Synthesis of isomeric 3-piperidinyl and 3-pyrrolidinyl benzo[5,6]cyclohepta[1,2-b]pyridines: Sulfonamido derivatives as inhibitors of Ras prenylation

Article abstract of DOI:10.1016/S0968-0896(98)00026-1

Blocking farnesylation of oncogenic Ras proteins is a mechanism based therapeutic approach that is of current interest for the development of antitumor agents to treat ras associated tumors. As part of a SAR study on the lead farnesyl protein transferase (FPT) inhibitor I, we report here the synthesis of novel geometric isomers II and III and the FPT inhibition activity of their N-acyl and N-sulfonamido derivatives 15-65. The N-acyl derivatives are markedly less active than the lead inhibitor I thereby demonstrating that the spatial location of the N-acyl group in I is critical for binding of the compound to FPT. In contrast to I, the N-sulfonamido-II series is a novel lead of nonsulfhydryl, nonpeptidic compounds that are dual FPT/GGPT inhibitors. In light of recent reports on the alternative prenylation of N- and K-Ras, dual FPT/GGPT inhibitors may be required to control cell proliferation in tumors containing activated Ras. Copyright (C) 1998 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(98)00026-1

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 673±686
Synthesis of Isomeric 3-Piperidinyl and 3-Pyrrolidinyl
Benzo[5,6]cyclohepta[1,2-b]pyridines: Sulfonamido Derivatives
as Inhibitors of Ras Prenylation
Joseph Kelly,a Ronald Wolin,a Michael Connolly,a Adriano Afonso,a,*
Linda James,a Paul Kirshmeier,a W. Robert Bishopa and Andrew T. McPhailb
aSchering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
bP. M. Gross Chemical Laboratory, Duke University, Durham, NC 27706, USA
Received 23 September 1997; accepted 17 November 1997
AbstractÐBlocking farnesylation of oncogenic Ras proteins is a mechanism based therapeutic approach that is of
current interest for the development of antitumor agents to treat ras associated tumors. As part of a SAR study on the
lead farnesyl protein transferase (FPT) inhibitor I, we report here the synthesis of novel geometric isomers II and III
and the FPT inhibition activity of their N-acyl and N-sulfonamido derivatives 15-65. The N-acyl derivatives are
markedly less active than the lead inhibitor I thereby demonstrating that the spatial location of the N-acyl group in I is
critical for binding of the compound to FPT. In contrast to I, the N-sulfonamido-II series is a novel lead of non-
sulfhydryl, nonpeptidic compounds that are dual FPT/GGPT inhibitors. In light of recent reports on the alternative
prenylation of N- and K-Ras, dual FPT/GGPT inhibitors may be required to control cell proliferation in tumors
containing activated Ras. # 1998 Elsevier Science Ltd. All rights reserved.
Introduction
proliferation.1 Ras proteins are expressed in the cytosol
and require a post-translational farnesylation on the
cysteine residue of the carboxyl terminus CAAX tetra-
peptide in order to acquire transforming ability; this
prenylation step is catalyzed by the enzyme farnesyl
protein transferase (FPT), and the farnesylated-Ras
becomes functional by attachment to the inner plasma
membrane.5 A majority of other cellular proteins are
prenylated with a geranylgeranyl residue on the cysteine
of their carboxyl-terminus sequence; these prenylations
are catalyzed by Geranylgeranyl protein transferase
(GGPT), an enzyme which is closely related to FPT.5,6
Selective inhibition of farnesylation of Ras by FPT has
been an attractive therapeutic target for the develop-
ment of antitumor agents to control tumorigenic cell
proliferation in ras associated tumors.7,8 However, it is
now known that N- and K-Ras can also undergo
alternative prenylation.9±11 Most of the potent FPT
inhibitors reported in the literature to date are peptido-
mimetics or peptides based on the CAAX sequence and
contain a free thiol group.12 FPT inhibitors that are
nonthiol peptides have also been reported.13 However,
the peptidic nature or the presence of a free thiol group
ras Oncogenes are present in a majority of human colon
and pancreatic carcinomas.1 The pathway by which Ras
proteins regulate cell proliferation is now known; in this
pathway, Ras proteins occupy a central role in a signal
transduction cascade which is initiated by the binding of
extra-cellular growth factors to their tyrosine kinase
receptors, and ends in the nucleus with phosphorylation
of key transcription factors that regulate gene expres-
sion.2 The upstream signals in this cascade induce a gua-
nine nucleotide exchange that converts the inactive
GDP-bound Ras to its active GTP-bound state.3 Down-
stream signalling, and hence cell proliferation, proceeds
until it is terminated by intrinsic GTPase activity of Ras
which returns the active GTP-bound Ras to the inactive
GDP-bound state.2,4 Oncogenic Ras is de®cient in
GTPase activity and this results in uncontrolled cell
Key words: FPT Inhibitors; inhibitors of Ras prenylation; dual
FPT/GGPT inhibitors; sulfonamido tricycles as FPT inhibi-
tors; farnesyl protein transferase inhibitors.
*Corresponding author.
0968-0896/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00026-1

674
J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
in these FPT inhibitors may have disadvantages in the
development of such compounds as therapeutic agents.
Recently, our laboratories have reported on the dis-
covery of Sch 44342 (I) as a novel, nonpeptidic, non-
thiol-containing selective FPT inhibitor.14 As part of a
structure±activity study based on this lead series,15 it
was of interest to determine the e€ect of shifting the
nitrogen atom in the pendant 4-piperidine ring of I, to
the adjoining position thereby rendering the molecule
non-symmetrical and placing the N-substituents in two
di€erent spatial locations relative to the top benzocyclo-
heptapyridine tricycle; we report here the synthesis of
such geometric isomers IIa±b and IIIa±b, which contain
a 3-piperidino or 3-pyrrolidino ring.16 The FPT inhibition
activities of various N-acyl and N-sulfonamido deriva-
tives of these novel tricycles are reported.
Chemistry
The synthesis of the novel heterocycles II and III are
shown in Scheme 1. Addition of the anion derived from
N-methyl-2-piperidinone or N-benzyl-2-pyrrolidinone to
the known tricyclic ketone 1 (R=H or Br)17,18 followed
by acid catalyzed dehydration of the resulting diastereo-
isomeric mixture of alcohols 2a±c a€ords the ole®nic Z-
amides 3a±c and the E-amides 4a±c. Dehydration of the
individual diastereoisomers of 2a±c gave the same ratio
of 3a±c/4a±c.19a
Figure 1.
Scheme 1. Reagents: (i) N-Methyl-3-piperidinone or N-benzyl-pyrrolidinone, LDA, THF; (ii) concd sulfuric acid; (iii) propionic acid/
p-TsOH; (iv) LAH in THF; (v) LAH in ether; (vi) ClCO2Et, toluene, triethylamine, 80 ꢀC; (vii) 10% pd/C, 1,4-cyclohexadiene, acetic
acid-methanol; (viii) concd HCl, 80 ꢀC.

J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
675
Reduction of the lactam 3a with LAH in THF a€orded
only the desired amine 5a. LAH reduction of the lac-
tams 3b±c on the other hand, a€orded the desired
amines 5b±c and also the novel rearrangement products
6b±c.19b LAH reduction of lactams 4b±c in THF a€or-
ded the E-piperidines 10b±c. Under these same condi-
tions, 4a was converted into the isomeric amines 10a
and 5a in a 1:1 ratio; however, 10a was formed selec-
tively when the LAH reduction was carried out in ether.
N-Dealkylation of the E-isomers 10a±c with ethyl
chloroformate a€orded the carbamates 11a±c, which
were hydrolyzed under acidic conditions to the desired
E-amines 12a±c.19b Under the same conditions, N-de-
alkylation of the Z-isomers 5b±c a€orded the expected
carbamates 7b±c and the novel indolizidene re-arrange-
ment products 8b±c; N-dealkylation of 5a using the
same reaction conditions favors exclusively the forma-
tion of the rearrangement product. The ®nal Z-amines
9a±c were obtained by acid hydrolysis of the carbamates
7b±c and by careful hydrogenolysis of 5a; catalytic
hydrogenation of 5a under less controlled conditions
a€orded 9±d, the product of hydrogenolyses of both the
N-benzyl and the 8-chloro groups.
The Z- and E-amines 9a±d and 12a±c were acylated with
various carboxylic acids using standard carbodiimide
reaction conditions to obtain the N-acyl derivatives 15±
22, and 47±50 in the piperidine series, and 45±46 and
63±65 in the pyrrolidine series. Similarly, the N-sulfon-
amido derivatives 23±40, and 52±60 in the piperidine
series and 41±44 and 61±62 in the pyrrolidine series were
prepared by conventional sulfonation employing the
appropriate sulfonyl chloride and Et3N in methylene
chloride.19c,20 Miscellaneous derivatives 21, 22, and 51
were obtained from the amines 9b and 12b. For com-
parison purposes, a few sulfonamides 67±73 in the lead
series I were prepared from 66.
Scheme 2. Reagents: (i) p-Nitrobenzenesulfonyl chloride, pyr-
idine, 0 ꢀC; (ii) ArCOOH, EDCI, HOBT, DMF, 0 ꢀC; (iii)
Method A: ArSO2Cl, pryidine, 0 ꢀC; Method B (Ref. 16c): 14,
pyridine, 0 ꢀC.
Sulfonamido derivatives of the Z- and E-isomers in both
the 3-piperidino (23±40 and 52±60) and 3-pyrrolidino
series (41±44 and 61±62) are generally more active than
sulfonamido derivatives of the 4-piperidino series (com-
pounds 67±73) and follow an opposite SAR. For exam-
ple the methyl sulfonamide of II (compound 23) is
inactive while the same derivative of I (compound 67) is
active in the FPT assay; the aromatic sulfonamides of II
(compounds 24, 36, and 37) are more active than the
corresponding derivatives of I (compounds 68, 72, and
73).
Biology
Compounds 15±73 were tested in an FPT assay; details
of this assay have been described previously.14 The
assay measures the inhibition of FPT catalyzed transfer
of [3H]farnesyl group from [3H]farnesyl-pyrophosphate
to H-Ras-CVLS. Results of these assays are given in
Tables 1±3.
Sulfonamides 52, 57, 59, 60 of the E-isomers are 10
times less active than the corresponding Z-compounds
24, 3, 36, and 38. The discussion that follows below
concerns the sulfonamides of the Z-isomer in the 3-
piperidine and 3-pyrrolidine series II.
Acyl derivatives of the Z- and E-isomers in both the 3-
piperidino (15±22 and 47±50) and 3-pyrrolidino series
(45±46 and 63±65) are generally less active as FPT
inhibitors relative to acyl derivatives in the 4-piperidino
series such as I.14,15 The 3-pyridylacetyl derivatives 16
and 47, and the 4-thiopyridylacetyl derivatives 45 and
63, are weakly active (IC50 4±7 mM). Thus far, no clear
SAR is evident from the acyl derivatives.
The activity of the phenylsulfonamide 24 was lost by
introducing para-substituents on the phenyl ring (e.g.
25±30). The loss in activity is not attributable to the
electronic nature of the substituent since both electron
withdrawing and donating groups give rise to less

