J. M. Elliott et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5752–5756
5753
Ph
CO2Me
Ph
CO2Me
Ph
CO2Me
N
N
N
O
NH
OH
Ph
O
NH
O
NH
i, ii
O
iii, iv
27%
O
OH
NMe2
66%
N
N
Ph
N
Ph
2
3
Ph
CO2Me
N
2tBu
CO
R =
5a
5b
O
NH
CO2Me
OH
CO2H
x
= H
R
v, vi
vii-ix
15%
O
N
R
O
N R
xi
Pyran-4-yl 5c
= tBu
R =
R
41%
5d
N
Ph
N
Ph
N
Ph
4
Ph
CO2Me
Ph
CO2Me
Ph
CO2Me
N
N
N
O
NH
O
NH
O
NH
xii, xiii, x
57-84%
xiv
Br
NR2
44-80%
N
Ph
N
Ph
N
Ph
X
X
X
6
7
8
X = H, F
Ph
CO2Me
N
O
NH
O
CO2H
OH
xv-xix
77%
xx
vii-ix
35%
N
CO2tBu
N R
Ph
N
19%
NH
CO2tBu
N
Ph
N
Ph
2tBu
= CO
11a
11b
Pyran-4-yl 11c
R
9
10
x
xi
H
R =
R =
Scheme 1. Reagents and conditions: (i) BrCH2CO2Me, NaI, K2CO3, THF; (ii) LiBH4, THF; (iii) CBr4, Ph3P, CH2Cl2; (iv) Me2NH; (v) 1-(1,1-
dimethylethyl)-4-piperidinol or 1,1-dimethylethyl 4-hydroxypiperidinecarboxylate, DTBAD, Ph3P, THF; (vi) KOH, MeOH; (vii) (COCl)2, DMF,
CH2Cl2; (viii) PhNHNH2, K2CO3, CH2Cl2, H2O; (ix) MeOCOCl, PhMe; (x) TFA, CH2Cl2; (xi) tetrahydro-4H-pyran-4-one, NaBH(OAc)3, AcOH,
CH2Cl2; (xii) (BOC)2O, NaH, THF; (xiii) NBS, CCl4, hm; (xiv) R2NH, Et3N, THF, reflux; (xv) (BOC)2O, CH2Cl2; (xvi) DMSO, (COCl)2, Et3N,
CH2Cl2; (xvii) acetophenone, LiHMDS, THF; (xviii) MeSO2Cl, Et3N, CH2Cl2; (xix) H2, Pd–C, EtOAc; (xx) isatin, KOH, EtOH, H2O.
bromoacetate followed by reduction and replacement of
the terminal hydroxyl group gave 3 as shown (Scheme
1). However, alkylation of 2 to give more hindered cyclic
O-linked substituents at C-3 was low yielding; it proved
more efficient to O-alkylate the ester 4 with a suitable
piperidin-4-ol under Mitsonobu conditions. The N-pro-
tecting group was removed and the compound was fur-
ther elaborated under reductive amination conditions
(Scheme 1).
i-iii
tBuO2C
N
NH
HN
N
X
73-81%
X = CH2, O
Scheme 2. Reagents and condition: (i) cyclohexanone or tetrahydro-
4H-pyran-4-one, 1,2,3-triazole, PhCH3, reflux; (ii) MeMgCl, THF; (iii)
HCl, MeOH.
In order to introduce aminomethyl groups at C-3, the
versatile 3-bromomethyl precursors 7 (X = H, F) were
targeted. These were most efficiently prepared via radi-
cal bromination of 6 after initial protection of the hydra-
zide 2-nitrogen. Deprotection and facile displacement
with amines gave 3-aminomethyl derivatives (hindered
N-tert-alkyl piperazines were prepared as shown in
Scheme 2).
oline C-3 position improved hNK3R affinity. Further
exploration of the SAR showed that much larger alkoxy
and amine-containing substituents were tolerated at this
position (Table 1). This led, in some cases, to improved
affinity relative to 1 (e.g., 8j). Simple lipophilic groups at
C-3 did not have an effect on hPXR activation, but we
saw that certain amine containing side chains did reduce
or abolish this unwanted activity. The disruption of
hPXR activation was found to be quite selective, requir-
ing a basic nitrogen held some distance from the quino-
line core by a rigid, cyclic structure (e.g., 8b and 11b). If
the side chain was flexible (3); if the basicity was reduced
by benzylation (8h), removed by acylation (8i) or sulf-
onylation (8j); or if the basic center was too close to
the quinoline (8a), hPXR activation persisted.
Compounds with a C-linked piperidine at C-3 were pre-
pared via reaction of ketone 9 (prepared from piperi-
dine-4-methanol) with isatin under basic Pfitzinger
conditions4 to give 10 (Scheme 1). This was further elab-
orated as shown.
We have already reported1 that substitution at most of
the aromatic positions on the quinoline core was poorly
tolerated, but a range of small substituents at the quin-
We next explored the effect of N-alkylation of 8b and
11b. We were pleased to find that the disruption of