Current Medicinal Chemistry, 2000, 7, 295-302 295

Synthesis of Tacrine Analogues and Their Structure-Activity

Relationships
G.R. Proctor
1
and A.L. Harvey,
*2
Department of
1
Pure and Applied Chemistry and
2
Physiology and Pharmacology, and
Strathclyde Institute for Drug Research, University of Strathclyde, 27 Taylor Street,
Glasgow G4 0NR
Abstract: Three man synthetic routes to analogues of tacrine are described:
reaction of anthranilonitriles with cyclohexanone and other ketones, reaction
of various anilines with -cyanoketones, and reactions involving anilines and
cyclic -ketoesters. Although tacrine has a wide range of pharmacological effects, it is best
known as an inhibitor of cholinesterase enzymes. Many of the analogues that have been made
have not been tested against acetylcholinesterase or butyrylcholinesterase activity.
Consequently, there is limited information from which a detailed understanding of structure-
activity relationships can be derived. However, some halogenated derivatives are not only more
potent acetylcholinesterase inhibitors than tacrine, they are also more selective for
acetylcholinesterase than for butyrylcholinesterase.
Chemistry of Tacrine and its Congeners
N
C
NH
2
b
a
A
B
C
1
2
3
4
5
6
7
8
Tacrine 1
Tacrine, which is 9-amino-1,2,3,4-
tetrahydroacridine, was formerly known by some
authors as one of the polymethylene quinoline
group, namely 4-amino-2,3-tetramethylene quinoline.
The generally accepted scheme of numbering is that
shown in Fig. (1). We define congeners in the present
context as derivatives of tacrine which have:-
Fig. (1). The structure of tacrine, indicating the sites of
different bond-disconnections (a, b, c).
a) Substituents or ring annelations (fusions) in ring A,
Route 1: Bond-disconnection a
b) Substituents on the amino group at C
9
,
c) Ring contractions or expansions in ring C,
Reaction of anthranilonitrile (2) with cyclohexanone
(3) in the presence of zinc chloride gives a complex (4)
which can be converted to tacrine (1) by aqueous alkali
treatment (Fig. 2) [1]. Recently, it has been shown that
BF
3
/etherate is a suitable alternative for ZnCl
2
[2].
d) Heteroatom substitutions in rings A or/and C,
e) Annelations of rings on to ring C
f) Substitutions in ring C.
Fluoro-substituted anthranilonitriles (5) and (6) (Fig.
3) have been employed in similar fashion with
cyclohexanone [3,4], cyclopentanone [5],
cycloheptanone [5] and other ketones [5] such as the
three methylcyclohexanones and compound (7) [11]
(Fig. 3). Bridged ketones (8)-(11) (Fig. 3) have
featured in reactions with several substituted
anthranilonitriles (12; X= 6-OMe, 4-Cl, 5-Cl, 6-Cl, 4-Me,
6-Me, 5-NO
2
, 4-CF
3
, 5-CF
3
, for example) [5]. A fair
number of heterocyclic ketones are known participants
in reactions with anthranilonitriles: in this way the
representative structures shown in Fig. (4) have been
reported.
In contemplating viable syntheses for tacrine and its
congeners, one is attracted to three possibilities for
bond-disconnection. These are designated as a, b and
c in Fig. (1). All have found use in practice: which
approach is employed depends, as always, on the
precise structural requirements for any particular
project.
*Address correspondence to this author at Physiology and
Pharmacology, and Strathclyde Institute for Drug Research, University of
Strathclyde, 27 Taylor Street, Glasgow G4 0NR; Tel: 0141 553 4155;
Fax: 0141 552 8376; E-mail: sidr@strath.ac.uk
0929-8673/00 $19.00+.00 2000 Bentham Science Publishers B.V.
296 Current Medicinal Chemistry, 2000, Vol. 7, No. 3 Proctor and Harvey
CN
NH
2
O
N
NH
2
ZnCl
2
N
NH
2
+
ZnCl
2 NaOH
H
2
O /
2 3 4 1
Fi g. (2). Synthesis of tacrine from anthranilonitrile (2) and cyclohexanone (3).
