Novel tacrine analogues for potential use against Alzheimer's disease: Potent and selective acetylcholinesterase inhibitors and 5-HT uptake inhibitors

Article abstract of DOI:10.1021/jm970150t

Several novel analogues of tactine have been synthesized and tested for their ability to inhibit acetylcholinesterase, butyrylcholinesterase, and neuronal uptake of 5-HT (serotonin) and noradrenaline. Changes in the size of the carbocyclic ring of tactine produced modest potency against cholinesterase enzymes. Addition of a fourth ring resulted in compounds with marked selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase [BChE): e.g. 6-amino-4,5-benzo-5H-cyclopenta[1,2-b]-quinoline (14a) had an IC₅₀ of 0.35μM against AChE and 3.1 μM against BChE. Some tetracyclic compounds are 100-400 times more active than tacrine as inhibitors of neuronal uptake of serotonin, in particular 13-amino-6,7-dihydro-5H- benzo[3,4]cyclohepta[1,2-b]quinoline (18), which had an IC₅₀ of 20 nM. These compounds would be expected to facilitate both cholinergic and monoaminergic transmission. They should be worth investigating in models of memory impairment.

Full text of DOI:10.1021/jm970150t

3516
J . Med. Chem. 1997, 40, 3516-3523
Novel Ta cr in e An a logu es for P oten tia l Use a ga in st Alzh eim er ’s Disea se: P oten t
a n d Selective Acetylch olin ester a se In h ibitor s a n d 5-HT Up ta k e In h ibitor s
Maureen T. McKenna,† George R. Proctor,† Louise C. Young,‡ and Alan L. Harvey*,‡
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K., and
Department of Physiology and Pharmacology, and Strathclyde Institute for Drug Research, University of Strathclyde,
204 George Street, Glasgow G1 1XW, U.K.
Received March 10, 1997X
Several novel analogues of tacrine have been synthesized and tested for their ability to inhibit
acetylcholinesterase, butyrylcholinesterase, and neuronal uptake of 5-HT (serotonin) and
noradrenaline. Changes in the size of the carbocyclic ring of tacrine produced modest potency
against cholinesterase enzymes. Addition of a fourth ring resulted in compounds with marked
selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase (BChE): e.g. 6-amino-
4,5-benzo-5H-cyclopenta[1,2-b]-quinoline (14a ) had an IC50 of 0.35 µM against AChE and 3.1
µM against BChE. Some tetracyclic compounds are 100-400 times more active than tacrine
as inhibitors of neuronal uptake of serotonin, in particular 13-amino-6,7-dihydro-5H-benzo-
[3,4]cyclohepta[1,2-b]quinoline (18), which had an IC50 of 20 nM. These compounds would be
expected to facilitate both cholinergic and monoaminergic transmission. They should be worth
investigating in models of memory impairment.
In tr od u ction
Dementia is the most common psychiatric disorder
of old age, and Alzheimer’s disease1 is its most common
cause. Alzheimer’s disease involves the degeneration
of cholinergic neurones in the cerebral cortex and
hippocampus, areas of the brain particularly associated
with memory, higher intellectual functioning, and con-
sciousness.2 The biochemical deficits also extend into
other neurochemical systems, affecting the levels of
monoamine transmitters for example,3 but the most
profound and consistent loss is that of cholinergic
transmission. Consequently, much research concerns
enhancing the cholinergic system in some way,4 ranging
from the use of acetylcholine-releasing agents such as
4-aminopyridine5 (1); the acetylcholine precursor, cho-
line6; cholinergic agonists, e.g. arecoline (2); and anti-
cholinesterase drugs, e.g. physostigmine (3). However,
linesterase activity and monoamine uptake processes
one drug in particular has become the subject of intense
and to elucidate criteria for designing more active
pharmacological scrutiny for its efficacy in alleviating
molecules for future testing. A more active and more
the symptoms of Alzheimer’s disease, namely 9-amino-
selective inhibitor of acetylcholinesterase activity than
1,2,3,4-tetrahydroacridine, commonly referred to as
tacrine that also had more potent ability to block
neuronal reuptake of 5-hydroxytryptamine (5-HT, sero-
tonin) and noradrenaline would be of interest as a
tacrine7 (4).
Tacrine (4)8 was found to be a potent acetylcholinest-
erase inhibitor9,10 in 1953 and, subsequently, an even
potential treatment to alleviate the symptoms of Alz-
stronger inhibitor of the butyrylcholinesterase family
heimer’s disease. Inhibition of acetylcholinesterase
of enzymes.11 More recently, tacrine has been shown
would potentiate the remaining cholinergic transmission
to possess a much broader pharmacological profile than
in affected brain regions, while block of monoamine
cholinesterase inhibition: blockage of potassium chan-
uptake would potentiate transmission in pathways
nels,12 inhibition of the neuronal monoamine uptake
involving 5-HT and noradrenaline, which are also
processes,13 and inhibition of monamine oxidase14 have
known to be affected in Alzheimer’s disease.3
all been reported. Since tacrine has been used to
alleviate the symptoms of Alzheimer’s disease with
greater apparent success than other anticholinesterase
From previously published work on tacrine analogues,
there is little information about structure-activity
relationships for inhibition of monoamine uptake pro-
drugs tried earlier, tacrine’s heightened efficacy could
cesses, but there has been some work on inhibition of
be related to these other pharmacological actions.15
cholinesterase activity. Our starting point, then, was
The aim of this study was to produce novel tacrine
analogues for pharmacological evaluation against cho-
the study by Kaul,14a who had compared the anticho-
linesterase activities of 4-aminopyridine (1), 4-amino-
quinoline (5), tetrahydroacridine (6), and 9-(N-n-bu-
tylamino)-1,2,3,4-tetrahydroacridine (7). His results
showed that 4-aminopyridine (1) and 4-aminoquinoline
† Department of Pure and Applied Chemistry.
‡ Department of Physiology and Pharmacology.
X Abstract published in Advance ACS Abstracts, October 1, 1997.
S0022-2623(97)00150-7 CCC: $14.00 © 1997 American Chemical Society

Novel Tacrine Analogues
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22 3517
Sch em e 1a
Sch em e 4a
a
(a) BF3‚Et2O.
Sch em e 2a
a
(a) BF3‚Et2O.
Sch em e 5a
a
(a) BF3‚Et2O.
Sch em e 3a
a
(a) PhP3CH2I, THF; (b) AgNO3, I2, MeOH, H2O; (c) BF3‚Et2O.
Sch em e 6a
a
(a) BF3‚Et2O; (b) molecular seives 5 Å, BF3‚Et2O.
(5) had only a very weak anticholinesterase activity
although their basicities were almost equal to that of
tacrine. The N-butyl derivative (7) was not particularly
active, with the butyl chain hindering the interaction
of the compound with the enzyme, but tetrahydroacri-
dine (6), a much weaker base, was found to be almost
as active as tacrine itself. These results indicate that
the cyclohexyl ring is important for anticholinesterase
activity. Subsequent examination of the X-ray crystal
structure of tacrine with acetylcholinesterase16 revealed
that the 4-aminoquinoline portion of the tacrine mol-
ecule seemed to be responsible for the binding of the
drug to the enzyme, while the cyclohexyl ring acted
mostly as a block to the substrate at the active site.
Hence, the series of compounds devised for synthesis
during this study was designed to investigate the effects
on anticholinesterase activity of changing the cyclohexyl
ring, i.e. by altering the ring size, bridging the ring,
fusing a benzene ring to the equivalent of the cyclohexyl
ring, and introducing heteroatoms and various substit-
uents. These investigations were considered necessary
because previous research had provided only sparse and
fragmentary information on compounds with structural
changes specific to only the cyclohexyl ring, and because
conventional substitutions of the aromatic ring and at
the amino nitrogen had proven relatively fruitless. In
addition, these structural changes were investigated for
their effects on inhibition of neuronal uptake of 5-HT
and noradrenaline.
a
(a) BF3‚Et2O.
ketones (Schemes 2-6). After experimentation with
various Lewis acids, the reagent of choice became boron
trifluoride diethyl etherate.
Ch em istr y
The Lewis acid mediated cyclodehydration reaction
between anthranilonitrile (8) and cyclohexanone (9)
which gave tacrine (4)17 (Scheme 1) was adapted to
produce the following ranges of compounds by substi-
tuting cyclohexanone (9) with the appropriate cyclic
6-Benzosuberone (17) was synthesized by the ring
expansion of 1,2,3,4-tetrahydro-1-methylenenaphtha-
lene (16) in a method using silver nitrate and iodine in
aqueous methanol devised by Proctor et al.18 1,2,3,4-
Tetrahydro-1-methylenenaphthalene (16) was itself syn-

3518 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22
MccKenna et al.
