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Compounds for treatment of inflammation, diabetes and related disorders

A compound, C1-C20 technology, applied in the direction of active ingredients of heterocyclic compounds, active ingredients of anhydride/acid/halide, anti-inflammatory agents, etc., can solve problems such as hindering the protective effect of COX-1

Inactive Publication Date: 2005-05-11
THERAKOS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

They are effective in reducing inflammatory pain and swelling, but because they block the protective effects of COX-1, they produce undesirable side effects in gastrointestinal pathology

Method used

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  • Compounds for treatment of inflammation, diabetes and related disorders
  • Compounds for treatment of inflammation, diabetes and related disorders
  • Compounds for treatment of inflammation, diabetes and related disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0154] 3-(3,5-dimethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidopropyl)-phenoxy]-phenyl]-

[0155] Synthesis of Methyl Acrylate (1) [see Scheme I]

[0156] Step 1: Synthesis of 3-(3,5-dimethoxyphenyl)-2-(4-hydroxyphenyl)-acrylic acid (2). To a mixture of 3,5-dimethoxybenzaldehyde (120 g, 0.72 mol) and p-hydroxyphenylacetic acid (110 g, 0.72 mol) was added acetic anhydride (240 mL) and triethylamine (161 mL, 1.6 equiv.). This heterogeneous solution became homogeneous at ~70°C upon heating. After stirring at 130 °C for 4 hrs, the mixture was cooled to room temperature. HCl (15%, 500 mL) was slowly added to the reaction mixture over 30 min to keep the temperature below 5-10 °C. The solid was dissolved in 3N aqueous NaOH (1.2 L) and stirred for 0.5 hr. The filtrate was acidified to pH 1 with concentrated HCl (-700 mL), maintaining the temperature at 25-30 °C. The precipitated product was filtered and washed with water to give the crude product (-300 g, wet cake). The cr...

Embodiment 2

[0163] 3-(3,5-dimethoxyphenyl)-2-{4-[4-(3-ethoxycarbonylamino-3-oxo-propyl)-phenoxy

[0164] Synthesis of methyl]-phenyl}-acrylate (8)

[0165] Proceeding essentially as shown in PCT / US99 / 09982 (WO 99 / 58127), 3-(3,5-dimethoxy-phenyl)-2-{4-[4-(2,4-diox In the synthesis of thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-methyl acrylate, 2-{4-[4-(2-carbamoyl-ethyl)-benzene Oxy]-phenyl}-3-(3,5-dimethoxyphenyl)-methyl acrylate (7). 7 (460 mg, 1.0 mmol) was taken up in dry THF (6 mL) and cooled to -78 °C. To this solution, lithium diisopropylamide (LDA) (2M, 0.55 mL, 1.1 mmol) was added and stirred for 10 min. Ethyl chloroformate (0.11 mL, 1.2 mmol) was added and stirred at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride, then ethyl acetate (50 mL) was added. The organic layer was washed with brine (2 x 20 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by ...

Embodiment 3

[0169] 2-{4-[4-(3-Benzoyloxycarbonylamino-3-oxo-propyl)-phenoxy]-phenyl]-3-(3,5-di

[0170] Synthesis of Methoxyphenyl)-Methyl Acrylate (9)

[0171] 7 (1.38, 3.0 mmol) as prepared in Example 2 was taken up in dry THF (20 mL) and cooled to -78 °C. To this solution, LDA (2M, 1.8 mL, 3.6 mmol) was added and stirred for 10 min. Benzyl chloroformate (0.67 g, 39 mmol) was added and stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride and added ethyl acetate (150 mL). The organic layer was washed with brine (2 x 25 mL), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel chromatography and eluted with hexane-ethyl acetate (7:3). Yield: 0.68 g, 37.3%.

[0172]

[0173] analyze: 1 HNMR (DMSO-d 6 ): δ10.65(s, 1H), 7.72(s, 1H), 7.38-7.39(m, 5H), 7.25(d, J=8.4Hz, 2H), 7.18(d, J=8.4Hz, 2H) , 7.00(d, J=8.4Hz, 2H), 6.94(d, J=8.4Hz, 2H), 6.41(t,...

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PUM

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Abstract

The present invention provides novel acyl, sulfur, carbamate, thiocarbamate, and related compounds that inhibit cytokine-mediated inflammatory responses in cultured cells and improve bone tissue in animal models of arthritis disrupts, and lowers blood glucose levels in animal models of type 2 diabetes. The present invention discloses that the compound can be used in various treatments, including the treatment of diabetes, insulin resistance, inflammation, inflammatory diseases, immune diseases, and cancer.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 60 / 334,818, filed November 29, 2001, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to compounds, such as heterocyclic derivatives of acylurea, thiourea, carbamate and thiocarbamate compounds, which provide various useful pharmacological effects. The compounds are useful in lowering blood glucose levels, eg, hyperglycemia, such as diabetes, and in treating related conditions, such as obesity and hyperlipidemia. In addition, these compounds are useful in the treatment of conditions associated with insulin resistance, such as polycystic ovary syndrome, and in the treatment of inflammation, inflammatory diseases and immune diseases, especially caused by pro-inflammatory cytokines (such as TNF- α, IL-1β and IL-6), phosphodiesterase types 4 and 3 (PDE4 and PDE3, respectively), p44 / 42 mitogen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P3/10C07C233/25C07C235/34C07C235/56C07C237/22C07C271/16C07C271/64C07C275/50C07C281/06C07C317/22C07D213/56C07D213/64C07D213/643C07D213/75C07D295/185
CPCA61P3/00A61P3/06A61P3/10A61P9/00A61P29/00A61P35/00A61P37/00A61P37/02C07C233/25C07C235/34C07C235/56C07C237/22C07C271/16C07C271/64C07C275/50C07C281/06C07C317/22C07D213/56C07D213/643C07D213/75C07D295/185C07C2601/14C07C235/28
Inventor P·尼奥吉D·戴伊T-K·李J·富勒L·陈
Owner THERAKOS INC
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