CN
NH
2
5
F
CN
NH
2
6
F
F
O
O
O O
7 8 9 10
O
N N
O
O
O NH
2
OH NH
2
CN
NH
2
X
11 12
13
14
15
Fi g. (3). Various substituents incorporated into tacrine analogues via bond-disconnection a.
N
N
Ph
NH
2
N
N
NH
2
CH
3
N
O
NH
2
N
S
NH
2
Ref (6) Ref (6) Ref s(3, 7) Ref (5)
N
S
F NH
2
N
S
MeO NH
2
N
N
NH
2
N
N
NH
2
Cl
Ref (5) Ref (5) Ref (2) Ref (5)
F
N
NH
NH
2
N
NH
NH
2
N
H
N
NH
2
Ref (2)
Ref (2)
Ref (46)
Fi g. (4). Representative tacrine analogues prepared using the route from bond disconnection a.
Synthesis of Tacrine Analogues Current Medicinal Chemistry, 2000, Vol. 7, No. 3 297
N
HN
N
NH
2
N
N
N
NH
2
OH
N
S
NH
2
N
N
NH
2
N
O
NH
2
N
S
NH
2
O
Ref (13) Ref (14) Ref (3) Ref (4)
Ref (4) Ref (15)
PhCH
2
Fi g. (5). Analogues of tacrine, modified in Ring A (figure 1).
Reactions of 1,3-diones with anthranilonitriles have
been much studied by the Hoechst-Roussel group [8-
12]. The clinically tested compound (13) [velnacrine] is
obtained by reduction of the ketone (14), itself arising
from reaction of anthranilonitrile with cyclohexan-1,3-
dione (15) (Fig. 3). Many variants of this reaction have
been reported [8].
The only significant limitation on this type of
synthesis is the accessibility of anthranilonitriles, which
are not always easily made. A partial solution involved
use of isatins [21]. The latter (e.g. 23) which are
commonly obtained from anilines by reaction with
chloral and hydroxylamine [22], when heated with
cyclohexanone and ammonia gave, for example, 24
(R=Br, OMe) [21] (Fig. 6). Hofmann degradation then
gave the amino compounds 25(R-Br,OMe, H) (Fig. 6).
Heterocyclic analogues of anthranilonitrile such as
the pyrazole (16) [13] have been used to react with
cyclic ketones. In this way, several Ring A modified
structures have been made (Fig. 5).
It has long been known [36] that heating anthranilic
acid with cyclohexanone led to 1,2,3,4-
tetrahydroacridone (26, X=H, n=2) (Fig. 7). Utilisation
of the latter will be discussed later. However, work
carried out in Russia [23-25] showed that N-substituted
tacrine and related analogues could be obtained by
condensing anthranilamides (27) with cyclic ketones
(5-, 6- and 7-membered) and then heating the products
with PCl
5
and POCl
3
. In this way amides 27 (X=H, 3-Me,
5-Me, 3-Cl, 5-Cl, 5-OMe, 5-Br: R=Me, Et, Bu, aryl) were
There appears to be scope for further work in this
section since methods are known for synthesis of other
-aminonitriles of potential use, for example (17), (18),
( 19) and (20) [16-18] (Fig. 6).
Carbocyclic partly saturated -aminonitriles (e.g. 21)
[19] were used to produce for example amiridin (22) by
reaction with cyclohexanone [20].
N
N
H
CN
NH
2
O
CN
NH
2
CH
3
N
CN
NH
2
CH
3
CO
2
Et
N
CN
NH
2
Ph
CO
2
Et
N
Aryl
CN
NH
2
Aryl
16 17 18 19 20
CN
NH
2
21
NH
2
N
H
O
O
N
R
CONH
2
R
N
R
NH
2
22 23
24
25
HCl
Fi g. (6). Various -aminonitriles and their likely end-products.
298 Current Medicinal Chemistry, 2000, Vol. 7, No. 3 Proctor and Harvey
N
H
(CH
2
)
n
O
X
N
(CH
2
)
n
NHR'
X
CONHR'
NH
2
X
N
(CH
2
)
n
NMe
2
R
26 27
28
29
Fi g. (7). Tacrine analogues prepared from anthranilic acid.
converted to the analogues 28 (n=1, 2, 3) [23-25].
