Effect of Oxime Ether Incorporation in Acyl Indole Derivatives on PPAR Subtype Selectivity

Article abstract of DOI:10.1002/cmdc.201200316

Compounds that simultaneously activate peroxisome proliferator-activated receptor (PPAR) subtypes α and γ have the potential to effectively treat dyslipidemia and type2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, were expected to be overcome by using additive PPARα activity, leading to dual PPARα/γ agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of α-ethoxyphenylpropionic acid bearing 5- or 6-substituted indoles. The incorporation of oxime ethers on the carbonyl portion of the benzoyl group can bring the PPARα/γ potency ratio equal to or slightly greater than one, as is the case for compounds 20c and 21a. Compound 20c shows high efficacy in an ob/ob mouse model of T2D and dyslipidemia, similar to that of rosiglitazone and tesaglitazar, but with a significant increase in body weight gain. In contrast, compound 21a, less potent as a dual PPARα/γ activator than 20c, showed an interesting pharmacological profile, as it elicits a decrease in body weight relative to reference compounds.

Full text of DOI:10.1002/cmdc.201200316

MED
DOI: 10.1002/cmdc.201200316
Effect of Oxime Ether Incorporation in Acyl Indole
Derivatives on PPAR Subtype Selectivity
Morgan Le Naour,[a] Veronique Leclerc,[a] Amaury Farce,[a] Daniel-Henri Caignard,[b]
Nathalie Hennuyer,[c] Bart Staels,[c] Valꢀrie Audinot-Bouchez,[d] Jean-Albert Boutin,[d]
Michel Lonchampt,[e] Catherine Dacquet,[e] Alain Ktorza,[e] Pascal Berthelot,[a] and
Nicolas Lebegue*[a]
Compounds that simultaneously activate peroxisome prolifera-
tor-activated receptor (PPAR) subtypes a and g have the po-
tential to effectively treat dyslipidemia and type 2 diabetes
(T2D) in a single pharmaceutically active molecule. The fre-
quently observed side effects of selective PPARg agonists, such
as edema and weight gain, were expected to be overcome by
using additive PPARa activity, leading to dual PPARa/g agonists
with balanced activity for both subtypes. Herein we report the
discovery, synthesis, and optimization of a new series of a-
ethoxyphenylpropionic acid bearing 5- or 6-substituted in-
doles. The incorporation of oxime ethers on the carbonyl por-
tion of the benzoyl group can bring the PPARa/g potency ratio
equal to or slightly greater than one, as is the case for com-
pounds 20c and 21a. Compound 20c shows high efficacy in
an ob/ob mouse model of T2D and dyslipidemia, similar to
that of rosiglitazone and tesaglitazar, but with a significant in-
crease in body weight gain. In contrast, compound 21a, less
potent as a dual PPARa/g activator than 20c, showed an inter-
esting pharmacological profile, as it elicits a decrease in body
weight relative to reference compounds.
Introduction
Metabolic syndrome remains one of the leading causes of mor-
tality in Western society and has become a major public health
challenge worldwide. The term metabolic syndrome refers to
a cluster of risk factors of metabolic origin that promote the
development of cardiovascular diseases and type 2 diabetes
mellitus. Metabolic syndrome includes such pathological fac-
tors as insulin resistance, hyperinsulinemia, abdominal obesity,
impaired glucose tolerance, type 2 diabetes, microalbuminuria,
high triglyceride levels, low HDL cholesterol levels, elevated
blood pressure, and pro-inflammatory and pro-thrombic
states.[1]
Given the importance of controlling both glucose and lipid
levels in T2D, the concept of identifying ligands that bind to
and activate both PPARa and g represent a logical continua-
tion in the field of PPAR research. PPARg agonists have been
associated with improved insulin sensitivity and glucose toler-
ance, but at the cost of increased weight gain and other side
effects such as liver dysfunction[8] and bone loss.[9] The fibrates
have shown specific efficacy in decreasing the angiographic
progression of coronary heart disease in T2D, and the effect is
[a] Dr. M. Le Naour, Dr. V. Leclerc, Dr. A. Farce, Prof. P. Berthelot, Dr. N. Lebegue
Laboratoire de Chimie Therapeutique, EA4481
Universitꢀ Lille-Nord de France
The peroxisome proliferator-activated receptors (PPARs)
were cloned in 1990[2] as orphan members of the nuclear re-
ceptor family, which includes receptors for steroid, retinoid
and thyroid hormones,[3] and vitamin D.[4] PPARs are transcrip-
tion factors that are activated by the binding of small lipophilic
ligands. They induce or repress the transcription of a large
number of various genes, thereby influencing cellular func-
tion.[5] Among these functions, PPARs contribute to the regula-
tion of glucose, lipid, and cholesterol metabolism, apparently
making them ideal targets for the development of oral agents
for the treatment of metabolic syndrome.[6] Consequently, for
years, PPAR agonists have represented a promising approach
to treat type 2 diabetes (T2D) and the associated metabolic
diseases, including obesity, hypertension, and dyslipidemia.
There are three known PPAR receptor subtypes, designated as
PPARa, g, and b/d. Although the PPAR subtypes share a high
degree of sequence and structural similarity, each PPAR sub-
type exhibits a unique tissue expression profile.[7]
Facultꢀ des Sciences Pharmaceutiques et Biologiques de Lille
3 rue du Prof. Laguesse, BP83, 59006 Lille (France)
E-mail: nicolas.lebegue@univ-lille2.fr
[b] Dr. D.-H. Caignard
Etudes Extꢀrieures et Alliances stratꢀgiques
Institut de Recherches Servier
125 Chemin de Ronde, 78290 Croissy sur Seine (France)
[c] Dr. N. Hennuyer, Prof. B. Staels
Dꢀpartement d’Athꢀrosclꢀrose, U1011 Institut Pasteur de Lille
1 Rue du Pr. Calmette, 59019 Lille Cedex (France)
[d] Dr. V. Audinot-Bouchez, Dr. J.-A. Boutin
Division de Recherche Pharmacologie Molꢀculaire et Cellulaire
125 Chemin de Ronde, 78290 Croissy sur Seine (France)
[e] Dr. M. Lonchampt, Dr. C. Dacquet, Prof. A. Ktorza
Division de Recherche Maladies Mꢀtaboliques
Institut de Recherches Servier
11 Rue des Moulineaux, 92150 Suresnes (France)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201200316: 13C NMR spectra of tested
compounds 16a–e, 18a–d, 20a–c, 21a–c, 25a–d, and 29a–b.
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N. Lebegue et al.
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most likely related to the correction of atherogenic dyslipide-
mia. In addition to their benefit on lipids, there are reports
that fibrates decrease body weight gain in rodents without af-
fecting food intake.[10] Thus, activation of PPARa may mitigate
the weight gain induced by PPARg activation observed in
humans. The hypothesis that dual PPARa/g agonism should
provide additive—and possibly synergistic—pharmacology has
resulted in an intense effort within the pharmaceutical industry
to develop and evaluate these agents. Dual activation of
PPARa and g could, in theory, also limit the occurrence of side
effects associated with thiazolidinedione (TZD) therapy.[11] Thus,
combined PPARa/g activation has emerged as an interesting
concept and has spawned the development of various co-ago-
nists. A number of dual PPARa/g agonists have been reported
in this class of compounds and have shown robust insulin-sen-
sitizing and hypolipidemic activities in clinical trials.[12]
In our continued search for PPAR ligands, we synthesized
a large series of a-ethoxyphenylpropionic acid bearing an acyl-
heteroaryl core and found that many of them are full PPARg
agonists.[13] Pharmacophore modulations performed within this
class of compounds led to the discovery of the potent com-
pound S73362, which exhibits better in vitro PPAR activity than
the dual PPARa/g agonist tesaglitazar, with higher selectivity
for the PPARg receptor.
Molecular modeling studies were conducted to understand
the PPARg selectivity of S73362, by docking S73362 into the
PPARa and g ligand binding domains (LBDs). The binding
poses of S73362 with the LBDs of PPARa and g are shown in
Figure 1; further details of the molecular modeling studies will
be reported in due course. From the results, it was apparent
that the benzoyl moiety and the indole core of S73362 are
buried in a binding cavity of PPARa LBD composed of a cluster
of hydrophobic residues (Ile241, Leu247, Ile272, Met330,
Val332, Ile339, and Leu344), closed on its lower part by
Met355. In the case of PPARg, the narrower pocket is spread
more in depth, and the carbonyl portion of the benzoyl group
is directed toward Phe264 and His266, while position 3 of the
indole is oriented toward Leu228 and Leu333. The overall pic-
ture suggests that the introduction of small hydrophobic sub-
stituents on the ketone tail portion of the acyl group or at the
3-position of the indole group would increase the contact sur-
face with the receptors and thus benefit binding at both PPAR
subtypes.
Figure 1. Molecular modeling results of S73362 (pink) docked into the LBD
of PPARa and PPARg: shown are the molecular surface maps and key resi-
dues (in white) showing the binding pose of S73362 in complex with
a) PPARa (PDB code: 3FEI) and b) PPARg (PDB code: 1KNU).
Herein we report the effect of linking oxime ethers to the
ketone tail of 5- or 6-acylindole and/or at position 3 of the
indole ring, on the selectivity between PPARa and g, while re-
taining the a-ethoxypropionic acid moiety of tesaglitazar as an
acidic head group (Figure 2). The binding affinity to human
PPARg was characterized by using a competitive binding assay
with [3H]rosiglitazone, and the in vitro PPAR agonist activity
and subtype selectivity of all test compounds were assessed
with in vitro pGal4–hPPAR transactivation assays. Furthermore,
several selected compounds with a PPARa:PPARg potency
ratio equal to or slightly greater than one, were subjected to
in vivo studies to assess their anti-hyperlipidemic, anti-hyper-
glycemic, and body weight effects in experimental animal
models.
Figure 2. Design of dual PPARa/g agonists.
Results and Discussion
Chemistry
The key a-ethoxypropionic acid ester intermediate was synthe-
sized as illustrated in Scheme 1. For the synthesis of the
ethoxy phosphonoacetate 3, benzenesulfonyl azide was pre-
pared by coupling sodium azide with benzenesulfonyl chlo-
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Oxime Ethers in Acyl Indole Derivatives
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Scheme 1. Reagents and conditions: a) benzenesulfonyl azide, NaH, dry THF, 08C, 16 h, 87%; b) EtOH, [Rh(OAc)2]2, toluene, reflux, 4 h, 80%; c) 1-bromo-2-
chloroethane, K2CO3, CH3CN, reflux, 15 h, 92%; d) NaH, dry THF, 08C!RT, 5 h, 86%; e) H2, Pd/C, EtOH, RT, 20 h, 93%; f) LiOH, THF/H2O, RT, 20 h, 85%; g) 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, Et3N, HOBT, (S)-(ꢀ)-2-phenylglycinol, CH2Cl2, 08C!RT, 12 h, 33–37%; h) 5m H2SO4, dioxane/H2O,
reflux, 8 h, 78–81%.
ride.[14] This azide was sufficiently stable for handling and was
used to synthesize diazo intermediate 2 from phosphonoace-
tate 1 using sodium hydride in dry THF as described by Moody
et al.[15] and Regitz et al.[16] Diazo intermediate 2 proved stable
to silica chromatography. Thereafter, the rhodium(II) acetate
dimer was used to generate a carbenoid from the diazo com-
pound which was inserted into the OꢀH bond of ethanol, as
per Haigh et al.[17] (Scheme 1). A Horner–Wadsworth–Emmons
(HWE) coupling[18] was carried out between ethoxy phospho-
noacetate 3 and benzaldehyde 5 to give compound 6 as a mix-
ture of E/Z isomers, which were not separated, but used direct-
ly in the next step. Reduction of the double bond was realized
by catalytic hydrogenation with 10% Pd/C, leading to the race-
mic a-ethoxypropionic acid ester 7. Ester 7 could be saponified
to the racemic acid 8, which was transformed into the optically
pure amides 9a and 9b via (S)-2-phenylglycinol coupling.[19]
Separation of the resulting two diastereomers and amide hy-
drolysis afforded the optically pure carboxylic acids 10a and
10b. Chiral liquid chromatography was used to determine
enantiomeric purity, estimated to be 98% ee.
or 6-bromoindole or 5-bromo-3-methylindole with potassium
hydride in THF at ꢀ788C allowed abstraction of the indole NH
to afford a homogeneous solution of the potassium salt, which
upon treatment with tert-butyllithium, underwent rapid and ef-
ficient lithium–halogen exchange.[20] The metalated species
12a–c were then treated with the appropriate methyl or
phenyl Weinreb amide to prepare 5- and 6-benzoylindole de-
rivatives 14a–c. This method cannot be used for the introduc-
tion of cycloalkylcarbonyl groups, and we recently developed
an effective procedure for the synthesis of acylindoles under
Stille conditions.[21] Compound 12a was then treated with trib-
utyltin chloride as electrophile to afford 5-tributylstannylindole
13 in 78% yield. Stannane 13 was then treated with cyclopro-
panoyl or cyclohexanoyl chloride under the Stille-type cross-
coupling conditions, leading to the corresponding acylindoles
14d,e in 70% yield. Condensation of acylindoles 14a–e with
intermediates 7 was carried out in the presence of potassium
carbonate in DMF at reflux, and the desired acids 16a–e were
obtained after lithium hydroxide mediated saponification.
Esters 15a,b,d,e were further functionalized into the required
oxime ethers 17a–d by treatment with O-methylhydroxyla-
mine hydrochloride in pyridine followed by alkaline hydrolysis
The general procedure for the synthesis of indole derivatives
16a–e and 18a–d is represented in Scheme 2. Reaction of 5-
Scheme 2. Reagents and conditions: a) 1. KH, dry THF, 08C, 2. tBuLi, ꢀ788C; b) N-methoxy-N-methylbenzamide, dry THF, ꢀ788C!RT, 12 h, 48–64%;
c) 1. Bu3SnCl, dry THF, ꢀ788C!RT, 2. H2O, 08C, 78%; d) cyclopropyl- or cyclohexylcarbonyl chloride, PdCl2(PPh3)2, dry toluene, reflux, 16 h, 70–71%; e) 7,
K2CO3, DMF, reflux, 15 h, 55–65%; f) O-methylhydroxylamine hydrochloride, pyridine, 1008C, 4 h, 75–81%; g) LiOH, THF/H2O, RT, 15 h, 78–85%.
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to provide the corresponding carboxylic acids 18a–d in
yields.
