Synthesis and SAR of adatanserin: Novel adamantyl aryl- and heteroarylpiperazines with dual serotonin 5-HT(1A) and 5-HT2 activity as potential anxiolytic and antidepressant agents

Article abstract of DOI:10.1021/jm9806704

Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared and examined in various receptor binding and behavioral tests to determine their serotonin receptor activities. Many compounds demonstrated modest to high affi

Full text of DOI:10.1021/jm9806704

J . Med. Chem. 1999, 42, 5077-5094
5077
Syn th esis a n d SAR of Ad a ta n ser in : Novel Ad a m a n tyl Ar yl- a n d
Heter oa r ylp ip er a zin es w ith Du a l Ser oton in 5-HT1A a n d 5-HT2 Activity a s
P oten tia l An xiolytic a n d An tid ep r essa n t Agen ts
Magid A. Abou-Gharbia,* Wayne E. Childers, J r., Horace Fletcher, Georgia McGaughey, Usha Patel,
Michael B. Webb, J ohn Yardley, Terrance Andree, Carl Boast, Robert J . Kucharik, J r., Karen Marquis,
Herman Morris, Rosemary Scerni, and J ohn A. Moyer
Chemical Sciences and CNS Disorders, Wyeth-Ayerst Research, CN 8000, Princeton, New J ersey 08543-8000
Received November 30, 1998
Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were
prepared and examined in various receptor binding and behavioral tests to determine their
serotonin receptor activities. Many compounds demonstrated modest to high affinity for 5-HT1A
receptors, with compounds 9, 13, 23, 33, 34, and 43 being the most potent at this site. Compound
1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively
high affinity for 5-HT1A receptors (Ki ) 8 nM) and acceptable selectivity versus D2 receptors
(Ki ) 708 mM); however, it lacked in vivo activity in serotonergic behavioral models. In contrast,
compounds 9 (WY-50,324, SEB-324, adatanserin), adamantyl-1-carboxylic acid 2-[4-(2-pyrim-
idinyl)-1-piperazinyl]ethylamide, and 13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-
1-piperazinyl]ethylamide, demonstrated high affinity for 5-HT1A binding sites (Ki ) 1 nM for
both) and moderate affinity for 5-HT2 receptors (Ki ) 73 and 75 nM, respectively). Both
compounds also demonstrated partial 5-HT1A agonist activity in vivo in rat serotonin syndrome
and 5-HT2 antagonist activity in quipazine- and DOI-induced head shake paradigms. The
selective 5-HT1A partial agonist and 5-HT2 antagonist activity of 9 was accompanied by
significant anxiolytic activity in an animal conflict model. On the basis of this profile, compound
9 entered development as a combined anxiolytic and antidepressant agent.
In tr od u ction
Considerable advances have occurred during the past
decade in the pharmacological treatment of anxiety and
depression. The introduction of buspirone in the mid-
1980s represented the first challenge in over 30 years
to the anxiolytic monopoly held by the benzodiazepines
and introduced the age of the azaspirones. The disclo-
sure of several non-benzodiazepine azaspirone-derived
arylpiperazine serotonergic agents, acting primarily on
the 5-HT1A receptor subtype, soon followed,1 including
gepirone, ipsapirone, tandospirone, and flesinoxan (Fig-
ure 1). Our interest in this area led to the discovery of
zalospirone (Figure 1), a 5-HT1A partial agonist which
down-regulates 5-HT2 receptors upon chronic adminis-
tration,2,3 and the 5-HT1A full agonist WY-48723 (Figure
1).3,4 Zalospirone entered clinical trials for the treatment
of anxiety.5
Similarly, the treatment of depression was revolu-
tionized by the marketing of the serotonin selective
reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine
in the mid to late 1980s, and this was quickly followed
by a series of SSRIs, including paroxetine and sertroline.
Another therapeutic approach focused on the identifica-
tion and development of a novel class of selective
serotonin and norepinephrine reuptake inhibitors (SN-
RIs),6 which resulted in the marketing of venlafaxine
(Effexor) in 1994.7
F igu r e 1. 5-HT1A agonists and partial agonists possessing the
azaspirone pharmacophore.
Among the deficiencies of current drugs are slow onset
of action, lack of efficacy in refractory patients, and
presence of unwanted gastrointestinal and sexual side
effects. In addition, although anxiety and depression are
considered to be separate neuropsychiatric diseases,
there is considerable overlap among the clinical symp-
toms of these disorders and differential diagnosis is
often difficult.8 Anxiety frequently coexists with depres-
sion or may precede the development of depressive
Despite these advances, unmet medical needs still
exist for the treatment of anxiety and depression.
* To whom correspondence should be addressed. Phone: (732) 274-
4522. Fax: (732) 274-4500. E-mail: Abougam@war.wyeth.com.
10.1021/jm9806704 CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/25/1999

5078 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Abou-Gharbia et al.
Sch em e 1a
a
Reagents and conditions: method A - (i) Et3N (3 equiv);
method D - (i) HO(CH2)nBr, Et3N; (ii) appropriate arylpiperazine,
Et3N.
Sch em e 2a
F igu r e 2. Evolution of 5-HT1A partial agonists from zalo-
spirone.
symptoms,9 and anxiety and depression may be bio-
chemically associated since there are many similarities
in the neurological substrates thought to play a role in
these diseases,10-12 including a recent report describing
a polymorphism in the serotonin transporter gene
associated with both anxiety- and depression-related
personality traits.13 In addition, anxiolytic agents may
have utility in treating depression,14 and there is
emerging clinical evidence that antidepressants may be
effective in treating generalized anxiety disorder.15
Taking these similarities into account, it should be
possible to identify and develop therapeutic agents with
combined anxiolytic and antidepressant activity. Drug
discovery efforts in this area have focused on agents
with serotonergic activity, because of considerable re-
search indicating their potential for anxiolytic16 and
antidepressant3,17 activity. In particular, the focus of
these efforts has been on combining 5-HT1A and 5-HT2
serotonin receptor activities which has led to the
identification and characterization of WY-50,324 (SEB-
324, adatanserin, 9),18 CGS 18102 A,19 S14761,20 FG
5893,21 LEK 8804,22 and BIM-17 (flibanserin).23 While
the previous agents are generally agonists or partial
agonists at the 5-HT1A receptor and antagonists at the
5-HT2A/C receptor, a recent publication discloses selec-
tive 5-HT1A and 5-HT2A antagonists with potential
anxiolytic activity.24
Our approach to this end included structural modi-
fication of the imide functionality in zalospirone to
generate novel agents with multireceptor activity. It was
postulated that these agents would possess either 5-HT
uptake inhibition or 5-HT2 antagonist activity in addi-
tion to their original 5-HT1A activity, a profile which
predicts combined clinical anxiolytic and antidepressant
activity.16a This investigation led to the synthesis of
several interesting series of compounds (Figure 2).
Reduction of both imide carbonyl moieties resulted in
polycyclic amines which possess 5-HT1A activity as well
as 5-HT uptake inhibitory property activity but lack in
vivo activity in serotonergic behavioral models. These
compounds will be the subject of another paper. Re-
a
Reagents and conditions: method B - (i) (EtO)2P(O)CN, Et3N;
method C - (i) DCC, DMAP; method G - (i) carbonyldiimidazole.
moval of one carbonyl group produced another series of
adamantyl aryl- and heteroarylpiperazines. Previous
work from our laboratories had demonstrated that the
incorporation of a tertiary center next to an amide
carbonyl could produce compounds with a favorable
5-HT1A/D2 profile.25 This idea was further extended to
the NAN-190 series by Glennon et al.,26 although the
greatest effect of this structural alteration was seen in
the 5-HT1A/adrenergic R1 selectivity. Still, the concept
of combining the tertiary center of the adamantyl group
with an imide bioisostere lent itself as a potential means
of producing high-affinity 5-HT1A ligands which might
possess selectivity versus D2.27 The resulting analogues
demonstrated 5-HT1A partial agonist and 5-HT2 antago-
nist activities and also possessed in vivo activity in
various serotonergic paradigms. This concept was sub-
jected to extensive studies to fully explore the role of
the amide functionality and its surrounding environ-
ment. These studies led to the discovery of novel 5-HT1A
antagonists such as WAY-100635,28 which is currently
widely used by many investigators as a standard silent
5-HT1A antagonist. The design and synthesis of these
selective 5-HT1A antagonists will also be the subject of
future publications. The present investigation describes
the synthesis, receptor binding profile, and behavioral
activity of our series of functionalized adamantyl aryl-
and heteroarylpiperazines, as well as the structure-
activity relationships (SARs) within this series which
led to the discovery of adatanserin (9), a compound
selected for development as an agent with mixed anxi-
olytic and antidepressant activities.
Ch em istr y
A variety of synthetic methods was used to prepare
the arylpiperazinyl alkyl amides, esters, and ureas
listed in Table 1, as illustrated in Schemes 1-8. The
required intermediate amino- and hydroxyalkyl arylpip-
erazines were prepared using procedures previously

Synthesis and SAR of Adatanserin
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5079
Sch em e 3
Sch em e 7a
L
Sch em e 4a
a
Reagents and conditions: method L - (i) N-benzylpiperazine;
(ii) LiAlH4; (iii) adamantane-1-carboxylic acid chloride, Et3N; (iv)
H2, Rh/Al2O3; (v) 2-chloropyrimidine, Na2CO3, Cs2CO3.
Sch em e 8a
a
Reagents and conditions: method H - (i) ref 29; (ii) Et3N;
method I - (i) 3-bromopropionyl chloride, Et3N; (ii) (i-Pr)2NEt.
Sch em e 5a
a
Reagents and conditions: method M - (i) acetone, sodium
cyanoborohydride; (ii) adamantane-1-carboxylic acid chloride,
Et3N.
a
Reagents and conditions: method J - (i) trichloromethyl
carboxylic acid with [4-(2-pyrimidinyl)-1-piperazinyl]-
ethanol in the presence of diethyl cyanophosphonate
yielded 1 (method B, Scheme 2). A similar procedure
employing dicyclohexylcarbodiimide/dimethylaminopyr-
idine was applied to the synthesis of compound 17
(method C, Scheme 2). Esters 2, 5, 7, and 8 were
prepared in a two-step sequence (method D, Scheme 1)
involving initial condensation of adamantanecarboxylic
acid chloride with either 2-bromoethanol or 3-bromopro-
panol followed by treatment with the appropriate
4-arylpiperazine to give the desired product.
chloroformate, Et3N.
Sch em e 6a
Using procedures which were identical to those
employed in methods A and D (Scheme 3), the 3-methyl-
1-adamantaneacetic acid analogues 50-54 and 56-62
were synthesized from 3-methyl-1-adamantaneacetic
acid via its acid chloride (method E), and compound 55
was prepared using a two-step sequence (method F). The
noradamantyl esters and amides 63-73 were prepared
in good yield from noradamantane-1-carboxylic acid and
the appropriate amino- or hydroxyalkyl arylpiperazine
in dry chloroform using carbonyldiimidazole to effect the
coupling (method G, Scheme 2).
Two synthetic sequences were used to prepare the
reversed adamantyl amides. Compounds 19-21, which
lack an alkyl spacer chain between the amide and
piperazine moieties, were synthesized by condensing
adamantane-1-isocyanate29 with the appropriate 4-aryl-
piperazine in the presence of triethylamine (method H,
Scheme 4). A two-step method was employed to obtain
the alkyl-containing analogues 22 and 23 (method I,
Scheme 4). Condensation of 1-adamantanamine with
3-bromopropionyl chloride in the presence of triethyl-
amine yielded the intermediate 3-bromopropylamide,
which was subsequently treated with the appropriate
4-arylpiperazine in the presence of Hunig’s base to give
the desired product.
a
Reagents and conditions: method K - R ) BOC for 25-27,
29, 30, and 33-37, R ) Cbz for 24 and 28; (i) (EtO)2P(O)CN,
N-methylmorpholine, HCl/EtOAc for R ) BOC, 30% aq HBr for
R ) Cbz; (iii) BH3/THF, ∆; (iv) adamantane-1-carboxylic acid,
(EtO)2P(O)CN, N-methylmorpholine; (v) H2, Pd/C; (vi) 2-chloro-
pyrimidine, K2CO3, Et3N.
described in the literature. In general, hydroxyalkyl
arylpiperazines were synthesized by treating com-
mercially available arylpiperazines with 2-bromoethanol
or 3-bromopropanol under basic catalysis. The desired
aminoalkyl arylpiperazines were obtained by reacting
arylpiperazines with bromoacetonitrile or bromopropi-
onitrile followed by catalytic reduction of the nitrile
grouping to the primary amine.
Three methods were used to synthesize the adaman-
tyl esters and amides. Compounds 3, 4, 6, 9-16, and
18 were prepared by condensing 1-adamantanecarbox-
ylic acid chloride with the appropriate amino- or hy-
droxyalkyl arylpiperazine in the presence of triethyl-
amine (method A, Scheme 1). Coupling of 1-adamantane-
The required adamantyl and noradamantyl ureas
40-49 and 74 were obtained by condensing 1-adaman-

