G-protein coupled receptor(GPR116) agonists and use thereof for treating obesity and diabetes
A compound, CR1 technology, applied in the direction of drug combination, active ingredient of heterocyclic compounds, metabolic diseases, etc., can solve problems such as blood lipid disorder and hyperglycemia that have not been fully resolved
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Embodiment 1
[0187] Example 1: tert-butyl 4-(3-pyridin-4-ylpropylsulfanylcarbonyl)piperidine-1-carboxylate
[0188]
[0189] A mixture of 1-(tert-butoxycarbonyl)hexahydroisonicotinic acid (90 mg, 390 μmol) and EDCI (94 mg, 490 μmol) in anhydrous dichloromethane (3 mL) was stirred for 30 minutes, then added to anhydrous dichloromethane DMAP (8 mg, 65 μmol) and 3-pyridin-4-ylpropan-1-thiol (50 mg, 326 μmol) in (1 mL) were treated. After 20 h, the reaction mixture was concentrated to about 1 mL, then Et 2 O (2 mL). The solvent was decanted from the resulting cement and the cement was chromatographed (Et 2 O), the title compound was obtained: RT=3.49min; m / z (ES + )=365.0[M+H] + .
[0190] The compounds shown in Table 2 were prepared by using a protocol similar to that described in Example 1 and condensing the thiol or alcohol with the appropriate acid.
[0191] Table 2
[0192]
[0193]
Embodiment 20
[0194] Example 20: (E)-tert-butyl 4-[methyl(3-pyridin-4-ylacryloyl)amino]piperidine-1-carboxylate
[0195]
[0196] (E)-3-pyridin-4-ylacrylic acid (100mg, 671μmol), EDCI (133mg, 671μmol), HOBt (91mg, 671μmol), Net 3 (94 μL, 671 μmol) and anhydrous dichloromethane (3 mL) were stirred for 20 minutes, then treated with 1-tert-butoxycarbonyl-4-methylaminopiperidine (131 mg, 610 μmol). After 3 days, the reaction mixture was diluted with dichloromethane (2 mL), then water (10 mL), saturated NaHCO 3 (10 mL) aqueous solution and brine (10 mL) washed. The dichloromethane solution was dried (MgSO 4 ), filtered and concentrated. The residue was purified by RP-HPLC to afford the title compound: RT = 2.81 min; m / z (ES + )=346.2[M+H] + .
[0197] Compounds shown in Table 3 were prepared using a protocol similar to that described in Example 20 to condense the appropriate acid with an amine.
[0198] table 3
[0199]
Embodiment 26
[0200] Example 26: tert-butyl 4-(2-pyridin-4-ylethylsulfanylmethyl)piperidine-1-carboxylate
[0201]
[0202] A stirred solution of 2-(4-pyridyl)ethanethiol (213 mg, 1.53 mmol) in anhydrous THF (2 mL) was treated with t-BuOK (63 mg, 0.56 mmol). tert-butyl 4-methanesulfonyloxymethylpiperidine-1-carboxylate (150 mg, 0.51 mmol) was added, and the mixture was stirred at 20° C. for 1 hour, then heated under reflux. After 18 hours, the reaction was cooled to 20°C and washed with Et 2 O (20 mL), washed with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), then dried (MgSO 4 ). Filtration, evaporation of solvent, and column chromatography (EtOAc) gave the title compound: RT = 2.92 min; m / z (ES + )=337.1[M+H] + .
[0203] As exemplified in Example 26, the compounds shown in Table 4 were prepared using t-BuOK-mediated alkylation of pyridine-containing thiols or alcohols with the appropriate piperidine-containing mesylate.
[0204] Table 4
[0205]
[0206] ...
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