Synthesis of enantiomerically pure 20a–c and 21a–c is out-
lined in Scheme 3. Treatment of 5- or 6-benzoylindole with O-
methylhydroxylamine hydrochloride led to the corresponding
oxime ethers, the E and Z isomers of which, respectively 19a
Scheme 5. Reagents and conditions: a) 7, K2CO3, DMF, reflux, 15 h, 56–62%;
b) O-methylhydroxylamine hydrochloride, pyridine, reflux, 4 h, 88%; c) LiOH,
THF/H2O, RT, 15 h, 83–85%.
with oxalyl chloride and DMF followed by acylation with ben-
zoyl chloride and excess aluminum chloride to provide the 5-
and 6-benzoyl-3-formylindoles 26a,b in a one-pot procedure
in 60 and 20% yields, respectively.[23] Condensation with inter-
mediate 7 followed by reaction with O-methylhydroxylamine
hydrochloride led to the formation of a racemic mixture of E
and Z isomers in the benzoyl group, whereas the E isomer was
exclusively obtained at the indole 3-position. Compounds
28a,b were finally saponified to afford the desired carboxylic
acids 29a,b.
Scheme 3. Reagents and conditions: a) O-methylhydroxylamine hydrochlo-
ride, pyridine, MeOH, RT, 24 h, 38–79%; b) NaH, 10a or 10b, HMPA, RT, 24 h,
47–63%.
and 19b, could be separated by liquid chromatography for the
5-benzoyl derivative, and the stereochemistry of each isomer
was assigned by NOE experiments. Condensation with the op-
tically pure carboxylic acids 10a and 10b under alkaline condi-
tions followed by acid hydrolysis provided the desired prod-
ucts 20a–c and 21a–c in >95% ee and 47–63% yield.
Synthesis of the target compounds 25a–d was realized from
5-acetylindole[22] 22 by using the same chemical pathway as
18a–d (Scheme 4). Condensation with intermediate 7 was fol-
lowed by introduction of various oxime ethers to provide the E
isomers exclusively, which were finally saponified to the corre-
sponding racemic acids.
In vitro biological evaluation
Compounds were characterized by determining the binding af-
finity to human PPARg using a competitive binding assay with
[3H]rosiglitazone, an appropriate radioligand for PPARg. The
binding profiles of test compounds were compared with those
of two references: rosiglitazone and tesaglitazar. Functional ac-
tivity was measured in a transient transfection assay using
human pGal4–hPPARa and pGal4–hPPARg constructs, and the
results are listed in Table 1. All tested compounds were func-
tionally inactive at 10 mm against human PPARd. As described
above, 16a (S73362) is a full dual PPARa/g agonist, with higher
selectivity for the PPARg receptor. Its 6-benzoyl regioisomer
16b shows increased a functional potency (EC50 ratio: 3.8)
while maintaining the same in vitro PPARg pharmacological
profile as S73362. Replacement of the 5-benzoyl substituent by
cycloalkylcarbonyl to give compounds 16d and 16e provided
the desired a/g potency ratio of approximately one or greater
(i.e., 16d EC50 ratio: 0.8; 16e EC50 ratio: 7). The weak a selectivi-
ty of 16d is not due to enhanced PPARa potency, but by de-
creased PPARg functional activity, while the g affinity is main-
tained. Acyl substitution with cyclohexyl or phenyl groups
seemed to be most tolerated among the steric bulk of sub-
stituents for PPARg activity.
Introduction of oxime ethers at position 3 of the indole ring
was carried out as depicted in Scheme 5. Formylation at the
indole 3-position was carried out by a Vilsmeier–Haack reaction
The incorporation of small hydrophobic substituents such as
methyl oxime ethers on the ketone tail portion of the acyl
group led to compounds 18a–d. In agreement with docking
studies, these compounds exhibited better a functional activity
than their carbonyl counterparts and proved to interact better
with the PPARa LBD, with an appropriate a/g ratio (com-
Scheme 4. Reagents and conditions: a) 7, K2CO3, DMF, reflux, 15 h, 56%; b) O-
substituted hydroxylamine hydrochloride, pyridine, MeOH, reflux, 4 h, 87–
93%; c) LiOH, THF/H2O, RT, 15 h, 76–81%.
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Table 1. In vitro profile of compounds 16a–e, 18a–d, 20a–c, 21a–c, 25a–d, and 29a–b as PPAR agonists.
Compd
Pos[a]
R1
X
R2
Stereo
hPPAR gene reporter
aEC50 [nm][e] gGal4 [%][d]
Ki [nm][b]
a/g[c]
aGal4 [%][d]
gEC50 [nm][e]
16a[f]
16b
16c
16d
16e
18a
18b
18c
18d
20a
21a
20b
21b
20c
21c
25a
25b
25c
25d
29a
29b
rosi[g]
tesa[h]
5
6
5
5
5
5
6
5
5
5
5
5
5
6
6
5
5
5
5
5
6
–
–
Ph
O
O
O
O
O
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Rac
Rac
Rac
Rac
Rac
Rac
Rac
Rac
Rac
S
105
96
117
74
332
165
94
302
79
109
78
107
77
78
80
60
64
97
115
129
88
28
89
117 90
0.9
5
6.5
151
16
7.6
5.5
102
5
0.3
700
8
0.9
1.2
1.4
1.2
0.7
2.8
14.4
2.4
2.7
2
157
3.1
183
4.8
841
5.5
2.7
3.4
17
130
3.8
Ph
Ph
cPr
cHex
Ph
Ph
cPr
cHex
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Ph
Ph
–
19
22
123
112
13
8.2
9
15
92
108
138
99
170
115
92
3.4
0.8
7
1.7
1.5
0.08
3
NOMe (E/Z)
NOMe (E/Z)
NOMe (E/Z)
NOMe (E/Z)
NOMe (E)
NOMe (E)
NOMe (Z)
NOMe (Z)
NOMe (E/Z)
NOMe (E/Z)
NOPh (E)
NOBn (E)
NOCH2cPr (E)
NOcHex (E)
NOMe (E/Z)
NOMe (E/Z)
–
90
3
107
72
10
R
S
R
S
1000
250
10000
50
1.4
31.2
9.1
129
71
66
1100
46
10000
3
1.1
R
212
200
2000
200
129
59
48
73
75
97
135
113
98
0.02
66.6
200
20
430
4.2
2
>100
Rac
Rac
Rac
Rac
Rac
Rac
–
10
10
0.3
14
12
CH=NOMe (E)
CH=NOMe (E)
–
–
25
65
8
18
24
10000
414
100
76
4
37
–
–
–
11.2
[a] Indole position. [b] hPPARg binding affinity: Ki is the test compound concentration required to achieve an apparent concentration value according to
the equation Ki =IC50/(1+[L]/Kd), for which IC50 is the test compound concentration required to inhibit 50% of specific binding of the radioligand, [L] is the
radioligand concentration used, and Kd is the dissociation constant for the radioligand at the receptor. [c] PPAR a/g selectivity ratio. [d] Potency. [e] Com-
pound concentration required to induce 50% maximum activity of WY14,643 (10 mm) for PPARa and rosiglitazone (1 mm) for PPARg; fold activation relative
to maximum activation obtained with WY14,643 (10 mm) and rosiglitazone (1 mm) corresponded to 100% in Gal4 chimeric PPARa and PPARg systems.
[f] S73362. [g] Rosiglitazone. [h] Tesaglitazar.
pounds 18a, 18b, and 18d have respective EC50 ratios of 1.7,
1.5, and 3). As for cyclopropyl carbonyl derivative 16d, which
has weak PPARa selectivity, its functionalization with O-methyl
oxime ether (giving compound 18c) enhanced a selectivity to
afford 10-fold more potent activity at the a receptor than the
PPARg subtype, and displaying threefold more activation than
the reference compound WY14,643. These results confirm that
the incorporation of small lipophilic substituents such as
methyl oxime ether strengthens the ligand–PPARa interaction
and likely increases activity while maintaining good PPARg po-
tency.
and might be better at filling the PPARa hydrophobic cavity. In
contrast, a longer oxime ether group introduced on the acetyl
derivative was not preferable and led to less potent PPARa ag-
onists. These results are consistent with the working hypothe-
sis that the shape and environment of the hydrophobic cavity
that hosts the acyl group substituted by oxime ethers differs
somewhat between the PPARa and g subtypes.
Further chemical modifications that may improve the poten-
cy and selectivity for the PPARa subtype were performed at
the 3-position of the indole ring by introducing small hydro-
phobic substituents such as methyl (compound 16c) or O-
methyl oxime ethers (compounds 29a,b). Altogether, com-
pounds 16c and 29a,b displayed higher PPARa activity and
lower PPARg activity than the unsubstituted indole analogue
16a, providing the desired a/g ratio of approximately one or
higher (i.e., 16c EC50 ratio: 3.4; 29a EC50 ratio: 4.2; 29b EC50
ratio: 2). These small substituents appear to lie closer to Ile272,
Ile339, and Leu344 of the PPARa LDB, thereby forming stron-
ger hydrophobic interactions than 16a. In the g receptor,
higher affinity was observed with a methyl substitution, where-
as an oxime ether group led to decreased affinity. The larger
We were also interested in synthesizing 5-acetylindoles, in
which bulkier oxime ethers such as phenyl (compound 25a),
benzyl (25b), methylcyclopropyl (25c), or cyclohexyl (25d)
substituents are introduced. Although these compounds dis-
played PPARg activities and affinities similar to those of their
parent O-methyl oxime ether derivatives 18a and 18d, these
modifications led to a significant decrease in PPARa potency
and so improved PPARg selectivity. Regarding PPARa, the intro-
duction of a short-chain oxime ether group on bulky acyl sub-
stituents was found to be favorable for transactivation activity,
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the size of the substituent, the greater the loss in PPARg bind-
ing affinity. From all the compounds synthesized, adjustment
of the PPARa/g potency ratio to an equal balance was ob-
served for racemates 18a and 18b, which were then resolved
into their pure enantiomers following the synthetic procedure
of Scheme 3. As described for other PPAR agonists,[24] ana-
logues containing (S)-ethoxypropanoic acid had higher activi-
ties than analogues containing (R)-ethoxypropanoic acid at
both PPARa and PPARg (20a vs. 21a, 20b vs. 21b, and 20c vs.
21c). Regarding the 5-substituted indole derivatives, E isomers
20a and 21a displayed better functional activities and affini-
ties than their Z isomer counterparts 20b and 21b. The opti-
cally pure S-configured derivative 20a represents the most
potent dual PPARa/g full agonist, but with a lower a/g ratio of
10, whereas its R-configured analogue provides the appropri-
ate ratio, slightly greater than one, with partial activity in the
micromolar range at both receptors. The resolution of race-
mate 18b into its optical antipodes first led to compound 20c,
which corresponds to the S enantiomer of the racemic mixture
of E/Z oxime ether isomers, and possesses the desired equal
potency ratio (i.e., 20c EC50 ratio: 1.1) with dual PPARa/g par-
tial agonist activity. In contrast, its R-configured counterpart
21c was found to be a selective PPARa partial agonist with no
activity and affinity for the PPARg subtype.
PPARa and g gene reporter assays. Body weight was also mea-
sured daily, and body weight variation was calculated as a per-
centage of the difference in body weight between days 4 and
0. Thus, at the end of treatment, body weight gain was three-
to fivefold higher for compounds 20a–c than for rosiglitazone
and tesaglitazar. PPARg activation is well known to enhance
body weight gain through two major mechanisms: increase in
fat mass by pre-adipocyte recruitment from bone marrow, and
adipocyte differentiation and fluid retention.[25] Whereas they
are highly potent agonists of both human PPARa and g in cel-
lular assays, compounds 20a–c appeared to be predominantly
PPARg activators in the ob/ob mice model. The functional activ-
ity of 20c, the best equally balanced PPARa/g ligand, was then
measured in a murine PPARa transient transfection assay and
was found to be 20-fold less potent toward the human recep-
tor, as observed for tesaglitazar (i.e., 20c and tesaglitazar
murine PPARa EC50 values of 1 and 10 mm, respectively). These
results are in accord with those of previous studies, which de-
scribe the beneficial effect of PPARa activity on body weight
as being dependent on the animal model used.[10b] The profile
of in vivo efficacy on both insulin sensitivity and energy ho-
meostasis of compounds 21a–c showed lower pharmacologi-
cal action in ob/ob mice than their S enantiomers, but without
promoting body weight gain relative to rosiglitazone and tesa-
glitazar. The triglyceride- and glucose-lowering activity of 21a
could be associated with its weak dual PPARa/g potency,
which down-regulated the adipocyte differentiation gene ex-
pression mediated by PPARg and decreased fluid retention and
body weight gain. The pharmacological profile of compound
21c could be partially due to the selective activation of PPARa
which decreased serum triglyceride levels and exerted its glu-
cose-lowering activity through insulin-sensitizing effects.
In vivo biological evaluation
The in vivo effects of test compounds were determined by
measuring glycemia, triglyceridemia, insulinemia, and body
weight in ob/ob mice, which are obese, insulin resistant with
hypertriglyceridemia and hyperglycemia, and have been used
as a rodent model of obesity-induced insulin resistance. In this
model, mice were dosed orally with either compounds 20a–
c and 21a–c or standard reference compounds (rosiglitazone
and tesaglitazar) at 3 mgkgꢀ1 for four days. As listed in Table 2,
Conclusions
In summary, a molecular docking design approach has led to
a novel series of a-ethoxyphenylpropionic acids bearing 5- or
-6-substituted indoles displaying highly potent activities
toward both PPARa and PPARg. Oxime ether introduction on
the carbonyl portion of the benzoyl group within this series
provided compounds 18a and 18b, and allowed adjustment
of the PPARa/g potency ratio to be equal to or slightly greater
than one. Enantiomeric resolution led to the best equally bal-
anced PPARa/g ligands 20c and 21a, with respective a/g po-
tency ratios of 1.1 and 1.4. Compound 20c shows high efficacy
in an ob/ob mice model of T2D and dyslipidemia, similar to ro-
siglitazone and tesaglitazar, but with a significant increase in
body weight gain. Our primary hypothesis, that equally bal-
anced dual PPARa/g agonists might overcome or diminish the
side effects of the glitazones as PPARg agonists, such as
weight gain, is not supported by our in vivo results. Com-
pound 20c seems to be a predominant PPARg activator in the
ob/ob mice model, as it was found to be 20-fold less potent in
the murine PPARa transactivation assay than on the human re-
ceptor. The beneficial effect of PPARa activity on body weight
could not be monitored by our in vivo study, as this depends
on the animal model employed. In contrast, compound 21a,
Table 2. In vivo efficacy of compounds 20a–c and 21a–c in ob/ob mice.
