Synthesis of polyamine derivatives having non-hypotensive Ca2+-permeable AMPA receptor antagonist activity

Article abstract of DOI:10.1016/S0960-894X(01)00170-6

In order to obtain non-hypotensive and Ca²⁺-permeable AMPA receptor antagonists, we have synthesized a series of 1,4-bis(4-piperidinylmethyl)diaminobutanes. Compounds 13b, c, f had desirable properties.

Full text of DOI:10.1016/S0960-894X(01)00170-6

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1261–1264
Synthesis of Polyamine Derivatives Having Non-hypotensive
Ca2+-Permeable AMPA Receptor Antagonist Activity
Yoshiyuki Yoneda,* Shinichi Kawajiri, Atushi Hasegawa, Fusako Kito,
Sumie Katano, Emi Takano and Tetuya Mimura
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd.,
16-13, Kitakasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan
Received 28 November 2000; accepted 3 March 2001
Abstract—In order to obtain non-hypotensive and Ca2+-permeable AMPA receptor antagonists, we have synthesized a series of
1,4-bis(4-piperidinylmethyl)diaminobutanes. Compounds 13b, c, f had desirable properties. # 2001 Elsevier Science Ltd. All rights
reserved.
Introduction
concentrated on the synthesis of non-hypotensive Ca2+
permeable AMPA receptor antagonists.
-
l-Glutamate is a major excitatory neurotransmitter in
the mammalian central nervous system.1 Glutamate
receptors are classified into two groups which are cou-
pled to the opening of cation ion channels (ionotropic
glutamate receptors) or linked to GTP binding proteins
(metabotropic receptors). Ionotropic receptors are fur-
ther classified into three groups, namely NMDA,
AMPA and kainate (KA) receptors.2 Overstimulation
of these receptors causes excessive Ca2+ influx which
triggers neuronal cell death in acute phase of cerebral
ischemia.3 Therefore, antagonists against the ionotropic
receptors seem to be promising therapeutic agents for
cerebral ischemia. Based on this assumption, a lot of
NMDA receptor antagonists have been synthesized and
evaluated for their pharmacological and clinical effects.4
On the other hand, Ca2+-permeable AMPA receptor
antagonists still remain to be studied. We therefore
focused on the Ca2+-permeable AMPA receptor
antagonists and designed them based on the structures
of prototype antagonist polyamines such as Joro spider
toxin-3, JSTX-3 (1),5 and 1-naphthylacetylspermine,
NAS (2).6 In the course of this study, we found that
these polyamines including 2 had potent hypotensive
activity in rats. Such hypotensive activity is unfavorable
for the therapeutic agents for acute cerebral ischemia
because it may cause reduction of the pressure-depen-
dent cerebral blood flow to the ischemic penumbra and
increase cerebral damage.7 In this paper, we therefore
The synthetic pathways of polyamine derivatives 9a–d
and 10 are shown in Scheme 1. The primary amino
group of 4-aminomethylpiperidine 3 was protected to
give phthalimide 4, which was converted to two com-
pounds 5 and 6 by protection with a tert-butoxy-
carbonyl (Boc) and benzyloxycarbonyl (Z) group,
respectively, and subsequent cleavage of the phthali-
mide moiety. Compound 6 was treated with 4-bromo-
butyl acetate in the presence of KF–Celite, followed by
protection with a Boc group, alkaline hydrolysis and
Swern oxidation, to give aldehyde 7. Aldehyde 7 was
used for reductive alkylation of 5, and the resulting pro-
duct was protected by a Boc group and reduced catalyti-
cally to give tri-Boc-protected amine 8. Condensation of
8 with arylacetic acids gave products 9a–d. Reaction of
*Corresponding author. Tel.:+81-3-3680-0151; fax: +81-3-56968344;
e-mail: yonedL0z@daiichipharm.co.jp
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00170-6

