m1-Selective Muscarinic Agonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2533
86.69, 83.16, 65.79; IR (KBr) 3504, 3498, 3085, 1790, 1738,
1727, 1704, 1612, 1469, 1449, 1387, 1260, 1219, 1188, 1124,
1004, 694 cm-1; MS (CI) M + 2 ) 297 (33), M + 1 296. (100),
164 (18), 163 (83), 148 (83), 133 (87). Anal. (C17H10FNO3) H,
N; C: calcd, 69.15; found, 69.63.
(m, 2H), 3.46-3.15 (m, 5H), 2.21 (m, 1H), 1.71 (m, 1H); 13C
NMR (DMSO) δ 164.24, 164.07, 159.89, 130.91 (d, J C-F ) 8.7
Hz), 127.96 (d, J C-F ) 3.0 Hz), 123.62 (d, J C-F ) 9.6 Hz), 118.12
(d, J C-F ) 22.9 Hz), 116.37 (d, J C-F ) 20.9 Hz), 95.92, 86.86,
84.54, 61.67, 58.86, 55.24, 50.83, 25.90; IR (KBr) 3407, 2928,
1610, 1581, 1404, 1280, 1172, 1152, 1033, 721 cm-1; MS (CI)
M + 1 ) 259. Anal. (C15H15FN2O‚C2H2O4) C, H, N.
(Z)-(()-1-Aza bicyclo[2.2.1]h ep ta n -3-on e, O-(3-(2′-Meth -
oxyp h en yl)-2-p r op yn yl)oxim e Oxa la te (30Z). 1. 5 (Ar )
2-MeOP h ): brown solid; yield 65%; mp 65-69 °C; 1H NMR δ
7.40-7.10 (m, 2H), 6.90-6.60 (m, 2H), 4.50 (d, 2H), 3.80 (s,
3H), 2.8 (broad, 1H).
3. 10p [R ) CH2CtC(2-F P h )] h yd r och lor id e: white
1
solid; yield 100%; mp 132-133 °C; H NMR (DMSO) O 11.4
(brOad, 2H), 7.8-7.61 (m, 1H), 7.58-7.48 (m, 1H), 7.39-7.25
(m, 1H), 5.11 (s, 2H); 13C NMR (DMSO) δ 164.11, 160.13,
133.97, 131.91, 131.78, 127.03, 124.88, 124.82, 115.94, 115.62,
109.51, 109.26, 87.13, 87.08, 82.08, 62.14; IR (KBr) 2950, 2923,
2915, 1492 cm-1; MS (CI + 1% NH3 in CH4) M + 1 ) 166 (7),
133 (43), 85 (100). Anal. (C9H8FNO‚HCl) H, N; C: calcd,
53.61; found, 52.20.
2. 9s [R ) CH2CtC(2-MeOP h )]: brown solid; yield 78%;
mp 147-148 °C; 1H NMR (CDCl3) δ 7.87-7.73 (m, 4H), 7.38-
4. 27Z: yield 64%; mp 141-142 °C; 1H NMR (DMSO) δ
12.25 (broad 5, 1.6H), 7.58-7.20 (m, 4H), 4.96 (s, 2H), 4.10-
3.85 (m, 2H), 3.47-3.15 (m, 5H), 2.21 (m, 1H), 1.71 (m, 1H);
13C NMR (DMSO) δ 164.29, 164.07, 160.00, 133.67, 131.31 (d,
7.28 (m, 2H), 6.90-6.79 (m, 2H), 5.16 (s, 2H), 3.73 (s, 3H); 13
C
NMR (CDCl3) δ 163.42, 160.16, 134.48, 133.83, 130.40, 128.94,
123.57, 120.57, 120.42, 117.97, 117.50, 117.01, 116.87, 110.96,
110.53, 86.29, 85.49, 66.11, 55.60; IR (KBr) 2220, 1741, 1606,
1510, 1380, 1298, 1186, 1030, 970, 699 cm-1; MS (CI) M + 2
) 309, M + 1 ) 308. Anal. (C18H13NO4) C, H, N.
