A novel pyridazinone derivative as a nonprostanoid PGI2 agonist

Article abstract of DOI:10.1016/S0960-894X(00)00571-0

A novel optically pure pyridazinone derivative was synthesized and identified as a nonprostanoid PGI₂ agonist. It inhibited ADP-induced aggregation of human platelets with an IC₅₀ value of 0.081 μM and has high oral bioavailability (

Full text of DOI:10.1016/S0960-894X(00)00571-0

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2787±2790
A Novel Pyridazinone Derivative as a Nonprostanoid
PGI2 Agonist
Kazunori Tsubaki,a,y Kiyoshi Taniguchi,a,* Seiichiro Tabuchi,a
Osamu Okitsu,a Kouji Hattori,a Jiro Seki,b Kazuo Sakanea
and Hirokazu Tanakaa
aMedicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, 1-6, 2-Chome, Kashima,
Yodogawa-ku, Osaka 532-8514, Japan
bMedicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, 1-6, 2-Chome, Kashima,
Yodogawa-ku, Osaka 532-8514, Japan
Received 22 August 2000; accepted 2 October 2000
AbstractÐA novel optically pure pyridazinone derivative was synthesized and identi®ed as a nonprostanoid PGI2 agonist. It
inhibited ADP-induced aggregation of human platelets with an IC50 value of 0.081 mM and has high oral bioavailability (56%) with
a long half-life (4.3 h) in rats. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
these actions are considered to be clinically useful, its
therapeutic application is limited by both chemical and
metabolic instability.1b Thus the preparation of PGI2
analogues with modi®ed chemical and biological prop-
PGI2 (prostacyclin) is a powerful endogenous inhibitor
of platelet function and a potent vasodilator.1 Although
*Corresponding author. Tel: +81-6-6390-1141; fax: +81-6-6304-5435; e-mail: kiyoshi_taniguchi@po.fujisawa.co.jp
yPresent address: Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00571-0

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erties has been encouraged.1c Beraprost Na, a clinically
useful synthetic PGI2, is a chemically stable and orally
active drug, but its duration is still short owing to its
metabolic instability.2
PGI2 mimetic possessing an alternative structure and
having long duration superior to that of beraprost Na.
We focused our attention on AP227 and AP437. On the
basis of similarities of the chemical structures of AP227
and AP437 to that of BMY45778, we speculated that
the phenoxyacetic acid moiety and the benzhydryl
group of the AP compounds played an important role
in binding to the PGI2 receptor (IP). The Ono group
also reported that the chemical modi®cations of the
oxime moiety to the other groups (ether, amide) or of
the pyrazole moiety to the other 5-membered hetero-
aromatics greatly a€ected the PGI2 mimetic
activities.4b e Thus we aimed to create a functional
group alternative to the oxime group or the pyrazole
group, key groups of the AP compounds. As a result,
Recently, nonprostanoid PGI2 mimetics with chemical
and metabolic stability have been reported.3,4 Octimibate
was shown to be a PGI2 mimetic.3a,b A Bristol-Myers
Squibb group demonstrated BMY45778 (1) as a non-
prostanoid PGI2 mimetic3d and an Ono group showed
that AP227 (2) and AP437 (3) were orally active PGI2
agonists.4a c Thus we aimed to ®nd a nonprostanoid
we generated
a
novel pyridazinone derivative,
FR181877 (4). In this report, we describe the synthesis
and pharmacological and pharmcokinetic properties of
optically pure FR181877 and related compounds.
Synthesis
The objective 3-pyridazinone derivative, FR181877 (4),
was prepared as shown in Schemes 1 and 2.
The right part of compound 4, benzhydrylpyridazinone
7, was prepared by cyclization of g-oxopentanoic acid 6,
which was prepared by condensation of 1,1-diphenyl-
acetone (5) with glyoxalic acid, with hydrazine as shown
in Scheme 1.
Scheme 1. Reagents and conditions: (a) HCOCOOH H2O, DME,
re¯ux, 3 days; (b) NH2NH2 H2O, water, re¯ux, (20% two steps).
Scheme 2. Reagents and conditions: (a) H2 (3 atm), 10% Pd/C, MeOH, rt (78%); (b) LiAlH4, THF, 70 ꢀC (99%); (c) (1) ( )-Menthyl chloro-
formate, pyridine, 0 ꢀC; (2) recrystallization from n-hexane (46%); (d) 3 N NaOH, THF±water, rt (99%); (e) CH3SO2Cl, NEt3, CH2Cl2, 0 ꢀC; (f) 7,
tert-BuOK, 18-crown-6, DMF, rt (77% two steps); (g) BBr3, CH2Cl2, 0 ꢀC±re¯ux (83%); (h) BrCH2COOCH2CH3, K2CO3, DMF, rt±50 ꢀC (95%);
(i) 1 N NaOH, DME, 85 ꢀC (82%).

