Glucose transport-enhancing and hypoglycemic activity of 2-methyl-2- phenoxy-3-phenylpropanoic acids

Article abstract of DOI:10.1021/jm950364f

A series of 2-phenoxy-3-phenylpropanoic acids has been prepared which contains many potent hypoglycemic agents as demonstrated by assessing glucose lowering in ob/ob mice. Some compounds (32, 33, 59) normalize plasma glucose in this diabetic model at doses of approximately 1 mg/kg. The mechanism of action of these drugs may involve enhanced glucose transport, especially in fat cells, but the compounds do not stimulate GLUT4 translocation and do not increase the levels of GLUT1 or GLUT4 in vivo. Thus, these compounds may enhance the intrinsic activity of the glucose transporter GLUT1 or GLUT4. Some compounds also modestly decrease hepatocyte gluconeogenesis in vitro, but this is not likely to be a major contributor to the hypoglycemic effect observed in vivo. Likewise, a modest decrease in food consumption observed with some of these compounds was shown by a pair-feeding experiment not to be the primary cause of the hypoglycemia observed.

Full text of DOI:10.1021/jm950364f

J . Med. Chem. 1996, 39, 4783-4803
4783
Glu cose Tr a n sp or t-En h a n cin g a n d Hyp oglycem ic Activity of
2-Meth yl-2-p h en oxy-3-p h en ylp r op a n oic Acid s
Reinhard Sarges, Richard F. Hank, J ames F. Blake, J on Bordner, Donald L. Bussolotti, Diane M. Hargrove,
J udith L. Treadway, and E. Michael Gibbs*
Pfizer Central Research, Pfizer Inc., Groton, Connecticut 06340
Received September 12, 1996X
A series of 2-phenoxy-3-phenylpropanoic acids has been prepared which contains many potent
hypoglycemic agents as demonstrated by assessing glucose lowering in ob/ ob mice. Some
compounds (32, 33, 59) normalize plasma glucose in this diabetic model at doses of
approximately 1 mg/kg. The mechanism of action of these drugs may involve enhanced glucose
transport, especially in fat cells, but the compounds do not stimulate GLUT4 translocation
and do not increase the levels of GLUT1 or GLUT4 in vivo. Thus, these compounds may
enhance the intrinsic activity of the glucose transporter GLUT1 or GLUT4. Some compounds
also modestly decrease hepatocyte gluconeogenesis in vitro, but this is not likely to be a major
contributor to the hypoglycemic effect observed in vivo. Likewise, a modest decrease in food
consumption observed with some of these compounds was shown by a pair-feeding experiment
not to be the primary cause of the hypoglycemia observed.
In tr od u ction
structure-activity relationship (SAR) explorations around
BM 13.0795 and found that R-phenoxycarboxylic acids,
particularly those with a 4-isopropyl group, shared some
of the in vitro and in vivo characteristics of BM 13.0795,
namely, enhanced 2-deoxyglucose uptake in adipocytes
and hypoglycemic activity in genetically diabetic ob/ ob
mice after acute or chronic administration. In particu-
lar, R-phenoxy-substituted 3-phenylpropanoic acids dis-
tinguished themselves with potent oral hypoglycemic
activity in ob/ ob mice. This interesting finding prompted
us to carry out a systematic SAR study in this subset
of compounds. The only structurally related compounds
described in the literature are R-phenoxy-3-phenyl-
propanoic acids with halogen substituents in the phe-
noxy ring, which are claimed in a Lilly patent to be
hypoglycemic in rats at doses of 50-100 mg/kg, but no
mechanism of action was reported.10
The search for antidiabetic agents has not been
rewarded with marketable novel agents in the last 20
years, and efforts to find such drugs continue. Of
particular interest have been hypoglycemic agents with
novel mechanisms, such as thiazolidinediones, typified
by englitazone,1,2 pioglitazone,3 and troglitazone,4 which
may act by sensitizing peripheral tissues to insulin and
increasing the level of glucose transporter protein
expression,2,5 and R-tosylated carboxylic acids such as
BM 13.0795 (Table 1) which are reported to acutely
Ch em istr y
The R-phenoxy-substituted 3-phenylpropanoic acids
with hydrogen in the R-position (Table 1) were prepared
by several routes. Conversion of R-haloacetic esters to
R-phenoxyacetic esters followed by proton abstraction
with lithium bis(trimethylsilyl)amide and alkylation
with benzyl halides (general method A) or conversion
of the R-phenoxyacetic esters to the acids followed by
dianion formation with 2 equiv of LDA and alkylation
with benzyl halides (general method D), as shown in
Scheme 1, proved to be convenient. Some compounds
were prepared by conversion of R-phenoxyacetic acids
to 4,5-dihydro-4,4-dimethyl-2-(phenoxymethyl)oxazoles
followed by proton abstraction with butyllithium, alkyl-
ation with benzyl halides, and hydrolysis to the acids
(general method B), as shown in Scheme 2. Yet another
route involved conversion of diethyl chloromalonate to
diethyl 2-phenoxymalonates, proton abstraction with
NaH, and alkylation with benzyl halides to give the
desired acids after saponification and decarboxylation
(general method C, Scheme 3). In the syntheses of
R-methyl-R-phenoxycarboxylic acids (Table 2), we found
stimulate the translocation of GLUT4 to the plasma
membrane.6 The relevance of targeting glucose trans-
port as a site for pharmacological intervention for the
treatment of non-insulin-dependent diabetes mellitus
was strongly supported by a recent study that demon-
strated that increasing GLUT4 expression in genetically
diabetic db/db mice markedly improved glycemic con-
trol.7 Furthermore, in the diabetic ob/ob mouse, which
is characterized by severe insulin resistance and im-
paired peripheral glucose utilization, enhancement of
muscle and adipose tissue glucose uptake and metabo-
lism due to pharmacological treatment with glitazone
agents is associated with glucose normalization.8,9 There-
fore, upregulation of glucose transporter protein expres-
sion or activity appears to be an efficacious means of
restoring glycemic control in non-insulin-dependent
diabetes mellitus.
In attempts to discover improved antidiabetic agents
that enhance glucose uptake, we conducted empirical
X Abstract published in Advance ACS Abstracts, November 1, 1996.
S0022-2623(95)00364-5 CCC: $12.00 © 1996 American Chemical Society

4784 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Sch em e 1. General Methods A and D
Sarges et al.
Sch em e 3. General Method C
Sch em e 4. General Method E
Sch em e 2. General Method B
with R-bromopropionitrile instead of ethyl R-bromo-
propionate, we obtained the nitrile of 26, which was
reduced with borane to the amine and then sulfonylated
to give sulfonamides 71 and 72 (general method F).
Treatment of the nitrile intermediate with HN3 gave
tetrazole 73; treatment with hydroxylamine gave amid-
oxime 76. Reduction of the acid 26 with borane gave
the alcohol 70, which was converted to the monophos-
phate ester 75 with POCl3. The acylguanidine 74 was
obtained from the ester of 26 by treatment with guani-
dine. The hydroxymethyl ketone 77 proved to be
sensitive to aqueous acid and base and was prepared
by mild hydrolysis of the acetoxymethyl ketone with
KCN; the acetoxymethyl ketone was obtained from acid
26 via the acid chloride, diazo ketone, and bromomethyl
ketone.
it advantageous to treat the ethyl esters of R-phenoxy-
propanoic acids with LICA (lithium cyclohexyliso-
propylamide)11 and to treat the intermediate anion with
the desired benzyl halide (general method E), as shown
in Scheme 4. Use of LDA (lithium diisopropylamide)
in place of LICA led in this case to considerable
formation of Claisen condensation products.
The compounds in which the carboxylic acid function
was modified are listed in Table 3. The sulfonimides
in this series were prepared by reaction of the parent
acid (e.g., 26) with sulfonamides and a water-soluble
carbodiimide in the presence of 4-(dimethylamino)-
pyridine (general method F). Using general method E
The compounds which probed the manipulation of the
R-methyl group of 26 and methyl substitution in the
â-position (Table 4) were synthesized by adaption of
general method E, as were the analogs of 26 in which

Phenoxyphenylpropanoic Acids as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4785
Sch em e 7. Synthesis of Compound 99
Sch em e 5. Synthesis of Compound 97
Sch em e 6. Synthesis of Compound 98
Sch em e 8. Synthesis of Compounds 100 and 101
the phenoxy group was replaced by isosteres (Table 5).
The synthesis of the ring-constrained derivatives of 26
(97-101; Table 6) is shown in Schemes 5-8.
Biology
For in vitro characterization, compounds were evalu-
ated for their acute effects on glucose transport by
measuring 2-deoxyglucose uptake in 3T3-L1 adipocytes
or L6 myocytes after 1 h pretreatment with the agents,
which may reflect glucose transporter translocation to
the plasma membrane from an intracellular storage pool
or an increase in the intrinsic activity of the trans-
porter.12 Glucose transporter translocation was as-
sessed by measuring cell surface glucose transporter
levels by immunocytochemistry13 following pretreat-
ment with the compounds. Chronic effects on glucose
transport activity were assessed by measuring 2-deoxy-
glucose transport in 3T3-L1 adipocytes after 48 h of
exposure to the experimental compounds. Chronic
effects on glucose transporter expression were assessed
by quantitative immunoblotting using isoform-specific
antibodies.14 Inhibition of gluconeogenesis was meas-
ured in hepatocytes which were isolated by collagenase
digestion from livers of fed male Sprague-Dawley
rats.15
In vivo testing for hypoglycemic activity was carried
out in 6-8 week old C57BL/6J -ob/ ob mice (obtained
from J ackson Laboratories, Bar Harbor, ME). The
compounds were dosed orally for 4 days, and plasma
glucose was measured on the fifth day 20-24 h after
the last dose to determine their effect after chronic
administration.16 To determine acute hypoglycemic
activity following a single oral dose of compound 26 or
84, ob/ ob mice were treated with vehicle alone on days
1-4 using the protocol above followed by administration
of the test compound on the morning of day 5 and

