GPCR agonists
A technology of CH2 and NR1R11, applied in the field of peripheral regulators and G-protein coupled receptor agonists, can solve problems such as dyslipidemia and hyperglycemia that cannot be fully resolved
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[0141] Further details of the preparation of compounds of formula (I) are found in the Examples.
[0142] Compounds of formula (I) may 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 using solution or solid phase chemistry, by combinatorial "split and mix" methods or by multiple parallel synthesis using methods known to those skilled in the art.
[0143] During 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 stage of the synthesis of compounds of formula (I), or may be present on the final compound of formula (I). A comprehensive review of the methods by which the various labile functional groups can be protected, as well as methods for cleaving the resulting protected derivatives, is fou...
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[0193] Materials and methods
[0194] Unless otherwise stated, the SiO 2 (40-63 mesh) for column chromatography. LCMS data were obtained as follows: Atlantis 3 μC 18 Column (3.0×20.0mm, flow rate=0.85L / min), with 0.1% HCO 2 H of H 2 O-CH 3 CN solution was eluted for 6 min with UV detection at 220 nm. Gradient information: 0.0-0.3 minutes at 100% H 2 O; 0.3-4.25 min: Gradient to 10% H 2 O-90%CH 3 CN; 4.25-4.4 min: Gradient up to 100% CH 3 CN; 4.4-4.9 minutes: keep at 100% CH 3 CN; 4.9-6.0 minutes: return to 100% H 2 O. Positive (ESI + ) or negative (ESI - ) ion mode to acquire mass spectra.
[0195]Abbreviations and abbreviations: Ac: acetyl; n-Bu: n-butyl; t-Bu: tert-butyl; dba: dibenzylidene acetone; DBU: 1,8-diazabicyclo [5.4.0] ten One-7-ene; DME: 1,2-dimethoxyethane; DMF: dimethylformamide; Et: ethyl; HATU: O-(7-azabenzotriazol-1-yl) -N, N, N', N-tetramethyluronium hexafluorophosphate; HBTU: O-benzotriazol-1-yl-N, N, N', N-tetramethyluronium hexafluorophosp...
preparation example 1
[0197] Preparation 1: 4-[4-(4-Methanesulfonylphenyl)butyl]piperidine
[0198]
[0199] Add trifluoroacetic acid (3.0 mL) to CH 2 Cl 2 In a stirred solution of tert-butyl 4-[4-(4-methanesulfonylphenyl)butyl]piperidine-1-carboxylate (Example 46, 500 mg, 1.27 mmol) in (10 mL). After 0.5 h, the solvent was removed and the residue was in CH 2 Cl 2 (20mL) and saturated Na 2 CO 3 (10 mL) partitioned between aqueous solutions. CH for aqueous phase 2 Cl 2 (20 mL) and re-extracted, the combined organics were washed with brine (10 mL) and dried (MgSO 4 ). Removal of solvent gave the title compound: RT = 2.29 min, m / z (ES + )=296.2[M+H] + .
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