Development of dual-acting agents for thromboxane receptor antagonism and thromboxane synthase inhibition. 3. Synthesis and biological activities of oxazolecarboxamide-substituted ω-phenyl-ω-(3-pyridyl)alkenoic acid derivatives and related compounds

Article abstract of DOI:10.1021/jm980173n

A novel series of oxazolecarboxamide-substituted ω-phenyl-ω-(3- pyridyl)alkenoic acid derivatives was discovered as potent dual-acting agents to block the TXA₂ receptor and to inhibit the thromboxane synthase (TRA/TSI). Synthesis, structure-activity relationship (SAR), and in vitro and in vivo pharmacology of this series of compounds are described. Modification of the series revolved around the oxazole moiety to increase the hydrophilicity of the compounds and to correlate the biological activity with lipophilicity of the compounds. The most potent in the series was (E)-7-[4- [4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]phenyl]-7-(3-pyridyl)hept- 6-enoic acid (14) with K(d) = 9.9 ± 0.4 nM for the thromboxane receptor antagonism and IC₅₀ = 55.0 ± 17.9 nM for thromboxane synthase inhibition. The compound 14 was a selective TRA/TSI which exhibited desirable characteristics for oral activity, 'shunt' effect to elevate PGI₂ level, and absence of agonist activity.

Full text of DOI:10.1021/jm980173n

5362
J . Med. Chem. 1998, 41, 5362-5374
Develop m en t of Du a l-Actin g Agen ts for Th r om boxa n e Recep tor An ta gon ism a n d
Th r om boxa n e Syn th a se In h ibition . 3. Syn th esis a n d Biologica l Activities of
Oxa zoleca r boxa m id e-Su bstitu ted ω-P h en yl-ω-(3-p yr id yl)a lk en oic Acid
Der iva tives a n d Rela ted Com p ou n d s
Kumiko Takeuchi,* Todd J . Kohn, Timothy A. True,† Dale E. Mais,‡ J ames H. Wikel, Barbara G. Utterback,
Virginia L. Wyss, and J oseph A. J akubowski
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285
Received September 11, 1998
A novel series of oxazolecarboxamide-substituted ω-phenyl-ω-(3-pyridyl)alkenoic acid derivatives
was discovered as potent dual-acting agents to block the TXA2 receptor and to inhibit the
thromboxane synthase (TRA/TSI). Synthesis, structure-activity relationship (SAR), and in
vitro and in vivo pharmacology of this series of compounds are described. Modification of the
series revolved around the oxazole moiety to increase the hydrophilicity of the compounds and
to correlate the biological activity with lipophilicity of the compounds. The most potent in the
series was (E)-7-[4-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]phenyl]-7-(3-pyridyl)hept-
6-enoic acid (14) with Kd ) 9.9 ( 0.4 nM for the thromboxane receptor antagonism and IC50
)
55.0 ( 17.9 nM for thromboxane synthase inhibition. The compound 14 was a selective TRA/
TSI which exhibited desirable characteristics for oral activity, “shunt” effect to elevate PGI2
level, and absence of agonist activity.
Thromboxane A2 (TXA2, 1)1 is an unstable endogenous
arachidonic acid metabolite that plays a pivotal role in
platelet aggregation and vasoconstriction and has been
implicated as a contributor to cardiovascular, renal, and
pulmonary diseases. Thromboxane synthase inhibitors
(TSIs) and thromboxane receptor antagonists (TRAs)
have been developed to treat such disorders.2 Because
of the lack of clinical efficacy with these agents, theo-
retical arguments have been made to support the
potentially superior antithrombotic efficacy of using a
combined TRA/TSI over either class of agent alone or
aspirin.3 The lack of efficacy of TSIs4 has been ascribed
to PGH2 (2) which accumulates due to the inhibition of
thromboxane synthase. Because of its agonist activity
at the thromboxane receptor, PGH2 activates the recep-
tor in the absence of TXA2 and nullifies the benefits of
reduced TXA2 levels. While TRAs appear to have greater
clinical potential than TSIs, they must show superior
efficacy than aspirin if they are to be widely utilized.
The combined TRA/TSI therapy has an advantage in
that its TSI activity would prevent the biosynthesis of
TXA2 while the accumulated PGH2 would be redirected
to produce beneficial prostaglandin metabolites such as
PGI2 (prostacyclin, 3), PGD2, and PGE2. This so-called
“shunt” effect is not achieved with the use of a TRA or
aspirin, in particular, which inhibits cyclooxygenase and
thus prostacyclin formation. TRA activity of the com-
bined dual-acting agent, meanwhile, would antagonize
the action of any residual TXA2 and accumulated PGH2.
Recently there has been an interest in developing agents
which combine a TRA activity with TSI within a single
molecule.5 Such agents would not only maximize the
beneficial effects of each agent but also address the
potential clinical problem of using two drugs with
different pharmacokinetics.3a Moreover, one could ex-
pect a synergistic effect from the combined therapeutic
agent in a single chemical entity.3c,6
In a preliminary report7 we have described a novel
series of ω-(3-pyridyl)alkenoic acids 4 as potent TRA/
TSIs that incorporate a phenyloxazole moiety. In this
paper we describe the synthesis, further structure-
activity relationship (SAR) study, and in vitro and in
vivo pharmacology of this series of compounds.
* Address all correspondence to this author.
† Current address: Glaxo Research Institute, Research Triangle
Park, NC 27709.
Com p ou n d Design
A simple approach to design compounds with dual
action for TRA/TSI in a single chemical entity has been
‡ Current address: Ligand Pharmaceuticals Inc., 10255 Science
Center Dr, San Diego, CA 92121.
10.1021/jm980173n CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/01/1998

A Novel TRA/ TSI, Phenyloxazoles
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27 5363
Sch em e 1a
a
(a) DL-Serine methyl ester, WSC, HOBT, NMM, DMF, 0 °C to rt; (b) (TfO)2O, Ph2SO, K3PO4, CH2Cl2, -78 to 0 °C, 2 h; (c) Ph3P, CCl4,
i-Pr2NEt, CH3CN, rt; (d) NiO2 or MnO2, PhH/dioxane (4:1) or PhH, rt, reflux or ultrasound; (e) 1.0 N NaOH, MeOH/THF (1:1); H+; (f)
RNH2 (9), WSC, HOBT, NMM, DMF, 0 °C to rt; (g) N-R-L-serinamide (10), WSC, HOBT, NMM, DMF, 0 °C to rt; (h) Br-Ph3P+(CH2)5CO2H,
1.0 M t-BuOK, THF, 0 °C, 2 h.
to incorporate the binding elements of each activity into
a “hybrid” structure, connecting each binding element
by a certain “spacer” allowing an appropriate distance.8
Such an approach has proven to be successful particu-
larly with the incorporation of a sulfonamide group, a
binding element for TRAs, into a TSI.9 It is important
to realize, however, that this “hybridization” should
introduce the desired pharmacological property in a new
molecule without the introduction of unwanted side
effects such as agonist activity and protein binding
which could be induced by the new physicochemical
nature of the compound designed.10 It is known that
sulfonamide-derived compounds have a tendency to
exhibit agonist activity.8 During the course of our TRA/
TSI research program, we therefore sought a different
binding element from a sulfonamide for TRA activity
and discovered a new class of phenyloxazole derivatives
4.7 A clinically useful TRA/TSI should possess well-
balanced pharmacological activities which secure >95%
of both thromboxane receptor blockade and suppression
of thromboxane synthesis at appropriate plasma levels.
We have undertaken further SAR study on this series
of compounds in order to minimize the protein binding
and obtain therapeutically useful in vivo activity.
Modification of the series centered around the oxazole
moiety to increase the hydrophilicity of the compounds
and to correlate the biological activity with the lipophi-
licity of the compounds.
pyridyl)alkenoic acid (A) is the preferred isomer for the
dual TRA/TSI activities. Two alternate routes to syn-
thesize the target compounds 14-36 from a common
intermediate, 4-[(3-pyridyl)carbonyl]benzoic acid (5), are
shown in Scheme 1. The benzoic acid 5 was prepared
in three steps from 3-bromopyridine: (1) formation of
methyl 4-[hydroxy(3-pyridyl)methyl]benzoate from a
reaction of 3-lithiopyridine with methyl 4-formylben-
zoate in Et2O at -78 °C to room temperature for 4 h
(47-64%); (2) oxidation of the resultant carbinol to the
ketone (MnO2, THF, reflux, overnight; 93%); and (3)
hydrolysis of the methyl ester (1.0 N NaOH, MeOH/THF
(1:1); H+). Alternatively, the same acid can be obtained
by J ones oxidation of 4-[(tert-butyldimethylsiloxy)meth-
yl]phenyl 3-pyridyl ketone which we reported pre-
viously.5a
In the first route A,7 the above crude acid was coupled
with DL-serine methyl ester in the presence of water-
soluble 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (WSC), 1-hydroxybenzotriazole hydrate
(HOBT), and N-methylmorpholine (NMM) in DMF at
room temperature overnight to give the N-acylserine
ester 6 in 55-81% yield. A preferred method for oxazo-
line formation is the treatment of the N-acylserine ester
6 with triflic anhydride and diphenyl sulfoxide in the
presence of K3PO4 in CH2Cl2 at -78 to 0 °C (65-75%).11
Modified Miller method12 gave 58-72% of the same
oxazoline 7 (Ph3P, CCl4, i-Pr2NEt, CH3CN, rt).7 Oxida-
tion of the oxazoline to oxazole was accomplished either
with NiO213 in benzene-dioxane at reflux (53%) or with
MnO2 in benzene at reflux (58%). The resultant methyl
oxazolyl carboxylate was hydrolyzed, and the crude acid
Ch em istr y
As previously reported,7 the (E)-isomer of ω-[4-[4-[(N-
substituted amino)carbonyl]-2-oxazolyl]phenyl]-ω-(3-

5364 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27
Takeuchi et al.
8 was coupled with an amine 9 under the same amide
coupling conditions described above to yield a pre-Wittig
ketone 13 (70-95%).
In the second route B, the benzoic acid 5 was coupled
with an N-substituted L-serinamide 10 (60-95%). Ox-
azoline formation was accomplished by the modified
Miller method12 in 60-80% yields. Nickel peroxide
oxidation of oxazoline 12 in benzene-dioxane (4:1) at
reflux yielded 38-74% of the corresponding oxazole 13
which was ready for the final Wittig reaction step. The
ketones thus generated by these two alternate routes
were then subjected to a Wittig reaction to yield the final
target compounds 14-36 in 60-95% yields ((5-carboxy-
pentyl)triphenylphosphonium bromide,5a t-BuOK, THF,
0 °C, 2 h). In all cases the Wittig reaction yielded (E)-
isomers predominantly (E/Z g 6:1).14,15
To have such interaction optimally at the lowest
conformational energy, the two termini need to be
located in a certain spatial and geometrical arrange-
ment within a certain distance. The optimal distance
between the binding elements of TRA and TSI was
found to be present in the C7 alkenoic acid chain linker
in the series of compounds A (n ) 4).7 If the above
hypotheses of hairpin turn and hydrogen bonding were
to be true for this series, A would form an 18-membered
macrocycle via hydrogen bonding between the amide
NH and the carboxyl terminus as shown above. We have
already seen a propensity of hydrogen bonding between
the amide hydrogen and the carboxylate of this series
of compounds.14 Such intramolecular interaction might
be favorably situating the molecule at the receptor site
and thereby crucially influencing the TRA activity. Even
though other conformational and binding modes might
be possible,21 we propose that the presence of an amide
and a carboxylic acid moiety and their interaction at
the receptor site plays a significant role for the antago-
nism of these compounds. For example, the compound
37 that lacks an amide tether was completely devoid of
the TRA activity, whereas even a â-elimination product
of an oxazoline derivative 38 which possesses an amide
functionality15 exhibited excellent TRA (Kd ) 27.3 ( 2.8
nM) as well as TSI (IC50 ) 35.7 ( 7.8 nM) activity. The
optimal distance of the acid side chain is consistent with
the reported value of 8-10 Å between the pyridyl
nitrogen and the carboxyl group of the TSI16 and TRA/
TSI’s binding elements.8 We extended our SAR on the
p-oxazole-substituted phenyl 3-pyridyl (E)-heptenoic
acid derivatives.
P h a r m a cology a n d Discu ssion
We have discovered a novel series of phenyloxazoles
A and their intermediates, oxazolines, as dual-acting
TRA/TSI agents. We have observed several character-
istics of these compounds relating to their biological
activities from our preliminary studies:7 first of all, the
(E)-isomer of the two geometrical alkenoic acids exhibits
more potent dual activity than the (Z)-isomer; second,
meta- and para-substituted phenyloxazoles are superior
TRA agents to the ortho-substituted derivatives; third,
the oxazoles and the corresponding oxazolines possess
comparable activities; and fourth, changes in the al-
kenoic acid chain length have a significant effect on both
the TRA and TSI activities. In other types of compounds
described as TRA/TSIs, preference for the (E)-isomer has
been reported.5a,e,f,16 In those sulfonamide-substituted
series reported,5a,e,f both the m- and p-sulfonamide
compounds, but not the ortho-substituted analogues,
were reported as potent TRA/TSIs. Though both the
oxazoles and the oxazoline intermediates were discov-
ered as novel and potent dual TRA/TSIs, we opted to
pursue the oxazole series for further SAR study rather
than the oxazolines because of the greater chemical
stability and somewhat better TRA activities observed
in the oxazole series.7 The effect of acid side-chain length
indicates that there is an optimal distance for each
binding element.8 The hairpin conformation hypothesis
proposed by Andersen et al.17 states that thromboxane
receptor binding requires a prostaglandin conformation
with a U-shaped or approximately parallel arrangement
of the R- and ω-side chains. The hypothesis has been
supported by the conformational analysis of TXA2 (1),
its receptor agonist U-46619 (40), and its potent receptor
antagonist such as S-145 (41),18 all of which have low-
energy conformations that adopt a hairpin-like turn
(shown by bold lines in the structures).19 Moreover,
Takasuka and co-workers supported the assumption
that a hairpin conformation is stabilized by hydrogen
bonding between the NH (sulfonamide) or OH (allylic
alcohol) of the ω-side chain and the carboxyl terminus
of the R-side chain.20 Using FTIR spectroscopy, they
have measured the degree of intramolecular hydrogen
bonding of 40 and 41 in CHCl3 and CCl4 and observed
12-15-membered macrocycles which were formed by
the intramolecular hydrogen bonds between the func-
tional groups of the R- and ω-side chains as shown:
The results in Table 1 show that the N-substituent
on the oxazole amide group, while affecting the TRA
activity significantly, did little to affect the TSI activity.
To determine whether the significant effect on TRA
activity was related to the lipophilicity of the amide