4786 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Sarges et al.
plasma glucose determination 3 h later. Resulting
plasma glucose values were compared to those of
vehicle-treated mice and analyzed by two-tailed un-
paired Student’s t-test. Values are expressed as percent
of plasma glucose lowering produced by racemic engli-
tazone given at 50 mg/kg in the same experiment; this
dose typically normalizes plasma glucose.
51, 52, 54; the 4-phenoxy derivative 57) and several
compounds that exhibited no hypoglycemic activity at
10 mg/kg (53, 56, 58). Exploring the simultaneous
substitution of the 4-chloro group and the 4-isopropyl
group of 26, we prepared compounds 59-65. Of these,
59, 62, and 65 showed notable hypoglycemic potency
(ED50 e 1 mg/kg).
The effects of the compounds in Table 2 on the acute
stimulation of 2-deoxyglucose uptake in 3T3-L1 adipo-
cytes or L6 myocytes was not measured for all com-
pounds. However, there are several examples of com-
pounds with an increased effect on uptake relative to
26 but without a concomitant increase in hypoglycemic
activity (e.g., 22, 39, 42, 56), and conversely there are
several agents (e.g., 33, 44) that induced glucose lower-
ing at low doses (∼1 mg/kg) which did not enhance acute
2-deoxyglucose uptake at the concentrations tested.
Resu lts a n d Discu ssion
As shown in Table 1, several compounds with differ-
ent substituents in the phenyl ring of the phenylpro-
panoic acids retained hypoglycemic activity in ob/ ob
mice. The parent compound 1 exhibited blood glucose-
lowering activity at 50 mg/kg. Halogen and alkyl
substitutions, particularly in the 4-position, produced
agents with hypoglycemic activity comparable to or
better than the parent compound. The 4-Cl (7) deriva-
tive demonstrated glucose-lowering activity at 10 mg/
kg. Modification of the 4-isopropyl group in the phenoxy
part of 7 led to analogs (15-18) that generally did not
exhibit hypoglycemic activity at 25 mg/kg. Similarly,
shortening (19) the distance between the R-carbon and
the phenyl ring of the 3-phenylpropanoic acids by one
C atom decreased the hypoglycemic activity, while
increasing this distance by four (21), but not one (20),
C atoms retained hypoglycemic activity. Although there
was some correlation between the ability of these
compounds to acutely enhance 2-deoxyglucose uptake
in 3T3-L1 adipocytes in vitro, we surprisingly found
several compounds which showed activity in one of, but
not both, the in vitro and in vivo screens (1, 2, 5, 11,
19).
Replacing the hydrogen on the R-carbon of compounds
3, 4, 6, and 7 with methyl led to compounds 23-26 in
Table 2, which showed in vivo glucose-lowering activity
(ED50 e 10 mg/kg), although this was not accompanied
by an increase in acute glucose transport activity in 3T3-
L1 adipocytes in vitro. The marked hypoglycemic
activity displayed by 26 (ED50 ) 1-5 mg/kg) caused us
to examine SAR around this structure more thoroughly.
Resolution of 26 showed that both isomers (27, 28) were
active at doses of 2.5 and 5 mg/kg in lowering blood
glucose and had equivalent effects to acutely stimulate
2-deoxyglucose transport in 3T3-L1 adipocytes.
Replacement of chlorine in compound 26 with a
variety of alkyl groups (29-39) gave many agents with
hypoglycemic activity at doses of e1 mg/kg (as exempli-
fied by the 4-ethyl derivative 33). Replacement of
chlorine with methoxy (40, 41) gave compounds that
exhibited little or no glucose-lowering activity at 10 mg/
kg and therefore appeared to be less potent than 26,
but replacement with phenyl (42-44), especially in the
3- and 4-positions, gave hypoglycemic agents with
activity comparable to 26. Addition of a chlorine to the
3-position of 26 (45) or substitution of chlorine with
three methyls (46) gave analogs that maintained hypo-
glycemic activity at e10 mg/kg. Replacement of chlo-
rine in 26 with the tail of gliburide (47) resulted in
diminished hypoglycemic activity. Substitution of chlo-
rine with a fused ring resulted in decreased activity in
the naphthyl derivative (48) and retained activity in the
indan (49) and tetralin (50) derivatives.
Compounds resulting from replacement of the car-
boxyl group of 26 with other groups or acidic bioisosteres
are listed in Table 3. It is apparent that certain sulfon-
imides (e.g., 66-69) showed enhanced effects on acute
2-deoxyglucose uptake in vitro, but these compounds did
not produce significant glucose lowering at 5 mg/kg and
thus appeared to be less potent than 26. These findings
support the unexpected conclusion that enhanced acute
glucose uptake in 3T3-L1 adipocytes does not necessar-
ily translate to hypoglycemic activity in ob/ ob mice.
However, poor bioavailability cannot be excluded as an
explanation for the discordance between potency in vitro
and poor in vivo activity. Furthermore, the carboxylic
acid group of 26 seems to be an essential ingredient for
the hypoglycemic activity of this series in the ob/ ob
mouse.
To explore the importance of the R-methyl group of
26 and the tolerance for substituents in the â-position
of the R-phenoxy substituted 3-phenylpropanoic acids,
we prepared the compounds shown in Table 4. Chang-
ing the R-methyl group to ethyl (81) or shifting the
methyl group from the R- to the â-position (82, 83)
resulted in decreased hypoglycemic potency. Addition
of a methyl to the â-position of 26 gave one diastereomer
(84, shown by X-ray analysis to be the 2R,3S/2S,3R
isomer) with enhanced effects on acute 2-deoxyglucose
uptake and comparable hypoglycemic activity. Its dia-
stereomer 85 was less active in the ob/ ob mouse.
Changing the â-methyls in 84 and 85 to â-ethyls gave
the diastereomers 86 and 87, respectively, with hy-
poglycemic activity in 86 but not in 87. Replacing the
carboxyl group in 84 with sulfonimides (88, 89) again
diminished hypoglycemic potency (ED50 > 10 mg/kg).
The effects of modifying the R-4-isopropylphenoxy
group in compounds 7 and 26 are summarized in Table
5. The R-tosyl derivative (90) of compound 7 did not
exhibit hypoglycemic activity at 50 mg/kg and, therefore,
appeared to be less potent than 7, while the thiophenoxy
analog 91 was active at 50 mg/kg. Among the analogs
of 26, the thiophenoxy congener 92 showed some effect
in stimulating acute 2-deoxyglucose uptake, but none
of the modified derivatives had superior hypoglycemic
activity.
Attempts to constrain the conformations of compound
26 in cyclic derivatives are summarized in Table 6.
Interestingly, only compound 100 showed hypoglycemic
activity comparable to 26. Since compound 101 was
Replacement of the 4-isopropyl group in 26 with other
groups (51-58) gave compounds that produced hypogly-
cemic activity at e10 mg/kg (the 4-benzyl derivatives

Phenoxyphenylpropanoic Acids as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4787
Ta ble 1
glucose-lowering
ob/ob mouseb dose
(mg/kg) (no. of
2DG uptake
experiments):%
stima [drug] glucose lowering
(µM): %
relative to
positive control
c
no.
X
R
R′
n
formula
C18H20O3
C19H19F3O3‚C12H23
C19H19F3O3‚C12H23
method mp ( °C) basal uptake
ED50
50
>50
∼25
∼10
<25
1
2
3
H
4-iPr
4-iPr
4-iPr
OH
1
1
1
A
B
C, D
91-2
164-5
165-7
100: 79
100: 191**
100: 284***
50: 50*
50: e0
50: 76**
25: 64
10: e0
50: 74***
10: 42
5: 30*
50: 100**
25: 65
2-CF3
3-CF3
O-DCAd
O-DCAd
N
N
4
5
4-CF3
3-F
4-iPr
4-iPr
OH
1
1
C19H19F3O3
B
B
134-8
165-7
100: 605***
60: 104
O-DCAd
C18H19FO3‚C12H23
N
100: 111
6
7
3-Cl
4-Cl
4-iPr
4-iPr
O-DCAd
OH
1
1
C18H19ClO3‚C12H23
N
D
D
166-8
148-9
100: 160**
100: 150*
50: 32
>50
∼10
C
C
18H19ClO3
18H19BrO3
50: 82***
10: 58**
5: 26*
50: 122**
10: e0
50: 113*
10: <0
50: e0
50: 70***
10: 30
8
4-Br
4-iPr
OH
1
D
171-3
100: 203**
10-50
9
4-Me
4-iPr
4-iPr
4-iPr
4-iPr
OH
OH
OH
OH
1
1
1
1
C
C
C
19H22O3
19H22O4
19H22O4
D
E
D
D
142-5
101-3
111-4
89-90
100: 147*
60: 78
100: 127**
100: 222**
<50
>10
>50
10
11
12
2-OMe
4-OMe
2,4-Cl2
C18H18Cl2O3
10-50
5: 45
50: 65
50: 45*
13
14
3,4-Cl2
4-iPr
4-iPr
O-DCAd
OH
1
1
C18H18Cl2O3‚C12H23
C22H22O3
N
D
D
172-3.5 100: 225***
140-2 100: 143***
<50
3,4-(CH)4
(â-naphthyl)
4-Cl
50
15
16
H
OH
OH
1
1
C
C
15H13ClO3
16H15ClO3
D
D
157-8.5 60: 100
60: 86
25: e0
>25
>25
4-Cl
4-Me
128-31
60: e100
60: 93
25: 33
30: 88
10: 82
17
18
4-Cl
4-Cl
4-OMe OH
4-tBu OH
1
1
C
C
16H15ClO4
19H21ClO3
D
D
117.5-20 60: 98
25: 23
25: 53
>25
25
127-30
60: <100
60: 84
30: 87
10: 92
19
20
4-Cl
4-Cl
4-iPr
4-iPr
OH
0
2
C
17H17ClO3
e
e
74-5
143-5
100: 248*
100: 89
60: 89
50: e0
25: 64
>50
<25
O-DCAd
C19H21ClO3‚C12H23Nf
21
4-Cl
4-iPr
ONa
5
C
22H26ClNaO3
e
275 dec
10: 180***
60: 44
50: 200**
10: 32
10-50
5: 35
BM 13.0795
100: 250***
30: 100
10: 93
50(3): 71**
25(4): 60***
10(3): 22
∼25
3: 114
100: 134***
60: 124**
30: 88
a
2-Deoxyglucose (DG) uptake values are presented as means of triplicate measurements and represent the percent basal uptake obtained
in vehicle-treated 3T3-L1 adipocytes unless printed in italics, in which case the data were obtained in L6 myocytes. Significant increases
b
from vehicle-treated cells: *p < 0.05, **p < 0.01; ***p < 0.001. Values presented are the percent glucose normalization compared to the
effect of racemic englitazone (CP-68,722) at 50 mg/kg (i.e., 100% normalization). Significant differences of drug-treated vs vehicle-treated
mice: *p < 0.05, **p < 0.01; ***p <0 .001, (two-tailed unpaired t-test). c ED50 ) approximate dose of compound that induces 50%
d
normalization of glucose relative to positive control (racemic englitazone). DCA ) dicyclohexylammonium salt. e See the Experimental
Section. f This compound was characterized by NMR and MS only.
shown by X-ray analysis to have the RS/SR configura-
tion, 100 must be RR/SS.
These SAR results can be rationalized by molecular
modeling studies. The goal of these computations was
to discover the common conformations of 7, 26, 84, and
99-101 and to rationalize the decreased activity of
compounds 7, 99, and 101 relative to the more potent
analogs. This was approached by overlapping all of the
conformational minima for the most potent analogs (26,
84, 100) to give maximum coincidence of the aromatic