K. Tsubaki et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2787±2790
2789
The key intermediate for the synthesis of compound 4,
optically pure (S)-2-tetralinemethanol 12, was prepared
as shown in Scheme 2. The starting material, (1R,2S)-1-
hydroxy-2-tetralinecarboxylic acid methyl ester 8 (90%
ee),5 was dehydroxylated by hydrogenation on palla-
dium/carbon to a€ord the corresponding 2-tetra-
linecarboxylic acid methyl ester 9. The methyl ester 9
was reduced quantitatively to the corresponding (S)-2-
tetralinemethanol 10 (70% ee) with lithium aluminum
hydride. In order to obtain the optically pure methanol
12, the obtained methanol 10 was acylated to the
corresponding ( )-menthyl carbonate 11 to give a mix-
ture of two diastereomers, the recrystallization of which
from n-hexane resulted in an improvement of its dia-
stereomeric excess. The recrystallized carbonate 11 was
hydrolyzed with NaOH to a€ord the optically pure
methanol 12. Its optical purity was determined by
HPLC with a chiral stationary-phase column (Chir-
alpak AD) to be > 99% ee. The methanol 12 was
mesylated, and the resulting mesylate 13, without isola-
tion, was treated with the anion of benzhydrylpyrid-
azinone 7 in the presence of 18-crown-6 to a€ord (S)-2-
[(2-tetralinyl)methyl]-3(2H)-pyridazinone 14. Compound
14 was demethylated with BBr3 to provide the corre-
sponding 5-hydroxytetralinyl derivative 15, which was
transformed to the objective compound 4 (FR181877)6
by treatment with bromoacetic acid ethyl ester, followed
by saponi®cation. The optical purity of the 5-(ethoxy-
carbonylmethoxy)tetralinyl derivative 16 was deter-
mined by HPLC with a chiral stationary-phase column
(Chiralcel AS) to be >99% ee.
The 3- or 5-benzhydryl-2-pyridinone derivatives 29 and
30 were prepared as shown in Scheme 3.
The reduction of the starting material, 3,4-dihydro-2-
naphthalenecarboxylic acid methyl ester7 17, to 3,4-
dihydro-2-naphthalenemethanol 18 with diisobutylalu-
minum hydride (DIBAL-H) was followed by treatment
with carbon tetrabromide and triphenylphosphine to
provide the corresponding bromide 19. The bromide 19
was treated with the anion of a mixture of 3- and
5-benzhydryl-2-pyridinone8 20 in the presence of
18-crown-6 and the resulting products were separated
by silica gel column chromatography to provide 3- and
5-benzhydryl-1-[(3,4-dihydro-2-naphthalenyl)methyl]-2(1H)-
pyridinones 21 and 22. Compounds 21 and 22 were
demethylated with BBr3 to provide the corresponding
5-hydroxydihydronaphthalenes 23 and 24, respectively,
which were transformed to the corresponding 5-car-
Table 1. Inhibition of ADP-induced aggregation of human platelets
Compounds
IC50 (mM)
4 (FR181877)
29
30
0.081
> 10
0.13
Scheme 3. Reagents and conditions: (a) DIBAL-H, toluene, 5 ꢀC (quantitative); (b) CBr4, PPh3, CH2Cl2, rt (quantitative); (c) (1) tert-BuOK, 18-
crown-6, DMF, rt; (2) SiO2 column chromatography (separation); (13 and 31% for 21 and 22, respectively); (d) BBr3, CH2Cl2, 0 ꢀC (66 and 99% for
23 and 24, respectively); (e) BrCH2COOCH2CH3, K2CO3, CH3CN, re¯ux (72 and 83% for 25 and 26, respectively); (f) 1 N NaOH, DME, rt (71 and
83% for 27 and 28, respectively); (g) H2 (1 atm), Pd/C, THF, rt (54 and 94%, for 29 and 30, respectively).