A Novel TRA/ TSI, Phenyloxazoles
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27 5365
Ta ble 1. In Vitro Activitiesa and clog Pb of Phenyloxazole Derivatives
K
P

5366 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27
Ta ble 1 (Continued)
Takeuchi et al.
K
P
a
The thromboxane receptor antagonism (TRA) and thromboxane synthase inhibition (TSI) were determined in triplicate using a human
platelet binding assay and human serum levels of TXB2; see the Experimental Section. The CLOGP program22 provided values for the
b
octanol/water partition coefficient.
position or the number of oxygens in the molecule,
affected the TRA potency, i.e., the lower the clog P, the
less potent the TRA (14 > 29 > 31 > 35). The difference
between the aromatic and cyclic rings, where clog P
differences were marginal, was not obvious (24 < 29,
whereas 25 ≈ 33). Stereochemistry rather than lipo-
philicity seems to have more effect on the TRA (19 >
18 > 20). It is interesting to note that the TRA activity
of the flexible side-chain compound 18 fell between those
of the rigid side-chain analogues 19 and 20, even though
the clog P of 18 was marginally higher than that of 19
and 20.
The modest effect on the TSI activity by the amide
substituent suggests that (1) the lipophilicity of the
compound does not affect the TSI activity; (2) those
substituents on the amide nitrogen do not participate
in a binding role for the TSI; and (3) interaction and/or
binding of the pyridyl ring and carboxylic acid terminus
F igu r e 1. Predicted log TRA from the correlation between
TRA and clog P. QSAR equation: log TRA ) 4.67((0.21) -
0.50((0.04)clog P (n ) 23; F ) 141.92; p < 0.001; r ) 0.93).
(the TSI pharmacophores) to thromboxane synthase is
possibly tight and is the key to enzyme inhibition. This
binding interaction might be steering the oxazole amide
side chain orienting itself in such a way that both the
electronic and steric effects of the oxazole and its side
chain have minimal effect on the enzyme inhibitory
activity.
terminus, CLOGP22 calculation was performed on these
compounds; the calculated values for the octanol/water
partition coefficient are listed in Table 1. We derived a
QSAR equation by plotting log TRA and clog P values:
The para-substituted phenyloxazole 14 (Table 1) was
the most potent TRA (Kd ) 9.9 nM) with excellent TSI
activity (IC50 ) 55 nM). It is important that a dual-
acting agent possesses the most potent TRA activity,
in particular, since the limited effectiveness of dual
agents such as CV415116 and R68070 (Ridogrel)24 could
well be attributed to their modest TRA activity. We
tested 14 for three important key factors in our develop-
ment of TRA/TSI agents: (1) oral activity, (2) shunt
effect to elevate prostacyclin formation, and (3) absence
of agonist activity. The ex vivo activity of 14 via the oral
route was examined in rats. Inhibition of TXA2 forma-
tion above 95% was observed at 1 h after dosing of 3
mg/kg (Figure 2). One of the advantages that a TSI
agent possesses is the so-called “shunt” effect whereby
accumulated PGH2, resulting from inhibition of TXA2
biosynthesis by the agent, is redirected to PGI2 synthe-
sis. We examined if such an effect was indeed exhibited
by our dual-acting compounds. Compound 14 signifi-
cantly increased the production of serum PGI2 in vitro
as measured by the amount of 6-keto-PGF1R, a stable
log TRA ) 4.67((0.21) - 0.50((0.04)clog P (1)
n ) 23; F ) 141.92; p < 0.001; r ) 0.93
where the numbers in parentheses are the standard
errors, n is the number of observations, F is a measure
for significance, p is the significance probability, and r
is the correlation coefficient. From this equation we
calculated predicted log TRA and generated a plot of
observed log TRA and predicted log TRA (Figure 1).
Regression analysis using the program J MP23 revealed
significant correlation between the TRA activity and
lipophilicity of the compounds: the more lipophilic the
compound, the more potent TRA activity it possessed.
The most potent TRA compound 14 (Kd ) 9.9 nM) had
a clog P value of 7.35. Compounds with clog P below
4.5 significantly lost the TRA activity commensurate
with the lower clog P values (35 > 16 > 26 > 27 > 34).
The same trend was observed with the cyclohexyl
analogues 14, 29, 31, and 35. The clog P values, not the

A Novel TRA/ TSI, Phenyloxazoles
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27 5367
Ta ble 2. Thromboxane Receptor Antagonism Activity:
Purified System versus Platelet-Rich Plasma
entry
Kd (nM)
IC50 (µM)a
clog P
14
22
28
20
36
9.9
52.2
58.2
62.6
165.4
0.4
0.5
5.0
5.0
4.0
7.35
5.54
5.72
4.88
5.24
a
Inhibition of U-46,619 (1 µM)-induced platelet aggregation in
human platelet-rich plasma (PRP).
in PRP was rather modest (IC50 ) 0.4 µM, Table 2)
possibly due to its protein binding.26 We speculated that
the difference in TRA activity in washed platelets (WP,
protein-free) versus PRP (protein-rich) was probably an
indication of the extent of protein binding of the
compound in PRP. We conducted platelet aggregation
studies on several selected compounds and attempted
to correlate the results with lipophilicity of the com-
pounds which may be an indicator of protein binding
(Table 2). The data do not appear to support our
speculation. For example, IC50 values of inhibition of
platelet aggregation in PRP for 14 and 22 were 0.4 and
0.5 µM, respectively, even though there was almost 2
orders of magnitude difference between their lipophi-
licity (∆clog P ) 1.81). Between 22 and 28, there was a
10-fold difference in their IC50 values (0.5 vs 5.0 µM)
even though their lipophilicity was about the same. The
cause for the poor inhibition of platelet aggregation in
PRP is not clear. One might speculate a problem by
metabolism of these compounds, but this has not been
elucidated.
F igu r e 2. Inhibition of ex vivo TSI activity of compound 14
in rat platelets as measured by TXB2 production.
Con clu sion
A novel series of oxazolecarboxamide-substituted
ω-phenyl-ω-(3-pyridyl)alkenoic acid derivatives was dis-
covered as potent dual-acting agents to block the TXA2
receptor and to inhibit the thromboxane synthase. The
most potent in the series was compound 14 which
exhibited desirable characteristics for oral activity,
“shunt” effect to elevate PGI2 level, and absence of
agonist activity. These compounds therefore are poten-
tially useful therapeutic agents for cardiovascular,
renal, and pulmonary disorders.
F igu r e 3. Prostacyclin shunt as measured by 6-keto-PGF1R
production in human serum.
metabolite of PGI2, produced (Figure 3). In contrast,
aspirin at the minimum dose to inhibit >95% TXA2
formation completely abolished PGI2 formation via its
nonspecific action against cyclooxygenase. The results
shown in Figure 3 also indicate that compound 14 is a
specific inhibitor of thromboxane synthase and is not
an inhibitor of cyclooxygenase or prostacyclin synthase.
As noted earlier, the sulfonamide derivatives are prone
to exhibit agonist activity10 even though many of those
analogues are excellent TRA agents, one of the most
noted examples of which is S-145.18 We tested 14 for
the pressor response to ensure that this series was
devoid of agonist activity.25 No pressor response was
observed by the iv administration of 14 up to 10 mg/kg
to pithed rats, whereas S-145 at 0.1 mg/kg iv raised
transient but significant mean arterial pressure at 1
min after dosing.
The best dual-acting compound was further tested for
its inhibition of platelet aggregation in human platelet-
rich plasma (PRP) since the activity in PRP would
represent the functional receptor antagonist property
in physiologically more relevant media. Moreover, this
additional test was important to identify compounds
that could function as dual antagonists in vivo where
protein binding might play a crucial role. We have found
that inhibition of platelet aggregation by compound 14
Exp er im en ta l Section
Gen er a l P r oced u r e. All solvents and reagents were pur-
chased from commercial sources and used as received, unless
otherwise indicated. Tetrahydrofuran (THF) was distilled from
sodium benzophenone ketyl prior to use. All reactions were
performed under a positive pressure of dry nitrogen. The
“preparative HPLC” was performed on a Waters PrepLC
System 500A with the solvent indicated. Analytical HPLC was
carried out on a Waters model 510 using a Nova C18 column
with CH3CN-MeOH-H2O solvent system which contained
0.5% NH4OAc or a Chiralcel OD-R column with CH3CN-H2O
solvent system which contained 0.1% NaClO4. Flash chroma-
tography was carried out on E. Merck Kieselgel 60 (230-400
mesh). 1H NMR spectra were recorded on a GE QE-300
(routine) and a Bruker AM-500 (NOE) spectrometer. The
chemical shifts are given in δ values relative to residual proton
resonances of the deuterated solvents used (CDCl3 7.26,
DMSO-d6 2.49). Field desorption (FDMS) and fast atom
bombardment mass spectra (FABMS) were obtained on a VG
ZAB-3F or VG 70-SE instrument. Optical rotation was ob-
tained on a Perkin-Elmer 241 polarimeter. Melting points are
uncorrected.