Methyl anthranilate [26] has also been shown to be
useful: when heated with HMPT
(hexamethylphosphoric triamide) plus a catalytic
amount of PPA (polyphosphoric acid) and
cyclohexanone, it gave the N,N-disubstituted tacrine
29 (R=H,

n=2) (Fig. 7): Several other congeners (29;
n=3, R=9-Cl, 9-I and 9-CH
3
) were also made [26].
Ar=C
6
H
5
-,p-FC
6
H
4
-
-,
p-OMeC
6
H
4
-, p-BrC
6
H
4-
-) and (37)
into tacrine analogues (38; X=H, OMe, Br, F) (Fig. 9).
Thus, in making a choice between routes 1 and 2, it
may be a question of whether it would be easier to
synthesise a relatively inaccessible anthranilonitrile-
type component for ring A of tacrine or to make an -
cyanoketone component of ring C.
Route 3: Bond-disconnection c
Route 2: Bond-disconnection b
This method depends upon displacement of a
leaving group (X in 39) by an amino nucleophile. Much
use has been made of this approach. Leaving groups
are most frequently halogen, particularly chlorine. More
esoteric was the use of CF
3
SO
3
- as leaving group in the
synthesis of compound 40 [35]. Phosphate appears to
have been involved as the leaving group in the case of
29 [26].
It is quite surprising that, until recently, this approach
was seldom employed. Lamant [27,28] was
responsible for introducing the protocol shown in Fig.
(8).
More recently [29], it has been demonstrated that a
wide variety of anilines (e.g. 30, 2-, 3-, 4-Cl, 2-, 3-, 4-F,
2-, 4-Me, and all possible diF) participates in these
reactions and that TiCl
4
is a convenient alternative to
AlCl
3
. It is noted that methoxy-substututed anilines
have a tendency to demethylate during the second
step of the procedure. Not surprisingly, nitroanilines
failed [30] at the second stage.
Virtually all of compounds 39 were obtained from
acridones (e.g. 26, n=2) [36] or similar structures. Two
methods are, in general, available: C
9
of the acridine
structure is either carried on the component forming
ring A or on that forming ring B. The original synthesis
[36] was of the first type utilising anthranilic acid or,
later, its esters [37]. This approach has limitations, for
although indanone and cycloheptanone [38] reacted
fruitfully with anthranilic acid, cyclopentanone did not
[39]. Accordingly the route (Fig. 10) involving reactions
of anilines (30) with cyclic -keto esters (e.g. 41)
became more popular [38-40]. Many workers have
chosen this route [37, 41-45]. Activation of most
substances (26) is usually brought about by POCl
3
[25,
38, 40, 41] to give 39 (X=Cl) [50,51], although some
workers favour a mixture of POCl
3
with PCl
5
[23,27].
Introduction of the CF
3
SO
2
- group was achieved by
The scope of this approach hinges on the availability
of the -cyano-ketone (31 e.g.). While -
cyanocyclanones of 5 to 8 membered rings are easily
made by the Thorpe-Ziegler [31-32] reaction
employing , -dinitriles, the synthesis of bicyclic -
cyanoketones requires several steps from the
corresponding ketones. For example, to make -
cyanotetralone (34) (Fig. 9) from -tetralone, it is
necessary to proceed in several steps via the fused
isoxazolo dihydronaphthalene (35) [33]. This approach
does not work for indanones. The latter, however, can
be converted via fused pyrazolo derivatives (36;
NH
2
X CN
O
N
CN X
N
NH
2
X
+
-H
2
O
AlCl
3
130-150
o
30 31 32 33
Fi g. (8). Synthesis of tacrine analogues via bond-disconnection b.
Synthesis of Tacrine Analogues Current Medicinal Chemistry, 2000, Vol. 7, No. 3 299
N
O
O
CN
H
N
N
H
Ar
CN
NHAryl
N
NH
2
X
N
(CH
2
)
n
X
N
N
40 39
38 37 36
35 34
Fi g. (9). Various reagents and products of bond-disconnection b.
quite mild treatment of 26 (X=H, n=2) with (CF
3
SO
2
)
2
O
and Na
2
CO
3
in CH
2
Cl
2
[35].