4788 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Sarges et al.
Ta ble 2
glucose-lowering
ob/ ob mouseb dose
(mg/kg) (no. of
experiments): %
glucose lowering
relative to
2DG uptake
stima [drug]
(µM): %
c
no.
X
R
R′
formula
method
E
mp (°C)
>200
basal uptake
positive control
ED50
22
H
4-iPr
ONa
C19H21NaO3
10: 126*
3: 162*
1: 100
10(2): 3
>10
23
3-CF3
4-iPr
ONa
C20H20F3NaO3
E
>200
30: 121
10: 104
3: 129
10: 64*
5: 46
1: 44
5-10
24
25
4-CF3
3-Cl
4-iPr
4-iPr
OH
ONa
C20H21F3O3
C19H20ClNaO3
E
E
122-4
>200
60: 103
5: 65*
10: 101***
5: 32
<5
5-10
1: 47*
26
4-Cl
4-iPr
OH
C19H21ClO3
E
132-3
100: 220**
60: 110
30: 100
10: 94
3: 98
1: 86
50: 83*
25: 90***
20: 104***
10(2): 111***
5(4): 77*
1: 50
1-5
0.3: 106
100: 88
60: 108
30: 87
10: 96
3: 97
1: 101
27
28
29
30
31
32
4-Cl
(d isomer)
4-iPr
4-iPr
4-iPr
4-iPr
4-iPr
4-iPr
OH
C19H21ClO3
C19H21ClO3
C20H23NaO3
C20H23NaO3
C21H25NaO3
C21H25NaO3
d
d
114-5
([R]D +15.1°)
100: 214**
5: 65**
2.5: 79**
1: 36
5 (2): 100***
2.5: 88*
1: 47
10: 83**
5: 83**
1-2.5
1-2.5
<1
4-Cl
(l isomer)
OH
114-6
[R]D -16.7°
100: 229**
3-Me
4-Me
2-Et
ONa
ONa
ONa
ONa
E
E
E
E
>230
>250
90-3
>200
30: 84
10: 98
3: 93
1: 63*
60: 92
10: 106***
5: 100***
1: 58
10: 95***
5: 53*
<1
5
1: 32
3-Et
30: 117*
10: 127**
3: 102
10: 147***
5: 101***
1: 76**
0.5-1
0.5: e0
33
4-Et
4-iPr
ONa
C21H25NaO3
E
>250
60: 109
10: 119***
5(2): 109***
1(2): 86***
0.5: 76**
0.1: 55
0.1-0.5
34
35
3-nPr
4-nPr
4-iPr
4-iPr
ONa
ONa
C22H27NaO3
C22H27NaO3
E
E
212-6
>200
30: 229***
10: 128
3: 136
1: 123
60: 282***
30: 97
10: 123***
5: 82***
1: 47*
1
10: 113***
5: 134***
1: 70***
0.5: 69
∼0.5
36
37
38
4-iPr
4-iPr
4-iPr
4-iPr
ONa
ONa
ONa
C22H27NaO3
C23H29NaO3
C23H29NaO3
E
E
E
>200
>200
>200
30: 93
10: 97
3: 97
30: 113
10: 129
3: 113
30: 200***
10: 94
3: 82
10: 93**
5: e0
5-10
1-5
3-nBu
4-nBu
10: 91**
5: 85*
1: e0
10: 130***
5: 92**
1: 17
1-5

Phenoxyphenylpropanoic Acids as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4789
Ta ble 2 (Continued)
glucose-lowering
ob/ ob mouseb dose
(mg/kg) (no. of
2DG uptake
stima [drug]
(µM): %
experiments): %
glucose lowering
relative to
c
no.
X
R
R′
formula
C23H30O3
method
E
mp (°C)
basal uptake
positive control
ED50
39
4-tBu
4-iPr
OH
65-8
30: 213***
10: 104
3: 103
10: 102*
5: 47
1: 41
5-10
40
2-OMe
4-iPr
OH
C20H24O4
E
118-20
60: 120
30: 122*
10: 100
10: e0
>10
41
42
4-OMe
2-Ph
4-iPr
4-iPr
OH
ONa
C20H24O4
C25H25NaO3
E
E
80-2
70-4
10: 41*
10: 54*
>10
10
30: 167*
10: 228*
3: 148*
1: 97
43
44
3-Ph
4-iPr
4-iPr
ONa
ONa
C25H25NaO3
C25H25NaO3
E
E
49-52
>230
30: 118*
10: 76
3: 87
10: 83**
5: 110**
1: 78*
0.5: 46**
10: 116***
5: 93***
1: 58*
0.5
4-Ph
30: 126
10: 129
3: 122
∼1
0.5: 21
45
46
47
3,4-Cl2
4-iPr
4-iPr
4-iPr
OH
C19H20Cl2O3
C22H27NaO3
C29H32ClNO5
E
98-9
>200
127-9
10: 111***
5: 24
1: e0
5-10
<10
2,4,6-Me3
ONa
OH
E
60: 173**
30: 106
10: 148
10: 77**
Ed
10: 24
>10
48
49
3,4-(CH)4
(â-naphthyl)
3,4-(CH2)3
4-iPr
4-iPr
OH
C23H24O3
E
E
88-90
10: 46
>10
ONa
C22H25NaO3
>230 dec
10: 126***
5: 121***
1: 83***
0.5: 34
0.5-1
50
51
3,4-(CH2)4
4-Cl
4-iPr
ONa
ONa
C23H27NaO3
E
E
>200
10: 99***
5: 75*
10: 96**
5: 100***
1: 44
<5
4-CH2-Ph
C23H20ClNaO3
228-30
60: 214***
30: 109
1-5
52
53
4-Cl
4-Cl
ONa
ONa
C24H22ClNaO4
C23H19Cl2NaO3
E
E
195-206
dec
10: 74**
<10
>10
200-20
dec
30: 112
10: 94
3: 90
10: e0
54
4-Cl
ONa
C23H19Cl2NaO3
E
190 dec
30: 97
10: 88
3: 100
10: 52*
10
55
56
4-Cl
4-Cl
ONa
ONa
C21H22ClNaO3Se
C25H22ClNaO3S
Ed
Ed
>250 dec
110-4
60: 108
10: 64**
10: 38
<10
>10
30: 157**
10: 118
3: 130
1: 98
57
58
59
4-Cl
4-Cl
3-Et
OH
C22H19ClO4
C16H14BrClO3
C25H25NaO3
E
E
E
120-2
10: 108***
5: 100**
1: 60*
<1
4-Br
OH
104-5
30: 134*
10: 109
3: 120
10: 22
>10
4-CH2-Ph
ONa
>210 dec
10: 101***
5(2): 102***
1: 87**
0.1-0.5
0.5(2): 52***
0.1: 73**

4790 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Ta ble 2 (Continued)
Sarges et al.
glucose-lowering
ob/ ob mouseb dose
(mg/kg) (no. of
experiments): %
glucose lowering
relative to
2DG uptake
stima [drug]
(µM): %
mp
(°C)
c
no.
X
R
R′
formula
method
Ed
basal uptake
positive control
ED50
60
3-Et
4-Et
4-Et
ONa
C27H27NaO3Sf
>200
30: 116
10: 113
3: 104
10: 35
>10
61
62
4-CH2-Ph
4-CO-Ph
ONa
OH
C25H25NaO3
C25H24O4
E
E
>220
10: 107***
5: 104***
1: 44
∼1
168.5-
9.5
10: 107***
5: 108***
1: 65**
∼0.5
0.5: 60*
10: 130***
5: 113***
1: 48*
10: 96***
5: 91**
63
64
65
4-Et
4-O-Ph
OH
C24H24O4
E
E
E
91-5
1
4-nPr
4-CH2-Ph
4-CH2-Ph
ONa
ONa
C26H27NaO3
C26H25NaO3
>185 dec
200 dec
1-5
1: 24
3,4-(CH2)3
10: 120***
5: 102***
1: 78**
0.5-1
0.5: 50
a
2-Deoxyglucose (DG) uptake values are presented as means of triplicate measurements and represent the percent basal uptake obtained
in vehicle-treated 3T3-L1 adipocytes unless printed in italics, in which case the data were obtained in L6 myocytes. Significant differences
b
of drug-treated vs vehicle-treated cells: *p < 0.05, **p < 0.01; ***p < 0.001. Values presented are the percent glucose normalization
compared to the effect of racemic englitazone (CP-68,722) at 50 mg/kg (i.e., 100% normalization). Significant differences of drug-treated
vs vehicle-treated mice: *p < 0.05; **p < 0.01; ***p < 0.001, (two-tailed unpaired t-test). c ED50 ) approximate dose of compound that
d
induces 50% glucose normalization relative to positive control (racemic englitazone). See the Experimental Section e Formula
C
21H22ClNaO3S anal. C; H: calcd, 5.37; found, 4.91. MS (free acid, CI) m/e 408 (M + NH4). f This compound was characterized by NMR
and MS only.
and carboxylate groups. Emphasis was also placed on
aligning the C4-H bond vector of the phenoxy substitu-
ent (corresponding to the point of attachment of the
isopropyl group) and the C5-H bond vector of the indan
(C4-H of 26) (position of the chloro substituent).
Interestingly, the best overall fit of 26, 84, and 100 was
obtained from the lowest energy conformation of each
molecule, illustrated in Figure 1. Given the overlap of
the most potent analogs, the next step was to fit 7, 99,
and 101 to the alignment in an attempt to understand
their decreased activity. As illustrated in Figure 1, both
99 and 101 fit the alignment reasonably well. Again,
the best overlap was obtained from the lowest energy
conformations of 99 and 101. However, none of the
minima of 7 were found to fit the alignment. Introduc-
tion of the R-methyl group in 7, to give 26, causes a
dramatic change in the lowest energy conformation
toward more potent activity. Given the similarity of 7
and 26, the lower activity of 7 can be explained by
computing the energetic cost of adopting the preferred
conformation of 26. The cost of achieving this confor-
mation was determined by constraining the C(phenyl)-
O-C(COOH)-C(H2) and O-C(COOH)-C(H2)-C(phen-
yl) dihedral angles of 7 to -163.3° and 67.4° (the
corresponding values found in 26). Additionally, the
plane of each aromatic ring in 7 was constrained to the
same relative orientation as found in 26. At the
6-31G(d)//6-31G(d) level of theory, this conformation of
7 is ca. 1.9 kcal/mol higher in energy than the lowest
energy conformation. This energetic difference is suf-
ficient to explain the lower activity of 7. The decreased
potency of 101 can be rationalized by assuming that
relatively precise positioning of the indan aromatic ring
is required for activity. As shown in Figure 1, the plane
of the indan aromatic ring in 101 occupies a unique
position, tilted ca. 44° relative to the other molecules
in the alignment. Evidently, the positioning of the plane
of the aromatic phenoxy substituent is not as critical
as demonstrated by the overlap of 99. Since all other
features of 99 are aligned reasonably well with the more
potent compounds (through the C6-H bond vector of
the benzopyran ring and C4-H bond vector of the
benzyl group), it can be assumed that the lower potency
of this constrained analog is due to the near perpen-
dicular positioning of the benzopyran ring.
In order to gain insight into the possible mechanism
of action of these compounds, we carried out further
biological experiments. It is clear that many compounds
in this series enhanced glucose transport in adipocytes
acutely, an effect that is consistent with GLUT4 trans-
location from an intracellular storage site to the plasma
membrane and which is the reported mechanism of
action of the lead compound BM 13.0795.6 In accord
with this, two compounds tested (26 and 84) displayed
acute (3 h) hypoglycemic activity in single-dose studies
in diabetic ob/ ob mice. Under this protocol, both
compounds displayed significant (p < 0.05) blood glucose-
lowering activity at 50 mg/kg, and the efficacy of these
compounds ranged from 54% to 82% of that observed
for chronic treatment with racemic englitazone. How-
ever, if the hypoglycemic activity of these compounds
is indeed mediated through GLUT4, it is unlikely they
do so by enhancing GLUT4 translocation since we have
been unable to show increased GLUT4 levels at the
plasma membrane in 3T3-L1 adipocytes treated with
26 in vitro (data not shown). For some compounds, the
assessment of acute effects on glucose transport after
acute exposure was carried out in L6 myocytes. When