Change [%][a]
Compound
TG[b]
Gly[c]
Ins[d]
DBW[e]
20a
20b
20c
21a
21b
21c
rosiglitazone
tesaglitazar
ꢀ57
ꢀ46
ꢀ40
ꢀ17
6
ꢀ19
ꢀ61
ꢀ60
ꢀ47
ꢀ41
ꢀ52
ꢀ32
ꢀ5
ꢀ86
ꢀ37
ꢀ49
ꢀ3
490
370
305
66
54
42
5
ꢀ22
ꢀ59
ꢀ51
ꢀ26
ꢀ54
ꢀ94
100
93
[a] Percent change versus control for ob/ob mice at day 4 (dose:
3 mgkgꢀ1 p.o.). [b] Triglycerides. [c] Glycemia. [d] Insulin. [e] Body weight
variation between day 0 and day 4.
S-enantiomer derivatives 20a–c elicited significant decreases in
serum triglyceride, glucose, and insulin levels and were found
to be similar to the two reference compounds. The good
in vivo efficacy of compounds 20a–c observed in the mouse
model is consistent with the good potency displayed in the
2184
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Oxime Ethers in Acyl Indole Derivatives
MED
Ethyl 2-(diethoxyphosphoryl)-2-(ethoxy)acetate 3: This conver-
a less potent dual PPARa/g activator than 20c, shows an inter-
esting pharmacological profile, with a decrease in body weight
gain relative to rosiglitazone and tesaglitazar; this could be
due to a down-regulation of adipocyte differentiation gene ex-
pression mediated by PPARg. Further in vivo studies are
needed to evaluate the efficacy of these equally balanced dual
PPARa/g agonists in order to provide insight into the proper-
ties of these molecules and their biological actions. Further
studies might also be useful in determining whether these
compounds exhibit an improved benefit–risk ratio for the
treatment of diabetes.
sion was performed according to the method of Haigh et al.[17]
A
mixture of diazo ester 2 (10 g, 40 mmol, 1.0 equiv), EtOH (23.0 mL,
400 mmol, 10 equiv), and [Rh(OAc)2]2 (176.8 mg, 0.4 mmol,
0.01 equiv) in toluene (60 mL) was heated with stirring at reflux for
4 h. Thereafter, the solution was concentrated in vacuo, hydrolyzed
and extracted three times with EtOAc. The combined organic ex-
tracts were washed with H2O, brine, dried over MgSO4, filtered off,
and concentrated under reduced pressure. The resulting colorless
liquid (8.6 g, 80%) was used in the next step without further purifi-
1
cation; H NMR (CDCl3): d=1.24–1.35 (m, 12H), 3.55 (m, 1H), 3.70
(m, 1H), 4.23–4.28 (m, 6H), 4.35 ppm (s, 1H); MS m/z 269.2 [M+
H]+.
4-(2-Chloroethoxy)benzaldehyde 5: A mixture of 4-hydroxyben-
zaldehyde (10 g, 80 mmol, 1.0 equiv), K2CO3 (22 g, 160 mmol,
2.0 equiv), and 1-bromo-2-chloroethane (30 mL, 320 mmol,
4.0 equiv) was held at reflux in CH3CN (80 mL) for 15 h. The reac-
tion mixture was filtered, and the filtrate was evaporated under re-
duced pressure. The residue was purified by flash column chroma-
tography (cyclohexane/EtOAc 7:3) to yield 4 as a white powder
Experimental Section
Chemistry
General methods: All commercially available reagents and sol-
vents were used without further purification. Melting points were
determined on a Bꢂchi B-540 apparatus and are uncorrected. NMR
spectra were acquired with NMR spectrometers operating at 300
(1H) or 75 MHz (13C); chemical shifts (d) are given in ppm. The fol-
lowing abbreviations are used: singlet (s), broad singlet (brs), dou-
blet (d), double doublet (dd), triplet (t). HPLC–MS analyses were
performed with an HPLC instrument combined with a Surveyor
MSQ (Thermo Electron) equipped with an APCI source (ODS-30
column, mobile phase of H2O/CH3CN/HCO2H (gradient mode). Ele-
mental analyses were performed by CNRS–Vernaison, and data are
in agreement with calculated values within ꢁ0.4%. Reference
compounds rosiglitazone[26] and tesaglitazar[27] were synthesized by
previously described procedures.
1
3
(13.6 g, 92%); mp: 29–328C; H NMR (CDCl3): d=3.86 (t, 2H, J=
3
3
6.1 Hz), 4.32 (t, 2H, J=6.1 Hz), 7.03 (d, 2H, J=8.9 Hz), 7.86 (d, 2H,
3J=8.9 Hz), 9.90 ppm (s, 1H); MS m/z 185 [M+H35Cl]+, 187 [M+
H37Cl]+.
Ethyl 3-[4-(2-chloroethoxy)phenyl]-2-ethoxypropionate 7: Phos-
phonoacetate 3 (5 g, 18.6 mmol, 1.2 equiv) in THF (50 mL) was
added dropwise to a suspension of 60% NaH (0.93 g, 23.2 mmol,
1.5 equiv) in anhydrous THF (100 mL) at 08C under a constant flow
of N2, and the reaction mixture was stirred at 08C for 1 h. Benzal-
dehyde 5 (2.85 g, 15.5 mmol, 1.0 equiv) was then added in dry THF
(50 mL). After stirring for a further 4 h at room temperature, the so-
lution was concentrated in vacuo, and the residue was dissolved in
EtOAc for washing with H2O and brine. Combined organic extracts
were dried over MgSO4, filtered off, and concentrated in vacuo to
give a residue that was purified by flash column (cyclohexane/
EtOAc 8:2) to yield 6 (3.95 g, 86%) as two isomers (Z/E=59:41)
which were not separated, but used directly in the next catalytic
hydrogenation step. A solution of 6 (3.95 g, 13.2 mmol) in EtOH
(150 mL) was stirred with 10% Pd/C catalyst at room temperature
under H2 (1 atm) for 20 h. The catalyst was separated by filtration,
and the solvent evaporated under reduced pressure. The crude
product was purified by flash column chromatography (cyclohex-
ane/EtOAc 7:3) to yield 7 as a colorless liquid (3.68 g, 93%);
Chiral HPLC method: A Waters HPLC system was equipped with
an HPLC 600 pump and a 2996 photodiode array detector. The
column used was a Daicel Chiralpak AD (250ꢃ4.6 mm) at a flow
rate of 1 mLminꢀ1 and 208C. The eluents were: A) IPA+0.1% TFA,
B) petroleum ether (PE), C) EtOH+0.2% TFA, and D) MeOH. Isocrat-
ic elution conditions involved a flow rate of 0.8 or 1 mLminꢀ1 at
208C with a total run time of 25 min.
Ethyl 2-diazo-2-(diethoxyphosphoryl)acetate 2: The formation of
benzenesulfonyl azide was carried out according to published pro-
cedures.[16] In brief, benzenesulfonyl chloride (10 g, 56.6 mmol,
1.0 equiv) in acetone (100 mL) and NaN3 (5.52 g, 84.9 mmol,
1.5 equiv) in H2O (20 mL) were combined to yield 9.6 g of the de-
3
3
1H NMR (CDCl3): d=1.17 (t, 3H, J=7.1 Hz), 1.24 (t, 3H, J=7.1 Hz),
1
sired reagent as a colorless liquid (93%); H NMR (CDCl3): d=7.63
3
3
2.97 (d, 2H, J=5.6 Hz), 3.33 (m, 1H), 3.59 (m, 1H), 3.81 (t, 2H, J=
3
3
4
(dd, 2H, J=7.2 and 8.3 Hz), 7.75 (dd, 1H, J=7.2 Hz, J=1.5 Hz),
7.97 ppm (dd, 2H, 3J=8.3 Hz, 4J=1.5 Hz); MS m/z 184 [M+H]+.
The next stage was carried out according to the procedure of
Regitz et al.[16] Triethyl phosphonoacetate 1 (10.4 mL, 52.4 mmol,
1.0 equiv) in dry THF (50 mL) was added dropwise to an ice-cold
suspension of 60% NaH (3.14 g, 78.6 mmol, 1.5 equiv) in dry THF
(50 mL). The reaction mixture was stirred at 08C for 1 h, after
which time benzenesulfonyl azide (9.6 g, 52.4 mmol, 1.00 equiv) in
dry THF (100 mL) was added under a constant flow of N2. The reac-
tion mixture was further stirred for 16 h at 08C, then quenched by
the addition of a 5% aqueous solution of NaHCO3 (200 mL). There-
after, the aqueous phase was extracted with EtOAc and washed
with H2O and brine. The organic extract was then dried over
MgSO4, filtered off and concentrated in vacuo. The residue was pu-
rified by flash column chromatography (cyclohexane/EtOAc 5:5) to
3
3
5.9 Hz), 3.98 (t, 1H, J=5.6 Hz), 4.12–4.25 (m, 4H), 6.85 (d, 2H, J=
8.6 Hz), 7.17 ppm (d, 2H, 3J=8.6 Hz); MS m/z 300.1 [M+H35Cl]+,
302.2 [M+H37Cl]+; Anal. calcd for C15H21ClO4: C 59.90, H 7.04,
found: C 60.02, H 6.98.
3-[4-(2-Chloroethoxy)phenyl]-2-ethoxypropionic acid 8: LiOH
(0.49 g, 20.4 mmol, 3.0 equiv) was added to a solution of 7 (2 g,
6.6 mmol, 1.0 equiv) dissolved in a 1:1 mixture of THF (30 mL) and
H2O (30 mL), and the mixture was then stirred at room tempera-
ture for 20 h. Thereafter, the whole was concentrated in vacuo, and
the concentrate was subjected to vigorous stirring at 08C as the
solution was adjusted to pH 1 with 1n HCl(aq). The resulting precip-
itate was filtered, washed with H2O and pentane, and dried under
reduced pressure to give 8 as a white solid (1.71 g, 85%); mp: 49–
518C; 1H NMR (CDCl3): d=1.19 (t, 3H, 3J=7.0 Hz), 2.95 (m, 2H),
3.45 (m, 1H), 3.63 (m, 1H), 3.82 (t, 2H, 3J=6.1 Hz), 4.06 (dd, 1H,
3J=7.9 Hz, 3J=4.4 Hz), 4.22 (t, 2H, 3J=6.1 Hz), 6.87 (d, 2H, 3J=
1
yield 2 as a pale-yellow liquid (11.4 g, 87%); H NMR (CDCl3): d=
3
3
1.19 (t, 3H, J=7.2 Hz), 1.36 (t, 6H, J=7.2 Hz), 4.18–4.23 ppm (m,
6H); MS m/z 251.1 [M+H]+.
3
8.7 Hz), 7.20 (d, 2H, J=8.7 Hz), 10.3 ppm (brs, 1H); MS m/z 273.2
ChemMedChem 2012, 7, 2179 – 2193
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2185

N. Lebegue et al.
MED
[M+H35Cl]+, 275.3 [M+H37Cl]+; Anal. calcd for C13H17ClO4: C 57.25,
H 6.28, O 23.47, found: C 57.41, H 6.19, O 23.52.
1H-indole (5 g, 25.5 mmol, 1 equiv) was added as a DMF solution
(10 mL). The mixture was then allowed to warm to room tempera-
ture and stirred for 1 h. The reaction became a heavy suspension
that required vigorous stirring. NaOH(aq) (9.3m, 30 mL, 11 equiv)
was added dropwise, and the mixture was heated at reflux over-
night. After cooling to room temperature, the precipitate was col-
lected by filtration, washed with H2O, and recrystallized from EtOH
to afford 5-bromo-3-formyl-1H-indole as a light-yellow solid (5.3 g,
93%); mp: 205–2078C; 1H NMR (DMSO): d=7.38 (dd, 1H, 3J=
2-(S)-3-[4-(2-Chloroethoxy)phenyl]-2-ethoxy-N-((S)-2-hydroxy-1-
phenylethyl)propanamide 9a and 2-(R)-3-[4-(2-chloroethoxy)-
phenyl]-2-ethoxy-N-((S)-2-hydroxy-1-phenylethyl)propanamide
9b: EDCI (2.87 g, 15.0 mmol, 1.2 equiv), (S)-(ꢀ)-2-phenylgycinol
(1.74 g, 12.5 mmol, 1.0 equiv), and HOBT (2.0 g, 15.0 mmol,
1.2 equiv) were added to a solution of 8 (3.4 g, 12.5 mmol,
1.0 equiv) in CH2Cl2 (150 mL) at 08C. Finally, Et3N (2.1 mL,
15.0 mmol, 1.2 equiv) was added dropwise at 08C. The reaction
mixture was then stirred for 12 h at room temperature, quenched
with saturated NH4Cl(aq), and diluted with CH2Cl2. The organic layer
so obtained was washed with H2O, dried over MgSO4, filtered off
and concentrated in vacuo. Purification of the residue by flash
column chromatography (PE/EtOAc 45:55) afforded 9a (1.8 g,
37%) as an off-white solid, and 9b (1.6 g, 33%) as a white solid.
4
3
4
8.7 Hz, J=2.0 Hz), 7.50 (d, 1H, J=8.7 Hz), 8.22 (d, 1H, J=2.0 Hz),
8.36 (s, 1H), 9.93 (s, 1H), 12.32 ppm (s, 1H). A solution of formylin-
dole (5.3 g, 23.6 mmol, 1 equiv) in dry THF (35 mL) was added
dropwise to a suspension of LiAlH4 (1.85 g, 47.2 mmol, 2 equiv) in
dry THF (10 mL) at 08C and then heated at 65–708C for 4 h under
N2. After cooling, the suspension was quenched with H2O, extract-
ed twice with EtOAc, and the combined organic extracts were
dried over MgSO4, filtered off and concentrated in vacuo. The resi-
due was purified by flash column chromatography (toluene/PE
75:25) to yield 3.4 g (68%) of 11 b as a pale-brown solid; mp: 80–
9a: mp: 135–1378C; 1H NMR (CDCl3): d=1.21 (t, 3H, 3J=7.0 Hz),
2.91 (dd, 1H, 2J=14.3 Hz, 3J=8.5 Hz), 3.09 (dd, 1H, 2J=14.3 Hz,
3J=8.5 Hz), 3.58 (m, 2H), 3.85 (m, 4H), 4.02 (dd, 1H, 3J=6.4 Hz,
1
818C; H NMR (CDCl3): d=2.32 (s, 3H), 6.69 (s, 1H), 7.18–7.32 (m,
2H), 7.72 (s, 1H), 7.93 ppm (brs, 1H); MS m/z 211.2 [M+H]+.