X=Cl, Br, Me, OMe, H; n=1,2,3). However, it should be
said that if primary amino compounds are required,
routes 1 and 2 are certainly preferable.
Amination of 39 (X=Cl, n=1) using ammonia in hot
(180
0
C) phenol gave the phenoxy compound [40] (39,
X=OPh, n=1): the amino compound (39, X=NH
2
, n=1)
was obtained when alcoholic ammonia in presence of
traces of copper salt was applied in sealed tubes at
220-240
o
C [40]. Later workers [41] demonstrated that
heating several examples of 39 (X=Cl, n=3) with
ammonia in hot cresol gave both cresoxy compounds
(39, X=OCres, n=3) and amines (39, X=NH
2
, n=3).
On the other hand, route 3 may be the method of
choice if the final products are secondary or tertiary
amines (e.g. 28, R=alkyl or aryl or 29). Since most
primary and secondary amines are liquids, it is relatively
easy [25, 37, 42] to bring them into reaction with the
halo compounds (e.g. 39, X=Cl, Br) either in traditional
solvents (e.g. benzene [37] or phenol [42,44,49]). A
catalytic amount of an acidic catalyst has been found
advantageous. Many substances of general formula 42
(R
2
=Alkyl NH, aryl NH or alkyl
2
N) (Fig. 11) have been
reported [44, 47-49]. Most of these contributions were
not undertaken in connection with Alzheimers
disease.
To overcome the difficulties encountered using
gaseous ammonia, Konshin and coworkers [47]
reacted various chloro compounds (39) with urea
(NH
2
CONH
2
) followed by hydrolysis. In this way a good
variety of amino compounds was obtained (28; R=H,
X
NH
2
O
CO
2
Et
N
H
O
X
+
26 (n = 1)
41
30
Fi g. (10). Production of tacrine analogues via bond-disconnection c.
300 Current Medicinal Chemistry, 2000, Vol. 7, No. 3 Proctor and Harvey
N
(CH
2
)
n
R
2
42
R
1
site. This conclusion is reinforced by the findings that
tacrine could still influence acetylcholinesterase which
had its active site blocked by the organophosphorus
anticholinesterase sarin [62], and that tacrine has only
slight effects on binding of propidium to the peripheral
active site [64]. Unfortunately, however, the study of
Wu and Yang did not extend to similar measurements
of the effect of tacrine on pseudocholinesterase or a
comparison of tacrine with structurally related
analogues.
Fig. (11). General formula of tacrine analogues typically
produced by route 3.
N-Acyltacrine analogues have been obtained from
the amino compounds using anhydrides [(alkylCO)
2
O]
in the usual way [6]. Similarly, condensation of various
aldehydes with the primary amino compounds by
heating in toluene with water removal, led to imine
compounds (42; R
2
= -N=CHR) [52].
The enzyme from Torpedo californica has been co-
crystallised with tacrine [65], which provided evidence
that there are aromatic interactions between tacrine and
tryptophan and phenylalanine residues within the
catalytic site of the enzyme.
The first structure-activity study involving tacrine
analogues and acetylcholinesterase activity was by
Kaul [57]. Tacrine was compared with
tetrahydroacridine, 4-aminoquinoline, 4-aminopyridine,
and 9-(N-butyl)-amino-1,2,3,4-tetrahydroacridine. The
N-butyl substituent seemed to reduce activity, and
there was little correlation between potency and
basicity. Subsequently, a more extensive series of
analogues was compared by Steinberg et al. [66]. From
the relatively small effects of additional substituents on
the amino nitrogen, it was concluded that the planar
ring system interacted with the enzyme. The saturated
ring could be reduced to five carbons or increased to
seven carbons without dramatic effects on potency,
and the benzene ring could be converted to a
saturated form without affecting potency. However,
activity was lost when the saturated ring was replaced
by methyl groups or small alkyl chains. Given the weak
blocking activity of 4-aminoquinoline, it may be thought
that tacrine binds to acetylcholinesterase through its 4-
aminoquinoline portion with the cyclohexyl ring being
important in blocking the catalytic site of the enzyme.