5080 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Abou-Gharbia et al.
tanamine or 1-noradamantanamine with the appropri-
ate aminoalkyl arylpiperazine in the presence of trichlo-
romethyl chlorofomate (method J , Scheme 5).
spiperone (30 nM ketanserin was present to exclude
5-HT2 binding), and 5-HT2 affinity was assessed in rat
brain cortex tissue using [3H]ketanserin. Results are
reported either as Ki values or as percent displacement
at the reported concentration. The 5-HT1A functional
activity was determined by examining the ability of the
test compounds to induce the serotonin syndrome and/
or antagonize agonist-induced serotonin syndrome in
the rat, while 5-HT2 antagonist activity was assessed
using the rat quipazine- and DOI-induced head shake
paradigms. Anxiolytic activity of lead compounds was
assessed in a rat Geller-Seifter conflict model.
To examine the steric effects surrounding the amide
moiety, analogues possessing branching on the R-carbon
were prepared. Both enantiomers of compounds pos-
sessing a single substituent on the alkyl chain next to
the amide nitrogen were stereospecifically synthesized
(method K, Scheme 6) starting with enantiomerically
pure alanine or phenylalanine which was protected as
the tert-butoxycarbonyl derivative (BOC). Because of the
lability of the pyrimidinyl group to borane, it was
necessary to carry out the initial steps of the synthetic
sequence on the N-benzylpiperazine derivatives and
then insert the pyrimidinyl group in the last step of the
synthesis. However, other arylpiperazines were stable
to borane and could be introduced early in the synthetic
sequence and carried through the reduction step.
Coupling of D-alanine-N-tert-butoxycarboxamide with
N-benzylpiperazine in the presence of diethyl cyano-
phosphonate followed by deprotection with hydrochloric
acid yielded the desired intermediate (R)-aminoamide
as its hydrochloride salt. Reduction of the amide was
accomplished using borane/THF followed by coupling
with 1-adamantanecarboxylic acid to yield the ben-
zylpiperazine derivative 29. An identical sequence was
applied to the synthesis of the (S)-enantiomer 30 from
L-alanine-tert-butoxycarboxamide and to the prepara-
tion of compounds 35 and 36 beginning with D- and
L-phenylalanine-tert-butoxycarboxamide, respectively.
Each of these compounds, in turn, was subjected to
catalytic hydrogenation to remove the benzyl group and
was then treated with 2-chloropyrimidine under basic
catalysis to yield the pyrimidyl analogues 25, 26, 33,
and 34. The dimethyl derivatives 24 and 28 were also
prepared using a similar sequence starting from 2-me-
thylalanine protected as the benzylcarbamate (Cbz).
Removal of the benzylcarbamate was accomplished
using 30% aqueous hydrobromic acid. This general
synthetic sequence was also applied to the synthesis of
the benzyloxy analogue 37 starting with D-O-ben-
zylserine-N-tert-butoxycarboxamide and N-benzylpip-
erazine (Scheme 6).
Resu lts a n d Discu ssion s
In Vitr o Stu d ies. The affinity of compounds 1-74
for central 5-HT1A and D2 receptors is shown in Tables
1-3. For derivatives with notable 5-HT1A affinity and
acceptable selectivity with respect to D2 activity, we also
evaluated the affinity for 5-HT2. Several of the com-
pounds in this series displayed affinity for the 5-HT1A
receptor which was equivalent or superior to that seen
for buspirone (Ki ) 10 nM). Most notable among these
were compounds 9, 10, 11, 13, and 34 with Ki values of
1 nM (Table 1) and the potent analogues 27, 33, 36, 68,
and 69, all of which displayed subnanomolar Ki values.
Variations were made to five regions of the basic
azaspirone pharmacophore, namely the imide, the lipo-
philic area associated with the imide, the steric zone
surrounding the imide, the distance between the imide
and basic nitrogen (i.e., the spacer chain), and the aryl
group associated with the piperazine.
Ar ylp ip er a zin e Va r ia n ts. The results shown in
Tables 1-3 lead to several conclusions regarding the
SARs of these compounds. By holding the adamantyl
amide moiety constant and varying the arylpiperazine
group, it was possible to study the effect of the arylpip-
erazine moiety on 5-HT1A affinity. The presence of either
a 2-pyrimidinylpiperazine or a 2-methoxyphenylpipera-
zine group generally enhanced 5-HT1A affinity, espe-
cially when combined with the amide functionality. The
2-methoxyphenylpiperazine moiety was better tolerated
within the 5-HT1A receptor than the 2-pyrimidinylpip-
erazine group, especially when the distance between the
adamantyl amide and the piperazine was lengthened,
as evidenced by the decrease in affinity seen in the
2-pyrimidinylpiperazine analogue 12 (Ki ) 89 nM)
compared to the Ki value of 1 nM for the analogous
2-methoxyphenylpiperazine derivative 13. The 3-chlo-
rophenylpiperazine group was also well-tolerated when
the 2-carbon spacer was present (compound 11) but
tended to suffer some loss in affinity when combined
with a 3-carbon spacer (e.g., analogue 14). Relocating
the chlorine to the 4-position of the aryl moiety also
resulted in a decrease in 5-HT1A affinity (as seen with
compound 18) as did the incorporation of the 2,3-
dimethylphenyl group (derivatives 31 and 32). Likewise,
5-HT1A affinity was decreased when the arylpiperazine
was extended to a benzylpiperazine (compound 17) and
lost altogether with the addition of another aryl group
(analogue 8). These results are in agreement with the
literature.30
Compounds 27, 31, and 32, which possessed aryl
groups which were stable to borane, could be synthe-
sized in a more direct application of the sequence.
Coupling of the intact arylpiperazine to the appropriate
BOC-protected alanine followed by removal of the
protecting group, reduction of the tertiary amide, and
coupling with 1-adamantanecarboxylic acid yielded the
desired compounds in four steps.
Analogues which exemplified substitution on the
amide nitrogen were also prepared. Compound 38, an
N-methyl amide, was synthesized in five steps (method
L, Scheme 7). The corresponding N-isopropyl analogue
39 was synthesized in a much shorter sequence (method
M, Scheme 8) using reductive amination conditions to
introduce the isopropyl group.
Bioch em istr y a n d P h a r m a cology
The 5-HT1A affinity values of compounds 1-74 were
determined from their ability to displace [3H]8-OH-
DPAT from its recognition sites in rat hippocampus. The
D2 affinity was measured in rat limbic tissue using [3H]-
Im id e Bioisoster es. While the role of the arylpip-
erazine in 5-HT1A affinity has been the subject of
numerous studies and theoretical pharmacophore mod-

Synthesis and SAR of Adatanserin
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5081
Ta ble 1. Adamantyl Aryl- and Heteroarylpiperazinyl Derivatives
affinities: Ki, nM (95% CI)b
or % inhibn at 1 µM
c
d
compd
X
R1
R2
n
R3
mp, °C
formulaa
method
5-HT1A
D2
buspirone
10 (6-15)
119 (98-144)
12
708 (508-944)
ritanserine
1
830
COO
COO
COO
COO
COO
COO
COO
COO
CONH
CONH
CONH
CONH
CONH
CONH
COO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1
1
2
2
2
2
2
1
1
1
1
2
2
2
2
0
1
1
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2-pyrimidinyl
2-MeOPh
2-pyrimidinyl
2-MeOPh
3-ClPh
232-35 C21H30N4O2‚2HClf
B
D
A
A
D
A
D
D
A
A
A
A
A
A
A
A
C
A
H
H
H
I
8.5 (7-10.5)
2.5 (1.98-3.14) 13.5 (11.5-15.5)
2
3
4
5
6
7
8
9
214-16
209-11
212-13
C
C
C
24H34N2O3‚2HCl
22H32N4O2‚2HClg
25H36N2O3‚2HCl
72%
8.5 (7.5-10)
80%
75%
63%
4%
1 (0.5-1.5)
1 (0.55-1.5)
0.89 (0.72-1.08) 129 (79-213)
89 (73-104)
1 (0.7-1.4)
19 (16-24)
5%l
33%
35 (29.5-42)
67%
220-22 C24H33N2O2Cl‚2HCl
233-34 C25H33N2O2‚HCl
263-65 C25H36N2O2‚2HClf
222-24 C31H38N4O2F2‚2HClf
235-38 C21H31N5O‚2HClf
3-CF3Ph
CH2Ph
54%
CH(4-FPh)2
2-pyrimidinyl
2-MeOPh
3-ClPh
2-pyrimidinyl
2-MeOPh
3-ClPh
6-Cl-2-pyrazinyl 252-53
2-pyrimidinyl
CH2Ph
166 (118-212)
24 (20-29.5)
10
11
12
13
14
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
47
48
49
219-21
213-14
140-48
186-92
C
C
C
C
24H35N3O2‚2HCl
23H32N3OCl‚2HClh
22H33N5O‚HClf
6%
25H37N3O2‚HClg
200 (175-227)
32%
209-10 C24H34N3OCl‚2HCli
C
22H31N4O2 Cl‚2HClj,k
CO
175-78 C19H26N4O‚HCl
259-60 C24H35N3O‚2HCl
108-09 C24H34N3OCl
9%
CONH
CONH
NHCO
NHCO
NHCO
NHCO
NHCO
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONMe
CONiPr
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCOO
NHCOO
NHCOO
H
H
H
H
46 (39-54)
96 (76-122)
3%
0%
0%
8%
4-ClPh
2-pyrimidinyl
2-MeOPh
3-ClPh
2-pyrimidinyl
2-MeOPh
2-pyrimidinyl
2-pyrimidinyl
2-pyrimidinyl
2-MeOPh
CH2Ph
174-75
179-80
131-32
C
C
C
19H27N5O
22H31N3O2
21H28N3OCl
H
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH2Ph
H
CH2Ph
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
H
CH3
CH3
CH3
H
CH3
H
273-75 C21H31N5O‚3HCl
131 (113-150) 14%
232-34
C
24H35N3O2‚2HCl
I
9 (7-13)
93 (76-114)
153-55 C23H35N5O
K
K
K
L
K
K
K
L
L
K
K
K
K
K
M
N
J
J
J
J
J
J
J
J
J
127 (95-161)
168-69 C22H33N5O
1.1 (0.95-1.39) 153 (121-192)
162-64 C22H33N5O
21%
1%
194-98 C25H37N3O2‚2HCl
256-58 C26H39N3O‚2HClg
240-42 C25H37N3O‚2HClj
236-38 C25H37N3Om‚2HClj,m
229-30 C26H39N3O‚2HClf,n
226-28 C26H36N2O3‚2HCl
172-75 C28H37N5Og
0.22 (0.18-0.28) 21.5 (17.5-26)
0%
CH2Ph
CH2Ph
37 (31-44)
14%
0%l
2,3(CH3)2Ph
2,3(CH3)2Ph
2-pyrimidinyl
2-pyrimidinyl
CH2Ph
0%l
0%l
CH2Ph
H
CH2Ph
H
0.43 (0.36-0.5) 20 (16.5-24)
1 (0.95-1.25)
2.3 (1.91-2.66) 1402 (1040-1891)
0.7 (0.63-0.85) 3394 (2128-5422)
62 (52-62.5)
60 (59-71)
36%
172-75 C28H37N5O
1693 (1261-2277)
261-63 C31H41N3O‚2HClo
263-66 C31H41N3O‚2HClo
140-42 C32H43N3O2‚2HClo
CH2Ph
CH2OBz 1 CH2Ph
76 (41-140)
H
H
H
H
H
H
H
H
H
H
H
H
1
1
1
1
1
2
2
2
1
1
1
1
2-pyrimidinyl
2-pyrimidinyl
2-pyrimidinyl
2-MeOPh
3-ClPh
2-pyrimidinyl
2-MeOPh
214-23
C
22H33N5O‚2HClg
194-210 C24H37N5O‚2HClj
170-71
108-10
136-37
C
C
C
21H32N6Og,p
24H36N4O2f
23H33N4OCl
77 (64-92)
9 (7.5-11)
61 (51-72)
7 (4.5-10)
1 (0.45-1.1)
45 (41-49)
9%l
72%
94%
56%
>10000
176 (132-233)
38%
172-73 C25H37N3O‚2HClj
182-83
175-76
C
C
25H37N3O‚2HClj,n
3-ClPh
26H39N3O‚2HClf,n
H
H
H
H
CH(4-ClPh)2
2-pyrimidinyl
2-MeOPh
212-13 C26H36N2O3‚2HCl
245
C28H37N5Og,q
34%l
40 (36-45)
76 (66-86)
215-17 C28H37N5O
198-200 C31H41N3O‚2HCl
95%
36%
3-ClPh
J
a
b
All compounds had elemental analyses (C,H,N) within (0.4% of the theoretical values. 95% CI indicates values for 95% confidence
interval. Data are the result of duplicate assays. c Rat hippocampal tissue. Rat limbic tissue. e Data from ref 31d. f Hydrate. g Hemihydrate.
d
3/4Hydrate. N: calcd, 8.14; found, 7.69. j Sesquihydrate. C: calcd, 58.17; found, 58.70. @0.1 µM. N: calcd, 8.12; found, 7.57. Hemi-
h
i
k
l
m
n
2-propanol. o Dihydrate. C: calcd, 64.10; found, 64.52. C: calcd, 49.17; found, 48.72.
p
q
els,31 the contributions of the azaspirone group are less
well-understood. Reports in the literature32 demonstrate
that an azaspirone group is not necessary for high
5-HT1A affinity. However, studies by the group of
Mokrosz33 also support the notion that the electron
density distribution within the amide group as well as
the arrangement of those bonds can enhance the 5-HT1A
affinity of some azaspirone compounds, thus suggesting
the possibility of multiple binding modes.
altering the amide group in our series was probed in
detail. The ester, amide, and urea moieties all proved
to be adequate substitutions for the azaspirone group.
However, the amide moiety was optimal for 5-HT1A
affinity within all three series of compounds (adamantyl,
3-methyladamantyl, and noradamantyl), giving ana-
logues with greater affinity than those with the corre-
sponding esters (compare, for example, amides 9, 67,
and 68 with esters 1, 63, and 64). Reversing the order
of the carbonyl and nitrogen components of the amide
to give reversed amides decreased 5-HT1A affinity, as
can be seen in analogues 19-23, although it was again
Early hints from the patent literature indicated that
ring-opened bioisosteres could serve as feasible replace-
ments for the imide moiety.34 Therefore, the effect of

