N-[1-(2-Phenylethyl)pyrrolidin-3-yl]-1-adamantanecarboxamides as Novel 5-HT2 Receptor Antagonists

Article abstract of DOI:10.1016/S0960-894X(00)00492-3

A series of 1-adamantanecarboxamides was synthesized and examined for their potency as a selective 5-HT₂ receptor antagonist. We found (S)-N-{1-[2-(4-fluorophenyl)ethyl]pyrrolidin-3-yl}-1-adamantanecarboxamide hydrochloride hydrate (10-(S), Y-3

Full text of DOI:10.1016/S0960-894X(00)00492-3

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2457±2461
N-[1-(2-Phenylethyl)pyrrolidin-3-yl]-1-adamantanecarboxamides
as Novel 5-HT2 Receptor Antagonists
Masakazu Fujio,a,* Takanobu Kuroita,b Yoko Sakai,c Haruto Nakagawac
and Yasuhiro Matsumotob
aExploratory Research I, Drug Discovery Laboratories, Wel®de Corporation, 7-25 Koyata 3-chome, Iruma,
Saitama, 358-0026, Japan
bExploratory Research II, Drug Discovery Laboratories, Wel®de Corporation, 25-1 Shodai-Ohtani 2-chome, Hirakata,
Osaka, 573-1153, Japan
cDepartment of Pharmacology, Drug Development Laboratories, Wel®de Corporation, 955 Koiwai Yoshitomi-cho, Chikujo-gun,
Fukuoka 871-8550, Japan
Received 3 July 2000; accepted 19 August 2000
AbstractÐA series of 1-adamantanecarboxamides was synthesized and examined for their potency as a selective 5-HT2 receptor
antagonist. We found (S)-N-{1-[2-(4-¯uorophenyl)ethyl]pyrrolidin-3-yl}-1-adamantanecarboxamide hydrochloride hydrate (10-(S),
Y-39241) to have a high anity and selectivity for 5-HT2 receptors, and this potent anti-platelet e€ect of Y-39241 was con®rmed
both in vitro and in vivo. # 2000 Elsevier Science Ltd. All rights reserved.
Serotonin (5-HT) not only induces potent vasoconstric-
tion and platelet aggregation, but also synergistically
ampli®es the e€ects of such vasoactive and/or platelet
aggregative substances such as TXA2, norepinephrine,
angiotensin II, ADP, and collagen.1 4 Since these activ-
ities have been demonstrated to be mediated through
5-HT2 receptors in platelets and vascular tissue,5 7 per-
ipheral 5-HT2 receptor antagonists are thus expected to
be useful in the treatment of cardiovascular diseases.
Ketanserin, which has high anity both for 5-HT2 and
a1 receptors, inhibits collagen-induced platelet aggrega-
tion.1,7 Sarpogrelate shows a more selective anity for
5-HT2 receptors than ketanserin, and is now clinically
available for the treatment of peripheral arterial occlu-
sive disease.8,9 However, its anti-platelet activity is still
not completely satisfactory, because its anity for
5-HT2 receptor is low. Therefore, a more potent and
ecacious 5-HT2 receptor antagonist is thus desired
(Fig. 1).
We previously reported that (S) - N - {[1 - (2 - phenyl-
ethyl)pyrrolidin - 2 - yl]methyl}cyclohexanecarboxamide
(1-(S)) had a high anity and selectivity for 5-HT1A
receptors.10 In the course of a further structure±activity
relationship study of cyclohexanecarboxamide deriva-
tives, we found that the replacement of the (S)-(pyrroli-
din-2-yl)methyl moiety of 1-(S) to the (S)-pyrrolidin-3-yl
moiety provides 5-HT2 receptor selective 2-(S), despite
Figure 1. Known 5-HT2 receptor antagonists.
*Corresponding author. Tel.: +81-42-963-3121; fax: +81-42-964-1906; e-mail: fujio@wel®de.co.jp
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00492-3