5368 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27
Takeuchi et al.
4-(3-P yr id ylca r bon yl)ben zoic Acid (5). To a cooled solu-
tion (-78 °C) of 10.6 mL (0.11 mol) of 3-bromopyridine in 1.2
L of anhydrous Et2O was added dropwise 93.8 mL (0.15 mol)
of 1.6 M n-BuLi in hexanes over a 1-h period. The turbid yellow
solution was stirred at -78 °C for 25 min, and then 24.62 g
(0.15 mol) of methyl 4-formylbenzoate in 300 mL of Et2O was
cannulated to the lithiopyridine solution. The mixture was
continually stirred at -78 °C for 2 h and at room temperature
for 2 more hours. The reaction was quenched with 400 mL of
brine and 200 mL of H2O. The organic layer was separated,
and the aqueous layer was extracted with 3 × 1.0 L of CH2Cl2.
To the combined organic layer was added 200 mL of MeOH to
dissolve the product that precipitated out. This was then dried
over MgSO4 and concentrated. The crude product was crystal-
lized from MeOH to afford 17.24 g (64%) of methyl 4-[hy-
droxy(3-pyridyl)methyl]benzoate: mp 151 °C; 1H NMR (CDCl3)
δ 8.62 (br s, 1H), 8.51 (br s, 1H), 8.02 (d, J ) 8.3 Hz, 2H), 7.70
(d, J ) 7.9 Hz, 1H), 7.45 (d, J ) 8.3 Hz, 2H), 7.30 (br s, 1H),
5.93 (s, 1H), 3.90 (s, 3H), 2.92 (br s, 1H); FDMS 244 (M + 1).
Anal. (C14H13NO3‚0.16CH3OH) C, H, N.
anhydrous CH2Cl2 was added dropwise 0.616 g (3.05 mmol)
of diphenyl sulfoxide in 6.1 mL of CH2Cl2 over a 10-min period.
After the mixture stirred at -78 °C for 30 min, 3.23 g (15.2
mmol) of K3PO4 was added, followed by 0.500 g (1.52 mmol)
of the serine ester 6 in 6.4 mL of CH2Cl2. The mixture was
stirred at -78 °C for another 30 min and then at 0 °C for 30
min. The reaction was quenched with 35 mL of H2O, and the
layers were separated. The aqueous layer was extracted with
2 × 50 mL of CH2Cl2. The combined organic layer was dried
over MgSO4 and concentrated. Flash chromatography with
EtOAc-CH2Cl2 (4:1) which contained 1% MeOH gave 0.306 g
(65%) of the oxazoline ester 7: mp 148 °C; 1H NMR (CDCl3) δ
8.98 (s, 1H), 8.82 (d, J ) 4.0 Hz, 1H), 8.12 (d, J ) 8.3 Hz, 2H),
8.12 (buried, 1H), 7.84 (d, J ) 8.3 Hz, 2H), 7.47 (dd, J ) 7.9,
5.0 Hz, 1H), 5.00 (dd, J ) 10.6, 8.0 Hz, 1H), 4.75 (dd, J ) 8.6,
8.2 Hz, 1H), 4.64 (dd, J ) 10.5, 9.0 Hz, 1H), 3.83 (s, 3H); FDMS
310 (M+). Anal. (C17H14N2O4) C, H, N.
2-[4-(3-P yr id ylca r b on yl)p h en yl]oxa zole-4-ca r b oxylic
Acid (8). To a solution of 606.6 mg (2.0 mmol) of the oxazoline
ester 7 in 20 mL of benzene-1,4-dioxane (4:1) was added 1.2
g (2× wt) of NiO2. The black suspension was heated at reflux
(∼95 °C bath temperature) for 2 h. Another 1.2 g of NiO2 (total
4× wt of the oxazoline) was added, and the mixture was heated
at reflux for 3 h. The reaction mixture was cooled to room
temperature and diluted with ca. 70 mL of CH2Cl2. This was
filtered through a Celite pad. The solid (including Celite) was
returned to the reaction flask, suspended in 50 mL of EtOAc-
CH2Cl2 (1:1), cooled to 0 °C, and treated with ca. 30 mL of
14% NH4OH at 0 °C for 10-15 min. The suspension was
diluted with ca. 100 mL of CH2Cl2 and filtered through a Celite
pad. This treatment of the solids was repeated twice. The
combined filtrate was then transferred to a separatory funnel,
and the layers were separated. The organic layer was washed
with ca. 100 mL of brine, and the aqueous layer was back-
extracted with 2 × 150 mL of CH2Cl2. The combined organic
layer was dried over MgSO4, concentrated, and purified by
flash chromatography with EtOAc-AcOH-CH2Cl2 (49:1:50)
to afford 321.2 mg (53%) of methyl 2-[4-(3-pyridylcarbonyl)-
phenyl]oxazole-4-carboxylate: mp 154-157 °C; 1H NMR (CDCl3)
δ 8.99 (d, J ) 1.7 Hz, 1H), 8.83 (dd, J ) 4.6, 1.2 Hz, 1H), 8.34
(s, 1H), 8.25 (d, J ) 8.4 Hz, 2H), 8.13 (dt, J ) 7.9, 1.8 Hz, 1H),
7.91 (d, J ) 8.4 Hz, 2H), 7.47 (m, 1H), 3.96 (s, 3H); FDMS 308
(M+). Anal. (C17H12N2O4) C, H, N.
To a solution of 2.01 g (6.5 mmol) of methyl 2-[4-(3-
pyridylcarbonyl)phenyl]oxazole-4-carboxylate in 40 mL of
THF-MeOH (1:1) was added 13.0 mL (13.0 mmol) of 1 N
NaOH at 0 °C. The milky solution was then stirred at room
temperature for 1.5 h. This was then neutralized with 13.0
mL of 1 N HCl and concentrated to dryness. The white solid
8 (containing 28.4% of NaCl by weight) was dried over P2O5
under vacuum overnight and used without further purification.
(Analytical sample was prepared by washing the crude product
with H2O and acetone.) 8: mp 281-282 °C; 1H NMR (DMSO)
δ 8.92 (s, 1H), 8.88 (s, 1H), 8.82 (br d, J ) 2.4 Hz, 1H), 8.15 (d,
J ) 8.3 Hz, 2H), 8.13 (buried, 1H), 7.91 (d, J ) 8.3 Hz, 2H),
7.59 (d, J ) 7.7, 4.8 Hz, 1H); FDMS 294 (M+). Anal.
(C16H10N2O4) C, H, N.
Am in e F or m a tion . Amines 9, not commercially available,
were prepared from corresponding alcohols in three steps.
3-(Cyclohexyloxy)propanol was prepared from 3-phenoxypro-
pionic acid in two steps (71%): (1) hydrogenation (H2, 5% Rh/
C, HOAc, 50 °C, 4 h) and (2) reduction of the acid (1.0 M LAH,
Et2O, 0 °C): 1H NMR (CDCl3) δ 3.78 (t, J ) 5.3 Hz, 2H), 3.66
(t, J ) 5.6 Hz, 2H), 3.26 (m, 1H), 2.87 (br s, 1H), 1.90-1.22
(m, 12H); FDMS 159 (M + 1).
A suspension of 9.34 g (4× by weight) of MnO2 and 2.34 g
(9.6 mmol) of the above carbinol in 100 mL of THF was heated
at 70 °C (bath temperature) overnight (17 h). The mixture was
filtered through a Celite pad with THF wash. The filtrate was
concentrated to yield 1.86 g (81%) of methyl 4-(3-pyridylcar-
1
bonyl)benzoate as a yellow fluffy solid which was clean by H
NMR: mp 144-146 °C; 1H NMR (CDCl3) δ 9.00 (br s, 1H),
8.84 (br s, 1H), 8.17 (d, J ) 8.4 Hz, 2H), 8.14 (dd, J ) ∼8.6,
1.3 Hz, 1H), 7.85 (d, J ) 8.3 Hz, 2H), 7.49 (dd, J ) 7.6, 5.0 Hz,
1H), 3.97 (s, 3H); FDMS 241 (M+). Anal. (C14H11NO3‚0.1C4H8O2)
C, H, N.
To a solution of 9.03 g (37.4 mmol) of the benzoate ester in
150 mL of THF-MeOH (1:1) was added 56.2 mL (56.2 mmol)
of 1.0 N NaOH at 0 °C. After 5 min, the ice bath was removed,
and the turbid solution was stirred at room temperature for 2
h. The mixture was then neutralized with 56.2 mL (56.2 mmol)
of 1.0 N HCl and concentrated to dryness. After drying over
P2O5 under vacuum overnight, the crude product 5 (containing
27.8% NaCl by weight) was used in the next reaction without
further purification. (Note: The acid 5 does not dissolve well
in conventional solvents such as MeOH and CH2Cl2, thus
making the purification difficult. Initially the acid was purified
by flash chromatography using MeOH-AcOH-CH2Cl2 (5:1:
94) which resulted in low yield. It was found that NaCl did
not interfere with the amide coupling in the next step; thus
no further purification was necessary for the hydrolysis
1
product.) 5: mp 266-267 °C; H NMR (DMSO) δ 13.31 (d, J
) 1.3 Hz, 1H), 8.86 (s, 1H), 8.81 (dd, J ) 4.9, 1.0 Hz, 1H), 8.11
(m, 1H), 8.07 (d, J ) 8.3 Hz, 2H), 7.84 (d, J ) 8.2 Hz, 2H),
7.58 (dd, J ) 7.9, 4.9 Hz, 1H); FDMS 227 (M+). Anal.
(C13H9NO3) C, H, N.
N-[4-(3-P yr id ylca r bon yl)ben zoyl]-DL-ser in e Meth yl Es-
ter (6). To a mixture of 2.29 g (10 mmol) of the benzoic acid 5,
1.57 g (10 mmol) of DL-serine methyl ester hydrochloride, and
1.36 g (10 mmol) of HOBT in 60 mL of DMF were added 2.2
mL (20 mmol) of NMM and 1.93 g (10 mmol) of water-soluble
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochlo-
ride (WSC) at 0 °C. The mixture was stirred overnight while
allowed to warm slowly to 20 °C on its own (16.5 h). The
reaction mixture was taken up in 500 mL of EtOAc and
washed with 2 × 250 mL of H2O and 250 mL of brine which
were back-extracted with 2 × 500 mL of EtOAc. The combined
organic layers were dried over MgSO4 and concentrated.
Preparative HPLC of the residue eluting with 3% MeOH-
CH2Cl2 gave 2.67 g (81%) of the hygroscopic serine ester 6:
1H NMR (CDCl3) δ 8.93 (s, 1H), 8.80 (d, J ) 4.1 Hz, 1H), 8.10
(d, J ) 7.9 Hz, 1H), 7.94 (d, J ) 8.3 Hz, 2H), 7.81 (d, J ) 8.2
Hz, 2H), 7.47 (dd, J ) 7.8, 4.9 Hz, 1H), 7.35 (d, J ) 7.3 Hz,
1H), 4.87 (dt, J ) 7.4, 3.7 Hz, 1H), 4.12 (dd, J ) 11.3, 3.5 Hz,
1H), 4.04 (dd, J ) 11.3, 3.2 Hz, 1H), 3.80 (s, 3H), 2.71 (br s,
1H); FDMS 329 (M + 1). Anal. (C17H16N2O5) C, H, N.
(()-2-(Tetrahydopyran-2-ylmethoxy)ethanol was prepared
from (()-tetrahydropyran-2-methanol in two steps (57%): (1)
alkylation (NaH, THF, 75 °C; methyl bromoacetate, 0 °C) and
(2) reduction of the ester (LAH, THF, 0 °C): 1H NMR (CDCl3)
δ 4.00 (br d, J ) 11.2 Hz, 1H), 3.70 (br d, J ) 4.1 Hz, 2H),
3.58 (m, 2H), 3.46 (m, 4H), 2.85 (s, 1H), 1.84 (m, 1H), 1.50 (m,
4H), 1.32 (m, 1H); FDMS 161 (M + 1). Anal. (C8H16O3) C, H.
Meth yl (4S)-4,5-Dih yd r o-2-[4-(3-p yr id ylca r bon yl)p h en -
h yl]oxa zole-4-ca r boxyla te (7). To a cooled solution (-78 °C)
of 0.38 mL (2.28 mmol) of triflic anhydride in 4.5 mL of
Likewise, 2-(cyclohexylmethoxy)ethanol was prepared from
cyclohexylmethanol in two steps (12%): 1H NMR (CDCl3) δ