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Y. Yoneda et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1261–1264
8 with 2-(1-naphthyl)ethyl methanesulfonate afforded
compound 10.
11 was alkylated with 4-bromobutylphthalimide and
followed by protection with a Boc group and succesive
removal of a phthaloyl group to give amine 12. Amine
12 was converted to compounds 13a–h by reductive
alkylation using a variety of aldehydes. Compound 11
was treated with 4-bromobutyl acetate, and followed by
protection with a Boc group, hydrolysis of an acetyl
group and Swern oxidation of the resulting alcohol to
afford aldehyde 14, which was converted to 15a–e in a
similar manner as described above.
Another series of compounds 13a–h and 15a–e were
synthesized as shown in Scheme 2. Compound 4 was
condensed with (1-naphthyl)acetic acid, and followed by
removal of a phthaloyl group to afford amine 11. Amine
Results and Discussion
Antagonist activity of test compounds against Ca2+
-
permeable AMPA receptors (IC50) was measured using
a two-electrode voltage clamp method:8 kainate (KA)
was used as an agonist for the receptors expressed in
Xenopus oocytes by injection of rat brain mRNA.
However, since KA non-selectively induces inward cur-
rents via stimulation of KA receptors, Ca2+-permeable
and Ca2+-impermeable receptors, antagonist activity of
test compounds for Ca2+-permeable AMPA receptors
was calculated by offsetting the inward currents due to
blockade of the other two receptors.9 Hypotensive activity
was evaluated after intravenous administration to Wistar
rats. These activities are shown in Tables 1 and 2.
Table 1. Inhibitory effect on Ca2+-permeable AMPA receptor and
effect on blood pressure (1)
Scheme 1. Synthesis of compounds 9a–d and 10. Reagents and condi-
tions: (a) phthalic anhydride, Á (61%); (b) (i) Boc2O, TEA, CH2Cl2
.
(59%), (ii) NH2NH2 H2O, EtOH (quant); (c) (i) Z-Cl, aq NaHCO3,
.
CH2Cl2 (74%), (ii) NH2NH2 H2O, EtOH (quant); (d) (i) 4-bromobutyl
Compound
R
IC50
(mM)a
ÁSBP
(mmHg)c
acetate, KF–Celite, MeCN, (ii) Boc2O, CH2Cl2 (two steps 71%), (iii)
K2CO3, MeOH (quant), (iv) Swern oxidation. (quant); (e) (i) 5, NaBH4,
MeOH, (ii) Boc2O, CH2Cl2 (two steps 64%), (iii) H2, Pd(OH)2–C, EtOH
(quant); (f) (i) carboxylic acid, EDC HCl, HOBt, NMM, CH2Cl2, (ii) c
HCl, EtOH (two steps 37–65%); (g) (i) 2-(1-naphthyl)ethyl methane-
sulfonate, K2CO3, DMF, (ii) c HCl, EtOH (two steps 34%).
.
9a
1.3
À120
9b
0.42
0.27
0.49
28%b
0.69
À40
À75
À50
NTd
À55e
9c
9d
10
NAS (2)
—
aIC50 (mM) was defined as the concentration of a compound that
reduced the inward current induced by kainate by 50%. The com-
pound was co-administered with kainate to Xenopus ooccytes where
the inward current was measured by the two-electrode voltage clamp
method.
Scheme 2. Synthesis of compounds 13a–h and 15a–e. Reagents and
.
conditions: (a) (i) (1-naphthyl)acetic acid, EDC HCl, TEA, CH2Cl2
.
(69%), (ii) NH2NH2 H2O, EtOH (quant); (b) (i) 4-bromobutyl phtha-
.
limide, KF–Celite, MeCN, (ii) Boc2O, CH2Cl2, (iii) NH2NH2 H2O,
EtOH (three steps 55%); (c) (i) aldehyde, NaBH4, MeOH, (ii) Boc2O,
CH2Cl2, (iii) c HCl, EtOH (three steps 25–57%); (d) (i) 4-bromobutyl-
acetate, KF–Celite, MeCN, (ii) Boc2O, CH2Cl2, (iii) K2CO3, MeOH
(three steps 48%), (iv) Swern oxidation (71%); (e) (i) amine,
NaBH4, MeOH, (ii) Boc2O, CH2Cl2, (iii) c HCl, EtOH (three steps
24–50%).
b% inhibition at the concentration of 1 mM is shown.
cChanges in systolic blood pressure (mmHg) after intravenous (iv)
administration at the dose of 3 mg/kg in rats were compared with the
systolic blood pressure before dosing (n=1–2).
dNot tested.
eThe dose of 1 mg/kg was used.

