Histamine N-Methyltransferase Activity
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5 1135
N-Eth yl 3-P ip er id in op r op a n -1-a m in e (4i). Oil. 1H NMR
(CF3COOD): δ 3.76 (m, 2H, Pip-2-Heq, Pip-6-Heq), 3.37 (m, 4H,
PipCH2, NHCH2CH3), 3.06 (m, 2H, Pip-2-Hax, Pip-6-Hax), 2.46
(m, 2H, CH2NHCH2CH3), 1.34-2.13 (m, 11H, PipCH2CH2,
CH2NHCH2CH3, 2Pip-3-H, 2Pip-4-H, 2Pip-5-H). Anal. C10H22N2.
Gen er a l P r oced u r e for 4-((ω-P ip er id in oa lk yl)a m in o)-
h eter ocycles. ω-Piperidinoalkan-1-amine (4, 2.5.mmol), the
chloro-substituted heterocycle (2.5 mmol), and phenol (3 g)
were heated at 140 °C for 12 h. After they were cooled, ethyl
acetate/water was added and the organic layer was washed
with 6 N NaOH until the phenol was removed. The solvent
was evaporated, and the residue was purified by column
chromatography. The product was crystallized as a salt of
oxalic acid from EtOH/Et2O.
4-((2-P iper idin oeth yl)am in o)qu in olin e (5). [Eluent: eth-
yl acetate/TEA (95:5)]; mp 194.9-195.5 °C. 1H NMR (CF3-
COOD): δ 8.44 (d, J ) 6.8 Hz, 1H, quin-2-H), 8.18 (d, J ) 8.5
Hz, 1H, quin-8-H), 8.05 (m, 1H, quin-7-H), 7.94 (d, J ) 8.5
Hz, 1H, quin-5-H), 7.82 (m, 1H, quin-6-H), 6.92 (d, J ) 7.0
Hz, 1H, quin-3-H), 4.28 (t, J ) 5.9, 2H, CH2NHquin), 3.90 (m,
2H, Pip-2-Heq, Pip-6-Heq), 3.75 (m, 2H, PipCH2), 3.13 (m, 2H,
1.91-2.13 (m, 5H, 2Pip-3-H, Pip-4-Heq, 2Pip-5-H), 1.61 (m, 1H,
Pip-4-Hax). Anal. (C18H25N3 × 2C2H2O4) C, H, N.
4-((3-P ip er id in op r op yl)(et h yl)a m in o)q u in olin e (11).
[Eluent: ethyl acetate/TEA (95:5)]; mp 174.7-175.5 °C. 1H
NMR (CF3COOD): δ 8.33 (d, J ) 6.9 Hz, 1H, quin-2-H), 8.25
(d, J ) 9.3 Hz, 1H, quin-8-H), 7.99 (m, 1H, quin-7-H), 7.93 (d,
J ) 8.4 Hz, 1H, quin-5-H), 7.76 (m, 1H, quin-6-H), 7.31 (br,
1H, NH), 7.03 (d, J ) 6.9 Hz, 1H, quin-3-H), 3.99 (q, J ) 7.1
Hz, 2H, CH3CH2Nquin), 3.95 (t, J ) 7.4 Hz, 2H, CH2CH2-
Nquin), 3.78 (m, 2H, Pip-2-Heq, Pip-6-Heq), 3.40 (m, 2H,
PipCH2), 3.05 (m, 2H, Pip-2-Hax, Pip-6-Hax), 2.46 (m, 2H,
PipCH2CH2), 1.87-2.11 (m, 5H, 2Pip-3-H, Pip-4-Heq, 2Pip-5-
H), 1.61 (m, 1H, Pip-4-Hax), 1.59 (t, J ) 7.0 Hz, 3H, CH3). Anal.
(C19H27N3 × 2C2H2O4 × 0.25H2O) C, H, N.
2-Meth yl-4-((3-p ip er id in op r op yl)a m in o)qu in olin e (12).