Phenoxyphenylpropanoic Acids as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4791
Ta ble 3
glucose-lowering
ob/ob mouseb dose
(mg/kg) (no. of
2DG uptake
stima [drug]
(µM): %
experiments): %
glucose lowering
relative to
c
no
X
R
R′
formula
method mp (°C) basal uptake
positive control
ED50
66 4-Cl
4-iPr CONHSO2Me
C20H24ClNO4S
F
141-1.5
60: 200**
30: 255***
10: 100
10: 96***
5: 0
10: 100
10(2): 91**
5: e0
5-10
67 4-Cl
4-iPr CONHSO2CF3
C20H21ClF3NO4S
F
160 dec
60: 79
5-10
30: 273***
10: 232***
3: 130
1: 108
68 4-Cl
69 4-Cl
4-iPr
4-iPr
C26H28ClNO4S
C26H28ClNO5S
F
F
150-1
30: 232***
10: 251***
3: 126
60: 67
30: 154***
10: 101
10: e0
>10
98-100
10: 22
>10
d
70 4-Cl
71 4-Cl
72 4-Cl
4-iPr CH2OH
4-iPr CH2NNaS(CF3)
4-iPr
C19H23ClO2
e
oil
30: 118*
10: 121**
3: 118*
30: 159**
10: 132*
3: 127
10: e0
10: e0
10: 7
>10
>10
>10
C20H22ClF3NNaO3Sf
C26H29ClNNaO3Sh
Gg
G
68-70
77-82
73 4-Cl
74 4-Cl
4-iPr
C19H21ClN4O
e
e
140-2
172-5
30: 159
10: 105
3: 105
10: e0
>10
4-iPr CONHC(NH2)dNOH C20H24ClN3O2‚HCl
10: 49***
5: 44
10
1: e0
75 4-Cl
76 4-Cl
4-iPr CH2OPO3Ca
4-iPr C(NH2)dNOH
C19H22CaClO5P
C19H23ClN2O2
e
e
168-70
foam
10: 50
10: 27
g10
>10
d
(E + Z
isomer)
77 4-Cl
78 3-Et
79 4-Et
80 4-nPr
d
4-iPr COCH2OH
C20H23ClO3
e
oil
10: 32
10: 43*
10: 27
10: 35
>10
g10
>10
>10
4-iPr CONNaS(CF3)O2
4-iPr CONHS(CF3)O2
4-iPr CONHS(CF3)O2
C22H25F3NNaO4S
C22H26F3NO4S
C23H28F3NO4S
F
F
F
>200
98-103
134-8
a
2-Deoxyglucose (DG) uptake values are presented as means of triplicate measurements and represent the percent basal uptake obtained
in vehicle-treated 3T3-L1 adipocytes unless printed in italics, in which case the data were obtained in L6 myocytes. Significant differences
b
from vehicle-treated cells are indicated: *p < 0.05, **p < 0.01, ***p < 0.001. Values presented are the percent glucose normalization
compared to the effect of racemic englitazone (CP-68,722) at 50 mg/kg (i.e., 100% normalization). Significant differences from vehicle-
treated mice are indicated: *p < 0.05, **p < 0.01, ***p < 0.001 (two-tailed unpaired t-test). c ED50 ) approximate dose of compound that
d
induces 50% normalization of glucose relative to the positive control (racemic englitazone). This compound was characterized by NMR
and MS only. e See the Experimental Section. f Formula C20H22ClF3NNaO3S‚1.5H2O anal. C, N; H: calcd, 5.05; found, 5.50. MS (free
g
h
acid, CI) m/e 467 (M + NH4). 2-Methylbenzenesulfonyl chloride was used instead of trifluoromethanesulfonic anhydride. Formula
C
26H29ClNNaO3S‚1.75H2O anal. C, H; N: calcd 2.65; found, 2.18. MS (FAB) m/e 494 (M + H); HR-MS calcd 494.1533, found 494.1516.
compounds were tested in both assays, activity was
generally lower in the myocyte than in the adipocyte
cell lines.
) 193-265%) at the maximal concentration tested (30
µM). Furthermore, none of the compounds presented
(32, 33, 35, 43, 59) displayed improved intrinsic potency
of glucose transport activity over 26 at 3 µM. In fact,
four compounds which were 2-10-fold more potent
hypoglycemics than 26 in the chronic ob/ ob mouse
model (32, 33, 43, 59) were not found to be superior to
26 in the chronic (48 h) glucose transport screen in 3T3-
L1 adipocytes. This indicated a poor direct mechanistic
relationship between the chronic increase of glucose
transport in vitro and blood glucose lowering in vivo in
this series.
Interestingly, examination of 26 also showed that it
had an even more potent effect on glucose transport
activity in adipocytes after chronic exposure compared
to acute exposure. Therefore, analogs of 26 were tested
at three doses (30, 10, and 3 µM) for effects on 2-deoxy-
glucose uptake after 48 h exposure; results of note are
shown in Table 7. Compared to 26, which at 30 µM
stimulated glucose transport activity in the 3T3-L1
adipocytes to 291% over basal levels, none of the related
analogs displayed significantly greater efficacy (range

4792 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Sarges et al.
Ta ble 4
glucose-lowering
ob/ob mouseb dose
(mg/kg): %
glucose lowering
relative to
2DG uptake
stima [drug]
(µM): %
c
no.
X
Y
R′
formula
method
Ed
mp (°C) basal uptake
positive control
ED50
81
H
Et
ONa
OH
C20H22ClNaO3
250 dec
110-2
>200
100: 156*
60: 111
60: 98
5: 36
>5
82 Me
(diast A)
83 Me
(diast B)
84 Me
(diast A; RS/SR by X-ray)
H
H
C
C
C
19H21ClO3
Ed
Ed
Ed
10: 17
10: 41
>10
>10
ONa
19H20ClNaO3
20H23ClO3
Me OH
160 dec
60: 214**
30: 128
10: 131
3: 102
10: 142***
5: 77*
2.5: 62**
1: <0
∼2.5
1: 99
0.3: 98
60: 209**
30: 131
10: 128
30: 95
10: 91
3: 97
30: 109
10: 96
3: 98
30: 113
10: 248***
3: 94
30: 162*
10: 113
3: 130
85 Me
(diast B; RR/SS)
Me OH
Me OH
Me OH
C
C
C
20H23ClO3
21H25ClO3
21H25ClO3
Ed
Ed
Ed
F
121-3
10: 46
10: 71*
10: 32
10: 7
>10
86 Et
(diast A; RS/SR?)
169-71
98-101
sublimes
120-2
<10
>10
>10
>10
87 Et
(diast B; RR/SS?)
88 Me
(RS/SR)
Me NHSO2CF3 C21H23ClF3NO4S
89 Me
(RS/SR)
Me
C27H30ClNO5S
F
10: 16
a
2-Deoxyglucose (DG) uptake values are presented as means of triplicate measurements and represent the percent basal uptake obtained
b
in vehicle-treated 3T3-L1 adipocytes. Significant differences from vehicle-treated cells: *p < 0.05, **p < 0.01, ***p < 0.001. Values
presented are the percent glucose normalization compared to the effect of racemic englitazone (CP-68,722) at 50 mg/kg (i.e., 100%
normalization). Significant differences of drug-treated vs vehicle-treated mice: *p < 0.05, **p < 0.01, ***p < 0.001 (two-tailed unpaired
t-test). c ED50 approximate dose of compound that induces 50% normalization of glucose relative to the positive control (racemic englitazone).
d
See the Experimental Section.
In order to better understand the intrinsic activity to
enhance glucose transport, we examined compound 26
for the ability to increase glucose transporter expression
in 3T3-L1 adipocytes after 48 h incubation. Quantita-
tive immunoblot analysis indicated that GLUT1 expres-
sion was increased to 4.3- and 5.9-fold basal levels at
10 and 30 µM 26 (p < 0.01), respectively. On the other
hand, GLUT4 expression was essentially unchanged by
these concentrations (data not shown). The increased
GLUT1 expression correlated with increased glucose
transport activity (Table 7) and is likely to be the
mechanism by which compound 26 stimulates glucose
transport in vitro after chronic treatment.
On the other hand, in vivo experiments with com-
pound 26 did not support an enhancement of glucose
transporter protein expression in skeletal muscle or
adipose tissue as being involved in its hypoglycemic
activity. The amount of immunoreactive GLUT1 and
GLUT4 in ob/ ob skeletal muscle did not differ between
the vehicle-treated and 5 day 26-treated groups at 50
mg/kg. Similarly, GLUT1 and GLUT4 levels were not
elevated in adipocytes of ob/ ob mice treated with 26
(Treadway et al., manuscript in preparation). Thus, a
mechanistic relationship between chronic upregulation
of skeletal muscle or adipocyte GLUT1 and GLUT4
protein content and blood glucose-lowering activity by
26 was not observed. Further evidence for the dissocia-
tion of antidiabetic effects from tissue GLUT protein
levels has been obtained from chronic 14 day adminis-
tration of 26 to normal rats, where a markedly increased
glucose transport rate was observed despite unchanged
GLUT1 or GLUT4 protein levels in adipose tissues and
skeletal muscle (Treadway et al., manuscript in prepa-
ration). It is possible that 26 increases glucose trans-
port activity in vivo through mechanisms similar to
those described for stimuli such as hypoxia, inhibition
of mitochondrial oxidative phosphorylation, and alkaline
pH, which regulate glucose transport activity in muscle,
liver, and adipose tissue and cells independent of
changes in transport protein expression or trans-
location.12
Because increased glucose uptake into adipose tissue
may not fully explain the glucose-lowering activity, we
examined additional mechanisms that might also con-
tribute to the compounds’ hypoglycemic action. One
potential mechanism that could explain the in vivo
hypoglycemic activity would be reduced glucose output
by the liver. Consequently, we tested four compounds

