Novel potent antagonists of human neuropeptide Y-Y5 receptor. Part 4: Tetrahydrodiazabenzazulene derivatives

Article abstract of DOI:10.1016/S0960-894X(02)00090-2

Novel tetrahydrodiazabenzazulene derivatives, designed from the lead compound 1 discovered by screening of our in-house chemical library, were prepared and found to be potent neuropeptide Y-Y5 (NPY-Y5) receptor antagonists. The structure-activity relationships are described. Compounds 7 (FR240662) and 16 (FR252384) were especially attractive owing to their high affinities for the NPY-Y5 receptors, oral absorption and permeability to brain.

Full text of DOI:10.1016/S0960-894X(02)00090-2

Bioorganic & Medicinal ChemistryLetters 12 (2002) 1009–1011
Novel Potent Antagonists of Human Neuropeptide
Y-Y5 Receptor. Part 4: Tetrahydrodiazabenzazulene Derivatives
Yoshinari Satoh,a,* Chie Hatorib and Harunobu Itob
aMedicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima,
Yodogawa-ku, Osaka 532-8514, Japan
bExploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 5-2-3 Tohkohdai, Tsukuba 300-2698, Japan
Received 19 December 2001; accepted 1 February2002
Abstract—Novel tetrahydrodiazabenzazulene derivatives, designed from the lead compound 1 discovered byscreening of our in-
house chemical library, were prepared and found to be potent neuropeptide Y-Y5 (NPY-Y5) receptor antagonists. The structure–
activityrelationships are described. Compounds 7 (FR240662) and 16 (FR252384) were especiallyattractive owing to their high
affinities for the NPY-Y5 receptors, oral absorption and permeabilityto brain. # 2002 Elsevier Science Ltd. All rights reserved.
Neuropeptide Y (NPY) is a 36 amino acid peptide that
was first isolated from porcine brain1 and is said to have
a relation to food intake.2À4 We have alreadyreported
some attempts to provide potent and novel chemical
entities, 2-oxobenzothiazolin-3-acetic acid derivatives,5
benzo[a]cycloheptene derivatives6 and tetraline deriva-
tives,7 as NPY-Y5 receptor antagonists for the treat-
ment of obesityand eating disorders. Unfortunately, the
compounds described were so far showed little absorp-
tion and permeabilityto brain byoral administration.
Figure 1.
The distinctive structural features of this compound
were considered as follows: (i) the molecular weight
(=235) is small enough to be well absorbed bypo
administration; (ii) the existence of a basic nitrogen
containing heterocyclic moieties such as pyridyl and
imidazolyl is related to some extent to its solubility in
water, oral absorption and permeabilityto brain; (iii)
the compact molecular shape is also connected to good
oral absorption and permeabilityto brain.
Byscreening of our in-house chemical libraryin our
ExploratoryResearch Laboratories, 2-phenyl-4-(3-pyr-
idyl)-5-methylimidazole (1, FR79620) was found to have
an interesting profile as a new lead compound in the
search for a novel NPY-Y5 receptor antagonist, that is
it showed an IC50 value of binding inhibition of
125I-PYY on human NPY-Y5 receptors of 4.27Â10À7
M. It also showed a dose dependent decrease of food
intake and bodyweight bycontinuous po administra-
tion of 10, 30 and 100 mg/kg for 4 days (b.i.d.) to SD
rats: It was also found to decrease food intake and body
weight of db/db mice bycontinuous po administration
of 100 mg/kg for 4 days (b.i.d.) and possess good oral
absorption and permeabilityto brain (Fig. 1).
We designed a new chemical entity 2 after consideration
of these features bya ring closure with trimethlyene
moietybetween the methyl group and the pyridine ring
of compound 1, as shown in Figure 2. Furthermore, we
used a methoxy substituted phenyl ring instead of pyri-
dine ring as compound 3 in Figure 2 because the start-
ing material 7-methoxy-1-tetralone was easily available
and we expected the electron donating methoxymoiety
to show a similar effect to the nitrogen atom of pyridine.
The ring closure with trimethylene bond formation was
owing to our thought that the phenyl and the imidazolyl
rings are not coplaner as similar to the pyridyl and the
imidazolyl rings of compound 1.
*Corresponding author. Tel.: +81-6-6390-1376; fax: +81-6-6304-
5435; e-mail: yoshinari_satoh@po.fujisawa.co.jp
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00090-2