5082 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Abou-Gharbia et al.
Ta ble 2. 3-Methyladamantyl Aryl- and Heteroarylpiperazinyl Derivatives
affinities: Ki, nM (95% CI)b
or % inhibn at 1 µM
c
d
compd
X
R1
R2
n
R3
mp, °C
formulaa
method
5-HT1A
D2
50
51
52
53
54
55
56
57
58
59
60
61
62
COO
COO
COO
COO
COO
COO
COO
CONH
CONH
CONH
CONH
CONH
CONH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1
1
1
1
2
2
2
1
1
1
2
2
2
2-pyrimidinyl
2-MeOPh
3-ClPh
3-CF3Ph
2-MeOPh
3-ClPh
202-07
199-206
176-78
159-63
203-06
182-84
177-80
251-53
197-99
182-85
188-90
210-18
200-02
C23H34N4O2‚2HCle
E
E
E
E
E
F
E
E
E
E
E
E
E
72%
86%
34%
35%
17 (14-20)
58%
39%
97%
19%
29%
95%
C
C
25H38N2O2Clh‚HClf
25H35N2O2‚2HClg
C26H35N2O2F3‚HCl
C
C
28H40N2O3‚2HCl
26H37N2O2Cl‚2HCl
3-CF3Ph
C27H37N2O2F3‚HCl
56%
2-pyrimidinyl
2-MeOPh
3-ClPh
2-pyrimidinyl
2-MeOPh
3-ClPh
C
C
C
C
C
C
23H35N5O‚2HClf
26H39N3O2‚2HCl
25H36N3OCl‚2HClh
24H37N5O‚2HCli
27H41N3O2‚2HCl
26H38N3OCl‚2HCl
30 (34-39.5)
11 (9.5-13)
38 (32-40)
68%
4.4 (3.3-6)
81%
27%
70%
40%
20%
79%
41%
a
b
All compounds had elemental analyses (C,H,N) within (0.4% of the theoretical values. 95% CI indicates values for 95% confidence
interval. Data are the result of duplicate assays. c Rat hippocampal tissue. Rat limbic tissue. e Hydrate. f Hemihydrate. H: calcd, 7.96;
found 7.49. 2 1/2Hydrate. Sesquihydrate.
d
g
h
i
Ta ble 3. Noradamantyl Aryl- and Heteroarylpiperazinyl Derivativesa
affinities: Ki, nM (95% CI)b
or % inhibn at 1 µM
c
d
compd
X
R1
R2
n
R3
mp, °C
formulaa
method
5-HT1A
D2
63
64
65
66
67
68
69
70
71
72
73
74
COO
COO
COO
COO
CONH
CONH
CONH
CONH
CONH
CONH
CONH
NHCONH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1
1
2
2
1
1
1
1
2
2
2
2
2-pyrimidinyl
2-MeOPh
2-pyrimidinyl
2-MeOPh
2-pyrimidinyl
2-MeOPh
3-ClPh
3-CF3Ph
2-pyrimidinyl
2-MeOPh
3-ClPh
2-pyrimidinyl
219-20
207-08
231-32
206-07
210-12
192-93
226-27
222-23
229-30
201-02
236-37
134-35
C20H28N4O2‚2HCl
G
G
G
G
G
G
G
G
G
G
G
J
23 (20-26)
47%
100%
C
C
23H33N2O2‚HCl
4.8 (4.3-5.5)
21H30N4O2‚2HCle
12%f
C24H34N2O3‚2HCl
26 (19-35)
2.4 (2-2.85)
0.24 (0.2-0.28)
0.7 (0.59-0.83)
83%
67 (49-90)
3.3 (2.7-3.95)
10 (6.5-14)
69%f
100%
67%
100%
94%
73%
27%
72%
31%
6%
C
C
C
20H29N5O‚2HClg
23H33N2O2‚2HCl
22H30N3OCl‚2HCl
C23H30N3OF3‚2HCl
C
C
C
C
21H31N5O‚2HCl
24H35N3O2‚2HCl
22H30N3OCl‚2HCl
21H32N6O‚2HClh
a
b
All compounds had elemental analyses (C,H,N) within (0.4% of the theoretical values. 95% CI indicates values for 95% confidence
interval. Data are the result of duplicate assays. c Rat hippocampal tissue. Rat limbic tissue. e Dihydrate. f @0.1 µM. Hydrate. Mono-
2-propanol.
d
g
h
Ta ble 4. 5-HT2 Affinity
form a tertiary amide as in compounds 38 and 39 also
5-HT2 affinity:a
5-HT2 affinity:a
curtailed 5-HT1A affinity in this series. Homologating
the amide to a urea resulted in compounds which were
potent 5-HT1A ligands. Again, the 2-methoxyphenylpi-
perazine group (e.g., 41 and 44) was more well-tolerated
than the 2-pyrimidinylpiperazine moiety (compounds 40
and 43, respectively). Replacement of the urea with a
carbamate caused a decrease in 5-HT1A affinity.
compd
Ki, nM (95% CI)b
compd
Ki, nM (95% CI)b
buspironec
2290
7.8
34
35
36
40
41
42
43
44
45
67
68
69
71
72
73
1360 (867-1856)
722 (630-745)
1890 (1272-2480)
71 (56-94.5)
38 (30-48)
ritanserinc
1
2
4
9
2180 (1490-2870)
712 (610-819)
180 (67-350)
73 (47-107)
274 (212-335)
16.4 (8.5-23.5)
21 (12-32)
89 (69-107)
10
11
12
13
22
23
25
27
33
1600 (950-2230)
348 (256-440)
277 (218-334)
262 (192-339)
8.2 (6.5-10)
Sp a cer Ch a in . The alkyl spacer chain also plays a
role in the ability of the azaspirone analogues to bind
to the 5-HT1A receptor. Opinions differ as to whether
the alkyl chain simply serves as a spacer between the
arylpiperazine and the lipophilic amide35 or actually
interacts with the receptor in a lipophilic manner.36
However, published SAR studies indicate that there is
a preference by the 5-HT1A receptor in most cases for
amide analogues containing either a 2-carbon or 4-car-
bon spacer chain, especially when the molecule incor-
porates a bulky cycloalkyl amide.32 The esters and
amides of our series followed this general trend, with
the 2-carbon spacer chain producing more potent 5-HT1A
ligands. This was especially true in the 2-pyrimidin-
75 (55-100)
47 (39-58)
77 (58.5-96)
961 (733-1220)
66 (48-85)
2.3 (2.1-2.6)
286 (217-355)
43.5 (34-42)
4.3 (3.6-5)
395 (269-521)
a
b
Rat cortical tissue. 95% CI indicates values for 95% confi-
dence interval. Data are the result of duplicate assays. c Data
taken from ref 63.
observed that the 2-methoxyphenylpiperazine was more
well-tolerated than the 2-pyrimidinylpiperazine moiety.
Likewise, substituting the amide with a third group to

Synthesis and SAR of Adatanserin
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5083
Ta ble 5. Effects of Compounds and Standards in 5-HT1A and 5-HT2 in Vivo Functional Assays
ED50, mg/kg ip (95% CI)a
induction of
serotonin syndrome
antagonism of 8-OH-DPAT-
induced serotonin syndrome
antagonism of quipazine-
induced head shakes
antagonism of DOI-
induced head shakes
compd
buspirone
ritanserin
7.3 (3.4-15.8)
3.9 (1.6-9.4)
0.4 (0.1-1.1)
0.6 (0.2-2.5)
4.5 (1.6-12.8)
0.3 (0.1-1.0)
1.8 (0.8-4.3)
4.4 (1.4-14.5)b
9
13
12.9 (4.1-40.8)
9.0 (4.5-20.1)
2.2 (0.1-6.7)
5.8 (1.9-9.8)
a
b
95% CI indicates values for 95% confidence interval. Data are the result of duplicate assays. Compound administered po.
ylpiperazine analogues, which were the most sensitive
to changes in the molecule. The exception to this trend
was the urea analogues, which preferred the 3-carbon
spacer chain as can be seen by comparing compounds
40 and 41 with the more potent analogues 43 and 44.
The reason for this preference is not clear, although one
possible explanation may be the need for the added
flexibility of the 3-carbon chain to accommodate the
electronic distribution of the extended amide pharma-
cophore of the urea into its binding site on the 5-HT1A
receptor. This extended amide nature might make the
urea analogue possessing a 3-carbon spacer look more
like an amide with a 4-carbon spacer to the 5-HT1A
receptor.
the less optimal benzyl moiety (compounds 29 and 30).
The result of this substitution was a pair of enantiomers
with expectedly reduced 5-HT1A affinity which still
obeyed the stereochemical order of (R) > (S). Introduc-
tion of a benzyl group R to the amide resulted in two
pairs of enantiomers with high affinity for the 5-HT1A
receptor. Again, the trend was observed, with the (R)-
enantiomers 33 (Ki ) 0.43 nM) and 35 (Ki ) 0.7 nM)
being more potent than their respective (S)-isomers 34
(Ki ) 1 nM) and 36 (Ki ) 2.3 nM). However, the
difference in potencies between the enantiomers in the
benzyl analogues was not as dramatic as that observed
for the methyl compounds. The effect of branching in
the 2-methoxyphenylpiperazine series was not exam-
ined in detail. However, incorporation of the (R)-methyl
group next to the amide did result in compound 27
(Ki ) 0.22 nM), which is one of the most potent 5-HT1A
ligands in the entire series. A similar steric effect was
reported earlier by Cliffe et al.38 in the binding profile
of the enantiomers of the 5-HT1A antagonist WAY-
100135, although the (S)-enantiomer was the more
potent 5-HT1A ligand in that case.
The dramatic improvement in 5-HT1A affinity ob-
tained by introduction of the R-benzyl group suggests
the presence of an additional binding interaction. This
possibility is supported by two observations. First, the
presence of the R-benzyl moiety compensates for much
of the loss in affinity seen when the 2-pyrimidinyl group
of the arylpiperazine is replaced by a benzyl functional-
ity in compounds 35 and 36. Second, substitution of an
R-phenoxymethyl group (compound 37) for the R-benzyl
group (compound 35) results in a loss of 5-HT1A affinity,
suggesting a limit to either the size or electronic
requirements of this putative binding site. Further
evidence can be seen in the structure of the potent
5-HT1A antagonist WAY-100635.28 The presence of the
aryl group on the amide nitrogen imparts high 5-HT1A
affinity (IC50 ) 1 nM) despite the tertiary amide
character of the molecule. The poor affinity of com-
pounds 38 and 39 (tertiary alkyl amides) suggests that
the high affinity seen with WAY-100635 is the result
of ligand/receptor interactions rather than conforma-
tional effects on the molecule itself.
Lip op h ilic Ar ea . Glennon et al.37 suggested that
there should exist a region of lipophilic tolerance
adjacent to the recognition site for the basic amine
which stabilizes the binding interaction of the aza-
spirone-like molecules to the 5-HT1A receptor. The
literature contains numerous examples of potent 5-HT1A
ligands which are derived from combining arylpipera-
zines, which possess moderate 5-HT1A affinity, with
bulky lipophilic aryl or cycloalkyl groups, either with
or without the inclusion of the azaspirone moiety.
Therefore, we varied the lipophilic portion of our
molecules to examine the effect on 5-HT1A affinity and
selectivity. Substitution of the adamantyl group (e.g.,
9, 10, and 11) with the 3-methyladamantylmethyl
functionality (30, 31, and 32, respectively) resulted in
compounds which displayed a decrease in 5-HT1A affin-
ity, regardless of the length of the spacer chain, thus
suggesting a limit to the size of the lipophilic binding
pocket located near the putative azaspirone binding site.
The noradamantyl derivatives (Table 3) were found to
be potent 5-HT1A ligands, with affinities similar to or
better than those seen with the adamantyl analogues.
In fact, one of the most potent 5-HT1A ligands in our
series was compound 68 (Ki ) 0.24 nM), which combines
the noradamantyl group, the optimal 2-carbon spacer,
and the well-tolerated 2-methoxyphenylpiperazine moi-
ety. Unfortunately, the noradamantyl group was also
quite attractive to the D2 receptor, and most of the
analogues incorporating this moiety lost selectivity.
Br a n ch ed Alk yl An a logu es. Variation of the steric
environment surrounding the amide produced interest-
ing results (Table 1). Addition of a methyl group to the
carbon of the spacer chain that is adjacent to the amide
nitrogen resulted in a pair of enantiomers which pos-
sessed dramatically differing affinity for the 5-HT1A
receptor. The (R)-isomer 25 retained much of the high
affinity seen in 9, while the affinity of the (S)-enanti-
omer 26 was greatly reduced. The R,R-dimethyl ana-
logue 24 also suffered a considerable loss in 5-HT1A
affinity. This trend was maintained when the 2-pyrim-
idinyl group of the arylpiperazine was substituted with
5-HT1A/D2 Selectivity. Compounds which possessed
acceptable 5-HT1A affinity were also examined for their
affinity at D2 receptors. The majority of the compounds
did not display suitable separation between the two
affinities to warrant detailed investigation. In the
adamantyl amides, the greatest impact on 5-HT1A/D2
selectivity was achieved by varying the arylpiperazine
moiety, a result which is in agreement with SAR studies
on flesinoxan.39 In general, the 2-pyrimidinylpiperazine
analogues displayed the greatest separation between
these two activities. Amides analogues possessing the
3-chlorophenylpiperazine moiety also demonstrated some