Sch em e 7a
Ta ble 1. Anticholinesterase Activity of Tacrine Analogues
IC50 (µM ( SEM, n ) 5)
compd
AChE
BChE
4
0.078 ( 0.001
0.056 ( 0.004
0.039 ( 0.008
9.1 ( 0.6
0.24 ( 0.03
110.0 ( 5.3
0.35 ( 0.06
37.4 ( 2.9
47.5 ( 2.3
144.1 ( 7.3
166.1 ( 74.3
68.8 ( 4.2
38.2 ( 8.1
no blocka
0.025 ( 0.002
0.052 ( 0.008
0.014 ( 0.002
2.3 ( 0.08
0.041 ( 0.005
88.0 ( 10
10a
10b
10c
12a
12b
14a
14b
14c
14d
14e
14f
18
20a
27
28
31a
31b
32a
32b
3.1 ( 0.4
3.3 ( 0.06
no blocka
10.3 ( 0.7
36.0 ( 9.0
>100 µM
a
(e) Sodium naphthalenide, DME.
26.4 ( 0.44
no blocka
Sch em e 8a
69.4 ( 3.6
391.1 ( 51.3
134.0 ( 0.4
91.0 ( 26.0
3.5 ( 0.4
18.9 ( 2.6
6.7 ( 0.64
12.2 ( 0.6
81.0 ( 3.8
5.9 ( 0.5
25.0 ( 1.3
42.0 ( 2.8
a
No significant block when tested at 100 µM.
Ta ble 2. Inhibition of 5-Hydroxytryptamine and
Noradrenaline Uptake by Tacrine Analogues
IC50 (µM)a
compd
5-HT uptake
noradrenaline uptake
4
10a
10b
10c
12a
12b
14a
14b
14c
14d
14e
14f
18
20a
27
28
7.6 ( 0.6
21.0 ( 1.9
3.6 ( 0.7
1.1 ( 0.3
0.2 ( 0.05
13.0 ( 2.9
2.2 ( 1.1
4.6 ( 0.6
5.8 ( 0.7
14.3 ( 1.8
4.7 ( 0.5
0.7 ( 0.3
0.02 ( 0.001
>95 µM
4.2 ( 0.7
6.9 ( 0.8
4.4 ( 0.4
7.1 ( 1.0
5.1 ( 0.6
13.0 ( 0.8
0.13 ( 0.03
nd
7.9 ( 0.7
0.6 ( 0.2
6.9 ( 0.8
0.8 ( 0.2
6.1 ( 0.4
nd
2.3 ( 1.0
12.1 ( 1.6
1.4 ( 0.1
41.04 ( 2.4
1.8 ( 0.3
3.6 ( 0.4
nd
0.2 ( 0.02
3.0 ( 0.8
2.5 ( 0.2
nd
12.0 ( 1.4
nd
31a
31b
32a
32b
fluoxetine
desipramine
a
(f) TsOH, toluene; (g) RLi, THF; R ) Me, n-Bu; (h) H2SO4 (aq).
nd
nd
1.7 ( 0.3
thesized by the Wittig methylenation of 1-tetralone19
(15) (Scheme 5).
a
(95% confidence limits; nd ) not determined.
Compounds 22 and 26 were detosylated20 to their
corresponding secondary amines (Scheme 7).
cholinesterase inhibition and inhibition of neuronal
uptake of 5-HT (serotonin) and noradrenaline. The
results are summarized in Tables 1 and 2.
Using a different chemical route (Scheme 8), the
ketone 2-hydroxy-3-methylcyclopent-2-enone (cyclo-
tene)21 (29) was successfully condensed with anthra-
nilonitrile (8) to produce the enamine intermediate N-(4-
methyl-5-oxocyclopenten-1-yl)-1-aminobenzonitrile (30a )
which was separated from its minor isomer (30b) by
column chromatography. Reaction of 30a with 2 equiv
of an organolithium reagent (methyllithium, n-butyl-
lithium) produced a nucleophilic attack on the carbonyl
group with a comcomitant cyclization to produce 9-amino-
2,3-dihydro-2-methyl-1H-cyclopenta[1,2-b]quinolines (31a
and 31b) of undetermined stereochemistry. Subsequent
dehydration of these tertiary alcohols 31a and 31b
produced the corresponding alkenes 32a and 32b.
Tacrine (4) is about three times more active at
inhibiting butyrylcholinesterase than acetylcholinest-
erase (Table 1). Changing the size of the carbocyclic
ring revealed that increasing from a cyclopentyl (com-
pound 10a ) to a cycloheptyl (compound 10b) ring
increased the potency against butyrylcholinesterase
activity significantly (almost 4-fold), although there was
a smaller increase in potency against acetylcholinest-
erase activity (2-fold). However, the cyclooctyl deriva-
tive (compound 10c) showed a 100-fold reduction in
anticholinesterase activity, possibly due to the increase
in bulk and flexibility of the carbocyclic ring.
Resu lts a n d Discu ssion
Insertion of a methylene bridge across the cyclohexyl
ring of tacrine (compound 12a ) produced a loss in
anticholinesterase activity that was markedly enhanced
Four different pharmacological actions of the novel
tacrine analogues were determined: acetyl- and butyryl-

Novel Tacrine Analogues
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22 3519
with increasing substituent bulk upon the bridge by
three methyl groups (compound 12b).
fusion of a benzene ring. However, the biological results
indicate that certain structures, derived from 12a , 14a ,
and 18, could be useful templates for further work in
this area. Compared with tacrine (4), 6-amino-4,5-
benzo-5H-cyclopenta[1,2-b]quinoline (14a ) is 30 times
more selective for acetylcholinesterase over butyrylcho-
linesterase, and it is also a 3-fold more potent inhibitor
of 5-HT and noradrenaline uptake than is tacrine.
8-Amino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quin-
oline (14e), its methoxy analogue (14f), and particularly
its structural isomer 13-amino-6,7-dihydro-5H-benzo-
[3,4]cyclohepta[1,2-b]quinoline (18) all gave potent amin-
ergic uptake inhibition. Given that Alzheimer’s disease
involves a loss of cholinergic and aminergic transmis-
sion, the availability of compounds with potent effects
on acetylcholinesterase and monoamine uptake pro-
cesses could be an exciting prospect, and they deserve
to be tested in models of memory impairment.
Fusing a benzene ring to the alicyclic ring to give
compounds 14a -f resulted in compounds with very
much reduced activity in the cholinesterase assays
compared to tacrine (4). However, the compound 14a
derived from indanone was highly selective for acetyl-
cholinesterase, rather than butyrylcholinesterase, in
contrast to tacrine (Table 1). Other tetracyclic com-
pounds (18, 20a , 27, 28) and their tosylated forms (20b,
22, 24, 26) had much weaker cholinesterase blocking
activity than that of tacrine (data not shown). Com-
pound 28 was about 50 times more effective against
butyrylcholinesterase than against acetylcholinesterase.
Compounds 31a and 31b had much less activity
against both cholinesterases in comparison with the
unsubstituted 9-amino-2,3-dihydro-1H-cyclopenta[b]-
quinoline (10a ). The corresponding dehydrated prod-
ucts, compounds (32a , 32b), were more active than 31a
and 31b but still weaker than 10c.
Exp er im en ta l Section
With respect to monoamine uptake, tacrine (4) has a
relatively weak inhibitor of both 5-HT and noradrena-
line uptake (Table 2). Decreasing the size of the
carbocyclic ring (10a ) resulted in a 3-fold loss of potency,
compared with tacrine, against 5-HT uptake, but a 10
times increase in potency against noradrenaline uptake.
Increasing the ring size from that of tacrine caused
about a 10-fold increase in potency against the two
uptake processes (compounds 10b and 10c).
Changing the bulk around the cycohexyl ring of
tacrine by inserting a methylene bridge resulted in a
more potent and more selective inhibitor of 5-HT uptake
than tacrine (see compounf 12a , Table 2). Addition of
methyl substituents to the methylene bridge resulted
in a marked loss of activity (in compound 12b).
Fusing a benzene ring to the carbocyclic ring gave
compounds 14a -f that were generally more active than
tacrine as uptake inhibitors (Table 2). 14f, with a
3-methoxy substituent on a seven-membered carbocyclic
ring, was 10 times more potent than tacrine on 5-HT
uptake and twice as active as tacrine on noradrenaline
uptake. When a benzene ring was fused at the 3,4-
position rather than the 6,7-position of the cycloheptyl
ring (compound 18), the activity against 5-HT uptake
was dramatically enhanced: 400 times more active than
tacrine (4) and 200 times more active than compound
14e. For reference, the IC50 of the standard compound
fluoxetine for 5-HT uptake was similar to that of
compound 12a and 6 times greater than that of com-
pound 18 (Table 2).
Compounds containing nitrogen within the carbocyclic
ring (compounds 20a , 27, 28) tended to have reduced
activity against 5-HT uptake, compared with tacrine (4)
(Table 2). However, compound 20a , a fully aromatic
dibenzonaphthyridine, demonstrated a potent and se-
lective block of noradrenaline uptake. The tosylated
compounds (20b, 22, 24, 26) were inactive.
