Isothiazole derivatives as gpr120 agonists for the treatment of type ii diabetes

A compound and substituent technology, applied in the field of novel isothiazole and thiophene derivatives, can solve problems such as increasing the potential of CLP-1

Active Publication Date: 2017-02-15
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although GPR120 is relatively poorly understood due to the lack of effective selective pharmacological tools or the documented metabolic phenotype of GPR120 knockout mice, the potential of elevating CLP-1 from a small molecule perspective as a novel approach is important in type II Attractive unmet medical needs in the treatment of diabetes and related disorders

Method used

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  • Isothiazole derivatives as gpr120 agonists for the treatment of type ii diabetes
  • Isothiazole derivatives as gpr120 agonists for the treatment of type ii diabetes
  • Isothiazole derivatives as gpr120 agonists for the treatment of type ii diabetes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0355] 3-(4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-difluorophenyl) Propionic acid, compound 106

[0356] Step 1: 5-(4-Chlorophenyl)-2H-1,3,4-oxthiazol-2-one

[0357]

[0358]To a 100 mL round bottom flask was added 4-chlorobenzamide (3.0 g, 19.28 mmol, 1.00 equiv), chloro(chlorosulfonyl)methanone (5.03 g, 38.40 mmol, 1.99 equiv), toluene (30 mL). The resulting solution was stirred overnight in a 100°C oil bath. The progress of the reaction was monitored by GCMS / TLC / LCMS (ethyl acetate / petroleum ether=1:20). The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column and eluted with petroleum ether. This gave 3.8 g (92%) of 5-(4-chlorophenyl)-2H-1,3,4-oxthiazol-2-one as a white solid.

[0359] Step 2: Ethyl 3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazole-4-carboxylate

[0360]

[0361] Add 5-(4-chlorophenyl)-2H-1,3,4-oxthiazol-2-one (2.2 g, 10.30 mmol, 1.00 equiv), 4,4,4-trifluorobutane t...

Embodiment 2

[0375] 3-(4-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorobenzene base) propionic acid, compound 70

[0376] Step 1: 5-(4-Ethylphenyl)-1,3,4-oxthiazol-2-one

[0377]

[0378] The title compound was prepared according to the procedure described in Example 1, Step 1, using 4-ethylbenzamide as starting material to afford the desired product as a yellow solid.

[0379] Step 2: Ethyl 3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazole-4-carboxylate

[0380]

[0381] To a 50 mL sealed test tube was added ethyl 4,4,4-trifluorobut-2-ynoate (1.25 g, 7.53 mmol, 1.56 equiv), 5-(4-ethylphenyl)-2H-1,3, 4-oxthiazol-2-one (1.0 g, 4.83 mmol, 1.00 equiv), 1,3-dichlorobenzene (8 mL). The resulting solution was stirred at 150 °C for 16 h. The progress of the reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column and eluted with petroleum ether (100). This gave 1.068 g (67%)...

Embodiment 3

[0395] 3-(4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl) Propionic acid, compound 79

[0396]

[0397] The title compound was prepared according to the following procedure described in Example 2: Starting from (3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate, Following steps 5 and 6, using tert-butyl 3-(3,5-difluoro-4-hydroxyphenyl)propionate as a coupling agent, the desired product was obtained as an off-white solid. 1 H NMR (300MHz, CD 3 OD) δ7.77(d, J=8.7Hz, 2H), 7.51(d, J=8.4Hz, 2H), 6.86(d, J=9.6Hz, 2H), 5.20(s, 2H), 2.87(t , J=7.5Hz, 2H), 2.59(t, J=7.5Hz, 2H). Mass Spectrum (ESI, m / z): for C 20 h 13 CIF 5 NO 3 S, calculated value is 478.0 (M+H), found value is 478.0.

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Abstract

Disclosed are compounds, compositions and methods for treating of disorders that are affected by the modulation of the GPR120 receptor. Such compounds are represented by Formula (I) as follows (refer to the description) wherein R1, G, and Q are defined herein.

Description

[0001] Cross References to Related Applications [0002] Not applicable. technical field [0003] The present invention relates to novel isothiazole and thiophene derivatives which are GPR120 agonists and are useful in the treatment of disorders affected by modulation of the GPR120 receptor. The present invention also relates to pharmaceutical compositions comprising such compounds, to methods of preparing such compounds and compositions, and to the use of such compounds or pharmaceutical compositions in the treatment of various diseases, syndromes and disorders, each of which Diseases, syndromes and disorders include obesity, obesity-related disorders, impaired oral glucose tolerance, insulin resistance, type II diabetes, metabolic syndrome, metabolic syndrome X, dyslipidemia, elevated LDL, elevated triglycerides, Obesity-induced inflammation, osteoporosis, and obesity-associated cardiovascular disorders. Background technique [0004] The diabetes epidemic is spreading gl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04C07D419/04C07D275/02A61K31/50A61P3/08
CPCC07D417/04C07D419/04C07D275/02A61P19/10A61P3/00A61P3/04A61P3/06A61P3/08A61P5/50A61P9/00A61P3/10
Inventor C.R.伊里格M.R.普拉耶张旭庆
Owner JANSSEN PHARMA NV
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