A Novel TRA/ TSI, Phenyloxazoles
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27 5369
3.70 (t, J ) 4.7 Hz, 2H), 3.50 (t, J ) 4.6 Hz, 2H), 3.26 (d, J )
6.5 Hz, 2H), 2.34 (br s, 1H), 1.71 (m, 6H), 1.18 (m, 3H), 0.88
(m, 2H); FDMS 158 (M+).
mmHg; 1H NMR (CDCl3) δ 3.59 (dt, J ) 9.3, 5.9 Hz, 1H), 3.39
(dt, J ) 9.3, 6.1 Hz, 1H), 3.10 (dq, J ) 6.2, 6.2 Hz, 1H), 2.85
(t, J ) 6.7 Hz, 2H), 2.42 (br s, 2H), 1.84-1.62 (m, 7H), 1.36
(m, 1H), 1.29-0.87 (m, 8H). Anal. (C11H23NO) C, H, N.
Ser in a m id e F or m a tion . Serinamides 10 were prepared
in two steps from N-Boc-L-serine and various amines as
described for N-(4-cyclohexylbutyl)-L-serinamide:29 (1) amide
coupling (WSC, HOBT, NMM, DMF, rt, overnight) and (2)
deprotection of Boc group (CF3CO2H, CH2Cl2, 0 °C to rt).
N-(Cyclop r op ylm eth yl)-L-ser in a m id e: 1H NMR (CDCl3)
δ 7.47 (br s, 1H), 3.85 (dd, J ) 10.7, 5.1 Hz, 1H), 3.70 (dd, J )
10.7, 6.0 Hz, 1H), 3.44 (t, J ) 5.5 Hz, 1H), 3.12 (ddd, J ) 18.4,
12.3, 5.4 Hz, 2H), 1.81 (br s, 3H), 0.95 (m, 1H), 0.51 (dt, J )
7.5, 5.4 Hz, 2H), 0.21 (dt, J ) 5.2, 4.9 Hz, 2H); FDMS 159 (M
+ 1).
The general procedure for amine formation was as follows.
Each alcohol was converted to the corresponding azide via a
mesylate in one-pot two reaction steps (70-99%): MsCl, Et3N,
DMF, 0 °C 1 h; then aqueous NaN3, 60-70 °C, 1-5.5 h (for a
pyran derivative, toluene was used as solvent and n-Bu4N+Br-
was added as a phase-transfer catalyst).27 The azide was then
reduced to a primary amine by Vaultier’s method:28 Ph3P, H2O,
THF, rt, overnight (89-98%).
2-(Ben zyloxy)eth yla m in e: 1H NMR (CDCl3) δ 7.33 (m,
5H), 4.53 (s, 2H), 3.51 (t, J ) 5.2 Hz, 2H), 2.89 (br t, J ) 4.6
Hz, 2H), 1.50 (br s, 2H); FABMS calcd for C9H14NO 152.1075,
found 152.1082, M + 1.
3-(4-Meth oxyp h en yl)p r op yla m in e: 1H NMR (CDCl3) δ
7.09 (d, J ) 8.5 Hz, 2H), 6.81 (d, J ) 8.5 Hz, 2H), 3.77 (s, 3H),
2.70 (t, J ) 7.0 Hz, 2H), 2.58 (t, J ) 7.7 Hz, 2H), 1.72 (m, 2H),
1.24 (s, 2H); FDMS 165 (M+).
N-Ben zyl-L-ser in a m id e: 1H NMR (CDCl3) δ 7.82 (br s,
1H), 7.26 (m, 5H), 4.42 (ddd, J ) 16.7, 15.0, 6.0 Hz, 2H), 3.85
(dd, J ) 10.8, 5.2 Hz, 1H), 3.70 (dd, J ) 10.8, 5.3 Hz, 1H),
3.44 (m, 1H), 2.22 (br s, 3H); FDMS 195 (M + 1). Anal.
(C10H14N2O2) C, H, N.
2-(Cycloh exyloxy)eth yla m in e: 1H NMR (CDCl3) δ 3.48
(t, J ) 5.1 Hz, 2H), 3.23 (m, 1H), 2.84 (t, J ) 5.3 Hz, 2H), 1.90
(m, 2H), 1.72 (m, 2H), 1.56 (m, 2H), 1.24 (m, 6H); FABMS calcd
for C8H18NO 144.1388, found 144.1386, M + 1.
Gen er a l P r oced u r e for P r ep a r a tion of Bisa m id es 11.
N-(4-Cycloh exylbu tyl)-Nr-[4-(3-pyr idylcar bon yl)ben zoyl]-
L-ser in a m id e. To a cooled (0 °C) mixture of 3.53 g (15.5 mmol)
of the crude benzoic acid 5, 3.77 g (15.5 mmol) of N-(4-
cyclohexylbutyl)-L-serinamide, and 2.10 g (15.5 mmol) of HOBT
in 70 mL of anhydrous DMF were added 2.0 mL (15.5 mmol)
of NMM and 2.98 g (15.5 mmol) of WSC. After the mixture
stirred for 1 h at 0 °C, the ice bath was removed, and the
reaction mixture was stirred at room temperature for 5.5 h.
The reaction was quenched with ca. 200 mL of H2O, and the
mixture was extracted with 3 × 500 mL of EtOAc which was
washed with 250 mL of H2O and 200 mL of brine. The
combined extracts were dried over MgSO4, concentrated, and
purified by preparative HPLC with 3-4% MeOH-CH2Cl2 as
eluent to yield 4.56 g of the bisamide (65%): 1H NMR (CDCl3)
δ 8.96 (s, 1H), 8.81 (dd, J ) 4.9, 1.4 Hz, 1H), 8.11 (dt, J ) 7.9,
1.8 Hz, 1H), 7.94 (d, J ) 8.3 Hz, 2H), 7.83 (d, J ) 8.2 Hz, 2H),
7.64 (d, J ) 6.9 Hz, 1H), 7.46 (m, 1H), 7.09 (t, J ) 5.5 Hz,
1H), 4.67 (m, 1H), 4.19 (dd, J ) 11.3, 3.5 Hz, 2H), 3.76 (dd, J
) 11.1, 5.5 Hz, 1H), 3.25 (dt, J ) 6.8, 6.2 Hz, 2H), 1.63-0.77
(m, 17H); FDMS 452 (M + 1).
3-(Cycloh exyloxy)p r op yla m in e: 1H NMR (CDCl3) δ 3.48
(t, J ) 6.2 Hz, 2H), 3.17 (m, 1H), 2.76 (t, J ) 6.7 Hz, 2H), 1.85
(m, 2H), 1.67 (m, 4H), 1.47 (br s, 2H), 1.19 (m, 6H); FABMS
calcd for C9H20NO 158.1545, found 158.1554, M + 1.
(()-2-(Tetr a h yd r op yr a n -2-ylm eth oxy)eth yla m in e: 1H
NMR (CDCl3) δ 4.00 (dt, J ) 11.3, 2.0 Hz, 1H), 3.54-3.35 (m,
8H), 2.86 (br s, 2H), 1.85-1.80 (m, 1H), 1.60-1.45 (m, 4H),
1.31 (m, 1H); FABMS calcd for C8H18NO2 160.1338, found
160.1347, M + 1.
2-(Cycloh exylm eth oxy)eth yla m in e: 1H NMR (CDCl3) δ
3.44 (t, J ) 5.2 Hz, 2H), 3.24 (d, J ) 6.5 Hz, 2H), 2.86 (t, J )
5.1 Hz, 2H), 1.78-1.55 (m, 8H), 1.20 (m, 3H), 0.94 (m, 1H);
FABMS calcd for C9H20NO 158.1545, found 158.1558, M + 1.
(cis)- an d (tr a n s)-3-(4-Meth oxycycloh exyl)pr opylam in e.
A solution of 1.18 g (7.1 mmol) of 3-(4-methoxyphenyl)propyl-
amine in 50 mL of dioxane was hydrogenated at 2000 psi and
at 160 °C for 16 h in the presence of 0.5 g of 5% Ru/Al2O3. The
catalyst was removed by filtration, and the filtrate was
concentrated to dryness. Preparative HPLC of the crude
product by elution with 10% (10% concentrated NH4OH in
MeOH)-CH2Cl2 furnished 723.5 mg (59%) of the cis/trans
mixture of cyclohexylpropylamine (cis:trans ) ∼3:1 by 1H
NMR): 1H NMR (CDCl3, cis-isomer only) δ 3.37 (br s, 1H),
3.27 (s, 3H), 2.64 (t, J ) 7.0 Hz, 2H), 2.10-0.87 (M, 15H);
FDMS 172 (M + 1).
4-(Cycloh exyloxy)bu tyla m in e. A solution of 2.0 g of
4-phenoxybutylamine in 95 mL of EtOH was hydrogenated at
60 psi in the presence of 2.0 g of 5% Rh/C at 60 °C for 24 h.
The catalyst was removed by filtration, and the filtrate was
concentrated. Preparative HPLC eluting with 10% (10%
concentrated NH4OH in MeOH)-CH2Cl2 furnished 279.7 mg
(13%) of the reduction product along with 461.2 mg (23%) of
the starting material: 1H NMR (CDCl3) δ 3.46 (t, J ) 6.1 Hz,
2H), 3.21 (m, 1H), 2.75 (br t, 2H), 2.00-1.15 (m, 16H); FDMS
172 (M+).
3-[Cycloh exyl(m eth yl)m eth oxy]p r op yla m in e. To a so-
lution of 38.4 g (0.3 mol) of cyclohexyl(methyl)carbinol in 100
mL of benzene was added 2.5 g of NaOMe in one portion at
20 °C, followed by dropwise addition of 16.9 g (0.32 mol) of
acrylonitrile. The mixture was stirred at room temperature
for 2 h, heated at reflux for 1 h, and then left standing
overnight at room temperature. The reaction mixture was
acidified with HOAc and filtered. The filtrate was concentrated
on the steam bath, and the residue was distilled under vacuum
to yield 30.3 g of colorless oil (bp 119-121 °C/6 mmHg). The
propionitrile obtained, 20 g (0.11 mol), in 100 mL of EtOH and
25 mL of liquid ammonia was hydrogenated at 1300 psi in the
presence of 0.5 teaspoon (ca. 8 g) of Raney nickel at 80-85 °C
for 2 h. The catalyst was filtered off, and the filtrate was
concentrated. Vacuum distillation of the residue gave 16.2 g
of the desired amine (44% for two steps): bp 108-109 °C/7
Gen er a l P r oced u r e for P r ep a r a tion of P r e-Wittig
Keton es 13 (via r ou te A; R gr ou p is ita licized ). N-[2-
(Cycloh exylm eth oxy)eth yl]-2-[4-(3-p yr id ylca r bon yl)p h en -
yl]-4-oxa zoleca r boxa m id e (13a ). To a cooled (0 °C) mixture
of 419.0 mg (1.02 mmol) of the crude oxazolecarboxylic acid 8
(71.6% purity), 206.6 mg (1.53 mmol) of HOBT, and 240.5 mg
(1.53 mmol) of 2-(cyclohexylmethoxy)ethylamine in 10 mL of
anhydrous DMF were added 293.2 mg (1.53 mmol) of WSC
and 168 µL of NMM. The mixture was stirred for 23 h while
allowed to warm slowly to room temperature on its own. The
reaction was quenched with 35 mL of H2O, and the mixture
was extracted with 3 × 50 mL of EtOAc. The combined organic
layer was washed with 3 × 100 mL of H2O and 100 mL of
brine, dried over MgSO4, and concentrated. Flash chromatog-
raphy with 4% MeOH-CH2Cl2 furnished 417.3 mg (94%) of a
1
yellow sticky solid: mp 121-124 °C; H NMR (CDCl3) δ 9.03
(s, 1H), 8.87 (d, J ) 3.9 Hz, 1H), 8.31 (s, 1H), 8.20 (d, J ) 8.3
Hz, 2H), 8.19 (buried, 1H), 7.94 (d, J ) 8.3 Hz, 2H), 7.53 (dd,
J ) 7.9, 4.9 Hz, 1H), 7.52 (br t, 1H), 3.63 (m, 4H), 3.31 (d, J )
6.4 Hz, 2H), 1.84-0.97 (m, 10H); FDMS 433 (M+). Anal.
(C25H27N3O4) C, H, N.
N-(2-P h en oxyeth yl)-2-[4-(3-p yr id ylca r bon yl)p h en yl]-4-
oxa zoleca r boxa m id e (13b): 1H NMR (CDCl3) δ 8.97 (s, 1H),
8.80 (d, J ) 4.1 Hz, 1H), 8.29 (s, 1H), 8.14 (d, J ) 8.3 Hz, 2H),
8.12 (buried, 1H), 7.88 (d, J ) 8.2 Hz, 2H), 7.52 (distorted t, J
) ∼5.9 Hz, 1H), 7.44 (dd, J ) 7.9, 5.0 Hz, 1H), 7.25 (dd, J )
8.3, 7.5 Hz, 2H), 6.93 (m, 3H), 4.13 (t, J ) 5.1 Hz, 2H), 3.85
(dt, J ) 5.4, 5.4 Hz, 2H); FDMS 413 (M+). Anal. (C24H19N3O4)
H, N; C: calcd, 69.73; found, 70.29.
N-(4-P h en oxybu tyl)-2-[4-(3-p yr id ylca r bon yl)p h en yl]-4-
oxa zoleca r boxa m id e (13c): 1H NMR (CDCl3) δ 9.01 (s, 1H),
8.84 (d, J ) 3.9 Hz, 1H), 8.29 (s, 1H), 8.16 (d, J ) 8.3 Hz, 2H),
8.16 (buried, 1H), 7.91 (d, J ) 8.4 Hz, 2H), 7.50 (dd, J ) 7.9,

