Discovery of new diphenyloxazole derivatives containing a pyrrolidine ring: Orally active prostacyclin mimetics. Part 2

Article abstract of DOI:10.1016/j.bmcl.2005.04.042

Synthetic and biological evaluation of novel diphenyloxazole derivatives containing a pyrrolidine ring, as a prostacyclin mimetic without the PG skeleton, are described. Asymmetric reduction of a ketone using a chiral Ru complex and reductive amination by

Full text of DOI:10.1016/j.bmcl.2005.04.042

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3279–3283
Discovery of new diphenyloxazole derivatives containing
a pyrrolidine ring: Orally active prostacyclin mimetics. Part 2
Kouji Hattori,a,* Osamu Okitsu,a Seiichiro Tabuchi,a Kiyoshi Taniguchi,a Mie Nishio,b
Satoshi Koyama,b Jiro Sekib and Kazuo Sakanea
aMedicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, 2-1-6 Kashima,
Yodogawa-ku, Osaka 532-8514, Japan
bMedicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, 2-1-6 Kashima,
Yodogawa-ku, Osaka 532-8514, Japan
Received 18 February 2005; revised 11 April 2005; accepted 22 April 2005
Abstract—Synthetic and biological evaluation of novel diphenyloxazole derivatives containing a pyrrolidine ring, as a prostacyclin
mimetic without the PG skeleton, are described. Asymmetric reduction of a ketone using a chiral Ru complex and reductive ami-
nation by NaBH4 produces four isomers of the tetrahydronaphthalene ring and the pyrrolidine ring with high stereoselectivity.
FR193262 (4), (R,R)-diphenyloxazolyl pyrrolidine derivative, displays high potency and agonist efficacy at the IP receptor and
has good bioavailability in rats and dogs.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
mimetics. Our design strategy is shown in Figure 2,
and involved construction of the tetrahydronaphthalene
skeleton from the cyclohexene skeleton of 3, and the
diphenyloxazole part as an important pharmacophore
for PGI2 activity was modified by incorporation to a
pyrrolidine ring to fix to the best position (Fig. 1).
Prostacyclin (PGI2) is primarily derived from vascular
endothelium and plays an extremely important inhibi-
tory role in platelet aggregation and as a vasodilator
in maintaining homeostatic circulation.1 Despite fasci-
nating pharmacological properties, the inherent instabil-
ity of prostacyclin limits its therapeutic applicability.
Several groups have already disclosed novel PGI2
analogs without a PG skeleton, which led us to design
a novel PGI2 mimetics with improved chemical and meta-
bolic stability.2 Hamanaka and co-workers proposed the
tetrahydronaphthalene-5-oxyacetic acid skeleton such as
AP-227 (2) in which the cyclopentane ring in the PG
structure is removed to construct a new skeleton.3 Re-
cently, we have also disclosed the non-prostanoid struc-
ture FR181157: (S)-3 having potent PGI2 activity with
improved pharmacokinetic properties.4 After extensive
optimization of this series, we found the more rigid
structure FR193262 (4), which had improved potency
for PGI2 and affinity for the IP receptor. Herein, we
disclose a stereoselective synthesis and biological evalu-
ation of diphenyloxazole derivatives as novel PGI2
Keywords: Diphenyloxazole; Prostacyclin mimetic; IP receptor.
*
Corresponding author. Tel.: +81 6 6390 1220; fax: +81 6 6304
5435; e-mail: kouji_hattori@po.fujisawa.co.jp
Figure 1.
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.04.042

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K. Hattori et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3279–3283
Figure 2.
2. Chemistry
(TsDPEN), and triethylamine, provided the optical pure
alcohol 9 in 99% yield and 99% ee. The optically pure
alcohol 9 was smoothly converted to the corresponding
azide with inversion of configuration using diphenyl
phosphorazidate and DBU,6 which was followed by cata-
lytic hydrogenation with Pd/C to afford the amine 10 in
94% yield. Treatment of amine 10 with acyldiphenylox-
azole derivative 11 in the presence of catalytic p-toluene-
sulfonic acid under reflux gave the intermediate imine,
which was immediately reduced to a mixture of the
amine 12 and 13 in a 4:1 ratio (as determined by
NMR) using NaBH4 in 53% yield. The mixture was
purified by column chromatography to separate the
Our synthetic strategy for the diphenyloxazole deriva-
tives is illustrated in Scheme 1. We need to make this
compound by controlling stereochemistry at two benzyl
centers. The required optically active alcohol 9 was ob-
tained via the chiral Ru complex reported by Noyori
and co-workers.5 Asymmetric reduction of commer-
cially available 5-methoxy-1-tetralone 8 by the standard
procedure in a 5:2 formic acid–triethylamine azeotrope
containing 0.5 mol % of the chiral Ru complex, which
was prepared by reacting [RuCl2(g6-mesitylene)]2,
(S,S)-N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine
Scheme 1. Reagents and conditions: (a) [RuCl2(g6-mesitylene)]2, (S,S)-TsDPEN, HCO2H–(C2H5)3N; (b) DPPA, DBU, Tol; (c) Pd/C, MeOH;
(d) cat. p-TsOH, Tol, then NaBH4MeOH–THF; (e) BBr3, CH2Cl2; (f) ethyl bromoacetate, K2CO3, DMF; (g) SOCl2, CH2Cl2; (h) K2CO3, DMF;
(i) NaOH, EtOH.

