3-fluoro-N-hydroxyl-4-methylthiobenzamidine was reacted with tert-butyl 4-(2-methoxycarbonylpropyl)piperidine-1-carboxylate , to obtain the title oxadiazole: RT=4.45min; m / z (ES + )=436.1[M+H] + .

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Abstract

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

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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IPC IPC(8): C07D413/06C07D413/12C07D413/14A61K31/422
Inventor L·S·伯特伦M·C·T·法伊夫M·J·普罗克特G·M·威廉斯
Owner PROSIDION LIMITED
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