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. Author manuscript; available in PMC: 2012 Oct 11.
Published in final edited form as: J Med Chem. 1991 Jul;34(7):2133–2145. doi: 10.1021/jm00111a032

Table I.

Synthesis and Binding Affinity of Novel Pirenzepine Analogues. All Compounds Were Analyzed for C, H, and N within ±0.4%, Except Where Noted. Ki Values (±sem) for Inhibition of Binding of [3H]-N-Methylscopolamine Are Given for m1–m4 Muscarinic Receptors, for One to Three Determinations, Each Performed in Triplicate. R″ = H, Except for Compound 17 As Indicated. Binding Was Carried Out for 90 min at 37 °C, Using Membranes from Rat Heart Tissue (m2 Receptors) and Transfected A9L Cells (m1 and m3 Receptors) and in NG108-15 Cells (m4 Receptors) in the Presence of 0.5 nM [3H]-NMS. Ki Values Are Expressed in Units of Micromolar

graphic file with name nihms406053u2.jpg
compd R = R′ = mp, °C Anal. m1 m2 m3 m4
1 CH3 H 0.029 0.61 ± 0.05 0.24 0.33
3 0.0018 0.0503 0.0069 0.0174
11a CH3 8-SCH3 >205dec C20H23N5O2S·1HCl·1.5H2O 4.66 ± 1.02 11.0 3.62 ± 0.14 n.d.l
11b CH3 8-SO2NH2 C19H22N6O4S·0.5H2Oa >30 >30 >30 n.d.
11c CH3 8-SO2NH(CH2)2NHBoc 210–213 dec C26H35N7O6S·3oxalate·0.25H2O >30 n.d. >30 n.d.
11d CH3 8-SO2NH(CH2)2NH2 155–158 C21H27N7O4S·1.5oxalate·0.5H2O >30 n.d. >30 n.d.
11e CH3 8-SO2NH(CH2)2NHAc 190–193 C23H29N7O5S·2oxalate·0.5H2O >30 n.d. >30 n.d.
15 CH3 9-CH2OSi(CH3)2-t-Bu 245–248 C26H37N5O3Si·0.25H2O >30 4.4 ± 0.3 >30 n.d.
16 CH3 9-CH2OH C20H23N5O3·1.5H2O 4.4 n.d. 4.4 n.d.
17aj CH3 H 108–111 C21H25N5O2·1HCl·1.75H2O 7.7 ± 2.1 8.00 n.d. n.d.
17bk CH3 H oil C26H32N6O2·0.5H2O 8.9 ± 4.7 n.d. n.d. n.d.
18 H H >230 0.37 3.34 1.31 1.67
19a COCH3 H >290 C20H21N5O3·0.25H2O >100 >100 >100 >100
19b COC6H5 H 202–205 C25H23N5O3·HCl·0.75H2O >100 >100 >100 >100
20 SO2CH3 H 180–183 C19H21N5O4S·HCl >100 >100 >100 >100
21 CSNHC6H5 H 204–206 C25H24N6O2S·0.75H2O >100 >100 >100 >100
22 CH2≡CH H 249–251 C21H21N5O2 1.67 ± 0.06 1.37 ± 0.06 n.d. n.d.
23 CH2C6H5 H 145–148 C25H25N5O2·oxalate·H2Ob 0.33 0.24 ± 0.10 0.24 0.22
24a CH2C6H4-p-CONHCH3 H 191–193 C27H28N6O3·oxalate·0.5H2O 2.84 2.65 4.02 2.94
24b CH2C6H4-p-CONH(CH2)2NHBoc H 155–158 C33H39N7O5·oxalate·H2Oc n.d. 2.50 n.d. n.d.
24c CH2C6H4-p-CONH(CH2)2NH2 H 208–212 C26H31N7O3·oxalate·5H2Od 1.39 0.96 3.65 1.04
24d CH2C6H4-p-CONH(CH2)4NHBoc H 173–175 C35H43N7O5·oxalate·0.5H2O 1.68 1.09 3.47 n.d.
25 (CH2)2OH H 197–200 C20H23N5O3 5.8 ± 1.0 3.2 9.5 n.d.