5370 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27
Takeuchi et al.
4.9 Hz, 1H), 7.26 (dd, J ) 8.2, 7.6 Hz, 2H), 7.19 (br t, 1H),
6.92 (m, 3H), 4.02 (t, J ) 5.7 Hz, 2H), 3.55 (dt, J ) 6.4, 6.3
Hz, 2H), 1.89 (m, 4H); FDMS 441 (M+). Anal. (C26H23N3O4) C,
H, N.
N-(5-P h en oxypen tyl)-2-[4-(3-p yr id ylca r bon yl)p h en yl]-
4-oxa zoleca r boxa m id e (13d ): mp 107-110 °C; 1H NMR
(CDCl3) δ 9.01 (s, 1H), 8.85 (br d, J ) 3.9 Hz, 1H), 8.29 (s,
1H), 8.19 (d, J ) 8.3 Hz, 2H), 8.16 (buried dt, 1H), 7.92 (d, J
) 8.4 Hz, 2H), 7.50 (dd, J ) 7.9, 4.9 Hz, 1H), 7.26 (m, 2H),
7.08 (t, J ) 5.8 Hz, 1H), 6.90 (m, 3H), 3.98 (t, J ) 6.3 Hz, 2H),
3.50 (dt, J ) 6.6, 6.6 Hz, 2H), 1.90-1.57 (m, 6H); FDMS 455
(M+). Anal. (C27H25N3O4) C, H, N.
N-[2-(Ben zyloxy)eth yl]-2-[4-(3-pyr idylcar bon yl)ph en yl]-
4-oxa zoleca r boxa m id e (13e): mp 133-136 °C; 1H NMR
(CDCl3) δ 9.01 (s, 1H), 8.85 (br d, J ) 3.8 Hz, 1H), 8.29 (s,
1H), 8.21 (d, J ) 8.3 Hz, 2H), 8.15 (dt, J ) 7.9, 1.7 Hz, 1H),
7.93 (d, J ) 8.3 Hz, 2H), 7.49 (dd, J ) 8.0, 4.9 Hz, 1H), 7.43
(br s, 1H), 7.34 (m, 5H), 4.59 (s, 2H), 3.68 (s, 4H); FDMS 427
(M+). Anal. (C25H21N3O4) C, H, N.
N-[3-(4-Meth oxyph en yl)pr opyl]-2-[4-(3-p yr id ylca r bon -
yl)p h en yl]-4-oxa zoleca r boxa m id e (13f): 1H NMR (CDCl3)
δ 9.00 (s, 1H), 8.84 (br d, J ) 3.4 Hz, 1H), 8.28 (s, 1H), 8.18 (d,
J ) 8.2 Hz, 2H), 8.16 (buried, 1H), 7.92 (d, J ) 8.2 Hz, 2H),
7.48 (dd, J ) 7.6, 4.9 Hz, 1H), 7.13 (d, J ) 8.4 Hz, 2H), 7.04
(br t, 1H), 6.83 (d, J ) 8.4 Hz, 2H), 3.76 (s, 3H), 3.48 (dt, J )
6.7, 6.6 Hz, 2H), 2.67 (t, J ) 7.5 Hz, 2H), 1.95 (tt, J ) 7.3, 7.2
Hz, 2H); FDMS 441 (M+). Anal. (C26H23N3O4) C, H, N.
N-(3-Eth oxypr opyl)-2-[4-(3-p yr id ylca r bon yl)p h en yl]-4-
oxa zoleca r boxa m id e (13g): mp 82-85 °C; 1H NMR (CDCl3)
δ 9.01 (s, 1H), 8.84 (d, J ) 4.1 Hz, 1H), 8.28 (s, 1H), 8.19 (d, J
) 8.3 Hz, 2H), 8.15 (buried, 1H), 7.92 (d, J ) 8.3 Hz, 2H), 7.66
(br s, 1H), 7.49 (dd, J ) 7.8, 4.9 Hz, 1H), 3.57 (m, 6H), 1.91
(tt, J ) 6.0, 5.8 Hz, 2H), 1.30 (t, J ) 7.0 Hz, 3H); FDMS 379
(M+). Anal. (C21H21N3O4) C, H, N.
acetonitrile were added 3.1 mL (18.0 mmol) of i-Pr2NEt and
1.7 mL (18.0 mmol) of CCl4 at room temperature. After stirring
overnight (∼16 h), the mixture was concentrated and purified
by preparative HPLC using EtOAc-HOAc-CH2Cl2 (50:1:49)
as eluent to afford 2.93 g (75%) of (4S)-N-(4-cyclohexylbutyl)-
4,5-dihydro-2-[4-(3-pyridylcarbonyl)phenyl]-4-oxazolecarbox-
amide (12): 1H NMR (CDCl3) δ 8.99 (s, 1H), 8.84 (d, J ) 2.2
Hz, 1H), 8.13 (buried m, 1H), 8.11 (d, J ) 8.1 Hz, 2H), 7.86 (d,
J ) 8.2 Hz, 2H), 7.48 (dd, J ) 11.8, 4.9 Hz, 1H), 6.65 (t, J )
5.3 Hz, 1H), 4.88 (m, 1H), 4.70 (m, 2H), 3.37-3.19 (m, 2H),
1.66-0.80 (m, 17H); FDMS 433 (M+).
A mixture of 1.3 g (3.0 mmol) of the oxazoline 12, 2.6 g of
NiO2, and a small amount of 4-Å molecular sieves in 30 mL of
benzene-1,4-dioxane (4:1) was heated at reflux for 2 h.
Another 2.6 g of NiO2 (4× wt in total) was added, and the
mixture was heated at reflux for another 2 h. The reaction
mixture was allowed to cool to room temperature and then
treated with 30-50 mL of 14% NH4OH at 0 °C for 15 min.
The solid was removed by filtration through a Celite pad and
thoroughly rinsed with EtOAc-CH2Cl2 (1:1). The filtrate was
separated, and the organic layer was washed with 100 mL of
brine. The aqueous layers were extracted with 2 × 100 mL of
CH2Cl2. Combined organic layers were dried over MgSO4,
concentrated, and purified by flash chromatography with
EtOAc-HOAc-CH2Cl2 (64:1:35) to yield 0.952 g of oxazole
amide 13m (74%): 1H NMR (CDCl3) δ 9.00 (s, 1H), 8.84 (br s,
1H), 8.28 (s, 1H), 8.18 (d, J ) 8.3 Hz, 2H), 8.16 (buried, 1H),
7.91 (d, J ) 8.2 Hz, 2H), 7.48 (dd, J ) 7.7, 5.1 Hz, 1H), 7.05 (t,
J ) 5.6 Hz, 1H), 3.44 (dt, J ) 6.8, 6.8 Hz, 2H), 1.69-0.83 (m,
17H); FDMS 431 (M+). Anal. (C26H29N3O3) C, H, N.
N-(2-P h en eth yl)-2-[4-(3-p yr id ylca r bon yl)p h en yl]-4-ox-
a zoleca r boxa m id e (13n ): 1H NMR (CDCl3) δ 9.01 (s, 1H),
8.85 (br d, J ) 4.2 Hz, 1H), 8.30 (s, 1H), 8.18 (buried, 1H),
8.16 (d, J ) 8.2 Hz, 2H), 7.92 (d, J ) 8.3 Hz, 2H), 7.51 (dd, J
) 8.8, 5.0 Hz, 1H), 7.31 (m, 5H), 7.12 (t, J ) 5.7 Hz, 1H), 3.72
(ddd, J ) 7.0, 6.8, 6.7 Hz, 2H), 2.95 (dd, J ) 7.2, 7.1 Hz, 2H);
FDMS 397 (M+). Anal. (C24H19N3O3‚0.24CH3CO2H) C, H, N.
(+)-N-[(tr a n s)-2-P h en ylcyclopr opyl]-2-[4-(3-p yr id ylca r -
bon yl)p h en yl]-4-oxa zoleca r boxa m id e (13o): mp 165-170
°C; [R]D ) +0.4° (c 1.0, MeOH); 1H NMR (CDCl3) δ 9.00 (br s,
1H), 8.85 (br s, 1H), 8.32 (s, 1H), 8.19 (d, J ) 8.4 Hz, 2H), 8.17
(buried, 1H), 7.93 (d, J ) 8.3 Hz, 2H), 7.51 (m, 1H), 7.25 (m,
6H), 3.09 (m, 1H), 2.24 (m, 1H), 1.37 (m, 2H); FDMS 409 (M+).
Anal. (C25H19N3O3) C, H, N.
N-[3-(2-Meth oxyeth oxy)p r op yl]-2-[4-(3-p yr id ylca r bon -
yl)p h en yl]-4-oxa zoleca r boxa m id e (13h ): 1H NMR (CDCl3)
δ 9.00 (s, 1H), 8.83 (br d, 1H), 8.30 (s, 1H), 8.20 (d, 2H), 8.18
(buried, 1H), 7.93 (d, 2H), 8.27 (m, 2H), 3.60 (m, 8H), 3.38 (s,
3H), 1.92 (m, 2H); FDMS 409 (M+).
N-[3-(1-Cycloh exyleth oxy)p r op yl]-2-[4-(3-p yr id ylca r -
b on yl)p h en yl]-4-oxa zoleca r b oxa m id e (13i): 1H NMR
(CDCl3) δ 9.01 (br s, 1H), 8.84 (br s, 1H), 8.28 (s, 1H), 8.19 (d,
J ) 8.4 Hz, 2H), 8.17 (buried, 1H), 7.91 (d, J ) 8.3 Hz, 2H),
7.60 (br t, 1H), 7.49 (dd, J ) 7.7, 4.9 Hz, 1H), 3.58 (m, 4H),
3.15 (dq, J ) 6.2, 6.2 Hz, 1H), 1.90 (m, 8H), 1.26-1.02 (m,
5H), 1.14 (d, J ) 6.3 Hz, 3H); FDMS 462 (M + 1). Anal.
(C27H31N3O4) C, H, N.
(-)-N-[(tr a n s)-2-P h en ylcyclopr opyl]-2-[4-(3-p yr id ylca r -
bon yl)p h en yl]-4-oxa zoleca r boxa m id e (13p ): mp 174-179
°C; FDMS 409 (M+). Anal. (C25H19N3O3) C, H, N.
N-[2-(Cycloh exyloxy)eth yl]-2-[4-(3-p yr id ylca r b on yl)-
p h en yl]-4-oxa zoleca r boxa m id e (13q): 1H NMR (CDCl3) δ
9.02 (d, J ) 1.8 Hz, 1H), 8.86 (dd, J ) 5.0, 1.4 Hz, 1H), 8.31
(s, 1H), 8.20 (d, J ) 8.3 Hz, 2H), 8.19 (buried, 1H), 7.94 (d, J
) 8.3 Hz, 2H), 7.52 (m, 1H), 7.45 (br s, 1H), 3.65 (m, 4H), 3.32
(m, 1H), 1.95-1.24 (m, 10H); FDMS 420 (M + 1). Anal.
(C24H25N3O4) C, H, N.
N-[3-(4-Mor ph olin yl)pr opyl]-2-[4-(3-p yr id ylca r bon yl)-
p h en yl]-4-oxa zoleca r boxa m id e (13j): mp 178-180 °C; 1H
NMR (CDCl3) δ 9.00 (d, J ) 1.8 Hz, 1H), 8.84 (dd, J ) 4.8, 1.4
Hz, 1H), 8.32 (br s, 1H), 8.29 (s, 1H), 8.18 (d, J ) 8.3 Hz, 2H),
8.14 (dt, J ) 8.0, 1.9 Hz, 1H), 7.94 (d, J ) 8.3 Hz, 2H), 7.43
(dd, J ) 8.0, 4.5 Hz, 1H), 3.86 (t, J ) 4.6 Hz, 4H), 3.58 (dt, J
) 6.1, 5.8 Hz, 2H), 2.55 (m, 6H), 1.82 (tt, J ) 6.0, 6.0 Hz, 2H);
FDMS 420 (M+). Anal. (C23H24N4O4) C, H, N.
N-[3-(Cycloh exyloxy)pr opyl]-2-[4-(3-p yr id ylca r bon yl)-
p h en yl]-4-oxa zoleca r boxa m id e (13r ): 1H NMR (CDCl3) δ
9.03 (s, 1H), 8.87 (br d, J ) 3.9 Hz, 1H), 8.30 (s, 1H), 8.21 (d,
J ) 8.3 Hz, 2H), 7.93 (d, J ) 8.4 Hz, 2H), 7.79 (br t, J ) ∼5.3
Hz, 1H), 7.54 (dd, J ) 7.9, 4.9 Hz, 1H), 3.63 (m, 4H), 3.32 (m,
(()-N-[2-(Tetr a h yd r opyr a n -2-ylm eth oxy)eth yl]-2-[4-(3-
pyr idylcar bon yl)ph en yl]-4-oxazolecar boxam ide (13k): mp
1
111-113 °C; H NMR (CDCl3) δ 9.03 (s, 1H), 8.87 (d, J ) 4.3
Hz, 1H), 8.31 (s, 1H), 8.21 (d, J ) 8.4 Hz, 2H), 8.20 (buried,
1H), 7.94 (d, J ) 8.3 Hz, 2H), 7.53 (dd, J ) 11.8, 7.0 Hz, 1H),
7.50 (buried, 1H), 4.05 (br dt, J ) 11.4, 1.9 Hz, 1H), 3.69 (m,
3H), 3.50 (m, 5H), 1.86 (m, 1H), 1.55 (m, 4H), 1.39 (m, 1H);
FDMS 436 (M + 1). Anal. (C24H25N3O5) C, H, N.
1H), 2.03-1.24 (m, 12H); FDMS 434 (M + 1). Anal. (C25H27
N3O4‚0.14CH3CO2C2H5) C, H, N.
-
N-[4-(Cycloh exyloxy)bu tyl]-2-[4-(3-p yr id ylca r b on yl)-
p h en yl]-4-oxa zoleca r boxa m id e (13s): 1H NMR (CDCl3) δ
9.01 (s, 1H), 8.84 (br d, J ) 3.8 Hz, 1H), 8.29 (s, 1H), 8.18 (d,
J ) 8.4 Hz, 2H), 8.14 (dt, J ) 7.9, 1.8 Hz, 1H), 7.92 (d, J ) 8.3
Hz, 2H), 7.49 (dd, J ) 7.8, 4.8 Hz, 1H), 7.19 (t, J ) 5.8 Hz,
1H), 3.50 (m, 4H), 3.22 (m, 1H), 1.93-1.16 (m, 14H); FDMS
447 (M+). Anal. (C26H29N3O4) C, H, N.
N-(4-Ch lor oph en yl)-2-[4-(3-p yr id ylca r bon yl)p h en yl]-4-
oxa zoleca r boxa m id e (13l): 1H NMR (DMSO-d6) δ 8.98 (s,
1H), 8.88 (s, 1H), 8.82 (d, J ) 4.5 Hz, 1H), 8.17-8.11 (m, 3H),
7.99-7.91 (m, 5H), 7.70 (d, J ) 8.5 Hz, 2H), 7.60 (m, 1H);
FDMS 468 (M + 1).
Gen er a l P r oced u r e for P r ep a r a tion of P r e-Wittig
Keton es 13 (via r ou te B; R gr ou p is ita licized ). N-(4-
Cycloh exylbu tyl)-2-[4-(3-p yr id ylca r b on yl)p h en yl]-4-ox-
a zoleca r boxa m id e (13m ). To a mixture of 4.07 g (9.0 mmol)
of N-(4-cyclohexylbutyl)-NR-[4-(3-pyridylcarbonyl)benzoyl]-L-
serinamide (11) and 4.73 g (18.0 mmol) of PPh3 in 100 mL of
N-[3-[(cis)- a n d (tr a n s)-4-Meth oxycycloh exyl]p r op yl]-
2-[4-(3-p yr id ylca r b on yl)p h en yl]-4-oxa zoleca r b oxa m id e
(13t): 1H NMR (CDCl3, cis-isomer only) δ 9.01 (d, J ) 1.2 Hz,
1H), 8.85 (dd, J ) 4.5, 1.0 Hz, 1H), 8.29 (s, 1H), 8.19 (d, J )
8.4 Hz, 2H), 8.15 (dd, J ) 1.8, 1.8 Hz, 1H), 7.93 (d, J ) 8.3 Hz,
2H), 7.50 (dd, J ) 7.9, 4.8 Hz, 1H), 7.07 (t, J ) 5.5 Hz, 1H),

