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As Analogues of Mirtazapine Via N-Acyliminium Ion Cyclization

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As Analogues of Mirtazapine Via N-Acyliminium Ion Cyclization Synthesis of Tetracyclic Pyrido[2,3-b]azepine Derivatives Bull. Korean Chem. Soc. 2002, Vol. 23, No. 11 1623 Synthesis of Tetracyclic Pyrid이 2,3-이 azepine Derivatives as Analogues of Mirtazapine via N-Acyliminium Ion Cyclization Jae Yeol Lee,* Sung Hun Bang,' Sook Ja Lee「Yun Seon Song, Changbae Jin, Hokoon Park, and Yong Sup Lee* Division of Life Sciences, Korea Institute of Science &Technology, P.O. Box 131, Cheongryang, Seoul 130-650, Korea ‘Department of Chemistry, Hankuk University of Foreign Studies, Yong-in 449-791, Korea Received August 13, 2002 Tetracyclic pyrido [2,3-b] azepine derivatives 4a-d and 4f as analogues of mirtazapine were synthesized via N- acyliminium ion cyclization by using aromatic rings such as benzene and thiophene ring as a 兀-nucleophile, and evaluated for the binding affinity for %-adrenoceptor. Among tested compounds, 2,3,9,13b-tetrahydro- 1H-benzo[f]pyrrolo [2,1 -a]pyrido [2,3-c] azepine (4a) was the most potent (Ki = 0.26 “M) but showed about 3­ fold less binding affinity than mirtazapine (Ki = 0.08 “M) for %-adrenoceptor. Key Words : Pyrido[2,3-b]azepine, N-Acyliminium ion cyclization, %-Adrenoceptor, Mirtazapine Introduction Experimental Section Tetracyclic azepines are presented as an important class of Materials and measurements. All compounds used in heterocyclic skeletons occurring in a number of bioactive the synthesis were of reagent grade and used without further molecules for a variety of biological targets1 and form, in purification, and the solvents were freshly distilled by using particular, the tetracyclic antidepressants such as mianserin standard purification methods. 1H NMR spectra were (1, Bolvidon®) and mirtazapine (2, Remeron®): Mirtazapine recorded on a Gemini Varian-300 (300 MHz) spectrometer. enhances noradrenaline (NA) and serotonin (5-HT) release 13C NMR spectra were recorded on a Gemini Varian-300 (75 by blocking the inhibitory presynaptic 怎-adrenergic auto­ MHz) spectrometer. Infrared (IR) spectra were recorded on receptors and stimulating the 5-HT1A receptors.2,3 Therefore, Perkin Elmer 16-PC FT-IR using a potassium bromide many synthetic efforts have been directed toward synthesis pellet. Low (EI) resolution mass spectra were determined on of tetracyclic azepine derivatives because of their unique HP GC 5972 and HP MS 5988A system at 70 eV Dibenzo- structural features and biological activities.4 Recently, we [cf|azepines (3a-b) and benzo [f|thieno[3,2-c] azepines (3c­ have also reported the synthesis of dibenzo[c,f]azepine and d) were obtained by the procedure reported in the literature.5 benzo[f]thieno[3,2-c]azepine derivatives (3) as analogues of General procedure for the preparation of cyclic imides mianserin.5 (6a-f). To a solution of 3 -benzyl-2-aminopyridine (5a, 2.9 g, In this work, we wish to describe the synthesis and the 15.2 mmol) in 50 mL of xylene was added succinic binding affinities of tetracyclic pyrido[2,3-b]azepine deriva­ anhydride (2.3 g, 22.9 mmol). The reaction mixture was tives 4 for 怎-adrenoceptor as analogues of mirtazapine heated at reflux for 5 h with Dean-Stark. After cooling to including the binding affinities data of benzo[b]azepine room temperature, the Dean-Stark was removed and acetyl derivatives 3. chloride (2.7 mL, 30.5 mmol) was added to the mixture. The reaction mixture was heated again at reflux for 3 h. The solvent was distilled off under reduced pressure and the residue was dissolved in 100 mL of EtOAc. The organic layers were washed with saturated aqueous NaHCOs solution, dried over MgSO4, concentrated, and purified by flash column chromatography (EtOAc/n-hexane = 1 : 3) to afford 6a (3.1 g, 75%) as a white solid: mp 128-130 oC; MS m/z: 266 (M+); IR (KBr) 3018, 1790, 1712, 1578 cm-1; 1H NMR (300 MHz, CDCla) S 8.50 (dd, J = 4.7, 1.6 Hz, 1H, pyridine C2-H), 7.63 (dd, J = 7.7, 1.2 Hz, 1H, pyridine C4-H), 7.35- 7.19 (m, 4H, pyridine C3-H, phenyl), 7.06 (d, J = 6.5 Hz, 2H, phenyl), 3.92 (s, 2H, pyridine-C旦2-Ar), 2.72 (m, 2H, 2 x-N-CO-CHa-), 2.52 (m, 2H, 2 x-N-CO-C旦b-)； 13C NMR (75 MHz, CDCla) S 175.7, 148.4, 145.7, 140.5, 138.3, 135.1, 129.1, 127.3, 127.2, 125.1, 37.8, 28.9. Preparation of 6b. The reaction of 5a (400 mg, 2.2 mmol) and glutaric anhydride (374 mg, 3.3 mmol) afforded Figure 1. Representative tetracyclic azepine compounds. 6b (233 mg, 38%) as a white solid according to the pro­ 1624 Bull. Korean Chem. Soc. 2002, Vol. 23, No. 11 Jae Yeol Lee et al. cedure described above: mp 102-103 oC; MS m/z: 280 (M+); CHa-), 2.29 (m, 1H, O=C-CH2-C旦b-), 1.87 (m, 1H, -CHa- IR (KBr) 3395, 2917, 1735, 1686, 1434 cm-1; 1H NMR (300 CH2-CH-OH), 1.70 (m, 1H, -CHb-CH2-CH-OH); 13C NMR MHz, CDCl3) S 8.48 (d, J = 5.0 Hz, 1H, pyridine C2-H), (75 MHz, CDCl3) S 174.0, 151.0, 146.2, 145.9, 140.6, 139.6, 7.53 (d, J = 7.6 Hz, 1H, pyridine C4-H), 7.32-7.23 (m, 5H, 133.3, 128.7, 126.7, 122.8, 85.6, 38.2, 29.6, 27.4. phenyl), 7.11 (d, J = 7.5 Hz, 1H, pyridine C3-H), 3.82 (s, 2H, Preparation of 7b and 8b. Prepared from 6b (197 mg, 0.7 pyridine-CH2-Ar), 2.81-2.55 (m, 4H, 2 xO=C-CH2-), 2.12-1.94 mmol) as described above: 7b (29 mg, 15%) as a yellow (m, 