Melting points were obtained on a Gallenkamp melting
point apparatus in open capillaries and are uncorrected. 1H
NMR spectra were recorded on a Perkin-Elmer R32 spectrom-
eter operating at 90 MHz, on a Bruker WM250 spectrometer
operating at 250.13 MHz, and on a Bruker AMX400 spectrom-
eter operating at 400.13 MHz, with the WM250 and the
AMX400 in Fourier Transform mode. J values are given in
hertz. Infrared spectra were recorded on a Unicam Mattson
1000 series FTIR spectrometer as thin films, as Nujol mulls,
or in solution cells. Flash column chromatography was carried
out using CAMLAB Art. Nr 81538 MN Kieselgel 60 (0.040-
0.063 mm) and Merck 7735 silica gel type 60 (0.125-0.250
mm). Samples were applied in solution or adsorbed onto silica.
Mass spectra were obtained on a AEIMST double-focusing
mass spectrometer, modified with a solid state console using
a GEC 905 computer based data system. Carbon, hydrogen,
and nitrogen analyses were determined on a Carlo Erba 1106
analyzer using a technique based on the classical Pregl Dumas
method. Halogens were determined by combusting the sample
in an oxygen flask containing hydrogen peroxide and potas-
sium hydroxide and titrating an alcoholic solution of the
products with mercuric nitrate using diphenylcarbazone as
indicator (Mercurimetric method). Sulfur was determined by
combusting the sample in an oxygen flask containing hydrogen
peroxide and water and titrating an alcoholic solution of the
products with barium perchlorate using the mixed indicator
THORON and methylene blue. Toluene was dried over
sodium; THF was predried with anhydrous sodium sulfate and
distilled over calcium hydride or sodium benzophenone ketyl.
All solutions were dried over anhydrous sodium sulfate or
anhydrous magnesium sulfate and filtered. Thin layer chro-
matography was carried out on plastic sheets pre-coated with
0.25 mm silica gel containing fluorescent indicator UV254, or
with 0.2 mm aluminum oxide also with fluorescent indicator
UV254, both supplied by CAMLAB. Elemental analyses are
indicated only by the symbol of the elements; analytical results
were within 0.4% of the theoretical values unless otherwise
noted.
Gen er a l Meth od for th e Cyclod eh yd r a tion Rea ction .
Anthranilonitrile (8), ketone (1.1 equiv) and sodium-dried
toluene (120 mL) were placed in
a three-necked round-
bottomed flask fitted with an overhead stirrer. Boron trifluo-
ride diethyl etherate (1.1 equiv) was added slowly via syringe,
and the reaction mixture was heated at reflux for 24 h. On
cooling, the toluene was decanted and, to liberate the product,
the remaining solids were treated with sodium hydroxide (2
M, 120 mL) and heated at reflux for 24 h. After cooling, the
organic components were extracted with chloroform, the
organic layers were combined and dried, and the solvent was
evaporated in vacuo to give the desired product. Maleate salts
were prepared by refluxing a solution of the free base with 1
equiv of maleic acid.
To summarize, systematic ranges of compounds have
been designed, synthesized, and subjected to pharma-
cological evaluation. Several criteria have been estab-
lished for the further design of tacrine analogues for
potential use against Alzheimer’s disease: i.e. avoidance
of (a) bridging across the cyclohexyl ring, (b) insertion
of a nitrogen heteroatom into the carbocyclic ring, (c)
carbocyclic ring greater than seven-membered, and (d)

3520 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22
MccKenna et al.
9-Am in o-1,2,3,4-tetr a h yd r oa cr id in e (4). Recrystallized:
mp 178-180 °C (aqueous EtOH) [lit.22 mp 178-179 °C]; M+,
decanted, and the remaining solids were heated at reflux with
sodium hydroxide (2 M, 100 mL) for 24 h. On cooling, the
organic components were extracted with chloroform, the
extracts were combined and dried, and the solvent was
evaporated in vacuo to give a golden oil. On trituration with
petroleum ether (60-80 °C) this gave a white precipitate which
was removed by filtration to give the title compound (12b) (0.4
1
198.1144; H NMR (CDCl3) δ 1.86-1.95 (4H, m, 2CH2), 2.57
(2H, t, J ) 6.2, CH2), 3.01 (2H, t, J ) 5.5, CH2), 4.68 (2H, br
s, exchanges with D2O, NH2), 7.33 (1H, td, J ) 8.2, 1.2, aryl-
H), 7.54 (1H, td, J ) 6.8, 1.3, aryl-H), 7.67 (1H, dd, J ) 8.4,
0.8, aryl-H), 7.88 (1H, d, J ) 8.4, aryl-H). Maleate salt: mp
50-55 °C. Anal. (C13H14N2) C, H, N.
1
g, 3.8%): mp 150-154 °C; M+, 252.1631; H NMR (CDCl3) δ
0.63 (3H, s, CH3), 0.83-1.43 (8H, m, 2CH3, 2H), 1.90 (1H, td,
J ) 9.66, 2.99), 2.07-2.17 (1H, m), 2.91 (1H, d, J ) 3.81), 4.43
(2H, br s, exchanges with D2O, NH2), 7.39 (1H, td, J ) 6.88,
1.27, aryl-H), 7.56 (1H, td, J ) 6.91, 1.46, aryl-H), 7.71 (1H,
dd, J ) 8.23, 1.32, aryl-H), 8.02 (1H, dd, J ) 8.39, 1.13, aryl-
H). Anal. (C17H20N2) C, H, N.
9-Am in o-2,3-d ih yd r o-1H -cyclop en t a [1,2-b]q u in olin e
(10a ). Anthranilonitrile (8) (5.0 g, 42.3 mmol), cyclopentanone
(9a ) (4.1 g, 46.7 mmol), boron trifluoride diethyl etherate (1
M, 10 mL, 81.8 mmol) gave the title compound (10a ) (3.2 g,
41% crude). Recrystallized: mp 180-182 °C (aqueous EtOH);
1H NMR (CDCl3) δ 2.19 (2H, quintet, J ) 7.6, CH2), 2.88 (2H,
t, J ) 7.5, CH2), 3.10 (2H, t, J )7.8, CH2), 4.65 (2H br s,
exchanges with D2O, NH2), 7.33 (1H, t, J ) 8.05, aryl-H), 7.57
(1H, t, J ) 8.11, aryl-H), 7.71 (1H, d, J ) 8.3, aryl-H), 7.89
(1H, d, J ) 8.4, aryl-H). Anal. (C12H12N2) C, H, N. Maleate
6-Am in o-4,5-ben zo-5H-cyclopen ta[1,2-b]qu in olin e (14a).
Anthranilonitrile (8) (4.6 g, 38.9 mmol), indan-1-one (13a ) (5.6
g, 42.4 mmol), and boron trifluoride diethyl etherate (1 M, 5.3
mL, 43.3 mmol) gave the title compound (14a ) (0.25 g, 2.6%
crude). Recrystallized: mp 239-240 °C dec (EtOH); M+
232.1006; 1H NMR (CD3OD) δ 3.78 (2H, s, CH2), 7.20-7.69
(5H, m, aryl-H), 7.94 (1H, d, J ) 8.5, aryl-H), 8.03 (1H, d, J )
8.4, aryl-H), 8.10-8.25 (1H, m, aryl-H). Anal. (C17H20N2) C,
1
salt mp: 100-105 °C; H NMR (CD3OD) δ 2.34 (2H, quintet,
J ) 7.8, CH2), 2.97 (2H, t, J ) 7.1, CH2), 3.23 (2H, t, J ) 7.8,
CH2), 6.23 (2H, s, maleate), 7.61 (1H, td, J ) 6.9, 1.3, aryl-H),
7.35 (1H, d, J ) 8.5, aryl-H), 7.86 (1H, td, J ) 6.9, 1.2, aryl-
H), 8.23 (1H, dd, J ) 8.5, 0.7, aryl-H). Anal. (C12H12N2) C,
H, N.
1
H, N. Maleate salt: mp 212-214 °C; H NMR (DMSO-d6) δ
3.91 (2H, s, CH2), 2.60-4.70 (2H, br s, exchanges with D2O,
NH2), 6.06 (2H, s, maleate), 7.50-8.00 (6H, m, aryl-H), 8.18
(1H, d, J ) 7.2, aryl-H), 8.43 (1H, d, J ) 8.4, aryl-H), 8.71
(2H, br s, exchanges with D2O, maleate). Anal. (C17H20N2‚
C4H4O4) C, H, N.
