Synthesis and biological properties of novel fluoroprostaglandin derivatives: Highly selective and potent agonists for prostaglandin receptors

Article abstract of DOI:10.2533/000942904777678073

Synthesis of novel 7,7-difluoroprostacyclin and 15-deoxy-15,15-difluoro- PGF_2α derivatives will be presented. These compounds show high affinity to prostaglandin receptors and potent biological activities.

Full text of DOI:10.2533/000942904777678073

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CHIMIA 2004, 58, No. 3
Chimia 58 (2004) 148–152
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
Synthesis and Biological Properties of
Novel Fluoroprostaglandin Derivatives:
Highly Selective and Potent Agonists
for Prostaglandin Receptors
Yasushi Matsumuraa*, Takashi Nakanob, Nobuaki Moria, and Yoshitomi Morizawab
Abstract: Synthesis of novel 7,7-difluoroprostacyclin and 15-deoxy-15,15-difluoro-PGF2α derivatives will be
presented. These compounds show high affinity to prostaglandin receptors and potent biological activities.
Keywords: Antiplatelet · Fluorination · Glaucoma · Prostaglandin · Receptor
lecular biology unveils novel physiological PG receptors have been characterized [6]. It
functions of PG receptors [6]. According to is reported that natural prostacyclin and its
Introduction
cDNA cloning and structural elucidation of agonists such as iloprost [9] and beraprost
PG receptors, exploratory research of new [10] have strong affinities not only for the
PG receptor agonists has been largely ac- IP receptor (prostacyclin receptor) but also
celerated [7]. In this article synthesis and for the EP1 receptor (one of the four PGE
some biological properties of novel difluo- receptor (EP) subtypes) [11]. Further re-
rinated PG derivatives will be presented. It search seeking for more selective prostacy-
gives an impression of the large applicabil- clin agonists is needed to elucidate the di-
ity and possibilities of a geminal difluoride verse functions of these receptors and the
moiety as one of the key units in drug de- overall mechanism of signal transduction at
sign to transform physical and biological the molecular level, and also to obtain po-
Fluorine-containing molecules have at-
tracted much attention recently in medici-
nal chemistry because fluorine has unique
physical properties such as small atomic
size, strong electron negativity, and high
carbon–fluorine bond energy [1]. Introduc-
tion of fluorine atoms into a variety of bio-
logically important substances, e.g. steroids
[2], amino acids and peptides [3], and nu-
cleosides [4], often brought significant im-
provement in their pharmacological pro-
files. A series of prostaglandin (PG) deriv-
atives are particularly attractive targets for
us because of their biological importance
and a broad range of therapeutic applicabil-
ity as medicines [5]. Recent advance in mo-
properties.
tentially valuable drugs without undesirable
side effects.
Our study has been focused on novel
Fluorinated Prostacyclin Derivatives prostacyclin derivatives fluorinated at the
7-position, particularly 7α-fluoroprostacy-
Since the discovery of prostacyclin clin (1) and 7,7-difluoroprostacyclin (AFP-
(PGI2) by Vane and coworkers in 1976 [8], 07) (2) (Fig. 1). The strong electron-with-
which is an unstable metabolite of arachi- drawing effect of fluorine atoms adjacent to
donic acid in the vascular cell wall, research the acid-sensitive enol ether should be par-
related to prostacyclin has been extensively ticularly effective in protecting against hy-
developed. Prostacyclin, a member of the drolysis.
PG family, has powerful actions as an an-
The monofluoroprostacyclin 1 bearing
tiplatelet agent which prevents platelet ag- a cyclobutyl group was synthesized by a
gregation, and as a vasodilator which in- three-component coupling approach [12] or
creases blood flow and produces hypoten- by use of methylenecyclopentanone [13]. It
sion. However, therapeutic applications of exerted potent antiplatelet and anti-anginal
natural prostacyclin are very limited due to activities in animal models in oral adminis-
its inherent chemical and metabolic insta- tration [14]. Next, we targeted a difluoro-
bility (Fig. 1). A large number of stabilized prostacyclin 2 to study the contribution of
analogs have been reported, and some have the second fluorine atom to the stability and
been used in clinical trials or marketed as biological activity. Retrosynthesis of AFP-
powerful agents for ischaemic peripheral 07 in both Route A and B was featured by
vascular disease, Raynaud’s disease, and difluorination of the Corey lactone and Wit-
primary pulmonary hypertension [5]. Re- tig reaction of the difluoro lactone (Scheme
cently, the structures and main functions of 1).
*Correspondence: Dr. Y. Matsumuraa
Tel.: + 81 436 23 3671
Fax: + 81 436 23 3672
E-Mail: Yasushi-Matsumura@agc.co.jp
aFine Chemicals Group
Chemicals Company
Asahi Glass Co., Ltd.
10 Goikaigan
Ichihara-shi, 290-8566, Japan
bResearch Center
Asahi Glass Co., Ltd.
1150 Hazawa-cho
Yokohama, 221-8755, Japan

