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Heterocyclic gpcr agonists

A nitrogen heterocycle, heteroaryl technology, applied in the field of GPR119 agonists, can solve the problems of insufficient treatment of dyslipidemia and hyperglycemia

Inactive Publication Date: 2011-07-20
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 fail to adequately treat dyslipidemia and hyperglycemia in a high proportion of patients

Method used

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  • Heterocyclic gpcr agonists
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Experimental program
Comparison scheme
Effect test

preparation example Construction

[0138] Processes for the preparation of compounds of general formula (I) as described above also represent a further aspect of the invention.

[0139] As indicated above, the compounds of general formula (I) are useful as GPR119 agonists, eg for the treatment and / or prevention of obesity and diabetes. For such use, the compounds of general formula (I) are usually administered in the form of pharmaceutical compositions.

[0140] The present invention also provides the compound of general formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicine.

[0141] The present invention also provides a pharmaceutical composition comprising a compound of general formula (I) in combination with a pharmaceutically acceptable carrier.

[0142] Preferably, the composition consists of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of the compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0143] Moreo...

Embodiment 1

[0335] Example 1: tert-butyl 4-{3-[3-fluoro-4-(5-methyltetrazol-1-yl)phenoxy]propyl}piperidine-1-carboxylate

[0336]

[0337] DIAD (335 μL, 1.70 mmol) was added to stirred 3-fluoro-4-(5-methyl-tetrazol-1-yl)phenol (Preparation 5, 150 mg, 773 μmol), tert-butyl 4-(3 -Hydroxypropyl)piperidine-1-carboxylate (207mg, 850μmol) and PPh 3 (264 mg, 1.00 mmol) in THF (7 mL) and the resulting solution was stirred at ambient temperature for 3.5 hours. add additional PPh 3 (80 mg, 309 μmol), stirring was continued at ambient temperature for 1.5 hours, then the reaction mixture was concentrated in vacuo. Purification by RP-HPLC afforded the title compound: RT = 4.13 min; m / z (ES + )=420.14[M+H] + (Method A).

Embodiment 2

[0338] Example 2: 4-{3-[3-fluoro-4-(3-methyl-[1,2,4]oxadiazol-5-yl)phenoxy]propyl}piperidine-1-carboxylic acid Isopropyl ester

[0339]

[0340] NaH (60%, 24.0 mg, 572 μmol, washed with IH) was added to a solution of N-hydroxy-acetamidine (40.0 mg, 630 μmol) in THF (4 mL), and the resulting solution was stirred at ambient temperature for 10 min. Add isopropyl 4-[3-(3-fluoro-4-methoxycarbonylphenoxy)propyl]piperidine-1-carboxylate (Preparation 6, 200 mg, 520 μmol) in THF (4 mL) and The resulting solution was stirred at temperature for 20 hours. with H 2 O quenched the reaction, diluted with EtOAc and washed the organic layer with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc-IH, 1:9 to 1:4) afforded the title compound: RT = 4.09 min; m / z (ES + )=406.10[M+H] + (Method A).

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Abstract

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

Description

technical field [0001] The present invention is directed to G protein coupled receptor (GPCR) agonists. In particular, the invention is directed to GPR119 agonists for use in the treatment of obesity, for example as a modulator of satiety, metabolic syndrome, and in the treatment of diabetes. Background technique [0002] Obesity is characterized by excess adipose tissue mass relative to body size. Clinically, by body mass index (BMI; weight (kg) / height (m) 2 ) or waist circumference to assess body fat mass. An individual is considered obese when the BMI is above 30, and being overweight has established medical consequences. For some time it has been accepted medical opinion that increased body weight (especially due to abdominal body fat) is associated with increased risk of diabetes, high blood pressure, heart disease, and many other health complications such as Arthritis, stroke, gallbladder disease, muscle and respiratory problems, back pain, and even some cancers. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/32C07D401/04C07D401/12C07D413/04C07D413/12C07D413/14A61K31/4525A61K31/454A61K31/4545A61P3/04A61P3/10
CPCC07D401/14C07D401/12C07D417/14C07D413/04C07D413/14C07D295/205C07D413/12C07D401/04A61P3/00A61P3/04A61P3/06A61P3/10A61P9/12
Inventor L·S·伯伦特P·G·克拉克G·J·道森P·T·弗赖伊M·C·T·法伊夫W·格特里尔R·P·吉瓦兰特纳姆J·凯利T·M·克鲁利M·J·普罗克特C·M·拉塞米森C·P·塞姆布鲁克-史密斯S·A·斯温A·J·W·斯图尔特
Owner PROSIDION LIMITED
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