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4-Aminophthalazin-1(2H)-one Derivatives as Melanin Concentrating Hormone Receptor 1 (MCH-R1) Antagonists
4-Aminophthalazin-1(2H)-one Derivatives as Melanin Concentrating Hormone Receptor 1 (MCH-R1) Antagonists
Bulletin of the Korean Chemical Society. 2013. Dec, 34(12): 3851-3854
Copyright © 2013, Korea Chemical Society
  • Received : August 26, 2013
  • Accepted : September 09, 2013
  • Published : December 20, 2013
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About the Authors
Chae Jo Lim
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Korea
Hye In Lee
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Korea
Nakjeong Kim
Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Korea
Byung Ho Lee
Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Korea
Kwang-Seok Oh
Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Korea
Kyu Yang Yi
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Korea

Abstract
Keywords
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Experimental Section
Synthesis of 4-(4-Chlorophthalazin-1-yl)thiomorpholine (4j). To a solution of 1,4-dichlorophthalazine (500 mg, 2.51 mmol) in DMF (10 mL) were added thiomorpholine (388 mg, 3.76 mmol) and K 2 CO 3 (1.04 g, 7.53 mmol). The mixture was stirred at 80 ℃ for 4 h, cooled, diluted with 50 mL of water, and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, giving a residue that was subjected to silica gel column chromatography (ethyl acetate/ n -hexane, 1/3) to give 4j (310 mg, 46%). 1 H NMR (300 MHz, CDCl 3 ) δ 8.20-8.26 (m, 1H), 7.97-8.03 (m, 1H), 7.86-7.94 (m, 2H), 3.77-3.81 (m, 4H), 2.90-2.94 (m, 4H).
Synthesis of 4-Thiomorpholinophthalazin-1(2H)-one (5j). A solution of 4j (310 mg, 1.16 mmol) in acetic acid (10 mL) was stirred at reflux for 2 h. The mixture was cooled and diluted with 10 mL of water. The resulting precipitate was separated by filtration, washed with ethyl acetate, and dried in vacu o to give 5j (250 mg, 87%). 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.13 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 7.86-7.91 (m, 2H), 7.79-7.84 (m, 1H), 3.28-3.38 (m, 4H), 2.80-2.90 (m, 4H).
Synthesis of 2-(3-Chloropropyl)-4-thiomorpholinophth alazin-1(2H)-one (6j). To a solution of 5j (250 mg, 1.01 mmol) in DMF (10 mL) were added sodium hydride (48 mg, 1.21 mmol) and 3-iodo-1-chloropropane (0.17 mL, 1.52 mmol) at 0 ℃. The mixture was stirred at room temperature for 1 h, diluted with water (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/ n -hexane, 1/3) to afford 6j (309 mg, 95%). 1 H NMR (300 MHz, CDCl 3 ) δ 8.42-8.45 (m, 1H), 7.72-7.84 (m, 3H), 4.32 (t, J = 6.7 Hz, 2H), 3.63 (t, J = 6.7 Hz, 2H), 3.45-3.48 (m, 4H), 2.87-2.90 (m, 4H), 2.28- 2.37 (m, 2H).
MCH-R1 binding affinities of C-4 amino substituted phthalazin-1(2H)-one derivatives
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aMCH-R1 binding affinities were determined by using a competitive binding with Eu-MCH and a TRF assay. bValues are means of at least two measurements
Synthesis of 2-{3-[4-(3-Acetamidophenyl)piperidin-1- yl]propyl}-4-thiomorpholinophthalazin-1(2H)-one (3j). To a solution of 6j (57 mg, 0.18 mmol) in DMF (1 mL) were added N -[3-(piperidin-4-yl)phenyl]acetamide (47 mg, 0.22 mmol), Na 2 CO 3 (57 mg, 0.54 mmol), and catalytic amount of NaI. The mixture was stirred at 100 ℃ for 3 h, cooled, diluted with 50 mL of water, and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, giving a residue that was subjected to silica gel column chromatography (10% MeOH/CH 2 Cl 2 ) to give 3j (22 mg, 25%). 1 H NMR (300 MHz, CDCl 3 ) δ 8.42-8.45 (m, 1H), 7.71-7.84 (m, 3H), 7.31-7.41 (m, 3H), 7.23 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 4.23 (t, J = 7.0 Hz, 2H), 3.45-3.48 (m, 4H), 3.14 (d, J = 11.3 Hz, 2H), 2.86-2.90 (m, 4H), 2.57-2.61 (m, 2H), 2.46-2.53 (m, 1H), 2.17 (s, 3H), 2.13-2.15 (m, 4H), 1.83- 1.90 (m, 4H).
Acknowledgements
Supporting Information.Experimental procedures and spectral data of compounds3a-3o. This material can be found in the online version.
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