3
3
3J=3.8 Hz), 4.19 (t, 2H, J=5.8 Hz), 5.01 (m, 1H), 6.78 (d, 2H, J=
8.7 Hz), 7.07 (dd, 2H, 3J=7.6 Hz, 4J=2.0 Hz), 7.13 (m, 3H),
7.33 ppm (m, 3H); MS m/z 393.0 [M+H35Cl]+, 395.1 [M+H37Cl]+;
Anal. calcd for C21H26ClNO4: C 64.36, H 6.69, N 3.57, found: C 64.45,
H 6.57, N 3.61.
5-Tributylstannylindole 13: A solution of 5-bromoindole 11 a
(3.98 g, 20 mmol, 1 equiv) in dry THF (40 mL) was added to a 35%
KH dispersion in mineral oil (2.29 g, 20 mmol, 1 equiv) in dry THF
(40 mL) at 08C. After 15 min the solution was cooled to ꢀ788C
and a solution of tBuLi in pentane (1.5m, 26.6 mL, 40 mmol,
2 equiv) precooled to ꢀ788C was added via cannula. A white pre-
cipitate immediately formed and after 10 min, tributyltin chloride
(13 g, 40 mmol, 2 equiv) dissolved in dry THF (10 mL) was added.
The reaction mixture was allowed to slowly warm to room temper-
ature, and the suspension was poured into 150 mL ice-cold H2O.
The organic layer was separated, and the aqueous layer was ex-
tracted twice with Et2O. The ether extracts were combined, dried
over MgSO4, filtered off and evaporated under reduced pressure.
The residue was purified by flash column chromatography (PE/
EtOAc/Et3N 90:9:1) previously neutralized with Et3N to yield 13 as
a colorless oil (6.3 g, 78%); 1H NMR (CDCl3): d=0.89 (t, 9H, 3J=
7.3 Hz), 1.07 (m, 6H), 1.34 (m, 6H), 1.55 (m, 6H), 6.55 (m, 1H), 7.17
(m, 1H), 7.27 (d, 1H, 3J=8.4 Hz), 7.40 (d, 1H, 3J=8.4 Hz), 7.76 (t,
9b: mp: 127–1288C; 1H NMR (CDCl3): d=1.16 (t, 3H, 3J=7.0 Hz),
2.96 (dd, 1H, 2J=14.3 Hz, 3J=6.4 Hz), 3.15 (dd, 1H, 2J=14.3 Hz,
3
3J=6.4 Hz), 3.52 (m, 2H), 3.71 (m, 2H), 3.83 (t, 2H, J=5.8 Hz), 4.00
(dd, 1H, 3J=6.7 Hz, 3J=3.9 Hz), 4.24 (t, 2H, 3J=5.8 Hz), 4.99 (m,
3
3
1H), 6.88 (d, 2H, J=8.7 Hz), 7.03 (d, 1H, J=7.3 Hz), 7.20 (m, 4H),
7.34 ppm (m, 3H); MS m/z 393.0 [M+H35Cl]+, 395.1 [M+H37Cl]+;
Anal. calcd for C21H26ClNO4: C 64.36, H 6.69, N 3.57, found: C 64.44,
H 6.61, N 3.60.
2-(S)-3-[4-(2-Chloroethoxy)phenyl]-2-ethoxypropionic acid 10a
and 2-(R)-3-[4-(2-chloroethoxy)phenyl]-2-ethoxypropionic acid
10b: 5m H2SO4 (82 mL, 408 mmol, 100 equiv) was added to a solu-
tion of 9a or 9b (1.6 g, 4.08 mmol, 1 equiv) in a 1:1 mixture of 1,4-
dioxane (80 mL) and H2O (80 mL). The reaction mixture was held at
reflux for 8 h, cooled to room temperature, diluted with EtOAc,
and the organic layer so obtained was washed with H2O, dried
over MgSO4, filtered off and concentrated in vacuo. The brown resi-
due was purified by flash column chromatography (CH2Cl2/MeOH/
Et3N 96:2:2) to afford the corresponding carboxylic acid 10a
(0.90 g, 81%) or 10b (0.87 g, 78%) as white solids.
3
1H, J=22 Hz), 8.16 ppm (brs, 1H); MS m/z 407.2 [M+H]+; Anal.
calcd for C20H33NSn: C 59.14, H 8.19, N 3.45, found: C 59.48, H 8.11,
N 3.51.
General procedure for the synthesis of 5- and 6-acylindole de-
rivatives 14a–c:
A solution of bromoindole 11 a–c (3.98 g,
20 mmol, 1 equiv) in dry THF (40 mL) was added to a 35% KH dis-
persion in mineral oil (2.29 g, 20 mmol, 1 equiv) in dry THF (40 mL)
at 08C. After 15 min the solution was cooled to ꢀ788C, and a solu-
tion of tBuLi in pentane (1.5m, 26.6 mL, 40 mmol, 2 equiv) pre-
cooled to ꢀ788C was added via cannula, and the solution was
stirred for 20 min. N-methoxy-N-methylbenzamide (3.96 g,
24 mmol, 1.2 equiv) in dry THF (40 mL) was added at ꢀ788C, and
the mixture was then allowed to warm to room temperature and
stirred for 12 h. The reaction mixture was hydrolyzed with an aque-
ous solution of H3PO4 (1m, 300 mL) and extracted twice with
EtOAc. The combined organic extracts were dried over MgSO4, fil-
tered off and concentrated in vacuo, and the residue was purified
by flash column chromatography (toluene/EtOAc 9:1) to afford the
corresponding benzoyl indole derivative.
10a: mp: 49–518C; 1H NMR (DMSO): d=1.04 (t, 3H, 3J=7.0 Hz),
2.83 (m, 2H), 3.29 (m, 1H), 3.52 (m, 1H), 3.92 (t, 2H, 3J=5.5 Hz),
4.21 (t, 2H, J=5.5 Hz), 6.87 (d, 2H, J=8.5 Hz), 7.14 ppm (d, 2H,
3J=8.5 Hz); MS m/z 273.1 [M+H35Cl]+, 275.0 [M+H37Cl]+; Anal.
calcd for C13H17ClO4: C 57.25, H 6.28, found: C 57.32, H 6.24; chiral
HPLC method: flow rate=1.0 mLminꢀ1, eluents=A/B 5:95, tR =
16.62 min.
3
3
10b: mp: 49–518C; 1H NMR (DMSO): d=1.04 (t, 3H, 3J=7.0 Hz),
2.83 (m, 2H), 3.29 (m, 1H), 3.52 (m, 1H), 3.92 (t, 2H, 3J=5.5 Hz),
3
3
4.21 (t, 2H, J=5.5 Hz), 6.87 (d, 2H, J=8.5 Hz), 7.14 ppm (d, 2H,
3J=8.5 Hz); MS m/z 273.1 [M+H35Cl]+, 275.0 [M+H37Cl]+; Anal.
calcd for C13H17ClO4: C 57.25, H 6.28, found: C 57.37, H 6.21; chiral
HPLC method: flow rate=1.0 mLminꢀ1, eluents=A/B 5:95, tR =
12.48 min.
5-Benzoyl-1H-indole 14a: Off-white solid (2.83 g, 64%); mp: 152–
1538C (PE); 1H NMR (CDCl3): d=6.67 (m, 1H), 7.32 (t, 1H, 3J=
3.1 Hz), 7.45–7.54 (m, 3H), 7.59 (t, 1H, 3J=7.5 Hz), 7.79–7.87 (m,
3H), 8.6 (s, 1H), 8.60 ppm (brs, 1H); MS m/z 222.2 [M+H]+; Anal.
5-Bromo-3-methyl-1H-indole 11c: Phosphorus oxychloride (4.3 g,
30 mmol, 1.15 equiv) was added dropwise to DMF (8.6 mL) with
ice-bath cooling. The mixture was stirred for 5 min, then 5-bromo-
2186
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Oxime Ethers in Acyl Indole Derivatives
MED
3
3
calcd for C15H11NO: C 81.43, H 5.01, N 6.33, found: C 81.52, H 4.96,
N 6.40.
3H, J=6.8 Hz), 1.23 (t, 3H, J=7.3 Hz), 2.92 (m, 2H), 3.33 (m, 1H),
3
3
3.59 (m, 1H), 3.95 (t, 1H, J=6.3 Hz), 4.17 (q, 2H, J=6.8 Hz), 4.30
(t, 2H, J=5.7 Hz), 4.58 (t, 2H, J=5.7 Hz), 6.62 (d, 1H, J=3.1 Hz),
6.78 (d, 2H, J=8.9 Hz), 7.17 (m, 3H), 7.32 (d, 1H, J=3.1 Hz), 7.50
(m, 3H), 7.58 (t, 1H, J=7.3 Hz), 7.82 (d, 2H, J=7.5 Hz), 8.12 ppm
(d, 1H, 3J=1.5 Hz); MS m/z 486.3 [M+H]+; Anal. calcd for
C30H31NO5: C 74.21, H 6.43, N 2.88, found: C 74.30, H 6.38, N 2.94.
3
3
3
6-Benzoyl-1H-indole 14b: Off-white solid (2.12 g, 48%); mp: 149–
1518C (PE); 1H NMR (CDCl3): d=6.67 (m, 1H), 7.44 (t, 1H, 3J=
2.9 Hz), 7.51 (t, 2H, 3J=6.1 Hz), 7.60 (t, 1H, 3J=7.6 Hz), 7.65 (dd,
1H, 3J=8.2 Hz, 4J=1.5 Hz), 7.73 (d, 1H, 3J=8.2 Hz), 7.84 (d, 2H,
3J=6.7 Hz), 7.97 (m, 1H), 8.46 ppm (brs, 1H); MS m/z 222.2 [M+
H]+; Anal. calcd for C15H11NO: C 81.43, H 5.01, N 6.33, found: C
81.49, H 4.95, N 6.38.
3
3
3
3
Ethyl 3-{4-[2-(6-benzoylindol-1-yl)ethoxy]phenyl}-2-ethoxypropi-
1
onate 15b: Colorless oil (1.43 g, 59%); H NMR (CDCl3): d=1.15 (t,
3
3
3H, J=7.0 Hz), 1.22 (t, 3H, J=7.2 Hz), 2.92 (m, 2H), 3.32 (m, 1H),
5-Benzoyl-3-methyl-1H-indole 14c: Light-brown solid (2.06 g,
3
3
3.60 (m, 1H), 3.93 (t, 1H, J=6.4 Hz), 4.19 (q, 2H, J=6.9 Hz), 4.28
(t, 2H, J=5.5 Hz), 4.60 (t, 2H, J=5.5 Hz), 6.61 (d, 1H, J=3.1 Hz),
6.74 (d, 2H, J=8.5 Hz), 7.12 (d, 2H, J=8.5 Hz), 7.42–7.61 (m, 5H),
7.68 (d, 1H, J=8.2 Hz), 7.83 (d, 2H, J=7.5 Hz), 8.05 ppm (d, 1H,
3J=1.7 Hz); MS m/z 486.1 [M+H]+; Anal. calcd for C30H31NO5: C
74.21, H 6.43, N 2.88, found: C 74.28, H 6.36, N 2.95.
1
49%); mp: 148–1508C (PE); H NMR (CDCl3): d=2.72 (s, 3H), 7.09
3
3
3
(m, 1H), 7.42 (d, 1H, 3J=8.5 Hz), 7.51 (t, 2H, 3J=6.3 Hz), 7.60 (t,
3
3
3
3
4
1H, J=7.6 Hz), 7.77 (dd, 1H, J=8.5 Hz, J=1.75 Hz), 7.84 (d, 2H,
3
3
3J=6.6 Hz), 8.13 (d, 1H, J=1.75 Hz), 8.17 (brs, 1H); MS m/z 236.3
[M+H]+; Anal. calcd for C16H13NO: C 81.68, H 5.57, N 5.95, found:
4
C 81.77, H 5.47, N 6.01.
Ethyl
3-{4-[2-(5-benzoyl-3-methylindol-1-yl)ethoxy]phenyl}-2-
General procedure for the synthesis of 5-cycloalkylcarbonyl
indole derivatives 14d,e: PdCl2(PPh3)2 (140.4 mg, 0.2 mmol,
0.02 equiv) was added to a solution of cyclopropylcarbonyl chlo-
ride (1.04 g, 10 mmol, 1 equiv) or cyclohexylcarbonyl chloride
(1.46 g, 10 mmol, 1 equiv) in anhydrous toluene (40 mL) under Ar.
The mixture was stirred at room temperature for 10 min, and 5-
tributylstannylindole 13 (5.3 g, 13 mmol, 1.3 equiv) in toluene
(10 mL) was added. The reaction mixture was stirred and heated at
110 8C for 16 h. After conversion was complete (checked by TLC),
the solvent was evaporated under reduced pressure, and the oily
mixture was treated with EtOAc and a solution of KF (1m) at room
temperature for 30 min to precipitate the formed tributyltin fluo-
ride. The resulting solution was filtered through a Celite pad and
extracted with EtOAc. The combined organic layers were dried
over MgSO4, filtered off and evaporated under reduced pressure.
The crude product was purified by flash column chromatography
(PE/EtOAc 75:25) to afford the corresponding 5-cycloalkylcarbonyl
indole derivative.
ethoxypropionate 15c: Colorless oil (1.55 g, 62%); 1H NMR
3
3
(CDCl3): d=1.16 (t, 3H, J=7.1 Hz), 1.24 (t, 3H, J=6.6 Hz), 2.33 (s,
3H), 2.93 (m, 2H), 3.33 (m, 1H), 3.60 (m, 1H), 3.95 (t, 1H, 3J=
5.9 Hz), 4.19 (q, 2H, J=6.6 Hz), 4.28 (t, 2H, J=5.6 Hz), 4.60 (t, 2H,
3J=5.6 Hz), 6.78 (d, 2H, J=8.3 Hz), 7.07 (s, 1H), 7.14 (d, 2H, J=
8.3 Hz), 7.41–7.61 (m, 4H), 7.75–7.87 (m, 3H), 8.10 ppm (d, 1H, J=
1.5 Hz); MS m/z 500.4 [M+H]+; Anal. calcd for C31H33NO5: C 74.53,
H 6.66, N 2.80, found: C 74.62, H 6.59, N 2.84.
3
3
3
3
4
Ethyl
3-{4-[2-(5-cyclopropanoylindol-1-yl)ethoxy]phenyl}-2-
ethoxypropionate 15d: Colorless oil (1.46 g, 65%); 1H NMR
3
(CDCl3): d=1.03 (m, 2H), 1.15 (t, 3H, J=7.0 Hz), 1.26 (m, 5H), 2.81
(m, 1H), 2.93 (m, 2H), 3.33 (m, 1H), 3.60 (m, 1H), 3.95 (t, 1H, J=
3
3
3
5.8 Hz), 4.17 (q, 2H, J=6.6 Hz), 4.28 (t, 2H, J=5.6 Hz), 4.57 (t, 2H,
3J=5.6 Hz), 6.67 (d, 1H, 3J=3.2 Hz), 6.78 (d, 2H, 3J=8.2 Hz), 7.14
(d, 2H, J=8.2 Hz), 7.31 (d, 1H, J=3.2 Hz), 7.46 (d, 1H, J=8.5 Hz),
7.98 (dd, 1H, 3J=8.5 Hz, 4J=1.5 Hz), 8.42 (d, 1H, 4J=1.5 Hz); MS
m/z 450.3 [M+H]+; Anal. calcd for C27H31NO5: C 72.14, H 6.95, N
3.12, found: C 72.25, H 6.89, N 3.21.