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M. Fujio et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2457±2461
the moderate 5-HT2 receptor anity (Fig. 2). This result
has prompted us to further investigate the structure±
activity relationship study of a series of these derivatives.
In this communication, we describe the in¯uence of the
bulky acyl substituent of carboxamides and the sub-
stituent on benzene ring at the 1-position of the pyrroli-
dine ring to the anity for 5-HT2 receptors, and the
discovery of (S)-N-{1-[2-(4-¯uorophenyl)ethyl]pyrrolidin-
3-yl}-1-adamantanecarboxamide hydrochloride hydrate
(10-(S), Y-39241) as a novel and potent 5-HT2 receptor
antagonist.
treated with 1-adamantanecarbonyl chloride 16c to give
the amide 5. N-Benzyl of amide 5 was removed by
hydrogenolysis with 10% Pd±C and hydrazine mono-
hydrate to give the amine 18. Subsequent N-alkylation
of 18 with variety of tosylates 19a±i in the presence of
K2CO3 a€orded target compounds 6±14.
Biological Assays
The anities for the serotonergic 5-HT2 and 5-HT1A
receptors were measured by the ability of the
compounds to displace [3H]ketanserin and [3H]8-OH-
DPAT from the 5-HT2 and 5-HT1A receptors isolated
from the striata of male Wistar rats, respectively. The
anity for adrenargic a1 and dopamine D2 receptor
binding was determined by a displacement of [3H]pra-
zosin and [3H]spiperone, respectively.12 The anti-platelet
activity was determind by the inhibition of 5-HT plus
collagen-induced platelet aggregation of rabbit platelet-
rich plasma in vitro. The anity of compounds 2-(S),
(R)±4-(S), (R), along with 1-(S), (R),10 and compounds
Chemistry
Compounds (2-(S), (R)±4-(S), (R)) were prepared by the
coupling of enantiomers of 3-amino-1-(2-phenylethyl)
pyrrolidine 1511 with the acid chlorides of corresponding
carboxylic acids 16a±c, as shown in Scheme 1. The com-
pounds (6±14) were prepared from commercially avail-
able (S)- and (R)-3-amino-1-benzylpyrrolidine 17 by
three steps, as shown in Scheme 2. Compound 17 was
Figure 2. Conversion of (pyrrolidin-2-yl)methyl moiety to pyrrolidin-3-yl moiety.
Scheme 1.
Scheme 2. 19a: n=3, R2 ˆ H; 19b: n=4, R2 ˆ H; 19c: n=2, R2=2-F; 19d: n=2, R2=3-F; 19e: n=2, R2=4-F; 19f: n=2, R2=4-Cl; 19g: n=2, R2
=4-OCH3; 19h: n=2, R2=4-CF3; 19i: n=2, R2=4-CN.