11-Am in o-2,3,4,5-tetr a h yd r o-1H-cycloh ep ta [1,2-b]qu in -
olin e (10b). Anthranilonitrile (8) (10.0 g, 84.7 mmol), cyclo-
heptanone (9b) (11.4 g, 101.8 mmol) and boron trifluoride
diethyl etherate (1 M, 12.5 mL, 102.3 mmol) gave the title
compound (10b) (10.9 g, 61% crude). Recrystallized: mp 167-
171 °C (EtOH) (lit.23 mp 178 °C); 1H NMR (CDCl3) δ 1.64-
1.92 (6H, m, 3CH2), 2.74 (2H, m, CH2), 3.13 (2H, m, CH2), 4.68
(2H, br s, exchanges with D2O, NH2), 7.39 (1H, td, J ) 7.00,
1.22, aryl-H), 7.56 (1H, td, J ) 6.89, 1.31, aryl-H), 7.68 (1H,
dd, J ) 8.31, 0.74, aryl-H), 7.91 (1H, d, J ) 8.41, 0.61, aryl-
H). Anal. (C14H16N2) C, H, N. Maleate salt: mp 161-163
11-Am in o-1,2-d ih yd r oben z[c]a cr id in e (14b). Anthra-
nilonitrile (8) (2.0 g, 16.9 mmol), 1-tetralone (3,4-dihydro-2H-
naphthalen-1-one) (13b) (2.7 g, 18.5 mmol), and boron triflu-
oride diethyl etherate (1 M, 2.3 mL, 18.8 mmol) were treated
according to the general procedure to give the title compound
(14b ) (3.75 g, 90% crude). Recrystallized: mp 138-140 °C
(EtOH); M+, 246.1159; 1H NMR (CDCl3) δ 2.6-3.1 (4H, m,
2CH2), 4.55 (2H, br s, exchanges with D2O, NH2), 7.10-7.80
(6H, m, aryl-H), 8.00-8.20 (1H, m, aryl-H), 8.5-8.7 (1H, m,
aryl-H). Anal. (C17H14N2) C, H, N. Maleate salt: mp 207-
209 °C; δH(250 MHz, CD3OD) 2.7-3.2 (4H, m, CH2), 6.22 (2H,
s, maleate), 7.3-7.7 (4H, m, aryl-H), 7.87 (1H, t, J ) 7.3, aryl-
H), 7.95-8.2 (2H, m, aryl-H), 8.35 (1H, d, J ) 7.6, aryl-H).
Anal. (C17H14N2‚C4H4O4) C, H, N.
11-Am in o-1,2-d ih yd r o-3-m eth oxyben z[c]a cr id in e (14c).
Anthranilonitrile (8) (5.0 g, 42.3 mmol), 5-methoxy-1-tetralone
(13c) (8.1 g, 46.0 mmol), and boron trifluoride diethyl etherate
(1 M, 5.7 mL, 46.6 mmol) gave the title compound (14c) (5.5
g, 47% crude). Recrystallized: mp 126-129 °C (CHCl3). M+,
276.1265; 1H NMR (CDCl3) δ 2.5-3.2 (4H, m, 2CH2), 3.9 (3H,
s, CH3), 4.6 (2H, br s, exchanges with D2O, NH2), 6.8-7.0 (1H,
d, J ) 9, aryl-H), 7.2-7.8 (2H, m, aryl-H), 8.0-8.35 (1H, m,
aryl-H). Anal. (C18H16N2O), C, H, N. Maleate salt: mp 210-
216 °C dec; 1H NMR (DMSO-d6) δ 2.70-3.05 (4H, m, CH2),
3.89 (3H, s, CH2), 6.03 (2H, s, maleate), 7.29 (1H, d, J ) 8.1,
aryl-H), 7.52 (1H, t, J ) 8.0, aryl-H), 7.64 (1H, t, J ) 7.3, aryl-
H), 7.81 (1H, d, J ) 7.8, aryl-H), 7.90 (1H, t, J ) 7.4, aryl-H),
7.13 (1H, d, J ) 8.3, aryl-H), 8.45 (1H, d, J ) 8.3, aryl-H),
8.57 (2H, br s, maleate). Anal. (C18H16N2O‚C4H4O4) C, H, N.
11-Am in o-1,2-d ih yd r o-4-ch lor oben z[c]a cr id in e (14d ).
Anthranilonitrile (8) (5.0 g, 42.3 mmol), 6-chloro-1-tetralone
(13d ) (8.8 g, 48.7 mmol), and boron trifluoride diethyl etherate
(1 M, 6.4 mL, 52.4 mmol) gave the title compound (14d ), 3.3
g, 28% (crude). Recrystallized: mp 205-208 °C (EtOH); M+,
280.0769; 1H NMR (CDCl3) δ 2.7-3.1 (4H, m, 2CH2), 4.6 (2H,
br s, exchanges with D2O, NH2), 7.1-8.2 (6H, m, aryl-H), 8.5
(1H, d, J ) 8.1, aryl-H). Anal. (C17H15N2Cl) C,H,N,Cl.
Maleate salt: mp 220-221 °C dec; 1H NMR (DMSO-d6) δ
2.30-3.06 (4H, m, 2CH2), 3.34 (2H, br s, NH2), 6.05 (2H, s,
maleate), 7.55-7.70 (3H, m, aryl-H), 7.88 (1H, t, J ) 7.9, aryl-
H), 8.07 (1H, d, J ) 8.5, aryl-H), 8.19 (1H, d, J ) 8.1, aryl-H),
8.43 (1H, d, J ) 8.3, aryl-H), 8.51 (2H, br s, maleate). Anal.
(C17H15N2Cl‚C4H4O4) C, H, N, Cl.
1
°C; H NMR (CD3OD) δ 1.65-1.96 (6H, m, 3CH2), 2.91 (2H,
m, CH2), 3.13 (2H, m, CH2), 6.25 (2H, s, maleate), 7.61(1H,
td, J ) 6.8, 1.4, aryl-H), 7.75 (1H, d, J )8.4, 0.5, aryl-H), 7.85
(1H, td, J ) 6.7, 1.2, aryl-H), 8.28 (1H, dd, J ) 8.5, 0.5, aryl-
H). Anal. (C14H16N2‚C4H4O4) C, H, N.
12-Am in o-1,2,3,4,5,6-h exa h yd r ocycloocta [1,2-b]qu in o-
lin e (10c). Anthranilonitrile (8) (5.0 g, 42.3 mmol), cyclooc-
tanone (9c) (6.1 mL, 46.7 mmol), and boron trifluoride diethyl
etherate (1 M, 5.6 mL, 46.7 mmol) gave the title compound
(10c) (7.4 g, 78% crude). Recrystallized: mp 198-200 °C
1
(EtOH) (lit.24 mp 198-200 °C); H NMR (CDCl3) δ 1.20-1.55
(4H, m, 2CH2), 1.60-1.95 (4H, m, 2CH2), 2.87 (2H, m, CH2),
3.10 (2H, m, CH2), 4.70 (2H, br s, exchanges with D2O, NH2),
7.39 (1H, td, J ) 6.8, 1.3, aryl-H), 7.57 (1H, td, J ) 8.3, 1.4,
aryl-H), 7.70 (1H, dd, J ) 8.3, 0.7, aryl-H), 7.95 (1H, dd, J )
8.4, 0.6, aryl-H). Anal. (C15H18N2) C, H, N. Maleate salt: mp
168-170 °C; 1H NMR (CD3OD) δ 1.35-1.56 (4H, m, 2CH2),
1.57-1.95 (4H, m, 2CH2), 2.9-3.0 (2H, m, CH2), 3.05-3.15 (2H,
m, 2CH2), 6.24 (2H, s, maleate), 7.62 (1H, t, J ) 8.1, aryl-H),
7.76 (1H, d, J ) 7.8, aryl-H), 7.83 (1H, t, J ) 6.7, aryl-H), 8.31
(1H, d, J ) 8.4, aryl-H). Anal. (C15H18N2‚C4H4O4) C, H, N.
9-Am in o-1,4-m eth a n o-1,2,3,4-tetr a h yd r oa cr id in e (12a ).
Anthranilonitrile (8) (5.0 g, 42.3 mmol), norcamphor (11a ) (5.0
g, 45.5 mmol) and boron trifluoride diethyl etherate (1 M, 5.1
mL, 41.7 mmol) gave the title compound (12a , 2.5 g, 29%
crude). Recrystallized: mp 186-187 °C (EtOH) (lit25 mp 186-
1
188 °C) M+, 210.1158; H NMR (CDCl3) δ 1.31-1.36 (1H, m,
CH2), 1.42-1.46 (1H, m, CH2), 1.66 (1H, dt, J ) 9.04, 1.52,
CH2), 1.87-1.90 (1H, m, CH2), 1.96-2.08 (2H, m, CH2), 3.49
(2H, d, J ) 11.44, CH2), 4.54 (2H, br s, exchanges with D2O,
NH2), 7.39 (1H, t, J ) 7.00, aryl-H), 7.57 (1H, t, J ) 6.96, aryl-
H), 7.71 (1H, d, J ) 8.32, aryl-H), 7.96 (1H, d, J ) 8.44, aryl-
H).