3
3
3
5-cyclopropylcarbonyl-1H-indole 14d: Off-white solid (1.64 g,
1
70%); mp: 114–1168C; H NMR (CDCl3): d=1.05 (m, 2H), 1.27 (m,
Ethyl 3-{4-[2-(5-cyclohexanoylindol-1-yl)ethoxy]phenyl}-2-ethox-
ypropionate 15e: Colorless oil (1.35 g, 55%); H NMR (CDCl3): d=
2H), 2.82 (m, 1H), 6.69 (m, 1H), 7.30 (m, 1H), 7.44 (d, 1H, 3J=
8.8 Hz), 7.93 (dd, 1H, 3J=8.8 Hz, 4J=1.7 Hz), 8.44 (d, 1H, 4J=
1.7 Hz), 8.51 (brs, 1H); MS m/z 236.2 [M+H]+; Anal. calcd for
C12H11NO: C 77.81, H 5.99, N 7.56, found: C 78.03, H 6.04, N 7.47.
1
3
3
1.16 (t, 3H, J=7.0 Hz), 1.23 (t, 3H, J=7.0 Hz), 1.32–1.66 (m, 6H),
1.72–2.0 (m, 4H), 2.93 (m, 2H), 3.38 (m, 2H), 3.59 (m, 1H), 3.95 (t,
1H, 3J=5.8 Hz), 4.19 (q, 2H, 3J=6.7 Hz), 4.28 (t, 2H, 3J=5.6 Hz),
4.55 (t, 2H, 3J=5.6 Hz), 6.62 (d, 1H, 3J=3.1 Hz), 6.75 (d, 2H, 3J=
8.4 Hz), 7.14 (d, 2H, 3J=8.4 Hz), 7.29 (d, 1H, 3J=3.1 Hz), 7.47 (d,
1H, 3J=8.3 Hz), 7.92 (dd, 1H, 3J=8.3 Hz, 4J=1.6 Hz), 8.32 (d, 1H,
4J=1.6 Hz); MS m/z 492.4 [M+H]+; Anal. calcd for C30H37NO5: C
73.29, H 7.59, N 2.85, found: C 73.36, H 7.48, N 2.94.
5-cyclohexylcarbonyl-1H-indole 14e: Off-white solid (1.61 g,
71%); mp: 119–1218C; 1H NMR (CDCl3): d=1.24–1.96 (m, 10H),
3
3
3.43 (m, 1H), 6.68 (m, 1H), 7.30 (t, 1H, J=2.9 Hz), 7.44 (d, 1H, J=
8.7 Hz), 7.88 (dd, 1H, 3J=8.7 Hz, 4J=1.65 Hz), 8.33 (d, 1H, 3J=
1.7 Hz), 8.48 ppm (brs, 1H); MS m/z 228.2 [M+H]+; Anal. calcd for
C15H17NO: C 79.26, H 7.54, N 6.16, found: C 79.34, H 7.48, N 6.22.
Ethyl 3-{4-[2-(5-acetylindol-1-yl)ethoxy]phenyl}-2-ethoxypropio-
1
nate 23: Pasty solid (1.18 g, 56%); H NMR (CDCl3): d=1.16 (t, 3H,
General procedure for the synthesis of compounds 15a–e and
23: To a solution of 5- or 6-substituted indole derivative 14a–e or
22 (5 mmol, 1.0 equiv) in DMF (50 mL) was added K2CO3 (15 mmol,
3 equiv), and the mixture was stirred for 1 h at 1008C. A solution
of 7 (6 mmol, 1.2 equiv) in DMF (10 mL) was added dropwise, and
the mixture was stirred at reflux for 15 h. After cooling, the reac-
tion mixture was filtered, hydrolyzed, and extracted twice with
EtOAc. The combined organic extracts were washed with H2O,
dried over MgSO4, filtered off and concentrated in vacuo. The
crude product was purified by flash column chromatography (tolu-
ene/EtOAc 95:5) to afford the corresponding N-alkylated indole de-
rivative.
3J=7.0 Hz), 1.24 (t, 3H, J=7.0 Hz), 2.69 (s, 3H), 2.93 (m, 2H), 3.33
3
(m, 1H), 3.60 (m, 1H), 3.95 (t, 1H, 3J=6.4 Hz), 4.18 (q, 2H, 3J=
3
3
7.0 Hz), 4.29 (t, 2H, J=5.5 Hz), 4.57 (t, 2H, J=5.5 Hz), 6.65 (d, 1H,
3J=3.2 Hz), 6.78 (d, 2H, 3J=8.2 Hz), 7.13 (d, 2H, 3J=8.2 Hz), 7.32
(d, 1H, J=3.2 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.93 (d, 1H, J=8.5 Hz),
8.32 ppm (s, 1H); MS m/z 424.1 [M+H]+; Anal. calcd for C25H29NO5:
C 70.90, H 6.90, N 3.31, found: C 70.81, H 6.97, N 3.42.
3
3
3
General procedure for the synthesis of oxime ethers 17a–d: O-
Methylhydroxylamine hydrochloride (10 mmol, 4 equiv) was added
to a solution of 15a,b,d,e (2.5 mmol, 1 equiv) in pyridine (20 mL),
and the mixture was stirred at 1008C for 4 h. The reaction mixture
was concentrated in vacuo, hydrolyzed with 1n HCl(aq), and extract-
ed twice with CH2Cl2. The combined organic extracts were dried
Ethyl 3-{4-[2-(5-benzoylindol-1-yl)ethoxy]phenyl}-2-ethoxypropi-
1
onate 15a: Colorless oil (1.48 g, 61%); H NMR (CDCl3): d=1.15 (t,
ChemMedChem 2012, 7, 2179 – 2193
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2187

N. Lebegue et al.
MED
over MgSO4, filtered off, evaporated under reduced pressure, and
the resulting residue was purified by flash column chromatography
(toluene/EtOAc 97:3) to afford the corresponding oxime ether as
a racemic mixture of E and Z isomers.
3J=5.7 Hz), 6.60 (d, 1H, 3J=2.6 Hz), 6.74 (d, 2H, 3J=8.5 Hz), 7.09
3
3
3
(d, 2H, J=8.5 Hz), 7.46 (d, 1H, J=8.2 Hz), 7.56 (t, 2H, J=7.3 Hz),
7.62–7.80 (m, 5H), 8.07 ppm (s, 1H); LC–MS: tR =4.12 min (96%),
m/z 458.0 [M+H]+; Anal. calcd for C28H27NO5: C 73.51, H 5.95, N
3.06, found: C 73.35, H 6.10, N 3.02.
Ethyl 2-ethoxy-3-{4-[2-(5-{[Z/E]-methoxyimino]phenylmethyl}in-
dol-1-yl)ethoxy]phenyl}propionate 17a: Colorless oil (0.97 g,
3-{4-[2-(5-Benzoyl-3-methylindol-1-yl)ethoxy]phenyl}-2-ethoxy-
propionic acid 16c: White solid (0.79 g, 84%); mp: 54–588C;
1H NMR (CDCl3): d=1.13 (t, 3H, 3J=7.3 Hz), 2.31 (s, 3H), 2.98 (m,
1
76%); H NMR (CDCl3): d=1.16 (m, 3H), 1.24 (m, 3H), 2.93 (m, 2H),
3.33 (m, 1H), 3.60 (m, 1H), 3.96 (m, 4H), 4.18 (m, 2H), 4.27 (m, 2H),
4.52 (m, 2H), 6.50 (m, 1H), 6.75 (m, 2H), 7.10–7.21 (m, 4H), 7.24–
7.45 (m, 4H), 7.51–7.67 ppm (m, 3H); MS m/z 515.1 [M+H]+; Anal.
calcd for C31H34N2O5: C 72.35, H 6.66, N 5.44, found: C 72.46, H
6.57, N 5.50.
3
2H), 3.43 (m, 1H), 3.57 (m, 1H), 4.02 (t, 1H, J=5.7 Hz), 4.21 (t, 2H,
3
3
3J=6.9 Hz), 4.47 (t, 2H, J=6.9 Hz), 6.75 (d, 2H, J=8.1 Hz), 7.05 (s,
3
1H), 7.11 (d, 2H, J=8.1 Hz), 7.39–7.62 (m, 4H), 7.72–7.82 (m, 3H),
8.09 ppm (d, 1H, 4J=1.5 Hz); LC–MS: tR =4.15 min (99%), m/z
472.2 [M+H]+; Anal. calcd for C29H29NO5: C 73.87, H 6.20, N 2.97,
found: C 73.76, H 6.24, N 3.01.
Ethyl 2-ethoxy-3-{4-[2-(6-{[Z/E]-methoxyimino]phenylmethyl}in-
dol-1-yl)ethoxy]phenyl}propionate 17b: Colorless oil (1.01 g,
1
79%); H NMR (CDCl3): d=1.18 (m, 3H), 1.23 (m, 3H), 2.96 (m, 2H),
3-{4-[2-(5-Cyclopropanoylindol-1-yl)ethoxy]phenyl}-2-ethoxypro-
pionic acid 16d: Pasty solid (0.66 g, 79%); 1H NMR (CDCl3): d=
1.04 (m, 2H), 1.17 (t, 3H, 3J=6.7 Hz), 1.27 (m, 2H), 2.82 (m, 1H),
2.93 (dd, 1H, 3J=14.0 Hz, 3J=7.6 Hz), 3.06 (dd, 1H, 3J=14.0 Hz,
3.35 (m, 1H), 3.61 (m, 1H), 3.96 (m, 1H), 4.03 (s, 3H), 4.21 (m, 4H),
4.50 (m, 2H), 6.54 (m, 1H), 6.75 (m, 2H), 7.10–7.21 (m, 4H), 7.23–
7.50 (m, 4H), 7.52–7.72 ppm (m, 3H); MS m/z 515.1 [M+H]+; Anal.
calcd for C31H34N2O5: C 72.35, H 6.66, N 5.44, found: C 72.42, H
6.60, N 5.49.
3
3J=7.6 Hz), 3.41 (m, 1H), 3.62 (m, 1H), 4.02 (t, 1H, J=5.8 Hz), 4.28
3
3
3
(t, 2H, J=5.9 Hz), 4.55 (t, 2H, J=5.9 Hz), 6.67 (d, 1H, J=3.2 Hz),
3
3
3
6.77 (d, 2H, J=8.5 Hz), 7.16 (d, 2H, J=8.5 Hz), 7.30 (d, 1H, J=
3.2 Hz), 7.46 (d, 1H, 3J=8.8 Hz), 7.97 (dd, 1H, 3J=8.8 Hz, 4J=
1.8 Hz), 8.42 ppm (d, 1H, 4J=1.8 Hz); LC–MS: tR =3.84 min (95%),
m/z 422.3 [M+H]+; Anal. calcd for C25H27NO5: C 71.24, H 6.46, N
3.32, found: C 71.31, H 6.40, N 3.38.
Ethyl 2-ethoxy-3-{4-[2-(5-{cyclopropyl-[Z/E]-methoxyimino]me-
thyl}indol-1-yl)ethoxy]phenyl}propionate 17c: Colorless oil
(0.97 g, 81%); H NMR (CDCl3): d=0.62–0.96 (m, 4H), 1.16 (m, 3H),
1.22 (m, 3H), 2.35 (m, 1H), 2.94 (m, 2H), 3.34 (m, 1H), 3.61 (m, 1H),
3.96 (m, 1H), 4.02 (s, 3H), 4.18 (m, 2H), 4.25 (m, 2H), 4.52 (m, 2H),
6.53 (m, 1H), 6.78 (m, 2H), 7.17 (m, 2H), 7.21–7.42 (m, 3H),
7.68 ppm (m, 1H); MS m/z 479.4 [M+H]+; Anal. calcd for
C28H34N2O5: C 70.27, H 7.16, N 5.85, found: C 70.35, H 7.08, N 5.92.
1
3-{4-[2-(5-Cyclohexanoylindol-1-yl)ethoxy]phenyl}-2-ethoxypro-
1
pionic acid 16e: White solid (0.78 g, 85%); mp: 72–768C; H NMR
(CDCl3): d=1.16 (t, 3H, 3J=7.0 Hz), 1.20–1.62 (m, 6H), 1.72–1.98
(m, 4H), 2.92 (m, 1H), 3.08 (m, 1H), 3.42 (m, 2H), 3.58 (m, 1H), 4.01
(t, 1H, J=5.9 Hz), 4.26 (t, 2H, J=6.2 Hz), 4.52 (t, 2H, J=6.2 Hz),
Ethyl 2-ethoxy-3-{4-[2-(5-{cyclohexyl-[Z/E]-methoxyimino]methy-
l}indol-1-yl)ethoxy]phenyl}propionate 17d: Colorless oil (0.97 g,
75%); 1H NMR (CDCl3): d=1.15 (m, 3H), 1.22–1.38 (m, 7H), 1.43–
1.92 (m, 6H), 2.95 (m, 2H), 3.34 (m, 2H), 3.60 (m, 1H), 3.80–3.95 (m,
4H), 4.18 (m, 2H), 4.24 (m, 2H), 4.52 (m, 2H), 6.57 (m, 1H), 6.73 (m,
2H), 7.13 (m, 2H), 7.26 (m, 2H), 7.39 (m, 2H), 7.48 (s, 0.5H),
7.63 ppm (s, 0.5H); MS m/z 521.2 [M+H]+; Anal. calcd for
C31H40N2O5: C 71.51, H 7.74, N 5.38, found: C 71.64, H 7.67, N 5.42.
3
3
3
3
3
3
6.64 (d, 1H, J=2.9 Hz), 6.74 (d, 2H, J=7.9 Hz), 7.12 (d, 2H, J=
7.9 Hz), 7.27 (d, 1H, 3J=2.9 Hz), 7.43 (d, 1H, 3J=8.8 Hz), 7.92 (d,
3
1H, J=8.8 Hz), 8.31 ppm (s, 1H); LC–MS: tR =4.33 min (94%), m/z
464.2 [M+H]+; Anal. calcd for C28H33NO5: C 72.55, H 7.18, N 3.02,
found: C 72.46, H 7.25, N 2.94.