5084 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Abou-Gharbia et al.
selectivity for 5-HT1A over D2 (e.g., compounds 11 and
14), while those incorporating or 3-trifluoromethylphen-
ylpiperazine group suffered a loss in selectivity, appar-
ently due to a decrease in 5-HT1A affinity. Almost all
derivatives possessing the 2-methoxyphenylpiperazine
functionality displayed potent affinity for the D2 recep-
tor and poor selectivity. The lone exceptions to this trend
were compounds 13 and 44, which possessed a 200- and
176-fold separation between Ki values for the two
affinities, respectively. It is not clear why compounds
13 and 44 disobey the trend, although it has been shown
that spacer chain length can influence D2 affinity,40 and
both compounds possess a 3-carbon spacer chain. The
selectivity obtained with compounds 13 and 44 is
reminiscent of that seen for BMY-7378 (Figure 1),
another 2-methoxyphenylpiperazine derivative.41
displayed a higher affinity for 5-HT2 receptors than the
corresponding esters (e.g., compare compounds 9 and
13 to compounds 1 and 4, respectively). 2-Pyrimidi-
nylpiperazine analogues (compounds 9 and 12) showed
somewhat greater affinity than the corresponding
2-methoxyphenylpiperazine derivatives (compounds 10
and 13), a trend which seemed to hold when the
components of the amide group were reversed (compare
compounds 22 and 23). Within the adamantyl amides,
the 3-carbon spacer chain (compound 9) was somewhat
preferred to the 2-carbon spacer (compound 12), al-
though the effect was not dramatic. In the adamantyl
ureas, the 2-methoxyphenylpiperazine group imparts
greater 5-HT2 affinity than the pyrimidinylpiperazine
moiety, a result which parallels the 5-HT1A affinity
results for these compounds. However, the shorter
2-carbon chain was preferred over the 3-carbon spacer
(compare compounds 40, 41, and 42 to compounds 43,
44, and 45, respectively) in the ureas. This finding is
in contrast to the 5-HT1A results, where the longer
3-carbon spacer chain is preferred.
In general, branching on the spacer chain improved
5-HT1A/D2 selectivity, usually by both increasing 5-HT1A
affinity and decreasing D2 affinity. As with their 5-HT1A
affinity, compounds possessing the (R)-configuration
(25, 33, and 34) displayed greater D2 affinity than their
(S)-isomers (26, 35, and 36, respectively). This steric
effect was more pronounced in analogues where the
arylpiperazine moiety was not optimal (e.g., the ben-
zylpiperazine seen with analogues 33-36). In these
compounds, 5-HT1A affinity was surprisingly high while
D2 affinity was reduced. The exception to this trend was
the R-phenoxymethyl analogue 37, where a loss in
5-HT1A affinity was accompanied by an apparent in-
crease in D2 affinity (relative to other branched ana-
logues).
In general, branching on the spacer chain resulted
in a decrease in 5-HT2 affinity. As was seen in the case
of both 5-HT1A and D2 affinity, the (R)-enantiomers (33
and 35) were somewhat more potent than the corre-
sponding (S)-isomers (34 and 36, respectively).
The 3-methyladamantylmethyl analogues were not
examined for 5-HT2 affinity because of their relatively
poorer 5-HT1A affinity and/or selectivity versus D2.
However, the noradamantyl amide analogues displayed
an unexpected range of affinities for 5-HT2. In contrast
to the adamantyl analogues, the noradamantyl amides
possessing the 2-methoxyphenylpiperazine group (com-
pounds 68 and 72) displayed superior affinity over those
which contained a 2-pyrimidinylpiperazine moiety (com-
pounds 67 and 71). The 3-chlorophenylpiperazine group
was also well-tolerated within the 5-HT2 pharmacophore
(e.g., 11, 69, and 73). In fact, compounds 69 (Ki ) 2.26
nM) and 73 (Ki ) 4.28 nM) were found to be the most
potent 5-HT2 ligands among the analogues tested.
The relatively inferior potency of the 3-methylada-
mantylmethyl analogues, when compared to the ada-
mantyl amides, precluded an exhaustive examination
of their 5-HT1A and D2 affinities. Indications of selectiv-
ity were observed in the urea analogues 42-44, but
these were not investigated in detail. In general, the
noradamantyl 2-pyrimidinylpiperazine derivatives pos-
sessed somewhat poorer 5-HT1A/D2 selectivity than their
adamantyl counterparts. The exception to this trend
was the 3-chlorophenylpiperazine derivative 73, which
incorporates the longer 3-carbon spacer chain. This
compound displayed reasonable 5-HT1A/D2 selectivity.
Molecu la r Mod elin g Resu lts. Several groups have
described topographic models of the interaction between
the arylpiperazine moiety and the 5-HT1A receptor.44
Most of these models can, in general, be described as
an aryl binding site and a recognition site for the basic
amine group separated by a certain distance and a small
torsion angle.45 However, it is clear from our work and
the vast body of SAR data in the literature that the
interaction between the 5-HT1A receptor and the aza-
spirone pharmacophore is a complex one which probably
involves not only the arylpiperazine group but also the
imide/amide moiety, the lipophilic group, and the spacer
chain.46 For example, additional binding stabilizations
resulting from adding lipophilic groups to simple arylpip-
erazines can reduce the minimum distance between the
aryl moiety and the basic nitrogen required for interac-
tion with the 5-HT1A receptor.47a Additionally, the
molecular volume of the lipophilic group can have
dramatic effects on 5-HT1A affinity in certain series of
ligands.47b
5-HT2 Affin ity. At the time of this work little was
known of the diversity of 5-HT2 receptor subtypes. Given
the fact that ketanserin was the standard ligand, it can
be assumed that the analogues in this paper interact
with the 5-HT2A receptor. However, no selectivity stud-
ies among the 5-HT2 subtypes were performed. It had
been shown that some simple arylpiperazines displayed
5-HT2 affinity,31f although extended arylpiperazine
analogues such as buspirone, gepirone, and ipsapirone
possess relatively poor affinity for the 5-HT2 site labeled
by either the 5-HT2 agonist DOB42 or the 5-HT2 antago-
nist spiperone.31d Nevertheless, more recent studies
have revealed that some extended arylpiperazines can
display 5-HT2 affinity which rivals that seen in some of
the more commonly acknowledged 5-HT2 pharmaco-
phores.37,43
Examination for 5-HT2 affinity was limited to ana-
logues which possessed both acceptable 5-HT1A affinity
and selectivity versus D2 (Table 4). Thus, a thorough
5-HT2 SAR analysis is not possible. However, some
trends were evident. In the adamantyl series, amides
Originating with buspirone, 2-pyrimidinylpiperazine
has often been considered as the quintessential arylpip-
erazine portion of the azaspirone pharmacophore, and
indeed many of the 2-pyrimidinylpiperazine analogues

Synthesis and SAR of Adatanserin
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5085
F igu r e 3. Minimum energy conformation of 2-methoxyphen-
ylpiperazine and rotational energies of the 2-methoxyphenyl
group.
F igu r e 4. Minimum energy conformation of 2-pyrimidinyl-
piperazine and rotational energies of the 2-pyrimidinyl group.
within our series were found to be strong ligands for
the 5-HT1A receptor. However, 2-methoxyphenylpipera-
zine analogues are also high-affinity ligands for the
5-HT1A receptor, often possessing greater affinity than
their 2-pyrimidinylpiperazine counterparts.48 Further-
more, 2-methoxyphenylpiperazine-derived azaspirones
appear to be more tolerant of changes to the spacer
chain and lipophilic portion of the molecule in our series
than the 2-pyrimidinylpiperazine analogues, as has
already been discussed above. One possible explanation
for this difference could be the conformational differ-
ences exhibited by the two arylpiperazine pharmaco-
phores.
MM3* calculations show that the preferred orienta-
tion of the aryl ring of the 2-methoxyphenyl group is
skewed out of the plane relative to the piperazine due
to the steric bulk of the 2-methoxy group (Figure 3).49
The minimum energy conformation depicted in Figure
3 correlates to a dihedral angle τ1 (τ1 ) C1-C2-N3-
C4) of 145°. Furthermore, there are several low-energy
conformations which the 2-methoxyphenylpiperazine
can conceivably achieve, and the energy barrier between
many of these is relatively small. In the 2-pyrimidin-
ylpiperazine, however, the lone pair of the mixed sp2/
sp3 nitrogen can delocalize into the aromatic system of
the pyrimidine. As a result, the orientation of the
pyrimidine prefers to be in the same plane as that of
the piperazine, and the dihedral angle τ2 (τ2 ) N1-C2-
N3-C4) is now 165° (Figure 4). There are only two low-
energy conformations, which are essentially isoenerget-
ic, and the energy barriers between them are large. The
skewed orientation of the 2-methoxyphenyl moiety, as
well as the abundance of acceptable, interchangeable
low-energy conformations, may result in an overall
greater flexibility. As a result, this arylpiperazine can
more easily adjust its overall interaction with the
5-HT1A receptor in response to changes at the other end
of the molecule as opposed to the 2-pyrimidinylpipera-
zine.
In Vivo Stu d ies. Because of their interesting in vitro
profile and favorable physicochemical properties, com-
pounds 1, 9, and 13 were assessed for in vivo functional
activity at the 5-HT1A and 5-HT2 receptors (Table 5).18
The serotonin syndrome paradigm was used to assess
5-HT1A functional activity. In these tests compound 1
was inactive, failing to produce 5-HT1A agonist-like
behavioral responses at doses up to 40 mg/kg ip (the
highest dose examined). However, both 9 and 13 in-
duced behavioral symptoms of the serotonin syndrome
(ED50 ) 12.9 and 9.0 mg/kg ip, respectively) and
antagonized the serotonin syndrome produced by the
selective 5-HT1A agonist 8-OH-DPAT (9: ED50 ) 2.2 mg/
kg ip; 13: ED50 ) 5.8 mg/kg ip) at doses which were
similar to that seen with the reference compound
buspirone. This profile indicates that both compounds
9 and 13 can be considered as 5-HT1A partial agonists.
Compound 9 demonstrated 5-HT2 antagonist activity by
inhibiting both quipazine- and DOI-induced head shakes,
with ED50 values of 0.6 and 1.8 mg/kg ip, respectively.

5086 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Abou-Gharbia et al.
F igu r e 5. Buspirone: Geller-Seifter conflict paradigm, punished/unpunished behavior.
F igu r e 6. Compound 9: Geller-Seifter conflict paradigm, punished/unpunished behavior.
F igu r e 7. Compound 13: Geller-Seifter conflict paradigm, punished/unpunished behavior.
The potency of 9 in these assays was similar to that seen
with the potent 5-HT2 antagonist ritanserin. As can be
seen from Table 5, compound 13 was somewhat less
potent in the 5-HT2 antagonist tests, inhibiting qui-
pazine- and DOI-induced head shakes with ED50 values
of 4.5 mg/kg ip and 4.4 mg/kg po, respectively. The
similarity in 5-HT2 antagonist potency between com-
pound 9 and ritanserin is unexpected, given the differ-
ence in potency as 5-HT2 ligands between these two
compounds. However, it has been shown that activation
of the 5-HT1A receptor can affect the expression of 5-HT2
receptor-mediated behavior,50,51 possibly through a pre-
synaptic mechanism. This functional interplay between
the two receptor subtypes might partially account for
the unexpected in vivo potency of compound 9 as a
5-HT2 antagonist.
To assess their anxiolytic potential, compounds 9 and
13 were compared to buspirone in the Geller-Seifter
conflict model.18 Results are presented in Figures 5-7.
As expected, buspirone significantly increased punished
responding (an indication of anxiolytic effect) at doses
of 1, 3, and 10 mg/kg ip (Figure 5). However, a
significant decrease in unpunished responding was also
seen at doses of 10 and 30 mg/kg ip, indicating the
presence of sedative effects. Compound 9 produced
increases in punished responding at doses of 3, 10, 17,
and 30 mg/kg ip, which were similar to those obtained
with buspirone as well as with a 0.5 mg/kg ip dose of