1010
Y. Satoh et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1009–1011
Figure 2.
Scheme 1. Reagents and conditions: (a) i-Amyl-ONO/aq HCl–THF; (b) Ph-CHO, NH4OAc; (c) PCl3/DMF, or H2/Pd–C, or HCOONH4 Pd–C.
Compound 3 was prepared as shown in Scheme 1. The
Table 1. Chemical structures and Y5 receptor affinities of com-
pounds 3, 7–12
starting material 8-methoxy-2-oxobenzo[a]cycloheptene
4 was reported in the previous paper,6 and was oxi-
mated with i-amylnitrite in an acidic medium to afford
oximeketone 5 followed byring closure with benzalde-
hyde and ammonium acetate to give 1-hydroxy-2-phenyl-
tetrahydrodiazabenzazulene
6 in high yield. The
dehydroxylation was performed by reduction with
phosphorus trichloride or hydrogenation with 10%
palladium on carbon leading to 3.
Compd
R1
X
n
R2
IC50 (M)a
3
–OCH3
–CH2–
2
2.5Â10À8
Fortunately, the firstly prepared compound 3 showed
about 20-fold improved affinities for both human and
rat NPY-Y5 receptors, when compared with the lead 1,
FR79620. This prompted us to search for related com-
pounds. We planned first of all to prepare a compound
in which we would exchange the phenyl ring at the 2-
position of the imidazole nucleus into a pyridine ring (7)
in order to confer similar water solubilityto the lead 1.
Next, an electron donating methoxygroup was exchan-
ged bya neutral hydrogen and an electron-withdrawing
chlorine (8 and 9). These compounds showed the same
or higher affinities when compared with compound 3.
Compounds 10, 11 and 12 were found to have lower
affinities than compound 3, except that 12 showed
comparable affinity. They were prepared by similar
methods to that carried out in the preparation of 3, and
their chemical structures and biological evaluation
results are summarized in Table 1.
7
–OCH3
–H
–CH2–
–CH2–
–CH2–
–O–
2
2
2
2
2
1
1.3Â10À8
5.8Â10À9
1.7Â10À9
6.1Â10À6
5.7Â10À7
5.2Â10À8
8
9
–Cl
10
11
12
–H
–H
–CH2–
–CH2–
–OCH3
We concluded that a pyridine ring was suitable for a
substituent at the 2-position of tetrahydrodiaza-
benzazulene when considering the oral absorption and
permeabilityof the brain owing to its hydrophobicity
and basicity. Furthermore, we thought that there was
little possibilityof potentiating the affinities for binding
aConcentration of compound that inhibited 50% of total specific
binding of 125I-PYY as a ligand to human NPY-Y5 receptors;
obtained from the mean value of two experiments at each concentra-
tion (10À6–10À10 M).