A Novel TRA/ TSI, Phenyloxazoles
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27 5371
1
3.44 (dt, J ) 6.9, 6.8 Hz, 2H), 3.39 (br s, 1H), 3.33 (s, 3H),
2.10-0.85 (m, 13H); FDMS 447 (M+). Anal. (C26H29N3O4) C,
H, N.
a cid (20): 29%, E/Z ) ∼10:1 by H NMR; mp 78-82 °C; [R]D
) -93.4° (c 1.0, MeOH); FDMS 508 (M + 1); 96% pure by
HPLC.
Gen er a l P r oced u r e for th e Wittig Rea ction To P r e-
p a r e 14-38. (E)-7-[4-[4-[[(4-Cycloh exylbu tyl)a m in o]ca r -
bon yl]-2-oxa zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic Acid
(14). To a mixture of 0.952 g (2.2 mmol) of pyridyl ketone 13m
and 2.00 g (4.4 mmol) of (5-carboxypentyl)triphenylphos-
phonium bromide in 6.0 mL of THF was added dropwise 8.8
mL (8.8 mmol) of 1.0 M t-BuOK in THF at 0 °C over a 20-min
period. After stirring at 0 °C for 2 h, the reaction was quenched
with ca. 50 mL of saturated aqueous NH4Cl, and the mixture
was extracted with 3 × 100 mL of CH2Cl2. The extract was
dried over MgSO4 and concentrated, followed by preparative
HPLC with MeOH-AcOH-CH2Cl2 (2:1:97) as eluent to fur-
nish 108.2 mg of (Z)-heptenoic acid and 941.8 mg (81%) of (E)-
heptenoic acid 14: mp 52-56 °C; 1H NMR (CDCl3) δ 8.55 (br
s, 1H), 8.47 (d, J ) 2.7 Hz, 1H), 8.27 (s, 1H), 8.04 (d, J ) 8.2
Hz, 2H), 7.47 (d, J ) 8.0 Hz, 1H), 7.26 (d, J ) 8.2 Hz, 2H),
7.33 (buried, 1H), 7.12 (t, J ) 5.9 Hz, 1H), 6.18 (t, J ) 7.5 Hz,
1H), 3.43 (ddd, J ) 6.9, 6.8, 6.6 Hz, 2H), 2.31 (dd, J ) 7.2, 6.9
Hz, 2H), 2.19 (ddd, J ) 7.3, 7.2, 7.1 Hz, 2H), 1.68-0.82 (m,
21H); FDMS 530 (M + 1). Anal. (C32H39N3O4‚0.2CH3CO2H) C,
H, N.
(E)-7-[4-[4-[(P en tylam in o)car bon yl]-2-oxazolyl]ph en yl]-
7-(3-p yr id yl)h ep t-6-en oic a cid (15): prepared by the pro-
cedure previously described;7 mp 55-58 °C; 1H NMR (CDCl3)
δ 8.61 (s, 1H), 8.51 (d, J ) 4.3 Hz, 1H), 8.26 (s, 1H), 8.07 (d, J
) 8.2 Hz, 2H), 7.65 (d, J ) 8.0 Hz, 1H), 7.39 (m, 1H), 7.27 (d,
J ) 8.2 Hz, 2H), 7.07 (t, J ) 5.9 Hz, 1H), 6.26 (t, J ) 7.4 Hz,
1H), 3.45 (dt, J ) 6.8, 6.7 Hz, 2H), 2.32 (dd, J ) 7.0, 6.9 Hz,
2H), 2.21 (ddd, J ) 7.3, 7.2, 7.0 Hz, 2H), 1.67-1.52 (m, 6H),
1.40-1.35 (m, 4H), 0.91 (t, J ) 6.9 Hz, 3H); FDMS 462 (M +
1). Anal. (C27H31N3O4) C, H, N.
(E)-7-[4-[4-[[(2-P h en oxyet h yl)a m in o]ca r b on yl]-2-ox-
a zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic a cid (21): ∼92%,
1
1
E/Z ) ∼7.7:1 by H NMR; mp 61-64 °C; H NMR (CDCl3) δ
8.57 (d, J ) 1.7 Hz, 1H), 8.47 (d, J ) 4.1 Hz, 1H), 8.28 (s, 1H),
8.05 (d, J ) 8.2 Hz, 2H), 7.52 (t, J ) 5.7 Hz, 1H), 7.45 (d, J )
8.0 Hz, 1H), 7.25 (m, 5H), 6.94 (d, J ) 8.2 Hz, 2H), 6.94 (buried,
1H), 6.18 (t, J ) 7.4 Hz, 1H), 4.15 (t, J ) 5.0 Hz, 2H), 3.87 (dt,
J ) 5.4, 5.3 Hz, 2H), 2.31 (dd, J ) 7.1, 6.7 Hz, 2H), 2.19 (ddd,
J ) 7.3, 7.1, 6.9 Hz, 2H), 1.67-1.51 (m, 4H); FDMS 512 (M +
1). Anal. (C30H29N3O5) C, H, N.
(E)-7-[4-[4-[[(4-P h en oxyb u t yl)a m in o]ca r b on yl]-2-ox-
a zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic a cid (22): 85%,
E/Z ) 97:3 by HPLC analysis; 1H NMR (CDCl3) δ 8.57 (d, J )
1.0 Hz, 1H), 8.46 (d, J ) 4.1 Hz, 1H), 8.25 (s, 1H), 8.02 (d, J
) 8.2 Hz, 2H), 7.42 (br d, J ) 7.9 Hz, 2H), 7.23 (m, 5H), 6.92
(buried, 1H), 6.89 (d, J ) 8.6 Hz, 2H), 6.16 (t, J ) 7.4 Hz, 1H),
4.00 (dd, J ) 5.8, 5.5 Hz, 2H), 3.54 (ddd, J ) 6.5, 6.3, 6.1 Hz,
2H), 2.29 (dd, J ) 7.1, 6.7 Hz, 2H), 2.17 (ddd, J ) 7.2, 7.1, 7.0
Hz, 2H), 1.87 (m, 4H), 1.65-1.48 (m, 4H); FDMS 540 (M + 1);
98.7% pure by HPLC.
(E)-7-[4-[4-[[(5-P h en oxyp en tyl)a m in o]ca r bon yl]-2-ox-
a zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic a cid (23): 89%,
E/Z ) 95:5 by HPLC analysis; mp 42-48 °C; 1H NMR (CDCl3)
δ 8.59 (s, 1H), 8.48 (d, J ) 4.4 Hz, 1H), 8.26 (s, 1H), 8.05 (d, J
) 8.1 Hz, 2H), 7.52 (br dd, J ) 7.9, 2.0 Hz, 1H), 7.46 (br dd, J
) 7.6, 2.6 Hz, 1H), 7.25 (m, 4H), 7.10 (t, J ) 6.0 Hz, 1H), 6.93
(buried, 1H), 6.88 (d, J ) 7.9 Hz, 2H), 6.22 (t, J ) 7.4 Hz, 1H),
3.96 (dd, J ) 6.4, 6.2 Hz, 2H), 3.49 (ddd, J ) 6.7, 6.6, 6.5 Hz,
2H), 2.32 (dd, J ) 7.2, 6.8 Hz, 2H), 2.20 (ddd, J ) 7.3, 7.1, 7.0
Hz, 2H), 1.89-1.51 (m, 10H:); FDMS 554(M + 1). Anal.
(C33H35N3O5) C, H, N.
(E)-7-[4-[4-[[(Cyclop r op ylm et h yl)a m in o]ca r b on yl]-2-
oxa zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic a cid (16): pre-
pared by the procedure previously described;7 mp 69-70 °C;
1H NMR (CDCl3) δ 8.55 (s, 1H), 8.47 (d, J ) 3.8 Hz, 1H), 8.27
(s, 1H), 8.05 (d, J ) 8.1 Hz, 2H), 7.47 (d, J ) 8.0 Hz, 1H), 7.26
(d, J ) 8.0 Hz, 2H), 7.22 (m, 2H), 6.18 (t, J ) 7.4 Hz, 1H),
3.30 (dd, J ) 6.4, 6.3 Hz, 2H), 2.31 (dd, J ) 7.2, 6.8 Hz, 2H),
2.19 (ddd, J ) 7.3, 7.1, 7.0 Hz, 2H), 1.67-1.50 (m, 4H), 1.06
(m, 1H), 0.55 (ddd, J ) 7.4, 5.5, 5.3 Hz, 2H), 0.28 (ddd, J )
5.0, 4.9, 4.8 Hz, 2H); FDMS 446 (M + 1). Anal. (C26H27N3-
O4‚0.4CH3CO2H) C, H, N.
(E)-7-[4-[4-[(Ben zylam in o)car bon yl]-2-oxazolyl]ph en yl]-
7-(3-p yr id yl)h ep t-6-en oic a cid (17): prepared by the pro-
cedure previously described;7 mp 57-62 °C; 1H NMR (CDCl3)
δ 8.57 (s, 1H), 8.46 (d, J ) 4.2 Hz, 1H), 8.30 (s, 1H), 8.02 (d, J
) 8.1 Hz, 2H), 7.47-7.21 (m, 10H), 6.19 (t, J ) 7.4 Hz, 1H),
4.65 (d, J ) 5.9 Hz, 2H), 2.31 (dd, J ) 7.1, 6.8 Hz, 2H), 2.18
(ddd, J ) 7.3, 7.1, 7.0 Hz, 2H), 1.66-1.50 (m, 4H); FDMS 482
(M + 1). Anal. (C29H27N3O4) C, H, N.
(E)-7-[4-[4-[(P h en et h yla m in o)ca r b on yl]-2-oxa zolyl]-
p h en yl]-7-(3-p yr id yl)h ep t-6-en oic a cid (18): 25%; mp 56-
61 °C; 1H NMR (CDCl3) δ 8.58 (s, 1H), 8.47 (d, J ) 4.1 Hz,
1H), 8.26 (s, 1H), 8.02 (d, J ) 8.2 Hz, 2H), 7.44 (dt, J ) 8.0,
1.5 Hz, 1H), 7.35-7.16 (m, 9H), 6.19 (t, J ) 7.4 Hz, 1H), 3.70
(dt, J ) 6.9, 6.7 Hz, 2H), 2.94 (t, J ) 7.2 Hz, 2H), 2.32 (t, J )
7.8 Hz, 2H), 2.20 (ddd, J ) 7.3, 7.2, 7.0 Hz, 2H), 1.68-1.51
(m, 4H); FDMS 496 (M + 1). Anal. (C30H29N3O4‚0.1CH3CO2H)
C, H, N.
(E)-7-[4-[4-[[[2-(Ben zyloxy)et h yl]a m in o]ca r b on yl]-2-
oxazolyl]ph en yl]-7-(3-pyr idyl)h ept-6-en oic acid (24): 58%;
mp 48-55 °C; H NMR (CDCl3) δ 8.60 (br s, 1H), 8.48 (br s,
1H), 8.26 (s, 1H), 8.06 (d, J ) 8.2 Hz, 2H), 7.48 (br s, 1H), 7.46
(br s, 1H), 7.38-7.25 (m, 6H), 7.27 (d, J ) 8.2 Hz, 2H), 6.20 (t,
J ) 7.4 Hz, 1H), 4.57 (s, 2H), 3.67 (s, 4H), 2.32 (dd, J ) 7.1,
6.8 Hz, 2H), 2.20 (ddd, J ) 7.3, 7.2, 6.8 Hz, 2H), 1.68-1.52
(m, 4H); FDMS 526 (M + 1). Anal. (C31H31N3O5) C, H, N.
1
(E)-7-[4-[4-[[[3-(4-Met h oxyp h en yl)p r op yl]a m in o]ca r -
bon yl]-2-oxa zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic a cid
1
(25): 74%, E/Z ) 94:6 by HPLC analysis; mp 49-58 °C; H
NMR (CDCl3) δ 8.59 (s, 1H), 8.48 (br d, J ) 4.1 Hz, 1H), 8.25
(s, 1H), 8.05 (d, J ) 8.3 Hz, 2H), 7.52 (br dd, J ) 8.1, 1.5 Hz,
1H), 7.27 (d, J ) 8.2 Hz, 2H), 7.27 (buried, 1H), 7.12 (d, J )
8.6 Hz, 2H), 7.09 (buried, 1H), 6.82 (d, J ) 8.6 Hz, 2H), 6.22
(t, J ) 7.4 Hz, 1H), 3.76 (s, 3H), 3.48 (ddd, J ) 6.8, 6.7, 6.6
Hz, 2H), 2.67 (dd, J ) 7.6, 7.5 Hz, 2H), 2.32 (dd, J ) 7.2, 6.8
Hz, 2H), 2.20 (ddd, J ) 7.3, 7.2, 7.0 Hz, 2H), 1.93 (m, 2H),
1.68-1.51 (m, 4H); FDMS 540 (M + 1). Anal. (C32H33N3O5) C,
H, N.
(E)-7-[4-[4-[[(3-E t h oxyp r op yl)a m in o]ca r b on yl]-2-ox-
a zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic a cid (26): 46%;
mp 67-72 °C; 1H NMR (CDCl3) δ 8.60 (s, 1H), 8.48 (br s, 1H),
8.25 (s, 1H), 8.05 (d, J ) 8.2 Hz, 2H), 7.62 (distorted t, J )
∼5.3 Hz, 1H), 7.43 (br d, J ) 7.8 Hz, 1H), 7.28 (buried, 1H),
7.26 (d, 2H), 6.22 (t, J ) 7.4 Hz, 1H), 3.50 (m, 6H), 2.30 (ddd,
J ) 7.1, 7.1, 6.9 Hz, 2H), 2.20 (ddd, J ) 7.6, 7.2, 6.9 Hz, 2H),
1.90 (tt, J ) 6.1, 6.1 Hz, 2H), 1.64-1.54 (m, 4H), 1.28 (t, J )
7.0 Hz, 3H); FDMS 478 (M + 1). Anal. (C27H31N3O5‚0.6CH3-
OH‚0.8H2O) C, H, N.
(+)-(E)-7-[4-[4-[[[2-(tr a n s)-P h en ylcyclop r op yl]a m in o]-
ca r b on yl]-2-oxa zolyl]p h en yl]-7-(3-p yr id yl)h ep t -6-en oic
a cid (19): 87%, E/Z ) 97:3 by HPLC analysis; mp 78-87 °C;
1
[R]D ) +116.2° (c 1.0, MeOH); H NMR (CDCl3) δ 8.58 (br s,
(E)-7-[4-[4-[[[3-(Meth oxyeth oxy)p r op yl]a m in o]ca r bon -
yl]-2-oxazolyl]ph en yl]-7-(3-pyr idyl)h ept-6-en oic acid (27):
1H), 8.47 (br d, J ) 2.7 Hz, 1H), 8.28 (s, 1H), 8.04 (d, J ) 8.3
Hz, 2H), 7.53 (dd, J ) 7.2, 1.1 Hz, 1H), 7.46 (br dd, J ) ∼8.3,
1.6 Hz, 2H), 7.28 (m, 4H), 7.20 (m, 3H), 6.19 (t, J ) 7.5 Hz,
1H), 3.09 (m, 1H), 2.32 (dd, J ) 7.2, 6.8 Hz, 2H), 2.19 (m, 3H),
1.64 (m, 2H), 1.55 (m, 2H), 1.36 (m, 2H); FDMS 508 (M + 1).
Anal. (C31H29N3O4) C, H, N.
1
83%, E/Z ) 8.8:1 by HPLC analysis; H NMR (CDCl3) δ 8.59
(s, 1H), 8.47 (br d, J ) 3.4 Hz, 1H), 8.25 (s, 1H), 8.06 (d, J )
8.1 Hz, 2H), 7.46 (m, 2H), 7.27 (d, 2H), 7.25 (buried, 1H), 6.19
(t, J ) 7.5 Hz, 1H), 3.59 (m, 8H), 3.38 (s, 3H), 2.31 (dd, J )
7.1, 6.8 Hz, 2H), 2.20 (ddd, J ) 7.4, 7.2, 6.7 Hz, 2H), 1.93 (tt,
J ) 6.2, 6.1 Hz, 2H), 1.68-1.52 (m, 4H); FDMS 508 (M + 1).
Anal. (C28H33N3O6) C, H, N.
(-)-(E)-7-[4-[4-[[[2-(tr a n s)-P h en ylcyclop r op yl]a m in o]-
ca r b on yl]-2-oxa zolyl]p h en yl]-7-(3-p yr id yl)h ep t -6-en oic