2-Ethoxy-3-{4-[2-(5-{[Z/E]-methoxyimino]phenylmethyl}indol-1-
yl)ethoxy]phenyl}propionic acid 18a: White solid (0.79 g, 82%);
General procedure for the synthesis of carboxylic acids 16a–e,
18a–d: LiOH (0.15 g, 6.0 mmol, 3.0 equiv) was added to a solution
of ester 15a–e or 17a–d (2.0 mmol, 1.0 equiv) dissolved in a 2:1
mixture of THF (20 mL) and H2O (10 mL), and the mixture was then
stirred at room temperature for 12 h. Thereafter, the whole was
concentrated in vacuo, and the concentrate was hydrolyzed with
1m HCl(aq), then extracted twice with CH2Cl2. The combined organic
extracts were dried over MgSO4, filtered off, evaporated under re-
duced pressure, and the resulting residue was purified by flash
column chromatography (CH2Cl2/MeOH 95:5) to afford the corre-
sponding carboxylic acids.
1
mp: 47–508C; H NMR (CDCl3): d=1.18 (m, 3H), 2.95 (m, 1H), 3.08
(m, 1H), 3.44 (m, 1H), 3.60 (m, 1H), 4.01 (m, 4H), 4.28 (m, 2H), 4.52
(m, 2H), 6.50 (m, 1H), 6.78 (m, 2H), 7.10–7.69 ppm (m, 11H); LC–
MS: tR =4.22 and 4.27 min (52 and 45%), m/z 487.1 [M+H]+; Anal.
calcd for C29H30N2O5: C 71.59, H 6.21, N 5.76, found: C 71.64, H
6.32, N 5.81.
2-Ethoxy-3-{4-[2-(6-{[Z/E]-methoxyimino]phenylmethyl}indol-1-
yl)ethoxy]phenyl}propionic acid 18b: White solid (0.81 g, 83%);
mp: 104–1058C; 1H NMR (DMSO): d=1.02 (m, 3H), 2.81 (m, 2H),
3.28 (m, 1H), 3.49 (m, 1H), 3.90 (m, 4H), 4.21 (m, 2H), 4.51 (m, 2H),
6.59 (m, 1H), 6.71 (m, 2H), 6.92 (m, 0.5H), 7.09 (m, 2.5H), 7.28–
7.63 ppm (m, 8H); LC–MS: tR =4.44 and 4.46 min (50 and 48%), MS
m/z 487.2 [M+H]+; Anal. calcd for C29H30N2O5: C 71.59, H 6.21, N
5.76, found: C 71.50, H 6.30, N 5.58.
3-{4-[2-(5-Benzoylindol-1-yl)ethoxy]phenyl}-2-ethoxypropionic
acid 16a: White solid (0.77 g, 84%); mp: 49–528C; 1H NMR
3
(DMSO): d=1.03 (t, 3H, J=6.8 Hz), 2.82 (m, 2H), 3.27 (m, 1H), 3.48
3
3
(m, 1H), 3.91 (t, 1H, J=6.3 Hz), 4.30 (t, 2H, J=5.9 Hz), 4.66 (t, 2H,
3J=5.9 Hz), 6.66 (d, 1H, 3J=3.1 Hz), 6.80 (d, 2H, 3J=8.6 Hz), 7.12
(d, 2H, 3J=8.6 Hz), 7.57 (m, 3H), 7.67 (m, 2H), 7.73 (m, 3H),
7.99 ppm (s, 1H); LC–MS: tR =4.19 min (98%), m/z 458.1 [M+H]+;
Anal. calcd for C28H27NO5: C 73.51, H 5.95, N 3.06, found: C 73.59, H
5.88, N 3.10.
2-Ethoxy-3-{4-[2-(5-{cyclopropyl-[Z/E]-methoxyimino]methyl}in-
dol-1-yl)ethoxy]phenyl}propionic acid 18c: Colorless oil (0.73 g,
1
81%); H NMR (CDCl3): d=0.62–0.96 (m, 4H), 1.18 (m, 3H), 1.82 (m,
0.5H), 2.36 (m, 0.5H), 2.92 (m, 1H), 3.07 (m, 1H), 3.47 (m, 1H), 3.58
(m, 1H), 3.82 (s, 1.5H), 4.01 (m, 2.5H), 4.25 (m, 2H), 4.51 (m, 2H),
6.52 (m, 1H), 6.73 (m, 2H), 7.05–7.44 (m, 5H), 7.60 (m, 0.5H),
7.62 ppm (m, 0.5H); LC–MS: tR =4.83 and 4.09 min (30 and 67%),
m/z 451.2 [M+H]+; Anal. calcd for C26H30N2O5: C 69.31, H 6.71, N
6.22, found: C 69.42, H 6.65, N 6.27.
3-{4-[2-(6-Benzoylindol-1-yl)ethoxy]phenyl}-2-ethoxypropionic
acid 16b: White solid (0.74 g, 81%); mp: 131–1328C; 1H NMR
3
(DMSO): d=1.01 (t, 3H, J=6.7 Hz), 2.80 (m, 2H), 3.28 (m, 1H), 3.49
3
3
(m, 1H), 3.90 (t, 1H, J=6.1 Hz), 4.27 (t, 2H, J=5.7 Hz), 4.65 (t, 2H,
2188
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ChemMedChem 2012, 7, 2179 – 2193

Oxime Ethers in Acyl Indole Derivatives
MED
2-Ethoxy-3-{4-[2-(5-{cyclohexyl-[Z/E]-methoxyimino]methyl}in-
dol-1-yl)ethoxy]phenyl}propionic acid 18d: Pasty solid (0.77 g,
78%); 1H NMR (CDCl3): d=1.18 (m, 3H), 1.22–1.40 (m, 4H), 1.42–
1.92 (m, 6H), 2.53 (m, 0.5H), 2.95 (m, 1H), 3.08 (m, 1H), 3.28 (m,
0.5H), 3.47 (m, 1H), 3.59 (m, 1H), 3.80 (s, 1.5H), 3.95 (s, 1.5H), 4.05
(m, 1H), 4.28 (m, 2H), 4.52 (m, 2H), 6.54 (m, 1H), 6.77 (m, 2H), 7.12
(m, 2H), 7.23 (m, 1.5H), 7.39 (m, 1.5H), 7.49 (s, 0.5H), 7.62 ppm (s,
0.5H); LC–MS: tR =4.28 and 4.56 min (41 and 57%), m/z 493.2 [M+
H]+; Anal. calcd for C29H36N2O5: C 70.71, H 7.37, N 5.69, found: C
70.62, H 7.46, N 5.61.
method: flow rate=0.8 mLminꢀ1
8.92 min.
,
eluents=C/D 50:50, tR =
(S)-2-Ethoxy-3-{4-[2-(5-{[Z]-methoxyimino]phenylmethyl}indol-1-
yl)ethoxy]phenyl}propionic acid 20b: White solid (0.52 g, 54%);
1
3
mp: 50–528C; H NMR (CDCl3): d=1.18 (t, 3H, J=7.0 Hz), 2.95 (dd,
3
3
3
3
1H, J=14.0 Hz, J=7.0 Hz), 3.08 (dd, 1H, J=14.0 Hz, J=7.0 Hz),
3.46 (m, 1H), 3.62 (m, 1H), 4.04 (m, 4H), 4.29 (t, 2H, 3J=5.3 Hz),
4.54 (t, 2H, 3J=5.3 Hz), 6.55 (d, 1H, 3J=2.9 Hz), 6.81 (d, 2H, 3J=
3
3
8.8 Hz), 7.17 (d, 2H, J=8.8 Hz), 7.25–7.38 (m, 5H), 7.46 (d, 1H, J=
8.8 Hz), 7.54 (dd, 2H, 3J=7.9 Hz, 4J=1.75 Hz), 7.68 ppm (s, 1H);
LC–MS: tR =4.43 min (97%), m/z 487.2 [M+H]+; Anal. calcd for
C29H30N2O5: C 71.59, H 6.21, N 5.76, found: C 71.51, H 6.36, N 5.67;
Chiral HPLC method: flow rate=0.8 mLminꢀ1, eluents=C/D 50:50,
tR =6.63 min.
General procedure for the synthesis of oxime ethers 19a–c: O-
Methylhydroxylamine hydrochloride (3.34 g, 40 mmol, 4 equiv) was
added to a solution of 5- or 6-benzoylindole 14a,b (2.22 g,
10 mmol, 1 equiv) in pyridine (40 mL), and the mixture was stirred
at 1008C for 4 h. The reaction mixture was concentrated in vacuo,
hydrolyzed with 1n HCl(aq), and extracted twice with CH2Cl2. The
combined organic extracts were dried over MgSO4, filtered off,
evaporated under reduced pressure, and the resulting residue was
purified by flash column chromatography (PE/CH2Cl2/EtOAc
75:24:1) to afford the corresponding oxime ethers 19a–c.
(S)-2-Ethoxy-3-{4-[2-(6-{[Z/E]-methoxyimino]phenylmethyl}indol-
1-yl)ethoxy]phenyl}propionic acid 20c: White solid (0.61 g, 63%);
mp: 104–1058C; 1H NMR (DMSO): d=1.02 (m, 3H), 2.81 (m, 2H),
3.28 (m, 1H), 3.49 (m, 1H), 3.90 (m, 4H), 4.21 (m, 2H), 4.51 (m, 2H),
6.59 (m, 1H), 6.71 (m, 2H), 6.92 (m, 0.4H), 7.09 (m, 2.6H), 7.28–
7.63 ppm (m, 8H); LC–MS: tR =4.30 and 4.33 min (59 and 38%), m/
z 487.2 [M+H]+; Anal. calcd for C29H30N2O5: C 71.59, H 6.21, N 5.76,
found: C 71.47, H 6.15, N 5.82; Chiral HPLC method: flow rate=
5-{[(E)-Methoxyimino]phenylmethyl}-1H-indole 19a: Brown solid
(1.10 g, 44%); mp: 101–1038C; 1H NMR (CDCl3): d=4.01 (s, 3H),
3
1.0 mLminꢀ1
,
eluents=A/B 10:90, tR =16.21 min (40%) and
6.53 (m, 1H), 7.21 (t, 1H, J=3.2 Hz), 7.35–7.48 (m, 6H), 7.54 (dd,
3
4
22.32 min (60%).
1H, J=8.2 Hz, J=1.8 Hz), 7.62 (s, 1H), 8.23 ppm (brs, 1H); MS m/
z 251.2 [M+H]+; Anal. calcd for C16H14N2O: C 76.78, H 5.64, N
11.19, found: C 76.65, H 5.71, N 11.25.
(R)-2-Ethoxy-3-{4-[2-(5-{[E]-methoxyimino]phenylmethyl}indol-1-
yl)ethoxy]phenyl}propionic acid 21a: White solid (0.59 g, 61%);
1
3
mp: 43–468C; H NMR (CDCl3): d=1.19 (t, 3H, J=7.0 Hz), 2.95 (dd,
5-{[(Z)-Methoxyimino]phenylmethyl}-1H-indole 19b: Brown solid
(0.95 g, 38%); mp: 113–1158C; 1H NMR (CDCl3): d=4.03 (s, 3H),
3
3
3
3
1H, J=14.0 Hz, J=7.0 Hz), 3.08 (dd, 1H, J=14.0 Hz, J=7.0 Hz),
3
3.48 (m, 1H), 3.58 (m, 1H), 4.01 (s, 3H), 4.05 (dd, 1H, J=7.0 Hz),
3
6.59 (m, 1H), 7.25 (m, 2H), 7.35 (m, 3H), 7.46 (d, 1H, J=8.5 Hz),
4.28 (t, 2H, 3J=5.6 Hz), 4.52 (t, 2H, 3J=5.6 Hz), 6.48 (d, 1H,=
4
7.54 (m, 2H), 7.68 (d, 1H, J=1.5 Hz), 8.28 ppm (brs, 1H); MS m/z
3
3
3
3.2 Hz), 6.76 (d, 2H, J=8.8 Hz), 7.13 (d, 2H, J=8.8 Hz), 7.22 (d, J
251.2 [M+H]+; Anal. calcd for C16H14N2O: C 76.78, H 5.64, N 11.19,
3
1H, J=3.2 Hz), 7.34–7.47 (m, 6H), 7.56 ppm (m, 2H); LC–MS: tR =
found: C 76.67, H 5.54, N 11.31.
4.36 min (96%), m/z 487.1 [M+H]+; Anal. calcd for C29H30N2O5: C
71.59, H 6.21, N 5.76, found: C 71.52, H 6.15, N 5.69; Chiral HPLC
6-{[(Z/E)-Methoxyimino]phenylmethyl}-1H-indole 19c: Brown
solid (1.97 g, 79%); mp: 168–1708C; H NMR (DMSO): d=3.93 (m,
3H), 6.57 (m, 1H), 6.90 (m, 0.5H), 7.11 (m, 0.5H), 7.30–7.65 ppm (m,
8H); MS m/z 251.2 [M+H]+; Anal. calcd for C16H14N2O: C 76.78, H
5.64, N 11.19, found: C 76.71, H 5.70, N 11.12.
1
method: flow rate=0.8 mLminꢀ1
,
eluents=C/D 50:50, tR =
11.22 min.
(R)-2-Ethoxy-3-{4-[2-(5-{[Z]-methoxyimino]phenylmethyl}indol-1-
yl)ethoxy]phenyl}propionic acid 21b: White solid (0.57 g, 59%);
1
3
mp: 50–528C; H NMR (CDCl3): d=1.18 (t, 3H, J=7.0 Hz), 2.95 (dd,
General procedure for the synthesis of optically pure carboxylic
acids 20a–c, 21a–c: A solution of 19a–c (0.5 g, 2 mmol, 1 equiv)
in HMPA (5 mL) was added dropwise to a 60% NaH dispersion in
mineral oil (0.12 g, 3 mmol, 1.5 equiv) in HMPA (5 mL) at 08C under
N2, and the solution was stirred for 30 min at room temperature. A
solution of 10a or 10b (0.66 g, 2.4 mmol, 1.2 equiv) in HMPA
(5 mL) was then added, and the mixture was stirred at room tem-
perature for 12 h under N2. The reaction mixture was hydrolyzed
with 1m HCl(aq), and the precipitate was filtered off, dried and puri-
fied by flash column chromatography (CH2Cl2/MeOH 95:5) to
afford the corresponding optically pure carboxylic acids 20a–c and
21a–c.
