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Piperidine gpcr agonists

A SO2R5, SO2CH3 technology, applied in the fields of metabolic diseases, drug combination, organic chemistry, etc.

Inactive Publication Date: 2010-01-06
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 are insufficient to address dyslipidaemia and hyperglycemia in a significant proportion of patients

Method used

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  • Piperidine gpcr agonists
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  • Piperidine gpcr agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0170] Example 1: 2-{3-[1-(3-isopropyl[1,2,4]oxadiazol-5-yl)piperidin-4-yl]propoxy}-5-methylsulfonyl Pyridine

[0171]

[0172] Under an argon atmosphere, to 3-[1-(3-isopropyl[1,2,4]oxadiazol-5-yl)piperidin-4-yl]propan-1-ol (Preparation 4,159mg, 0.628mmol) in anhydrous THF (5mL) was added sodium hydride (60% suspension in mineral oil, 34.3mg, 0.857mmol), and the mixture was stirred for 15min, followed by the addition of 2-fluoro-5-methylsulfonylpyridine (Preparation 6,100 mg, 0.571 mmol). The reaction mixture was stirred for 20h, then the solvent was removed in vacuo, and then the residue was dissolved in CH 2 Cl 2 Partition between (30mL) and water (30mL), use CH 2 Cl 2 (30mL) Back extract this aqueous phase. The organic extract is collected through a hydrophobic glass frit, and then the solvent is removed in vacuo to obtain a residue. The residue is obtained by flash chromatography (SiO 2 ) The residue was purified and eluted with 40% EtOAc and 60% IH to obtain the title comp...

Embodiment 2

[0173] Example 2: 2-{(R)-3-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]butoxy}- 5-methylsulfonylpyridine

[0174]

[0175] Make (R)-3-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]butan-1-ol (Preparation 12) and 2 -Fluoro-5-methylsulfonylpyridine (Preparation 6) is reacted to obtain the title compound: δ H (CDCl 3 ) 0.99 (d, 3H), 1.31 (d, 6H), 1.33-1.80 (m, 7H), 1.92-2.01 (m, 1H), 2.92 (septet, 1H), 2.99-3.10 (m, 2H), 3.11 (s, 3H), 4.19-4.25 (m, 2H), 4.40-4.56 (m, 2H), 6.85 (d, 1H), 8.04 (dd, 1H), 8.76 (dd, 1H); RT = 3.77min ; M / z(ES + )=422.94[M+H] + .

[0176] The compounds shown in Table 1 were also prepared using the method described in Example 1 from the appropriate alcohol and 2-fluoropyridine.

[0177] Table 1

[0178]

Embodiment 7

[0179] Example 7: N-((R)-2-hydroxy-1-methylethyl)-6-{3-[1-(3-isopropyl-[1,2,4]oxadiazole-5 -Yl)-piperidin-4-yl]propoxy}nicotinamide

[0180]

[0181] Add 6-{3-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yl]-propoxy}nicotinic acid (preparation 13, 100mg , 270μmol), EDCI (61mg, 320μmol), HOBt (44mg, 320μmol) and DIPEA (141μL, 810μmol) in anhydrous DMF (3mL) solution was stirred for 30min. (R)-2-Aminopropan-1-ol (21 μL, 270 μmol) was added, and then stirring was continued for 16 hours. In H 2 The reaction mixture was partitioned between O (100 mL) and EtOAc (75 mL). The aqueous phase was further extracted with EtOAc (75 mL), and then NaHCO 3 (10mL) The combined organic extracts were washed with a saturated aqueous solution and then dried (MgSO 4 ). After filtration, solvent evaporation and purification by RP-HPLC, the title compound was obtained: RT = 3.41 min; m / z (ES + )=431.98[M+H] + .

[0182] Using methods similar to those described in Example 7, the amides listed in Ta...

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Abstract

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

Description

Technical field [0001] The present invention relates to G-protein coupled receptor (GPCR) agonists. Specifically, the present invention relates to GPCR agonists that can be used to treat obesity (e.g., as a regulator of satiety), metabolic syndrome, and diabetes. Background technique [0002] Obesity is characterized by an excessive amount of fat tissue relative to body size. Clinically, body fat mass is determined by body mass index (BMI; weight (kg) / height (m) 2 ) Or waist evaluation. When an individual's BMI is higher than 30, and has proven medical consequences of being overweight, it is considered obese. Weight gain, especially weight gain caused by abdominal fat, is associated with diabetes, high blood pressure, heart disease and many other health complications such as arthritis, stroke, gallbladder disease, muscle and breathing problems, back pain and even certain cancers The increased risk is related, which has been a recognized medical opinion for some time. [0003] P...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61K31/454A61P3/04A61P3/10
Inventor L·S·伯特伦M·C·T·法伊夫R·P·吉瓦拉特纳姆J·凯利S·A·斯温
Owner PROSIDION LIMITED