676
J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
Table 1. Structure±activity of Z-piperidine and pyrrolidine derivatives
No.
n
R
R1 R2
Formulaa
mp (ꢀC)b
FPT Activity
IC50 (mM) %Inhib. (mM)c
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
Br
H
H
H
H
H
H
Cl 3-Pyridyl-CO-
C25H22ON3Cl
C26H24ON3Cl
C26H24ON3Cl
>14
Cl 3-Pyridyl-CH2CO-
Cl 4-Pyridyl-CH2CO-
Cl Phenyl-CO-
7.8
9 (14)
NA
>14
C
26H23ON2Cl
215±216
Cl Phenyl-CH2CO-
C27H25ON2Cl
C28H27ON2Cl
Cl Phenyl-CH2CH2CO-
Cl Phenyl-NH-CO-
Cl Phenyl-S-CO-
NA
C
26H24ON3Cl
184±185
187±188
189±190
10 (46)
6 (13)
15 (15)
0.71
C26H23ON2ClS
C20H21O2N2ClS
C25H23O2N2ClS
C27H26O3N3ClS
C26H25O3N2ClS
C25H22O4N3ClS
C25H22O2N2FS
C26H25O2N2ClS
C28H29O2N2ClS
C26H25O2N2ClS
C23H21O2N2ClS2
C23H20O2N2ClS2
C24H21O4N2ClS
C25H23O4N2ClS
C24H22O2N3ClS
C23H20O2N2BrClS2
C23H19O2N2BrCl2S2
C25H22O2N2BrClS
C24H23O2N4BrCl2S
C24H21O2N2ClSd
C24H22O2N2Sd
Cl CH3SO2-
Cl Phenyl-SO2-
Cl p-Acetamido-Phenyl-SO2-
Cl p-Methoxy-Phenyl-SO2-
Cl p-Nitro-Phenyl-SO2-
Cl p-Fluoro-Phenyl-SO2-
Cl 4-Methyl-Phenyl-SO2-
Cl 2,4,6-Tri-Me-Phenyl-SO2-
Cl Phenyl-CH2SO2-
Cl 2-Thienyl-SO2-
162±163
160±161
178±179
173±174
NA
33 (42)
33 (42)
1.34
35 (13)
12 (12)
13 (13)
0.44
227±229
198±199
Cl 5-Chloro-2-Thienyl-SO2-
Cl 5-Carboxy-2-Thienyl-SO2-
Cl 5-CO2CH3-2-Thienyl-SO2-
Cl 3-Pyridyl-SO2-
154±155
228±229
134±136
158±159
183±184
165±167
184±185
251±252
0.19
47 (40)
4.4
0.97
Cl 2-Thienyl-SO2-
Cl 5-Chloro-2-Thienyl-SO2-
Cl Phenyl-SO2-
0.84
0.47
0.58
Cl 5-Cl-1,3-diMe-4-Pyrazole-SO2-
Cl Phenyl-SO2-
NA
0.59
2.8
H
Phenyl-SO2-
Cl 2-Thienyl-SO2-
2-Thienyl-SO2-
d
C22H19O2N2ClS2
d
0.52
3.3
H
C22H20N2S2
C25H22ON3CISd
C25H22ON3Cl
Cl 4-Pyridyl-S-CH2-CO-
Cl 4-Pyridyl-CH2CO-
4.2
37 (14)
aExcept where noted, elemental analysis within 0.4% of theoretical values was obtained.
bMelting points are uncorrected; no entries indicates that the compound is amorphous.
cSee Refs 14 and 21 for assay details; NA indicates that no inhibition activity was observed.
dHigh-resolution mass spectra data was obtained.
potent compounds. Heteroaromatic sulfonamides, such
as the 2-thienyl analogues 32±35 and the 3-pyridyl deri-
vative 36 are potent FPT inhibitors, with the 5-chloro-
2-thienyl analogue 33 displaying an IC50=0.19 mM.
Incorporation of a 3-bromo substituent as in 37±39 does
not have a signi®cant e€ect on the FPT activity; in
contrast to this, an 8-chloro substituent enhances the
FPT inhibition activity sixfold as in 41, 43 versus 42,
44.
Since prenylation by GGPT is common to many cellular
proteins, selectivity in FPT versus GGPT inhibition has
been an important criterion for the development of an
FPT inhibitor as an antitumor agent. A selected number
of the above FPT inhibitors were therefore evaluated in
a GGPT assay, which measures the ability of a com-
pound to inhibit GGPT catalyzed transfer of the [3H]-
geranyl-geranyl group from [3H]-geranyl-geranyl pyro-
phosphate to H-Ras-CVLL. A few compounds from

J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
Table 2. Structure±activity of E-piperidine and pyrrolidine derivatives
677
FPT Activityc
IC50 (mM) %Inhib. (mM)
No.
n
R
R2
Formulaa
mp (ꢀC)b
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
1
H
H
H
H
H
H
H
H
H
H
H
H
H
3-Pyridyl-CH2CO-
4-Pyridyl-CH2CO-
3-Pyrdyl-CH=CHCO-
Phenyl-CH2CH2CO-
p-NO2-Phenyl-S-
C26H24ON3Cl
C26H24ON3Cl
157±158
165±166
5.1
42 (14)
8 (45)
C27H24ON3Cl
C28H27ON2Cl
27 (45)
12 (43)
C25H22O2N3ClS
C25H23O2N2ClS
C27H26O3N3ClS
C26H25O3N2ClS
C25H22O4N3ClS
C25H22O2N2ClFS
C23H21O2N2ClS
C31H28O3N3ClS2
C24H22O2N3ClS
C23H19O2N2BrCl2S2
C24H21N2O2ClSd
173±174
235±236
147±149
168±169
232±233
154±155
254±255
Phenyl-SO2-
3.3
33.5
p-Acetamido-Phenyl-SO2-
p-Methoxy-Phenyl-SO2-
p-Nitro-Phenyl-SO2-
p-Fluoro-Phenyl-SO2-
2-Thienyl-SO2-
32 (42)
29 (40)
45 (43)
4.8
5-PhCONHCH2-2-Thienyl-SO2-
3-Pyridyl-SO2-
17 (34)
214±215
171±172
181 (dec)
173 (dec)
8.8
8.0
4.0
5.1
6.9
Br 5-Chloro-2-Thienyl-SO2-
H
H
H
H
H
Phenyl-SO2-
d
2-Thienyl-SO2-
4-Pyridyl-S-CH2-CO-
4-Pyridyl-CH2CO-
2-Furanyl-CO-
C22H19N2O2ClS2
C25H22N3OClSd
C25H22N3OCld
C23H19N2O2Cld
11 (14)
33 (50)
190-192
a-dRefer to footnotes under Table 1.
Table 3. Structure±activity of piperidino sulfonamides
FTP Activityc
No.
R3
Formulaa
mp (ꢀC)b
174±175
IC50 (mM)
1.9d
%Inhib. (mM)
67
68
69
70
71
72
73
CH3
Phenyl-
C25H23O2N2ClS
C26H25O2N2ClS
NA
NA
p-CH3-Phenyl-
p-AcNH-Phenyl-
p-NO2-Phenyl-
2-Thienyl-
3-Pyridyl-
C27H26O3N3ClS
C25H22O4N3ClS
157±158
230±231
NA
>12d
13d
6.6
C24H22O2N3ClS
103±105
a-cRefer to footnotes under Table 1.
dData from Ref. 15c.
this group were also evaluated in a COS assay which
measures transient expression and processing (farnesyl-
ation) of H-Ras-CVLS in COS monkey kidney cells.
Details of these assays have been reported previously,14
and the results are shown in Table 4. The data in Table 4
indicate that none of the compounds tested shows
high selectivity for FPT versus GGPT inhibition; the
GGPT inhibitory concentration for these compounds is

678
J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
Table 4. Prenylation selectivity
leads to nonselective binding resulting in dual FPT/
GGPT inhibitors.
FPTc
GGPT
% Inhib.
COSc
No.
Selective inhibition of farnesylation of Ras by FPT has
been an important criterion for the development of
antitumor agents to control tumorigenic cell prolifera-
tion in tumors containing activated Ras.7,8 However, it
has been recently reported that N-Ras, K-Ras4B and K-
Ras4A are in vitro substrates for both FPT and
GGPT;9,10 a more recent report demonstrated that in
the presence of the potent FPT inhibitor 3-bromo-I, Ras
proteins in the human colon carcinoma cell line DLD-1
are alternatively prenylated by GGPT.11 In light of
these reports on the alternative prenylation of N- and
K-Ras, dual FPT/GGPT inhibitors may be required to
block Ras prenylation and to control cell proliferation
in tumors containing activated Ras. In summary, the
present N-sulfonamido series II is a novel lead of non-
sulfhydryl, nonpeptidic compounds that are dual FPT/
GGPT inhibitors; further chemical modi®cations of the
series are needed to attain potency and the proper bal-
ance of FPT/GGPT inhibition. The SAR developed
from this study is being used to design improved FPT
inhibitors of the lead compound I.
IC50
(mM)
% Inhib.
(mM)
IC50
(mM)
IC50
(mM)
(mM)
21
24
25
28
32
33
37
39
41
42
43
44
16
10 (46)
1 (39)
0.8
2.6
2.6
4.9
4.4
0.71
2.5
1.34
0.44
0.19
0.84
0.58
0.59
2.8
68 (4)
18 (37)
29 (38)
>5
>5
7.1
47 (50)
56 (4.5)
39 (49)
17 (12)
0.52
3.3
7.8
cRefer to footnotes under Table 1.
only 4±100 times less than their FPT IC50. A 3-bromo
substituent decreases the GGPT inhibitory activity
thereby increasing the FPT/GGPT selectivity as in 37,
39 versus 32, 24. The prenylation inhibition selectivity
can be o€set to favor GGPT inhibition by changing the
nitrogen substituent as in the acyl derivative 21 and the
sulfonamide analogue 25, which are selective GGPT
inhibitors. Of the three compounds tested in the COS
assay, 24 has a reasonable ratio for cell-based/in vitro
enzyme FPT inhibitory activity.
Experimental
Reactions were performed under conventional techni-
ques: employing oven dried glassware, nitrogen atmo-
sphere, and commercial or freshly dried/distilled
solvents. Extracts of crude reaction products were dried
over anhydrous magnesium sulfate (MgSO4) or sodium
sulfate (Na2SO4), evaporated under reduced pressure
and puri®ed by ¯ash chromatography using Selecto
Scienti®c 32-63 mesh silica gel. Melting points are
uncorrected. 1H NMR spectra were determined on a
Varian VXR 200 or Gemini 300 MHz spectrometer
using CDCl3, CD3OD, or DMSO-d6 solutions and TMS
as internal standard. 13C NMR spectra were obtained at
75 MHz with the chemical shifts reported in ppm rela-
tive to the central line of CDCl3 (77.00 ppm). Mass
spectra were determined either on Extrel 401, Jeol or
VG Zab-SE mass spectrometer. Unless otherwise noted
elemental analyses were within 0.4% of theoretical
value.
Conclusions
Several conclusions are evident from the above study.
Foremost, it demonstrates that the spatial location of
the N-acyl group in the lead compound I is critical for
binding of the compound to FPT; alteration in the
location of this N-acyl functionality as in N-acyl deri-
vatives of II and III leads to a marked loss in FPT
inhibition activity. The N-sulfonamido derivatives of
the Z-isomer II, on the other hand, are potent FPT
inhibitors relative to the corresponding sulfonamido
derivatives of E-isomer III and the lead tricycle I. These
N-sulfonamido compounds of type II do not follow the
SAR of the corresponding derivatives of the lead tri-
cycle I. More detailed studies of the FPT active N-sul-
fonamido analogues showed that the compounds are
also inhibitors of GGPT; the degree of this dual inhibi-
tion ranges from 4- to 100-fold in favor of FPT inhibi-
tion; a 3-bromo substituent increases the FPT/GGPT
selectivity. These ®ndings suggest that the binding mode
of II to the FPT protein is di€erent from that of I, and
this change in the spatial location of the N-functionality
3-Bromo-8-chloro-6,11-dihydro-11-hydroxy-11-(1-methyl-
2-oxo-piperidin-3-yl)-5H-benzo[5,6]cyclohepta[1,2-b]pyr-
idine (2c). n-Butyllithium (2.5 M in hexanes, 18 mL,
45.0 mmol) was added dropwise to a solution of diiso-
propylamine (7.0 mL, 49.4 mmol) in THF (100 mL) at
78 ꢀC, stirred for 30 min and N-methyl-2-piperidone
(7.0 mL, 64 mmol) was added dropwise. The resultant
solution was stirred for 30 min and then allowed to warm
to 5 ꢀC over a 60 min period. The reaction mixture was