Synthesis and SAR of Adatanserin
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5087
combustion analyses were determined on either a Perkin-
Elmer 240 or 2400 analyzer, and all analyzed compounds are
within (0.4% of the theoretical value unless otherwise indi-
cated. Flash chromatography was performed on 230-400 mesh
silica. Preparatory HPLC was performed using a Waters Prep
500 instrument with silica Prep-Pak cartridges. Thin-layer
chromatography was performed on silica gel 60 F-254 (0.25-
mm thickness) plates. Visualization was accomplished with
UV light and/or iodine vapor. Optical rotations were measured
using a Perkin-Elmer 241-MC polarimeter.
lorazepam (Figure 6). No significant sedative effects (as
measured by decreases in unpunished responding) were
evident for 9 at doses up to 10 mg/kg ip. Compound 13
was less potent than 9 in this model (Figure 7), causing
a significant increase in punished responding only at a
dose of 30 mg/kg ip. Significant sedative effects were
also displayed at this dose. Compound 9 also demon-
strated efficacy in this model as well as an unexpectedly
good separation between anxiolytic activity and sedative
side effects following oral administration (no decreases
in unpunished responding at doses up to 54 mg/kg po).
Additionally, the efficacy of 9 has been confirmed in
conflict studies in pigeons, a model extremely sensitive
to anxiolytic effects of serotonergic agents.52,53
The antidepressant effects of compound 9 have been
previously published, where it demonstrated potent
preclinical antidepressant activity in a rat forced swim-
ming model.3 On the basis of its favorable anxiolytic and
antidepressant profile, compound 9 was entered into
clinical trials as adatanserin.
Meth od A. Gen er al P r ocedu r e for For m ation of Am ides
a n d Ester s. Ad a m a n ta n e-1-ca r boxylic Acid N-[3-[4-(2-
P yr im id in yl)-1-p ip er a zin yl]p r op yl]ca r boxa m id e Hyd r o-
ch lor id e Dih yd r a te (12). To a solution of 4-(2-pyrimidinyl)-
1-piperazinepropanamine (1.12 g, 5.06 mmol) and triethylamine
(2.2 g, 21 mmol) in 40 mL of dry dichloromethane was added
solid adamantane-1-carboxylic acid chloride (1.0 g, 5.03 mmol)
at room temperature. The resulting mixture was stirred at
room temperature for 2 days. The mixture was then washed
with two 40-mL portions of water, dried over anhydrous
magnesium sulfate, and concentrated on a rotary evaporator.
The desired compound 12 was isolated by HPLC on silica gel
using a gradient of methanol and ethyl acetate and converted
to its hydrochloride salt with ethanolic HCl (1.59 g, 72%): mp
1
140-148 °C; H NMR (DMSO-d6) δ 8.45 (d, J ) 5.1 Hz, 2H),
Con clu sion s
7.64 (t, J ) 6.1 Hz, 1H), 6.77 (t, J ) 5.1 Hz, 1H) 4.68 (m, 2H),
3.49 (m, 4H), 3.38 (m, 2H), 3.11 (m, 2H), 3.00 (m, 4H), 1.94 (s,
3H), 1.76 (s, 6H), 1.65 (m, 6H); IR (KBr) 1650 cm-1. Anal.
(C22H33N5O‚HCl‚2H2O) C, H, N.
In summary, a series of adamantyl and noradamantyl
arylpiperazines was synthesized which possess high
affinity for both 5-HT1A and 5-HT2 receptors. Many of
these analogues also possess selectivity for 5-HT1A/5-
HT2 versus the D2 receptor. Certain trends were seen
in the SAR, including the ability of the 2-methoxyphenyl
derivatives to tolerate changes to the lipophilic group
and spacer chain more readily than the 2-pyrimidin-
ylpiperazine analogues. One possible explanation for
this enhanced flexibility might be the preference of the
2-methoxyphenyl group to exist in a conformation in
which the plane of the aromatic ring is skewed relative
to the plane of the piperazine ring, while the plane of
the 2-pyrimidinyl ring is parallel to that of the pipera-
zine due to delocalization of the sp2/sp3 nitrogen into
the aromatic system.
Two compounds, 9 and 13, which possessed acceptable
affinities and selectivity, were assessed in in vivo
functional models, where they exhibited potent 5-HT1A
partial agonist and 5-HT2 antagonist properties. Com-
pound 9 also displayed potent anxiolytic activity in a
Geller-Seifter conflict model in both rats and pigeons
and a superior separation between efficacy and sedative
side effects compared to buspirone. Previously published
studies have also demonstrated potent preclinical an-
tidepressant activity for 9. Thus, compound 9 has been
shown to be a combined 5-HT1A partial agonist/5-HT2
antagonist which demonstrates potent preclinical mixed
anxiolytic and antidepressant activities. Compound 9
was entered into clinical trials as adatanserin.
Using a similar procedure, 3, 4, 6, 9-11, 13-16, and 18
were also prepared.
Meth od B. Ad a m a n ta n e-1-ca r boxylic Acid 2-[4-(2-P y-
r im id in yl)-1-p ip er a zin yl]eth yl Ester Dih yd r och lor id e
Dih yd r a te (1). Adamantane-1-carboxylic acid (5.0 g, 28
mmol), 4-(2-pyrimidinyl)-1-piperazineethanol (6.25 g, 30 mmol),
and 4-(dimethylamino)pyridine (0.34 g, 2.8 mmol) were dis-
solved in 200 mL of dry dichloromethane. To the stirred
solution was then added dicyclohexylcarbodiimide (6.19 g, 30
mmol) at room temperature. A white precipitate formed and
the resulting mixture was stirred at room temperature over-
night. The precipitate was then filtered and discarded and the
supernatant was washed with three 50-mL portions of water,
dried over anhydrous sodium sulfate, and concentrated on a
rotary evaporator. Chromatography of the resulting gum on
silica gel (ethyl acetate/methanol) followed by treatment with
ethereal HCl gave 2.70 g (21%) of the desired compound 1 as
1
the dihydrochloride salt: mp 232-235 °C; H NMR (DMSO-
d6) δ 8.48 (d, J ) 4.8 Hz, 2H), 6.83 (t, J ) 4.8 Hz, 1H); 4.84
(bd, J ) 14.4 Hz, 2H), 4.48 (m, 2H), 3.50 (m, 6H), 3.18 (m,
2H), 1.90 (m, 3H), 1.84 (m, 6H), 1.67 (m, 6H); IR (KBr) 1650
cm-1 (CdO); MS m/z 370 (M+). Anal. (C21H30N4O2‚2HCl‚2H2O)
C, H, N.
Meth od C. Ad a m a n ta n e-1-ca r boxylic Acid N-[2-(4-
Ben zyl-1-p ip er a zin yl)eth yl]ca r boxa m id e Dih yd r och lo-
r id e (17). A stirred solution of adamantane-1-carboxylic acid
(11.85 g, 65.8 mmol) and 4-benzyl-1-piperazineethanamine
(12.0 g, 52.8 mmol) in 200 mL of dry dichloromethane was
treated at 4 °C with a solution of diethyl cyanophosphonate
(11.8 mL, 65.8 mmol) in 50 mL of dry dichloromethane over a
period of 30 min. Triethylamine (9.2 mL, 65.8 mmol) was then
added and the mixture stirred at room temperature overnight.
The resulting mixture was washed with 100 mL of 10%
aqueous potassium carbonate followed by 100 mL of water.
The resulting organic layer was dried over anhydrous sodium
sulfate and concentrated on a rotary evaporator, and the
desired compound 17 was isolated by crystallization from
boiling hexane. The dihydrochloride salt (11.1 g, 51%) was
prepared with HCl/ethyl acetate and recrystallized from
methanol/2-propanol: mp 259-260 °C; 1H NMR (DMSO-d6) δ
7.80 (t, J ) 8 Hz, 1H), 7.65 (m, 2H), 7.44 (m, 3H), 4.37 (bs,
2H), 3.70 (m, 2H), 3.6-3.3 (m, 8H), 3.10 (t, J ) 14 Hz, 2H),
1.95 (m, 3H), 1.80 (m, 6H), 1.65 (q, J ) 12 Hz, 6H); IR (KBr)
1665 cm-1 (CdO); MS m/z 381 (M+). Anal. (C24H35N3O‚2HCl)
C, H, N.
Exp er im en ta l Section
Ch em istr y. Melting points were determined on a Thomas-
Hoover capillary or an Electrothermal melting point apparatus
and are uncorrected. 1H NMR spectra were recorded on a
Varian XL-200 or Bruker AM-400 spectrometer using tetra-
methylsilane (TMS) as an internal standard. The chemical
shifts are reported in parts per million (δ) downfield from TMS,
and coupling constants are reported in hertz (Hz). Solvate,
hydrate, and HCl protons are not included. Mass spectra were
recorded on a Hewlett-Packard 5995A spectrometer or a
Finnigan 8230 high-resolution instrument. The infared spectra
were recorded on a Perkin-Elmer 784 spectrometer. C,H,N

5088 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Abou-Gharbia et al.
Meth od D. Tw o-Step Syn th esis of Ester s. Ad a m a n -
ta n e-1-ca r boxylic Acid 2-[4-(2-Meth oxyp h en yl)-1-p ip er -
a zin yl]eth yl Ester Dih yd r och lor id e (2). Adamantane-1-
carboxylic acid chloride (5.6 g, 28 mmol), 2-bromoethanol (5.0
g, 40 mmol), and triethylamine (4.0 g, 40 mmol) were dissolved
in 200 mL of dry dichloromethane and allowed to stir overnight
at room temperature. The resulting solution was concentrated
on a rotary evaporator to remove excess triethylamine and
then partitioned between 200 mL of dichloromethane and 100
mL of water. The organic layer was washed with two ad-
ditional 100 mL portions of water, dried over anhydrous
sodium sulfate, and concentrated on a rotary evaporator to
give 10.7 g of a residue which contained the desired adaman-
tane 1-(2-bromoethyl) ester. This residue was used in the next
step without further purification.
The adamantane 1-(2-bromoethyl) ester described above (4.0
g, 13.9 mmol), 1-(2-methoxyphenyl)piperazine (2.7 g, 14 mmol),
and triethylamine (1.5 g, 15 mmol) were dissolved in 100 mL
of dry dimethylformamide and allowed to stir at room tem-
perature overnight. The reaction mixture was concentrated on
a rotary evaporator to remove the DMF, and the residue was
partitioned between 150 mL of dichloromethane and 100 mL
of water. The organic layer was washed with two additional
100-mL portions of water, dried over anhydrous sodium
sulfate, and concentrated on a rotary evaporator. The desired
compound 2 was isolated by chromatography on silica gel
(ethyl acetate) and converted to its dihydrochloride salt with
ethereal HCl (1.29 g, 21%): mp 214-216 °C; 1H NMR (DMSO-
d6) δ 7.00 (m, 4H), 4.47 (t, J ) 6 Hz, 2H), 3.78 (s, 3H), 3.52
(m, 6H), 3.25 (m, 4H), 1.95 (m, 3H), 1.84 (m, 6H), 1.67 (m,
6H); IR (KBr) 1635 cm-1 (CdO); MS m/z 398 (M+). Anal.
(C24H34N4O2‚2HCl) C, H, N.
acetic acid (2.3 g, 11 mmol), 3-bromopropanol (1.53 g, 11
mmol), and 4-(dimethylamino)pyridine (0.15 g, 1.2 mmol) in
100 mL of dry dichloromethane at room temperature was
added dicyclohexylcarbodiimide (2.3 g, 11 mmol). The resulting
mixture was stirred at room temperature overnight. The white
precipitate was then filtered and the supernatant was washed
with three 50-mL portions of water, dried over anhydrous
sodium sulfate, and concentrated on a rotary evaporator. The
resulting residue, which was used without further purification,
was then reacted with 1-(3-chlolophenyl)piperazine (2.57 g, 11
mmol) and triethylamine (3.08 g, 30.5 mmol) in 100 mL of dry
dimethylformamide using a procedure identical to that de-
scribed in general method D. Desired compound 55 was
isolated by chromatography on silica gel (ethyl acetate) and
converted to its dihydrochloride salt with ethereal HCl (0.57
g, 10%): mp 182-4 °C; 1H NMR (DMSO-d6) δ 7.22 (t, J ) 9.1
Hz, 1H), 7.03 (t, J ) 3.1 Hz, 1H), 6.95 (dd, J a ) 3.1 Hz, J b
)
9.1 Hz, 1H), 6.83 (dd, J a ) 9.1 Hz, J b ) 2.5 Hz, 1H), 4.72 (d,
J ) 15 Hz, 2H), 4.06 (t, J ) 7.5 Hz, 2H), 3.58 (m, 4H), 3.12
(m, 6H), 2.10 (s, 2H), 2.05 (m, 2H), 1.95 (m, 2H), 1.60-1.20
(m, 10H), 0.79 (s, 3H); IR (KBr) 1645 cm-1; MS m/z 444 (M+).
Anal. (C26H37N2O2Cl‚2HCl) C, H, N.
Meth od G. Gen er a l P r oced u r e for Nor a d a m a n ta n e
Am id es a n d Ester s. Nor a d a m a n ta n e-3-ca r boxylic Acid
2-[4-(2-P yr im id in yl)-1-p ip er a zin yl]eth yl Ester Dih yd r o-
ch lor id e (63). A solution of noradamantane-3-carboxylic acid
(1.0 g, 6 mmol) and carbonyldiimidazole (0.98 g, 6 mmol) in
25 mL of dry chloroform was stirred at room temperature
under a nitrogen atmosphere for 2 h. Then a solution of 4-(2-
pyrimidinyl)-1-piperazineethanol (1.25 g, 6 mmol) in 10 mL
of dry chloroform was added and the reaction mixture was
stirred at room temperature under nitrogen for 48 h. The
resulting solution was diluted to 100 mL with chloroform and
washed with three 50-mL portions of water. The organic layer
was then dried over anhydrous sodium sulfate and concen-
trated on a rotary evaporator. The desired compound 63 was
isolated by chromatography on silica gel (methanol/ethyl
acetate) and converted to its dihydrochloride salt with 2-pro-
Using a similar procedure, 5, 7, and 8 were also prepared.
Meth od E. Gen er a l P r oced u r e for 3-Meth yl-1-a d a m a n -
ta n e Ester s a n d Am id es. Syn th esis of 3-Meth yl-1-a d a -
m a n ta n ea cetic Acid Am id es a n d Ester s. 3-Meth yl-1-
a d a m a n ta n ea cetic Acid N-[3-[4-(3-Ch lor op h en yl)-1-p ip -
er a zin yl]p r op yl]ca r b oxa m id e Dih yd r och lor id e (62).
3-Meth yl-1-a d a m a n ta n ea cetic Acid Ch lor id e. To a stirred
solution of 3-methyladamantane-1-acetic acid (15 g, 72 mmol)
in 250 mL of dry dichloromethane under a nitrogen atmo-
sphere was added, at room temperature, oxalyl chloride (9.5
g, 75 mmol). When the evolution of gas had ceased, dimeth-
ylformamide (2 mL) was added dropwise in order to make the
mixture homogeneous, and stirring was continued for 2 h. The
mixture was then concentrated on a rotary evaporator. Fresh
dichloromethane was added and the resulting mixture was
concentrated again in order to remove all residual oxalyl
chloride. In this way 16.64 g of crude intermediate 3-methyl-
adamantane-1-acetic acid chloride was isolated.
3-Met h yl-1-a d a m a n t a n ea cet ic Acid N-[3-[4-(3-Ch lo-
r op h en yl)-1-p ip er a zin yl]p r op yl]ca r boxa m id e Dih yd r o-
ch lor id e (62). A solution of the above-described 3-methylad-
amantane-1-acetic acid chloride (1.25 g, 5.5 mmol), 4-(3-
chlorophenyl)-1-piperazinepropanamine (1.4 g, 5.5 mmol), and
triethylamine (2.8 g, 27 mmol) in 50 mL of dry dichlo-
romethane was stirred at room temperature overnight. The
resulting mixture was washed with two 50-mL portions of
water, dried over anhydrous magnesium sulfate, and concen-
trated on a rotary evaporator. The desired compound 62 was
isolated by chromatography on silica gel (methanol/ethyl
acetate) and converted to its dihydrochloride salt with etha-
nolic HCl (1.49 g, 52%): mp 200-202 °C; 1H NMR (DMSO-d6)
δ 7.94 (t, J ) 6 Hz, 1H), 7.26 (t, J ) 8.5 Hz, 1H), 7.05 (m, 1H),
6.94 (m, 1H), 6.85 (m, 1H), 3.85 (d, J ) 13.5 Hz, 2H), 3.49 (d,
J ) 12 Hz, 2H), 3.22 (t, J ) 12 Hz, 2H), 3.15-3.00 (m, 6H),
1.95 (m, 2H), 1.92-1.80 (m, 4H), 1.55-1.02 (m, 12H), 0.98 (s,
3H); IR (KBr) 1660 cm-1; MS m/z 443 (M+). Anal. (C26H38N3-
OCl‚2HCl) C, H. N.
1
panolic HCl (1.0 g, 74%: mp 219-220 °C; H NMR (DMSO-
d6) δ 8.44 (d, J ) 4.8 Hz, 2H), 6.76 (t, J ) 4.8 Hz, 1H), 4.67
(bd, J ) 14 Hz, 2H), 4.47 (bt, J ) 4.7 Hz, 2H), 3.48 (m, 6H),
3.10 (dd, J a ) 8.5 Hz, J b ) 10.8 Hz, 2H), 2.60 (m, 1H), 2.24
(m, 2H), 1.97 (bd, J ) 10.8 Hz, 2H), 1.75 (m, 4H), 1.55 (m,
4H); IR (KBr) 1625 cm-1; MS m/z 356 (M+). Anal. (C20H28N4O2‚
2HCl) C, H, N.
Using a similar procedure, 64-73 were also prepared.
Meth od H. Gen er a l P r oced u r e for Rever sed Am id es
La ck in g a n Alk yl Ch a in . 4-(2-P yr im id in yl)p ip er a zin e-
1-ca r boxylic Acid N-(1-Ad a m a n tyl)ca r boxa m id e (19). A
solution of adamantane 1-isocyanate29 (1.8 g, 10 mmol), 1-(2-
pyrimidinyl)piperazine hydrochloride (2.37 g, 10 mmol), and
triethylamine (2.02 g, 20 mmol) in 50 mL of dry dichlo-
romethane was stirred at room temperature overnight. The
mixture was then washed with three 50-mL portions of water,
dried over anhydrous sodium sulfate, and concentrated on a
rotary evaporator. The desired compound 19 (2.5 g, 74%) was
isolated by crystallization of the residue from hexane (100
1
mL): mp 174-5 °C; H NMR (CDCl3) δ 8.30 (d, J ) 4.7 Hz,
2H), 6.50 (t, J ) 4.7 Hz, 1H), 4.2 (s, 1H), 3.8 (m, 4H), 3.4 (m,
4H), 2.1 (m, 3H), 1.9 (m, 6H), 1.6 (m, 6H); IR (KBr) 1650 cm-1
(CdO); MS m/z 321 (M+). Anal. (C19H27N5O) C, H, N.
Using a similar procedure, 20 and 21 were also prepared.
Meth od I. Gen er a l P r oced u r e for Rever sed Am id es
P ossessin g a n Alk yl Ch a in . 3-[4-(2-P yr im id yl)-1-p ip er -
a zin yl]p r op a n oic Acid 1-Ad a m a n tylca r boxa m id e Dih y-
d r och lor id e Hem ih yd r a te (22). 3-Br om op r op yl 1-Ad a -
m an tylcar boxam ide. To a stirred suspension of 1-adamantan-
amine hydrochloride (12.2 g, 65 mmol) and 3-bromopropionyl
chloride (11.14 g, 65 mmol) in 330 mL of dichloromethane was
added diisopropylethylamine (22.5 mL, 130 mmol) over a
period of 0.5 h at room temperature. The mixture became
homogeneous after all of the amine had been added. The
reaction was stirred for an additional 3 h at room temperature
and then washed with three 200-mL portions of water. The
Using a similar procedure, 50-54 and 56-61 were also
prepared.
Meth od F . 3-Meth yl-1-a d a m a n ta n ea cetic Acid 3-[4-(3-
Ch lor op h en yl)-1-p ip er a zin yl]p r op yl Ester Dih yd r och lo-
r id e (55). To a stirred solution of 3-methyladamantane-1-

