4090
J. S. Mojarrad et al. / Bioorg. Med. Chem. 13 (2005) 4085–4091
aromatic), 1525, 1353 (NO2) cmÀ1; 1H NMR (CDCl3) d
7.78 (d, J3,4 = 8.1 Hz, 1H, phenyl H-3), 7.47 (dd,
J4,5 = 8.1, J5,6 = 7.2 Hz, 1H, phenyl H-5), 7.29–7.36
(m, 2H, phenyl H-4, H-6), 4.89 (br s, 1H, NH), 4.49
(s, 1H, H-5), 3.37 (s, 3H, OCH3), 3.33 (dd, J1,6 = 10.2,
J1,NH = 2.4 Hz, 1H, H-1), 2.39 (d, J1,6 = 10.2 Hz, 1H,
H-6), 2.33 (s, 3H, C-3 CH3). Anal. Calcd for
C15H14Br2N2O4: C, 40.39; H, 3.16; N, 6.28. Found: C,
40.66; H, 3.01; N, 6.13.
3.71–3.91 (m, 2H, OCH2), 3.30 (dd, J1,6 = 10.4,
J1,NH = 2.4 Hz, 1H, H-1), 2.39 (d, J1,6 = 10.4 Hz, 1H,
H-6), 2.34 (s, 3H, C-3 CH3), 0.85 (t, J = 7.3 Hz, 3H,
CH2CH3). Anal. Calcd for C16H16Br2N2O4Æ3/4H2O: C,
40.57; H, 3.72; N, 5.93. Found: C, 40.40; H, 3.37; N,
5.53.
5.2.6. Isopropyl 7,7-dibromo-3-methyl-5-(2-nitrophenyl)-
2-azabicyclo[4.1.0]hept-3-ene-4-carboxylate (8f). Yellow
crystals (CH2Cl2/hexanes); mp 73–74 ꢁC (dec); yield
9%; IR (CHCl3) m 3118 (NH), 3027 (aromatic CH),
1672 (C@O), 1605 (C@C aromatic), 1530, 1356, 757
5.2.2. Methyl 7,7-dibromo-3-methyl-5-(3-nitrophenyl)-2-
azabicyclo[4.1.0]hept-3-ene-4-carboxylate (8b). Yellow
crystals (Et2O); mp 155–157 ꢁC (dec); yield 8%; IR
(NaCl) m 3302 (NH), 1677 (C@O), 1676 (C@C aro-
(NO2) cmÀ1
;
1H NMR (CDCl3)
d
7.63 (d,
J3,4 = 7.6 Hz, 1H, phenyl H-3), 7.47 (dd, J4,5 = 7.3,
J5,6 = 7.6 Hz, 1H, phenyl H-5), 7.29–7.39 (m, 2H, phenyl
H-4, H-6), 4.84 (br s, 1H, NH), 4.71 (heptet, J = 6.4 Hz,
1H, OCHMe2), 4.40 (s, 1H, H-5). 3.28 (dd, J1,6 = 10.4,
J1,NH = 2.4 Hz, 1H, H-1), 2.38 (d, J1,6 = 10.4 Hz, 1H,
H-6), 2.35 (s, 3H, C-3 CH3), 1.43 [d, J = 6.4 Hz, 3H,
CH(Me)2], 0.58 [d, J = 6.4 Hz, 3H, CH(Me)2]. Anal.
Calcd for C17H18Br2N2O4: C, 43.06; H, 3.83; N, 5.51.
Found: C, 43.10; H, 3.51; N, 5.71.