J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
679
cooled to 78 ꢀC and a solution of 3-bromo-8-chloro-
5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-
one (1, R=Br)18 (12 g, 37.2 mmol) in THF (200 mL) was
added dropwise. The mixture was stirred at 78 ꢀC for
1 h, then warmed to 10 ꢀC over a 1 h period. Water
(25 mL) was added, the mixture concentrated to ca.
100 mL, then extracted with methylene chloride
(500 mL). The product crystallized on addition of acet-
one:ether (50 mL, 1:1). The solid was ®ltered, washed
with ether (10 mL) and dried yielding 11.89 g of 2c. The
mother liquor was concentrated and upon chromato-
graphy using ethyl acetate:hexanes (1:3) yielded an
additional 1.0 g of 2c (79.56% total yield, mixture of
diastereoisomers): MS(CI) m/z 435 (MH+); Anal. (C19
H18BrClN2O2) C, H, N.
THF/CH2Cl2) as an amorphous solid (45%): H NMR
(300 MHz, CDCl3) d 8.5 (d, 1H, J=4.2 Hz), 8.1 (d,
J=8.5 Hz), 7.8 (s, 1H), 7.6 (d, J=7.8 Hz), 7.2±7.5 (m,
8H), 4.5 (apparent q, 2H, J=14.7 Hz), 3.9±4.0 (m, 1H),
3.6±3.9 (m, 2H), 3.4±3.5 (m, 1H), 3.1±3.3 (m, 3H), 2.15±
2.30 (m, 1H), 1.8±1.95 (m, 1H). 13C NMR (75 MHz,
CDCl3) d 172.95, 157.51, 144.00, 143.95, 141.76, 139.61,
137.67, 136.83, 133.31, 132.29, 130.72, 128.82, 128.78,
128.37, 127.59, 126.50, 123.52, 50.05, 46.91, 45.48,
32.31, 31.33, 21.02. MS (CI) m/z 385 (MH+); Anal
(C25H23N2O2Cl), C, H, N.
1
3-(3-Bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclo-
hepta[1,2-b]pyridin-11-ylidene)-1-methyl-2-piperidinone
(3c and 4c). A solution of 2c (11.4 g, 26.1 mmol) in con-
centrated sulfuric acid (100 mL) was stirred at 80 ꢀC for
4 h, then cooled to 20 ꢀC. The reaction mixture was
poured into ice (300 g) and basi®ed with 50% NaOH.
The precipitated solid was ®ltered, washed with water
(200 mL), dried and chromatographed eluting with ethyl
acetate:methanol, 98:2 to yield the Z-isomer (3c) as a
8-Chloro-6,11-dihydro-11-hydroxy-11-(1-methyl-2-oxo-pip-
eridin-3-yl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (2b).
Reaction of N-methyl-2-piperidone with 8-chloro-5,6-
dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one
(1, R=H)17 using the procedure for 2c a€orded 2b
(76% yield, 10:1 mixture of diastereoisomers). The dia-
stereoisomers were isolated by chromatography. Dia-
stereomer A (minor product), higher Rf on TLC (40%
1
white solid (4.48 g, 41%): H NMR d 8.38 (s, 1H), 7.58
(s, 1H), 7.17 (s, 3H), 3.3±3.6 (m, 4H), 2.92 (s, 3H), 2.7±2.9
(m, 3H), 2.30±2.45 (m, 1H), 1.95±2.15 (m, 2H); MS(CI)
m/z 417 (MH+); Anal. (C20H18BrClN2O) C, H, N. The
E-isomer (4c) was eluted as a white solid (4.68 g, 43%):
1H NMR (300 MHz, CDCl3) d 8.46 (s, 1H), 7.61(s, 1H),
7.14 (s, 1H), 7.10 (s, 2H), 3.25±3.60 (m, 4H), 2.94 (s,
3H), 2.70±2.90 (m, 3H), 1.80±2.20 (m, 3H); MS(CI) m/z
417 (MH+); Anal. (C20H18BrClN2O) C, H, N.
EtOAc-Hexanes): mp 164±166 ꢀC; H NMR (300 MHz,
1
CDCl3) d 8.30 (d, 1H), 7.95 (d, 1H), 7.47 (d, 1H), 7.35
(s, 1H), 7.16 (m, 2H), 7.01 (s, 1H), 3.75 (m, 2H), 3.40
(m, 2H), 3.15 (m, 5H), 2.91 (s, 3H), 1.85 (m, 1H), 1.30
(m, 1H); MS(CI), m/z 357 (MH+). Anal (C20H21
ClN2O2) C, H, N. Diastereomer B (major product)
Lower Rf on TLC: mp 164±165 ꢀC; 1H NMR (300 MHz,
CDCl3) d 8.30 (d, 1H), 7.95 (d, 1H), 7.67 (s, 1H), 7.42
(d, 1H), 7.15 (m, 2H), 7.08 (s, 1 H), 3.60-3.80 (m, 2H),
3.45 (m, 2H), 3.15 (m, 1H), 3.05 (m, 2H), 2.86 (s, 3H),
1.90 (m, 2H), 1.60(m, 1H), 1.50 (m, 1H); MS(CI) m/z
357 (MH+); Anal (C20H21ClN2O2) C, H, N.
Dehydration of 2b and 2a by the above procedure fol-
lowed by chromatography a€orded the following com-
pounds 3b, 4b and 3a, 4a
(Z)-3-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta
[1,2-b]pyridin-11-ylidene)-1-methyl-2-piperidinone (3b).
White solid (40%): mp 179±181 ꢀC; 1H NMR
(300 MHz, CDCl3) d 8.35 (d, 1H), 7.55 (d 1H), d 8.35 (d,
1H), 7.55 (d, 1H), 7.2 (m, 2H), 7.0±7.1 (m, 2H), 3.3±3.6
(m, 4H), 2.92 (s, 3H), 2.7±2.9 (m, 3H), 2.0±2.2 (m, 2H),
1.90 (m, 1H); MS(CI) m/z 339 (MH+).
8-Chloro-6,11-dihydro-11-hydroxy-11-(1-benzyl-2-oxo-pyr-
rolidin-3-yl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (2a).
Reaction of N-methyl-2-pyrrolidinone with 8-chloro-
5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-
one (1, R=H)17 using the procedure for 2c a€orded 2a.
The less polar diastereoisomer A was insoluble in warm
EtOAc and was isolated as a white crystalline solid
(E)-3-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta
[1,2-b]pyridin-11-ylidene)-1-methyl-2-piperidinone (4b).
White solid (40%): mp 133 ꢀC; 1H NMR (300 MHz,
CDCl3) d 8.40 (d, 1H), 7.44 (d, 1H), 7.18 (d, 1H), 7.0±
7.15 (m, 3H), 3.3±3.6 (m, 4H), 2.92 (s, 3H), 2.7±2.9 (m,
3H), 2.0±2.2 (m, 2H), 1.90 (m, 1H); MS(CI) m/z 339
(MH+).
(42%): mp 164±166 ꢀC; H NMR (300 MHz, CDCl3) d
1
8.4 (d, 1H, J=4.8 Hz), 8.1 (d, 1H, J=8.6 Hz), 7.6 (d,
1H, J=6.7 Hz), 7.19±7.45 (m, 9H), 4.5 (apparent q, 2H,
J=14.7 Hz), 3.75±3.90 (m, 2H), 3.5±3.6 (m, 1H), 3.35±
3.45 (m, 1H), 3.1±3.2 (m, 3H), 1.7±1.9 (m, 2H). 13C
NMR (75 MHz, CDCl3) d 172.83, 157.96, 144.33,
141.02, 140.03, 137.21, 136.95, 133.13, 132.13, 130.25,
129.78, 128.76, 128.38, 127.53, 126.22, 123.76, 49.79,
46.89, 45.17, 32.56, 31.31, 20.70. MS (CI) m/z 385
(MH+); Anal. (C25H23N2O2Cl), C, H, N. The more
polar diastereoisomer B was isolated by chromato-
graphy from the EtOAc soluble fraction (solvent: 2±5%
(Z)-3-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta
[1,2-b]pyridin-11-ylidene)-1-benzyl-2-pyrrolidinone (3a).
(83% for 3a/4a combined): mp 178±180 ꢀC; 1H NMR
(300 MHz, CDCl3) d 8.5 (d, 1H, J=5.1 Hz), 7.2±7.6 (m,
10H), 4.63 (AB quartet, 2H, J=14.4 Hz), 3.25±3.60 (m,