[Eluent: ethyl acetate/TEA (95:5)]; mp 185.5-186.3 °C. 1H
NMR (CF3COOD): δ 8.13 (d, J ) 8.5, 1H, quin-8-H), 7.97 (m,
1H, quin-7-H), 7.81 (d, J ) 8.4 Hz, quin-5-H), 7.74 (m, 1H,
quin-6-H), 7.27 (br, 1H, NH), 6.65 (s, 1H, quin-3-H), 3.80 (t, J
) 6.1 Hz, 2H, CH2NHquin), 3.78 (m, 2H, Pip-2-Heq, Pip-6-Heq),
3.46 (m, 2H, PipCH2), 3.03 (m, 2H, Pip-2-Hax, Pip-6-Hax), 2.78
(s, 3H, quinCH3), 2.47 (m, 2H, PipCH2CH2), 1.88-2.13 (m, 5H,
2Pip-3-H, Pip-4-Heq, 2Pip-5-H), 1.60-1.63 (m, 1H, Pip-4-Hax).
Anal. (C18H25N3 × 2C2H2O4) C, H, N.
Pip-2-Hax, Pip-6-Hax), 1.90-2.14 (m, 5H, 2Pip-3-H, Pip-4-Heq
,
2Pip-5-H), 1.65 (m, 1H, Pip-4-Hax). Anal. (C16H21N3 x 2 C2H2O4)
C, H, N.
4-((2-P iper idin oeth yl)(m eth yl)am in o)qu in olin e (6). [Elu-
ent: ethyl acetate/TEA/petrolether (95:5:50)]; mp 135.3-136.4
9-((3-P ip er id in op r op yl)a m in o)-1,2,3,4-tetr a h yd r oa cr i-
d in e (13). [Eluent: ethyl acetate/TEA/petrolether (95:5:150)];
1
°C. H NMR (CF3COOD): δ 8.43 (d, J ) 7.0 Hz, 1H, quin-2-
1
mp 147.6-148.5 °C. H NMR (CF3COOD): δ 8.29 (d, J ) 8.7
H), 8.32 (d, J ) 8.7 Hz, 1H, quin-8-H), 8.04 (m, 1H, quin-7-
H), 7.97 (d, J ) 8.3 Hz, 1H, quin-5-H), 7.80 (m, 1H, quin-6-
H), 7.14 (d, J ) 7.0 Hz, 1H, quin-3-H), 4.41 (t, J ) 7.4, 2H,
CH2Nquin), 3.87 (m, 2H, Pip-2-Heq, Pip-6-Heq), 3.81 (t, J ) 7.0,
2H, PipCH2), 3.78 (s, 3H, NCH3), 3.19 (m, 2H, Pip-2-Hax, Pip-
6-Hax), 1.90-2.14 (m, 5H, 2Pip-3-H, Pip-4-Heq, 2Pip-5-H), 1.65
(m, 1H, Pip-4-Hax). Anal. (C17H23N3 × 2C2H2O4 × 0.5H2O) C,
H, N.
Hz, 1H, Acr-5-H), 7.91 (m, 1H, Acr-7-H), 7.78 (d, J ) 8.5 Hz,
1H, Acr-8-H), 7.66 (m, 1H, Acr-6-H), 7.26 (br, 1H, NH), 4.56
(t, J ) 7.0 Hz, 2H, CH2NHAcr), 3.78 (m, 2H, Pip-2-Heq, Pip-
6-Heq), 3.42 (m, 2H, PipCH2), 3.09 (t, J ) 5.6 Hz, 2H, 2Acr-4-
H), 3.06 (m, 2H, Pip-2-Hax, Pip-6-Hax), 2.71 (m, 2H, 2Acr-1-
H), 2.49 (m, 2H, PipCH2CH2), 1.86-2.11 (m, 9H, 2Pip-3-H, Pip-
4-Heq, 2Pip-5-H, 2Acr-2-H, 2Acr-3-H), 1.62 (m, 1H, Pip-4-Hax).
Anal. (C21H29N3 × 2C2H2O4 × H2O) C, H, N.