Synthesis and SAR of Adatanserin
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5089
organic layer was dried over anhydrous magnesium sulfate
and concentrated on a rotary evaporator to give 12.52 g (76%)
of the desired 3-bromopropyl 1-adamantylcarboxamide, which
was used without further purification: mp 95-102 °C; IR
(KBr) 1669 cm-1 (CdO).
ceased), 250 mL of dry diethyl ether was added. The desired
dihydrochloride salt of (R)-alanine-N-(4-benzyl-1-piperazinyl)-
carboxamide (13.25 g, 83%) precipitated and was isolated by
filtration, washed with diethyl ether, and dried in vacuo: mp
1
199-200 °C; [R]25 ) -3.7° (c ) 1, MeOH); H NMR (DMSO-
D
d6) δ 8.49 (s, 1H), 8.42 (s, 1H), 7.56 (d, J ) 3 Hz, 2H), 7.40 (t,
J ) 3 Hz, 3H), 4.35 (m, 4H), 4.12 (m, 1H), 3.70 (t, J ) 12 Hz,
1H), 3.25 (m, 4H), 3.00 (m, 1H), 1.36 (m, 3H); CIMS 249 (MH+);
IR (KBr) 1668 cm-1 (CdO).
4-[(2-P yr im id in yl)-N-(1-a d a m a n tyl)]-1-p ip er a zin ep r o-
p a n a m id e Tr ih yd r och lor id e (22). To 150 mL of anhydrous
dimethylformamide were added 3-bromopropyl 1-adamantyl-
carboxamide (5.51 g, 19.2 mmol), 1-(2-pyrimidinyl)piperazine
dihydrochloride (4.56 g, 19.2 mmol), and diisopropylethylamine
(10.5 mL, 59 mmol) at room temperature. The mixture was
then stirred at 55 °C for 48 h. The dimethylformamide was
removed on a rotary evaporator and the residue was parti-
tioned between dichloromethane (250 mL) and water (200 mL).
The organic layer was washed with two 100-mL portions of
water and then dried over magnesium sulfate. The solvent was
removed on a rotary evaporator and the desired product 22
was isolated by chromatography on silica gel (EtOAc/MeOH)
and converted to its trihydrochloride salt with ethanolic HCl:
yield ) 0.70 g (5% overall yield); mp 273-75 °C; 1H NMR
(DMSO-d6) δ 8.45 (d, J ) 4.8 Hz, 2H), 7.67 (s, 1H), 6.76 (t,
J ) 4.8 Hz, 1H), 4.65 (m, 2H), 3.44 (m, 4H), 3.25 (m, 2H), 3.01
(m, 2H), 2.64 (t, J ) 7.2 Hz, 2H), 1.99 (m, 3H), 1.91 (m, 6H),
1.59 (m, 6H); IR (KBr) 1635 cm-1 (CdO); MS m/z 369 (M+).
Anal. (C21H31N5O‚3HCl) C, H, N.
(R)-[1-Meth yl-2-(4-ben zyl-1-p ip er a zin yl)eth yl]a m in e. A
solution of (R)-alanine-N-(4-benzyl-1-piperazinyl)carboxamide
dihydrochloride (12.8 g, 40 mmol) in 350 mL of 0.5 M borane/
tetrahydrofuran was refluxed with stirring for 4 h under a
nitrogen atmosphere. The resulting mixture was cooled in an
ice bath and quenched by slow addition of 100 mL of 2 N
aqueous HCl. The resulting mixture was then refluxed with
stirring overnight. The precipitate was removed by filtration.
The filtrate was washed with five 50-mL portions of dichlo-
romethane and then made strongly basic with 50% aqueous
sodium hydroxide solution. The resulting alkaline mixture was
then extracted with three 100-mL portions of dichloromethane.
The combined organic layers were dried over anhydrous
sodium sulfate and concentrated on a rotary evaporator to
yield the desired (R)-[1-methyl-2-(4-benzyl-1-piperazinyl)ethyl-
amine (9.6 g, 87%) as an oil which was used without further
purification: [R]25D ) -33.9° (c ) 1, MeOH); 1H NMR (CDCl3)
δ 7.30 (d, J ) 4.8 Hz, 5H), 3.50 (t, J ) 6 Hz, 2H), 3.05 (m, 1H),
2.87-2.27 (m, 8H), 2.19-2.07 (m, 2H), 1.50 (s, 2H), 1.0 (d,
J ) 6 Hz 3H); IR (film) 3430 cm-1 (NH).
(R)-Ad a m a n t a n e-1-ca r boxylic Acid N-[1-Met h yl-2-(4-
ben zyl-1-p ip er a zin yl)eth yl]ca r boxa m id e Dih yd r och lo-
r id e Sesqu ih yd r a te Hem i-2-p r op a n ola te (29). To an ice-
cooled solution of 1-adamantanecarboxylic acid (14.6 g, 81
mmol) and (R)-[1-methyl-2-(4-benzyl-1-piperazinyl)ethyl]amine
(9.6 g, 41 mmol) in 150 mL of dry dichloromethane was added
with stirring diethyl cyanophosphonate (14.6 g, 81 mmol) over
a period of 30 min. Upon completed addition N-methylmor-
pholine (8.2 g, 81 mmol) was added and the resulting mixture
was stirred overnight during which time it came up to room
temperature. The reaction mixture was then washed with 100
mL of 10% aqueous potassium carbonate solution followed by
100 mL of water. The resulting organic layer was dried over
Using a similar procedure, 23 was also prepared.
Meth od J . Gen er a l P r oced u r e for Ad a m a n tyl a n d
Nor a d a m a n tyl Ur ea s. N-1-Ad a m a n tyl-N′-2-[4-(2-p yr im -
id in yl)-1-p ip er a zin yl]eth ylu r ea Hem ih yd r a te (40). To a
stirred suspension of 1-aminoadamantane hydrochloride (2.5
g, 13 mmol) in dry dichloromethane (50 mL) was added
triethylamine (5.3 g, 52 mmol) under a nitrogen atmosphere.
The resulting mixture was stirred at room temperature for
30 min and then trichloromethyl chloroformate (0.81 mL, 6.5
mmol) was added slowly via syringe. The reaction mixture was
refluxed for 3 h, then
a solution of 4-(2-pyrimidinyl)-1-
piperazineethanamine (2.70 g, 13 mmol) in 30 mL of dry
dichloromethane was added, and the resulting mixture was
stirred at room temperature overnight. The reaction mixture
was diluted to 200 mL with dichloromethane and washed with
three 100-mL portions of 5% aqueous sodium bicarbonate
solution. The organic layer was dried over anhydrous sodium
sulfate and concentrated on a rotary evaporator. The desired
compound 40 (3.55 g, 71%) was isolated by chromatography
on silica gel (methanol/ethyl acetate): mp 170-171 °C; 1H
NMR (CDCl3) δ 8.32 (d, J ) 4.7 Hz, 2H), 6.54 (t, J ) 4.7 Hz,
1H), 5.37 (bs, 1H), 4.55 (bs, 1H), 3.98 (t, J ) 4.6 Hz, 4H) 3.39
(dd, J a ) 11 Hz, J b ) 5.3 Hz, 2H), 2.73 (m, 6H), 2.07 (m, 3H),
1.98 (m, 6H), 1.66 (m, 6H); IR (KBr) 1660, 1590 cm-1 (urea
CdO); MS m/z 384 (M+). Anal. (C21H32N6O‚1/2H2O) C, H, N.
anhydrous sodium sulfate and concentrated on
a rotary
evaporator. The desired compound 29 was isolated by chro-
matography on silica gel using a gradient of ethyl acetate and
hexane and then converted to its dihydrochloride salt (1.54 g,
32%) with HCl/ethyl acetate: mp ) 240-242 °C; [R]25
)
D
1
-12.6° (c ) 1, MeOH); H NMR (DMSO-d6) δ 7.65 (t, J ) 5
Hz, 2H), 7.44 (t, J ) 5 Hz, 3H), 4.33 (s, 2H), 4.00-3.00 (m,
12H), 1.95 (s, 3H), 1.8 (s, 6H), 1.65 (t, J ) 6 Hz, 6H), 1.13 (d,
J ) 7 Hz, 3H), 1.00 (d, J ) 7 Hz, 3H); IR (KBr) 1630 cm-1
(CdO); MS m/z 395 (M+). Anal. (C25H37N3O‚2 HCl‚1 1/2H2O‚
1/2C3H8O) C, H, N.
Using a similar procedure, 41-49 and 74 were also pre-
pared.
Meth od K. Syn th esis of Br a n ch ed Ad a m a n tyl Am id es.
Tota l Syn th esis of (R)-Ad a m a n ta n e-1-ca r boxylic Acid
N-[1-Met h yl-2-(4-b en zyl-1-p ip er a zin yl)et h yl]ca r boxa m -
id e Dih yd r och lor id e Sesqu ih yd r a te Hem i-2-p r op a n ola te
(29). (R)-Ala n in e-N-(4-ben zyl-1-p ip er zin yl)ca r boxa m id e
Dih ydr och lor ide. D-Alanine-N-tert-butoxycarboxamide (BOC-
D-alanine; 9.45 g, 50 mmol) and 1-benzylpiperazine (8.9 g, 50
mmol) were dissolved in 125 mL of dry dichloromethane and
cooled in an ice bath. The stirred mixture was then treated
with a solution of diethyl cyanophosphonate (8.34 g, 55 mmol)
in 50 mL of dry dichloromethane over a period of 45 min. A
solution of triethylamine (7.37 g, 52.5 mmol) in 50 mL of dry
dichloromethane was then added over a period of 1 h. The
resulting reaction mixture was stirred overnight, during which
time it came up to room temperature. The solution was then
washed with 100 mL of 10% aqueous potassium carbonate,
dried over anhydrous sodium sulfate, and concentrated on a
rotary evaporator to yield 19 g of the crude intermediate BOC-
(R)-alanine-N-(4-benzyl-1-piperazinyl)carboxamide. This oil
was dissolved in 50 mL of dichloromethane and treated with
a 4.6 N solution of HCl in ethyl acetate (250 mL). After stirring
at room temperature for 1 h (at which time CO2 evolution
(S)-Ad a m a n ta n e-1-ca r boxylic Acid N-[1-Meth yl-2-(4-
ben zyl-1-pip er a zin yl)eth yl]-1-ca r boxa m id e Dih yd r och lo-
r id e Sesqu ih yd r a te Hem i-2-p r op a n ola te (30). Using a
synthetic sequence identical to that described for the synthesis
of compound 29 and starting with L-alanine-N-tert-butoxycar-
boxamide, compound 30 was prepared as its dihydrochloride
salt in 12% yield: mp 236-38 °C; [R]25 ) +13.8 (c ) 1.02,
D
MeOH); 1H NMR identical to that described for compound 29;
IR (KBr) 1630 cm-1 (CdO); MS m/z 395 (M+). Anal. (C25H37N3O‚
2HCl‚1 1/2H2O‚1/2C3H8O) C, H, N.
(R)-Ad a m a n ta n e-1-ca r boxylic Acid N-[1-Ben zyl-2-(4-
ben zyl-1-p ip er a zin yl)eth yl]ca r boxa m id e Dih yd r och lo-
r id e Dih yd r a te (35). Beginning with D-phenylalanine-N-tert-
butoxycarboxamide, compound 35 was prepared using a
synthetic sequence identical to that described for the synthesis
of 29 from D-BOC-alanine. It was isolated as its dihydrochlo-
ride dihydrate salt in 9% overall yield: mp 261-263 °C;
1
[R]25 ) -12.5 (c ) 1, MeOH); H NMR (DMSO-d6) δ 7.65 (t,
D
J ) 3.5 Hz, 1H), 7.43 (m, 4H), 7.30-7.10 (m, 5H), 4.46 (m,
2H). 4.00-3.15 (m, 12H), 2.93 (d, J ) 2 Hz, 1H), 2.88 (t, J )
4.5 Hz, 1H), 1.97 (m, 3H), 1.80-1.50 (m, 12H); IR (KBr) 1640

