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GPR119 agonist and application thereof

A solvate and selected technology, applied in the field of medicine, can solve the problems of decreased GIP activity, loss of sensitivity, and unclear exact reasons

Active Publication Date: 2013-01-30
BEIJING HANMI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in patients with type 2 diabetes it has been shown that the insulinotropic effect of GIP is decreased, although the insulinotropic effect of GLP-1 is maintained
What is puzzling is that patients with type 2 diabetes still respond well to a large injection of GIP, but lose sensitivity to continuous small injections (Meier et al.2004 Diabetes 53 S220-S224), so the activity of GIP decreases The exact cause of the

Method used

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  • GPR119 agonist and application thereof
  • GPR119 agonist and application thereof
  • GPR119 agonist and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0197] tert-butyl 4-((5-(4-methylsulfonylphenyl)thiazol-2-yloxy)methyl)piperidine-1-carboxylate

[0198]

[0199] Intermediate 1 (200 mg, 0.53 mmol), p-methylsulfonylphenylboronic acid (233 mg, 1.16 mmol), palladium acetate (35 mg, 0.15 mmol), triphenylphosphine (167 mg, 0.63 mol), sodium carbonate (416 mg, 3.92 mmol) were dispersed in 1,4-dioxane (4 ml) / water (1 ml), heated to 80°C under the protection of argon, and stirred for 2 hours , cooled to room temperature, filtered, and the filtrate was concentrated, followed by silica gel column chromatography to obtain a light yellow solid product (140 mg, 58%). 1 H NMR (CDCl 3 )δ (ppm): 7.93 (d, J=8.4Hz, 2H), 7.61 (d, J=8.4Hz, 2H), 7.46 (s, 1H), 4.31 (d, J=6.3Hz, 2H), 4.16 -4.23(m, 2H), 3.07(s, 3H), 2.74(t, J=12.3Hz, 2H), 2.00-2.07(m, 1H), 1.80(d, J=12.6Hz, 2H), 1.46( s, 9H), 1.27-1.35 (m, 2H). MS (m / z) 453 (M+1), 475 (M+23).

Embodiment 2

[0201] tert-butyl 4-((5-(3-fluoro-4-methanesulfonylphenyl)thiazol-2-yloxy)methyl)piperidine-1-carboxylate

[0202]

[0203] Intermediate 1 (80 mg, 0.21 mmol), Intermediate 7 (102 mg, 0.46 mmol), palladium acetate (14 mg, 0.06 mmol), triphenylphosphine (67 mg, 0.25 mmol), carbonic acid Sodium (166 mg, 1.56 mmol) was dispersed in 1,4-dioxane (4 mL) / water (1 mL), heated to 80 ° C under argon protection, stirred for 2 hours, and cooled to room temperature , filtered, and the filtrate was concentrated and then silica gel column chromatography to obtain a white solid product (50 mg, 50%). 1 H NMR (CDCl 3 )δ(ppm): 7.92(t, J=7.8Hz, 1H), 7.47(s, 1H), 7.35(d, J=8.1Hz, 1H), 7.28(d, J=7.8Hz, 1H), 4.32 (d, J=6.6Hz, 2H), 4.14-4.23(m, 2H), 3.23(s, 3H), 2.74(t, J=12.6Hz, 2H), 1.99-2.07(m, 1H), 1.79( d, J=12.3Hz, 2H), 1.46(s, 9H), 1.25-1.33(m, 2H). MS(m / z) 493(M+23).

Embodiment 3

[0205]tert-butyl 4-((5-(4-(tetrazol-1-yl)phenyl)thiazol-2-yloxy)methyl)piperidine-1-carboxylate

[0206]

[0207] Intermediate 1 (48 mg, 0.12 mmol), Intermediate 9 (69 mg, 0.25 mmol), palladium acetate (9 mg, 0.03 mmol), triphenylphosphine (40 mg, 0.15 mmol), carbonic acid Sodium (97 mg, 0.91 mmol) was dispersed in 1,4-dioxane (4 mL) / water (1 mL), heated to 80°C under argon protection, stirred for 1.5 hours, and cooled to room temperature , filtered, and the filtrate was concentrated, followed by silica gel column chromatography to obtain a white solid product (25 mg, 44%). 1 H NMR (CDCl 3 )δ (ppm): 9.00 (s, 1H), 7.72 (d, J = 8.1Hz, 2H), 7.63 (d, J = 8.1Hz, 2H), 7.41 (s, 1H), 4.32 (d, J = 6.6Hz, 2H), 4.14-4.23(m, 2H), 2.75(t, J=12.9Hz, 2H), 2.01-2.04(m, 1H), 1.81(d, J=12.6Hz, 2H), 1.47( s, 9H), 1.34-1.38 (m, 2H). MS (m / z) 443 (M+1), 465 (M+23).

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Abstract

The present invention discloses a GPR119 agonist, with a structural formula shown in a general formula (I). The present invention also provides methods for treating diseases with GPR119 as a treatment target, by administration of any pharmaceutically acceptable compound shown in the general formula (I), and the pharmaceutically acceptable salt of the compound; and method for treating or preventing metabolic disorders and obesity by administration of any pharmaceutically acceptable compound shown in the general formula (I), and the pharmaceutically acceptable salt of the compound.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a GPR119 agonist and its application. Background technique [0002] Diabetes is increasingly threatening human health. In the United States today, approximately 16 million people are suffering from diabetes. [0003] Type 1 diabetes, also known as insulin-dependent diabetes, is an autoimmune disease. It is caused by the destruction of the pancreatic islet β cells that can produce insulin by the autoimmune system. There is currently no cure for this disease in the world, so patients must receive insulin injections. Without insulin injections, cells cannot absorb glucose for energy. Symptoms associated with type 1 diabetes usually appear in childhood and adolescence. Because the course of the disease is usually urgent and the symptoms are obvious, patients will be prompted to actively seek medical help. [0004] Type 2 diabetes, also known as non-insulin-dependent diabetes, manifests i...

Claims

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Application Information

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IPC IPC(8): A61P3/04C07D417/12C07D277/42C07D277/34A61K31/4545A61P3/06A61P3/00A61P3/10A61K31/506C07D417/04A61K31/427A61K31/454
Inventor 文聖煥苏衡马龙张波周良薛宝玉王丹丹陈冬梅高畅張永佶金孟燮
Owner BEIJING HANMI PHARMA CO LTD
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