396
L. Savini et al./Bioorg. Med. Chem. 6 (1998) 389±399
since compd 426 which does bear a 2-heterocyclic sub-
stituent, was a BzR agonist. The testing of further, and
eventually newly designed PQs, has been planned to
fully evaluate the in¯uence of the nature and position of
the substituents in the quinoline ring on the intrinsic
activity of congeners bearing a 2-heterocyclic substitu-
ent. Also in this case, theoretical and a molecular mod-
elling studies based on quantomechanical and 3-D
QSAR methods47 should lead to a better interpretation
of the structure±ecacy relationships data.
Chemical Experimental
Melting points were determined on a Buchi 510 capil-
lary melting point apparatus and are uncorrected.
Elemental analyses were performed on a Perkin±Elmer
elemental analyzer Mod. 240 and the data for C, H, N
are within 0.40% of calculated values. Spectral ana-
lyses (IR and 1H NMR) are consistent with the chemical
structures indicated. IR spectra were determined in
nujol mull on a Perkin±Elmer 398 or a Perkin±Elmer
Table 3. 1H NMR and IR spectral data of some representative PQ 4
1
Compound
1H NMR(d, ppm, J=Hz)
IR(cm
)
41
(DMSO-d6) d 7.44±7.67 (m, 3H, H-(7,8,9)), 8.08 (u dd, 1H, H-6, J6±7=7.8 Hz), 8.51 (s, 1H,
H-4), 11.37 (s, 1H, NH, D2O exchangeable), 12.43 (br s, 1H, NH, D2O exchangeable)
(DMSO-d6): 4.00 (s, 3H, OCH3), 7.14 (t, 1H), 7.27 (d, 1H, Jorto=8.0 Hz), 7.38±7.51 (m,
3H), 7.75 (d, 1H, Jorto=8.0 Hz), 8.18 (d, 2H), 8.31 (s, 1H, H-4), 12.24 (br s, 1H, NH, D2O
exchangeable).
1654 (CO)
1634 (CO)
410
412
413
(DMSO-d6) d 7.60 (td, 1H), 7.71±7.85 (m, 2H), 7.95 and 8.03 (2dd, 2H), 8.67 (u dd, 1H),
8.83 (s, 1H, H-4), 9.12 (t, 1H, H-20), 13.07 (br s, 1H, NH, D2O exchangeable).
(DMSO-d6) d 5.13 (br s, 2H, NH2, D2O exchangeable), 6.36 (u dd, 1H), 7.03 (t, 1H, H-50),
7.33 (u dd, 1H), 7.43 (t, 1H, H-20), 7.53 (td, 1H, H-7), 7.71±7.85 (m, 2H, H-(6,9)), 8.67 (s,
1H, H-4), 12.78 (br s, 1H, NH, D2O exchangeable).
1654 (CO)
1654 (CO)
418
(DMSO-d6) d 2.47 (t, 3H, CH3±CH2O), 4.16 (q, 2H, CH3±CH2O), 7.14 (t, 1PhH), 7.25 (dd,
1H, H-7, J7±6=9.0 Hz, J7±9=2.7 Hz), 7.42 (t, 2PhH), 7.55 (d, 1H, H-9, J9±7=2.7 Hz), 7.64
(d, 1H, H-6, J6±7=9.0 Hz), 8.21 (dd, 2PhH), 8.61 (s, 1H, H-4), 12.75 (br s, 1H, NH, D2O
exchangeable).
1625 (CO)
1670 (CO)
421
(DMSO-d6) d 0.94 (t, 3H, CH3±CH2±CH2±CH2±), 1.36 (st, 2H, CH3±CH2±CH2±CH2±),
1.66 (qt, 2H, CH3±CH2±CH2±CH2±), 2.77 (t, 2H, CH3±CH2±CH2±CH2±), 7.31 (td, 1H, H-5
pyridyl), 7.56 (u dd, 1H, H-7, J7±6=8.7 Hz), 7.69 (d, 1H, H-6, J6±7=8.7 Hz), 7.95±8.05 (m,
2H, H-9 and H-4 pyridyl), 8.34 (u dd, 1H, H-3 pyridyl, J3±4=8.4 Hz), 8.56 (u dd, 1H, H-6
pyridyl), 8.75 (s, 1H, H-4), 12.70 (br s, 1H, NH, D2O exchangeable).