Phenoxyphenylpropanoic Acids as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4793
Ta ble 5
-
b
ob ob
a
:
c
(
)
f
90
91
92
93
94
d
d
d
95
e
96
a
2-Deoxyglucose (DG) uptake values are presented as means of triplicate measurements and represent the percent basal uptake obtained
in vehicle-treated 3T3-L1 adipocytes unless printed in italics, in which case the data were obtained in L6 myocytes. Significant differences
b
from vehicle-treated cells are indicated: *p < 0.05, **p < 0.01, ***p < 0.001. Values presented are the percent glucose normalization
compared to the effect of racemic englitazone (CP-68,722) at 50 mg/kg (i.e., 100% normalization). Significant differences from vehicle-
treated mice: *p < 0.05, **p < 0.01, ***p < 0.001 (two-tailed unpaired t-test). c ED50 ) approximate dose of compound that induces 50%
d
normalization of glucose relative to the positive control (racemic englitazone). See the Experimental Section. e This compound was
characterized by NMR and MS only.
from this series, 1, 5, 7, and 26, for antigluconeogenic
activity in isolated rat hepatocytes in vitro. A summary
of the results is presented in Table 8. The results
indicated that 1, 5, and 26 significantly inhibited the
basal rate of gluconeogenesis in isolated rat hepatocytes.
Compounds 1, 7, and 26 also marginally inhibited
glucagon-stimulated hepatocyte gluconeogenesis. These
results suggest that the in vivo blood glucose-lowering
activity of these compounds could, in part, be explained
by their ability to suppress hepatic glucose production
via an inhibition of gluconeogenesis in vivo. Whether
this suppression of gluconeogenesis observed in vitro
contributes significantly to blood glucose lowering ob-
served in ob/ ob mice is unclear. However, preliminary
experiments in fasted normoglycemic rats indicate that
basal hepatic glucose production (determined by
[3-3H]glucose infusion17) is not decreased by acute or
chronic treatment with compound 26 (data not shown).
In the chronic ob/ ob mouse experiments, most of the
compounds that produced hypoglycemia also decreased
food intake by 15-50%. To examine whether the
hypoglycemic activity of these compounds was attribut-
able to decreased food intake, a pair-feeding study was
performed in ob/ ob mice with compound 26 dosed at 5
mg/kg for 5 days. Relative to mice dosed with vehicle,
compound 26 decreased food intake by 26%. Three
groups of five mice, dosed with vehicle, were pair-fed to
the same level as mice dosed with compound 26. As
shown in Table 9, food restriction alone had no effect
on the plasma glucose concentration relative to the
vehicle group fed ad libitum. However, compound 26
lowered plasma glucose by 43% relative to the pair-fed
group. These results suggest that the glucose-lowering
activity of compound 26 is independent of its effects on
food intake.
Con clu sion
This series contains many potent hypoglycemic agents,
with some compounds (32, 33, 59) able to normalize
plasma glucose in ob/ ob mice at doses of approximately
1 mg/kg. The mechanism of action of these drugs is not
entirely clear, but many compounds enhance glucose
transport in vitro, especially in fat cells, and this action
likely contributes to in vivo glucose lowering. The
glucose transport effect does not seem to involve GLUT4
translocation, nor does it involve increased levels of
GLUT1 or GLUT4 in vivo, but may be related to
enhanced efficiency and/or intrinsic activity of glucose
transporters. Further experiments are needed to con-
firm this mechanism. Some compounds also modestly
decrease hepatocyte gluconeogenesis in vitro, but this
is unlikely to contribute significantly to the hypogly-
cemic effect observed since gluconeogenesis inhibition
was not observed in fasted rats treated with 26. The

4794 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Sarges et al.
Ta ble 6
-
b
ob ob
a
c
(
)
d
97
98
d
d
99
d
100
RR
SR
SS
d
101
RS
a
2-Deoxyglucose (DG) uptake values are presented as means of triplicate measurements and represent the percent basal uptake obtained
in vehicle-treated 3T3-L1 adipocytes unless printed in italics, in which case the data were obtained in L6 myocytes. Significant differences
b
from vehicle-treated cells: *p < 0.05, **p < 0.01, ***p < 0.001. Values presented are the percent glucose normalization compared to the
effect of racemic englitazone (CP-68,722) at 50 mg/kg (i.e., 100% normalization). Significant differences of drug-treated vs vehicle-treated
mice are indicated: *p < 0.05. **p < 0.01; ***p < 0.001, (two-tailed unpaired t-test). c ED50 ) approximate dose of compound that induces
d
50% normalization of glucose relative to the positive control (racemic englitazone). See the Experimental Section.
F igu r e 1. Overlap of 26 (blue), 84 (magenta), 99 (green), 100 (gray), and 101 (orange). The isopropyl and chloro substituents
have been omitted. The stereodiagram was generated via the Sybyl33 program.
spectra were obtained with a Hewlett Packard 5890 series II
gas chromatograph with a 5971 mass selective detector or a
Hewlett Packard 59980B particle beam LC/MS interface with
a Hewlett Packard 5989A mass spectrometer. 1H-NMR spec-
tra were obtained on a Varian XL300 or a Bruker AC300
spectrometer with tetramethylsilane as internal standard.
Microanalyses were performed by Schwarzkopf Microanalyti-
cal Laboratory Inc. and agreed within 0.4% of calculated values
unless otherwise noted in the tables.
modest decrease in food consumption observed with
some of these compounds is not the cause of the
hypoglycemia as shown by the pair-feeding experiment
with 26. Compounds 26, 33, and 59 have been selected
for further evaluation and profiling after chronic ad-
ministration in the ob/ ob mouse.
Exp er im en ta l Section
Ch em istr y. Melting points were determined with a Thomas-
Gen er a l Meth od A. P r ep a r a tion of 2-(4-Isop r op ylp h e-
Hoover melting point apparatus and are uncorrected. Mass
n oxy)-3-p h en ylp r op a n oic Acid (1). To a suspension of 7.35