680
J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
5H), 2.85±3.10 (m, 2H), 2.45±2.60 (m, 1H). 13C NMR
(75 MHz, CDCl3) d 166.81, 156.22, 146.55, 143.01,
138.21, 138.14, 136.27, 138.83, 133.48, 133.22, 131.46,
131.42, 128.52, 128.17, 128.09, 127.45, 125.32, 122.77,
46.95, 42.96, 31.42, 31.39, 24.60; MS(CI), m/z 401
(MH+); Anal. (C25H23N2OCl), C, H, N.
12-Chloro-1,2,3,4,9,10-hexahydro-4-methyl-benzo[4,5]-
cyclohepta[1,2,3-hi]pyrido[3,2-b]indolizine (6b). Yellow
crystals (25%): mp 170±172 ꢀC; 1H NMR (300 MHz,
DMSO-d6) d 7.70 (d, 1H), 7.49 (d, 1H), 7.26 (s, 1H),
7.23 (d, 1H), 6.51 (m 1H), 6.46 (m, 1H), 3.17 (m, 4H),
2.70 (m, 4H), 2.66 (s, 3H), 1.80-1.95 (m, 2H); MS(CI) m/
z
C20H20N2Cl 322.1237, measured 322.1233.
322 (MH+); X-ray; HRMS calcd (MH+) for
(E)-3-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta-
[1,2-b]pyridiꢀn-11-ylidene)-1-benzyl-2-pyrrolidinone (4a).
1
Mp 90±100 C; H NMR (300 MHz, CDCl3), d 8.5 (d,
(Z)-8-Chloro-6,11-dihydro-11-(1-benzyl-3-pyrrolidene)-
5H-benzo[5,6]cyclohepta[1,2-b]pyridine (5a). (54%) 1H
NMR (300 MHz, CDCl3) d 8.4 (d, 1H, J=ꢁ5 Hz), 7.0±
7.4 (m, 10H), 3.55±3.75 (m, 3H), 3.18±3.42 (m, 3H),
2.68±2.94 (m, 4H), 2.5±2.58 (m, 1H), 2.2±2.3 (m, 1H).
13C (75 MHz, CDCl3) d 156.52, 146.68, 144.34, 140.58,
139.22, 139.11, 138.11, 132.99, 132.91, 131.63, 130.48,
129.04, 128.46, 127.14, 126.55, 122.20, 60.99, 59.39,
53.88, 32.53, 31.68, 31.54. MS(CI) m/z 386 (MH+).
HRMS calcd. for C25H24N2Cl: 387.1628; Found,
387.1609. Anal. (C25H23N2ClÂ0.25 mol H2O) C, H, N.
1H, J=5.1 Hz), 7.6 (d, 1H, J=7.2 Hz), 7.2±7.5 (m, 9H),
4.5 (AB quartet, 2H, J=14.7 Hz), 3.25±3.58 (m, 4H),
3.1±3.21(m, 1H), 2.85±3.10 (m, 2H), 2.59±2.65 (m, 1H).
13C NMR (75 MHz, CDCl3) d 166.49, 157.02, 146.81,
143.72, 139.22, 136.77, 136.52, 136.45, 133.83, 132.23,
131.52, 130.27, 129.06, 128.84, 128.66, 127.78, 126.52,
123.16, 47.37, 43.33, 32.32, 30.78, 24.62; MS(CI), m/z
401 (MH+); Anal, (C25H23N2OCl), C, H, N.
(Z)-3-Bromo-8-chloro-6,11-dihydro-11-(1-methyl-3-piper-
idinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (5c)
and 7-bromo-12-chloro-1,2,3,4,9,10-hexahydro-4-methyl-
benzo[4,5]cyclohepta[1,2,3-hi]pyrido[3,2-b]indolizine (6c).
LAH (110 mg, 2.78 mmol) was added to 3c (1.0 g,
2.39 mmol) in THF (10 mL) at 5 ꢀC and the resultant
solution was stirred at this temperature for 2 h. The
reaction was quenched by addition of ethyl acetate
(2 mL) followed by a solution of 10% potassium sodium
tartrate tetrahydrate (20 mL) and 10% sodium hydr-
oxide (5 mL). The mixture was extracted with methylene
chloride (150 mL) and chromatographed on silica gel
eluting with hexanes:ethylacetate 5:1 yielding the title
compound (6c) as a solid, which was recrystallized from
methanol:ether as yellow needles (240 mg, 25%): mp
155±156 ꢀC; 1H NMR (300 MHz, CDCl3) d 7.83 (s, 1H),
7.55 (d, 1H), 7.30 (s, 1H), 7.25 (d, 1H), 6.58 (s, 1H),
3.20±3.40 (m, 4H), 2.70±2.90 (m, 4H), 2.67 (s, 3H), 1.80±
1.95 (m, 2H); MS(CI) m/z 402 (MH+); Anal.
(C20H18BrClN2) C, H, N. The title product (5c) was
eluted with ethyl acetate:methanol (97:3) containing 1%
NH4OH, yielding the product as a tan solid (480 mg,
50%): mp 160±161 ꢀC; 1H NMR (300 MHz, CDCl3) d
8.45 (s, 1H), 7.56 (s, 1H), 7.10±7.17 (m, 3H), 3.35±3.50
(m, 3H), 2.60±2.95 (m, 2H), 2.78 (s, 3H), 2.0±2.3 (m,
5H), 1.75 (m, 2H); MS(CI) m/z 403 (MH+) Anal.
(C20H20BrClN2) C, H, N.
(Z)-Ethyl-3-(3-bromo-8-chloro-5,6-dihydro-11H-benzo-
[5,6]cyclohepta[1,2 - b]pyridin - 11 - ylidene) - 1 - piperidine-
carboxylate (7c) and ethyl-[3-(5-bromo-10-chloro-7,8-di-
hydro-benzo[4,5]cyclohepta[1,2,3-hi]indolizin-1-yl)propyl]-
methylcarbamate (8c). Ethylchloroformate (1.0 mL,
10.4 mmol) and triethylamine (1.0 mL, 13.6 mmol) were
added to a solution of 5c in toluene (20 mL) at 0 ꢀC,
then stirred at 70 ꢀC for 3 h. The solvent was evaporated
under reduced pressure, and the residual oil extracted
with CH2Cl2 (50 mL), washed with H2O (20 mL) and
chromatographed on silica gel. Elution with hex-
anes:ethylacetate (5:1) yielded an oil which crystallized
on standing from ether to a€ord 8c as yellow crystals
(600 mg, 46.1%): mp 112±114 ꢀC; H NMR (300 MHz,
1
CDCl3) d 7.86 (s, 1H), 7.43 (d, 1H), 7.15±7.25 (m, 3H),
6.53 (s, 1H) 4.12 (q, 2H), 3.32 (m, 2H), 2.90 (m, 6H),
2.85 s, 3H), 1.80±2.0 (m, 2H), 1.24 (t, 3H); MS(CI) m/z
475 (MH+); Anal. (C23H24BrClN2O2) C, H, N. The
second title compound 7c eluted from the column
yielding a solid, which crystallized from ether:methyl-
ene chloride as white crystals (510 mg, 40.8%): mp
182±183 ꢀC; 1H NMR (300 MHz, CDCl3) d 8.47 (s,
1H), 7.62 (s, 1H), 7.11±7.17, (m, 3H), 4.55 (d, 1H), 4.02
(q, 2H), 4.0 (m, 1H), 3.75 (m, 1H), 3.3 (m, 2H), 3.1 (m,
1H), 2.82 (m, 2H), 2.55 (m, 1H), 2.32 (m, 1H), 1.75 (t,
3H), 1.0 (m, 2H); MS(CI) m/z 461(MH+); Anal.
(C22H22BrClN2O2) C, H, N. Ethylchloroformate de-
alkylation of 5b using the above procedure a€orded 7b
and 8b.
LAH reduction of 3a and 3b by the above procedure
a€orded 5a, 5b, and 6b.
(Z)-8-Chloro-6,11-dihydro-11-(1-methyl-3-piperidinylidene)-
5H-benzo[5,6]cyclohepta[1,2-b]pyridine (5b). White solid
(50%): 1H NMR (300 MHz, CDCl3) d 8.39 (d, 1H), 7.40
(d, 1H), 7.0±7.2 (m, 4H), 3.50 (m, 3H), 2.79 (s, 3H), 2.7±
2.9 (m, 2H), 2.42 (m, 1H), 2.21 (m, 4H), 1.6±1.8 (m,
2H); MS (CI) m/z 325 (MH+).
(Z)-Ethyl-3-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclo-
hepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate
(7b). White solid (45%): H NMR (300 MHz, CDCl3) d
8.45 (d, 1H), 7.43 (d, 1H) , 7.13 (m, 4H), 4.55 (d, 1H),
4.02 (q, 2H), 4.0 (m, 1H), 3,75 (m, 1H), 3.30 (m, 2H), 3,1
1