428
(DMSO-d6) d 1.36±1.54 and 1.73±1.88 (2m, 10H, 5CH2 cyclohexyl), 2.53±2.72 (m, 1H, CH
cyclohexyl), 7.58±7.70 (m, 2H, H-(6,7)), 8.05 (d, 1H, H-9, J9±7=1.3 Hz), 8.48 and 8.60 (2d,
2H, H-(5,6)pyrazinyl, Jorto=2.6 Hz), 8.77 (s, 1H, H-4), 9.57 (u d, 1H, H-3 pyrazinyl), 12.89
(br s, 1H, NH, D2O exchangeable).
1665 (CO)
432
435
(DMSO-d6) d 7.36±7.74 (m, 5H, H-7 and 4PhH), 7.88 (d, 1H, H-6, J6±7=9.2 Hz), 7.99 (u d,
1H, H-9), 8.85 (s, 1H,H-4), 12.95 (br s, 1H, NH, D2O exchangeable).
(DMSO-d6) d 7.37±7.49 (m, 2PhH), 7.73 (dd, 1H, H-7, J7±6=9.1 Hz, J7±9=2.3 Hz), 7.88 (d,
1H, H-6, J6±7=9.1 Hz), 8.13 (u d, 1H, H-9), 8.28 (dt, 1H, H-60), 8.50 (s, 1PhH), 8.85 (s, 1H,
H-4), 13.00 (br s, 1H, NH, D2O exchangeable).
1625 (CO)
1633 (CO)
445
(DMSO-d6) d 7.69 (dd, 1H, H-7), 7.82 (d, 1H, H-6, J6±7=9.0 Hz), 8.03 (u d, 1H, H-9), 8.30
and 8.47 (2d, 4PhH, Jorto=9.5 Hz), 8.85 (s, 1H, H-4), 13.11 (br s, 1H, NH, D2O
exchangeable).
1620 (CO)
1654 (CO)
446
(DMSO-d6) d 5.03 (br s, 2H, NH2, D2O exchangeable), 6.61 (d, 2PhH, Jorto=8.8 Hz), 7.62
(dd, 1H, H-7, J7±6=9.1 Hz, J7±9=2.4 Hz), 7.73 (d, 2PhH, Jorto=8.8 Hz), 7.80 (d, 1H, H-6,
J6±7=9.1 Hz), 7.99 (u d, 1H, H-9), 8.69 (s, 1H, H-4), 12.85 (br s, 1H, NH, D2O exchange-
able).
456
463
465
(DMSO-d6) d 7.38 (u d, 1H, H-7), 7.72 (t, 2H, H-9 and H-5 pyrimidinyl), 8.51 (s, 1H, H-4),
8.86 (u d, 2H, H-(4,6) pyrimidinyl), 12.91 (br s, 1H, NH, D2O exchangeable).
(DMSO-d6) d 3.77 (s, 3H, OCH3), 7.01 (d, 2PhH, Jorto=9.1 Hz), 7.97±8.04 (m, 3H, H-9 and
2PhH), 8.56 (s, 1H, H-4), 13.15 (br s, 1H, NH, D2O exchangeable).
1655 (CO)
1635 (CO)
1660 (CO)
(DMSO-d6) d 3.83, 3.88, and 3.97 (3s, 9H, 3OCH3), 7.03 (s, 1H, H-6), 7.99 (d, 2PhH,
Jorto=8.7 Hz), 8.37 (d, 2PhH, Jorto=8.7 Hz), 8.60 (s, 1H, H-4), 12.60 (br s, 2H, NH and
COOH, D2O exchangeable).
468
(DMSO-d6) d 3.82, 3.88, and 3.93 (3s, 9H, 3OCH3), 7.04 (s, 1H, H-6), 8.42 and 8.55 (2d,
2H, H-(5,6)pyrazinyl, Jorto=2.5 Hz), 8.62 (s, 1H, H-4), 9.36 (u d, 1H, H-3 pyrazinyl), 12.61
(br s, 1H, NH, D2O exchangeable).
1660 (CO)