Pharmacological Effects of Tacrine and
its Analogues
Since tacrine was synthesised in 1945 [53], many
analogues have been made and tested for a variety of
pharmacological effects. Tacrine itself was produced
during an investigation of the antibacterial properties of
acridine derivatives, and although it lacks antibacterial
effects it has several other actions. Tacrine was found
to antagonise the respiratory depression caused by
morphine [54] before it was known to inhibit both
acetylcholinesterase [55] and butyrylcholinesterase
[56]. Additional actions of tacrine were discovered later:
block of monamine oxidase activity [57], inhibition of
neuronal uptake of 5-HT and dopamine [58], blockade
of certain potassium ion channels [59], interaction with
muscarinic acetylcholine receptors [60]. It is still not
clear whether the therapeutic effect of tacrine in
Alzheimers disease results from its effects on
acetylcholinesterase activity or on some of its additional
pharmacological properties.
Several other early studies involved different
analogues of tacrine, but these were not tested for
activity on acetylcholinesterase. Examples include
Plotnikoff et al. [67], Patnaik et al. [43], Lee [68], and
Bindra et al. [44]. The synthesis of some of these
analogues has been described earlier in this review.
However, inhibition of acetylcholinesterase activity
is one of tacrines most potent effects, and most of the
work on tacrine analogues has concentrated on effects
on this enzyme. Tacrine has complex effects on
acetylcholinesterase, producing reversible but non-
competitive inhibition (e.g. 61, 62, 63). A meticulous
examination of tacrines interaction with
acetylcholinesterase was published by Wu and Yang
[64]. Tacrine was found to change the circular
dichroism spectrum of purified Torpedo
acetylcholinesterase, and this was used to monitor the
interaction of tacrine with the enzyme in the presence
of other drugs. Evidence was obtained to support the
suggestion that tacrine binds to the anionic site in the
substrate binding region of the enzyme with a large
contribution from hydrophobic binding, rather than
directly to the esteratic site, or to the peripheral anionic
More recent structure-activity work concerned with
inhibition of acetylcholinesterase has been published
by Morita and colleagues [6] and Shutske and
colleagues [7, 8, 10, 11, 12, 15, 37, 52]. Among the
synthetic variations were different substitutions of the
amino nitrogen, replacement of the aromatic ring, and
incorporation of additional heterocyclic functions into
the rings. However, there seems to have been no
systematic improvement in potency against
acetylcholinesterase.
Synthesis of Tacrine Analogues Current Medicinal Chemistry, 2000, Vol. 7, No. 3 301
Another study concentrated on variations around
the cyclohexyl ring of tacrine: alterations of ring size,
bridging the ring, fusing a benzene ring, and
introducing additional heteroatoms [2]. Tacrine itself is
about three times more active against butyryl- than
acetylcholinesterase, and it was found that the
cycloheptyl compound was even more potent against
butyrylcholinesterase. Increasing the ring size to
cyclooctyl resulted in a 100-fold decrease in potency
against both enzymes, presumably as a result of the
increased bulk and flexibility of the saturated ring.
Introduction of a methylene bridge across the
cyclohexyl ring also resulted in a dramatic loss of
activity. Similarly, fusing a benzene ring to the alicyclic
ring generally gave compounds that were less active
than tacrine against the cholinesterase enzymes.
However, when a benzene ring was fused to the
cyclopentyl ring, the compound (6-amino-4,5-benzo-
5H-cyclopenta [1,2-b]quinoline) was 10-fold more
active against acetyl- than butyryl-cholinesterase [2].
Overall, it appears that it is possible to prepare
analogues of tacrine with increased activity against
acetylcholinesterase and with increased selectivity for
acetyl- over butyryl-cholinesterase. However, none of
these more active and selective acetylcholinesterase
inhibitors appears to have been tested in vivo.
Therefore it is not known whether the enhanced
anticholinesterase activity will translate into more
powerful effects on learning and memory or less side
effects than found with tacrine.