Y. Satoh et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1009–1011
1011
Table 2. Chemical structures and Y5 receptor affinities of com-
pounds 7, 13–23
as the affinities of compounds substituted bythe neutral
hydrogen or the electron withdrawing fluorine when
compared in a series. However, the compounds sub-
stituted by a 3-pyridyl moiety at the 2-position were
found to be several or 10-fold more potent than com-
pounds substituted by 2- or 4-pyridyl groups in all ser-
ies. Compound 16 showed the most potent affinities for
the NPY-Y5 receptors of all compounds we prepared.
Compd
R
Bonding position of pyridine ring
IC50 (M)a
Compounds 7 (FR240662) and 16 (FR252384) were
investigated in more detail byadministration orallyto
Zucker fattyrats for development as an anti-obesitydrug.
Unfortunately, we have obtained some biological data
suggesting that there is little relation between the NPY-Y5
receptor activation and food intake in spite of enough
concentrations to show activities of unchanged compounds
7 and 16 in both plasma and brain. These detailed
evaluation results, such as selectivityfor Y5 receptors over
Y1 receptors, functional assayresults byc-AMP produc-
tion induced byforskoline in human Y5 receptors, effects
on food intake and bodyweight in both SD rats and
Zucker fattyrats, effects on plasma glucose, insulin and
triacylglycerol levels, effects on GOT and GPT and so
on, will be disclosed elsewhere in the near future.
13
14
7
–OCH3
–OCH3
–OCH3
–CH3
–CH3
–CH3
–H
–H
–H
–F
–F
2-
3-
4-
2-
3-
4-
2-
3-
4-
2-
3-
4-
1.1Â10À7
6.3Â10À9
1.3Â10À8
3.2Â10À8
2.3Â10À9
6.4Â10À9
1.1Â10À7
7.3Â10À9
2.0Â10À8
4.6Â10À8
6.4Â10À9
1.3Â10À8
15
16
17
18
19
20
21
22
23
–F
aSee footnote to Table 1.
bychanging the ring-closing bond from a trimethylene
moietywhen comparing compound 10 with 8 and com-
pound 12 with 3 as shown in Table 1. Although there
was a tendencyfor phenyl substituents to increase affi-
nities byincreasing the electron withdrawing properties,
further investigation was necessary.
Summary
We prepared novel tetrahydrodiazabenzazulene deriva-
tives and found that some of them showed potent NPY-
Y5 receptor antagonistic activities. Compounds 7
(FR240662) and 16 (FR252384) were especiallyattrac-
tive owing to their high affinities for the NPY-Y5
receptors, oral absorption and permeabilityto brain.
We next investigated the combination between 9-sub-
stituents and the bonding position of the pyridine ring
at the 2-position of tetrahydrodiazabenzoazulene. We
selected –OCH3, –CH3, –H and –F moieties as the sub-
stituents at the 9-position and 2-, 3- and 4-pyridyl
groups as the substituent at the 2-position. 7-Fluoro-1-
tetralone was prepared from 3-(4-fluorobenzoyl)-pro-
pionic acid byWolff–Kishner reduction followed by
ring closure with polyphosphoric acid and other sub-
stituted 1-tetralones where commerciallyavailable. The
starting materials, 8-substituted benzo[a]cyclohepten-2-
ones, were synthesized by similar procedures to that
described in a previous paper6 and the target com-
pounds were obtained bysimilar methods to that car-
ried out in the preparation of compound 3.
Acknowledgements
The authors would like to acknowledge Dr. D. Barrett
for helpful discussions and critical reading of the
manuscript.
References and Notes
The chemical structures and biological evaluation
results of the obtained compounds 13–23 are summar-
ized in Table 2 accompanied with those of compound 7.
1. Tatemoto, K.; Carlquist, M.; Mutt, V. Nature 1982, 296, 651.
2. Stanley, B. G.; Leibowitz, S. F. Proc. Natl. Acad. Sci.
U.S.A. 1985, 82, 3940.
3. Kalra, S. P.; Dube, M. G.; Fournier, A.; Kalra, P. S. Phy-
siol. Behav. 1992, 50, 5.
Considering the evaluation results shown in Table 2, it
was found that the electronic effect of the substituent
(R) was not so important to increase the affinityfor
NPY-Y5 receptors, but the bonding positions of the
pyridine ring at the 2-position of the imidazole nucleus
related closelyto their potencies. Thus, the affinities for
receptor binding of the compounds possessing an elec-
tron donating methoxyor methyl group were as potent
4. Beck, B.; Stricker-Krongrad, A.; Nicolas, J.-P.; Burlet, C.
Int. J. Obesity 1991, 16, 295.
5. Tabuchi, S.; Itani, H.; Sakata, Y.; Oohashi, H.; Satoh, Y.;
Bioorg. Med. Chem. Lett., submitted for publication.
6. Itani, H.; Ito, H.; Sakata, Y.; Hatakeyama, Y.; Oohashi,
H.; Satoh, Y.; Bioorg. Med. Chem. Lett., 2002, 12, 757.
7. Itani, H.; Ito, H.; Sakata, Y.; Hatakeyama, Y.; Oohashi,
H.; Satoh, Y.; Bioorg. Med. Chem. Lett., 2002, 12, 799.