J C-F ) 8.2 Hz), 124.82 (d, J C-F ) 3.6 Hz), 115.75 (d, J C-F
)
20.7 Hz), 109.98 (d, J C-F) 15.1 Hz), 90.98 (d, J ) 2.9 Hz),
79.13, 61.73, 58.85, 55.24, 50.81, 25.92; IR (KBr) 2858, 1636,
1492, 1214, 1006, 721 cm-1; MS (CI) M + 1 ) 259. Ana1.
(C15H15FN2O‚C2H2O4) C, H, N.
3. 10s [R ) CH2CtC(2-MeOP h )]: white solid; yield 100%;
1
mp 113-114 °C; H NMR (DMSO) δ 11.3 (broad, 2H), 7.85-
7.39 (m, 2H), 7.11-7.07 (d, 1H), 6.97-6.94 (t, 2H), 5.06 (s, 1H),
3.83 (s, 3H); 13C NMR (DMSO) δ 160.00, 133.67, 131.12,
120.44, 111.35, 109.90, 85.57, 85.37, 62.43, 55.58; MS (CI +
1% NH3 in CH4) M + 2 ) 179 (32), M + 1 ) 178 (100), M )
177 (65), 176, 146 (73), 145 (94), 133 (64), 105 (78); IR (KBr)
(Z)-(()-1-Aza bicyclo[2.2.1]h ep ta n -3-on e, O-(3-(4′-F lu o-
r op h en yl)-2-p r op yn yl)oxim e Oxa la te (28Z). 1. 5 (Ar )
4-F P h ): dark brown liquid; yieid 90%; 1H NMR (CDCl3) δ
7.48-7.18 (m, 2H), 7.10-6.70 (m, 2H), 4.50 (broad, 2H), 2.75-
2.48 (broad, 1H).
2908, 2900, 2896, 2834, 2653, 2646, 1266, 747. Anal. (C10H11
-
NO2‚HCl) H, N; C: calcd, 56.21; found, 55.69.
2. 9q [R ) CH2CtC(4-FPh)]: yellow solid; yield 73%; mp
124-125 °C; 1H NMR (CDCl3) δ 7.88-7.75 (m, 4H), 7.41-7.27
(m, 2H), 7.02-6.95 (m, 2H), 5.08 (s, 2H); 13C NMR (CDCl3) δ
164.85, 163.47, 160.86, 134.63, 133.86, 133.72, 128.81, 123.67,
117.88, 115.83, 115.48, 113.48, 88.61, 85.89, 81.44; MS (CI)
M + 2 ) 297 (16), M + 1 ) 296 (79), 164 (30), 163 (100), 148
(92), 133 (93), 121 (42). Anal. (C17H10FNO3) C, H, N.
3. 10q [R ) CH2CdC(4-F P h )] obtained as a white solid:
4. 30Z: yield 34%; mp 155-157 °C; 1H NMR (DMSO) δ
11.60 (broad s, 1.2H), 7.41-7.35 (m, 2H), 7.06 (d, 1H, J ) 8.9
Hz), 6.94 (t, 1H, J ) 7.1 Hz), 4.91 (s, 2H), 4.06-3.86 (m, 2H),
3.81 (s, 3H), 3.45-3.15 (m, 5H), 2.21 (m, 1H), 1.71 (m, 1H);
13C NMR (DMSO) δ 164.31, 159.86, 159.62, 133.41, 130.58,
120.44, 111.33, 110.60, 96.12, 89.13, 82.62, 62.05, 58.85, 55.53,
55.26, 50.81, 25.91; IR (KBr) 2937, 1762, 1639, 1493, 1264,
1028, 721 cm-1; MS (CI) M + 1 ) 271. Anal. (C16H18
N2O2‚C2H2O4) C, H, N.