9-Am in o-1,4-m e t h a n o-1,2,3,4-t e t r a h yd r o-4,11,11-t r i-
m eth yla cr id in e (12b). Anthranilonitrile (8) (5.0 g, 42.3
mmol) and (R)-(+)-camphor (11b) (7.0 g, 46.7 mmol) were
placed in toluene (70 mL). Molecular sieves 5 Å (50 g) were
added and the reaction was heated at reflux for 1 h. On
cooling, the mixture was filtered, boron trifluoride diethyl
etherate (1 M, 7.7 mL, 63.0 mmol) was added, and the reaction
mixture was heated at reflux for 24 h. The toluene was
8-Am in o-6,7-d ih yd r o-5H-b en zo[6,7]cycloh ep t a [1,2-b]-
qu in olin e (14e). Anthranilonitrile (8) (2.0 g, 16.9 mmol),
5-benzosuberone (6,7,8,9-tetrahydrobenzocyclohepten-5-one)
(13e) (3.0 g, 18.7 mmol), and boron trifluoride diethyl etherate
(1 M, 2.6 mL, 18.7 mmol) gave the title compound (14e) (3.5

Novel Tacrine Analogues
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22 3521
g, 80% crude). Recrystallized: mp 190-192 °C (EtOH); found
8-Am in o-6,7-d ih yd r o-5-N-tosylqu in olin o[3,2-d ][5H]-1-
ben za zep in e (22). Anthranilonitrile (8) (2.0 g, 16.9 mmol),
1,2,3,4-tetrahydro-1-N-tosyl-benzazepin-5-one (21)27 (5.9 g,
18.9 mmol), and boron trifluoride diethyl etherate (1 M, 2.3
mL, 18.8 mmol) were treated according to the general pro-
cedure to give the title compound (22) (5.4 g, 76% crude).
Recrystallized: mp >250 °C (EtOH/MeOH); M+, 415.1347; 1H
NMR (DMSO-d6) δ 1.76 (3H, s, Ts-CH3), 2.30 (1H, br s, CH2),
3.10 (1H, br s, CH2), 3.91 (1H, br s, CH2), 4.20 (1H, br s, CH2),
6.45 (2H, br s, exchanges with D2O, NH2), 6.51 (2H, d, J ) 7.9,
Ts-aryl-H), 6.92 (2H, dt, J ) 8.3, 2.0, Ts-aryl-H), 7.36 (1H, ddd,
J ) 6.7, 1.3, aryl-H), 7.39-7.41 (1H, m, aryl-H), 7.51-7.58
(3H, m, aryl-H), 7.69 (1H, dd, J ) 8.4, 0.7, aryl-H), 7.72-7.74
(1H, m, aryl-H), 8.06 (1H, dd, J ) 8.3, 0.8, aryl-H). Anal.
(C24H21N3O2S) C, H, N, S.
8-Am in o-6,7-d ih yd r o-7-N-tosylqu in olin o[3,2-d ][5H]-3-
ben za zep in e (24). Anthranilonitrile (8) (0.7 g, 6.3 mmol),
1,2,3,4-tetrahydro-3-N-tosylbenzazepin-5-one29 (23) (2.0 g, 6.4
mmol), and boron trifluoride diethyl etherate (1 M, 0.8 mL,
6.5 mmol) gave the title compound (24) (1.6 g, 63% crude).
Chromatography of a sample on neutral alumina with chlo-
roform (100%), chloroform/methanol (1:1), and then ethanol
(100%) as eluents yielded the pure title compound: mp 227-
229 °C; M+, 415.1329; 1H NMR (CDCl3) δ 2.32 (3H, s, Ts-CH3),
2.58 (1H, dd, J ) 14.24, 4.48, CH2), 2.71 (1H, td, J ) 13.78,
6.28, CH2), 4.14-4.18 (1H, m, CH2), 4.47 (1H, td, J ) 13.68,
5.32, CH2), 5.61 (2H, br s, exchanges with D2O, NH2), 6.83 (2H,
d, J ) 8.24 aryl-H), 6.98 (3H, dt, J ) 8.36, 1.8, aryl-H), 7.04
(1H, td, J ) 7.52, 1.2, aryl-H), 7.13 (1H, td, J ) 7.42, 1.52,
aryl-H), 7.17 (1H, dd, J ) 7.51, 1.4, aryl-H), 7.49 (1H, ddd, J
) 7.62, 1.36, aryl-H), 7.69 (1H, ddd, J ) 7.7, 1.32, aryl-H),
7.84 (1H, dd, J ) 8.42, 0.8, aryl-H), 8.01 (1H, dd, J ) 8.44,
0.72, aryl-H). Anal. (C24H21N3O2S) C, H, N, S.
9-Am in o-5,6,7,8-tetr a h yd r o-5-N-tosylqu in olin o[3,2-e]-
1-ben za zocin e (26). Anthranilonitrile (8) (0.5 g, 4.5 mmol),
2,3,4,5-tetrahydro-N-tosyl-1H-benzazocin-6-one30 (25) (2.0 g,
4.6 mmol), and boron trifluoride diethyl etherate (1 M, 0.56
mL, 4.6 mmol) gave the title compound (26), 0.7 g, 35% (crude).
Recrystallized: mp >250 °C (EtOAc/EtOH); M+ 429.1507; 1H
NMR (CDCl3/CD3OD) δ 1.52-1.75 (2H, m, CH2), 1.93 (3H, s,
Ts-CH3), 2.06 (1H, ddd, J ) 14.2, 10.2, 1.4, CH2), 2.59 (1H,
dd, J ) 7.5, CH2), 3.06-3.17 (1H, m, CH2), 4.32 (1H, dd, J )
15.0, 4.8, CH2), 6.48 (1H, d, J ) 7.9, aryl-H), 6.91 (2H, dt, J )
8.5, 2.0, Ts-H, aryl-H), 7.10-7.13 (1H, m, aryl-H), 7.26-7.37
(3H, m, aryl-H), 7.45 (1H, ddd, J ) 6.8, 1.3, aryl-H), 7.49-
7.52 (1H, m, aryl-H), 7.67-7.73 (1H, m, aryl-H). Anal.
(C25H12N3O2S) C, H, N, S.
1
M+, 260.1304; H NMR (DMSO-d6) δ 1.9-2.8 (6H, m, 3CH3),
6.55 (2H, br s, exchanges with D2O, NH2), 7.1-7.95 (7H, m,
aryl-H), 8.2-8.35 (1H, m, aryl-H). Anal. (C18H16N2) C, H, N.
Maleate salt: mp 186-188 °C; 1H NMR (CD3OD) δ 2.25 (2H,
br s, CH2), 2.63 (2H, br s, CH2), 5.07 (2H, br s, CH2), 6.19 (2H,
s, maleate), 7.35-8.05 (7H, m, aryl-H), 8.35 (1H, d, J ) 8.4,
aryl-H). Anal. (C18H16N2‚C4H4O4) C, H, N.
8-Am in o-6,7-d ih yd r o-3-m et h oxy-5H -b en zo[6,7]cyclo-
h ep ta [1,2-b]qu in olin e (14f). Anthranilonitrile (8) (5.0 g,
42.3 mmol), 2-methoxy-5-benzosuberone (13f) (8.7 g, 45.8
mmol) and boron trifluoride diethyl etherate (1 M, 6.2 mL, 50.7
mmol) were treated according to the general procedure to give
the title compound (14f) (9.1 g, 75% crude). Recrystallized:
mp 206-210 °C (EtOH); M+, 290.1419; 1H NMR (DMSO-d6) δ
1.8-2.8 (6H, m, 3CH2), 3.85 (3H, s, CH3), 6.5 (2H, br s,
exchanges with D2O, NH2), 6.75-8.4 (7H, m, aryl-H). Anal.
(C19H18N2O) C, H, N. Maleate salt: mp 216-218 °C; 1H NMR
(CD3OD) δ 2.20-2.75 (6H, m, 3CH3), 3.89 (3H, s, CH3), 6.21
(2H, s, maleate), 6.95-7.10 (2H, m, aryl-H), 7.60-7.72 (2H,
m, aryl-H), 7.85-7.95 (2H, m, aryl-H), 8.35 (1H, d, J ) 8.7,
aryl-H). Anal. (C19H18N2O‚C4H4O4) C, H, N.
1,2,3,4-Tet r a h yd r o-1-m et h ylen en a p h t h a len e (16).19
1-Tetralone (15) (3.3 mL, 24.8 mmol) was reacted with the
+
phosphonium salt PPh3CH2 I- (184) (10 g, 24.8 mmol)
according to the published procedure to give a purple oil (14.0
g). This was purified by Kugelro¨hr distillation (0.2 mmHg,
65 °C) to give the title compound (16) as a clear oil (1.9 g,
54%): 1H NMR (CDCl3) δ 1.9 (m, 2H, CH2), 2.5 (t, 2H, CH2),
2.8 (t, 2H, CH2), 4.95 (s, 1H, CH), 5.45 (s, 1H, CH), 7.0-7.6
(m, 4H, aryl-H).
2,3,4,5-Tetr a h yd r oben zocycloh ep ten -2(1H)-on e (17).18
Silver nitrate (17.9 g, 92 mmol) was stirred vigorously in
methanol (50 mL) and water (50 mL) until it had dissolved. A
solution of 1,2,3,4-tetrahydro-1-methylenenaphthalene (16)
(6.6 g, 45.8 mmol) in THF (100 mL) was added, followed
immediately by iodine (12.7 g, 50 mmol), and reacted according
to the published procedure18 to give the title compound (17)
as a clear oil (3.9 g, 53% crude): 1H NMR (CDCl3) δ 2.0 (2H,
m, CH2), 2.55 (2H, t, CH2), 3.0 (2H, m, CH2), 3.8 (2H, s, CH2),
7.2 (4H, s, aryl-H). IR (thin film) 1705 cm-1 CdO stretch.