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CHIMIA 2004, 58, No. 3
Fig. 1. Degradation of natural prostacyclin
and fluorinated prostacyclin analogs
Scheme 1. Retrosynthesis of AFP-07
Because separation of the (E)-5 isomer lactone 10 with N-fluorobenzensulfon-
Electrophilic fluorination is an attrac-
became a problem for scale-up, we further imide in the presence of manganese dibro-
studied the Wittig reaction of the difluoro- mide gave the desired difluoride 11 in
lactone 7 in the Route B. It was supposed 67% yield. Wittig reaction of 11 with
that the steric bulkiness of the side chain the phosphonium salt and sodium N,N-
should affect the selectivity of the Wittig re- bis(trimethylsilyl)amide in THF at 0 °C
action. The synthesis of the difluorolactone furnished the vinyl ether 12, as a 99.5:0.5
tive method to synthesize fluorinated build-
ing blocks from rather complicated mole-
cules. Several new electrophilic fluorinat-
ing agents have been developed [15],
however, selective difluorination of the α-
position of carbonyl compounds remains an
unsolved issue. We examined various fluo-
rinating agents and found N-fluorobenzen-
sulfonimide [11b] with manganese dibro-
mide to be suitable for the reaction of ke-
tones and esters (Table 1). Applying this
method, the Corey lactone 3 was converted
to the difluorolactone 4 in 57% yield and
the vinyl ether 5 was subsequently obtained
by Wittig reaction as a 87:13 mixture of the
(Z) and (E) isomers according to the Route
A [16].
11 is shown in Scheme 2.
mixture of the desired (Z) and (E) iso-
The Corey lactone 8 was transformed to mers in 50% yield (Scheme 3). After re-
the enone 9 in 75% yield by Moffatt oxida- moval of tert-butyldimethylsilyl group in
tion, Horner-Emmons reaction with the AcOH/THF/H2O and salt formation with
known phosphonate [17], and deprotection NaOH, the desired AFP-07 (2) was ob-
of the THP group. Reduction with di- tained in 95% yield.
isobutylaluminum
2,6-di(tert-butyl)-4-
The half lives of prostacyclin deriva-
methylphenoxide [18] gave a 91:9 mixture tives in an aqueous solution are shown in
of the (S) and (R) diastereomers. After pro- Table 2. The stability of fluorinated prosta-
tection of the diol with tert-butyl- cyclin derivatives, especially AFP-07 (2) is
dimethylsilyl groups, fluorination of the extraordinarily increased compared to nat-