-
1
yield 100%; mp 160-161 °C; H NMR (DMSO) δ 11.4 (broad,
2H), 7.67-7.61 (m, 2H), 7.56-7.25 (m, 2H), 5.06 (s, 2H); 13C
NMR (DMSO) δ 164.34, 160.39, 134.24, 134.10, 117.57, 11619,
115.84, 87.81, 81.81, 62.20; IR (KBr) 3019, 3013, 3000, 2983,
2870, 2655, 1511, 1241, 838 cm-1; MS (CI + 1% NH3 in CH4)
M + 1 ) 166 (7), 133 (30), 85 (100). Anal. (C9H8FNO‚HCl)
H, N; C: calcd, 53.61; found, 4.56.
(Z)-(()-1-Aza bicyclo[2.2.1]h ep ta n -3-on e, O-(3-(2′-Ch lo-
r op h en yl)-2-p r op yn yl)oxim e Oxa la te (31Z). 1. 5 (Ar )
1
2-ClP h ): brown liquid; yield 66%; H NMR (CDCl3) δ 7.58-
6.92 (m, 4H), 4.55 (s, 2H), 3.12 (s, 1H).
1
2. 9t [R ) CH2CtC(2-CIP h )]: mp 104-105 °C; H NMR
4. 28Z: yield 60%; mp 144-145 °C; 1H NMR (DMSO) δ
11.32 (broad s, 1.5H), 7.60-7.45 (m, 2H), 7.30-7.20 (m, 2H),
4.91 (s, 2H), 4.10-3.87 (m, 2H), 3.47-3.16 (m, 5H), 2.22 (m,
1H), 1.72 (m, 1H); 13C NMR (DMSO) δ 164.40, 164.09, 160.15,
159.66, 133.94 (d, J C-F ) 8.6 Hz), 118.13 (d, J C-F ) 3.1 Hz),
115.99 (d, J C-F ) 22.3 Hz), 85.51, 84.79, 61.75, 58.82, 55.18,
50.77, 25.87; IR (KBr) 2939, 1726, 1636, 1601, 1507, 1358,
1223, 1032, 1003, 840, 712 cm-1; MS (CI) M + 1 ) 259. Anal.
(C15H15FN2O‚C2H2O4) C, H, N.
(CDCl3) δ 7.89-7.83 (m, 2H), 7.79-7.74 (m, 2H), 7.47-7.44
(m, 1H), 7.33-7.16 (m, 3H), 5.17 (s, 3H); 13C NMR (CDCl3) δ
163.42, 135.90, 134.59, 133.70, 129.99, 129.21, 128.88, 126.49,
123.65, 121.77, 86.65, 86.34, 65.73; IR (KBr) 1784, 1736, 1730,
1727, 1718, 1380, 1355, 1186, 1124, 1016, 980, 972, 877, 767,
762, 707 cm-1; MS (CI) M + 2 ) 314 (38), M + 1 ) 315 (15),
M ) 312 (100), 167 (12), 166 (34), 165 (33), 164 (78), 151 (79),
149 (94), 148 (66). Anal. (C17H10ClNO3) C, H, N.
3. 10t [R ) CH2CtC(2-CIP h )] h yd r och lor id e: yield 41%;
mp 161-163 °C; 1H NMR (DMSO) δ 11.2 (broad s, 2H), 7.74-
7.71 (m, 1H), 7.69-7.58 (m, 1H), 7.62-7.38 (m, 2H), 5.11 (s,
2H); 13C NMR (DMSO) δ 134.74, 134.07, 131.08, 129.39,
120.82, 96.26, 87.05, 85.15, 62.15; IR (KBr) 3058, 3021, 2989,
2977, 2968, 2877, 2653, 1507, 1477, 1021, 857 cm-1; MS (CI +
1% NH3 in CH4) M + 2 ) 184 (9), M + 1 ) 183 (5), M ) 182
(29), 180 (19), 151 (66), 149 (10), 137 (60), 85 (81). Anal. (C9H8-
ClNO‚HCl) C, H, N.