Acknowledgements
The authors thank the British Technology Group,
Strathclyde Institute for Drug Research, and Tanabe
Seiyaku Co. Ltd. for financial support for some of their
work described in this review.
References
Other studies have explored the consequences of
introducing a halogen atom into the benzene ring of
tacrine or its cyclopentyl analogue [5, 69]. It seemed to
be difficult to improve on the potency of the parent
analogue (9-amino-2,3-dihydro-[1H]-cyclopenta-[1,2-
b]-quinoline) against acetylcholinesterase. Addition of
Cl at position 6 (9-amino-6-chloro-2,3-dihydro-[1H]
cyclopenta [1,2-b]-quinoline) gave a 6-fold increase in
potency, while the corresponding 6F compound was
equiactive as the parent. F or Cl substitutents at other
positions caused small (8Cl; 8F; 7F; 5F) or marked (7Cl;
5Cl) losses in potency against acetylcholinesterase. A
bromo-substituent (7Br) had only weak activity against
acetylcholinesterase (IC
50
10M).
[1] Moore, J.A; Kornreich, L.D. Tetrahedron Lett., 1963, 20, 1277.
[2] McKenna, M.T; Proctor, G.R; Young, L.C; Harvey, A.L. J. Med.
Chem., 1997, 40, 3516.
[3] Desai, M.C. W.O. Patent 8902739 (1989), Chem. Abstr., 1989,
111, 153657e.
[4] Desai, M.C. Eur. Patent 311303 (1989), Chem. Abstr., 1989, 111,
153658f.
[5] Kawakami, H; Ohuchi, R; Kitano, M; Ono, K. Eur. Patent, 268871
(1988), Chem. Abstr. 1988, 109, 110275v.
[6] Morita, S.; Saito, K.; Ninomiya, K.; Tobe, A.; Nitta, I.; Sugano, M.
Eur. Patent 319429 (1989), Chem. Abstr., 1989, 111, 232602m.
[7] Shutske, G.M.; Effland, R.C., Eur. Patent 287977 (1989), Chem
Abstr., 1989, 110, 154283w.
Most of the monohalogen derivatives were less
active than the parent cyclopentyl analogue against
butyrylcholinesterase: only the 6F compound was as
active as the parent. Therefore, the selectivity for
acetylcholinesterase in preference to butyrylcholi -
nesterase activity (the B/A ratio) was increased in these
derivatives. The most selective compounds were the
8F, 6Cl, 7F, 5Cl and 8Cl derivatives, which had B/A
ratios of 19, 13, 6.2, 4.1 and 3.8, respectively (B/A ratio
of the cyclopentyl parent was 0.93).
[8] Shutske, G.M.; Pierrat, F.A.; Kapples, K.J.; Cornfeldt, M.L.;
Szewczak, M.R.; Huger, F.P.; Bores, G.M.; Haroutunian, V.;
Davis, K.L. J. Med. Chem., 1989, 32, 1805.
[9] Puri, S.K.; Hsu, R.; Ho, I.; Lassman, H.B. Curr. Ther. Res.,
1988, 44, 766-80, Chem. Abstr. 1989, 110, 68926b.
[10] Shutske, G.M.; Pierrat, F.A.; Cornfeldt, M.L.; Szewczak, M.R.;
Huger, F.P.; Bores, G.M.; Haroutunian, V.; Davis, K.L. J. Med.
Chem. 1988, 31, 1278.
[11] Shutske, G.M., US Patent 4762841 (1988). Chem. Abstr. 1989,
110, 8059m. Addition of a second F substituent tended to
reduce potency against both forms of cholinesterase,
with the effect on potency against
butyrylcholinesterase activity being more pronounced
than that against acetylcholinesterase. Only 6,7-diF
derivative was more active than the corresponding
mono F derivatives. Thus, the B/A ratios were higher
for the diF derivatives than for the monoF derivatives:
286 for 6,7 diF, 36.6 for 7,8-diF, 16.3 for 5,7-diF, 11.7
for 6,8-diF, and 10.2 for 5,8-diF.