3
3
3
3
1H, J=14.0 Hz, J=7.0 Hz), 3.08 (dd, 1H, J=14.0 Hz, J=7.0 Hz),
3.46 (m, 1H), 3.62 (m, 1H), 4.04 (m, 4H), 4.29 (t, 2H, 3J=5.3 Hz),
4.54 (t, 2H, 3J=5.3 Hz), 6.55 (d, 1H, 3J=2.9 Hz), 6.81 (d, 2H, 3J=
3
3
8.8 Hz), 7.17 (d, 2H, J=8.8 Hz), 7.25–7.38 (m, 5H), 7.46 (d, 1H, J=
8.8 Hz), 7.54 (dd, 2H, 3J=7.9 Hz, 4J=1.75 Hz), 7.68 ppm (s, 1H);
LC–MS: tR =4.43 min (94%), m/z 487.1 [M+H]+; Anal. calcd for
C29H30N2O5: C 71.59, H 6.21, N 5.76, found: C 71.70, H 6.14, N 5.70;
Chiral HPLC method: flow rate=0.8 mLminꢀ1, eluents=C/D 50:50,
tR =6.94 min.
(R)-2-Ethoxy-3-{4-[2-(6-{[Z/E]-methoxyimino]phenylmethyl}indol-
1-yl)ethoxy]phenyl}propionic acid 21c: White solid (0.52 g, 54%);
mp: 104–1058C; 1H NMR (DMSO): d=1.02 (m, 3H), 2.81 (m, 2H),
3.28 (m, 1H), 3.49 (m, 1H), 3.90 (m, 4H), 4.21 (m, 2H), 4.51 (m, 2H),
6.59 (m, 1H), 6.71 (m, 2H), 6.92 (m, 0.4H), 7.09 (m, 2.6H), 7.28–
7.63 ppm (m, 8H); LC–MS: tR =4.30 and 4.33 min (60 and 37%), m/
z 487.2 [M+H]+; Anal. calcd for C29H30N2O5: C 71.59, H 6.21, N 5.76,
found: C 71.47, H 6.15, N 5.82; Chiral HPLC method: flow rate=
1.0 mLminꢀ1, eluents=A/B 20:80, tR =7.09 min (40%) and 8.43 min
(60%).
(S)-2-Ethoxy-3-{4-[2-(5-{[E]-methoxyimino]phenylmethyl}indol-1-
yl)ethoxy]phenyl}propionic acid 20a: White solid (0.46 g, 47%);
1
3
mp: 43–468C; H NMR (CDCl3): d=1.19 (t, 3H, J=7.0 Hz), 2.95 (dd,
3
3
3
3
1H, J=14.0 Hz, J=7.0 Hz), 3.08 (dd, 1H, J=14.0 Hz, J=7.0 Hz),
3
3.48 (m, 1H), 3.58 (m, 1H), 4.01 (s, 3H), 4.05 (dd, 1H, J=7.0 Hz),
4.28 (t, 2H, 3J=5.6 Hz), 4.52 (t, 2H, 3J=5.6 Hz), 6.48 (d, 1H, 3J=
3.2 Hz), 6.76 (d, 2H, 3J=8.8 Hz), 7.13 (d, 2H, 3J=8.8 Hz), 7.22 (d,
3
1H, J=3.2 Hz), 7.34–7.47 (m, 6H), 7.56 ppm (m, 2H); LC–MS: tR =
4.36 min (95%), m/z 487.1 [M+H]+; Anal. calcd for C29H30N2O5: C
General procedure for the synthesis of oxime ethers 24a–d: O-
71.59, H 6.21, N 5.76, found: C 71.45, H 6.30, N 5.69; Chiral HPLC
Substituted hydroxylamine hydrochloride (10 mmol, 2 equiv) and
ChemMedChem 2012, 7, 2179 – 2193
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
2189

N. Lebegue et al.
MED
pyridine (0.60 mL, 15 mmol, 3 equiv) were added to a solution of
23 (2.11 g, 5 mmol, 1 equiv) in MeOH (60 mL), and the mixture was
stirred at reflux for 4 h. The reaction mixture was concentrated in
vacuo, hydrolyzed with 1n HCl(aq), and extracted twice with EtOAc.
The combined organic extracts were dried over MgSO4, filtered off,
evaporated under reduced pressure, and the resulting residue was
purified by flash column chromatography (cyclohexane/EtOAc
80:20) to afford the corresponding E isomers of oxime ethers 24a–
d.
8.1 Hz), 7.28 (m, 2H), 7.36 (t, 2H, 3J=7.3 Hz), 7.50 (d, 1H, 3J=
3
3
3.3 Hz), 7.63 (d, 1H, J=8.6 Hz), 7.70 (d, 1H, J=8.6 Hz), 8.01 ppm
(s, 1H); LC–MS: tR =4.55 min (98%), m/z 487.1 [M+H]+; Anal. calcd
for C29H30N2O5: C 71.59, H 6.21, N 5.76, found: C 71.74, H 6.18, N
5.69.
2-Ethoxy-3-{4-[2-(5-{1-[E]-benzyloxyimino]ethyl}indol-1-yl)ethox-
y]phenyl}propionic acid 25b: Off-white solid (0.79 g, 79%); mp:
1
3
72–748C; H NMR (DMSO): d=1.02 (t, 3H, J=7.0 Hz), 2.29 (s, 3H),
2.81 (m, 2H), 3.27 (m, 1H), 3.49 (m, 1H), 3.92 (t, 1H, 3J=5.7 Hz),
3
3
Ethyl 2-ethoxy-3-{4-[2-(5-{1-[E]-phenoxyimino]ethyl}indol-1-yl)e-
4.27 (t, 2H, J=5.9 Hz), 4.59 (t, 2H, J=5.9 Hz), 5.20 (s, 2H), 6.51 (d,
1H, 3J=3.1 Hz), 6.78 (d, 2H, 3J=8.3 Hz), 7.10 (d, 1H, 3J=8.3 Hz),
7.27–7.49 (m, 6H), 7.54 (m, 2H), 7.82 ppm (s, 1H); LC–MS: tR =
4.50 min (98%), m/z 501.2 [M+H]+; Anal. calcd for C30H32N2O5: C
71.98, H 6.44, N 5.60, found: C 71.91, H 6.52, N 5.71.
1
thoxy]phenyl}propionate 24a: Colorless oil (2.39 g, 93%); H NMR
3
3
(CDCl3): d=1.18 (t, 3H, J=7.0 Hz), 1.24 (t, 3H, J=7.0 Hz), 2.56 (s,
3H), 2.96 (m, 2H), 3.33 (m, 1H), 3.60 (m, 1H), 3.96 (t, 1H, 3J=
3
3
6.3 Hz), 4.18 (q, 2H, J=7.0 Hz), 4.29 (t, 2H, J=5.7 Hz), 4.55 (t, 2H,
3J=5.7 Hz), 6.59 (d, 1H, 3J=3.1 Hz), 6.78 (d, 2H, 3J=8.3 Hz), 7.05
3
2-Ethoxy-3-{4-[2-(5-{1-[E]-cyclopropylmethoxyimino]ethyl}indol-
1-yl)ethoxy]phenyl}propionic acid 25c: Pasty solid (0.75 g, 81%);
1H NMR (CDCl3): d=0.38 (m, 2H), 0.60 (m, 2H), 1.27 (m, 4H), 2.39
(s, 3H), 3.0 (m, 2H), 3.51 (m, 2H), 4.05 (m, 3H), 4.25 (t, 2H, 3J=
(m, 2H), 7.15 (m, 3H), 7.31 (m, 3H), 7.45 (d, 1H, J=8.7 Hz), 7.81 (d,
1H, 3J=8.7 Hz), 8.02 ppm (s, 1H); MS m/z 515.2 [M+H]+; Anal.
calcd for C31H34N2O5: C 72.35, H 6.66, N 5.44, found: C 72.19, H
6.75, N 5.39.
3
3
5.8 Hz), 4.52 (t, 2H, J=5.8 Hz), 6.55 (d, 1H, J=3.0 Hz), 6.76 (d, 2H,
3J=8.4 Hz), 7.13 (d, 2H, 3J=8.4 Hz), 7.22 (d, 1H, 3J=3.0 Hz), 7.35
Ethyl
2-ethoxy-3-{4-[2-(5-{1-[E]-benzyloxyimino]ethyl}indol-1-
3
3
yl)ethoxy]phenyl}propionate 24b: Colorless oil (2.33 g, 91%);
(d, 2H, J=8.5 Hz), 7.64 (d, 1H, J=8.5 Hz), 7.86 ppm (s, 1H); LC–
MS: tR =4.49 min (95%), m/z 465.2 [M+H]+; Anal. calcd for
C27H32N2O5: C 69.81, H 6.94, N 6.03, found: C 69.94, H 6.88, N 6.12.
3
3
1H NMR (CDCl3): d=1.17 (t, 3H, J=7.0 Hz), 1.24 (t, 3H, J=7.0 Hz),
2.38 (s, 3H), 2.95 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.96 (t, 1H,
3
3
3J=5.8 Hz), 4.18 (q, 2H, J=7.0 Hz), 4.27 (t, 2H, J=5.7 Hz), 4.52 (t,
3
3
2H, J=5.7 Hz), 5.29 (s, 2H), 6.55 (d, 1H, J=2.9 Hz), 6.78 (d, 2H,
2-Ethoxy-3-{4-[2-(5-{1-[E]-cyclohexyloxyimino]ethyl}indol-1-yl)e-
thoxy]phenyl}propionic acid 25d: Pasty solid (0.75 g, 76%);
3
3
3J=8.1 Hz), 7.14 (d, 2H, J=8.1 Hz), 7.24 (d, 1H, J=2.9 Hz), 7.31–
3
3
4
3
1H NMR (CDCl3): d=1.18 (t, 3H, J=7.0 Hz), 1.25–1.62 (m, 6H), 1.78
7.44 (m, 4H), 7.47 (d, 2H, J=7.3 Hz), 7.66 (dd, 1H, J=8.7 Hz, J=
1.75 Hz), 7.88 ppm (d, 1H, 4J=1.75 Hz); MS m/z 515.2 [M+H]+;
Anal. calcd for C32H36N2O5: C 72.70, H 6.86, N 5.30, found: C 72.61,
H 6.75, N 5.41.
(m, 2H), 2.04 (m, 2H), 2.32 (s, 3H), 2.93 (m, 1H), 3.05 (m, 1H), 3.41
3
(m, 1H), 3.59 (m, 1H), 4.01 (t, 1H, J=7.1 Hz), 4.22 (m, 3H), 4.50 (t,
2H, 3J=5.8 Hz), 6.53 (d, 1H, 3J=2.9 Hz), 6.76 (d, 2H, 3J=8.1 Hz),
3
3
3
7.13 (d, 2H, J=8.1 Hz), 7.22 (d, 1H, J=2.9 Hz), 7.36 (d, 2H, J=
Ethyl 2-ethoxy-3-{4-[2-(5-{1-[E]-cyclopropylmethoxyimino]ethy-
l}indol-1-yl)ethoxy]phenyl}propionate 24c: Colorless oil (2.14 g,
3
4
4
8.8 Hz), 7.63 (dd, 1H, J=8.8 Hz, J=1.75 Hz), 7.85 ppm (d, 1H, J=
1.75 Hz); LC–MS: tR =4.46 min (94%), m/z 493.2 [M+H]+; Anal.
calcd for C29H36N2O5: C 70.71, H 7.37, N 5.69, found: C 70.59, H
7.45, N 5.62.
1
87%); H NMR (CDCl3): d=0.36 (m, 2H), 0.60 (m, 2H), 1.17 (t, 3H,
3J=7.0 Hz), 1.23 (m, 4H), 2.38 (s, 3H), 2.95 (m, 2H), 3.35 (m, 1H),
3
3
3.60 (m, 1H), 3.95 (t, 1H, J=7.3 Hz), 4.06 (d, 2H, J=7.0 Hz), 4.18
3
3
3
(q, 2H, J=7.0 Hz), 4.27 (t, 2H, J=5.3 Hz), 4.52 (t, 2H, J=5.3 Hz),
Synthesis of compounds 26a,b: Oxalyl chloride (8.2 mL,
93.4 mmol, 1.1 equiv) in 1,2-dichloroethane (170 mL) was added
dropwise over a period of 15 min into a stirred, ice-cold solution of
DMF (7.35 mL, 100.7 mmol, 1.15 equiv) in 1,2-dichloroethane
(170 mL) under a N2 atmosphere, and then the mixture was al-
lowed to warm to room temperature for 15 min. The mixture was
cooled to 08C, and a solution of indole (10 g, 85.4 mmol, 1.0 equiv)
in 1,2-dichloroethane (170 mL) was added rapidly. The resulting
mixture was warmed to room temperature for 15 min and then
cooled. AlCl3 (42 g, 315 mmol, 3.7 equiv) was added rapidly, and
the mixture was allowed to warm to room temperature for 15 min.
The mixture was cooled, and a solution of benzoyl chloride
(13.32 g, 93.4 mmol, 1.1 equiv) in 1,2-dicloroethane (84 mL) was
added rapidly, and the reaction was allowed to proceed overnight
at room temperature. The reaction mixture was poured into ice/
H2O, alkalinized to pH 8 with solid NaOH and stirred vigorously for
4 h. Concentrated HCl was added (100 mL), and the resulting mix-
ture was extracted twice with CH2Cl2. The combined extracts were
washed with brine, dried over MgSO4, filtered off and evaporated
under reduced pressure. The residue was purified by flash column
chromatography (PE/EtOAc 65:35) to afford the two regioisomers
26a,b.
3
3
3
6.54 (d, 1H, J=3.1 Hz), 6.78 (d, 2H, J=8.4 Hz), 7.13 (d, 2H, J=
8.4 Hz), 7.22 (d, 1H, 3J=3.1 Hz), 7.39 (d, 2H, 3J=8.8 Hz), 7.67 (d,
1H, 3J=8.8 Hz), 7.88 ppm (s, 1H); MS m/z 493.1 [M+H]+; Anal.
calcd for C29H36N2O5: C 70.71, H 7.37, N 5.69, found: C 70.62, H
7.48, N 5.60.
Ethyl 2-ethoxy-3-{4-[2-(5-{1-[E]-cyclohexyloxyimino]ethyl}indol-1-
yl)ethoxy]phenyl}propionate 24d: Colorless oil (2.36 g, 91%);
3
1H NMR (CDCl3): d=1.18 (t, 3H, J=7.0 Hz), 1.21–1.62 (m, 9H), 1.80
(m, 4H), 2.35 (s, 3H), 2.93 (m, 2H), 3.32 (m, 1H), 3.60 (m, 1H), 3.95
3
3
(t, 1H, J=6.9 Hz), 4.18 (m, 3H), 4.27 (t, 2H, J=5.5 Hz), 4.52 (t, 2H,
3J=5.5 Hz), 6.54 (d, 1H, 3J=3.2 Hz), 6.76 (d, 2H, 3J=8.2 Hz), 7.14
3
3
3
(d, 2H, J=8.2 Hz), 7.22 (d, 1H, J=3.2 Hz), 7.39 (d, 2H, J=8.6 Hz),
7.66 (d, 1H, J=8.6 Hz), 7.88 ppm (s, 1H); MS m/z 521.3 [M+H]+;
3
Anal. calcd for C31H40N2O5: C 71.51, H 7.74, N 5.38, found: C 71.63,
H 7.68, N 5.47.