2H, O=C-CH2-CH2-)； 13C NMR (75 MHz, CDCI3) S solid; mp 94-95 oC; IR (KBr) 3335, 2947, 2366, 1624 cm-1; 178.0, 153.9, 152.7, 144.7, 144.3, 140.4, 134.7, 134.4, 133.9, 1H NMR (300 MHz, CDCk) S 8.23 (dd, J = 4.8, 1.6 Hz, 1H, 131.9, 129.8, 41.3, 37.5, 22.4. pyridine C2-H), 7.51 (dd, J = 7.6, 1.0 Hz, 1H, pyridine C4- Preparation of 6c. Prepared from 5a (1.64 g, 8.9 mmol) H), 7.24-7.10 (m, 5H, phenyl), 6.94 (d, J = 7.0 Hz, 1H, and diglycolic anhydride (1.56 g, 13.4 mmol) as described pyridine C3-H), 4.77 (t, J = 2.6 Hz, 1H, -N-C旦(OH)-CH2-) above. A yellow oil (1.05 g, 41%): MS m/z: 282 (M+); IR 3.90 and 3.79 (ABq, J = 16.2 Hz, 2H, pyridine-C旦2-Ar), (KBr) 3425, 2924, 1696, 1581 cm-1; 1H NMR (300 MHz, 2.46 (dd, J = 11.3, 1.4 Hz, 1H, O=C-C旦a-), 2.27-2.21 (m, CDCls) S 8.52 (d, J = 5.6 Hz, 1H, pyridine C2-H), 7.62 (d, J 2H, O=C-CH2-C旦2-), 1.72 (dd, J = 12.2, 2.0 Hz, 1H, O=C- = 7.7 Hz, 1H, pyridine C4-H), 7.37-7.13 (m, 5H, phenyl), CHb-), 1.57 (m, 1H, -N-CH(OH)-CHa-), 1.01 (m, 1H, -N- 7.12 (d, J = 7.0 Hz, 1H, pyridine C3-H), 4.41 and 4.31 (ABq, CH(OH)-CHb-); 13C NMR (75 MHz, CDCk) S 171.0, 155.1, J= 16.5 Hz, 2H, pyridine-C旦2-Ar), 3.87 (s, 4H, 2 xO=C- 146.4, 140.6, 140.0, 134.2, 129.0, 128.8, 126.9, 123.3, 82.2, C旦2-O-); 13C NMR (75 MHz, CDCls) S 170.0, 156.4, 148.1, 38.6, 33.1, 28.5, 16.6. 8b (over-reduced product, 59 mg, 140.1, 139.1, 129.6, 129.1, 128.9, 127.1, 125.5, 67.5, 36.3. 30%) as a yellow solid; mp 104 oC; IR (KBr) 3334, 3186, Preparation of 6d. Prepared from 5a (600 mg, 3.3 mmol) 2937, 1722, 1656 cm-1; 1H NMR (300 MHz, CDCh) S 8.18 and thiodiglycolic anhydride (737 mg, 4.9 mmol)) as (d, J = 3.3 Hz, 1H, pyridine C2-H), 7.46 (d, J = 7.5 Hz, 1H, described above. A brown solid (461 mg, 47%): mp 83-87 pyridine C4-H), 7.28-7.21 (m, 5H, phenyl), 7.10 (t, J = 3.8 oC; MS m/z: 298 (M+); IR (KBr) 3395, 2924, 2388, 1730, Hz, 1H, pyridine C3-H), 4.00 (s, 2H, pyridine-C旦2-Ar), 3.58 1686 cm-1; 1H NMR (300 MHz, CDCh) S 8.47 (dd, J = 4.7, (t, J = 6.2 Hz, 2H, -NH-CO-C旦2-) 2.41 (t, J = 7.2 Hz, 2H, 1.7 Hz, 1H , pyridine C2-H), 7.53 (dd, J = 7.7, 1.7 Hz, 1H, HO-CH2-CH2-), 1.80-1.70 (m, 2H, HO-CH2-CH2-), 1.61­ pyridine C4-H), 7.32-7.23 (m, 5H, phenyl), 7.13 (d, J = 7.3 1.54 (m, 2H, O=C-CH2-C旦2-); 13C NMR (75 MHz, CDCk) Hz, 1H, pyridine C3-H), 3.83 (s, 4H, 2 xO=C-CH2-S-), 3.67 S 173.4, 149.8, 146.2, 140.2 139.3, 129.5, 129.0, 126.9, and 3.48 (ABq, J = 16.7 Hz, 2H, pyridine-C旦2-Ar); 13C 122.3, 62.2, 37.9, 36.3, 32.336, 22.041 397, 174.0, 151.0, NMR (75 MHz, CDCk) S 168.5, 148.3, 148.2, 140.0, 138.2, 146.2, 145.9, 140.6, 139.6, 133.3, 128.7, 126.7, 122.8, 85.6, 135.4, 129.7, 129.0, 127.2, 125.0, 37.1, 32.7.
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