26 (CH2)2Cl H 188–190 C20H22N5O2Cl·2HCl·1.5H2O 0.052 0.21 0.078 0.13
27 (CH2)2NH2 H 190–193 C20H24N6O2·1H2O 1.19 3.04 1.97 2.84
28 (CH2)2NHAc H 93–95 C22H26N6O3·0.75H2O 0.67 2.52 0.97 2.57
29a (CH2)2NHCO(CH2)2NHBoc H 112–115 C28H37N7O5·1CHCl3·0.5H2O 13.3 ± 5.95 6.06 6.19 ± 0.28 n.d.
29b (CH2)2NHCO(CH2)3NHBoc H 130–133 C29H39N7O5e 4.80 ± 1.36 3.34 4.10 ± 0.52 n.d.
30a (CH2)2NHCO(CH2)2NH2 H 85–88 C23H29N7O3·2.67TFA·1.55H2O 4.34 ± 0.26 5.84 6.65 ± 0.43 n.d.
30b (CH2)2NHCO(CH2)3NH2 H C24H31N7O3·3TFA 9.53 ± 2.46 6.34 11.5 ± 1.98 n.d.
31a (CH2)2NHCO(CH2)2NHAc H 180–183 C25H31N7O4·0.75H2O 39.4 ± 16.6 34.5 >100 n.d.
31b (CH2)2NHCO(CH2)3NHAc H 162–165 C26H33N7O4·2.75H2Of 9.65 ± 2.98 8.82 10.8 ± 0.45 n.d.
32d (CH2)6NHBoc H C29H40N6O4·oxalate·H2Og 0.0371 ± 0.0017 0.0214 ± 0.0039 0.0460 ± 0.0155 0.0232 ± 0.0053
33a (CH2)3NPth H 202–204 C29H28N6O4·0.75H2O 1.81 ± 0.40 0.84 ± 0.35 n.d. n.d.
33b (CH2)4NPth H 195–196 C30H30N6O4·oxalate·0.5H2O 0.17 ± 0.006 0.089 ± 0.005 0.12 0.21
33c (CH2)5NPth H 120–122 C30H32N6O4 0.060 ± 0.001 0.020 ± 0.001 n.d. n.d.
33d (CH2)6NPth H 157–158 C32H34N6O4·1DMF 0.018 ± 0.008 0.018 ± 0.003 n.d. n.d.
34a (CH2)3NH2 H 111–113 C21H26N6O2·1.5H2O 3.87 ± 0.12 5.12 ± 0.93 n.d. n.d.
34b (CH2)4NH2 H 121–123 C22H28N6O2·1H2O 3.08 ± 0.22 1.74 ± 0.03 n.d. n.d.
34c (CH2)5NH2 H 200–202 C23H30N6O2·1H2O 1.17 ± 0.01 5.89 ± 0.13 n.d. n.d.
34d (CH2)6NH2 H 138–140 C24H32N6O2·0.5CHCl3·0.67H2Oh 1.31 ± 0.02 1.34 ± 0.12 n.d. n.d.
34e (CH2)7NH2 H 72–75 C25H34N6O2·1.5-H2O 0.066 0.057 n.d. n.d.
34f (CH2)8NH2 H 65–68 C26H36N6O2·H2O 0.020 ± 0.001 0.026 ± 0.0005 n.d. n.d.
34g (CH2)9NH2 H 140–143 C27H38N6O2 0.024 ± 0.001 0.024 ± 0.007 n.d. n.d.
34h (CH2)10NH2 H 95–97 C28H40N6O2·1.5H2O 0.0158 ± 0.0009 0.0117 ± 0.0007 n.d. n.d.
35g (CH2)9NHAc H 170–173 C29H40N6O3·2oxalate 0.052 ± 0.001 0.050 ± 0.018 n.d. n.d.
35h (CH2)10NHAc H 87–90 C30H48N6O3·0.5H2O 0.075 ± 0.013 0.043 ± 0.025 n.d. n.d.
36 (CH2)10NEt2 H 168–171 C32H48N6O2·4oxalate·3H2O 0.0030 ± 0.0004 0.0135 ± 0.0009 n.d. n.d.
37 (CH2)10NHCH2-(o-MeO)Ph H 153–156 C36H48N6O3· 4oxalate·4H2Oi 0.0033 ± 0.0006 0.022 ± 0.0012 n.d. n.d.
a

Calcd 5.28 H, found 5.87.

b

Calcd 13.08 N, found 11.93.

c

Calcd 13.58 N, found 12.58.

d

Calcd 6.25 H, found 5.45.

e

Calcd 17.33 N, found 16.73.

f

Calcd 6.97 H, found 6.17.

g

Calcd 13.04 N, found 12.26.

h

Calcd 16.53 N, found 18.01.

i

Calcd 8.04 N, found 6.84.

j

R″ = Et.

k

R″ = (CH2)6CN.

l

n.d. = not determined.