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Based on the bioisosteric replacement of the pyrazole C3-carboxamide of rimonabant with a 5-alkyl oxadiazole ring, a novel class of oxadiazole derivatives with promising biological activity towards CB1 receptors was discovered. Among them, compounds with an alkyl linker containing a strong electron-withdrawing group (e.g., CF(3)) and a sterically f...
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... the past two decades, intensive studies on the cannabinoid-CB1 receptor axis have been fulfilled, showing that appetite control and weight loss in animals could be significantly induced through CB1 blockers, 15-18 leading to the discovery of SR141716A ( Fig. 1; rimonabant, Acomplia TM ), the first anti- obesity drug behaving as a selective CB1 inverse agonist 19 and launched in Europe in 2006. Although rimonabant has been shown to afford weight reduction and improvements in cardiometabolic risk factors after one year and two years of treatment, 20-23 a higher incidence of psychiatric adverse ...
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... (10 mL) was added to quench the reaction. The aqueous layer was separated and extracted with dichloromethane (3 × 10 mL); the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, which was purified by flash chromatography on silica gel with EtOAc-n-hexane (1 : 12) 5 -(4 -Chlorophenyl) -1 -(2,4 -dichlorophenyl) -4-methyl -1H - pyrazol-3-yl)-3-isopropyl-1,2,4-oxadiazole (4f). Compound 4f was obtained by a similar procedure to that used for compound 4a. ...
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... 4f was obtained by a similar procedure to that used for compound 4a. Treatment of acid 1 (0.155 g, 0.40 mmol) with thionyl chloride (0.18 mL, 2.50 mmol), and N-hydroxyisobutyramidine (0.122 g, 1.20 mmol) gave compound 4f (0.084 g, 46% yield) as a white solid: mp 130 5 -(4 -Chlorophenyl) -1 -(2,4 -dichlorophenyl) -4 -methyl -1H- pyrazol-3-yl)-3-(pentan-3-yl)-1,2,4-oxadiazole (4g). Compound 4g was obtained by a similar procedure to that used for compound 4a. ...
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... (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (4h). Compound 4h was obtained by a similar procedure to that used for compound 4a. ...
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... 4h was obtained by a similar procedure to that used for compound 4a. pyrazol-3-yl)-3-(cyclopropylmethyl)-1,2,4-oxadiazole (4k). Com- pound 4k was obtained by a similar procedure to that used for compound 4a. ...
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... general procedure is illustrated immediately below with compound 4c as a specific example. ) -1 -(2,4 -dichlorophenyl) -4 -methyl -1H- pyrazol-3-yl)-3-propyl-1,2,4-oxadiazole (4c). To a stirred solu- tion of the acid 1 (0.150 g, 0.39 mmol) in toluene (5 mL) was added thionyl chloride (0.17 mL, 2.36 mmol) at room temperature. ...
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... 135.6, 135.1, 132.8, 130.7, 130.5, 130.0, 128.9, 127.7, 126.6, 117.5, 29.0, 25.6, 22.1, 13.5, 9.4; MS (EI, 70 eV) m/z (% intensity) 460 (M + , 55.0); HRMS calcd for C 22 H 19 Cl 3 N 4 O 460.0619, found 460.0636. 1H-pyrazol-3-yl)-3-pentyl-1,2,4-oxadiazole (4e). Compound 4e was obtained by a similar procedure to that used for compound 4c. ...
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... 4e was obtained by a similar procedure to that used for compound 4c. Treatment of acid 1 (0.150 g, 0.39 mmol) with thionyl chloride (0.17 mL, 2.36 mmol), lithium bis(trimethylsilyl)amide (1.0 mL, 1.00 mmol) and hexanamide (0.095 g, 0.83 mmol) gave compound 4e (0.110 g, 59% yield) as a white solid: mp 150 5 -(4 -Chlorophenyl) -1 -(2,4 -dichlorophenyl) -4 -methyl -1H- pyrazol-3-yl)-3-cyclopropyl-1,2,4-oxadiazole (4i). Compound 4i was obtained by a similar procedure to that used for compound 4c. ...
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... (5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra- zol-3-yl)-3-isobutyl-1,2,4-oxadiazole (4j). Compound 4j was obtained by a similar procedure to that used for compound 4c. ...
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... reaction mixture was stirred for an additional 30 min at room temperature. The combined organic extracts were washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, which was purified by flash chromatography on silica gel with EtOAc-n-hexane (3 : 10) gave carboxamide 5 (1.160 g, 90% yield) as a white solid: mp 185-186 • C; IR (CH 2 Cl 2 , cast) m max 3458,3287,1678,1592,1573,1494,1484 1-(2,4-dichlorophenyl)-4-methyl-1H -pyra- zole-3-carbonitrile (6). To a stirred solution of carboxamide 5 (1.160 g, 3.05 mmol) in CH 2 Cl 2 (20 mL) was added triethylamine (1.28 mL, 9.15 mmol) and trifluoroacetic anhydride (0.85 mL, 6.10 mmol) at 0 • C. The resulting solution was stirred at 0 • C for 1 h. ...
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... by flash chromatography on silica gel with EtOAc-n- hexane (1 : 10) gave carbonitrile 6 (1.050 g, 95% yield) as a white solid: mp 90-92 • C; IR (CH 2 Cl 2 , cast) m max 3089, 2239, 1604, 1560, 1496, 1487 cm −1 ; 1 H NMR (600 MHz, CDCl 3 ) d 7.40 (d, J = 2.0 Hz, 1H), 7.30-7.23 (m, 4H), 7.04-7.02 (m, 2H), 2.22 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) d 142.1, 136.5, 135.5, 135.1, 132.6, 130.4, 130.3, 130.2, 129.1, 127.6, 125.9, 120.9, 113.1, 8.7; ESMS m/z: 362.0 (MH + ...
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... 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N -hydroxy-4- methyl-1H-pyrazole-3-carboximidamide (7). To a stirred solu- tion of compound 6 (0.863 g, 2.28 mmol) in MeOH (20 ml) was added 50% aqueous hydroxylamine solution (4.56 ml, 2.99 mmol) at room temperature. ...
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... (5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyra- zol-3-yl)-5-methyl-1,2,4-oxadiazole (8a). To a stirred solution of carboximidamide 7 (0.150 g, 0.38 mmol) in anhydrous toluene (5 mL) was added a solution of acetyl chloride (0.036 g, 0.49 mmol). ...
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... 8e was obtained by a similar procedure to that used for compound 8a. Treatment of carboximidamide 7 (0.155 g, 0.39 mmol) with 2-ethylbutanoyl chloride (0.066 g, 0.49 mmol) gave compound 8e (0.137 g, 76% yield) as a white solid: mp [195][196][197] -3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl- 1H-pyrazol-3-yl)-1,2,4-oxadiazole (8f). Compound 8f was obtained by a similar procedure to that used for compound 8a. ...
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... On the other hand, it is known that 1,2,4-and 1,3,4-oxadiazoles often serves as bioisosteric replacement of carboxamide group [10,11]. Based on this fact, we decided to synthesize the series of 1,2,4-triazoles containing 1,2,4-or 1,3,4-oxadiazole moiety. ...
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