Novel a7 Nicotinic Acetylcholine Receptor Agonists
3.16 (d, J=17.2, 1H), 3.39 (d, J=14.3, 1H), 3.43 (d, J=14.3, 1H),
4.97 (s, 2H), 6.49 (s, 1.5H), 7.26 ppm (m, 5H); 13C NMR (75 MHz,
D2O): d=17.6, 19.4, 28.9, 41.5, 45.9, 46.5, 58.5, 72.4, 84.2, 128.3,
128.9, 129.0, 134.7, 135.0, 167.8, 171.5 ppm; Anal. calcd for
C19H23N2O5: C 63.50, H 6.45, N 7.79, found: C 63.77, H 6.22, N 7.54.
J=1.8 and 14.3, 1H); 13C NMR (75 MHz, [D6]DMSO): d=20.7, 24.4,
32.4, 44.8, 51.4, 55.0, 55.5, 65.9, 68.2, 143.5 ppm; Anal. calcd for
C10H16BrIN2O: C 31.03, H 4.17, N 7.24, found: C 31.22, H 3.98, N
7.38.
(ꢀ)-3-Methyl-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene
methyl iodide (4b): Colorless prisms; mp: 201–2038C (2-propanol/
(ꢀ)-3-Propargyloxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-
ene fumarate 10ꢀ0.5 C4H4O4 (10a): Colorless prisms; mp: 193–
1968C (2-propanol/MeOH); 1H NMR (300 MHz, D2O): d=1.71 (m,
2H), 1.85 (m, 1H), 2.08 (m, 1H), 2.24 (m, 1H), 2.79 (t, J=2.2, 1H),
2.99 (d, J=16.8, 1H), 3.02–3.17 (m, 4H), 3.16 (d, J=16.8, 1H), 3.41
(m, 2H), 4.56 (d, J=2.2, 2H), 6.35 ppm (s, 1H); 13C NMR (75 MHz,
D2O): d=17.4, 19.3, 28.9, 41.3, 45.9, 46.4, 57.9, 58.6, 77.1, 77.5, 84.6,
135.2, 167.2, 173.5 ppm; Anal. calcd for C14H18N2O4: C 60.42, H 6.52,
N 10.07, found: C 60.11, H 6.85, N 10.38.
1
MeOH); H NMR (300 MHz, D2O): d=1.75–1.85 (m, 2H), 1.81 (s, 3H),
1.93 (m, 1H), 2.14 (m, 2H), 2.85 (s, 3H), 2.95 (d, J=17.9, 1H), 3.17
(d, J=17.9, 1H), 3.15–3.38 (m, 4H), 3.52 ppm (br s, 2H); 13C NMR
(75 MHz, D2O): d=12.4, 19.4, 20.9, 29.0, 47.6, 51.8, 56.2, 56.8, 68.6,
83.8, 159.5 ppm; Anal. calcd for C11H19IN2O: C 41.01, H 5.94, N 8.69,
found: C 41.11, H 5.75, N 8.87.
(ꢀ)-3-Methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene
methyl iodide (6b): Colorless prisms; mp: 221–2228C (MeOH);
1H NMR (300 MHz, D2O): d=1.79 (m, 2H), 1.95 (m, 1H), 2.15 (m,
1H), 2.29 (m, 1H), 2.85 (s, 3H), 2.99 (d, J=17.0, 1H), 3.15 (d, J=
17.0, 1H), 3.14–3.37 (m, 4H) 3.56 (m, 2H), 3.65 ppm (s, 3H);
13C NMR (75 MHz, D2O): d=19.1, 20.8, 28.9, 41.3, 51.8, 56.3, 56.8,
57.7, 68.1, 84.9, 168.9 ppm; Anal. calcd for C11H19IN2O2: C 39.07, H
5.66, N 8.28, found: C 39.35, H 5.81, N 7.97.
(ꢀ)-1-Oxa-2,7-diaza-7,10-ethanospiro[4.5]decan-3-one fumarate
11ꢀ0.75 C4H4O4 (11a): Colorless prisms; mp: 172–1738C (n-
hexane/EtOAc/MeOH); 1H NMR (300 MHz, D2O): d=1.76 (m, 2H),
1.94 (m, 1H), 2.17 (m, 1H), 2.37 (br s, 1H), 2.87 (d, J=16.7, 1H),
2.95 (d, J=16.7, 1H), 3.08–3.30 (m, 4H), 3.42 (dd, J=2.2 and 14.3,
1H), 3.51 (dd, J=2.2 and 14.3, 1H), 6.47 ppm (s, 1.5H); 13C NMR
(75 MHz, D2O): d=17.4, 18.9, 28.1, 41.9, 46.1, 46.5, 57.2, 80.5, 134.8,
166.7, 171.6 ppm; Anal. calcd for C12H17N2O5: C 53.52, H 6.36, N
10.40, found: C 53.23, H 6.58, N 10.72.