(Z)-(() -1-Aza bicyclo[2.2.1]h ep ta n -3-on e, O-(3-(3′-F lu o-
r op h en yl)-2-p r op yn yl)oxim e Oxa la te (29Z). 1. 5 (Ar )
3-F -P h ): dark brown liquid; yield 97%.
2. 9r [R ) CH2CtC(3-F P h )]: yellow solid; yield 71%; mp
124-125 °C; 1H NMR (CDCl3) δ 7.89-7.84 (m, 2H), 7.81-7.75
(m, 2H), 7.31-7.24 (m, 2H), 7.22-7.04 (m, 2H), 5.09 (s, 2H);
13C NMR (CDCl3) δ 164.18, 163.46, 160.86, 134.68, 130.04,
129.90, 128.80, 127.68, 127.63, 123.71, 123.47, 118.74, 118.38,
116.52, 116.19, 88.34, 82.65, 65.78; IR (KBr) 1735, 1611, 1582,
1386, 1188, 1174, 1152, 1019, 977, 878, 783, 699 cm-1; MS (CI)
M + 2 ) 297 (16), M + 1 ) 296 (19), 164 (17), 163 (89), 148
(50), 133 (100). Anal. (C17H10FNO3).
4. 31Z: yield 51%; mp 143-145 °C; 1H NMR (DMSO) δ
11.46 (broad s, 1.1H), 7.61-7.33 (m, 4H), 4.97 (s, 2H), 4.06-
3.86 (m, 2H), 3.45 (d, 1H, J ) 4.1 Hz), 3.40-3.14 (m, 4H), 2.21
(m, 1H), 1.71 (m, 1H); 13C NMR (DMSO) δ 164.24, 160.10,
134.69, 133.68, 130.60, 129.40, 127.40, 121.41, 90.96, 82.42,
61.72, 58.88, 55.28, 50.84, 25.95; IR (KBr) 2843, 2707, 2566,
3. 10r [R ) CH2CtC(3-F P h )] h yd r och lor id e: yield
1
100%; mp 147-151 °C; H NMR (DMSO) δ 11.3 (broad, 2H),
2534, 1718, 1702, 1636, 1474, 1404, 1228, 995, 762, 722 cm-1
;
7.53-7.24 (m, 4H), 5.06 (s, 2H); 13C NMR (DMSO) δ 163.66,
159.77, 130.78, 130.83, 128.04, 128.03, 123.11, 122.95, 118.51,
118.14, 116.93, 116.60, 87.47, 87.42, 83.11, 62.12; IR (KBr)
3019, 2990, 2896, 2849, 2664, 1582, 1488, 1176, cm-1; MS (CI
+ 1% NH3 in CH4) M ) 165 (35), 134 (100), 122 (60). Anal.
(C9H8FNO‚HCl) C, H, N.
MS (CI) M + 1 ) 275. Anal. (C15H15ClN2O‚C2H2O4) C, H, N.
(Z)-(()-1-Aza bicyclo[2.2.1]h ep ta n -3-on e, O-(3-(3′-Nitr o-
p h en yl) -2-p r op yn yl)oxim e Oxa la t e (32Z). 1. 5 (R 2
3-NO2P h ): yield 78%.
)
2. 9u [R ) CH2CtC(3-NO2P h )]: yield 82%; mp 162-163
°C; 1H NMR (CDCl3) δ 8.22-8.17 (m, 2H), 7.91-7.86 (m, 2H),
7.82-7.72 (m, 3H), 7.54-7.27 (t, 1H, J ) 8.0 Hz), 5.11 (s, 2H);
4. 29Z: yield 37%; mp 123-125 °C; 1H NMR (DMSO) δ
8.25 (broad s, 2H), 7.50-7.25 (m, 4H), 4.92 (s, 2H), 4.10-3.86