M. Fujio et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2457±2461
2459
6±14 for 5-HT2, 5-HT1A and adrenergic a1 receptors,
and inhibitory activities on platelet aggregation in vitro
are shown in Tables 1 and 2.
benzene ring had a substantial e€ect on the 5-HT2 a-
nity. Compared with 4-(S), the one carbon chain ana-
logue 5 and the four carbon chain analogue 7 both have
a considerably reduced 5-HT2 binding anity (Ki=240
nmol/L and 12 nmol/L, respectively). The three carbon
chain analogue 6 preserved 5-HT2 anity (Ki=0.32
nmol/L), despite a complete loss of selectivity versus 5-
HT1A receptor binding (Ki=0.19 nmol/L). The position
of the substituents on the benzene ring has some e€ect
on 5-HT2 anity. The compound bearing a ¯uorine
atom on the 4-position of the benzene ring (10-(S)13)
has a higher anity for 5-HT2 receptors than 2-sub-
stituted analogue 8 and 3-substituted analogue 9. Com-
pounds 4-(S), 8 and 10-(S), which have a potent 5-HT2
binding anity (Ki=0.24 nmol/L, 0.14 nmol/L, and
0.09 nmol/L respectively) also possess a potent anti-
platelet activity (IC50=3.0 nmol/L, 3.8 nmol/L and 1.9
nmol/L, respectively). 4-Chloro-analogue 11 has a
slightly reduced 5-HT2 anity (Ki=0.44 nmol/L). Not
only compound 12, which has an electron donating
methoxy group on the 4-position of the benzene ring,
decreased the 5-HT2 anity, but also compounds 13
and 14, which have an electron withdrawing tri-
¯uoromethyl group and cyano group on the 4-position
of the benzene ring, respectively, decreased the 5-HT2
Results and Discussion
A replacement of the (S)-(pyrrolidin-2-yl)methyl moiety
of 1-(S) to the (S)-pyrrolidin-3-yl moiety inverts the
selectivity for 5-HT2 over 5-HT1A. A replacement of the
cyclohexyl ring of compound 2-(S) to the benzene ring
(3-(S)) reduced the anity for 5-HT2 receptors, how-
ever, the compound 4-(S) bearing a more bulky ada-
mantan-1-yl group signi®cantly increased the 5-HT2
anity and the anti-platelet activity without 5-HT1A
binding markedly increased. Opposite enantiomers (1-
(R)±4-(R)) were similarly examined, thus resulting in an
inverse selectivity (5-HT1A>5-HT2). As a result, the
bulky acyl substituent appears to be necessary in order
to increase the anity for 5-HT2 receptors.
We next investigated the e€ects of various arylalkyl
groups, while focusing on the chain length of the alkyl
chain and substituents on the benzene ring. The length
of the alkyl chain between the pyrrolidine ring and
Table 1. Anities of substituted carboxamides for 5-HT2, 5-HT1A and a1 receptors
Binding anity
Ki (nmol/L)
Anti-platelet aggregationh
IC50 (nmol/L)
Compound no.a
R1
Con®guration
5-HT2
5-HT1A
a1
b
c
d
1-(S)e
1-(R) e
S
R
240
>1000f
0.49
190
NTg
NTg
NTg
NTg
2-(S)
2-(R)
S
14
160
1.1
140
NTg
NTg
R
300
>1000f
3-(S)
3-(R)
4-(S)
4-(R)
S
R
S
59
370
14
>1000f
93
NTg
NTg
3.0
200
0.24
7.2
26
6.4
R
0.17
6.7
>1000f
3.5
180
Sarpogrelate
Ketanserin
7.9
0.66
>1000f
>1000f
260
26
aAll compounds gave satisfactory IR, 1H NMR, MS and elemental analysis. The enantiomeric purities of the enantiomers were con®rmed to be >98% ee by
HPLC (column: Chiralpac OD (DAICEL Chemical Industries, Ltd)).
b[3H]Ketanserin binding.
c[3H]8-OH-DPAT binding.
d[3H]Prazosin binding.
e5-HT2, 5-HT1A and a1 receptor anities of compounds 1-(S), (R) have previously been reported.10
fIC50 value.
gNot tested.
hInhibitory activities of the compounds on platelet aggregation in vitro. Values represent the concentration required for a 50% inhibition of platelet aggregation.