13-Am in o-6,7-d ih yd r o-5H-ben zo[3,4]cycloh ep ta [1,2-b]-
qu in olin e (18). Anthranilonitrile (8) (1.0 g, 8.5 mmol),
6-benzosuberone (6,7,8,9-tetrahydrobenzocyclohepten-6(5H)-
one) (17) (1.5 g, 9.4 mmol) and boron trifluoride diethyl
etherate (1 M complex, 1.2 mL, 9.8 mmol) were treated
according to the general procedure to give the title compound
(18), 0.7 g, 30% (crude). Recrystallized: mp 177-179 °C
(EtOH); M+, 260.1315; 1H NMR (CDCl3) δ 2.08-2.68 (5H, m),
2.82-2.90 (1H, m), 4.96 (2H, br s, exchanges with D2O, NH2),
7.34-7.66 (6H, m, aryl-H), 7.79 (1H, d, J ) 8.35, aryl-H), 7.00
(1H, d, J ) 8.43, aryl-H). Anal. (C18H16N2) C, H, N.
Detosyla tion Meth od w ith Sod iu m Na p h th a len id e.20
Sodium naphthalenide was prepared by the addition, under
nitrogen, of clean pieces of sodium metal to a stirred solution
of naphthalene (1 equiv) in anhydrous, degassed dimethoxy-
ethane (DME) to which was added the tosylated compound
in dry DME was added, according to the published proce-
dure.20
7-Am in o-3-ch lor odiben zo[b,h ][1,6]n aph th yr idin e (20a).
Anthranilonitrile (8) (0.3 g, 2.5 mmol), 4-keto-7-chloro-1,2,3,4-
tetrahydroquinoline26 (19a ) (0.5 g, 2.8 mmol), and boron
trifluoride diethyl etherate (1 M, 0.34 mL, 2.8 mmol) were
treated according to the general procedure to give the title
compound (20a ) (0.15 g, 21% yield crude). Recrystallized: mp
8-Am in o-6,7-d ih yd r o-5H -q u in olin o[3,2-d ]-1-b en za ze-
p in e (27). Sodium (0.7 g, 32.3 mmol), naphthalene (4.1 g, 32.0
mmol), and degassed DME (120 mL) were treated according
to the above procedure, giving a solution of sodium naphtha-
lenide to which was added the tosylated compound, 8-amino-
6,7-dihydro-5-N-tosyl-5H-quinolino[3,2-d]-1-benzazepine (22)
(6.1 g, 14.7 mmol) in dry DME. After reaction the title
compound (27) was isolated (1.9 g, 51.2% crude); 1H NMR (CD3-
OD) δ 2.87 (2H, t, J ) 6.09, CH2), 3.64 (2H, t, J ) 6.27, CH2),
6.95 (1H, d, J ) 7.86, aryl-H), 7.12 (1H, t, J ) 7.54, aryl-H),
7.26-7.44 (2H, m, aryl-H), 7.59 (1H, t, J ) 7.01, aryl-H), 7.74
(1H, d, J ) 7.63, aryl-H), 7.90 (1H, d, J ) 8.15, aryl-H), 8.07
(1H, d, J ) 8.42, aryl-H); M+ 261.1259. Hydrated hydro-
chloride salt formed for analysis, mp 308-313 °C; 1H NMR
1
>220 °C (MeOH); H NMR (DMSO-d6) δ 7.49 (1H, ddd, J )
8.24, 1.24, aryl-H), 7.66 (1H, dd, J ) 8.7, 2.2, aryl-H), 7.82
(1H, ddd, J ) 8.4, 1.3, aryl-H), 7.98 (2H, m, aryl-H), 8.43 (2H,
br s, exchanges with D2O, NH2), 8.51 (1H, dd, J ) 8.5, 0.8,
aryl-H), 9.04 (1H, d, J ) 8.7, aryl-H), 9.76 (1H, s, aryl-H). Anal.
(C16H10N3Cl) C, H, N, Cl.
7-Am in o-3-ch lor o-5,6-dih ydr o-5-N-tosyldiben z[b,h ][1,6]-
n a p h th yr id in e (20b). Anthranilonitrile (8) (0.6 g, 5.4 mmol),
4-keto-7-chloro-1,2,3,4-tetrahydro-N-tosylquinoline26 (19a ) (2.0
g, 5.9 mmol), and boron trifluoride diethyl etherate (1 M, 0.7
mL, 5.7 mmol) were treated according to the general procedure
to give the title compound (20b) (3.4 g, 60% crude). Recrystal-
lized: mp 246-248 °C (EtOH); M+, 435.0805; 1H NMR (DMSO-
d6) δ 1.70 (3H, s, CH3), 4.94 (2H, s, CH2), 6.68 (2H, d, J )
8.26, Ts-H, aryl-H), 6.87 (2H, br s, exchanges with D2O, NH2),
7.06 (2H, d, J ) 8.19, Ts-H, aryl-H), 7.47-7.68 (5H, m, aryl-
H), 8.11 (1H, d, J ) 8.35, aryl-H), 8.21 (1H, d, J ) 8.43, aryl-
H). Anal. (C23H18N3O2SCl) C, H, N, S, Cl.
(CD3OD/D2O)
δ
2.98 (2H, t,
J
) 6.56Hz, CH2), 4.00
(2H, t, J ) 7.23, CH2), 7.72-8.00 (7H, m, aryl-H), 8.34 (1H,
d, J ) 8.51, aryl-H). Anal. (C17H15N3‚2HCl‚2H2O) C, H, N,
Cl.
9-Am in o-5,6,7,8-tetr a h yd r oqu in olin o[3,2-e]-1-ben za zo-
cin e (28). Sodium (0.2 g, 8.7 mmol) and naphthalene (1.1 g,
8.2 mmol) in DME (60 mL) were treated according to the above
procedure, giving a sodium naphthalenide solution to which

3522 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22
MccKenna et al.
was added the tosylated compound, 9-amino-5,6,7,8-tetrahy-
dro-5-N-tosylquinolino[3,2-e]-1-benzazocine (26) (0.7 g, 1.6
mmol) in dry DME. After reaction the title compound (28)
was isolated (0.1 g, 24% crude): mp 237-240 °C; M+ 275.1416;
1H NMR (CD3OD) δ 1.63-1.72 (1H, m, CH2), 1.83-1.94 (1H,
m, CH2), 2.85-3.17 (4H, m, 2CH2), 6.59-6.65 (2H, m, aryl-
H), 7.07 (1H, t, 1J ) 7.77, aryl-H), 7.16 (1H, d, J ) 8.07, aryl-
H), 7.40 (1H, t, J ) 7.17, aryl-H), 7.57 (1H, t, J ) 7.68, aryl-
H), 7.85 (1H, d, J ) 8.49, aryl-H), 8.04 (1H, d, J ) 8.40, aryl-
H).
N-(4-Met h yl-5-oxocyclop en t en -1-yl)-2-a m in ob en zon i-
t r ile (30a ) a n d N-(2-Met h yl-5-oxocyclop en t en -1-yl)-2-
a m in oben zon itr ile (30b). Anthranilonitrile (8) (5.0 g, 42.3
mmol), 2-hydroxy-3-methyl-2-cyclopenten-1-one (cyclotene) (29)
(5.2 g, 46.6 mmol), and p-toluenesulfonic acid (1.0 g, 5.8 mmol)
in toluene (150 mL) were refluxed with a Dean-Stark water
separator for 40 min. On cooling, the solvent was evaporated
in vacuo to give a dark red oil which solidified on standing.
Chromatography on silica gel with ethyl acetate-petroleum
ether (60-80 °C) (1:4 then 1:3) gave two products. (a ) N-(4-
Meth yl-5-oxocyclopen ten -1-yl)-2-am in oben zon itr ile (30a)
(7.2 g, 80%). Recrystallized: mp 79-81 °C [diethyl ether-
petroleum ether (60-80 °C) (3:1)]; M+, 212.0952; 1H NMR
(CDCl3) δ 1.25 (3H, d, J ) 7.48, CH3), 2.23 (1H, ddd, J ) 18.15,
2.11, 1.00, CH2), 2.49 (1H, quintet of d, J ) 7.43, 2.08, CH2),
2.95 (1H, ddd, J ) 18.15, 3.31, CH2), 6.78-6.81 (2H, m, 1H
exchanges with D2O, NH, to give t, 1H, J ) 3.22, CH2), 6.93
(1H, td, J ) 7.56, 0.98, aryl-H), 7.32 (1H, d, J ) 9.09, aryl-H),
7.50 (2H, t, J ) 9.73, aryl-H); IR (Nujol mull) 3361 (NH
stretch), 2213 (CN stretch), 1753 cm-1 (CdO stretch). Anal.