Y. Yoneda et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1261–1264
1263
In this paper, we first synthesized a series of 1,4-bis(4-
piperidinylmethyl)diaminobutane derivatives, which
was designed from prototype antagonists JSTX-3 (1)
and NAS (2) with the intention of elevating lipophilicity
that would affect permeability into the brain. Com-
pound 9a, 1-(1-(1-naphthylacetyl)piperidin-4-ylmethyl)-
4-(4-piperidinylmethyl)diaminobutane, exhibited mod-
erate potency with an IC50 value of 1.3 mM. Reduction
of the amide function of 9a significantly decreased in
potency (10), suggesting that the carbonyl group plays
an important role in exhibiting potent activity. Insertion
of an amino acid moiety between the naphthaleneacetyl
and piperidine groups of 9a gave 9b–d showing 3- to 4-fold
higher potency.
Table 2. Inhibitory effect on Ca2+-permeable AMPA receptor and
effect on blood pressure (2)
Subsequently, we modified the 4-piperidinylmethyl
group on the other terminal of 9a. Compounds 13a,b,
isomeric 2- and 3-piperidinylmethyl congeners of 9a,
showed potency almost similar to that of 9a. Pyrrolidine
derivative 13c had similar potency. N-Methylpiperidine
derivative 15a showed 2-fold higher potency than non-
methylated compound 9a. N-Methylation of 13b,c
resulted in a decrease in potency (13d,e). Amino-propyl
and -ethyl derivatives 13g,h had potency 4-fold higher
than that of 9a. Compound 15d with an imidazole
group retained potency, suggesting that an aromatic
heterocyclic moiety is a replaceable substituent on the
terminal. This would be supported by the fact that N-(4-
pyridinyl)piperidine derivative 15e had the most potent
activity. Interestingly, compound 13f with a piperidin-
1-yl group showed potent activity, while compound 15c
Compound
R
IC50 (mM)a
ÁSBP (mmHg)c
À58
13a
0.82
13b
13c
13d
13e
13f
13g
13h
15a
15b
15c
15d
15e
1.1
0.73
27%b
41%b
0.19
0.32
0.33
0.57
0.78
18%b
0.26
0.17
0
0
11
with a morpholin-1-yl group exhibited markedly
reduced potency.
13
With respect to hypotensive activity, compound 9a
showed potent activity at a dose of 3 mg/kg. Insertion of
an amino acid moiety between the naphthaleneacetyl
and piperidine groups of 9a resulted in a moderate
decrease in potency (9b–d). On the other hand, com-
pounds 13b,c,f and 15c showed no hypotensive effect at
a dose of 3 mg/kg. Among the piperidinyl derivatives,
the order of the hypotensive activity is 9a>13a
ꢀ13b=13f. Thus, the basic nitrogen atom in the piper-
idinine ring apparently contributes to the activity. The
nitrogen atom in the piperidin-2-yl and piperidin-1-yl
groups would have difficulty in interacting with the
undetermined receptors mediating blood pressure,
possibly because of its steric hindrance. Interest-
ingly, (1-methylpyrrolidin-2-yl)methyl derivative 13e
showed no hypotensive activity, while (1-methylpyrroli-
din-2-yl)ethyl derivative 15b had the strong activity.
These results would indicate that non-hypotensive com-
pounds have the two common characteristics: (1) the
two-carbon length between the terminal nitrogen atom
and the closest nitrogen atom; and (2) the steric hin-
drance around the terminal nitrogen atom.
5
À35
À50
À50
À55
0
À25
À43
Thus, we synthesized non-hypotensive and Ca2+
-
permeable AMPA receptor antagonists and evaluated
their structure–activity relationships.
aIC50 (mM) was defined as the concentration of a compound that
reduced the inward current induced by kainate by 50%. The com-
pound was co-administered with kainate to Xenopus ooccytes where
the inward current was measured by the two-electrode voltage clamp
method.
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b% inhibition at the concentration of 1 mM is shown.
cChanges in systolic blood pressure (mmHg) after intravenous (iv)
administration at the dose of 3 mg/kg in rats were compared with the
systolic blood pressure before dosing (n=1–2).

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C)Â100.