2460
M. Fujio et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2457±2461
Table 2. Anities of adamantanecarboxamides for 5-HT2, 5-HT1A and a1 receptors
Binding anity
Ki (nmol/L)
Anti-platelet aggregationg
IC50 (nmol/L)
b
c
d
Compound no.a
R2
n
Con®guration
5-HT2
240
5-HT1A
a1
5
4-(S)
6
7
8
H
H
H
H
2-F
3-F
4-F
1
2
3
4
2
2
2
2
2
2
2
2
S
S
S
S
S
S
S
R
S
S
S
S
91
26
>1000e
2200
3.0
0.24
0.32
6.4
0.19
1.1
20
14
79
0.53
77
29
21
7.6
97
3.0
17
12
110
62
41
12
NTf
3.8
0.14
0.55
0.09
26
0.44
11
11
5.5
9
99
10-(S)
10-(R)
11
12
13
1.9
4-F
NTf
54
4-Cl
4-OCH3
4-CF3
4-CN
>1000e
92
>1000e
NTf
NTf
NTf
14
110
aAll compounds gave satisfactory IR, 1H NMR, MS and elemental analysis. The enantiomeric purities of the enantiomers were con®rmed to be
>98% ee by HPLC (column: Chiralpac OD (DAICEL Chemical Industries, Ltd)).
b[3H]Ketanserin binding.
c[3H]8-OH-DPAT binding.
d[3H]Prazosin binding.
eIC50 value.
fNot tested.
gInhibitory activities of the compounds on platelet aggregation in vitro. Values represent the concentration required for a 50% inhibition of platelet
aggregation.
anity. These facts suggest that the bulk of the sub-
stituents is therefore more important than the electronic
features.
In conclusion, we found (S)-N-{1-[2-(4-¯uorophenyl)
ethyl]pyrrolidin-3-yl}-1-adamantanecarboxamide hydro-
chloride hydrate (10-(S), Y-39241) to have a potent a-
nity for 5-HT2 receptor. Y-39241 was also e€ective in
preventing 5-HT plus collagen-induced platelet aggre-
gation both in vitro and in vivo. In the future we intend
to perform further biochemical and pharmacological
studies on compound Y-39241.15
We ®nally selected compound 10-(S) to examine the
inhibitory e€ect on mouse pulmonary thromboembolic
death induced by both collagen and 5-HT. Compound
10-(S) signi®cantly decreased the mortality rate at 0.1
mg/kg, po or higher in a dose-dependent manner (Fig.
3A).14 Sarpogrelate also signi®cantly inhibited mouse
thromboembolic death at 10 mg/kg, po (Fig. 3B).
However, the ED50 value for compound 10-(S) (0.04
mg/kg) was lower than that for sarpogrelate (2.2 mg/kg).
Acknowledgements
We thank Ms. F. Matsugaki and Ms. T. Nozue for their
excellent technical assistance. We also thank Dr. H.
Tanaka and Dr. M. Arita for their many stimulating
discussions.
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Figure 3. E€ect of compound 10-(S) and sarpogrelate on the 5-HT
plus collagen-induced pulmonary thromboembolic death in mice
ÃÃP<0.01 versus vehicle.

M. Fujio et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2457±2461
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14. The test drugs were administered orally to male ddY mice
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the mortality rate based on the number of animals and their
percentages, and the statistical analysis between the vehicle
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15. Other adamantanecarboxamide derivatives, 4-[4-(1-ada-
mantanecarboxamido)butyl]-1-(2-methoxyphenyl)piperazine16
and LY-35343317 are known as 5-HT1A and 5-HT4 antagonists,
respectively.
13. Data of 10-(S): colourless crystals, mp 201±204 ꢀC. 1H
NMR (DMSO-d6, 270 MHz) d: 1.58±2.05 (16H, m), 2.05±2.45
(1H, m), 2.90±3.82 (8H, m), 4.27±4.60 (1H, m), 7.10±7.23 (2H,
m), 7.28±7.40 (2H, m), 7.71±7.91 (1H, m), 10.99±11.18 (0.4H,
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.
m), 11.18±11.41 (0.6H, m). Anal. calcd for C23H31FN2O HCl
H2O: C, 65.00; H, 8.06; N, 6.59. Found: C, 64.95; H, 7.87; N,
6.81. Optical rotations were measured in methanol at 25 ꢀC for
compound 10-(S) (+1.2ꢀ, c=1.0) and 10-(R) ( 1.4ꢀ, c=1.0).
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