Phenoxyphenylpropanoic Acids as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4795
Ta ble 7a
night and then evaporated. The residue was treated with H2O
and extracted with Et2O. The organic layer was dried with
Na2SO4 and evaporated and the residue distilled to give 27.97
g (73%) of methyl 2-(4-isopropylphenoxy)acetate: bp 160-8
°C/ 0.2 mmHg; MS (EI) m/e 208 (M); NMR (CDCl3) δ 1.2 (d,
6H, Me), 2.85 (m, 1H, CH), 3.8 (s, 3H, OMe), 4.6 (s, 2H, CH2),
6.85 (d, 2H, H-2), 7.15 (d, 2H, H-3).
A flame-dried 3-neck round-bottom flask was charged with
5 mL of THF and 4.81 mL of 1 M lithium bis(trimethylsilyl)-
amide in THF (Aldrich) and cooled to -78 °C. To this mixture
was added dropwise a solution of 1.0 g (4.81 mmol) of methyl
2-(4-isopropylphenoxy)acetate in 10 mL of THF. After being
stirred at -78 °C for 1 h, the mixture was treated dropwise
with 0.57 mL (0.82 g, 4.8 mmol) of benzyl bromide at -78 °C
and then allowed to come to room temperature overnight. The
reaction mixture was treated with 1 equiv of AcOH and
evaporated. The residue was dissolved in EtOAc, washed with
1 N HCl and H2O, dried over Na2SO4, and chromatographed
on silica gel with hexane/EtOAc (10:1) to give 0.45 g (31%) of
methyl 2-(4-isopropylphenoxy)-3-phenylpropionate: MS (EI)
m/e 298 (M).
This material was dissolved in 6 mL of dioxane, treated with
70 mg (1.1 equiv) of LiOH‚H2O in 3 mL of H2O, and stirred at
room temperature for 2 h. After evaporation, the residue was
treated with H2O, acidified, extracted with EtOAc, and dried
over Na2SO4 to give 360 mg (84%) of 2-(4-isopropylphenoxy)-
3-phenylpropanoic acid which crystallized from hexane: MS
(FAB) m/e 285 (M + 1); NMR (DMSO-d6) δ 1.15 (d, 6H, Me),
2.75 (m, 1H, CH) 3.15 (dd, 2H, CH2), 4.45 (dd, 1H, H-R), 6.7
(d, 2H, H-2), 7.0 (d, 2H, H-3), 7.15 (m, 1H), 7.25 (t, 2H), 7.3
(m, 2H, aromatic H′).
Gen er a l Meth od B. P r ep a r a tion of 2-(4-Isop r op ylp h e-
n oxy)-3-[2-(tr iflu or om eth yl)p h en yl]p r op a n oic Acid (2).
To a suspension of 7.35 g (0.184 mol) of 60% NaH in 100 mL
of THF was added dropwise at 0 °C 25 g (0.184 mol) of
4-isopropylphenol in 50 mL of THF. After 1 h at 0 °C, 15.85
mL of ethyl chloroacetate was added dropwise, and the mixture
was allowed to come to room temperature and worked up as
described above in general method A to give after distillation
20.65 g (51%) of ethyl 2-(4-isopropylphenoxy)acetate: bp 123-
52 °C/0.2 mmHg; MS (EI) m/e 222 (M); NMR (CDCl3) δ 1.2 (d,
6H, Me), 1.3 (t, 3H, Me), 2.85 (m, 1H, CH), 4.25 (q, 2H, CH2),
4.6 (s, 2H, CH2), 6.8 (d, 2H, H-2), 7.15 (d, 2H, H-3).
A 10 g (45 mmol) sample of this material was dissolved in
20 mL of THF and treated with 1.8 g (45 mmol) of NaOH in
20 mL of H2O. After stirring at room temperature overnight,
the mixture was evaporated, the residue was taken into H2O,
acidified with 1 N HCl, and extracted with EtOAc to give after
recrystallization from EtOAc/hexane 5.89 g (67%) of 2-(4-
isopropylphenoxy)acetic acid: mp 84.5-6 °C; MS (FAB) m/e
194 (M).
A 3 g (15.5 mmol) sample of this material was treated with
288 mg (5 mmol) of boric acid and 1.65 g (18.5 mmol) of
2-amino-2-methylpropanol according to the procedure of Bar-
ton et al.18 by refluxing in xylene overnight to give 3.15 g (82%)
of 4,5-dihydro-4,4-dimethyl-2-(4-isopropylphenoxymethyl)-
oxazole as an oil: MS (FAB) m/e 248 (M + H); NMR (DMSO-
d6) δ 1.2 (d, 6H, Me), 1.3 (s, 6H, Me), 2.85 (m, 1H, CH), 4.05
(s, 2H, CH2), 4.65 (s, 2H, CH2), 6.9 (d, 2H, H-2), 7.15 (d, 2H,
H-3).
A 1 g (4.05 mmol) sample of this material in 20 mL of THF
was treated at -78 °C with 1.78 mL (1.1 equiv) of 2.5 M BuLi
and then after 1 h at -78 °C dropwise with 0.68 mL (1.06 g,
1.1 equiv) of 2-(trifluoromethyl)benzyl bromide. After 2 h at
-78 °C the reaction mixture was worked up and chromato-
graphed on silica gel with EtOAc/hexane (1:2) to give 863 mg
(53%) of 4,5-dihydro-4,4-dimethyl-2-[2-(4-isopropylphenoxy)-
3-[2-(trifluoromethyl)phenyl]ethyl]oxazole as an oil: MS (FAB)
m/e 406 (M + H); NMR (CDCl3) δ 1.15 (d, 6H, Me), 1.25 (s,
6H, Me), 2.8 (m, 1H, CH), 3.4-3.5 (m, 2H, CH2), 4.05 (q, 2H,
CH2), 5.0 (q, 1H, CH-R), 6.75 (d, 2H, H-2), 7.1 (d, 2H, H-3),
7.45-7.6 (m, 4H, aromatic H′).
[
14C]-2-deoxy-D-glucose uptake
no. (n ) no. of
experiments)
conctn
(µM)
p
dpm/10 min
% basal value
basal
6 607 ( 285
100
(n ) 3)
insulin
(n ) 3)
1
62 505 ( 2 790
946
***
***
insulin + CP-68,722 1 and 30 69 762 ( 4 530
(n ) 3)
26
1056
30
10
3
30
10
3
30
10
3
30
10
3
30
10
3
30
10
3
19 227 ( 2 422
13 261 ( 1 701
9 169 ( 1 717
16 239 ( 551
12 797 ( 416
8 642 ( 934
14 285 ( 1 183
7 166 ( 734
6 238 ( 618
15 392 ( 902
6 598 ( 37
6 800 ( 760
12 810 ( 2 643
7 765 ( 787
7 202 ( 440
17 538 ( 1 954
11 824 ( 749
8 455 ( 471
291
200
139
246
194
131
216
108
94
233
100
103
193
118
109
265
179
128
***
***
NS
***
***
*
***
NS
NS
***
NS
NS
*
(n ) 3)
32
(n ) 1)
33
(n ) 1)
35
(n ) 2)
43
(n ) 2)
NS
NS
***
***
**
59
(n ) 2)
a
Values are the mean ( SEM and percent of basal (unstimu-
lated) rate of glucose transport observed. Data are from n ) 1-3
independent experiments, each performed in triplicate; statistical
analysis was performed by t-test for experimentals versus the
basal control; significant differences: *p e0.05, **p e0.01, and
***p e0.001.
Ta ble 8. Effects of 100 µM 1, 5, 7, 26, and Racemic
Englitazone (CP-68,722) on the Rates of Basal and
Glucagon-Stimulated Gluconeogenesis in Isolated Rat
Hepatocytes in Vitroa
no.
% basal inhibition
% GGN inhibition
1
5
7
26
41**
38*
32
36*
45**
25
3
20
22
59**
CP-68,722b
a
Values are the mean percent inhibition of triplicate determi-
nations compared to the basal (unstimulated) rate of gluconeo-
genesis in the absence (basal) or presence (GGN) of glucagon.
Statistical analysis was performed by t-test for drug-treated vs
basal (untreated) control in the absence and presence of glucagon.
b
Significant differences: *p < 0.05, **p < 0.01. CP-68,722 served
as a positive control for antigluconeogenic effects as reported in
ref 15.
Ta ble 9. Summary of Data from Pair-Feeding Study with
Compound 26 in ob/ob Micea
5 day
basal
glucose
(mg/dL)
day 5
glucose
(mg/dL)
food intake
(g/5 mice/
5 days)
net body
wt ∆ (g)
group
vehicle
vehicle-food 342 ( 7
restricted
26 (5 mg/kg/ 341 ( 8
day)
330 ( 16 368 ( 23
1.8 ( 0.14
178 ( 8
390 ( 34
0.12 ( 0.37* 137 ( 0.2*
223 ( 8*,** 0.40 ( 0.15* 132 ( 2*
a
Values are mean ( SEM (n ) 15, except for food intake where
n ) 3 groups of 5 mice). *Significantly different from vehicle.
**Significantly different from vehicle-food intake restricted (p <
0.05 by ANOVA with PLSD follow up).
g (0.184 mol) of 60% NaH in 150 mL of THF was added
dropwise at 0 °C a solution of 25 g (0.184 mol) of 4-isopropyl-
phenol in 200 mL of THF. The mixture was stirred at room
temperature for 30 min, cooled to 0 °C, and treated dropwise
with 18.03 mL (28.12 g, 0.184 mol) of methyl 2-bromoacetate.
The reaction mixture was stirred at room temperature over-
A 605 mg (1.6 mmol) sample of this material, dissolved in
15 mL of THF, was treated with 15 mL of 4.5 N aqueous HCl
and kept at reflux overnight. After workup and chromatog-
raphy on silica gel with EtOAc/hexane (1:1) containing 1%

