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Benzoxazole carboxamides for treating cinv and ibs-d

A technology based on formamide and phenyl, which can be used in medical preparations containing active ingredients, allergic diseases, metabolic diseases, etc., and can solve problems such as reluctance to participate in social and family activities

Inactive Publication Date: 2008-04-09
ALBANY MOLECULAR RESEARCH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The most common secondary side effects include panic, depression, reluctance to participate in social and family activities, and malnutrition

Method used

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  • Benzoxazole carboxamides for treating cinv and ibs-d
  • Benzoxazole carboxamides for treating cinv and ibs-d
  • Benzoxazole carboxamides for treating cinv and ibs-d

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1: Preparation of N-[3-(2-methylimidazol-1-yl)propyl]-2-phenylbenzoxazole-4-formamide

[0077]

[0078] Step A: Benzoyl chloride (0.830 g, 5.90 mmol) was added to a suspension of 3-hydroxyanthranilic acid (0.300 g, 1.96 mmol) in toluene (10 mL) at room temperature, followed by pyridine (0.545 g, 6.92 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then heated to 80 °C for 1 hour. The reaction was then cooled and poured into a mixture of ethyl acetate (50 mL) and 5% aqueous hydrochloric acid (50 mL). The layers were then separated and the organics were dried over magnesium sulfate and filtered to give an orange solution. The solution was concentrated to an orange solid, which was redissolved directly in xylene (20 mL), and the solution was treated with p-toluenesulfonic acid (0.800 g, 4.20 mmol). The reaction mixture was then heated to reflux for 6 hours. After this time the reaction was cooled and poured into water (50 mL), the ...

Embodiment 2

[0081] Example 2: Preparation of N-[2-(2-methylimidazol-1-yl)ethyl]-2-phenylbenzoxazole-4-carboxamide

[0082]

[0083] Step A: 2-(2-Methylimidazol-1-yl)ethylamine was prepared from 2-methylimidazole and 2-chloroethylamine hydrochloride using the procedure described in Example 1, Step B. This material was obtained in 47% yield as a pale yellow oil. 1 H NMR (300MHz, CD 3 OD) δ6.95(br s, 1H), 6.82(br s, 1H), 4.90(bs, 2H), 3.90(t, J=6.9Hz, 2H), 2.93(t, J=6.9Hz, 2H) , 2.35(s, 3H); MS(APCI) m / z 126[M+H] + .

[0084] Step B: Preparation of N-[2- (2-methylimidazol-1-yl)ethyl]-2-phenylbenzoxazole-4-carboxamide. The compound was obtained in 35% yield as a white solid: melting point 125-127°C; 1 H NMR (300MHz, CD 3 OD) δ8.11(dd, J=7.8, 1.0Hz, 2H), 7.96(d, J=7.8Hz, 1H), 7.73(d, J=8.2Hz, 1H), 7.63-7.52(m, 3H) , 7.42(t, J=8.0Hz, 1H), 7.13(s, 1H), 6.86(s, 1H), 4.22(t, J=5.8Hz, 2H), 3.87(t, J=6.0Hz, 2H) , 2.34(s, 3H); MS(APCI) m / z 347[M+H] + .

Embodiment 4

[0085] Example 4: Preparation of N-(1-methylpiperidin-4-yl)-2-phenylbenzoxazole-4-carboxamide

[0086]

[0087] Step A: A slurry of ammonium formate (10.2 g, 162 mmol) in water (4.4 mL) was added to a solution of 1-methyl-4-piperidone (1.84 g, 16.2 mmol) in methanol (40 mL), and The reaction was stirred until all solids had dissolved. Palladium on carbon (3.78 g, 10% Pd, 50% humidity) was then added and the reaction was stirred at room temperature for 18 hours. The mixture was then filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The resulting viscous clear oil was dissolved in ethanol (33 mL), and the solution was treated with 37% hydrochloric acid (4.1 mL). After stirring at room temperature for 1 hour, the resulting solution was concentrated into a white solid, which was recrystallized from ethanol to obtain 0.62 g (yield 25%) of 4-amino-1-methylpiperidine dihydrochloride as a white solid: 1 H NMR (300MHz, DMSO-d 6 )δ10.95(br ...

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Abstract

Compounds of formulae (I) and (II) are disclosed as 5-HT3inhibitors. Those compounds that exhibit central activity are useful in treating chemotherapy-induced nausea and vomiting (CINV); those that peripheral receptors are useful to treat diarrhea-predominant Irritable Bowel Syndrome (IBS-D).

Description

technical field [0001] The present invention relates to compounds of the genus benzoxazole genus useful in the treatment of chemotherapy-induced nausea and vomiting (CINV) and in the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D). Background technique [0002] Nausea and vomiting caused by chemotherapy remain among the most distressing side effects of patients undergoing cancer treatment. Depending on the chemotherapy agent or treatment regimen given, up to 90% of patients may experience some form of chemotherapy-induced nausea and vomiting (CINV). CINV symptoms can be severely debilitating and often lead patients to refuse further chemotherapy procedures, with clear adverse consequences for cancer development. Furthermore, CINV is onerous in the medical system, consuming the time of healthcare personnel who would otherwise be able to care for other patients or be involved in other medical events. [0003] CINV is mainly divided into two categories: acu...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D451/14C07D451/04C07D453/02C07D498/08A61K31/423A61P1/08A61P1/06
CPCC07D451/04C07D451/14C07D413/12C07D453/02A61P1/00A61P1/04A61P1/06A61P1/08A61P1/12A61P1/14A61P11/06A61P21/00A61P25/00A61P25/02A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P25/32A61P25/36A61P29/00A61P3/02A61P3/04A61P37/08A61P43/00C07D451/02
Inventor D·J·费尔法克斯杨智才
Owner ALBANY MOLECULAR RESEARCH INC
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