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Bicyclic pyrrole derivatives useful as agonists of gpr120

A compound, pyridyl-based technology, for the treatment of GPR120-mediated disorders and conditions, which can address the potential to increase CLP-1, among other issues

Inactive Publication Date: 2015-10-28
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 2 Attractive unmet medical needs in the treatment of diabetes and related disorders

Method used

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  • Bicyclic pyrrole derivatives useful as agonists of gpr120
  • Bicyclic pyrrole derivatives useful as agonists of gpr120
  • Bicyclic pyrrole derivatives useful as agonists of gpr120

Examples

Experimental program
Comparison scheme
Effect test

Synthetic example

[0180] The following examples are given to aid in the understanding of the invention and are not intended and should not be construed as limiting in any way the invention as set forth in the claims that follow the examples.

[0181] In the following examples, some synthesis products that have been isolated as residues are listed. Those skilled in the art will appreciate that the term "residue" does not limit the physical state of the product when it is isolated, and may include, for example, solids, oils, foams, gums, slurries, and the like.

example 1

[0183] 3-(4-{[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrol-2-yl]methoxy}-3,5-difluorophenyl) Propionic acid (Compound #70)

[0184]

[0185] Step A: 1-(Benzenesulfonyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid methyl ester

[0186]

[0187] in N 2 3-Bromo-1-(benzenesulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (3.07g, 8.0mmol, 1 equivalent), 2,2-difluoro-2-(fluorosulfonyl)acetic acid A suspension of the methyl ester (6.32 mL, 48.1 mmol, 6 equiv) and CuI (1.53 g, 8.0 mmol, 1 equiv) in NMP (20 mL) was heated to 80 °C overnight. Additional methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (6.32 mL, 48.1 mmol, 6 equiv) and CuI (1.53 g, 8.0 mmol, 1 equiv) were added and the resulting mixture was heated overnight. The resulting brown suspension was filtered through CELITE with diethyl ether, water, saturated NaHCO 3 , brine washing the diethyl ether solution, and then through MgSO 4 Dried and then concentrated. The resulting residue was purified by fla...

example 2

[0211] 3-(4-{[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrol-2-yl]methoxy}-2,3-dimethylbenzene base) propan-1-ol (compound #46)

[0212]

[0213] at 0°C in N 2 Next, to a solution of the product prepared in Example 1, Step E (46 mg, 0.10 mmol, 1 eq) in THF (2 mL) was added LAH (0.20 mL of 1M in THF, 0.20 mmol, 2 eq). After 1 hour, firstly saturated potassium sodium tartrate (0.5 mL) was added dropwise, the solution was warmed to room temperature, diethyl ether was added, washed with brine, washed over MgSO 4 Dried and concentrated. The resulting residue was purified by flash chromatography (4 g column) eluting with 10 to 30% EtOAc / heptane to give 3-(4-{[1-(4-chlorophenyl)-3-(trifluoro Methyl)-1Hpyrrol-2-yl]methoxy}-2,3-dimethylphenyl)propan-1-ol.

[0214] 1 H NMR (300MHz, CD 3 OD)δ: 7.56(s, 4H), 7.05(d, J=3.0Hz, 1H), 6.76-6.83(m, 2H), 4.49(d, J=3.0Hz, 1H), 5.00(s, 2H) , 3.55 (t, J=5.7Hz, 2H), 2.61-2.66 (m, 2H), 1.71-1.84 (m, 2H). Mass Spectrum (ESI, m / z): For C...

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Abstract

The present invention is directed to bicyclic pyrrole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by GPR120. More particularly, the compounds of the present invention are agonists of GPR120, useful in the treatment of, such as for example, Type II diabetes mellitus.

Description

[0001] Cross References to Related Applications [0002] This patent application claims the benefit of US Provisional Application 61 / 783,158, filed March 14, 2013, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to bicyclic pyrrole derivatives, pharmaceutical compositions containing said bicyclic pyrrole derivatives and their use in the treatment of disorders and conditions mediated by GPR120. More specifically, the compounds of the present invention are agonists of GPR120, which are useful in the treatment of related diseases and disorders, such as type II diabetes. Background technique [0004] The diabetes epidemic is spreading globally, with the World Health Organization (WHO) reporting a global prevalence of 177 million diabetics. The estimated incidence of all forms of diabetes adds up to approximately 2.8% of the global population. The number of newly diagnosed diabetic patients increases by 4-5% ever...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D207/333A61K31/401A61P3/10
CPCC07D401/04A61K31/40C07D207/333C07D207/337C07D207/34A61P3/04A61P3/06A61P3/10A61P9/00A61P19/10A61P29/00
Inventor Z.隋M.P.温特斯
Owner JANSSEN PHARMA NV
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