4796 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Sarges et al.
AcOH, 259 mg (46%) of 2-(4-isopropylphenoxy)-3-[2-(trifluoro-
methyl)phenyl]propanoic acid was obtained as a colorless oil
which did not crystallize: MS (FAB) m/e 353 (M + H); NMR
(CDCl3) δ 1.15 (d, 6H, Me), 2.8 (m, 1H, CH), 3.2-3.6 (m, 2H,
CH2), 4.7 (q, 1H, CH), 6.85 (d, 2H, H-2), 7.05 (d, 2H, H-3),
7.35-7.65 (m, 4H, aromatic H′). This material was converted
by treatment with dicyclohexylamine in Et2O to the dicyclo-
hexylammonium salt: MS (FAB) m/e 534 (M + H).
Gen er a l Meth od C. P r ep a r a tion of 2-(4-Isop r op ylp h e-
n oxy)-3-[3-(tr iflu or om eth yl)p h en yl]p r op a n oic Acid (3).
A suspension of 1.47 g (37 mmol) of 60% NaH in 10 mL of
THF was cooled to 0 °C and treated dropwise with 5 g (37
mmol) of 4-isopropylphenol in 20 mL of THF. After warming
to room temperature and stirring for 30 min, 5.94 mL (7.15 g,
37 mmol) of diethyl chloromalonate was added dropwise over
30 min. The mixture was stirred for 2 h, poured into water,
and extracted with Et2O to give 9.51 g (88%) of diethyl 2-(4-
isopropylphenoxy)malonate as a colorless oil: MS (FAB) m/e
294 (M + H); NMR (CDCl3) δ 1.15 (d, 6H, Me), 1.25 (m, 6H,
Me), 2.8 (m, 1H, CH), 4.3 (m, 4H, CH2), 5.15 (s, 1H, H-R), 6.8
(d, 2H, H-2), 7.15 (d, 2H, H-3).
A 2 g (6.8 mmol) sample of this material in 10 mL of THF
was added dropwise at 0 °C to a suspension of 0.27 g (6.8
mmol) of 60% NaH in 10 mL of THF. After the gas evolution
ceased, 1.32 g (6.8 mmol) of 3-(trifluoromethyl)benzyl chloride
was added dropwise at 0 °C. After standing overnight at room
temperature, the reaction mixture was worked up and chro-
matographed on silica gel with hexane/EtOAc (10:1) to give
1.04 g (34%) of diethyl 2-(4-isopropylphenoxy)-2-[3-(trifluoro-
methyl)benzyl]malonate as an oil: MS (EI) m/e 452 (M); NMR
(CDCl3) δ 1.1-1.3 (m, 12H, Me), 2.85 (m, 1H, CH), 3.7 (s, 2H,
CH2), 4.15 (m, 4H, CH2), 6.9 (d, 2H, H-2), 7.15 (d, 2H, H-3),
7.3-7.6 (m, 4H, aromatic H′).
A 390 mg (0.86 mmol) sample of this material was dissolved
in 3 mL of dioxane, treated with 70 mg (1.75 mmol) of NaOH
in 1 mL of H2O, and stirred at room temperature overnight.
After evaporation, addition of water, acidification with 1 N
HCl, and extraction with EtOAc, 220 mg of a mixture of mono-
and diacids was obtained, which was fully decarboxylated by
heating for 10 min at 110 °C to give 2-(4-isopropylphenoxy)-
3-[3-(trifluoromethyl)phenyl]propanoic acid as an oil: NMR
(CDCl3) δ 1.2 (d, 6H, Me), 2.85 (m, 1H, CH), 3.3 (q, 2H, CH2),
4.85 (t, 1H, H-R), 6.8 (d, 2H, H-2), 7.15 (d, 2H, H-3), 7.4-7.55
(m, 4H, aromatic H′), 11.2 (bs, 1H, COOH); 19F-NMR (CDCl3)
s at 63 ppm. Treatment with dicyclohexylamine in Et2O gave
95 mg (20%) of the dicyclohexylammonium salt: MS (FAB)
m/e 534 (M + H).
Gen er a l Meth od D. P r ep a r a tion of 3-(3-Ch lor op h en -
yl)-2-(4-isop r op ylp h en oxy)p r op a n oic Acid (6). A solution
of 1 g (5.15 mmol) of (4-isopropylphenoxy)acetic acid (see
general method B) in 10 mL of THF was cooled to -78 °C and
treated dropwise with 6.87 mL (2 equiv) of 1.5 M LDA in THF.
After stirring at -78 °C for 1h, 0.68 mL (1.06 g, 5.15 mmol) of
3-chlorobenzyl chloride was added dropwise. The reaction
mixture was allowed to warm to room temperature overnight,
poured into water, acidified with 1 N HCl, and evaporated to
dryness. The residue was extracted with EtOAc and chro-
matographed on silica gel with hexane/EtOAc (1:1) containing
1% AcOH to give 3-(3-chlorophenyl)-2-(4-isopropylphenoxy)-
propanoic acid: NMR (CDCl3) δ 1.2 (d, 6H, Me), 2.85 (m, 1H,
CH), 3.2 (d, 2H, CH2), 4.8 (t, 1H, H-R), 6.8 (d, 2H, H-2), 7.1 (d,
2H, H-3), 7.2-7.4 (m, 4H, aromatic H′). Conversion to the
dicyclohexylammonium salt gave 450 mg (17%): MS (FAB)
m/e 500 (M + H).
Gen er a l Meth od E. P r ep a r a tion of 3-(4-Ch lor op h en -
yl)-2-(4-isop r op ylp h en oxy)-2-m eth ylp r op a n oic Acid (26).
A mixture of 65.26 g (0.479 mol) of 4-isopropylphenol and 72.79
g (0.527 mol) of K2CO3 in 100 mL of anhydrous DMF was
treated dropwise under mechanical stirring with 62.23 mL of
ethyl 2-bromopropionate at room temperature. The reaction
mixture was then heated to 70 °C and kept at that tempera-
ture under stirring overnight. After cooling, the mixture was
poured into 600 mL of water, the pH was adjusted to 6 with 2
N HCl, and the product was extracted with 2 × 250 mL of
EtOAc. The organic extracts were washed with 5 N NaOH to
remove excess phenol and with water, dried over MgSO4, and
filtered and the filtrate evaporated. The oily residue was
distilled in a Kugelrohr apparatus at 0.5 mmHg to give 91.25
g (80%) of ethyl 2-(4-isopropylphenoxy)propionate: bp 90-115
°C; MS (EI) m/e 236 (M); NMR (CDCl3) δ 1.2 (d, 6H, Me), 1.24
(t, 3H, Me), 1.38 (d, 3H, R-Me), 2.85 (m, 1H, CH), 4.2 (q, 2H,
CH2), 4.7 (q, 1H, H-R), 6.8 (d, 2H, H-2), 7.1 (d, 2H, H-3).
A 4-neck 2 L round-bottom flask equipped with addition
funnels, a mechanical stirrer, an internal thermometer, and
a nitrogen inlet was flame-dried under nitrogen, allowed to
cool to room temperature, and charged with 1 L of dry THF
and 55.31 mL (47.51 g, 0.336 mol) of N-isopropylcyclohexyl-
amine. The mixture was cooled to -78 °C and treated
dropwise with 134.5 mL (0.336 mol) of 2.5 M n-butyllithium
in hexane at such a rate that the internal temperature did
not rise above -65 °C (this required about 40 min). After
removal of the cooling bath the mixture was stirred for 1 h,
allowed to come to room temperature, and then cooled again
to -78 °C and treated dropwise over 30 min with a solution of
72.25 g (0.3057 mol) of ethyl 2-(4-isopropylphenoxy)propionate
in 25 mL of THF, keeping the internal temperature below -70
°C. The reaction mixture was stirred at -78 °C for 20 min
and then treated dropwise with a solution of 125.66 g (0.611
mol) of 4-chlorobenzyl bromide in 80 mL of THF, keeping the
internal temperature below -70 °C. The reaction mixture was
stirred overnight and allowed to come to room temperature,
and the solvent was removed by evaporation in vacuo. The
residue was treated with water, the pH was adjusted to 5-6
with 2 N HCl, and the mixture was extracted with EtOAc.
The aqueous layer was saturated with NaCl and again
extracted with EtOAc. The combined organic extracts were
washed with water, dried over MgSO4, and evaporated in
vacuo to give 159.8 g of an oil which contained 54% of the
desired ethyl 3-(4-chlorophenyl)-2-(4-isopropylphenoxy)-2-
methylpropionate by GC/MS: MS (EI) m/e 360 (M); NMR of
pure product (CDCl3) δ 1.2 (m, 9H, Me), 1.4 (s, 3H, R-Me), 2.85
(m, 1H, CH), 3.1 and 3.3 (ABq, 2H, CH2), 4.2 (q, 2H, CH2),
6.75 (d, 2H, H-2), 7.1 (d, 2H, H-3), 7.25 (ABq, 4H, aromatic
H′).
To a solution of 149.25 g (0.2233 mol) of this crude ester in
950 mL of EtOH was added 179 mL of 5 N NaOH, and the
mixture was warmed to 60 °C for 4h. After cooling to room
temperature, the EtOH was removed in vacuo, and the residue
was partitioned between water and Et2O. The aqueous phase
was acidified with 6 N HCl to pH 1 and extracted twice with
CHCl3. The CHCl3 extracts were dried over MgSO4 and
evaporated to give 18.7 g of a crystalline solid which was
mostly the desired product by NMR. The Et2O phase was
shaken with 6 N HCl, dried over MgSO4, and evaporated to
112 g of a solid which contained about 50% of desired product
by NMR. Both solids were triturated with hexane to give a
total of 68.96 g (92%) of clean (NMR) product. A recrystalli-
zation from cyclohexane gave 55.7 g (75%) of 3-(4-chlorophen-
yl)-2-(4-isopropylphenoxy)-2-methylpropionic acid: MS (CI)
m/e 350 (M + NH4); NMR (CDCl3) δ 1.2 (d, 6H, Me), 1.4 (s,
3H, R-Me), 2.85 (m, 1H, CH), 3.1 and 3.3 (ABq, 2H, CH2), 6.8
(d, 2H, H-2), 7.2 (d, 2H, H-3), 7.25 (ABq, 4H, aromatic H′).
Gen er a l Meth od F . P r ep a r a tion of Su lfon im id es:
N-[3-(4-Ch lor op h en yl)-2-(4-isop r op ylp h en oxy)-2-m eth yl-
p r op a n oyl]-2-m eth ylben zen esu lfon a m id e (68). To a solu-
tion of 530 mg (1.59 mmol) of 26 in 30 mL of CH2Cl2 were
added at 0 °C 291 mg (1.5 equiv) of 4-(dimethylamino)pyridine,
458 mg (1.5 equiv) of 1-[3-(dimethylamino)propyl]-3-ethyl-
carbodiimide hydrochloride, and 273 mg (1 equiv) of 2-meth-
ylbenzenesulfonamide. After stirring for 15 min at 0 °C, the
reaction mixture was allowed to stir at room temperature
overnight, diluted with CH2Cl2, washed with aqueous citric
acid and brine, dried, and evaporated. The residue was
chromatographed on silica gel with EtOAc/hexane (35:65) to
give 551 mg (71%) of N-[3-(4-chlorophenyl)-2-(4-isopropylphe-
noxy)-2-methylpropanoyl]-2-methylbenzenesulfonamide. After
crystallization form hexane was obtained 346 mg (45%): MS
(CI) m/e 504 (M + NH4); NMR (CDCl3) δ 1.2 (d, 6H, Me), 1.36
(s, 3H, R-Me), 2.26 (s, 3H, 2′′-Me), 2.88 (m, 1H, CH), 3.03 (ABq,
2H, CH2), 6.8 (d, 2H, H-2), 7.1 (d, 2H, H-3), 6.94 and 7.06 (ABq,
4H, aromatic H′), 7.28 (d, 1H, H-3′′), 7.39 (t, 1H, H-5′′), 7.56
(t, 1H, H-4′′), 8.14 (d, 1H, H-6′′), 9.0 (bs, 1H, NH).