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K. Tsubaki et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2787±2790
boxymethoxydihydronaphthalene derivatives 27 and 28,
respectively, by treatment with bromoacetic acid ethyl
ester and subsequent saponi®cation. Hydrogenation of
compounds 27 and 28 on palladium/carbon in THF
provided the objective 3- and 5-benzhydryl-1-[(2-tetra-
linyl)methyl]-2-pyridinones 299 and 30,10 respectively.
References and Notes
1. (a) Moncada, S.; Gryglewski, R.; Bunting, S.; Vane, J. R.
Nature 1976, 263, 663. (b) Meanwell, N. A.; Romine, J. L.;
Seiler, S. M. Drugs Future 1994, 19, 361. (c) Collins, P. W.;
Djuric, S. W. Chem. Rev. 1993, 93, 1533.
2. (a) Kato, R.; Uji, Y.; Matsumoto, K. Jpn. J. Clin. Phar-
macol. Ther. 1989, 20, 515. (b) Matsumoto, K.; Tajima, A.;
Hirano, Y.; Ohno, K.; Yuge, T.; Hamasaki, T.; Hase, T.;
Horiba, M. Xenobio. Metabol. Dispos. 1989, 4, 713. (c)
Kato, R.; Uji, Y.; Ono, K.; Matsumoto, K.; Hisano, K.;
Sakai, I.; Kagawa, Y.; Isai, M. Jpn. J. Clin. Pharmacol. Ther.
1986, 17, 267. (d) Kato, R.; Uji, Y.; Matsumoto, K. Jpn. J.
Clin. Pharmacol. Ther. 1989, 20, 529. (e) Isaka, Y.; Handa, N.;
Imaizumi, M.; Kimura, K.; Kamada, T. Thromb. Haemost.
1991, 65, 344.
3. (a) Seiler, S. M.; Brassard, C. L.; Arnold, A. J.; Meanwell,
N. A.; Fleming, J. S.; Keely, S. L., Jr. J. Pharm. Exp. Ther.
1990, 255, 1021. (b) Merritt, J. E.; Hallam, T. J.; Brown, A.
M.; Boy®eld, I.; Cooper, D. G.; Hickey, D. M. B.; Jaxa-Cha-
miec, A. A.; Kaumann, A. J.; Keen, M.; Kelly, E.; Kozlowski,
U.; Lynham, J. A.; Moores, K. E.; Murray, K. J.; MacDer-
mot, J.; Rink, T. J. Brit. J. Pharmacol. 1991, 102, 251. (c)
Meanwell, N. A.; Rosenfeld, M. J.; Kim Wright J. J.; Bras-
sard, C. L.; Buchanan, J. O.; Federici, M. E.; Fleming, J. S.;
Seiler, S. M. J. Med. Chem. 1992, 35, 389. (d) Meanwell, N.
A.; Romine, J. L.; Rosenfeld, M. J.; Martin, S. W.; Trehan, A.
K.; Kim Wright, J. J.; Malley, M. F.; Gougoutas, J. Z.; Bras-
sard, C. L.; Buchanan, J. O.; Federici, M. E.; Fleming, J. S.;
Gamberdella, M.; Hartl, K. S.; Zavoico, G. B.; Seiler, S. M. J.
Med. Chem. 1993, 36, 3884.
Biological Results
The activities of the PGI2 agonists were evaluated in
terms of inhibition against ADP-induced aggregation of
human platelets in platelet-rich plasma (PRP) and against
[3H]-iloprost binding to human IP (PGI2) receptor.
Beraprost Na, AP227 (2), AP437 (3), and FR181877 (4)
inhibited ADP-induced aggregation of human platelets
with IC50 values of 4.3 nM, 0.15 mM, 0.041 mM, and
0.081 mM, respectively. Beraprost Na and FR181877
inhibited [3H]-iloprost binding to the human IP receptor
with Ki values of 0.080 and 0.094 mM, respectively.
The inhibitory activity of 2-pyridinones 29 and 30,
FR181877 analogues, against ADP-induced aggregation
of human platelets is shown in Table 1 in comparison
with that of FR181877. Replacement of the pyrid-
azinone of FR181877 with pyridinone did not greatly
a€ect the activity (compound 30). Shifting the benzhy-
dryl group of compound 30 from the 5-position to the
3-position resulted in complete loss of the activity
(compound 29). These facts show that the 1-position
nitrogen atom of the pyridazinone ring of FR181877 is