J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
681
(m, 1H), 2.82 (m, 2H), 2.55 (m, 1H), 2.32 (m, 1H), 1.75
(t, 3H), 1.0 , (m, 2H); MS(CI), m/z 383 (MH+).
solid; 1H NMR (300 MHz, CDCl3) d 8.3 (d, 1H,
J=4.7 Hz), 7.3 (d, 1H, J=6.7 Hz), 7.2 (d, 1H,
J=7.8 Hz), 7.10±7.19 (m, 2H), 7.06 (d, 1H, J=4.8 Hz),
7.03 (d, 1H, J=7.8 Hz), 4.09 (d, 1H, J=16.4 Hz), 3.2±3.4
(m, 3H, containing a d, J=16.2 Hz), 3.12±3.18 (m, 1H),
2.6±2.9 9m, 5H), 2.12±2.22 (m, 1H); 13C NMR (75 MHz,
CDCl3) d 154.68, 146.49, 139.56, 138.93, 138.75, 137.17,
135.51, 134.01, 128.71, 128.42, 126.74, 126.55, 122.74,
48.68, 44.80, 32.95, 31.64, 30.09; MS(CI), 296 (MH+);
Anal. (C18H18NClÂ0.25 mol H2O) C, H, N.
Ethyl-[3-10-chloro-7,8-dihydro-benzo[4,5]cyclohepta[1,2,3-
hi]indolizin-1-yl) propyl]methylcarbamate (8b). White
1
solid (44%): H NMR (300 MHz, DMSO-d6) d 8.08 (d,
1H), 7.57 (s, 1H), 7.50 (d, 1H), 7.29 d, 1H), 7,25 (d, 1H),
6.48 (m, 2H), 4.0 (q, 2H), 3.32 (m, 2H), 2.90 (m, 6H),
2.79 (s, 3H), 1.85 (m, 2H), 1.15 (t, 3H); MS(CI) m/z 397
(MH+). HRMS calcd (MH+) for C23H26N2O2Cl
397.1683, measured 397.1681.
(Z)-6,11-Dihydro-11-(3-pyrrolylidene)-5H-benzo[5,6]
cyclohepta[1,2-b]pyridine (9d). Compound 5a (2.3 g,
5.95 mmol) was dissolved in a solution of MeOH
(70 mL) and acetic acid (8 mL) along with Pd(OH)2 cat-
alyst (800 mg). The mixture was pressurized to 35 psi
with hydrogen gas, and shaken for 3 h. The catalyst was
removed by ®ltration through celite, and the e‚uent
was concentrated under reduced pressure and chromato-
graphed on silica gel eluting with 5% MeOH:CH2Cl2
increasing gradually to 10% MeOH:CH2Cl2:1%
NH4OH), which a€ored 1.49 g (84%) of material as a
(Z)-3-Bromo-8-chloro-6,11-dihydro-11-(3-piperidinylidene)-
5H-benzo[5,6]cyclohepta[1,2-b]pyridine (9c). A solution
of 7c (400 mg, 0.866 mmol) in conc HCl (5 mL) was
stirred at 100 ꢀC overnight, then cooled to 0 ꢀC, poured
into ice (10 g) and basi®ed with 30% NaOH. The mix-
ture was extracted with CH2Cl2 (100 mL), and the
organic layer was dried, ®ltered, and evaporated yield-
ing 9c as a white foam (320 mg, 94.8%): 1H NMR
(300 MHz, CDCl3) d 8.37 (s, 1H), 7.40 (d, 1H), 7.14±
7.34 (m, 3H), 3.46 (m, 4H), 2.86 (m, 4H), 2.38, (m, 2H),
1.75 (m, 1H), 1.62 (m, 1H); MS(CI) m/z 389 (MH+);
Anal. (C19H18BrClN2) C, H, N.
1
light tan solid. H NMR (CDCl3) d 8.35 (bs, 1H), 7.0±
7.4 (m, 6H), 4.5 (d, 1H, J=16.3 Hz), 3.7 (d, 1H,
J=16.4 Hz), 3.2±3.5 (m, 4H), 2.7±3.0 (m, 3H), 2.4±2.50
(m, 1H); 13C NMR (75 MHz, CDCl3) d 155.48, 146.45,
139.95, 138.79, 138.63, 138.49, 135.59, 133.82, 128.82,
128.47, 128.10, 126.46, 122.54, 49.58, 45.62, 32.80,
31.72, 31.18; MS(CI) m/z 263 (MH+).
Hydrolysis of 7b by this procedure a€orded 9b.
(Z)-8-Chloro-6,11-dihydro-11-(3-piperidinylidene)-5H-
benzo[5,6]cyclohepta[1,2-b]pyridine (9b). White solid
(90%): mp 170±171 ꢀC; H NMR (300 MHz, CDCl3) d
1
8.38 (d, 1H), 7.41 (d, 1H), 7.05±7.30 (m, 4H), 3.45 (m,
4H), 2.88 (m, 4H), 2.40 (m, 2H), 1.75 (m, 1H), 1.62 (m,
1H); MS (CI) m/z 311(MH+); Anal. (C19H19ClN2) C,
H, N.
(E)-3-Bromo-8-chloro-6,11-dihydro-11-(1-methyl-3-piper-
idinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (10c).
LAH (470 mg, 11.9 mmol) was added to a solution of 4c
(3.4 g, 8.15 mmol) in THF (40 mL, anhydrous) at 0 ꢀC.
The solution was stirred at 0 ꢀC for 5 h, then water
(5 mL), 10% potassium sodium tartrate tetrahydrate
(20 mL), 10% sodium hydroxide (5 mL), and CH2Cl2
(150 mL) were added sequentially. The crude product
obtained from the organic layer was chromatographed
on silica gel eluting with EtOAc:MeOH (98:2) yielding
the product as a white solid (1.3 g, 40% ): mp 140±
141 ꢀC; 1H NMR (300 MHz, CDCl3) d 8.45 (s, 1H), 7.62
(s, 1H), 7.16 (s, 1H), 7.14 (d, 1H), 7.05 (d, 1H), 3.50 (m,
3H), 3.0 (m, 1H), 2.75±2.80 (m, 3H), 2.26 (m, 2H), 2.23
(s, 3H, NCH3), 2.20 (m, 1H), 1.75 (m, 2H); MS(CI) m/z
403 (MH+); Anal. (C20H20BrClN2) C, H, N.
(Z)-8-Chloro-6,11-dihydro-11-(3-pyrrolylidene)-5H-benzo
[5,6]cyclohepta[1,2-b]pyridine (9a). To a two-necked ¯ask
equipped with a re¯ux condenser and a three-way valve
(allowing for evacuation under vacuum and puringing
with nitrogen) was added 5a (1.29 mmol, 500 mg),
MeOH (20 mL), acetic acid (5 mL), cyclohexadiene
(5 mL), and 10% Pd/C (210 mg). After three cycles of
evacuation-nitrogen purging was performed, an empty
balloon was placed on top of the condenser so as to expand
as hydrogen was evolved. The mixture was heated care-
fully to 70 ꢀC at which time hydrogen evolution began.
If starting material was still present by TLC after 1 h, a
full hydrogen balloon was placed over the reaction
mixture. The reduction was continued at ꢁ40 ꢀC for an
additional 1 h (or until complete by TLC). The contents
were then ®ltered through celite, and the e‚uent was
concentrated under reduced pressure. Toluene was
added and the material was evaporated once again to
remove the HOAc. Chromatography on SiO2 using (5%
MeOH:CH2Cl2 increasing gradually to 10% MeOH:
CH2Cl2:1% NH4OH) gave 9a (221 mg, 58%) as a tan
LAH reduction of 4b by the above procedure a€orded
10b.
(E)-8-Chloro-6,11-dihydro-11-(1-methyl-3-piperidinyl-
idene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine
(10b).
White solid (45%): mp 125±126 ꢀC; 1H NMR
(300 MHz, CDCl3) d 8.38 (d, 1H), 7.45 (d, 1H), 7.13 (s,
1H), 7.06±7.12 (d, 1H), 7.06 (d, 1H), 3.50 (m, 3H), 3.0
(m, 1H), 2.78±2.80 (m, 3H), 2.25 (m, 2H), 2.23 (s, 3H,

682
J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
NCH3), 2.20 (m, 1H), 1.75 (m, 2H); MS(CI), m/z 325
(MH+); Anal. (C20H21N2Cl) C, H, N.
2H), 2.45 (m, 2H), 1.75 (m, 1H), 1.7 (t, 3H), 1.0 (m, 2H);
MS(CI), m/z 383 (MH+).
(E)-8-Chloro-6,11-dihydro-11-(1-benzyl-3-pyrrolylidene)-
5H-benzo[5,6]cyclohepta[1,2-b]pyridine (10a). To a two-
necked ¯ask containing LAH (27.7 mmol, 1.04 g) was
added Et2O (75 mL) under a N2 atmosphere. The solu-
tion was cooled to 0 ꢀC, and a THF solution of 4a
(5.49 mmol, 2.20 g) was added via syringe. After the
addition was complete a heterogeneous brick red solu-
tion resulted. TLC analysis after 2 h indicated all the
starting material had been consumed, with no iso-
merization taking place. The reaction mixture was
quenched with EtOAc and MeOH, followed by the
addition of 1% NaOH. The aqueous portion was
extracted 4Â75 mL with EtOAc then with EtOAc:THF
(4:1), and the combined organics were washed with
brine, dried over MgSO4, ®ltered and concentrated
under reduced pressure to give a reddish foam. Chro-
matography on SiO2 using (15% acetone:EtOAc
increasing gradually to 5% MeOH:EtOAc) gave 10a
(1.08 g, 51%) as a tan solid: 1H NMR (300 MHz,
CDCl3) d 8.4 (d, 1H, J=ꢁ5 Hz), 7.0±7.4 (m, 10H), 3.5±
3.7 (m, 3H), 3.20±3.42 (m, 3H), 2.70±2.92 (m, 4H), 2.48±
2.58 (m, 1H), 2.18±2.28 (m, 1H); 13C NMR (75 MHz,
CDCl3) d 156.21, 146.37, 146.15, 144.01, 140.25, 138.89,
138.78, 137.79, 132.68, 132.58, 131.31, 130.14 128.72,
128.12, 126.81, 126.21, 121.81, 60.67, 59.06, 53.55,
32.21, 31.36, 31.18; MS (CI) m/z 387 (MH+); Anal.
(C25H23N2Cl (0.25 mol H2O) C, H, N.
(E)-Ethyl-3-(3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]
cyclohepta[1,2b]pyridin-11-ylidene)-1-pyrrollidenecarb-
oxylate (11a). (49%): 1H NMR (300 MHz, CDCl3) d 8.4
(d, 1H, J=4.7 Hz), 7.4 (d, 1H, J=6.8 Hz), 7.1±7.3 (m,
4H), 4.2±4.3 (m, 1H), 4.05±4.15 (q, 2H, J=7.2 Hz), 3.6±
3.8 (m, 2H), 3.2±3.4 (m, 3H), 3.0±3.2 (m, 1H), 2.7±3.0
(m, 2H), 2.4±2.5 (m, 1H), 1.2 (t, 3H, J=7.2 Hz). 13C
(75 MHz, CDCl3) d 156.08, 155.24, 146.77, 139.85,
138.09, 133.48, 133.17, 130.00, 128.73, 126.71, 122.55,
61.25, 50.38, 49.84, 45.86, 45.66, 32.20, 31.76, 31.16,
30.51, 15.03. MS(CI), m/z 369 (MH+). Anal (C21
H21N2O2Cl) C, H, N.
(E)-3-Bromo-8-chloro-6,11-dihydro-11-(3-piperidinylidene)-
5H-benzo[5,6]cyclohepta[1,2-b]pyridin (12c). A solution
of 11c (170 mg, 0.36 mmol) in concn HCl (2 mL) was
stirred at 80 ꢀC overnight, then cooled to 0 ꢀC, diluted
with H2O (10 mL), basi®ed with 10% NaOH (10 mL)
and extracted with CH2Cl2 (3Â50 mL). The organic
layer was separated, washed with H2O (20 mL), and the
solvent was evaporated yielding a solid, which was
recrystallized from CH2Cl2:Et2O as white crystals
(140 mg, 97%): mp 166±167 ꢀC; 1H NMR (300 MHz,
CDCl3) d 8.46 (s, 1H), 7.60 (s, 1H), 7.15( s, 1H), 7.11 (d,
1H), 7.05 (d,1H), 3.55 (d, 1H), 3.39 (d, 1H), 3.0 (m, 1H),
2.85 (m, 3H), 2.40 (m, 2H), 2.0 (m, 2H), 1.75 (m, 1H),
1.55 (m, 1H); MS(CI) m/z 389 (MH+); Anal.
.
(C19H18BrClN2 0.25H2O) C, H, N.
(E)-Ethyl-3-(3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]
cyclohepta[1,2b]pyridin-11-ylidene)-1-piperidinecarboxyl-
ate (11c). Ethylchloroformate (0.5 mL, 5.2 mmol) and
triethylamine (1.0 mL, 13.6 mmol) were added to a
solution of 10c in toluene (15 mL) at 0 ꢀC then stirred at
70 ꢀC for 3 h. The solvent was evaporated under reduced
pressure, and the residual oil extracted with CH2Cl2
(50 mL) and washed with H2O (20 mL). The crude pro-
duct isolated from the organic extract was chromato-
graphed on silica gel eluting with hexanes:ethylacetate,
then crystallized from ether as white crystals (230 mg,
51%): mp 186±187 ꢀC; 1H NMR (300 MHz, CDCl3) d
8.46 (s, 1H), 7.60 (s, 1H), 7.11±7.18 (m, 3H), 4.25 (m, 1H),
4.05 (q, 2H), 3.75 (m, 1H), 3.35 (m, 3H), 2.80 (m, 2H), 2.45
(m, 2H), 1.75 (m, 1H), 1.7 (t, 3H), 1.05 (m, 2H); MS(CI)
m/z 461(MH+); Anal. (C22H22BrClN2O2) C, H, N.
This procedure was used to convert 11a and 11b to 12a,
12b.
(E)-8-Chloro-6,11-dihydro-11-(3-piperidinylidene)-5H-benzo
[5,6]cyclohepta[1,2-b]pyridine (12b). (90%): mp 139±
140 ꢀC; 1H NMR (300 MHz, CDCl3) d 8.40 (d, 1H), 7.45
(d, 1H), 7.10 (m, 4H), 3.55 (d, 1H), 3.39 (m, 3H), 3.0 (m,
1H), 2.85 (m, 3H), 2.41 (m, 2H), 1.75 (m, 1H), 1.55 (m,
1H); MS(CI) m/z 311 (MH+); Anal. (C19H19ClN2) C, H, N.
(E)-8-Chloro-6,11-dihydro-11-(3-pyrrolylidene)-5H-benzo
[5,6]cyclohepta[1,2-b]pyridine (12a). (76%): 1H NMR
(300 MHz, CDCl3) d 8.4 (d, 1H, J=4.7 Hz), 7.4 (d, 1H,
J=7.7 Hz), 7.02±7.24 (m, 4H), 3.2±3.4 (m, 3H), 3.0±3.2
(m, 3H), 2.7±2.9 (m, 3H). MS (CI) m/z 297 (MH+)
HRMS calcd. (MH+) for (C18H18N2Cl) 297.1159, mea-
sured 297.1153.
Dealkylation of 10a and 10b by the above procedure
a€orded 11a and 11b.
(Z)-3-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta
[1,2-b]pyridin-11-ylidene)-N-phenyl-1-piperidinecarbox-
amide (21). Triethylamine (0.2mL, 2.72 mmol) was
added to a solution of the amine (9b) (70 mg, 0.225 mmol)
and phenylisocyanate (0.2 mL, 1.53 mmol) in CH2Cl2
(15 mL) at 0 ꢀC. The reaction was stirred overnight at
(E)-Ethyl-3-(3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]
cyclohepta[1,2b]pyridin-11-ylidene)-1-piperidinecarboxyl-
ate (11b). (foam 47%); H NMR (300 MHz, CDCl3) d
8.45 (d, 1H), 7.60 (d, 1H), 7.11±7.16 (m, 4H), 4.25 (m,
1H), 4.0 (q, 2H), 3.75 (m, 1H), 3.35 (m, 3H), 2.80 (m,
1