5372 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27
Takeuchi et al.
(E)-7-[4-[4-[[[3-(1-Cycloh exyleth oxy)p r op yl]a m in o]ca r -
4H), 3.50 (m, 5H), 2.33 (dd, J ) 7.1, 6.7 Hz, 2H), 2.21 (ddd, J
) 7.2, 7.0, 6.7 Hz, 2H), 1.89-1.26 (m, 10H); FDMS 534 (M +
1). Anal. (C30H35N3O6‚0.25C2H4O2) C, H, N.
bon yl]-2-oxa zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic a cid
1
(28): 50%, E/Z ) 96:4 by HPLC analysis; mp 80-85 °C; H
NMR (CDCl3) δ 8.57 (d, 1H), 8.46 (d, J ) 4.1 Hz, 1H), 8.24 (s,
1H), 8.04 (d, J ) 8.1 Hz, 2H), 7.59 (t, J ) 5.5 Hz, 1H), 7.41 (br
d, J ) 8.0 Hz, 1H), 7.25 (d, J ) 8.1 Hz, 2H), 7.20 (m, 1H), 6.16
(t, J ) 7.4 Hz, 1H), 3.57 (m, 4H), 3.13 (dq, J ) 6.2, 6.2 Hz,
1H), 2.29 (dd, J ) 7.1, 6.8 Hz, 2H), 2.17 (ddd, J ) 7.3, 7.1, 6.9
Hz, 2H), 1.87 (m, 3H), 1.69-1.40 (m, 10H), 1.24-0.95 (m, 3H),
1.12 (d, J ) 6.0 Hz, 3H); FDMS 560 (M + 1). Anal.
(C33H41N3O5‚0.8H2O) C, H, N.
(E)-7-[4-[4-[[(4-Ch lor oph en ylsu lfon yl)am in o]car bon yl]-
2-oxa zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic Acid (36)
a n d (E)-7-[4-(4-Ca r boxy-2-oxa zolyl)p h en yl]-7-(3-p yr id yl)-
h ep t-6-en oic Acid (37). Acid 36 was prepared according to
the general procedure described (∼38%): 1H NMR (CDCl3) δ
8.56 (s, 1H), 8.48 (dd, J ) 4.0, 1.0 Hz, 1H), 8.28 (s, 1H), 8.11
(d, J ) 8.5 Hz, 2H), 8.02 (d, J ) 8.1 Hz, 2H), 7.53 (d, J ) 8.4
Hz, 2H), 7.46 (br d, J ) 7.9 Hz, 2H), 7.29 (d, J ) 8.1 Hz, 2H),
7.24 (m, 1H), 6.19 (t, J ) 7.4 Hz, 1H), 2.32 (dd, J ) 6.9, 6.6
Hz, 2H), 2.19 (ddd, J ) 7.2, 7.1, 6.6 Hz, 2H), 1.67-1.51 (m,
4H); FDMS 566 (M+); 96.0% pure by HPLC analysis. To purify
the Wittig product 36 which was contaminated with a byprod-
uct from the Wittig salt and difficult to isolate pure, esterifi-
cation of acid 36 with CH2N2 in Et2O-THF was attempted.
This esterification was rather reactive and gave several
products, two of which were identified as the N-methylated
methyl ester of 36 and the diester of new compound 37.
Hydrolysis of the latter diester with 1.0 N NaOH in THF-
MeOH furnished diacid 37 (12% in three steps from the Wittig
precursor ketone): 1H NMR (CD3OD) δ 8.58 (s, 1H), 8.41 (br
s, 2H), 8.15 (d, J ) 8.2 Hz, 2H), 7.70 (d, J ) 7.9 Hz, 1H), 7.39
(buried, 1H), 7.36 (d, J ) 8.2 Hz, 2H), 6.31 (t, J ) 7.5 Hz, 1H),
2.24 (m, 4H), 1.58 (m, 4H); FDMS 393 (M + 1).
(E)-7-[4-[4-[[[2-(Cycloh exylm eth oxy)eth yl]a m in o]ca r -
bon yl]-2-oxa zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic a cid
1
(29): 87%, E/ Z ) ∼6.1:1 by H NMR; mp 49-56 °C; 1H NMR
(CDCl3) δ 8.63 (br s, 1H), 8.50 (br s, 1H), 8.28 (s, 1H), 8.07 (d,
J ) 8.0 Hz, 2H), 7.49 (:distorted br d, J ) 7.0 Hz, 2H), 7.29 (d,
J ) 7.9 Hz, 2H), 7.29 (buried, 1H), 6.23 (t, J ) 7.4 Hz, 1H),
3.64 (m, 4H), 3.31 (d, J ) 6.4 Hz, 2H), 2.35 (dd, J ) 7.1, 6.5
Hz, 2H), 2.23 (ddd, J ) 7.3, 7.1, 6.8 Hz, 2H), 1.83-0.92 (m,
15H); FDMS 532 (M + 1). Anal. (C31H37N3O5) C, H, N.
(E)-7-[4-[4-[[[2-(Cycloh exyloxy)eth yl]a m in o]ca r bon yl]-
2-oxa zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic a cid (30):
60%, E/Z ) ∼5.5:1 by 1H NMR; mp 51-59 °C; 1H NMR (CDCl3)
δ 8.59 (s, 1H), 8.49 (br d, J ) 2.9 Hz, 1H), 8.28 (s, 1H), 8.07 (d,
J ) 8.2 Hz, 2H), 7.50 (distorted br d, J ) 7.3 Hz, 2H), 7.29 (d,
J ) 8.2 Hz, 2H), 7.27 (buried, 1H), 6.21 (t, J ) 7.4 Hz, 1H),
3.65 (s, 4H), 3.32 (m, 1H), 2.34 (dd, J ) 7.2, 6.8 Hz, 2H), 2.22
(ddd, J ) 7.4, 7.2, 6.9 Hz, 2H), 1.95-1.19 (m, 14H); FDMS
518 (M + 1); 97.5% pure by HPLC. Anal. (C30H35N3O5) C, H;
N: calcd, 8.12; found, 7.60.
(E)-7-[4-[[[1-[[(4-Cycloh exylbu tyl)am in o]car bon yl]eth en -
1-yl]a m in o]ca r b on yl]p h en yl]-7-(3-p yr id yl)h ep t -6-en oic
Acid (38) a n d (4S)-(E)-7-[4-[4-[[(4-Cycloh exylbu tyl)a m i-
n o]car bon yl]-4,5-dih ydr o-2-oxazolyl]ph en yl]-7-(3-pyr idyl)-
h ep t-6-en oic Acid (39). These were prepared from 1.472 g
(3.4 mmol) of the oxazoline-substituted phenyl 3-pyridyl ketone
12, 3.08 g (6.8 mmol) of (5-carboxypentyl)triphenylphos-
phonium bromide, and 13.6 mL (13.6 mmol) of 1.0 M t-BuOK
in 10.0 mL of THF at 0 °C for 2.5 h. Preparative HPLC with
MeOH-AcOH-CH2Cl2 (3:0.5:96.5) yielded ∼670 mg (37%) of
the â-elimination Wittig product 38 (less polar material) and
(E)-7-[4-[4-[[[3-(Cycloh exyloxy)pr opyl]am in o]car bon yl]-
2-oxa zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic a cid (31):
86%, E/Z ) ∼6.4:1 by 1H NMR; mp 57-62 °C; 1H NMR (CDCl3)
δ 8.62 (s, 1H), 8.49 (br d, J ) 3.7 Hz, 1H), 8.27 (s, 1H), 8.07 (d,
J ) 8.1 Hz, 2H), 7.77 (distorted t, J ) ∼3.5 Hz, 1H), 7.48 (br
d, J ) 8.0 Hz, 1H), 7.27 (d, J ) 8.2 Hz, 2H), 7.26 (buried, 1H),
6.22 (t, J ) 7.4 Hz, 1H), 3.62 (m, 4H), 3.30 (m, 1H), 2.34 (dd,
J ) 7.2, 6.8 Hz, 2H), 2.22 (ddd, J ) 7.3, 7.2, 7.1 Hz, 2H), 2.02-
1.22 (M, 16H); FDMS 532 (M + 1). Anal. (C31H37N3O5) C, H,
N.
(E)-7-[4-[4-[[[4-(Cycloh exyloxy)bu tyl]a m in o]ca r bon yl]-
2-oxa zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en oic a cid (32):
63%, (E)-isomer ) 88.3% by HPLC analysis; 1H NMR (CDCl3)
δ 8.60 (s, 1H), 8.48 (br d, J ) 4.1 Hz, 1H), 8.27 (s, 1H), 8.06 (d,
J ) 8.2 Hz, 2H), 7.45 (br d, J ) 7.9 Hz, 1H), 7.29 (d, 2H), 7.22
(m, 2H), 6.20 (t, J ) 7.4 Hz, 1H), 3.51 (m, 4H), 3.23 (m, 1H),
2.33 (dd, J ) 7.1, 6.7 Hz, 2H), 2.20 (ddd, J ) 7.3, 7.1, 6.9 Hz,
2H), 1.95-1.14 (m, 18H); FDMS 546 (M + 1). Anal. (C32H39N3O5)
C, H, N.
1
∼700 mg (38%) of 39. 38: mp 61-63 °C; H NMR (CDCl3) δ
9.05 (s, 1H), 8.58 (s, 1H), 8.48 (d, J ) 3.3 Hz, 1H), 7.89 (d, J
) 8.2 Hz, 2H), 7.43 (br d, J ) 8.0 Hz, 1H), 7.26 (d, J ) 8.0 Hz,
2H), 7.25 (buried, 1H), 6.63 (d, J ) 1.1 Hz, 1H), 6.55 (br s,
1H), 6.21 (t, J ) 7.4 Hz, 1H), 5.35 (s, 1H), 3.37 (dt, J ) 6.8,
6.3 Hz, 2H), 2.32 (dd, J ) 7.1, 6.9 Hz, 2H), 2.18 (ddd, J ) 7.3,
7.2, 7.1 Hz, 2H), 1.69-0.83 (m, 21H); FDMS 532 (M + 1). Anal.
(C32H41N3O4) C, H, N. 39:7 [R]D ) +1.6° (c 1.0, MeOH); mp
65-70 °C; 1H NMR (CDCl3) δ 8.55 (s, 1H), 8.45 (d, J ) 3.3 Hz,
1H), 7.98 (d, J ) 8.1 Hz, 2H), 7.42 (d, J ) 8.0 Hz, 1H), 7.22 (d,
J ) 8.2 Hz, 2H), 7.20 (buried, 1H), 6.80 (t, J ) 5.8 Hz, 1H),
6.18 (t, J ) 7.4 Hz, 1H), 4.86 (dd, J ) 9.6, 9.5 Hz, 1H), 4.66
(m, 2H), 3.35-3.17 (m, 2H), 2.31 (dd, J ) 7.2, 6.8 Hz, 2H),
2.17 (ddd, J ) 7.3, 7.2, 7.0 Hz, 2H), 1.65-0.79 (m, 21H); FDMS
532 (M + 1). Anal. (C32H41N3O4) C, H, N.
(E)-7-[4-[4-[[[3-[(cis)-4-Meth oxycycloh exyl]p r op yl]a m i-
n o]ca r bon yl]-2-oxa zolyl]p h en yl]-7-(3-p yr id yl)h ep t-6-en o-
ic a cid (33): 87%, major (E)-cis-isomer ) 88% by HPLC
1
analysis; H NMR (CDCl3) δ 8.60 (br s, 1H), 8.50 (br s, 1H),
Mea su r em en t of Th r om boxa n e Recep tor An ta gon ism .
1. Recep tor Bin d in g Assa y. Membranes from outdated
human platelets were prepared as previously described.30
Incubations (220 µL) containing 10 µg of platelet membranes
were performed in silanized glass tubes (12 × 75 mm) at 30
°C for 30 min. The incubation media consisted of 10 mM Hepes,
2 mM CHAPS, 10 µM indomethacin (pH 7.4), and ∼0.05 nM
(∼25 000 cpm) [125I]IBOP per tube and varying concentrations
of competing ligands ranging from 10-10 to 10-5 M. The
reaction was terminated by addition of 4 mL of ice-cold buffer
(25 mM Tris) at pH 7.4, followed by rapid filtration through
Whatman GF/C glass filters presoaked in 0.3% poly(ethylen-
imine) (Whatman, Inc., Clifton, NJ ) using a Brandel M-24 cell
harvester (Gaithersburg, MD). Nonspecific binding was defined
as that amount of radioactivity bound in the presence of a large
molar excess (l0 µM) of SQ29548, a potent TXA2/PGH2 receptor
antagonist.
8.28 (s, 1H), 8.08 (d, J ) 8.3 Hz, 2H), 7.50 (br d, J ) 7.5 Hz,
2H), 7.29 (d, J ) 8.2 Hz, 2H), 7.11 (distorted t, 1H), 6.22 (t, J
) 7.5 Hz, 1H), 3.45 (m, 3H), 3.31 (s, 3H), 2.33 (dd, J ) 7.2, 6.9
Hz, 2H), 2.22 (ddd, J ) 7.3, 7.2, 6.8 Hz, 2H), 1.88-1.24 (m,
17H); FDMS 546 (M + 1). Anal. (C32H39N3O5) C, H, N.
(E)-7-[4-[4-[[(3-Mor p h olin op r op yl)a m in o]ca r bon yl]-2-
oxazolyl]ph en yl]-7-(3-pyr idyl)h ept-6-en oic acid (34): 92%,
E/Z ) ∼4:1 by 1H NMR; 1H NMR (DMSO) δ 8.66 (s, 1H),
8.52(m, 1H), 8.40 (dd, J ) 4.5, 1.1 Hz, 1H), 8.36 (d, J ) 1.9
Hz, 1H), 8.01 (d, J ) 8.2 Hz, 2H), 7.47 (m, 2H), 7.29 (d, J )
8.1 Hz, 2H), 6.20 (t, J ) 7.4 Hz, 1H), 3.57 (br t, J ) 4.4 Hz,
4H), 3.28 (br dt, J ) ∼6.2, 5.8 Hz, 2H), 2.30 (br s, 6H), 2.02
(m, 4H), 1.63 (br t, J ) 6.6 Hz, 2H), 1.40 (m, 4H); FDMS 519
(M + 1); 97.5% pure by HPLC.
(()-(E)-7-[4-[4-[[[2-(Tetr a h yd r op yr a n -2-ylm eth oxy)eth -
yl]am in o]car bon yl]-2-oxazolyl]ph en yl]-7-(3-pyr idyl)h ept-
6-en oic a cid (35): quantitative, E/Z ) ∼15:1 by 1H NMR;
1
2. P la telet Aggr ega tion Stu d ies. The ability of the test
compounds to antagonize TXA2/PGH2 receptor-induced human
platelet aggregation was studied in the following manner.
Blood was collected from volunteers who denied taking any
mp 68-73 °C; H NMR (CDCl3) δ 8.61 (br s, 1H), 8.49 (br s,
1H), 8.28 (s, 1H), 8.06 (d, J ) 8.1 Hz, 2H), 7.52 (br s, 1H), 7.46
(br d, J ) 8.0 Hz, 1H), 7.28 (d, 2H), 7.27 (buried, 1H), 6.21 (t,
J ) 7.4 Hz, 1H), 4.04 (dt, J ) 13.3, 1.9 Hz, 1H), 3.69 (br s,