5090 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Abou-Gharbia et al.
cm-1 (CdO); CIMS m/z 472 (MH+). Anal. (C31H41N3O‚2HCl‚
(m, 14H), 1.95 (s, 3H), 1.85-1.78 (m, 6H), 1.75-1.60 (m, 6H);
IR (KBr) 1630 cm-1 (CdO); CIMS m/z 502 (MH+). Anal.
(C32H43N3O2‚2HCl‚2H2O) C, H, N.
2H2O) C, H, N.
(S)-Ad a m a n ta n e-1-ca r boxylic Acid N-[1-Ben zyl-2-(4-
ben zyl-1-p ip er a zin yl)eth yl]ca r boxa m id e Dih yd r och lo-
r id e Dih yd r a te (36). Beginning with L-phenylalanine-N-tert-
butoxycarboxamide, 36 was prepared using a synthetic sequence
identical to that described for the synthesis of 29 from D-BOC-
alanine. It was isolated as its dihydrochloride dihydrate salt
Ad a m a n ta n e-1-ca r boxylic Acid N-[(1,1-Dim eth yl-2-(4-
ben zyl-1-p ip er a zin yl)eth yl]ca r boxa m id e Dih yd r och lo-
r id e Hem ih yd r a te (28). Using a synthetic sequence similar
to that described for the preparation of compound 29, com-
pound 28 was prepared from 2-methylalanine-N-benzylcar-
bamate (Cbz) and 1-benzylpiperazine in 12% overall yield, with
the exception that removal of the Cbz group was accomplished
using the following procedure. N-Cbz-2-methylalanine(4-ben-
zyl-1-piperazinyl)carboxamide was stirred in a mixture of 30%
aqueous HBr in acetic acid for 1 h at room temperature. Ether
was added to the reaction mixture and the resulting dihydro-
bromide salt of the product was isolated by vacuum filtration.
The desired 2-methylalanine(4-benzyl-1-piperazinyl)carbox-
amide was isolated by partitioning the hydrobromide salt
between dichloromethane and aqueous NaOH. This intermedi-
ate was then converted to the desired compound 28, which
was isolated as its dihydrochloride hemihydrate salt: mp 256-
in 5% overall yield: mp 263-266 °C; [R]25 ) +11.3 (c ) 1.03,
D
MeOH); 1H NMR identical to that described for compound 35;
IR (KBr) 1635 cm-1 (CdO); CIMS m/z 472 (MH+). Anal.
(C31H41N3O‚2HCl‚2H2O) C, H, N.
(R)-Ad a m a n t a n e-1-ca r boxylic Acid N-[1-Met h yl-2-[4-
(2-p yr im id in yl)-1-p ip er a zin yl]et h yl]ca r b oxa m id e (25).
Compound 29 (6.9 g, 13.3 mmol) was hydrogenated over 10%
Pd/C (1 g) in 200 mL of ethanol on a Parr shaker at a pressure
of 36 psi overnight (until H2 was no longer taken up). The
catalyst was removed by filtration through Celite and the
mixture concentrated on a rotary evaporator to yield the crude
(R)-adamantane-1-carboxylic acid N-[1-methyl-2-(1-piperazin-
yl)ethyl]carboxamide (3.5 g) as an oil. This oil was dissolved
in 50 mL of dry dimethylformamide. To the stirred solution
was added 2-chloropyrimidine (1.05 g, 9.2 mmol), anhydrous
potassium carbonate (12.4 g, 90 mmol), and triethylamine (1
mL), and the resulting mixture was heated at 70 °C overnight.
The DMF was removed on a rotary evaporator and the residue
was triturated with water. The resulting precipitate was
washed with water, air-dried, and recrystallized from 50%
aqueous methanol to yield the desired compound 25 (3.05 g,
1
58 °C; H NMR (DMSO-d6) δ 7.50 (m, 5H), 6.43 (s, 1H), 3.55
(s, 2H), 2.85 (s, 2H), 2.61 (m, 4H), 2.40 (m, 4H), 2.05 (s, 3H),
1.86 (s, 6H), 1.79-1.65 (m, 6H), 1.33 (s, 6H); IR (KBr) 1635
cm-1; MS m/z 409 (M+). Anal. (C26H39N3O‚2HCl‚1/2H2O) C, H,
N.
Ad a m a n ta n e-1-ca r boxylic Acid N-[1,1-Dim eth yl-2-[4-
(2-p yr im id in yl)-1-p ip er a zin yl]et h yl]ca r boxa m id e (24).
Compound 24 was prepared from compound 28 in 39% yield
using a procedure identical to that for the synthesis of com-
pound 25. The desired product was purified by recrystallization
42%): mp 168-9 °C; [R]25 ) -26.4° (c ) 1, MeOH); 1H NMR
D
1
(CDCl3) δ 8.30 (d, J ) 4.5 Hz, 2H), 6.55 (t, J ) 4.5 Hz, 1H),
6.05 (s, 1H), 4.00 (t, J ) 4.5 Hz, 1H), 3.86 (t, J ) 11 Hz, 4H),
2.60-2.30 (m, 6H), 2.05 (s, 3H), 1.93 (m, 6H), 1.75 (m, 6H),
1.27 (d, J ) 3 Hz, 3H); IR (KBr) 1660 cm-1 (CdO); MS m/z
383 (M+). Anal. (C22H33N5O) C, H, N.
from methanol: mp 153-55 °C; H NMR (CDCl3) δ 8.30 (d,
J ) 5.4 Hz, 2H), 6.5 (t, J ) 5.4 Hz, 1H), 6.2 (s, 1H), 2.90 (s,
2H), 2.70 (m, 4H), 2.45 (m, 4H), 2.05 (s, 3H), 2.85 (s, 6H), 2.70
(s, 6H), 1.45 (s, 6H); IR (KBr) 1640 cm-1; MS m/z 397 (M+).
Anal. (C23H35N5O) C, H, N.
(S)-Ad a m a n ta n e-1-ca r boxylic Acid N-[1-Meth yl-2-[4-(2-
pyr im idin yl)-1-p iper a zin yl]eth yl]ca r boxa m id e (26). Com-
pound 26 was prepared from compound 30 in 66% yield using
a procedure identical to that described for the synthesis of
(R)-Ad a m a n t a n e-1-ca r boxylic Acid N-[1-Met h yl-2-[4-
(2-m eth oxyp h en yl)-1-p ip er a zin yl]eth yl]ca r boxa m id e Di-
h yd r och lor id e (27). Compound 27 was prepared from D-ala-
nine-N-tert-butoxycarboxamide and 1-(2-methoxyphenyl)pip-
erazine using a synthetic sequence identical to that described
for the synthesis of compound 29. It was isolated in 30% overall
compound 25: mp 162-164 °C; [R]25 ) +28.6 (c ) 1.04,
D
MeOH); 1H NMR identical to that described for compound 25;
IR (KBr) 1660 cm-1 (CdO); MS m/z 383 (M+). Anal. (C22H33N5O)
C, H, N.
yield as its dihydrochloride salt: mp 195-198 °C; [R]25
)
D
-20.6 (c ) 1.04, MeOH); 1H NMR (DMSO-d6) δ 7.63 (d, J ) 8
Hz, 1H), 7.04-6.90 (m, 3H), 6.35 (m, 1H), 4.34 (s, 1H), 3.75
(s, 3H), 3.50-3.00 (m, 10H), 1.95 (s, 3H), 1.85 (m, 6H), 1.66
(m, 6H), 1.12 (m, 3H); IR (KBr) 1645 cm-1 (CdO); MS m/z 411
(M+). Anal. (C25H37N3O2‚2HCl) C, H, N.
(R)-Ad a m a n ta n e-1-ca r boxylic Acid N-[1-Ben zyl-2-[4-(2-
p yr im id in yl)-1-p ip er a zin yl]eth yl]ca r boxa m id e Hem ih y-
d r a te (33). Using a procedure identical to that described for
the synthesis of 29, compound 33 was synthesized from 35
and 2-chloropyrimidine in 12% yield as a hemihydrate. It was
(R)-Ad a m a n t a n e-1-ca r boxylic Acid N-[1-Met h yl-2-[4-
(2,3-d im et h ylp h en yl)-1-p ip er a zin yl]et h yl]ca r b oxa m id e
Dih yd r och lor id e Hyd r a te (31). Compound 31 was prepared
from D-alanine-N-tert-butoxycarboxamide and 1-(2,3-dimeth-
ylphenyl)piperazine using a synthetic sequence identical to
that described for the synthesis of compound 29. It was isolated
purified by recrystallization from boiling hexane: mp 172-
1
175 °C; [R]25 ) -9.7 (c ) 1.07, MeOH); H NMR (DMSO-d6)
D
δ 8.30 (d, J ) 4.5 Hz, 2H), 7.20-7.00 (m, 4H), 6.93 (d, J ) 8
Hz, 1H), 6.55 (t, J ) 4.5 Hz, 1H), 4.15 (m, 1H), 3.60 (t, J ) 4
Hz, 3H), 3.35 (m, 3H), 2.78 (, 1H), 2.65 (, 1H), 2.55 (m, 3H),
2.33 (d, J ) 7 Hz, 2H), 1.87 (m, 3H), 1.65-1.50 (m, 12H); IR
in 71% yield as its dihydrochloride monohydrate salt: mp 229-
(KBr) 1635 cm-1 (CdO); CIMS m/z 460 (MH+). Anal. (C28H37
N5O‚1/2H2O) C, H, N.
-
30 °C; [R]25 ) -21.8 (c ) 1, MeOH); H NMR (DMSO-d6) δ
1
D
7.65 (d, J ) 9 Hz, 1H), 7.08 (t, J ) 8 Hz, 1H), 6.95 (t, J ) 9
Hz, 1H), 6.51 (m, 1H), 4.30 (m, 1H), 3.55 (m, 2H), 3.40-3.00
(m, 8H), 2.22 (s, 3H), 2.19 (s, 3H), 1.95 (s, 3H), 1.85 (s, 6H),
1.72 (s, 6H), 1.15 (s, 3H); IR (KBr) 1635 cm-1 (CdO); MS m/z
409 (M+). Anal. (C26H39N3O‚2HCl‚H2O) C, H, N.
(S)-Ad a m a n ta n e-1-ca r boxylic Acid N-[1-Ben zyl-2-[4-(2-
p yr im id in yl)-1-p ip er a zin yl]eth yl]ca r boxa m id e (34). Us-
ing a procedure identical to that described for the synthesis
of 29, compound 34 was synthesized from 36 and 2-chloro-
pyrimidine in 78% yield. It was purified by recrystallization
from boiling hexane: mp 172-175 °C; [R]25D ) +7.2 (c ) 1.03,
MeOH); 1H NMR identical to that described for compound 33;
IR (KBr) 1635 cm-1 (CdO); CIMS m/z 460 (MH+). Anal.
(C28H37N5O) C, H, N.
(R)-Ad a m a n ta n e-1-ca r boxylic Acid N-[1-Ben zyloxy-
m eth yl-2-(4-ben zyl-1-p ip er a zin yl)eth yl]ca r boxa m id e Di-
h yd r och lor id e Dih yd r a te (37). Using a synthetic sequence
identical to that described for the preparation of compound
29, compound 37 was prepared from d-O-benzylserine-N-tert-
butoxycarboxamide and 1-benzylpiperazine in 5% overall yield.
(S)-Ad a m a n ta n e-1-ca r boxylic Acid N-[1-Meth yl-2-[4-
(2,3-d im et h ylp h en yl)-1-p ip er a zin yl]et h yl]ca r b oxa m id e
Dih yd r och lor id e Sesqu ih yd r a te (32). Compound 32 was
prepared from L-alanine-N-tert-butoxycarboxamide and 1-(2,3-
dimethylphenyl)piperazine using a synthetic sequence identi-
cal to that described for the synthesis of compound 29. It was
isolated in 34% yield as its dihydrochloride sesquihydrate
1
salt: mp 226-28 °C; [R]25 ) +20.6 (c ) 1, MeOH); H NMR
D
identical to that described for compund 31; IR (KBr) 1635 cm-1
(CdO); MS m/z 409 (M+). Anal. (C26H39N3O‚2HCl‚1 1/2H2O)
C, H, N.
It was isolated as its dihydrochloride dihydrate salt: mp 140-
Met h od L. Syn t h esis of N-Su b st it u t ed Ad a m a n -
t yl Am id es. Tot a l Syn t h esis of Ad a m a n t a n e-1-ca r b ox-
ylic Acid N-[2-[4-(2-P yr im id in yl)-1-p ip er a zin yl]eth yl]-N-
1
42 °C; [R]25 ) +19.0 (c ) 0.98, MeOH); H NMR (DMSO-d6)
D
δ 7.45 (m, 5H), 7.30 (m, 5H), 4.55-4.30 (m, 4H), 4.20-3.05