J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
683
20 ꢀC. The reaction was quenched by addition of H2O
(15 mL), and the organic layer was separated, dried and
chromatographed on silica gel eluting with 20% v/v
EtOAc:Hexanes as a white foam, which crystallized from
Ether (10 mL) as white crystals (75 mg, 78%): mp 184±
185 ꢀC; H NMR (300 MHz, CDCl3) 10.05 (brs, 1H),
8.20 (d, 1H), 7.30 (dd, 2H), 7.0±7.4 (m, 8H), 4.75 (d, 1H),
4.50 (m, 1H), 3.50 (m, 1H), 3.30 (m, 2H), 2.90 (m, 2H),
2.80 (m, 1H), 2.60 (m, 1H), 2.05 (m, 1H), 1.75 (m, 2H);
MS(CI) m/z 430 (MH+); Anal. (C26H24ClN3O) C, H, N.
1H NMR (300 MHz, CDCl3) d 8.55 (d, 1H), 8.43 (dd,
2H), 7.48 (d, 1H), 7.09±7.23 (m, 4H), 7.06 (d, 1H), 6.72
(d, 1H), 4.50 (m, 1H), 4.35 (d, 1H), 3.65 (d, 1H), 3.60 (d,
1H), 3.35 (d, 1H), 3.25 (m, 2H), 3.15 (d, 1H), 2.85 (m,
2H), 2.45-2.60 (m, 2H), 1.75 (m, 1H), 1.65 (m, 1H);
1
ꢀ
+
.
MS(CI) m/z 430 (MH ); Anal. (C26H24N3ClO 1.25
H2O) C, H, N.
Compounds 15±20, 45±50, 63±65. The acylation proce-
dure described for 17 was used to prepare these N-acyl
compounds.
(Z)-3-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta
[1,2-b]pyridin-11-ylidene)-1-piperidinecarbothioc acid S-
phenyl ester (22). Phenylchlorothiolformate (0.2 g,
1.13 mmol) was. added to a solution of 9b (25 mg,
0.0806 mmol) and triethylamine (0.2 mL, 2.72 mmol) in
pyridine (2 mL) at 0 ꢀC. 4-Dimethylamino pyridine,
DMAP (5 mg, 0.0416 mmol) was added and the solution
stirred at 20 ꢀC overnight. The solvent was evaporated,
and the residue extracted with EtOAc (25 mL), washed
with H2O (20 mL) and and chromatographed on silica
gel eluting with 5% v/v MeOH/EtOAc as a solid, which
was triturated with hexanes yielding a white solid
(30 mg, 83%): mp 187±188 ꢀC; 1H NMR (300 MHz,
CDCl3) d 8.42 (d, 1H), 7.48 (d, 1H), 7.37 (m, 2H), 7.16
(s,1H), 7.14 (d, 1H,), 4.52 (d, 1H), 3.95 (d, 1H), 3.45 (m,
3H), 3.10 (m, 1H), 2.85 (m, 2H), 2.55 (m, 2H), 1.85 (m,
1H), 1.65 (m, 1H); MS (CI) m/z 447 (MH+); HRMS
calcd (MH+) for C26H24ClN2OS 447.1298, measured
1
Compound 41: H NMR (300 MHz, CDCl3) d 8.39 (d,
1H, J=ꢁ3 Hz), 7.81 (apparent d, 2H, J=7.4 Hz), 7.50±
7.64 (m, 3H), 7.41 (d, 1H, J=6.7 Hz), 7.08±7.20 (m,
4H), 4.27 (d, 2H, J=15.4 Hz), 3.84 (d, 1H, J=15.4 Hz),
3.10±3.40 (m, 4H), 2.60±2.94 (m, 3H), 2.25±2.38 (m,
1H). HRMS calcd (MH+) for (C24H21N2O2ClS)
437.1087, measured 437.1091.
1
Compound 42: H NMR (300 MHz, CDCl3) d 8.39 (d,
1H, J=4.7 Hz), 7.81 (apparent d, 2H, J ꢁ7 Hz), 7.50±
7.64 (m 3H), 7.41 (d, 1H, J=7.6 Hz), 7.08±7.21 (m, 5H),
4.28 (d, 1H, J=15.2 Hz), 3.86 (dd, 1H, J=1.6, 15.2 Hz),
3.2±3.4 (m, 4H), 2.60±2.95 (m, 3H), 2.25±2.40 (m, 1H).
HRMS calcd (MH+) for (C24H22N2O2S) 403.1480,
measured 403.1480.
Compound 43: 1H NMR (300 MHz, CDCl3) d 8.4 (d,
1H, J=4.7), 7.56±7.64 (m, 2H), 7.42 (d, 1H,
J=7.3 Hz), 7.10±7.20 (m, 5H), 4.34 (d, 1H,
J=15.6 Hz), 3.85 (d, 1H, J=15.5 Hz), 3.36 (apparent t,
2H, J=7.1 and 7.4 Hz), 3.16±3.26 (m, 2H), 2.80±2.94
(m, 1H), 2.64±2.78 (m, 2H), 2.30±2.42 (m, 1H); HRMS
calcd. (MH+) for (C22H19N2O2ClS2) 443.0655, mea-
sured 443.0649.
.
447.1297; Anal. (C26H23ClN2OS 2H20) C, H, N.
(Z)-3-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta
[1,2-b]pyridin-11-ylidene)-1-[(4-pyridinyl)acetyl]-piperidine
(17). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide,
EDCI (50 mg, 0.26 mmol) and 1-hydroxybenztriazole,
HOBT (40 mg, 0.296 mmol) were added sequentially to
a solution of 9b (50 mg, 0.161 mmol) and 4-pyridylacetic
acid (30 mg, 0.22 mmol) in DMF (5 mL) and N-methyl-
morpholine, NMM (0.5 mL) at 0 ꢀC, then stirred over-
night at 20 ꢀC. The solvent was evaporated under
reduced pressure, and the residual oil extracted with
EtOAc (50 mL), washed with H2O (25 mL), dried and
chromatographed on silica gel eluting with 5% v/v
MeOH:EtOAc containing 2% v/v NH4OH, yielding the
1
Compound 44: H NMR (300 MHz, CDCl3) d 8.40 (d,
1H, J=ꢁ3 Hz), 7.56±7.62 (m, 2H), 7.4 (d, 1H,
J=7.0 Hz), 7.01±7.21 (m, 6H), 4.36 (d, 1H, J=15.4 Hz),
3.85 (d, 1H, J=15.4 Hz), 3.36 (apparent t, 2H, J=6.8
and 7.7 Hz), 3.15±3.30 (m, 2H), 2.80±2.94 (m, 1H), 2.60±
2.80 (m, 2H), 2.30±2.42 (m, 1H). 13C NMR (75 MHz,
CDCl=) d 155.16, 146.40, 139.32, 138.26, 138.14,
137.94, 135.83, 135.08, 133.20, 132.42, 131.85, 128.45,
128.22, 127.81, 127.52, 126.17, 122.34, 52.05, 47.51,
32.38, 31.37, 30.67. HRMS calcd. (MH+) for
(C22H20N2OS) 448.1259, measured 448.1250.
1
product as a white solid (foam, 52 mg, 75%): H NMR
(300 MHz, CDCl3) d 8.55 (d, 1H), 8.43 (dd, 2H), 7.48 (d,
1H), 7.09±7.20 (m, 4H), 6.83 (dd, ), 4.35 (d, 1H), 4.20
(m, 1H), 4.05 (d, 1H), 3.65 (m, 1H), 3.45 (d, 1H), 3.35
(d, 1H), 3.25 (m, 2H), 2.80 (m, 2H), 2.40 (m, 2H), 1.77
(m, 1H), 1.55 (m, 1H); MS(CI) m/z 430 (MH+); Anal.
Compound 45: 1H NMR (300 MHz, CDCl3) d 8.36±8.44
(m, 3H), 7.43 (dd, 1H, J=1.6, 7.8 Hz), 7.05±7.35 (m,
6H), 4.91 (d, 1H, rotomer A, J=15.9 Hz), 4.67 (d, 1H,
rotomer B, J=17.9 Hz), 3.88±4.08 (m, 1H), 3.48±3.82
(m, 5H), 3.2±3.4 (m, 2H), 2.72±3.02 (m, 2H), 2.40±2.62
(m, 1H); HRMS calcd (MH+) for (C25H22N3OClS)
448.1250, measured 448.1248.
.
(C26H24N3ClO H2O) C, H, N.
(E)-3-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta
[1,2-b]pyridin-11-ylidene)-1-[(4-pyridinyl)acetyl]-piperidine
(48). The procedure as described for 17 was used to
acylate 12b, to obtain 48 as a white solid (foam, 73%):