9-((2-P ip er id in oet h yl)a m in o)-1,2,3,4-t et r a h yd r oa cr i-
d in e (7). [Eluent: ethyl acetate/TEA/petrolether (95:5:200)];
9-((3-P ip er id in op r op yl)(m eth yl)a m in o)-1,2,3,4-tetr a h y-
d r oa cr id in e (14). [Eluent: ethyl acetate/TEA/petrolether (95:
1
mp 191.2-191.7 °C. H NMR (CF3COOD): δ 8.22 (d, J ) 8.3
1
5:200)]; mp 72.8-124.5 °C (decomp). H NMR (CF3COOD): δ
Hz, 1H, Acr-5-H), 7.93 (m, 1H, Acr-7-H), 7.83 (d, J ) 8.1 Hz,
1H, Acr-8-H), 7.70 (m, 1H, Acr-6-H), 4.61 (m, 2H, CH2NAcr),
3.88 (m, 2H, Pip-2-Heq, Pip-6-Heq), 3.77 (m, 2H, PipCH2), 3.12
(m, 4H, 2Acr-1-H, Pip-2-Hax, Pip-6-Hax), 2.76 (m, 2H, 2Acr-4-
H), 1.94-2.07 (m, 9H, 2Pip-3-H, Pip-4-Heq, 2Pip-5-H, 2Acr-2-
8.19 (d, J ) 8.6 Hz, 1H, Acr-5-H), 7.92-7.95 (m, 2H, Acr-8-H,
Acr-7-H), 7.79 (m, 1H, Acr-6-H), 3.85 (t, J ) 7.1 Hz, 2H, CH2-
NAcr), 3.73 (m, 2H, Pip-2-Heq, Pip-6-Heq), 3.44 (s, 3H, NCH3),
3.23-3.30 (m, 4H, PipCH2, 2Acr-1-H), 2.97-3.00 (m, 2H, Pip-
2-Hax, Pip-6-Hax), 2.94 (t, J ) 5.7 Hz, 2H, 2Acr-4-H), 2.38 (m,
2H, PipCH2CH2), 1.84-2.12 (m, 9H, 2Pip-3-H, Pip-4-Heq, 2Pip-
5-H, 2Acr-2-H, 2Acr-3-H), 1.59 (m, 1H, Pip-4-Hax). Anal.
(C22H31N3 × 3C2H2O4) C, H, N.
H, 2Acr-3-H), 1.62 (m, 1H, Pip-4-Hax). Anal. (C20H27N3
2C2H2O4) C, H, N.
×
9-((2-P ip er id in oeth yl)(m eth yl)a m in o)-1,2,3,4-tetr a h y-
d r oa cr id in e (8). [Eluent: ethyl acetate/TEA/petrolether (bp
40-60 °C) (95:5:200)]; mp 149.0-149.5 °C. 1H NMR (CF3-
COOD): δ 8.19 (d, J ) 8.5 Hz, 1H, Acr-5-H), 8.00 (m, 2H, Acr-
8-H, Acr-7-H), 7.83 (m, 1H, Acr-6-H), 4.22 (t, J ) 7.4 Hz, 2H,
CH2NAcr), 3.76 (m, 2H, Pip-2-Heq, Pip-6-Heq), 3.68 (m, 2H,
PipCH2), 3.41 (s, 3H, NCH3), 3.34 (t, J ) 6.5 Hz, 2H, 2Acr-1-
H), 3.09 (m, 2H, Pip-2-Hax, Pip-6-Hax), 2.96 (t, J ) 5.4 Hz, 2H,
2Acr-4-H), 1.87-2.14 (m, 9H, 2Pip-3-H, Pip-4-Heq, 2Pip-5-H,
2Acr-2-H, 2Acr-3-H), 1.59 (m, 1H, Pip-4-Hax). Anal. (C21H29N3
× 2C2H2O4 × 0.75H2O) C, H, N.
7-Ch lor o-4-((3-p ip er id in op r op yl)a m in o)qu in olin e (16).
[Eluent: ethyl acetate/TEA (95:5)]; mp 202.9-204.0 °C. 1H
NMR (CF3COOD): δ 8.34 (d, J ) 5.2, 1H, quin-2-H), 8.19 (d,
J ) 8.5 Hz, 1H, quin-5-H), 7.91 (s, 1H, quin-8-H), 7.74 (d, J )
9.1 Hz, quin-6-H), 7.29 (br, 1H, NH), 6.86 (d, J ) 5.2 Hz, 1H,
quin-3-H), 3.81 (m, 4H, Pip-2-Heq, Pip-6-Heq, CH2NHquin), 3.45
(m, 2H, PipCH2) 3.04 (m, 2H, Pip-2-Hax, Pip-6-Hax), 2.44 (m,
2H, PipCH2CH2), 1.91-2.04 (m, 5H, 2Pip-3-H, Pip-4-Heq, 2Pip-
5-H), 1.62 (m, 1H, Pip-4-Hax). Anal. (C17H22ClN3 × 2C2H2O4)
C, H, N.