General procedure for the synthesis of carboxylic acids 25a–d:
Compounds 24a–d were treated according to the same procedure
described for the preparation of 16a–e and 18a–d.
2-Ethoxy-3-{4-[2-(5-{1-[E]-phenoxyimino]ethyl}indol-1-yl)ethoxy]-
phenyl}propionic acid 25a: Off-white solid (0.74 g, 76%); mp: 87–
3
898C; 1H NMR (DMSO): d=1.02 (t, 3H, J=7.0 Hz), 2.50 (s, 3H), 2.81
5-Benzoyl-1H-indole-3-carboxaldehyde 26a: Pale-brown solid
(11.91 g, 56%); mp: 198–2008C; 1H NMR (DMSO): d=7.58 (t, 2H,
3
(m, 2H), 3.26 (m, 1H), 3.48 (m, 1H), 3.92 (t, 1H, J=5.3 Hz), 4.28 (t,
3
2H, 3J=5.9 Hz), 4.59 (t, 2H, 3J=5.9 Hz), 6.55 (d, 1H, 3J=3.3 Hz),
6.79 (d, 2H, 3J=8.1 Hz), 7.03 (t, 1H, 3J=7.3 Hz), 7.11 (d, 1H, 3J=
3J=7.6 Hz), 7.63–7.78 (m, 5H), 8.49 (d, 2H, J=7.6 Hz), 9.98 (s, 1H),
12.50 ppm (brs, 1H); MS m/z 250.2 [M+H]+.
2190
www.chemmedchem.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2012, 7, 2179 – 2193

Oxime Ethers in Acyl Indole Derivatives
MED
6-Benzoyl-1H-indole-3-carboxaldehyde 26b: White needles
(4.89 g, 23%); mp: 166–1688C; 1H NMR (DMSO): d=7.58 (t, 2H,
(brs, 1H); LC–MS: tR =4.27 and 4.37 min (47 and 49%), m/z 544.1
[M+H]+; Anal. calcd for C31H33N3O6: C 68.49, H 6.12, N 7.73, found:
C 68.56, H 6.01, N 7.62.
3
3J=7.3 Hz), 7.62–7.80 (m, 4H), 7.91 (s, 1H), 8.23 (d, 1H, J=8.2 Hz),
4
8.53 (d, 1H, J=2.6 Hz), 10.01 (s, 1H), 12.42 ppm (brs, 1H); MS m/z
2-Ethoxy-3-{4-[2-(3-[E]-methoxyiminomethyl-6-{[Z/E]-methoxyi-
250.2 [M+H]+.
mino]phenylmethyl}indol-1-yl)ethoxy]phenyl}propionic
acid
29b: Pale-yellow foam (0.80 g, 74%); mp: 53–568C; 1H NMR
(DMSO): d=1.01 (m, 3H), 2.79 (m, 2H), 3.24 (m, 1H), 3.47 (m, 1H),
3.80–4.01 (7H), 4.22 (m, 2H), 4.60 (m, 2H), 6.69 (m, 2H), 7.08 (m,
2H), 7.30–7.50 (m, 6H), 7.59 (m, 1H), 7.84 (m, 1H), 7.95 (m, 0.5H),
8.05 (m, 0.5H), 8.36 (m, 1H), 12.54 (brs, 1H); LC–MS: tR =4.17 and
4.31 min (48 and 49%), MS m/z 544.2 [M+H]+; Anal. calcd for
C31H33N3O6: C 68.49, H 6.12, N 7.73, found: C 68.36, H 6.22, N 7.60.
Synthesis of compounds 27a,b: Compounds 26a,b were treated
according to the same procedure described for the preparation of
15a–e and 23. The crude products were purified by flash column
chromatography (toluene/EtOAc 75:25) to afford the correspond-
ing N-alkylated indole derivatives.
Ethyl
3-{4-[2-(5-benzoyl-3-formylindol-1-yl)ethoxy]phenyl}-2-
ethoxypropionate 27a: Colorless oil (1.95 g, 76%); 1H NMR
3
3
(CDCl3): d=1.15 (t, 3H, J=6.8 Hz), 1.23 (t, 3H, J=7.3 Hz), 2.96 (m,
3
2H), 3.34 (m, 1H), 3.60 (m, 1H), 3.96 (t, 1H, J=6.5 Hz), 4.18 (q, 2H,
Docking
3J=6.8 Hz), 4.36 (t, 2H, J=6.2 Hz), 4.65 (t, 2H, J=6.2 Hz), 6.77 (d,
3
3
3
3
Molecular modeling studies were performed with SYBYL 6.9.1 run-
ning on SGI Octane 2 workstations. The geometry of S73362 was
subsequently optimized using the Tripos force field[28] including
the electrostatic term calculated from Gasteiger–Hꢂckel atomic
charges. The method of Powell, available in the Maximin2 proce-
dure, was used for energy minimization until the gradient value
was <0.001 kcalmolꢀ1 ꢄꢀ1. The crystallographic data for PPARa and
g were retrieved from the RCSB Protein Data Bank (PDB) with par-
ticular concern for the structural proximity of the co-crystallized
ligand and S73362. We therefore chose PDB codes 3FEI[29] for
PPARa and 1KNU[30] for PPARg. S73362 was docked using
GOLD 3.2[31] in both receptors, and the consistency of the 30 solu-
tions generated was assessed before selecting the most represen-
tative.
2H, J=8.4 Hz), 7.17 (d, 2H, J=8.4 Hz), 7.47–7.63 (m, 4H), 7.84 (d,
3
2H, J=7.5 Hz), 7.97 (m, 2H), 8.72 (s, 1H), 10.05 ppm (s, 1H); MS
m/z 514.3 [M+H]+; Anal. calcd for C31H31NO6: C 72.50, H 6.08, N
2.73, found: C 72.41, H 6.17, N 2.79.
Ethyl
3-{4-[2-(6-benzoyl-3-formylindol-1-yl)ethoxy]phenyl}-2-
ethoxypropionate 27b: Colorless oil (1.72 g, 67%); 1H NMR
3
3
(CDCl3): d=1.16 (t, 3H, J=7.2 Hz), 1.23 (t, 3H, J=7.3 Hz), 2.95 (m,
2H), 3.33 (m, 1H), 3.59 (m, 1H), 3.95 (t, 1H, J=6.2 Hz), 4.18 (q, 2H,
3
3J=7.2 Hz), 4.35 (t, 2H, J=6.5 Hz), 4.65 (t, 2H, J=6.5 Hz), 6.78 (d,
2H, 3J=8.3 Hz), 7.16 (d, 2H, 3J=8.3 Hz), 7.52 (t, 2H, 3J=7.6 Hz),
7.62 (t, 1H, 3J=7.6 Hz), 7.74 (d, 1H, 3J=8.5 Hz), 7.82 (d, 2H, 3J=
7.6 Hz), 8.08 (m, 2H), 8.38 (d, 1H, 3J=8.5 Hz), 10.08 ppm (s, 1H);
MS m/z 514.2 [M+H]+; Anal. calcd for C31H31NO6: C 72.50, H 6.08,
N 2.73, found: C 72.64, H 6.16, N 2.62.
3
3
Synthesis of compounds 28a,b: Compounds 27a,b were treated
according to the same procedure described for the preparation of
24a–d. The crude products were purified by flash column chroma-
tography (PE/EtOAc 70:30) to afford the corresponding oxime de-
rivatives.
In vitro assays
Membrane-bound PPARg binding assay: Binding assays were per-
formed in 96-well plate format using a classical filtration assay with
a human full-length PPARg construct [GST–PPAR LBD (25 mgmLꢀ1)]
expressed in bacteria with some modifications regarding the con-
ditions of the experiments. Membrane-associated PPARg was used
as the biological source as previously described. Binding buffer
consisted of 10 mm Tris·HCl (pH 8.2) containing 50 mm KCl and
1 mm dithiothreitol. Membrane preparations (5 mgmLꢀ1) were incu-
bated for 180 min at 48C in the presence of [3H]rosiglitazone
[BRL49653, Amersham] (4 nm) and the tested compounds. Nonspe-
cific binding was defined by using excess unlabeled rosiglitazone
(10 mm). Incubation was terminated by the addition of ice-cold
50 mm Tris·HCl buffer (pH 7.4) followed by rapid filtration under re-
duced pressure through Whatman GF/C filter plates presoaked
with ice-cold buffer, followed by three successive washes with the
same buffer. Radioactivity was measured in a TopCount apparatus
(Packard). The receptor preparation used during these experiments
gave a Bmax value of 49 pmol(mg protein)ꢀ1 and a Kd value of
5.58 nm for [3H]rosiglitazone. The compounds were solubilized in
pure DMSO and diluted to the appropriate working concentrations
(100 mm to 0.1 nm). For each compound tested, plots of ligand
concentration versus DPM of radioligand bound were constructed,
and apparent Ki values were estimated from nonlinear least-
squares fit of the data, assuming simple competitive binding. The
details of this assay have been reported previously.[32]
Ethyl
2-ethoxy-3-{4-[2-(3-[E]-methoxyiminomethyl-5-{[Z/E]-me-
thoxyimino]phenylmethyl}indol-1-yl)ethoxy]phenyl}propionate
1
28a: Colorless oil (2.37 g, 83%); H NMR (CDCl3): d=1.18 (m, 3H),
1.24 (m, 3H), 2.94 (m, 2H), 3.32 (m, 1H), 3.60 (m, 1H), 3.82–3.99 (m,
4H), 4.01–4.12 (m,3H), 4.18 (m, 2H), 4.28 (m, 2H), 4.54 (m, 2H),
6.78 (m, 2H), 7.15 (m, 2H), 7.31–7.68 (m, 9H), 8.22 ppm (m, 1H);
MS m/z 572.2 [M+H]+; Anal. calcd for C33H37N3O6: C 69.33, H 6.52,
N 7.35, found: C 69.21, H 6.62, N 7.40.
Ethyl
2-ethoxy-3-{4-[2-(3-[E]-methoxyiminomethyl-6-{[Z/E]-me-
thoxyimino]phenylmethyl}indol-1-yl)ethoxy]phenyl}propionate
1
28b: Colorless oil (2.22 g, 78%); H NMR (CDCl3): d=1.17 (m, 3H),
1.25 (m, 3H), 2.94 (m, 2H), 3.33 (m, 1H), 3.61 (m, 1H), 3.92–4.04 (m,
7H), 4.15 (m, 2H), 4.25 (m, 2H), 4.49 (m, 2H), 6.74 (m, 2H), 7.13 (m,
2H), 7.20–7.62 (m, 8H), 8.09 (d, 0.5H, 3J=8.1 Hz) 8.27 ppm (m,
1.5H); MS m/z 572.3 [M+H]+; Anal. calcd for C33H37N3O6: C 69.33,
H 6.52, N 7.35, found: C 69.18, H 6.58, N 7.24.
Synthesis of compounds 29a,b: Compounds 28a,b were treated
according to the same procedure described for the preparation of
16a–e and 18a–d.
2-Ethoxy-3-{4-[2-(3-[E]-methoxyiminomethyl-5-{[Z/E]-methoxyi-
mino]phenylmethyl}indol-1-yl)ethoxy]phenyl}propionic
acid
Gene reporter assays: cell culture and transfection: Cos-7 cells were
transiently transfected with luciferase reporter plasmid (pG5-TK-
pGL3) in the presence of pGal4–hPPARg expression vector; this
vector expresses chimeric proteins containing the Gal4 DNA bind-
ing domain fused to the human PPARg LBD coding sequence. Plas-
29a: White foam (0.74 g, 69%); mp: 68–708C; 1H NMR (DMSO): d=
1.02 (m, 3H), 2.82 (m, 2H), 3.29 (m, 1H), 3.51 (m, 1H), 3.72 (m, 3H),
3.91 (m, 4H), 4.31 (m, 2H), 4.62 (m, 2H), 6.81 (m, 2H), 7.15 (m, 2H),
7.28–7.52 (m, 6H), 7.69 (m, 1H), 7.90 (m, 2H), 8.32 (m, 1H), 12.65
ChemMedChem 2012, 7, 2179 – 2193
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2191

N. Lebegue et al.
MED
mids pGal4–hPPARg and pG5-TK-pGL3 were constructed as de-
scribed previously.[33] Cells were seeded in 1=60 mm dishes at
a density of 5.5ꢃ105 cells per dish in DMEM supplemented with
10% FCS and incubated at 378C for 24 h prior to transfection. Cells
were transfected in OptiMEM without FCS for 3 h at 378C using
polyethylenimine (PEI) with reporter and expression plasmids. The
plasmid pBluescript (Stratagene, La Jolla, CA, USA) was used as car-
rier DNA to set the final amount of DNA to 5.5 mg per dish. The
pCMV-b-galactosidase expression plasmid was co-transfected as
a control for transfection efficiency. Transfection was stopped by
the addition of DMEM supplemented with 10% FCS, and cells
were then incubated at 378C. After 16 h, cells were trypsinized and
seeded in 96-well plates at a density of 2ꢃ104 cells per well and in-
cubated for 6 h in DMEM containing 10% FCS. Cells were then in-
cubated for 24 h in DMEM containing 0.2% FCS and various con-
centrations of test compound or vehicle (DMSO). At the end of the
experiment, cells were washed once with ice-cold PBS, and lucifer-
ase and b-galactosidase assays were performed as described previ-
ously.[34] Cells were incubated for 24 h in the presence of indicated
concentrations of compound. Luciferase activity was measured and
normalized to internal control b-galactosidase activity. Compounds
that elicited, on average, at least 80% activation of PPARa or
PPARg versus WY14,643 or rosiglitazone, respectively, (positive con-
trols) were considered full agonists. EC50 values were estimated
using GraphPad Prism software. All transfection experiments were
performed at least three times.
Acknowledgements
We gratefully acknowledge Ghislaine Zanirato for technical assis-
tance with the in vivo experiments and the determination of plas-
matic biochemical parameters.
Keywords: 2-ethoxypropionic acid · diabetes · docking · drug
design · PPAR
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Received: June 25, 2012
Revised: September 13, 2012
Published online on October 9, 2012
ChemMedChem 2012, 7, 2179 – 2193
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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