A Novel TRA/ TSI, Phenyloxazoles
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27 5373
(5) (a) Takeuchi, K.; Happ, A. M.; Mais, D. E.; Layman, N.;
Utterback, B. G.; Wyss, V. L.; J akubowski, J . A. Development
of Dual-Acting Agents for Thromboxane Receptor Antagonism
and Thromboxane Synthase Inhibition. 1. Synthesis, Structure
Activity Relationship, and Evaluation of Substituted ω-Phenyl-
ω-(3-Pyridyl)alkenoic Acids. Bioorg. Med. Chem. 1994, 2, 743-
755. (b) Faull, A. W.; Gaskin, H.; Hadfield, P. S.; J essup, R.;
Russell, K.; Watkins, W. J .; Wayne, M. Dual-Acting Thrombox-
ane Receptor Antagonist/Synthase Inhibitors: Heterocyclic Varia-
tions. Bioorg. Med. Chem. Lett. 1992, 2, 1181-1186. (c) Russell,
K.; Gaskin, H.; J essup, R. Discovery of Dual Activity Molecules
with Thromboxane Antagonist and Thromboxane Synthase
Inhibitory Activity. Bioorg. Med. Chem. Lett. 1992, 2, 979-984.
(d) Bhagwat, S. S.; Gude, C.; Boswell, C.; Contardo, N.; Cohen,
D. S.; Dotson, R.; Mathis, J .; Lee, W.; Furness, P.; Zoganas, H.
Thromboxane Receptor Antagonism Combined with Thrombox-
ane Synthase Inhibition. 4. 8-[[(4-Chlorophenyl)sulfonyl]amino]-
4-(3-(3-pyridinyl)propyl)octanoic Acid and Analogues. J . Med.
Chem. 1992, 35, 4373-4383 and references therein. (e) Camp-
bell, I. B.; Collington, E. W.; Finch, H.; Hayes, R.; Lumley, P.;
Mills, K.; Pike, N. B.; Robertson, G. M.; Watts, I. S. Synthesis
and Pharmacological Evaluation of Combined Thromboxane
Receptor Antagonist/Synthase Inhibitors: Pyridine-Containing
Sulphonamido Acids. Bioorg. Med. Chem. Lett. 1991, 1, 699-
704. (f) Soyka, R.; Heckel, A.; Nickl, J .; Eisert, W.; Mu¨ller, T.
H.; Weisenberger, H. 6,6-Disubstituted Hex-5-enoic Acid Deriva-
tives as Combined Thromboxane A2 Receptor Antagonists and
Synthetase Inhibitors. J . Med. Chem. 1994, 37, 26-39.
(6) Vandeplassche, G.; Hermans, C.; Van de Water, A.; Xhonneux,
R.; Wouters, L.; Van Ammel, K.; De Clerck, F. Differential
Effects of Thromboxane A2 Synthase Inhibition, Singly or
Combined with Thromboxane A2/Prostaglandin Endoperoxide
Receptor Antagonism, on Occlusive Thrombosis Elicited by
Endothelial Cell Injury or by Deep Vascular Damage in Canine
Coronary Arteries. Circ. Res. 1991, 69, 313-324.
medication known to influence platelet aggregation within the
previous 10 days. The blood was collected into 1/10 volume of
3.8% trisodium citrate and mixed by gentle inversion. Platelet-
rich plasma was prepared by centrifugation at 100g for 12 min
and platelet-poor plasma by centrifugation at 12000g for 2 min.
Receptor activation and subsequent platelet aggregation were
induced by the addition of the stable analogue of TXA2/PGH2,
U46619 (1 µM). Aggregation was monitored in a Biodata PAP4
platelet aggregation profiler for 3 min after the addition of
U46619. Test compound or vehicle was preincubated with
platelet-rich plasma for 1 min at 37 °C prior to the induction
of aggregation with U46619. Data are expressed as the IC50
,
i.e., concentration of test compound required to inhibit U46619-
induced platelet aggregation by 50%.
Mea su r em en t of Th r om boxa n e Syn th a se In h ibition
a n d P r osta cyclin F or m a tion . Compound or vehicle was
incubated with whole human blood for 30 min at 37 °C prior
to the preparation of serum as previously described.31 Serum
TXB2 and 6-keto-PGF1R, the stable metabolites of TXA2 and
prostacyclin, respectively, were measured by radioimmuno-
assay as described.32
Ex Vivo Exp er im en ts. Sprague-Dawley rats (300 g,
males) were dosed by oral gavage with either vehicle (5%
acacia) or 1-10 mg/kg compound. Blood samples were collected
1 h after dosing. Animals were anesthetized (sodium pento-
barbital, 87 mg/kg ip) 15 min before sample collection. Blood
samples were obtained by cardiac puncture via a butterfly
catheter, and the first milliliter of blood was discarded. Blood
samples were divided into duplicates and incubated at 37 °C
for 1 h in 13- × 100-mm glass tubes. Serum was separated by
centrifugation at 2000g for 15 min at 25 °C, transferred to
polypropylene tubes, and stored at -20 °C for subsequent
assay.
(7) Takeuchi, K.; Kohn, T. J .; Mais, D. E.; True, T. A.; Wyss, V. L.;
J akubowski, J . A. Development of Dual-Acting Agents for
Thromboxane Receptor Antagonism and Thromboxane Synthase
Inhibition. 2. Design, Synthesis, and Evaluation of A Novel
Series of Phenyl Oxazole Derivatives. Bioorg. Med. Chem. Lett.
1998, 8, 1943-1948.
(8) (a) Main, A. J .; Goldstein, R.; Cohen, D. S.; Furness, P.; Lee, W.
Thromboxane Receptor Antagonism Combined with Thrombox-
ane Synthase Inhibition. 2. Synthesis and Biological Activity of
8-(Benzenesulfonamido)-7-(3-pyridinyl)octanoic Acid and Related
Compounds. J . Med. Chem. 1992, 35, 4362-4365. (b) Main, A.
J .; Bhagwat, S. S.; Boswell, C.; Goldstein, R.; Gude, C.; Cohen,
D. S.; Furness, P.; Lee, W.; Louzan, M. Thromboxane Receptor
Antagonism Combined with Thromboxane Synthase Inhibition.
3. Pyridinylalkyl-Substituted 8-[(Arylsulfonyl)amino]octanoic
Acids. J . Med. Chem. 1992, 35, 4366-4372.
Ack n ow led gm en t. The authors would like to thank
Mr. Larry E. Sachs for HPLC analyses, Mr. J onathan
W. Paschal for NOE experiments, Dr. Marlene L. Cohen
and Mr. William E. Bloomquist for the pressor response
experiments, and the Physical Chemistry Department
of Lilly Research Laboratories for mass spectrometric
and elemental analyses.
(9) For example, see ref 5a,e,f; see also: Bhagwat, S. S.; Roland, D.
M.; Main, A. J .; Gude, C.; Grim, K.; Goldstein, R.; Cohen, D. S.;
Dotson, R.; Mathis, J .; Lee, W. Thromboxane Receptor Antago-
nism Combined with Thromboxane Synthase Inhibition. 7.
Pyridinylalkyl-Substituted Arylsulfonylamino Arylalkanoic Ac-
ids. Bioorg. Med. Chem. Lett. 1992, 2, 1623-1626 and their
preceding series of publications.
(10) Such unwanted side effects have been observed; see ref 8 for
agonist activity and Bhagwat et al. in refs 5d and 9 for protein
binding.
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