Synthesis and SAR of Adatanserin
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5091
m eth ylca r boxa m id e Dih yd r och lor id e Hem ih yd r a te (38).
2-(4-Ben zyl-1-p ip er a zin yl)-N-m eth yla ceta m id e. To a solu-
tion of 1-benzylpiperazine (26.5 g, 150 mmol) in 800 mL of dry
dimethylformamide at room temperature was added a solution
of N-methylchloroacetamide54 (16.1 g, 150 mmol) in 400 mL
of dry tetrahydrofuran. The resulting solution was stirred at
70 °C for 48 h. The reaction mixture was then concentrated
carbonate (2.20 g, 20.8 mmol) and cesium carbonate (1.07 g,
3.28 mmol). The heterogeneous mixture was stirred at 65 °C
overnight. The DMF was then removed on a rotary evaporator
and the residue partitioned between 250 mL of dichloro-
methane and 200 mL of water. The organic layer was dried
over anhydrous sodium sulfate and concentrated on a rotary
evaporator. The desired adamantane-1-carboxylic acid N-[2-
[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]-N-methylcarboxam-
ide (38) was isolated by HPLC on silica gel using a gradient
of methanol and ethyl acetate. A 3.0-g portion of the free base
was converted to the dihydrochloride hemihydrate salt with
ethanolic HCl (1.45 g, 40%): mp 214-23 °C; 1H NMR (DMSO-
d6) δ 8.44 (d, J ) 5.6 Hz, 2H), 6.76 (t, J ) 5.6 Hz, 1H), 3.73
(m, 2H), 3.66 (m, 2H), 3.55 (m, 2H), 3.41 (t, J ) 12.5 Hz, 2H),
3.13 (s, 3H), 3.24-3.00 (m, 4H), 1.97 (m, 3H), 1.90 (m, 6H),
1.60-1.75 (m, 6H); IR (KBr) 1615 cm-1 (CdO); MS m/z 383
(M+). Anal. (C22H33N5O‚2HCl‚1/2H2O) C, H, N.
on
a rotary evaporator and the residue was partitioned
between 400 mL of dichloromethane and 200 mL of 1 M
aqueous sodium hydroxide. The organic layer was washed with
200 mL of brine, dried over anhydrous magnesium sulfate, and
concentrated on a rotary evaporator. The desired 2-(4-benzyl-
1-piperazinyl)-N-methylacetamide (28.5 g, 68%) was isolated
by HPLC on silica gel using a gradient of methanol and ethyl
acetate: 1H NMR (CDCl3) δ 7.30 (m, 5H), 7.15 (bs, 1H), 3.53
(s, 2H), 3.00 (s, 2H), 2.86 (s, 3H), 2.83 (s, 3H), 2.68-2.36 (m,
8H).
2-(4-Ben zyl-1-piper azin yl)eth ylm eth ylam in e. To a warm
solution of 2-(4-benzyl-1-piperazinyl)-N-methylacetamide (10.94
g, 44.2 mmol) in 450 mL of dry tetrahydrofuran under a
nitrogen atmosphere was added portionwise, with stirring,
lithium aluminum hydride (7.70 g, 20.3 mmol). The resulting
mixture was then refluxed under nitrogen overnight. The
excess LAH was quenched by slow addition of water (7.7 mL)
followed by 15% aqueous sodium hydroxide (7.5 mL). Another
portion of water was added (23 mL) and the resulting
precipitate was removed by filtration. The precipitate was
washed with 500 mL of tetrahydrofuran followed by 300 mL
of dichloromethane. The washings were added to the original
filtrate and the combined organic layers were dried over
Meth od M. Tota l Syn th esis of Ad a m a n ta n e-1-ca r box-
ylic Acid N-[2-[4-(2-P yr im id in yl)-1-p ip er a zin yl]eth yl]-N-
isop r op ylca r boxa m id e Dih yd r och lor id e Sesqu ih yd r a te
(39). N-Isop r op yl-4-(2-p yr im id in yl)-1-p ip er a zin eeth a n -
a m in e. To a solution of 4-(2-pyrimidinyl)-1-piperazineethan-
amine (2.46 g, 11.9 mmol) in 45 mL of methanol at room
temperature were added in rapid succession acetone (0.71 g,
12 mmol) and zinc chloride/sodium cyanoborohydride complex
(24 mL of a 0.5 M solution, 12 mmol). After 1 h, additional
ZnCl2‚NaBH3CN (2 mL of a 0.5 M solution, 1 mmol) was added
and stirring was continued overnight. 1 M aqueous sodium
hydroxide (15 mL) was then added and the reaction mixture
was concentrated on a rotary evaporator. The resulting residue
was partitioned between 250 mL of dichloromethane and 200
mL of brine. The aqueous layer was reextracted with 100 mL
of dichloromethane and the combined organic layers were dried
over anhydrous sodium sulfate and then concentrated on a
rotary evaporator. The desired N-isopropyl-4-(2-pyrimidinyl)-
1-piperazineethanamine (1.28 g, 43%) was isolated by HPLC
on silica gel using a gradient of methanol and ammonia: 1H
NMR (CDCl3) δ 8.31 (d, J ) 5.2 Hz, 2H), 6.47 (t, J ) 5.2 Hz,
1H), 3.83 (m, 4H), 2.78 (m, 3H), 2.44-2.60 (m, 6H), 1.75 (s,
1H), 1.10 (d, J ) 6.5 Hz, 6H).
anhydrous sodium sulfate and concentrated on
a rotary
evaporator. The desired 2-(4-benzyl-1-piperazinyl)ethylmethyl-
amine (8.50 g, 82%) was isolated by HPLC on silica gel using
a gradient of methanol, ethyl acetate, and ammonia: 1H NMR
(CDCl3) δ 7.30 (m, 5H), 3.52 (s, 2H), 2.67 (t, J ) 6 Hz, 2H),
2.48 (m, 10H), 2.45 (s, 3H), 1.82 (bs, 1H).
Ad a m a n ta n e-1-ca r boxylic Acid N-[2-(4-Ben zyl-1-p ip -
er a zin yl)eth yl]-N-m eth ylca r boxa m id e. A solution of ada-
mantane-1-carboxylic acid chloride (7.23 g, 36.4 mmol) and (2-
[4-benzyl-1-piperazinyl]ethyl)methylamine (8.49 g, 36.4 mmol)
in 200 mL of dry dichloromethane was stirred for 1 h. Then
triethylamine (4.9 g, 49 mmol) in 80 mL of dry dichlo-
romethane was added and the resulting mixture was stirred
at room temperature overnight. The reaction mixture was
washed with 200 mL of brine. The aqueous layer was extracted
with 100 mL of dichloromethane and the combined organic
layers were dried over anhydrous sodium sulfate. Concentra-
tion on a rotary evaporator afforded the desired adamantane-
1-carboxylic acid 2-(4-benzyl-1-piperazinyl)ethyl-N-methylcar-
boxamide (13.58 g, 94%), which was used in the next reaction
without further purification: 1H NMR (CDCl3) δ 7.36 (m, 5H),
3.55 (t, J ) 6.5 Hz 2H), 3.16 (s, 3H), 2.64-2.38 (m, 12H), 2.08
(m, 9H), 1.76 (m, 6H).
Ad a m a n t a n e-1-ca r boxylic Acid N-[2-(1-P ip er a zin yl)-
eth yl]-N-m eth ylca r boxa m id e. A solution of adamantane-
1-carboxylic acid N-[2-(4-benzyl-1-piperazinyl)ethyl]-N-meth-
ylcarboxamide (13.58 g, 34.3 mmol) in 450 mL of ethanol was
subjected to hydrogenation on a Parr shaker at 50 psi over
5% Rh/Al2O3 (8.55 g) at room temperature for 72 h. The
catalyst was removed by filtration through Celite 545 and the
solvent was removed on a rotary evaporator. The desired
adamantane-1-carboxylic acid 2-(1-piperazinyl)ethyl-N-meth-
ylcarboxamide (6.84 g, 65%) was isolated by chromatography
on silica gel using dichloromethane/methanol. A significant
amount of starting material (4.40 g) was also recovered: 1H
NMR (CDCl3) δ 3.52 (t, J ) 7 Hz, 2H), 3.16 (s, 3H), 2.93 (m,
4H), 2.52 (m, 7H), 2.04 (m, 9H), 1.74 (m, 6H).
Ad a m a n ta n e-1-ca r boxylic Acid N-[2-[4-(2-P yr im id in -
yl)-1-p ip er a zin yl]eth yl]-N-isop r op ylca r boxa m id e Dih y-
d r och lor id e Sesqu ih yd r a te (39). To a solution of adaman-
tane-1-carboxylic acid chloride (1.09 g, 5.5 mmol) and triethyl-
amine (1.5 g, 1.4 mmol) in 30 mL of dry dichloromethane was
added a solution of N-isopropyl-4-(2-pyrimidinyl)-1-pipera-
zineethanamine (1.27 g, 5.5 mmol) in 15 mL of dry dichlo-
romethane. The resulting reaction mixture was stirred at room
temperature overnight. The mixture was then washed with
30 mL of water and the aqueous layer reextracted with 30 mL
of dichloromethane. The combined organic layers were dried
over anhydrous sodium sulfate and concentrated on a rotary
evaporator. The desired adamantane-1-carboxylic acid N-[2-
[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]-N-isopropylamide was
isolated by HPLC on silica gel using a gradient of methanol
and ethyl acetate and converted to its dihydrochloride ses-
quihydrate salt with ethanolic HCl (1.87 g, 71%): mp 194-
1
210 °C; H NMR (DMSO-d6) δ 8.45 (d, J ) 5.4 Hz, 2H), 6.77
(t, J ) 5.4 Hz, 1H), 4.64 (m, 2H), 4.54 (m, 1H), 3.64-3.51 (m,
4H), 3.43 (t, J ) 11 Hz, 2H), 3.14-3.01 (m, 4H), 1.98 (m, 3H),
1.88 (m, 6H), 1.67 (m, 6H), 1.19 (d, J ) 7.5 Hz, 6H); IR (KBr)
1625 cm-1 (CdO); MS m/z 411 (M+). Anal. (C24H37N5O‚2HCl‚
3/4H2O) C, H, N.
Molecu la r Mod elin g Ca lcu la tion s. All computations
were performed on a Silicon Graphics Indigo2 workstation.
Molecules were built de novo and minimized using the MM3*
force field as implemented in Macromodel 6.0.55 Calculations
were performed on the unprotonated form of the piperazine.
Dihedral angles τ1 (Figure 3, τ1 ) C1-C2-N3-C4) and τ2
(Figure 4, τ2 ) N1-C2-N3-C4) were defined and rotated in
1° increments from 0° to 360° using MM3*. The dihedral
angles were then held constant, and the molecules were
minimized. Relative energies in kcal/mol were plotted against
Ad a m a n ta n e-1-ca r boxylic Acid N-[2-[4-(2-P yr im id in -
yl)-1-p ip er a zin yl]et h yl]-N-m et h ylca r b oxa m id e Hyd r o-
ch lor id e Hem ih yd r a te (38). To a stirred solution of ada-
mantane-1-carboxylic acid N-[2-(1-piperazinyl)ethyl]-N-meth-
ylcarboxamide (6.84 g, 22.4 mmol) and 2-chloropyrimidine
(3.65 g, 31.9 mmol) in 200 mL of dry dimethylformamide under
a nitrogen atmosphere were added solid anhydrous sodium

5092 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Abou-Gharbia et al.
the dihedral angle. The conformations depicted in Figures 3
and 4 refer to the global minimum energy structures.
of either quipazine (2.5 mg/kg) or (()-1-(2,5-dimethoxy-4-
iodophenyl)-2-aminopropane hydrochloride (DOI) (1.0 mg/kg).
The volume of all injections was 1 mL/kg. Head shakes were
counted for 30 min after injection of the 5-HT2 agonist. The
head shake response was defined as a rhythmic shaking of
the head in a radial motion. The total number of head shakes
was recorded for each rat. ED50 values were determined using
nonlinear regression analysis with inverse prediction.
Geller -Seifter Con flict Mod el. The experimental method
used for the Geller-Seifter conflict studies has been published
elsewhere.2 The procedure is a variation on the original method
described by Geller and Seifter.62
P h a r m a cology. Bin d in g Assa ys. All radioligand binding
assays were performed using membranes from male Sprague-
Dawley rats weighing 150-250 g. Rats were killed by decapi-
tation, and the respective brain regions were dissected and
prepared as described below prior to storage at -70 °C.
Aliquots were taken for protein determination by the Lowry
method.56 All radioligand receptor binding assays were ter-
minated by addition of cold Tris buffer and rapid filtration
through Whatman GF/B glass-fiber filters. The filters were
then washed three times with buffer, dried, and placed in
scintillation vials for counting.
Ack n ow led gm en t. The authors gratefully acknowl-
edge and thank the members of the Wyeth-Ayerst
Analytical Chemistry Department (past and present) as
well as Adam Bartolomeo, Dan Carcanague, Elaine
Hernadi, Diane Kowal, Xiaojie Shi, and Sheryl White
for their contributions to the preparation and the
chemical and biological characterization of the com-
pounds described in this manuscript.
5-HT1A R ecep t or . The receptor binding studies were
performed using a modification of a previously described
procedure.57 Hippocampal tissue was homogenized on ice in
40 volumes of buffer (50 mM Tris HCl, pH ) 7.7) and
centrifuged at 20 000 rpm for 20 min. The membrane pellet
was resuspended in 40 volumes of buffer at 37 °C and
incubated for 10 min to remove endogenous serotonin. The
homogenate was then centrifuged as above, and the pellet was
resuspended in 100 volumes of a second buffer (50 mM Tris
HCl, pH ) 7.4, containing 0.1% ascorbate, 10 µM pargyline,
and 4 mM CaCl2) and sonicated. Fractions of the homogenate
(0.4-0.6 mg of protein/sample) were incubated at 37 °C for 10
min with 100 µL (1.5-1.8 nM) of [3H]8-OH-DPAT and various
concentrations of the test drug in a final volume of 1 mL of
buffer (50 nM Tris HCl, pH ) 7.7, containing 0.1% ascorbate,
10 µM pargyline, and 4 mM CaCl2). Specific binding was
determined with 1 µM 5-HT.
5-HT2 Recep tor . The receptor binding studies were per-
formed by NovaScreen using a modification of previously
described procedures.58,59 Fractions containing rat cortical
membranes were incubated at 37 °C for 15 min in 50 mM Tris
buffer (pH 7.6) with 1.0 nM [3H]ketanserin and various
concentrations of the test drug. Specific binding was deter-
mined using 100 µM methysergide.
Su p p or tin g In for m a tion Ava ila ble: References for the
hydroxy- and aminoalkyl arylpiperazines used in this manu-
script. This material is available free of charge via the Internet
at http://pubs.acs.org.
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