684
J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
Compound 46: 1H NMR (300 MHz, CDCl3) d 8.48±8.58
(m, 2H), 8.39±8.46 (m, 1H), 7.44 (dd, 1H, J=1.2,
7.5 Hz), 7.08±7.26 (m, 6H), 4.81 (d, 1H, rotomer A,
J=15.9 Hz), 4.66 (d, 1H, rotomer B, J=17.9 Hz), 4.0 (d,
1H, J=17.1 Hz), 3.9 (d, 1H, J=15 Hz), 3.54±3.76 (m,
2H), 3.18±3.44 (m, 3H), 2.7±3.0 (m, 3H), 2.38±2.58 (m,
1H); Anal. (C25H22N3OCl) C, H, N.
1H), 8.10 (d, 2H), 7.65 (d, 1H), 7.28±7.31 (m, 4H), 7.07
(s, 2H), 3.77 (q, 2H), 3.55 (m, 2H), 3.25 (m, 1H), 3.15
(m, 1H), 2.91 (m, 2H), 2.45 (m, 2H), 1.82 (m, 2H); Anal.
(C25H22ClN3O2S) C, H, N.
(E)-3-(3-Bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclo-
hepta[1,2-b]pyridin-11-ylidene)-1-[(5-chloro-2-thienyl)sulf-
onyl]-piperidine (60). Method A. 5-Chloro thiophene-2-
sulfonyl chloride (0.2 g, 0.921 mmol) was added to a
solution of 12c (80 mg, 0.204 mmol) in pyridine (2 mL)
at 0 ꢀC. DMAP (3 mg, 0.0245 mmol) was added, and the
solution was stirred at 20 ꢀC overnight. The solvent was
evaporated under reduced pressure, and the residue
extracted with methylene chloride (40 mL), and the
crude product was chromatographed on silica gel elut-
ing with 20% EtOAc:hexanes as a solid which recrys-
tallized from ether (15 mL) as white crystals (70 mg,
Compound 61: 1H NMR (300 MHz, CDCl3) d 7.74±7.80
(m, 2H), 7.40±7.66 (m, 4H), 7.04±7.22 (m, 4H), 3.9 (d,
1H, J=14.6 Hz), 3.7 (d, 1H, J=14.8 Hz), 3.3±3.4 (m,
2H), 3.04±3.24 (m, 3H), 2.66±2.90 (m, 2H), 2.30±2.41
(m, 1H); HRMS calcd (MH+) for (C24H21N2O2ClS)
437.1092, measured 437.1091.
Compound 63: 1H NMR (300 MHz, CDCl3) d 8.30±8.42
(m, 3H), 7.30±7.50 (m, 1H), 7.02±7.25 (m, 6H), 4.89 (d,
1H, rotomer A, J=16 Hz), 4.66 (d, 1H, rotomer B,
J=18 Hz), 3.6-6±4.04 (m, 4H), 3.10±3.36 (m, 3H), 2.70±
3.00 (m, 3H), 2.40±2.56 (m, 1H); HRMS calcd (MH+)
for (C25H22N3OClS) 448.1255, measured 448.1250.
59.8%): mp 171±172 ꢀC; H NMR (300 MHz, CDCl3) d
1
8.45 (s, 1H), 7.60 (s, 1H), 7.20 (s, 1H), 7.16 (m, 2H), 7.08
(d, 1H), 6.91 (d, 1H), 3.79 (d, 1H), 3.63 (d, 1H), 3.2±3.5
(m, 3H), 3.05 (m, 1H), 2.85 (m, 2H), 2.35 (m, 2H), 1.85
(m, 1H), 1.65 (m, 1H); MS (CI) m/z (569 (MH+); Anal.
(C23H19BrCl2N2O2S2) C, H, N, S.
1
Compound 62: H NMR (300 MHz, CDCl3) d 8.4 (bs,
1H), 7.45±7.65 (m, 3H), 7.10±7.30 (m, 5H), 3.99 (d, 1H,
J=15.1 Hz), 3.75 (d, 1H, J=15 Hz), 3.38±3.46 (m, 2H),
3.15±3.30 (m, 3H), 2.70±2.90 (m, 2H), 2.33±2.44 (m,
1H); HRMS calcd (MH+) for (C22H219N2O2ClS2)
443.0654, measured 443.0655.
(Z)-3-(3-Bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclo-
hepta[1,2-b]pyridin-11-ylidene)-1-[(5-chloro-2-thienyl)sulf-
onyl]-piperidine (38). Prepared from 9c by following
Method A described for 60. Obtained 38 as white crys-
tals (65.4%): mp 165±167 ꢀC; 1H NMR (300 MHz,
CDCl3) d 8.47 (s, 1H), 7.64 (s, 1H), 7.20 (s, 1H), 7.16 (m,
2H), 7.08 (d, 1H), 6.93 (d, 1H), 4.25 (d, 1H), 3.75 (d,
1H), 3.51 (d, 1H), 3.37 (m, 2H), 2.79 (m, 3H), 2.48 (m,
1H), 2.10 (m, 1H), 1.85 (m, 1H), 1.65 (m, 1H); MS(CI)
m/z 569 (MH+); Anal. (C23H19BrCl2N2O2S2) C, H, N.
The above Method A was used to prepare sulfonamides
23±35, 37±44, 52±58, and 60±62.
1
Compound 64: H NMR (300 MHz, CDCl3) d 8.5 (bs,
2H), 4.4 (d, 1H, J=4.6 Hz), 7.4 (d, 1H, J=7.3 Hz),
7.10±7.26 (m, 7H), 7.30±7.44 (m, 1H), 3.70±3.88 (m,
2H), 3.06±3.58 (m, 6H), 2.70±3.00 (m, 2H), 2.44±2.62
(m, 1H); HRMS calcd (MH+) for (C25H22N3OCl)
416.1550, measured 416.1530.
Compound 65: 1H NMR (300 MHz, CDCl3) d 8.4 (d,
1H, J=3.0 Hz), 7.12±7.60 (m, 7H), 6.7 (bs, 1H), 4.85±
4.52 (m, 1H), 3.80±4.20 (m, 2H), 3.20±3.70 (m, 4H),
2.70±3.00 (m, 2H), 2.45±2.65 (m, 1H); HRMS calcd
(MH+) for (C23H19N2O2Cl) 391.1218, measured
391.1213.
(Z)-3-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta
[1,2-b]pyridin-11-ylidene)-1-(3-pyridinesulfonyl)-piperidine
(36) and (Z)-3-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclo-
hepta[1,2-b]pyridin-11-ylidene)-1-[(4-nitrophenyl)sulfonyl]-
piperidine (27). Method B. 4-Nitrobenzenesulfonyl-
chloride (100 mg, 0.406 mmol) was added to a solution
of 3-pyridinesulfonic acid(100 mg, 0.626 mmol) in pyr-
idine (3 mL) at 0 ꢀC. DMAP (5 mg) was added and
the mixture stirred at 0 ꢀC for 7 h. (Z)-8-Chloro-6,11-
dihydro-11-(3-[piperidinylidene)-5H-benzo[5,6]cyclo-
hepta[1,2-b]pyridine (9b) (80 mg) was added and the
mixture stirred 1 h at 0 ꢀC, then overnight at 20 ꢀC.
Water (25 mL) and CH2Cl2 (50 mL) were added and the
organic layer separated, washed with water (10 mL),
dried, and chromatographed on silica gel eluting with
20% v/v EtOAc:Hexanes to a€ord the less polar pro-
duct 27, which was recrystallized from methanol as
white crystals (37 mg, 15%): mp 178±179 ꢀC; MS(CI) m/
(E)-8-Chloro-6,11-dihydro-11-[1-[(4-nitrophenyl)thio]-3-
piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine
(51).
4-Nitrobenzenesulfenyl
chloride
(130 mg,
0.65 mmol) was added to a solution of 12b (100 mg,
0.322 mmol) in methylene chloride (3 mL) at 20 ꢀC.
Triethylamine (0.3 mL) was added and the solution stir-
red overnight. Water (20 mL) was added and the reac-
tion was extracted with methylene chloride (25 mL). The
organic layer was separated, dried and chromato-
graphed on silica gel eluting with 20% v/v EtOAc:hex-
anes yielding an oil, which crystallized from methanol as
yellow crystals (100 mg, 66%): mp 173±174 ꢀC; MS(CI)
m/z 464 (MH+); 1H NMR (300 MHz, CDCl3) d 8.47 (d,
1
z 496 (MH+); H NMR (300 MHz, CDCl3) d 8.43 (d,