[12] Shutske, G.M.; Pierrat, F.A. Eur Patent 179383 (1986). Chem.
Abstr. 1986, 105, 172311e.
[13] Deeb, A.; Elmobayed, M.; Essawy, A.N.; Elhamid, A.A.;
Elhamid, A.M.A. Coll. Czech. Chem. Commun., 1990, 55, 728.
[14] Gatta, F.; Pomponi, M.; Marta, M. J. Heterocycl. Chem., 1991,
28, 1301.
[15] Shutske, G.M.; Kapples, K.J. US Patent 4753950 (1988). Chem.
Abstr. 1988, 109. 128990j.
302 Current Medicinal Chemistry, 2000, Vol. 7, No. 3 Proctor and Harvey
[16] Corsaro, A.; Perrini, G.; Puglisi, G.; Purrello, G. J. Chem. Res.
1989(S), 246, M1772.
[43] Patnaik, G.K.; Vohra, M.M.; Bindra, J.S.; Garg, C.P.; Anand, N.
J. Med. Chem. 1966. 9, 483.
[17] Dave, C.G.; Shah, P.R.; Upadhyaya, S.P. Indian J. Chem. Sect.
B., 1988, 27, 1046.
[44] Bindra, J.S.; Rastogi, S.N.; Patnaik, G.K.; Anand, N.; Rao,
K.G.G.; Dwivedi, P.C..; Rao, C.N.R. Indian J. Chem. B., 1987,
26, 318. Chem. Abstr. 1988, 108, 112192u.
[18] Verma, S.S.; Taneja, P.; Prakash, L.; Mital, R.L. J. Indian Chem.
Soc. 1988, 65, 798. [45] Stephen, J.M.L.; Tonkin, I.M.; Walker, J. J. Chem. Soc. 1947,
1034.
[19] Vieillescazes, C.; Coen, S.; Ragonnet, B.; Roggero, J.
Heterocycles 1985, 23, 927. [46] Gatta, F.; Delgiudice,; Pomponi, M.; Marta, M. Heterocycles,
1992, 34. 991.
[20] Upadysheva, A.V.; Grigoreva, N.D.; Znamenskaya, A.P.;
Sarkisyan, D.A.; Metkalova, S.E.; Antonyan, S.G.; Fleiderman,
S.N.; Lavretskaya, E.F. Khim. Farm. Zh. 1977, 11, 40. Chem
Abstr. 1977, 86, 189676q.
[47] Konshin, M.E.; Uvarov, D.I.; Abramochkin, E.S.; Zaks, A.S.;
Kapitonenko, T.A. Khim-Farm. Zh. 1974, 8, 17, Chem. Abstr.
1974, 81, 120411d.
[21] Bielavsky, J. Coll. Czech. Chem. Commun. 1977, 42, 2802. [48] Prasad, M.; Rastogi, S.N.; Kar, K. Indian J. Chem. B., 1986, 25,
729, Chem. Abstr. 1987. 106, 196226c.
[22] Perkin, Jnr. W.H.; Sedgewith, W.G. J. Chem. Soc., 1924, 2437.
[49] Brian, W.P.; Souther, B.L. J.M. Chem., 1965, 8, 144.
[23] Konshin, M.E.; Abramochkin, E.S. Khim. Getero. Soedin, 1970,
1667, Chem. Abstr., 1971, 74, 53475t. [50] Sargent, L.J.; Small, L. J. Org. Chem. 1946, 11, 359.
[24] Konshin, M.E., Khim. Getero Soedin, 1973, 528. Chem. Abstr.
1973, 79, 42310n.
[51] Basu, U.P.; Gupta, S.T. Indian Chem. Soc. 1937, 14, 468.
[52] Shutske, G.M. European Patent 306825 (1989), Chem. Abstr.,
1989, 111, 194612c. [25] Konshin, M.E.; Uvarov, D.I.. Khim. Getero. Soedin, 1973, 531,
Chem. Abstr., 1973, 79, 42311p.
[53] Albert, A.; Gledhill, W.J. J. Soc. Chem. Ind., 1945, 64, 169.