1
matic), 1530, 1346 (NO2) cmÀ1; H NMR (CDCl3) d
8.11 (d, J2,4 = 2.1, 1H, phenyl H-2), 8.07 (dd,
J2,4 = 2.1, J4,5 = 7.8 Hz, 1H, phenyl H-4), 7.64 (d,
J5,6 = 7.8 Hz, 1H, phenyl H-6), 7.46 (dd, J4,5 = 7.8,
J5,6 = 7.8 Hz, 1H, phenyl H-5), 4.87 (br s, 1H, NH),
4.20 (s, 1H, H-5), 3.49 (s, 3H, OCH3), 3.35 (dd,
J1,6 = 10.5, J1,NH = 2.1 Hz, 1H, H-1), 2.33 (s, 3H,
CH3), 2.19 (d, J1,6 = 10.5 Hz, 1H, H-6). Anal. Calcd
for C15H14Br2N2O4: C, 40.39; H, 3.16; N, 6.28. Found:
C, 40.36; H, 2.98; N, 6.06.
5.2.7. Isobutyl 7,7-dibromo-3-methyl-5-(2-nitrophenyl)-2-
azabicyclo[4.1.0]hept-3-ene-4-carboxylate (8g). Yellow
crystals (CH2Cl2/hexanes); mp 158–159 ꢁC (dec); yield
11%; IR (CHCl3) m 3316 (NH), 3010 (aromatic CH),
1673 (C@O), 1597 (C@C aromatic), 1524, 1351, 751
5.2.3. Methyl 7,7-dichloro-3-methyl-5-(2-nitrophenyl)-2-
azabicyclo[4.1.0]hept-3-ene-4-carboxylate (8c). Yellow
crystals (Et2O/hexanes); mp 166–168 ꢁC (dec); yield
10%; IR (NaCl) m 3318 (NH), 1683 (C@O), 1608
(NO2) cmÀ1
;
1H NMR (CDCl3)
d
7.84 (d,
(C@C aromatic), 1518, 1345 (NO2) cmÀ1
;
1H NMR
J3,4 = 7.9 Hz, 1H, phenyl H-3), 7.48 (dd, J4,5 = 7.4,
J5,6 = 7.9 Hz, 1H, phenyl H-5), 7.38 (d, J5,6 = 7.9 Hz,
1H, phenyl H-6), 7.32 (ddd, J3,4 = 7.9, J4,5 = 7.4,
J4,6 = 1.5 Hz, 1H, phenyl H-4), 4.84 (br s, 1H, NH),
4.51 (s, 1H, H-5), 3.58 (d, J = 6.7 Hz, 2H, OCH2), 3.29
(dd, J1,6 = 10.4, J1,NH = 2.4 Hz, 1H, H-1), 2.39 (d,
J1,6 = 10.4 Hz, 1H, H-6), 2.36 (s, 3H, C-3 CH3), 1.60
[m, 1H, CH(Me)2], 0.65 [d, J = 6.7 Hz, 3H, CH(Me)2],
0.57 [d, J = 6.7 Hz, 3H, CH(Me)2]. Anal. Calcd for
C18H20Br2N2O4: C, 44.29; H, 4.13; N, 5.74. Found: C,
44.58; H, 4.14; N, 5.67.
(CDCl3) d 7.77 (d, J3,4 = 8.1 Hz, 1H, phenyl H-3), 7.47
(dd, J4,5 = 7.5, J5,6 = 7.5 Hz, 1H, phenyl H-5), 7.29–
7.36 (m, 2H, phenyl H-4, H-6), 4.81 (br s, 1H, NH),
4.57 (s, 1H, H-5). 3.37 (s, 3H, OCH3), 3.28 (dd,
J1,6 = 10.2, J1,NH = 2.4 Hz, 1H, H-1), 2.34 (s, 3H, C-3
CH3), 2.30 (d, J1,6 = 10.2 Hz, 1H, H-6). Anal. Calcd
for C15H14Cl2N2O4: C, 50.44; H, 3.95; N, 7.84. Found:
C, 50.59; H, 4.22; N, 7.54.