(C13H12N2O) C, H, N.
dihydro-2,3-dimethyl-3-hydroxy-1H-cyclopenta[b]quinoline (31a)
(4.3 g, 18.6 mmol) was heated at reflux for 24 h. On cooling,
the solution was basified with sodium hydroxide (2 M), and
the organic components were extracted with chloroform. The
organic extracts were combined and dried, and the solvent was
evaporated in vacuo to give the title compound (32a ) (3.9 g,
99% yield, crude). Recrystallized: mp >320 °C (MeOH); M+,
1
210.1161; H NMR (CD3OD) δ 2.02 (3H, s, CH3), 2.05 (3H, s,
CH3), 3.05* (1.5H, br s, CH2), 7.32 (1H, td, J ) 6.87, 1.23, aryl-
H), 7.52 (1H, td, J ) 6.87, 1.39, aryl-H), 7.89 (1H, d, J ) 8.49,
aryl-H), 7.99 (1H, d, J ) 8.33, aryl-H). Anal. (C14H14N2) C,
H, N.
*This signal disappeared after several days exchanging with
D2O.
9-Am in o-3-n -bu tyl-2-m eth yl-1H-cyclopen ten -2-yl[1,2-b]-
qu in olin e (32b). Sulfuric acid (98%, 30 mL) was added to
9-amino-3-n-butyl-2,3-dihydro-3-hydroxy-2-methyl-1H-cyclo-
penta[b]quinoline (31b) (1.3 g, 4.9 mmol), and the mixture was
heated at reflux for 24 h. On cooling, the solution was basified
with sodium hydroxide (2 M) and extracted with chloroform.
The organic extracts were combined and dried, and the solvent
was evaporated in vacuo to give the title compound (32b) (0.89
g, 72%, crude): M+ 252.1628; 1H NMR (CD3OD) δ 0.97 (3H, t,
J ) 7.15, CH3), 1.40-1.59 (4H, m, 2CH2), 2.27 (3H, s, CH3),
2.70 (2H, t, J ) 7.23, CH2), 3.34 (1H, s, CH2), 3.47 (1H, s, CH2),
7.60 (1H, t, J ) 7.28, aryl-H), 7.84 (1H, t, J ) 8.26, aryl-H),
8.03 (1H, d, J ) 8.84, aryl-H), 8.27 (1H, d, J ) 8.40, aryl-H).
Anal. (C17H20N) C, H, N.
P h a r m a cology. An tich olin ester a se Activity. This was
based on measuring the hydrolysis of acetylthiocholine and
the subsequent reaction of thiocholine with 4,4-dithiopyridine
to form 4-thiopyridine.31,32 Acetylcholinesterase was obtained
from homogenates of rat brain32 and butyrylcholinesterase was
obtained from human plasma.
(b ) N-(2-Met h yl-5-oxocyclop en t en -1-yl)-2-a m in ob en -
zon itr ile (30b) (0.7 g, 7%). Recrystallized: mp 96-98 °C
[diethyl ether-petroleum ether (60-80 °C) (3:1)]; M+, 212.0921;
1H NMR (CDCl3) δ 1.98 (3H, s, CH3), 2.50-2.67 (4H, m, 2CH2),
5.91 (1H, br s, exchanges with D2O, NH), 6.52 (1H, d, J ) 8.31,
aryl-H), 6.83 (1H, td, J ) 7.51, 0.97, aryl-H), 7.36 (1H, td, J )
7.89, 1.63, aryl-H), 7.46 (1H, dt, J ) 7.80, 0.35, aryl-H); IR
(Nujol mull) 3350 (NH stretch), 2220 (CN stretch), 1750 cm-1
(CdO stretch). Anal. (C13H12N2O) C, H, N.
Mon oa m in e Up ta k e In h ibition . Synaptosomes were
prepared from homogenates of rat brain. Inhibition of uptake
of [3H]5-HT and [3H]noradrenaline was measured at 37 °C as
described previously.33,34 Nonspecific uptake was determined
in the presence of 10 µM fluoxetine (for 5-HT) or 1 µM
desipramine (for noradrenaline).
9-Am in o-2,3-d ih yd r o-2,3-d im eth yl-3-h yd r oxy-1H-cyclo-
p en ta [1,2-b]qu in olin e (31a ). N-(4-Methyl-5-oxocyclopenten-
1-yl)-2-aminobenzonitrile (30a ) (4.0 g, 18.9 mmol) in anhydrous
THF (75 mL) under nitrogen was cooled to -78 °C while
stirring. Methyllithium (1.5 M solution in diethyl ether,
complexed with LiBr, 31.5 mL, 47.2 mmol) was added dropwise
via syringe and the reaction left to stir and warm up to room
temperature over 24 h. Water (30 mL) was added to quench
the reaction. The organic layer was separated and dried and
the solvent evaporated in vacuo to give the title compound
(31a ) (4.2 g, 99% crude). Recrystallized: mp 229-230 °C dec
(MeOH/Et2O); M+, 228.1265; 1H NMR (CD3OD) δ 1.19 (3H, d,
J ) 6.95, CH3), 1.16 (3H, s, CH3), 2.25 (1H, q, J ) 7.07, CH2),
2.51 (1H, q, J )7.99, CH2), 2.93 (1H, q, J ) 7.59, CH2), 7.37
(1H, td, J ) 6.81, 1.26, aryl-H), 7.56 (1H, td, J ) 6.83, 1.43,
aryl-H), 7.90 (1H, dd, J ) 8.50, 0.66, aryl-H), 8.03 (1H, dd, J
) 8.46, 1.02, aryl-H). Anal. (C14H16N2O) C, H, N.
9-Am in o-3-n -bu tyl-2,3-d ih yd r o-3-h yd r oxy-2-m eth yl-1H-
cyclop en ta [1,2-b]qu in olin e (31b). N-(4-Methyl-5-oxocyclo-
penten-1-yl)-2-aminobenzonitrile (30a ) (1.0 g, 4.7 mmol) in
anhydrous THF under nitrogen was cooled to -78 °C, n-
butyllithium (1.6 M solution in hexanes, 7.4 mL, 11.8 mmol)
was added dropwise via syringe, and the reaction was left to
stir and warm up to room temperature over 24 h. Water
(20 mL) was then added to quench the reaction. The organic
layer was separated and dried and the solvent evaporated in
vacuo to give the title compound (31b) (0.67 g, 52% crude).
Recrystallized: mp 172-173 °C (MeOH/Et2O); M+, 270.1733;
1H NMR (CDCl3) δ 0.87 (3H, t, J ) 6.76, CH3), 1.13-1.36 (7H,
m, CH2CH2CH3), 1.85-2.08 (2H, m, CH2), 2.43-2.89 (2H, m,
CH2), 2.96 (1H, q, J ) 9.81), 7.36 (1H, td, J ) 6.79, 1.26, aryl-
H), 7.55 (1H, td, J ) 6.82, 1.41, aryl-H), 7.90 (1H, dd, J )
8.51, 0.66, aryl-H), 8.03 (1H, dd, J ) 8.42, 0.91, aryl-H). Anal.
(C17H22N2O) C, H, N.
Ack n ow led gm en t. We thank the British Technol-
ogy Group for some financial support, the Dow Chemical
Co. for samples of cyclotene, and Organon Laboratories
for samples of 6-chloro-1-tetralone.
Refer en ces
(1) (a) Wurtman, R. J . Alzheimer’s disease. Sci. Am. 1985, 252, 48-
56. (b) Altman, H. J ., Ed. Alzheimer’s DiseasesProblems,
Prospects and Perspectives; Plenum Press: New York, 1987.
(2) (a) Davies, P.; Maloney, A. J . F. Selective loss of cholinergic
neurones in Alzheimer’s disease. Lancet 1976, No. 2, 1403. (b)
Bowen, D. M.; Smith, C. B.; White, P.; Dawson, A. N. Neu-
rotransmitter-related enzymes and indices of hypoxia in senile
dementia. Brain 1976, 99, 459.
(3) Iversen, L. L.; Rossor, M. Non-cholinergic neurotransmitter
abmormalities in Alzheimer’s disease. Br. Med. Bull. 1986, 42,
70-74.
(4) Perry, E. K. The cholinergic hypothesis-ten years on. Br. Med.
Bull. 1986, 42, 63-69.
(5) Wesseling, A.; Agoston, S. The effects of 4-aminopyridine in
elderly patients with Alzheimer’s disease. N. Engl. J . Med. 1988,
310, 988.
(6) (a) Mohs, R. C.; Davis, K. L. The experimental pharmacology of
Alzheimer’s disease and related dementias.In Psychopharma-
cology: The Third Generation of Progress; Meltzer, H. Y., Ed.;
Raven Press: New York, 1987. (b) Signoret, J . L.; Whitely, A.;
Lhermitte, F. Influence of choline on amnesia in early Alz-
heimer’s disease. Lancet 1978, No. 2, 837. (c) Cohen, E. I.;
Wurtman, R. J . Brain acetylcholine: control by dietary choline.