4-((3-P ip er id in op r op yl)a m in o)qu in olin e (9). [Eluent:
1
4-((4-P ip er id in obu tyl)a m in o)qu in olin e (17). [Eluent:
ethyl acetate/TEA (95:5)]; mp 193.8-194.4 °C. H NMR (CF3-
1
ethyl acetate/TEA (95:5)]; mp 178.5-179.1 °C. H NMR (CF3-
COOD): δ 8.36 (d, J ) 7.0 Hz, 1H, quin-2-H), 8.21 (d, J ) 8.4
Hz, 1H, quin-8-H), 8.02 (m, 1H, quin-7-H), 7.89 (d, J ) 8.4
Hz, 1H, quin-5-H), 7.78 (m, 1H, quin-6-H), 7.24 (br, 1H, NH),
6.85 (d, J ) 7.0 Hz, 1H, quin-3-H), 3.77-3.84 (m, 4H, CH2-
NHquin, Pip-2-Heq, Pip-6-Heq), 3.45 (m, 2H, PipCH2), 3.06 (m,
2H, Pip-2-Hax, Pip-6-Hax), 2.47 (m, 2H, PipCH2CH2), 1.91-2.03
(m, 5H, 2Pip-3-H, Pip-4-Heq, 2Pip-5-H), 1.62 (m, 1H, Pip-4-
COOD): δ 8.31 (d, J ) 7.1 Hz, 1H, quin-2-H), 8.19 (d, J ) 8.6
Hz, 1H, quin-8-H), 8.00 (m, 1H, quin-7-H), 7.87 (d, J ) 8.5
Hz, 1H, quin-5-H), 7.78 (m, 1H, quin-6-H), 6.92 (br, 1H, NH),
6.82 (d, J ) 7.1 Hz, 1H, quin-3-H), 3.76 (m, 4H, CH2NHquin,
Pip-2-Heq, Pip-6-Heq), 3.30 (m, 2H, PipCH2), 3.02 (m, 2H, Pip-
2-Hax, Pip-6-Hax), 1.90-2.11 (m, 9H, 2Pip-3-H, Pip-4-Heq, 2Pip-
5-H, PipCH2(CH2)2), 1.61 (m, 1H, Pip-4-Hax). Anal. (C18H25N3
× 2C2H2O4) C, H, N.
H
ax). Anal. (C17H23N3 × 2C2H2O4) C, H, N.
4-((3-P ip er id in op r op yl)(m eth yl)a m in o)qu in olin e (10).
[Eluent: ethyl acetate/ TEA (95:5)]; mp 175.1-175.6 °C. 1H
NMR (CF3COOD): δ 8.31 (m, 2H, quin-2-H, quin-8-H), 8.00
(m, 1H, quin-7-H), 7.91 (d, J ) 8.4 Hz, 1H, quin-5-H), 7.75
(m, 1H, quin-6-H), 7.29 (br, 1H, NH), 7.01 (d, J ) 6.7 Hz, 1H,
quin-3-H), 3.98 (t, J ) 7.2 Hz, 2H, CH2Nquin), 3.80 (m, 2H,
Pip-2-Heq, Pip-6-Heq), 3.64 (s, 3H, NCH3), 3.39 (m, 2H, PipCH2),
3.05 (m, 2H, Pip-2-Hax, Pip-6-Hax), 2.51 (m, 2H, PipCH2CH2),
7-Ch lor o-4-((4-p ip er id in obu tyl)a m in o)qu in olin e (18).
[Eluent: ethyl acetate/TEA (95:5)]; mp 162.6-163.5 °C. 1H
NMR (CF3COOD): δ 8.30 (d, J ) 7.1, 1H, quin-2-H), 8.17 (d,
J ) 9.1 Hz, 1H, quin-5-H), 7.89 (s, 1H, quin-8-H), 7.73 (d, J )
9.0 Hz, quin-6-H), 6.99 (br, 1H, NH), 6.82 (d, J ) 7.1 Hz, 1H,
quin-3-H), 3.76 (m, 4H, Pip-2-Heq, Pip-6-Heq, CH2NHquin), 3.30
(m, 2H, PipCH2), 3.02 (m, 2H, Pip-2-Hax, Pip-6-Hax), 1.87-2.12