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4-Aminophthalazin-1(2H)-one Derivatives as Melanin Concentrating Hormone Receptor 1 (MCH-R1) Antagonists

  • Lim, Chae Jo (Division of Drug Discovery Research, Korea Research Institute of Chemical Technology) ;
  • Lee, Hye In (Division of Drug Discovery Research, Korea Research Institute of Chemical Technology) ;
  • Kim, Nakjeong (Division of Drug Discovery Research, Korea Research Institute of Chemical Technology) ;
  • Lee, Byung Ho (Division of Drug Discovery Research, Korea Research Institute of Chemical Technology) ;
  • Oh, Kwang-Seok (Division of Drug Discovery Research, Korea Research Institute of Chemical Technology) ;
  • Yi, Kyu Yang (Division of Drug Discovery Research, Korea Research Institute of Chemical Technology)
  • Received : 2013.08.26
  • Accepted : 2013.09.09
  • Published : 2013.12.20
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Abstract

Keywords

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 K2CO3 (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%). 1H NMR (300 MHz, CDCl3) 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 vacuo to give 5j (250 mg, 87%). 1H NMR (300 MHz, DMSO-d6) 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%). 1H NMR (300 MHz, CDCl3) 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).

Table 1.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), Na2CO3 (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/CH2Cl2) to give 3j (22 mg, 25%). 1H NMR (300 MHz, CDCl3) 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).

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