not essential in binding to the IP receptor but its
benzhydryl group plays an important role in the binding.
4. (a) Kondo, K.; Hamanaka, N. Folia Pharmacol. Jpn. 1995,
106, 181. (b) Hamanaka, N.; Takahashi, K.; Nagao, Y.; Tor-
isu, K.; Takada, H.; Tokumoto, H.; Kondo, K. Bioorg. Med.
Chem. Lett. 1995, 5, 1071. (c) Hamanaka, N.; Takahashi, K.;
Nagao, Y.; Torisu, K.; Tokumoto, H.; Kondo, K. Bioorg.
Med. Chem. Lett. 1995, 5, 1083. (d) Hamanaka, N.; Takaha-
shi, K.; Nagao, Y.; Torisu, K.; Tokumoto, H.; Kondo, K.
Bioorg. Med. Chem. Lett. 1995, 5, 1077. (e) Nagao, Y.; Taka-
hashi, K.; Torisu, K.; Kondo, K.; Hamanaka, N. Heterocycles
1996, 42, 517.
FR181877 exhibited excellent pharmacokinetic proper-
ties, namely good oral bioavailability and a long half-
life (t1/2b). It was administered (10 mg/kg po (n=3),
3.2 mg/kg iv (n=2)) to fasted male rats. Its oral bio-
availability is 56%, and its half-life (t1/2b) is 4.3Æ0.2 h
which is longer compared with that of beraprost Na
(0.43 and 3.3 h in male and female rats, respectively).2b
5. Genet, J. P.; P®ster, X.; Ratovelomanana-Vidal, V.; Pinel,
C.; Latte, J. A. Tetrahedron Lett. 1994, 35, 4559.
6. Physical data for compound FR181877 (4): mp 82±83 ꢀC
25
D
1
(AcOEt); ‰aŠ
27.6ꢀ (c 0.75, CH2Cl2); IR (Nujol) cm
:
1730, 1655, 1635, 1565; 1H NMR (DMSO-d6) d: 1.34 (1H, m),
1.77 (1H, m), 2.20 (1H, m), 2.35±2.85 (4H, m), 3.90±4.10 (2H,
m), 4.65 (2H, s), 5.57 (1H, s), 6.56±6.62 (2H, m), 6.92 (1H, d,
J=9.5 Hz), 7.01 (1H, t, J=7.9 Hz), 7.20±7.37 (11H, m), 12.94
(1H, br s); (+)APCI-MS m/z: 481 (M++1).
Summary
FR181877 (4) possessing a pyridazinone group as a key
functional group alternative to the oxime group of
AP227 (2) or the pyrazole group of AP437 (3) was
shown to be a novel nonprostanoid PGI2 agonist. Its
high optical purity was accomplished by increasing the
diastereomeric excess of ( )-menthylcarbonate 11
transformed from 2-tetralinemethanol 10 (70% ee) by
recrystallization. It exhibited potent PGI2 mimetic
functional activity in human platelets and has good oral
bioavailability with a long half-life (t1/2b) in rats.
7. Cook, C.; Cho, Y.; Jew, S.; Lee, Y.; Chung, T. Soul Tae-
hakkyo Yakhak Nonmunjip 1983, 8, 1.
8. Sherlock, M. H.; Roebke, H. US Patent 4,138,488, 1979;
Chem. Abstr. 1979, 90, 168465n.
9. Physical data for compound 29: mp 185±187 ꢀC (Et2O); IR
(Nujol) cm 1: 1730, 1645, 1590, 1560; 1H NMR (DMSO-d6) d:
1.35 (1H, m), 1.80 (1H, m), 2.15 (1H, m), 2.35±2.95 (4H, m),
3.89 (2H, m), 4.30 (2H, s), 5.64 (1H, s), 6.20 (1H, t, J=6.7 Hz),
6.54 (2H, d, J=7.9 Hz), 6.85 (1H, d, J=6.7 Hz), 6.95 (1H, t,
J=7.9 Hz), 7.05±7.30 (10H, m), 7.62 (1H, d, J=6.7 Hz);
(+)APCI-MS m/z: 480 (M++1).
Acknowledgements
10. Physical data for compound 30: mp 162±163 ꢀC (Et2O);
1
IR (Nujol) cm 1: 1665, 1605, 1590; H NMR (DMSO-d6) d:
We thank Mr. Yoshihiko Sakai of Biopharmaceutical
and Pharmacokinetic Research Laboratories, Fujisawa
Pharmaceutical Co., Ltd for performing the pharmaco-
kinetic experiments.
1.30 (1H, m), 1.80 (1H, m), 2.10 (1H, m), 2.35±2.95 (4H, m),
3.70±3.95 (2H, m), 4.28 (2H, s), 5.39 (1H, s), 6.39 (1H, d,
J=10.1 Hz), 6.48±6.56 (2H, m), 6.95 (1H, t, J=7.9 Hz), 7.14±
7.35 (12H, m); (+)APCI-MS m/z: 480 (M++1).