Compound with substituted cyclobutane structure, production method and medicine use thereof

A kind of technology of cyclobutane and compound, applied in a kind of compound with substituted cyclobutane structure, and the field of preparation and medical use thereof

Inactive Publication Date: 2008-06-11
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Except for GLP-1 and its peptide analogues, there are no reports on the successful development of non-peptide small molecule GLP-1R agonists

Method used

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  • Compound with substituted cyclobutane structure, production method and medicine use thereof
  • Compound with substituted cyclobutane structure, production method and medicine use thereof
  • Compound with substituted cyclobutane structure, production method and medicine use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] Embodiment 1: the preparation of compound GLP-A-1

[0164] NMR calibration: δH 2.50ppm (DMSO-d 6 ).

[0165]

[0166] Compound 0601 (1 g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, added 1 ml of water, and continued to irradiate for 25-30 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-A-1 was obtained as light yellow powdery solid.

[0167] 1 HNMR (300MHz, DMSO-d 6 ) 10.118 (2H, br.s), 8.615 (2H, br.s), 8.095 (2H, dd, J 1 = 4.8Hz,J 2 =1.2Hz), 8.027(2H,dd,J 1 =3.9Hz,J 2= 1.5Hz), 7.569 (4H, d, J = 8.4Hz), 7.365 (4H, d, J = 8.7Hz), 7.318 (2H, dd, J 1 =3.9Hz,J 2 =5.1Hz), 7.280(2H, m), 7.260(2H, m), 7.203(2H, br.d, J=8.1Hz), 4.981(2H, s), 3.228(6H, s), 2.015(6H , s).

Embodiment 2

[0168] Embodiment 2: the preparation of compound GLP-A-2

[0169] NMR calibration: δH 2.50ppm (DMSO-d 6 ).

[0170]

[0171] Compound 0602 (10 g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, added 1 ml of water, and continued to irradiate for 25-30 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-A-2 was obtained as light yellow powdery solid.

[0172] 1 H NMR (300MHz, DMSO-d 6 )δ8.770 (2H, br.s), 8.090 (2H, d, J=5.1Hz), 8.026 (2H, d, J=3.9Hz), 7.2-7.5 (18H, m), 5.011 (2H, s ), 3.231 (6H, s).

Embodiment 3

[0173] Embodiment 3: the preparation of compound GLP-B-1

[0174] NMR calibration: δH 2.50ppm (DMSO-d 6 ).

[0175]

[0176] Compound 0603 (1.5g) was dissolved in an appropriate amount of DMSO, placed under a 150W high-pressure mercury lamp for 3 days of irradiation, added 1ml of water, and continued to irradiate for 25-30 days, during which the reaction was detected and followed by HPLC. After the reaction was completed, the solvent was removed by lyophilization, and the residue was separated by reverse phase silica gel column chromatography. Compound GLP-B-1 was obtained as light yellow powdery solid.

[0177] 1 H NMR (300MHz, DMSO-d 6 )δ9.532 (2H, br.s), 8.433 (2H, br.s), 7.534 (4H, m), 7.428 (4H, d, J=8.7Hz), 7.329 (4H, d, J=8.4Hz ), 7.234 (6H, m), 4.912 (2H, s), 1.453 (18H, s).

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PUM

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Abstract

The invention provides a compound with substituted cyclobutane structure represented as formula I or II, a relative preparation method, and an application of being glucagon-like peptide-1 receptor modulator to prevent and / or treat metabolic disorder (as diabetes, insulin resistance and obesity or the like), cardiovascular disease and neurodegenerative disease (as Alzheimer's) or the like.

Description

technical field [0001] The present invention relates to a class of compounds with a substituted cyclobutane structure, a preparation method and its role as a regulator of glucagon like peptide-1 receptor (GLP-1R) in preventing and / or treating metabolic disorders Medical applications for diseases (including but not limited to diabetes, insulin resistance, obesity, etc.), cardiovascular diseases, neurodegenerative diseases (such as Alzheimer's disease), etc. Background technique [0002] Glucose metabolism disorder, especially diabetes, has become a major disease that seriously threatens human health and life in modern society. It is predicted that diabetes patients in the world are increasing at an annual rate of 6%, and by the end of 2006 there were 320 million patients (60 million people in my country, ranking second). Diabetes mellitus is a group of clinical syndromes caused by the interaction of genetic and environmental factors. It is mainly divided into type 1 and type...

Claims

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Application Information

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IPC IPC(8): C07D333/40C07D333/14C07C233/87A61K31/381A61P3/00A61P9/00A61P25/28
CPCC07C233/81C07C237/42C07D409/12C07C2101/02C07D333/40C07C271/28C07D333/20C07C2101/04A61P3/00A61P3/04A61P3/10A61P5/48A61P9/00A61P25/28C07C2601/02C07C2601/04
Inventor 王明伟李娜刘青林黎琳张月云廖嘉渝
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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