Structural Requirements for MAO-Catalyzed Oxidation
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3699
4-substituted phenyl-lithiated reagent (1 equiv) on the 1-meth-
yl-4-piperidone 10 (1 equiv), in anhydrous THF (10 mL/mmol
of compound) at -78 °C.15 Compound 8 was prepared by
addition of the lithiated reagent derived from 4-bromo(tert-
butyldimethylsilyl)phenol.23 After 3-5 h reaction at -78 °C,
water was added and the mixture extracted with Et2O. After
drying over MgSO4 and evaporation of the organic solvent
under reduced pressure, the piperidinols 11-16 were directly
dehydrated in acidic medium (acetic acid/HCl, 3:1) to afford
the tetrahydropyridines which were crystallized as their
oxalate salts. The 1-ethyl-4-phenyl-1,2,3,6-tetrahydropyridine
(5) was obtained by ethylation of 4-phenylpyridine with ethyl
iodide (2.5 equiv) in anhydrous acetone, followed by reduction
of the corresponding pyridinium with NaBH4 in methanol,25
and crystallized as its oxalate salt.
Oxa la te sa lt of 1-m eth yl-4-(4-m eth ylp h en yl)-1,2,3,6-
tetr a h yd r op yr id in e (3): obtained in 71% yield after recrys-
tallization from methanol; mp 185-186 °C; 1H NMR (DMSO-
d6) δ 7.37 (2H, d like, J ) 8.2 Hz), 7.17 (2H, d like, J ) 8.2
Hz), 6.12 (1H, bs), 3.78 (2H, bd, J ) 2.5 Hz), 3.33 (2H, t, J )
6.0 Hz), 2.80 (3H, s), 2.72 (2H, bm), 2.30 (3H, s); 13C NMR
(DMSO-d6) δ 164.8, 137.2, 135.6, 133.6, 129.1, 124,6, 115.9,
51.3, 49.6, 41.8, 23.8, 20.7; MS (m/ z, rel int) 187 (100), 186
(74), 158 (25), 144 (21), 129 (72), 115 (33), 105 (23), 96 (56), 82
(18); UV (nm, MeOH) 209, 249. Anal. (C15H19NO4) C, H, N.
Oxa la te sa lt of 1-m eth yl-4-(4-ch lor op h en yl)-1,2,3,6-
tetr a h yd r op yr id in e (4): obtained in 66% yield after recrys-
tallization from methanol; mp 178-179 °C; 1H NMR (DMSO-
d6) δ 7.49 (2H, m), 7.41 (2H, m), 6.21 (1H, m), 3.75 (2H, bd, J
) 3.2 Hz), 3.31 (2H, t, J ) 6.0 Hz), 2.78 (3H, s), 2.72 (2H, bm);
13C NMR (DMSO-d6) δ 165.0, 137.7, 133.1, 132.8, 128.9, 127.0,
118.3, 51.8, 49.9, 42.3, 24.3; MS (m/ z, rel int) 209 (12), 208
(13), 207 (36), 206 (28), 178 (10), 149 (4), 129 (41), 115 (9), 96
(32), 82 (12), 42 (100); UV (nm, MeOH) 209, 250. Anal.
(C14H16ClNO4) C, H, N.
Oxa la te sa lt of 1-m eth yl-4-(4-m eth oxyp h en yl)-1,2,3,6-
tetr a h yd r op yr id in e (9): obtained in 70% yield after recrys-
tallization from methanol; mp 182-183 °C; 1H NMR (DMSO-
d6) δ 7.40 (2H, m), 6.92 (2H, m), 6.06 (1H, bm), 3.74 (3H, s),
3.73 (2H, bs), 3.31 (2H, t, J ) 6.0 Hz), 2.78 (3H, s), 2.69 (2H,
m); 13C NMR (DMSO-d6) δ 164.9, 159.4, 133.6, 131.3, 115.3,
114.3, 55.6, 51.9, 50.2, 42.3, 24.4; MS (m/ z, rel int) 203 (100),
202 (83), 188 (24), 179 (21), 160 (21), 145 (23), 121 (20), 115
(23), 96 (29), 94 (24); UV (nm, MeOH) 209, 258. Anal. (C15H19
NO5) C, H, N.
-
Ack n ow led gm en t. This work was supported by a
Lavoisier fellowship to S. Mabic (Ministe`re des Affaires
Etrange`res, France), by the National Institute of Neu-
rological and Communicative Disorders and Stroke (NS
28792), and by the Harvey W. Peters Center for the
Study of Parkinson’s Disease.
Su p p or tin g In for m a tion Ava ila ble: Kinetic data of the
compounds used for this study (3 pages). Ordering information
is found on any current masthead page.
Refer en ces
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Oxa la te sa lt of 1-eth yl-4-p h en yl-1,2,3,6-tetr a h yd r op y-
r id in e (5): obtained in 82% yield after recrystallization from
1
methanol; mp 172-173 °C; H NMR (DMSO-d6) δ 7.47 (2H,
m), 7.38 (2H, m), 7.32 (1H, tt, J ) 2.8, 7.2 Hz), 6.19 (1H, m),
3.79 (2H, bd, J ) 2.8 Hz), 3.35 (2H, t, J ) 6.0 Hz), 3.14 (2H,
q, J ) 7.2 Hz), 2.75 (2H, bm), 1.25 (3H, t, J ) 7.2 Hz); 13C
NMR (DMSO-d6) δ 164.9, 138.9, 134.6, 129.0, 128.3, 125.3,
117.4, 50.5, 48.8, 48.1, 24.4, 9.8; MS (m/ z, rel int) 187 (100),
186 (44), 158 (13), 129 (38), 115 (41), 110 (31), 91 (27), 77 (15),
56 (32); UV (nm, MeOH) 210, 248. Anal. (C15H19NO4) C, H,
N.