J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
685
1H), 8.32 (d, 2H), 7.88 (d, 2H), 7.48 (d, 1H), 7.15±7.19
(m, 3H), 7.02 (d, 1H), 4.31 d, 1H), 3.75 (d, 1H), 3.50
(d, 1H), 3.34 (m, 2H), 2.78 (m, 3H), 2.50 (m, 1H), 2.10
(m, 1H), 1.75 (m, 1H), 1.65 (m, 1H); Anal. (C25H22
ClN3O4S) C, H, N. Compound 36 was eluted with 5%
v/v MeOH:EtOAc containing 1% NH4OH yielding a
solid that was crystallized from ether as white crystals
Symons, M.; Hancock, J. F. Science 1994, 264, 1463; (c)
Leevers, S. J.; Paterson, H. F.; Marshall, C. J. Nature (London)
1994, 369, 411.
5. (a) Casey, P. J.; Solski, P. A.; Der, C. J.; Buss, J. E. Pro.
Nat. Acad. Sci. U. S. A. 1989, 86, 8323; (b) Zhang, F. L.;
Casey, P. J. Ann. Rev. Biochem. 1996, 65, 241.
6. (a) Casey, P. J.; Thissen, J. A.; Moomaw, J. F. Proc. Natl.
Acad. Sci. U.S.A. 1991, 88, 8631; (b) Yokoyama, K.; Goodwin,
G.; Ghomsashchi, F.; Glomset, J. A.; Gelb, M. H. ibid, 1991,
88, 5302.
(180 mg, 68.9%): mp 158±159 ꢀC; H NMR (300 MHz,
1
CDCl3) d 8.87 (s, 1H), 8.80 (d, 1H), 8.48 (d, 1H), 7.95
(d, 1H), 7.5 (m, 2H), 7.19 (m, 3H), 7.04 (d, 1H), 4.38
(d, 1H), 3.80 (d, 1H), 3.45 (m, 3H), 2.85 (m, 3H), 2.50
(m, 1H), 2.05 (m, 1H), 1.75 (m, 1H), 1.65 (m, 1H);
MS(CI) m/z 452 (MH+) Anal. (C24H22ClN3O2S) C,
H, N.
7. (a) Gibbs, J. B.; Oli€, A.; Kohl, N. E. Cell 1990, 62, 81; (b)
Gibbs, J. B. Cell 1991, 65, 1; (c) Gibbs, J. B.; Oli€, A.; Kohl, N.
Cell 1994, 77, 175; (d) Kohl, N. E.; Conner, M. W.; Gibbs, J.
B.; Graham, S. L.; Hartman, G. D.; Oli€, A. J. Cell. Biochem.
1995, Suppl. 22, 145.
8. We have previously reported Ras inhibition based on
blocking the nucleotide-exchange process: (a) Wolin, R.; Wang,
D.; Kelly, J.; Afonso, A.; James, L.; Kirschmeier, P.; McPhail,
A. Bioorg. Med. Chem. Lett. 1996, 6, 195. And by a novel
mechanism: (b) Kumar, C. C.; Prorock-Rogers, C.; Kelly, J.;
Dong, Z.; Lin, J.; Armstrong, L.; Kung, H.; Weber, M. J.;
Afonso. A. Cancer Res. 1995, 55, 5106.
(E)-3-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]
pyridin-11-ylidene)-1-(3-pyridinesulfonyl)-piperidine (59)
and (E)-3-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclo-
hepta[1,2-b]pyridin-11-ylidene)-1-[(4-nitrophenyl)sulfonyl]-
piperidine (55). Prepared from 12b by using Method B
described for 36. The less polar sulfonamide 55 was
obtained as white crystals from methanol (25%): mp
9. James, G. L.; Goldstein, J. L.; Brown, M. S. J. Biol. Chem.
1995, 270, 6221.
232±233 ꢀC; H NMR d 8.39 (d, 1H), 8.31 (d, 2H), 7.88
1
10. Zhang, F. L.; Kirschmeier, P.; Carr, D.; James, L.; Bond,
R. W.; Wang, L.; Patton, R.; Windsor, W. T.; Syto, R.; Zhang,
R.; Bishop, R. W. J. Biol. Chem. 1997, 272, 10232.
(d, 2H), 7.43 (d, 1H), 7.09±7.15 (m, 3H), 7.06 (d, 1H),
3.84 (d, 1H), 3.58 (d, 1H), 3.55 (m, 1H), 3.25 (m, 2H),
3.10,(m, 1H), 2.80 (m, 2H), 2.35 (m, 2H), 1.85 (m, 1H),
1.65 (m, 1H); MS(CI) m/z 496 (MH+); Anal (C25H22
ClN3O4S) C, H, N. The major product 59 was obtained
as white crystals (67%): mp 214±215 ꢀC; 1H NMR
(300 MHz, CDCl3) d 8.89 (s, 1H). 8.80 (d, 1H). 8.48 (d,
1H). 7.95 (d, 1H). 7.45 (m, 2H), 7.15 (m, 3H), 7.08 (d,
1H), 3.85 (d, 1H), 3.55 (d, 1H), 3.50 (m, 1H), 3.65 (m,
2H), 3.05 (m, 1H), 2.75 (m, 2H), 2.33 (m, 2H), 1.85 (m,
1H), 1.75 (m, 1H); MS(CI) m/z 452 (MH+); Anal
(C24H22ClN3O2S) C, H, N.
11. Whyte, D. B.; Kirschmeier, P.; Hockenberry, T. N.;
Nunez-Olivia, I.; James, L.; Catino, J. L.; Bishop, R. W.; Pai,
J.-K. J. Biol. Chem. 1997, 272, 14459.
12. (a) Leftheris, K.; Kline, T.; Vite, G. D.; Cho, Y. H.; Bhide,
R. S.; Patel, D. V.; Patel, M. M.; Schmidt, R. J.; Weller, H. N.;
Andahazy, M. L.; Carboni, J. M.; Gullo-Brown, J. L.; Lee, F.
Y. F.; Ricca, C.; Rose, W. C.; Yan, N.; Barbacid, M.; Hunt, J.
T.; Meyers, C. A.; Seizinger, B. R.; Zahler, R.; Manne, V. J. J.
Med. Chem. 1996, 39, 224. For recent reviews covering most of
the reported FPT inhibitors, see: (b) Kaloustian, S. A.; Skot-
nicki, J. S. Ann. Reports. Med. Chem. 1996, 31, 171; (c) Graham,
S. L. Exp. Opin. Ther. Patents 1995, 5, 1269; (d) Qian, Y; Vogt,
A.; Sebti, S. M.; Hamilton, A. D. J. Med. Chem. 1996, 39, 217.
Acknowledgements
13. (a) Hunt, J. H.; Lee, V. G.; Lefheris, K.; Seizinger, B.;
Carboni, J.; Mabus, J.; Ricca, C.; Yan, N.; Manne, V. J. Med.
Chem. 1996, 39, 353; (b) Leonard, D. M.; Shuler, K. R.; Poul-
ter, C. J.; Eaton, S. R.; Sawyer, T. K.; Hodges, J. C.; Su, T. Z.;
Scholten, J. D.; Gowan, R. C.; Sebolt-Leopold, J. S.; Doherty,
A. M. J. Med. Chem. 1997, 40, 192.
The authors thank Dr M. Puar and sta€ for the NMR
studies, the Analytical services group for physical data,
and Drs A. K. Ganguly and S. McCombie for helpful
chemical discussions.
14. (a) Bishop, R. W.; Bond, R.; Petrin, J.; Wang, L.; Patton,
R.; Doll, R.; Njoroge, G.; Cattino, J.; Schwartz, J.; Windsor,
W.; Syto, R.; Schwartz, J.; Carr, D.; James, L.; Kirshmeier, P.
J. Biol. Chem. 1995, 270, 30611; (b) I has an FPT IC50 of 0.
25 mM.
References and Notes
1. For leading references describing the biology of ras see: (a)
Barbacid, M. Ann. Rev. Biochem. 1987; (b) Bos, J. L. Cancer
Res. 1989, 49, 4682.
15. For more recent reports on structures related to I see: (a)
Mallams, A. K.; Njoroge, G.; Doll, R. J.; Snow, M. E.;
Kaminski, J. J.; Rossman, R.; Vibulbhan, B.; Bishop, W. R.;
Kirshmeier, P.; Liu, M.; Bryant, Petrin, J.; Remiszewski, S.;
Taveras, A.; Wang, S.; Wong, J.; Catino, J.; Girijavallabhan,
V.; Ganguly, A. K. Bioorg. Med. Chem. Lett. 1997, 5, 93; (b)
Njoroge, G.; Doll, R. J.; Vibulbhan, B.; Alvarez, C ; Bishop,
W. R.; Petrin, J.; Kirshmeier, P.; Carruthers, N. I.; Wong, J.;
2. (a) Egan, S. E.; Weinberg, R. A. Nature (London) 1993, 365,
781; (b) Marshal, M. S. Trends Biochem. Sci. 1993, 18, 250; (c)
Hall, A. Science 1994, 264, 1413.
3. Boguski, M. S.; McCormick, F. Nature (London) 1993, 366,
643.
4. (a) Nishida, E.; Gotoh, Y. Trends. Biochem. Sci. 1993, 18,
128; (b) Stokoe, D.; MacDonald, S. G.; Caldwallader, K.;

686
J. Kelly et al./Bioorg. Med. Chem. 6 (1998) 673±686
Albanese, M.; Piwinski, J. J.; Catino, J.; Girijavallabhan, V.;
Ganguly, A. K. Bioorg. Med. Chem. 1997, 5, 101; (c) Njoroge,
G.; Vibulbhan, B.; Alvarez, C.; Bishop, W. R.; Petrin, J.; Doll,
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between the C-10 proton and the allylic protons on the lactam
ring. (b) X-Ray crystallographic data on 6b and 56 is available
from the authors. (c) The mixed sulfonic anhydride 14 obtained
by reacting 3-pyridinesulfonic acid with p-nitrobenzenesulfonyl
chloride (Scheme 2) was used to preparare the 3-pyridyl-
sulfonamides 36 and 59.
16. The terms 4-piperidino, 3-piperidino and 3-pyrrolidino are
used for convenience to denote the carbon of the pendant
piperidine or pyrrolidine ring that forms the ole®nic bond at C-
11 of the benzocycloheptapyridine tricycle.
20. The chemical shifts of the allylamino protons in the sulfo-
namido derivatives of Z-compounds II are deshielded by 0.2±
0.3 ppm relative to the corresponding derivatives of the E-
compounds III.
17. Villani, F. J.; Daniels, P. J. L.; Ellis, C. A.; Mann, T. A.;
Wang, K. C. J. Heterocycl. Chem. 1971, 8, 73.
21. FPT and GGPT assays were performed over a wide range
of inhibitor concentrations in half-log increments. Each data
point was typically generated by duplicate determinations and
the mean value was used to calculate percent inhibition relative
to a vehicle (DMSO) control. Duplicates were within ‹5% of
the mean value.
18. Wong, J. K.; Piwinski, J. J.; Green, M. J.; Ganguly, A. K.;
Anthes, J. C.; Billah, M. M. Bioorg. Med. Chem. Lett. 1993, 3,
1073.
19. (a) The ole®nic geometries were established by NMR stu-
dies wherein an NOE e€ect in the Z-isomers 3b was observed