Science 1976, 191, 561-562. (d) Hanbrich, D. R.; Wang, P. F.
L.; Clody, D. E.; Wedeking, P. W. Increase in rat brain acetyl-
choline induced by choline or deanol. Life Sci. 1975, 17, 975-
980.
(7) Summers, W. K.; Majovski, L. V.; Marsh, G. M; Tachiki, K; Kling,
A. Oral tetrahydroaminoacridine in long term treatment of senile
dementia, Alzheimer type. N. Engl. J . Med. 1986, 315, 1241-
1245.
9-Am in o-2,3-d im eth yl-1H-cyclop en t-2-en yl[1,2-b]qu in -
olin e (32a ). Sulfuric acid (30%, 150 mL) and 9-amino-2,3-

Novel Tacrine Analogues
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22 3523
(8) Albert, A.; Gledhill, W. J . Improved synthesis of aminoacridines,
Part IV. Substituted 5-aminoacridines. J . Soc. Chem. Ind. 1945,
64, 169-172.
(9) Shaw, F. H.; Bentley, G. The pharmacology of some new anticho-
linesterases. Aust. J . Exp. Biol. Med. Sci. 1953, 31, 573-576.
(10) Heilbronn, E. Inhibition of cholinesterases by tetrahydroami-
nacrin. Acta Chem. Scand. 1961, 15, 1386-1390.
(11) Maayani, S.; Weinstein, H.; Ben-Zvi, N.; Cohen, S.; Sokolovsky,
M. Psychotomimetics as anticholinergic agents. I. 1-Cyclohexy-
lpiperidine derivatives: anticholinesterase activity and antago-
nistic activity to acetylcholine. Biochem. Pharmacol. 1974, 23,
1263-1281.
(12) Harvey, A. L.; Rowan, E. G. Action of THA, 3,4-diaminopyridine,
physostigmine and galanthamine on neuronal K+ currents at a
cholinergic nerve terminal. Current Research in Alzheimer
Therapy; Giacobini, E., Becker, R., Eds.; Taylor and Francis:
New York, pp 191-197.
(13) (a) Drukarch, B.; Leysen, J . E.; Stoof, J . C. Further analysis of
the neuropharmacological profile of 9-amino-1,2,3,4-tetrahy-
droacridine (THA), an alleged drug for the treament of Alz-
heimer’s disease. Life Sci. 1988, 42, 1011-1017. (b) Sokhwinder,
J .; Adem, A.; Winblad, B.; Oreland, L. Characterisation of
dopamine and serotonin uptake inhibitory effects of tetrahy-
droaminoacridine in rat brain. Pharmacol. Toxicol. 1992, 71,
213-215.
(20) J i, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson,
W. D.; Wriede, P. Cleavage of sulfonamides with sodium
naphthalene. J . Am. Chem. Soc. 1967, 89, 5311-5312.
(21) (a) Schwarzenbach, G.; Wittwer, C. Uber das Keto-enol gleich-
gewicht bei cyclischen R-diketonen. Helv. Chem. Acta 1947, 30,
663-669. (b) Bredenberg, J . B. The enol structure of 3-methyl-
cyclopentane-1,2-dione. Acta Chem. Scand. 1959, 13, 1733-1736.
(c) Enkvis, T.; Alfredsson, B.; Merikallio, M.; Pa¨a¨kko¨nen, P.;
J a¨rrela¨, O. Formation of methylcyclopentenolone by digestion
of spruce wood or galactose with NaOH solutions. Acta Chem.
Scand. 1954, 8, 51-59. (d) Fray, G. I. The formation of 3(or 5)-
methylcyclopent-2-en-2-ol-1-one from acetone. Tetrahedron 1961,
14, 161-163. (e) Gianturco, M. A.; Giammarino, A. S.; Pitcher,
R. G. The structures of five cyclic diketones isolated from coffee.
Tetrahedron 1963, 19, 2051-2059.
(22) Merck Index; p 1298, no. 8907.
(23) Plotnikoff, N.; Keith, J .; Heimannm, M.; Keith, W.; Perry, C.
Stimulant effects of tetrahydrocycloheptaquinoline derivatives.
Arch. Int. Pharmacodyn. 1963, 146, 406-443.
(24) Bindra, J . S.; Rastogi, S. N.; Patnaik, G. K.; Anand, N.; Rao, K.
G. G.; Dwivedi, P. C.; Rao, C. N. R. Synthesis, pharmacological
activities and physiochemical properties of 4-(substituted) ami-
no(N4-arylpiperazinyl)aminocarbonyl)-2,3-polymethylene quino-
lines. Ind. J . Chem. 1987, 26B, 318-329.
(25) Shutske, G. M.; Kapples, K. J . U.S. Pat. US 5,037,833.
(26) J ohnson, W. S.; Woroch, E. L.; Buell, B. H. Cyclization studies
in the quinoline series. A new synthesis of 4-aminoquinolines.
J . Am. Chem. Soc. 1949, 71, 1901-1905.
(27) Proctor, G. R. Azabenzocycloheptenones. III. 2,3,4,5-Tetrahydro-
5-oxo-1-toluene-p-sulphonylbenz [b]azepine J . Chem. Soc. 1961,
3989-3996.
(28) Prevost, C. Compt. Rend. 1933, 196, 1129; Chem. Abstr. 1933,
27, 3195.
(29) Rehman, M. A.; Proctor, G. R. Preparation and some reactions
of 1,2,4,5-tetrahydro-1-oxo-3-toluene-p-sulphonylbenz[d]azepine.
J . Chem. Soc. C 1967, 58-61.
(30) Proctor, G. R.; Ross, W. I. Synthesis of 1-benzazocin-6-one
derivative by direct cyclisation. J . Chem. Soc., Perkin Trans. 1
1972, 885-889.
(31) .Ellman, G. L.; Courtney, D.; Andres, V., J r.; Featherstone, R.
M. A new and rapid colorimetric determination of acetylcho-
linesterase activity. Biochem. Pharmacol. 1961, 7, 88-95.
(32) Rotundo, R. L. Purification and properties of the membrane-
bound form of acetylcholinesterase from chicken brain-evidence
for two distinct polypeptide chains. J . Biol. Chem. 1984, 251,
13186.
(33) Snyder, S. H.; Coyle, J . T. Regional differences in norepineph-
rine-3H and dopamine-3H uptake into rat brain homogenates.
J . Pharmacol. Exp. Ther. 1969, 165, 78-86.
(34) Horn, A. S. Structure activity relations for the inhibition of 5-HT
[5-hydroxytryptamine] uptake into rat hypothalamic homoge-
nates by serotonin and tryptamine analogues. J . Neurochem.
1973, 21, 883-888.
(14) (a) Kaul, P. N. Enzyme inhibition action of tetrahydroaminacri-
dine and its structural fragments. J . Pharm. Pharmacol. 1962,
14, 243-248. (b) Neilsen, J . A.; Mena, E. E.; Williams, I. H.;
Nocerini, M. R.; Liston, D. Correlation of brain levels of 9-amino-
1,2,3,4-tetrahydroacridine (THA) with neurochemical and be-
havioural changes. Eur. J . Pharmacol. 1988, 173. 53-64. (c)
McNally, W.; Rothom, Young, R.; Brockbrader, H.; Chang, T.
Quantitative whole-body autoradiographic determination of
tacrine tissue distribution in rats following intravenous or oral
dose. Pharm. Res. 1989, 924-930.
(15) Dutar, P.; Bassant, M. H.; Lamour, Y. Effects of tetrahydro-9-
aminoacridine on cortical and hippocampal neurons in the rat.
Brain Res. 1990, 527, 32-40.
(16) Silman, I.; Harel, M.; Axelsen, P.; Raves, M.; Sussman, J . L.
Three-dimensional structures of acetylcholinesterase and of its
complexes with anticholinesterase agents. Biochem. Soc. Trans.
1994, 22, 745-749.
(17) Moore, J . A.; Kornreich, L. D. A direct synthesis of 4-amino-
quinolines. Tetrahedron. Lett. 1963, 20, 1277-1281.
(18) (a) da Conceicao, C. M. M.; MacRitchie, J . A.; Middlemiss, D.;
Proctor, G. R. Benzosuberones: syntheses, some reaction and
formation of benzo[3,4]cyclohepta[1,2-b]pyrrole derivatives. J .
Chem. Res. Synop. 1995, 347. (b) El-Hossini, M. S.; McCullough,
K. J .; McKay, R.; Proctor, G. R. Ring-expansion by a Wittig-
Prevost sequence. Tetrahedron Lett. 1986, 27, 3783-3786.
(19) (a) Boutagy, J .; Thomas, R. Olefin synthesis with organic
phosphonate carbanions. Chem. Rev. 1974, 74, 87-99. (b)
Wadsworth, W. S., J r. Synthetic applications of phosphoryl-
stabilised anions. Org. React. 1977, 25, 73-253. (c) Maercker,
A. The Wittig reaction. Org. React. 1965, 14, 270-490.
J M970150T