(ꢀ)-3-Ethoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene
methyl iodide (7b): Colorless prisms; mp: 180–1818C (abs EtOH);
1H NMR (300 MHz, D2O): d=1.14 (t, J=7.0, 3H), 1.79 (m, 2H), 1.95
(m, 1H), 2.15 (m, 1H), 2.28 (br s, 1H), 2.85 (s, 3H), 2.98 (d, J=17.0,
1H), 3.15 (d, J=17.0, 1H), 3.17–3.38 (m, 4H), 3.55 (m, 2H),
3.98 ppm (q, J=7.0, 2H); 13C NMR (75 MHz, D2O): d=13.8, 19.1,
20.8, 28.9, 41.6, 51.8, 56.3, 56.8, 67.3, 68.1, 84.5, 168.2 ppm; Anal.
calcd for C12H21IN2O2: C 40.92, H 6.01, N 7.95, found: C 50.16, H
5.87, N 8.12.
(ꢀ)-2-Methyl-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]decan-3-one
fumarate 12ꢀ0.5 C4H4O4 (12a): Colorless prisms; mp: 162–1638C
(n-hexane/abs EtOH); 1H NMR (300 MHz, D2O): d=1.77 (m, 2H),
1.95 (m, 1H), 2.16 (m, 1H), 2.36 (br s, 1H), 2.84 (d, J=16.8, 1H),
2.89 (d, J=16.8, 1H), 3.03 (s, 3H), 3.08–3.32 (m, 4H), 3.40 (dd, J=2.
6 and 14.3, 1H), 3.56 (dd, J=2.6 and 14.3, 1H), 6.54 ppm (s, 1H);
13C NMR (75 MHz, D2O): d=17.4, 19.0, 28.4, 31.6, 41.6, 46.0, 46.4,
57.7, 80.7, 134.8, 168.4, 171.5 ppm; Anal. calcd for C12H18N2O4: C
56.68, H 7.13, N 11.02, found: C 56.90, H 7.19, N 10.76.
(ꢀ)-3-Propoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene
methyl iodide (8b): Colorless prisms; mp: 134–1358C (EtOAc/2-
1
propanol); H NMR (300 MHz, D2O): d=0.78 (t, J=7.3, 3H), 1.57 (m,
General procedure for the preparation of iodomethylates: CH3I
(450 mL, 7.23 mmol) was added to a solution of the free base
(0.5 mmol) in MeOH (3 mL). The solution was left overnight at RT,
then the solvent was removed under reduced pressure, quantita-
tively affording the crude quaternary salt.
2H), 1.83 (m, 2H), 1.99 (m, 1H), 2.18 (m, 1H), 2.32 (br s, 1H), 2.88
(s, 3H), 3.04 (d, J=17.2, 1H), 3.16–3.38 (m, 5H), 3.59 (m, 2H),
3.93 ppm (t, J=6.6, 2H); 13C NMR (75 MHz, D2O): d=9.7, 19.1, 20.9,
21.8, 28.9, 41.5, 51.8, 56.3, 56.8, 68.1, 72.9, 84.5, 168.3 ppm; Anal.
calcd for C13H23IN2O2: C 42.63, H 6.33, N 7.65, found: C 42.90, H
6.12, N 7.38.
(ꢀ)-3-Ethoxycarbonyl-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-
2-ene methyl iodide (1b): Light yellow prisms; mp: 162–1638C
(abs EtOH); 1H NMR (300 MHz, D2O): d=1.23 (t, J=7.0, 3H), 1.93
(m, 2H), 2.07 (m, 1H), 2.27 (m, 1H), 2.34 (br s, 1H), 2.97 (s, 3H),
3.31 (d, J=18.4, 1H), 3.33–3.48 (m, 4H), 3.50 (d, J=18.4, 1H), 3.73
(br s, 2H), 4.26 ppm (q, J=7.0, 2H); 13C NMR (75 MHz, D2O): d=
13.5, 19.1, 20.6, 29.4, 42.6, 51.8, 56.3, 56.9, 63.5, 68.1, 88.0, 152.9,
161.2 ppm; Anal. calcd for C13H21IN2O3: C 41.07, H 5.57, N 7.37,
found: C 41.38, H 5.22, N 7.10.