5.2.4. Methyl 7,7-dichloro-3-methyl-5-(3-nitrophenyl)-2-
azabicyclo[4.1.0]hept-3-ene-4-carboxylate (8d). Yellow
crystals (Et2O/hexanes); mp 162–164 ꢁC (dec); yield
12%; IR (NaCl) m 3326 (NH), 1678 (C@O), 1602
5.2.8. tert-Butyl 7,7-dibromo-3-methyl-5-(2-nitrophenyl)-
2-azabicyclo[4.1.0]hept-3-ene-4-carboxylate (8h). Yellow
crystals (MeOH/H2O); mp 78–79 ꢁC (dec); yield 11%;
IR (CHCl3) m 3328 (NH), 3056 (aromatic CH), 1684
(C@O), 1616 (C@C aromatic), 1528, 1352, 762 (NO2)
(C@C aromatic), 1527, 1348 (NO2) cmÀ1 1H NMR
;
(CDCl3) d 8.11 (dd, J2,4 = 2.1, J2,6 = 2.1 Hz, 1H, phenyl
H-2), 8.06 (dd, J2,4 = 2.1, J4,5 = 7.8 Hz, 1H, phenyl H-4),
7.64 (d, J5,6 = 7.8 Hz, 1H, phenyl H-6), 7.46 (dd,
J4,5 = 7.8, J5,6 = 7.8 Hz, 1H, phenyl H-5), 4.80 (br s,
1H, NH), 4.28 (s, 1H, H-5), 3.50 (s, 3H, OCH3), 3.30
(dd, J1,6 = 10.5, J1,NH = 2.4 Hz, 1H, H-1), 2.34 (s, 3H,
C-3 CH3), 2.10 (d, J1,6 = 10.5 Hz, 1H, H-6). Anal. Calcd
for C15H14Cl2N2O4: C, 50.44; H, 3.95; N, 7.84. Found:
C, 50.61; H, 3.79; N, 7.65.
1
cmÀ1; H NMR (CDCl3) d 7.90 (d, J3,4 = 7.9 Hz, 1H,
phenyl H-3), 7.49 (dd, J4,5 = 7.3, J5,6 = 7.6 Hz, 1H, phe-
nyl H-5), 7.38 (d, J5,6 = 7.6 Hz, 1H, phenyl H-6), 7.35
(ddd, J3,4 = 7.8, J4,5 = 7.3, J4,6 = 1.5 Hz, 1H, phenyl H-
4), 4.72 (br s, 1H, NH), 4.34 (s, 1H, H-5), 3.23 (dd,
J1,6 = 10.4, J1,NH = 2.4 Hz, 1H, H-1), 2.36 (d,
J1,6 = 10.4 Hz, 1H, H-6), 2.32 (s, 3H, C-3 CH3), 1.06
(s, 9H, t-Bu). Anal. Calcd for C18H20Br2N2O4: C,
44.29; H, 4.13; N, 5.74. Found: C, 44.70; H, 4.12; N,
5.56.
5.2.5. Ethyl 7,7-dibromo-3-methyl-5-(2-nitrophenyl)-2-aza-
bicyclo[4.1.0]hept-3-ene-4-carboxylate (8e). Yellow crys-
tals (CH2Cl2/hexanes); mp 148–149 ꢁC (dec); yield
10%; IR (CHCl3) m 3331 (NH), 3012 (aromatic CH),
1690 (C@O), 1605 (C@C aromatic), 1527, 1348, 757
5.3. In vitro calcium channel antagonist assay
(NO2) cmÀ1
;
1H NMR (CDCl3)
d
8.55 (d,
Smooth muscle calcium channel antagonist activity
was determined as the molar (M) concentration of
the test compound required to produce 50% inhibition
of the muscarinic receptor-mediated (carbachol,
J3,4 = 8.5 Hz, 1H, phenyl H-3), 7.47 (dd, J4,5 = 7.0,
J5,6 = 7.0 Hz, 1H, phenyl H-5), 7.29–7.39 (m, 2H, phenyl
H-4, H-6), 4.87 (br s, 1H, NH), 4.49 (s, 1H, H-5).