K. Hattori et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3279–3283
3281
Scheme 2. Reagents and conditions: (a) K2CO3, DMF for 18 (95%), n-BuLi, THF for 19 (75%); (b) t-BuNF, THF; (c) ethyl bromoacetate, K2CO3,
DMF; (d) NaOH, EtOH; (e) diethylsuccinate, t-BuOK, t-BuOH; (f) HCl, AcOH; (g) SOCl2, CH2Cl2; (h) benzoin, Et3N, CH2Cl2; (i) AcONH4,
AcOH; (j) Pd/C, MeOH; (k) BBr3, CH2Cl2.
desired amine 12 and isomers 13. The enantiomerically
pure 12 was subsequently treated with BBr3 followed
by alkylation with ethyl bromoacetate to give the ethyl
ester 14. Treatment of 14 with SOCl2 and then K2CO3
formed the corresponding pyrrolidine ring. Finally,
hydrolysis of the ester furnished 4 in 91% yield and
>99% ee from 14. The stereoisomer 15 was prepared
from 13 and the other isomers 16 and 17 were prepared
using similar methods except for using (R,R)-TsDPEN.7
The assignment of the absolute configuration of 4 was
confirmed by the alternative synthetic.8 The synthetic
route of acyclic derivatives is illustrated in Scheme 2.
The enatiomerically pure 6 and 7 were prepared from
alkylation of the optically active amine 18 and alcohol
19 with diphenyloxazolylmethyl bromide, followed
prepared as a mixture of isomers from 22 using standard
method.
3. Biological activity
FR193262 (4) displayed potent PGI2 agonist activity
and especially good pharmacokinetic properties. Table
1 shows the in vitro SAR results for the diphenyloxazole
derivatives. PGI2 receptor binding was examined by the
conventional ligand binding assay based on the displace-
ment of [3H]-Iloprost from the cloned human IP recep-
tor.9 IC50 values in the functional assay were obtained
by measuring inhibition of ADP-induced platelet aggre-
gation using human, rat, dog, and monkey platelet rich
plasma. Compound 4 exhibited high binding affinity for
by the similar method. Compound
5 was also
Table 1. SAR of diphenyloxazole derivativesa
Compounds
Human
Function assay: IC50 (nM)
Rat Dog
630 71 780 72
Binding assay: Ki (nM)
Human
Monkey
59 0.25
4
15
19 3.8
640 21
870 41
63 9.7
1000
12 0.25
>10,000
>10,000
2200
16
17
5
>10,000
5000
(R-6)
(S-6)
(R-7)
(S-7)
190
1500
140
1400
1: Iloprost
2: AP-227
3: FR181157
2.5 0.14
150 17
60 5.2
6.5 0.12
54 0.36
5600 470
1200 170
1300 180
a Results are the average of two or three experiments.

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K. Hattori et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3279–3283
Table 2. Pharmacokinetic profile of 4a,b
po (fasted) n = 3
iv n = 3
Ba (%)
Dose (mg/kg)
Cmax (ng/mL)
AUC (ng h/mL)
t1/2b (h)
CLtot (mL/min/kg)
Rat
Dog
3.2
0.032
187 0.057
61.2 9.3
172 0.01
327 11.7
0.21 0.01
2.25 0.13
89.25 5.6
1.00 0.10
31
66
a Result were shown as the mean SE.
b Administration of 4 as the HCl salt.
Scheme 3.
the IP receptor with a Ki of 12 nM and high antiaggre-
gative potency in the functional assay with an IC50 of
19 nM. The enatiomer 17 was 3-fold less potent and
other isomers 15 and 16 were also approximately 30-fold
less potent under the same conditions. In general, the
acyclic analogs 5, 6, and 7 had decreased activity com-
pared to the pyrrolidine analogs. It is well known that
this class of PGI2 mimetic has significant species differ-
ence. Compound 4 also displayed similar results, since
inhibition of ADP-induced platelet aggregation using
rat, dog, and monkey platelet rich plasma was less
potent than human (rat: IC50 = 630 nM, dog:
IC50 = 780 nM, monkey: IC50 = 59 nM). Table 2 shows
the pharmacokinetic profiles in rats and dogs. Com-
pound 4 without a PG skeleton displayed good oral bio-
availability (rat: F = 31%, dog: F = 66%) in both species.
The detailed SAR results and pharmacological proper-
ties of 4 will be published in the future.
References and notes
1. (a) Bley, K. R.; Hunter, J. C.; Eglen, R. M.; Smith, J. A. M.
TIPS 1998, 19, 141; (b) Therapeutic Applications of Pros-
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In summary, we designed a series of diphenyloxazole
derivatives with tetrahydronaphthalene skeleton as a
prostacyclin mimetic compound 4, containing a pyrroli-
dine ring, which was prepared by stereoselective synthe-
sis at two chiral centers and exhibited high potency and
agonist efficacy at the IP receptor and good bioavailabil-
ity in rats and dogs. The detailed pharmacological work
will be published in the near future.
5. Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori,
N. J. Am. Chem. Soc. 1996, 118, 2521.
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Mathre, D. J.; Grabowski, J. J. J. Org. Chem. 1993, 58, 5886.
7. The purity of each isomer was determined by HPLC
(Chiralcel OD-R, 25 cm · 0.46 cm I.D., flow rate 0.8 mL/
min, 40% acetonitrile/0.02 M, pH 6.0, phosphate buffer)
Rt = 7.2 min for 4, 10.3 min for 15, 10.9 min for 16, and
15.2 min for 17. These compounds should be handled with
Acknowledgments
We express our thanks to Dr. David Barrett for his crit-
ical reading of the manuscript.

K. Hattori et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3279–3283
3283
extreme caution because of potent PGI2 agonist activity
and high skin permeability.
8. Compounds 4 and 16 were prepared from the optical active
amine 24, which was transformed from D-pyrroglutamic
acid, with a ratio 9:1 (Scheme 3).
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