(ꢀ)-3-Benzyloxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene
methyl iodide (9b): Yellow prisms; mp: 184–185.58C (abs EtOH);
1H NMR (300 MHz, D2O): d=1.77 (m, 2H), 1.94 (m, 1H), 2.14 (m,
1H), 2.27 (br s, 1H), 2.84 (s, 3H), 3.03 (d, J=17.1, 1H), 3.18 (d, J=
17.1, 1H), 3.12–3.38 (m, 4H), 3.54 (m, 2H), 4.98 (s, 2H), 7.27 ppm
(m, 5H); 13C NMR (75 MHz, D2O): d=19.1, 20.8, 28.9, 41.5, 51.8,
56.3, 56.8, 68.0, 72.5, 84.7, 128.4, 128.9, 129.1, 135.0, 167.7 ppm;
Anal. calcd for C17H23IN2O2: C 49.29, H 5.60, N 6.76, found: C 49.57,
H 5.87, N 6.58.
(ꢀ)-3-Hydroxymethyl-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-
2-ene methyl iodide (2b): Light yellow prisms; mp: 155–1708C,
dec. (2-propanol/abs EtOH); 1H NMR (300 MHz, CD3OD): d=2.01
(m, 2H), 2.14 (m, 1H), 2.29 (m, 1H), 2.39 (m, 1H), 3.04 (s, 3H), 3.17
(d, J=17.6, 1H), 3.36 (dd, J=17.6, 1H), 3.42–3.55 (m, 4H), 3.71 (dd,
J=2.5 and 13.5, 1H), 3.79 (dd, J=2.5 and 13.5, 1H), 4.30 ppm (s,
2H); 13C NMR (75 MHz, D2O): d=19.3, 20.8, 29.0, 44.2, 51.8, 56.2,
56.6, 56.8, 68.4, 84.5, 160.7 ppm; Anal. calcd for C11H19IN2O2: C
39.07, H 5.66, N 8.28, found: C 38.85, H 5.41, N 8.54.
(ꢀ)-3-Propargyloxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-
ene methyl iodide (10b): Colorless prisms; mp: 186–1878C (2-
propanol/MeOH); 1H NMR (300 MHz, D2O): d=1.74 (m, 2H), 1.92
(m, 1H), 2.12 (m, 1H), 2.26 (m, 1H), 2.78 (t, J=2.2, 1H), 2.81 (s, 3H),
2.99 (d, J=17.2, 1H), 3.12–3.37 (m, 5H), 3.54 (m, 2H), 4.56 ppm (d,
J=2.2, 2H); 13C NMR (75 MHz, D2O): d=18.9, 20.7, 28.8, 41.3, 51.8,
56.2, 56.7, 58.0, 68.0, 84.6, 85.1, 167.0, 169.0 ppm; Anal. calcd for
C13H19IN2O2: C 43.11, H 5.29, N 7.73, found: C 42.81, H 5.55, N 7.95.
(ꢀ)-3-Bromo-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene
methyl iodide (3b): Colorless prisms; mp: 112–1148C (MeOH);
1H NMR (300 MHz, CD3OD): d=2.01 (m, 2H), 2.13 (m, 1H), 2.37 (m,
2H), 3.05 (s, 3H), 3.34 (m, 2H), 3.40 (d, J=18.0, 1H), 3.51 (m, 2H),
3.60 (d, J=18.0, 1H), 3.78 (dd, J=1.8 and 14.3, 1H), 3.84 ppm (dd,
(ꢀ)-2-Methyl-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]decan-3-one
methyl iodide (12b): Colorless prisms; mp: 181–1828C (2-propa-
nol); H NMR (300 MHz, D2O): d=1.86 (m, 2H), 2.03 (m, 1H), 2.22
(m, 1H), 2.42 (br s, 1H), 2.88 (d, J=18.0, 1H), 2.92 (s, 3H), 3.03 (d,
J=18.0, 1H), 3.06 (s, 3H), 3.17–3.42 (m, 4H), 3.60 (dd, J=2.3 and
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ChemMedChem 2011, 6, 889 – 903
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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