[26] Osbirk, A.; Petersen, E.B. Acta Chem. Scand., 1979, B33, 313.
[54] Shaw, F.H.; Bentley, G. Med. J. Aust., 1949, 2, 868.
[27] Lamant, M, Ann. Chim. 1959, 4, 87. Chem. Abstr. 1960, 54,
14148c.
[55] Shaw, F.H.; Bentley, G. Aust. J. Exp. Biol. Med. Sci., 1953, 31,
573
[28] Lamant, M. Bull. Soc. Chim. Fr., 1959, 782; 1958, 1064.
[56] Heilbronn, E. Acta Chem. Scand., 1961. 15, 1386.
[29] Harvey, A.L.; McKenna, M.; Mullins, S.J.; Proctor, G.R. UK.
Patent 9524346-5 (1996).
[57] Kaul, P.N. J. Pharm. Pharmacol., 1962, 14, 243.
[58] Drukarch, B.; Leysen, J.E.; Stoof, J.C. Life Sci., 1988, 42, 1011.
[30] Mullins, S.J., unpublished.
[59] Halliwell, J.V.; Grove, E.A. Eur. J. Pharmacol., 1989, 163, 369.
[31] Thorpe, J.F. J. Chem. Soc. 1909, 1901.
[60] Perry, E.K.; Smith, C.J.; Court, J.A.; Bonham, J.R.; Rodway, M.;
Atack, J.R. Neurosci. Lett., 1988, 91, 211.
[32] Ziegler, K.; Eberle, H.; Ohlinger, H. Liebigs Ann. Chem., 1933,
504, 94.
[61] Patocka, J.; Bajgar, J.; Bielvasky, J.; Fusek, J. Collect. Czech.
Chem. Comm., 1976, 41, 816.
[33] Johnson, W.S.; Shelberg, W.E., J. Am. Chem. Soc., 1945, 67,
1745.
[62] Dawson, R.M. Neurosci. Lett., 1989, 227, 227.
[34] Harvey, A.L.; MacTavish, J.; Mullins, S.J.; Proctor, G.R. J.
Chem. Res. (S), 1997, 420.
[63] Hunter, A.J.; Murray, T.K.; Jones, J.A.; Cross, A.J.; Green, A.R.
Brit. J. Pharmacol., 1989, 98, 79.
[35] Michalson, E.T.; Dandrea, S.; Freeman, J.P.; Szmuszkovicz, J.
Heterocycles 1990, 30, 415.
[64] Berman, H.A.; Leonard, K. Mol. Pharmacol. 1992, 41, 412.
[36] Tiedke, H. Chem. Ber. 1909, 42, 621.
[65] Sussman, J.L.; Harel, M.; Silman, I. Chemico-Biol. Interactions,
1991, 87, 187.
[37] Shutske, G.M.; Helsley, G.C. Eur. Patent 282,959 (1998). Chem.
Abstr. 1989 110, 212633y.
[66] Steinberg, G.M.; Mednick, M.L.; Maddox, J.; Rice, R. J. Med.
Chem. 1975, 18, 1056.
[38] Blount, B.K.; Perkin Jnr., W.H.; Plant, S.G.B. J. Chem. Soc.,
1929, 1975.
[67] Plotnikoff, N.; Keith, J.; Heinemann, M.; Keith, W.; Perry, C.
Arch. Int. Pharmacodyn. Ther. 1963, 146, 406.
[39] Blount, B.K.; Plant, S.G.P. J. Chem. Soc. 1937, 376.
[68] Lee, C.-M. J. Med. Chem., 1966, 9, 483.
[40] Petrow, V. J. Chem. Soc., 1947, 634.
[69] Proctor, G.R.; Harvey, A.L.; McKenna, M.T.; Mullins, S.J.
International Patent Application, 1997, WO 97/19929.
[41] Sigal Jnr, M.V.; Brent, B.J.; Marchini, P. US Patent 3,232,945
(1966). Chem. Abstr. 1966, 64, 14174g.
[42] Joshi, K.C.; Dubey, K. Indian J. Chem. B. 1978, 16, 156. Chem.
Abstr. 1978, 89. 43073f.