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CHIMIA 2004, 58, No. 3
Table 1. Difluorination of ketones and esters
ural prostacyclin. Protonation of the double
bond in the vinyl ether, the rate-limiting
step in the hydrolysis, should be strongly re-
tarded by the adjacent difluoromethylene
group of 2 [19].
.)
.)
.)
The inhibitory activity of the derivatives
on ADP-induced human platelet aggrega-
tion in vitro is indicated as a relative poten-
cy to PGE1 in Table 2. The activity of 2 is
much higher than that of natural prostacy-
clin. In the binding study to PG receptors, 2
shows a very strong affinity for IP receptor
with little affinity for four kinds of the PGE
receptor (EP) subtype [20].
As for animal models in vivo, in the mi-
crocirculation of the hamster cheek pouch
oral administration of 2 at 1 or 10 µg/kg
produced a maximum percentage inhibition
of ADP-induced thrombi of 27% and 39%,
respectively [21]. Oral dosage of AFP-07
(2) at 40 µg/kg twice a day prevented chron-
ic hypoxic pulmonary hypertension in rats
exposed to a simulated altitude of 17,000 ft
for 28 days [22].
substrate
difluorinated product
yield [%] selectivity (di:mono)
93
80
>99:1
>98:2
complex mixture
Fluorinated PGF2α Derivatives
p
(S)/(R) 91:9
Glaucoma is one of the most common,
but serious eye diseases that gradually
steals sight without warning and often with-
out symptoms. Vision loss is caused by
damage to the optic nerve. The main risk
factor is thought to be high intraocular pres-
sure (IOP). Since the discovery that PGF2α
reduces intraocular pressure in an animal
model [23], extensive efforts have been
dedicated to develop PGF receptor (FP) ag-
onists as new antiglaucoma agents [24]. La-
tanoprost, the representative FP agonist,
has been first developed and widely used
for the treatment of glaucoma [24b]. How-
ever, long-term application of the drug
causes chronic adverse effects, such as
iris/skin pigmentation [25]. In the search
for a new FP agonist having more potent
IOP reducing activity and weaker side ef-
fects than latanoprost, we have recently
Scheme 2. Synthesis of difluorolactone 11
found
15-deoxy-15,15-difluoro-PGF2α,
AFP-168 which shows highly potent affin-
ity to the prostanoid FP receptor (Fig. 2)
[26].
(Z)-5/(E)-5 99.5:0.5
A synthetic route to AFP-168 (18) is
shown in Scheme 4. The synthesis started
from the Corey aldehyde 13 [27], which
was converted to the enone 15 by Horner-
Emmons reaction with the phosphonate 14
[28].Although a geminal difluoride unit has
drawn more attention recently in medicinal
chemistry, there is no general method to
prepare an allyl difluoride from the corre-
sponding enone efficiently [29]. We studied
the fluorination reaction and found that re-
action of the enone 15 with morpholinosul-
fur trifluoride [30] and successive depro-
tection of the benzoyl group with potassium
carbonate in MeOH gave the geminal diflu-
Scheme 3. Stereoselective Wittig reaction

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CHIMIA 2004, 58, No. 3
Table 2. Half life in saline and inhibitory effects on human platelet aggregation in vitro of
protacylin derivatives
acid of AFP-168 did not show the stimula-
tory effects on melanin content in cultured
B16-F10 melanoma cells [33]. It is sup-
posed the application of AFP-168 may
cause less pigmentation than latanoprost.
AFP-168 has a potent intraocular pressure
reducing effect in animal models [26] and
proceeds to clinical trial.
Compounds
Half life in salinea
Inhibitory effects on human
platelet aggregation in vitro
(PGE1 = 1)c
Prostacyclin
10 min
10
7α-Fluoroprostacyclin (1) 2–3 hb
AFP-07 (2) >90 d
3–13
237
Conclusions
a25 °C, pH 7, conc. 10 µg/ml. b37 °C, pH 7, conc. 2 µg/ml. cRelative potency, ADP = 2 µM
Synthesis and biological properties of
novel 7,7-difluoroprostacyclin (AFP-07, 2)
and 15-deoxy-15,15-difluoro-PGF2α (AFP-
168, 18) derivatives are presented. Further
studies of these PG agonists are in progress as
potential new drugs. New approaches using
geminally difluorinated building blocks in
drug design are important tools to improve
the physical and pharmacological profiles.
Acknowledgments
Fig. 2. Prostaglandin F2α derivatives
The authors thank Dr. Yasutaka Takagi, Mr.
Tadashi Nakajima, Mr. Atsushi Shimazaki, Dr.
Takeshi Matsugi, Ms. Wakana Goto, Dr. Masaa-
ki Kageyama, Dr. Hideaki Hara at Research &
Development Center, Santen Pharmaceutical
Co., Limited for pharmacological evaluation of
AFP-168.
Received: December 23, 2003
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The affinity for the FP receptor of the
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