Oxa la te sa lt of 1-m eth yl-4-(4-eth ylp h en yl)-1,2,3,6-tet-
r a h yd r op yr id in e (6): obtained in 73% yield after recrystal-
lization from methanol; mp 179-181 °C; 1H NMR (DMSO-d6)
δ 7.36 (2H, m, d like, J ) 8.0 Hz), 7.20 (2H, m, d like, J ) 8.0
Hz), 6.10 (1H, bs), 3.75 (2H, bd, J ) 3.2 Hz), 3.31 (2H, t, J )
6.4 Hz), 2.78 (3H, s), 2.71 (2H, bm), 2.58 (2H, q, J ) 7.6 Hz),
1.16 (3H, t, J ) 7.6 Hz); 13C NMR (DMSO-d6) δ 165.0, 143.9,
136.4, 134.2, 128.3, 125.2, 116.4, 51.9, 50.1, 42.3, 28.2, 24.4,
15.9; MS (m/ z, rel int) 201 (100), 200 (78), 186 (16), 172 (26),
129 (70), 115 (35), 96 (57); UV (nm, MeOH) 209, 249. Anal.
(C16H21NO4) C, H, N.
(5) Efange, S. M. N.; Michelson, R. H.; Tan, A. K.; Krueger, M. J .;
Singer, T. P. Molecular size and flexibility as determinants of
selectivity in the oxidation of N-methyl-4-phenyl-1,2,3,6-tetrahy-
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(8) Note 1: We do not attempt to reduce the correlation enzyme
activity-molecular structure to the size of the molecule, but we
do attempt to define the maximum substrate length that the
MAO-B active site can accommodate. Therefore, lipophilicity,
molecular refractometry, polarizability, volume, and other pa-
rameters usually included in QSAR studies were not considered.
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rochem. 1987, 929-934.
(11) Youngster, S. K.; Sonsalla, P. K.; Sieber, B.-A.; Heikkila, R. E.
Structure-activity study of the mechanism of 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. I. Evalu-
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(12) Youngster, S. K.; McKeon, K. A.; J in, Y.-Z.; Ramsay, R. R.;
Heikkila, R. E.; Singer, T. P. Oxidation of analogs of 1-methyl-
4-phenyl-1,2,3,6-tetrahydropyridine by monoamine oxidases A
and B and the inhibition of monoamine oxidases by the oxidation
products. J . Neurochem. 1989, 53, 1837-1842.
Oxa la te sa lt of 1-m eth yl-4-(4-br om op h en yl)-1,2,3,6-
tetr a h yd r op yr id in e (7): obtained in 58% yield after recrys-
1
tallization from methanol; mp 203 °C; H NMR (DMSO-d6) δ
7.50 (2H, m), 7.38 (2H, m), 6.11 (1H, bs), 3.78 (2H, dd, J )
2.4, 3.6 Hz), 3.36 (2H, t, J ) 6.0 Hz), 2.83 (3H, s), 2.71 (2H,
m); 13C NMR (DMSO-d6) δ 164.9, 138.0, 133.7, 131.8, 127.5,
121.6, 117.4, 52.0, 50.4, 42.3, 24.1; MS (m/ z, rel int) 253 (74),
252 (60), 251 (76), 250 (54), 224 (12), 222 (13), 172 (24), 171
(22), 129 (100), 115 (21), 96 (76); UV (nm, MeOH) 210, 253.
Anal. (C14H16BrNO4) C, H, N.
Oxa la te sa lt of 1-m eth yl-4-(4-h yd r oxyp h en yl)-1,2,3,6-
tetr a h yd r op yr id in e (8): obtained in 67% yield after recrys-
tallization from methanol/water; mp 224-225 °C; 1H NMR
(DMSO-d6) δ 7.30 (2H, m), 6.76 (2H, m), 5.99 (1H, bm), 3.75
(2H, bs), 3.32 (2H, t, J ) 6.0 Hz), 2.80 (3H, s), 2.69 (2H, m);
13C NMR (DMSO-d6) δ 165.2, 157.8, 133.8, 129.5, 126.4, 115.7,
114.1, 51.8, 50.1, 42.1, 40.6, 24.3; MS (m/ z, rel int) 189 (100),
188 (75), 160 (29), 145 (24), 131 (24), 96 (32), 94 (21); UV (nm,
MeOH) 209, 259. Anal. (C14H17NO5) C, H, N.
(13) Kiselev, M. F.; Shcherbo, S. N.; Sinyakoz, Y. V.; Kryukov, L. N.
Link between electron structure and the biological activity of
some 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine derivatives.
Biophysics 1990, 35, 952-956.
(14) Singer, T. P.; Ramsay, R. R. The interaction of monoamine
oxidases with tertiary amines. Biochem. Soc. Trans. 1991, 19,
211-214.