Phenoxyphenylpropanoic Acids as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4797
Gen er a l Met h od G. P r ep a r a t ion of N-[3-(4-Ch lor o-
p h en yl)-2-(4-isop r op ylp h en oxy)-2-m eth ylp r op yl]tr iflu o-
r om eth a n esu lfon a m id e (71). A 10.17 g (75 mmol) sample
of 4-isopropylphenol was converted with 10 g (75 mmol) of
2-bromopropionitrile and 11.35 g of K2CO3 in 25 mL of DMF,
in analogy to the procedure described in General Method E,
to 10.25 g (73%) of 2-(4-isopropylphenoxy)propionitrile: MS
(EI) m/e 189 (M); NMR (CDCl3) δ 1.2 (d, 6H, Me), 1.7 (d, 3H,
R-Me), 2.84 (m, 1H, CH), 4.84 (q, 1H, CH), 6.9 (d, 2H, H-2),
7.16 (d, 2H, H-3).
A 4.31 g (22.8 mmol) sample of this material was treated
with 1.1 equiv of LICA and 1.1 equiv of 4-chlorobenzyl bromide
according to the procedure described in General Method E to
give 4.78 g (67%) of 3-(4-chlorophenyl)-2-(4-isopropylphe-
noxy)-2-methylpropionitrile: MS (EI) m/e 313 (M); NMR
(CDCl3) δ 1.2 (d, 6H, Me), 1.5 (s, 3H, R-Me), 2.88 (m, 1H, CH),
3.2 (ABq, 2H, CH2), 7.0 (d, 2H, H-2), 7.14 (d, 2H, H-3), 7.2
(ABq, 4H, aromatic H′).
A solution of 4.78 g (15 mmol) of this material in 25 mL of
THF was cooled to 0 °C, treated dropwise with 61 mL (4 equiv)
of 1 M BH3 in THF, and then allowed to come to room
temperature and stirred overnight. Another 25 mL of BH3 in
THF was then added, and the mixture was refluxed for 4h
and then cooled to 0 °C, and treated with 6 N HCl. The solvent
was stripped, the residue treated with water and made
alkaline with 2 N NaOH. The product was extracted with
EtOAc and chromatographed on silica gel to give 2.58 g (53%)
of 3-(4-chlorophenyl)-2-(4-isopropylphenoxy)-2-methylpropan-
amine: MS (CI) m/e 318 (M + H); NMR (CDCl3) δ 1.25 (d, 6H,
Me), 1.1 (s, 3H, R-Me), 1.55 (bs, 2H, NH2), 2.65 (ABq, 2H, CH2),
2.8 (m, 1H, CH), 2.95 (ABq, 2H, CH2), 6.8 (d, 2H, H-2), 7.0 (d,
2H, H-3), 7.24 (ABq, 4H, aromatic H′).
A 301 mg (0.95 mmol) sample of this material was dissolved
in 10 mL of CH2Cl2, cooled to -78 °C, and treated with 0.16
mL (116 mg, 1.2 equiv) of triethylamine and 0.175 mL (294
mg, 1.1 equiv) of trifluoromethanesulfonic anhydride. The
mixture was allowed to stir at -78 °C for 45 min, poured over
ice, and worked up to give 350 mg (82%) of N-[3-(4-chloro-
phenyl)-2-(4-isopropylphenoxy)-2-methylpropyl]trifluoro-
methanesulfonamide: MS (CI) m/e 467 (M + NH4); NMR
(CDCl3) δ 1.2 (d, 6H, Me), 1.1 (s, 3H, R-Me), 2.9 (m, 1H, CH),
2.92-3.04 (ABq, 2H, CH2), 3.3-3.44 (ABq, 2H, benzylic CH2),
5.4 (bs, 1H, NH), 6.8 (d, 2H, H-2), 7.1 (d, 2H, H-3), 7.2 (ABq,
4H, aromatic H′). This material was converted with NaOH
in EtOH to the crystalline sodium salt.
2-(4-Ch lor op h en yl)-2-(4-isop r op ylp h en oxy)a cetic Acid
(19). A 5 g sample of dl-4-chloromandelic acid was converted
to 2-bromo-2-(4-chlorophenyl)acetic acid according to the
method of Gotthardt et al.19 to give 4.03 g (60%): MS (EI) m/e
249 (M); NMR (CDCl3) δ 5.3 (s, 1H), 7.4 (d, 2H), 7.5 (d, 2H).
A 3 g (12 mmol) sample of this material was esterified with
MeOH/HBr to give 3.04 g (86%) of crude methyl 2-bromo-2-
(4-chlorophenyl)acetate. A 1 g (3.8 mmol) sample of this
material was treated with 0.52 g (3.8 mmol) of 4-isopropyl-
phenol and 0.17 g (3.8 mmol) of 60% NaH as described in
General Method A to give 1.04 g (86%) of methyl 2-(4-chloro-
phenyl)-2-(4-isopropylphenoxy)acetate: MS (EI) m/e 318 (M).
This material was saponified with 165 mg (1.2 equiv) of
LiOH‚H2O in 8 mL of THF and 8 mL of H2O at room
temperature overnight to give after recrystallization from
EtOAc/hexane 230 mg (23%) of 2-(4-chlorophenyl)-2-(4-isopro-
pylphenoxy)acetic acid: MS (FAB) m/e 304 (M + H); NMR
(CDCl3) δ 1.2-1.3 (m, 6H, Me), 2.85 (m, 1H, CH), 5.6 (s, 1H,
CH), 6.85 (d, 2H, H-2), 7.15 (d, 2H, H-3), 7.35 (d, 2H) and 7.5
(d, 2H) (aromatic H′).
4-(4-Ch lor op h en yl)-2-(4-isop r op ylp h en oxy)b u t a n oic
Acid (20). A 410 mg (1.34 mmol) sample of 2-bromo-4-(4-
chlorophenyl)butyrate, obtained by the method of Dice and
Bowden20 by alkylation of diethyl malonate with 2-(4-chlo-
rophenyl)ethyl chloride in the presence of NaOEt in EtOH
followed by monosaponification with KOH to the potassium
salt followed by treatment with Br2 in CCl4, was converted
with 53 mg of 60% NaH and 182 mg of 4-isopropylphenol as
described in General Method A to 200 mg (41%) of ethyl
4-(4-chlorophenyl)-2-(4-isopropylphenoxy)butyrate: MS (EI)
m/e 360 (M); NMR (CDCl3) δ 1.2-1.3 (m, 9H, Me), 2.1-2.4
(m, 2H, CH2), 2.6-2.9 (m, 3H, CH, benzylic CH2), 4.15 (q, 2H,
O-CH2), 4.5 (dd, 1H, (R-H), 6.8 (d, 2H, H-2), 7.15 (m, 4H,
aromatic H′), 7.2 (d, 2H, H-3).
This material was saponified with 28 mg of LiOH‚H2O in 5
mL of dioxane and 5 mL of water at room temperature
overnight to give 12 mg (4.2%) of 4-(4-chlorophenyl)-2-(4-
isopropylphenoxy)butanoic acid as the dicyclohexylammonium
salt: MS (FAB) m/e 332 (M); NMR (CDCl3) δ 1.25 (d, 6H, Me),
2.2-2.3 (m, 2H, CH2), 2.7-2.9 (m, 3H, CH, benzylic CH2), 4.55
(dd, 1H, R-H), 6.8 (d, 2H, H-2), 7.2 (d, 2H, H-3), 7.15 (ABq,
4H, aromatic H′).
7-(4-C h lo r o p h e n y l)-2-(4-i s o p r o p y lp h e n o x y )h e p -
ta n oic Acid (21). This compound was prepared in analogy
to the synthesis of 20 by alkylation of diethyl malonate with
5-(4-chlorophenyl)pentyl bromide in K2CO3/DMF, saponifica-
tion to the monopotassium salt with KOH/EtOH, treatment
with Br2/AcOH and K2CO3/THF according to the procedure of
Goel and Krolls,21 reaction with 4-isopropylphenol and NaH,
and saponification with 1 N NaOH in MeOH: MS (CI) m/e
392 (M + NH4); NMR (DMSO-d6) δ 1.1 (d, 6H, Me), 1.25 (m,
2H, CH2), 1.4 (m, 2H, CH2), 1.55 (m, 2H, CH2), 1.65 (m, 2H,
CH2), 2.55 (t, 2H, benzylic CH2), 2.75 (m, 1H, CH), 4.0 (dd 1H,
R-H), 6.65 (d, 2H, H-2), 7.0 (d, 2H, H-3), 7.15 (d, 2H) and 7.25
(d, 2H) aromatic H′).
Resolu tion of 26 in to Its En a n tiom er s 27 a n d 28. A 1
g (3 mmol) sample of 26 was dissolved in 5 mL of Et2O and
treated with a solution of 0.365 g (3 mmol) of (S)-R-methyl-
benzylamine in 5 mL of Et2O. The solution was stripped and
the residue recrystallized seven times from hexane when no
further resolution could be observed by NMR. Conversion of
this salt to the free acid and recrystallization from hexane gave
180 mg (36%) of the d isomer of 26: mp 114-5 °C; [R]D + 15.1°
(c ) 1, MeOH). Similarly, resolution of a 1 g sample of 26
with (R)-R-methylbenzylamine gave 93 mg (18%) of the l
isomer of 26 (mp 114-6 °C) after recrystallization from
hexane: [R]D -16.7° (c ) 1, MeOH).
3-[4-[2-[(5-Ch lor o-2-m e t h oxyb e n zoyl)a m in o]e t h yl]-
p h en yl]-2-(4-isop r op ylp h en oxy)-2-m eth ylp r op a n oic Acid
(47). A 1.46 g (4 mmol) sample of ethyl 3-[4-(cyanomethyl)-
phenyl]-2-(4-isopropylphenoxy)-2-methylpropanoate, prepared
as in General Method E from 4-(cyanomethyl)benzyl bromide,
was reduced with NaBH4/CF3COOH to give 668 mg (44%) of
ethyl 3-[4-(2-aminoethyl)phenyl]-2-(4-isopropylphenoxy)-2-
methylpropanoate: MS (CI) m/e 370 (M + H); NMR (CDCl3)
δ 1.2-1.3 (m, 9H, Me), 1.4 (s, 3H, R-Me), 1.6 (bs, 2H, NH2),
2.7 (t, 2H, CH2), 2.8 (m, 1H, CH), 2.95 (t, 2H, benzylic CH2),
3.2 (ABq, 2H, CH2), 4.2 (q, 2H, CH2), 6.75 (d, 2H, H-2), 7.05
(d, 2H, H-3), 7.15 (ABq, 4H, (aromatic H′).
This material was condensed with 0.33 g (1 equiv) of
5-chloro-2-methoxybenzoic acid, 0.52 g (1.5 equiv) of 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, and
0.33 g (1.5 equiv) of 4-(dimethylamino)pyridine in CH2Cl2 at
0 °C to give after workup 0.51 g (52%) of ethyl 3-[4-[2-
[(5-chloro-2-methoxybenzoyl)amino]ethyl]phenyl]-2-(4-isopro-
pylphenoxy)-2-methylpropanoate: MS (CI) m/e 538 (M + H);
NMR (CDCl3) δ 1.2 (m, 9H, Me), 1.4 (s, 3H, R-Me), 2.82 (m,
1H, CH), 2.9 (t, 2H, benzylic CH2), 3.2 (ABq, 2H, CH2), 3.7
(m, 5H, Me, CH2), 4.2 (q, 2H, CH2), 6.7 (d, 2H, H-2), 6.8 (d,
1H, H-3′′), 7.0 (d, 2H, H-3), 7.2 (ABq, 4H, aromatic H′), 7.3
(dd 1H, H-4′′), 7.8 (bs, 1H, NH), 8.1 (d, 1H, H-6′′).
This material was saponified as described in General
Method E to give after crystallization from benzene the desired
acid in 58% yield: MS (CI) m/e 510 (M + H); NMR (CDCl3) δ
1.2 (d, 6H, Me), 1.4 (s, 3H, R-Me), 2.8 (m, 3H, CH, benzylic
CH2), 3.2 (ABq, 2H, CH2), 3.7 (m, 5H, Me, CH2), 6.8 (m, 3H,
H-2, H-3′′), 7.04 (d, 2H, H-3), 7.2 (ABq, 4H, aromatic H′), 7.3
(dd, 1H, H-4′′), 7.85 (bs, 1H, NH), 8.1 (d, 1H, H-6′′).
P r ep a r a t ion of 4-(4-H yd r oxyp h en yl)-4H -t et r a h yd r o-
t h iop yr a n a n d 4-(4-H yd r oxyp h en yl)-4H -2,3-d ih yd r o-
th iop yr a n (Sta r tin g Ma ter ia l for 55). A 60 g (0.347 mol)
sample of 4-bromophenol was converted to its tert-butyldi-
methylsilyl ether by the method of Kendall et al.22 A 74.18 g
(0.258 mol) sample of this ether was then treated with 6.277
g (1 equiv) of Mg in THF to form the Grignard reagent, which
was allowed to react with 20 g (0.1721 mol) of tetrahydropyran-
4-one. The crude adduct was isolated and heated at reflux

4798 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Sarges et al.
with 200 mL of MeOH and 57 mL of 12 N HCl for 1.5 h to
give, after recrystallization from diisopropyl ether, 25.86 g
(78%) of 4-(4-hydroxyphenyl)-4H-2,3-dihydrothiopyran: mp
100-2 °C dec; MS (EI) m/e 192 (M); NMR (CDCl3) δ 2.66 (m,
2H, CH2-S), 2.88 (m, 2H, CH2), 3.34 (m, 2H, allylic CH2-S),
6.88 (m, 1H, vinyl-CH), 6.80 (d, 2H, H-3), 7.2 (d, 2H, H-2).
A 5.25 g (27.3 mmol) sample of this material was hydrogen-
ated in EtOH over 5% Pd/BaSO4 in a Parr shaker at 46 psi.
This hydrogenation required 1 week with five changes of fresh
catalyst. We ultimately obtained 3.0 g (57%) of 4-(4-hydroxy-
phenyl)-4H-tetrahydrothiopyran as a tan solid, 95% pure by
GC/MS: MS (EI) m/e 194 (M); NMR (CDCl3) δ 1.7 (m, 2H),
2.0 (m, 2H), 2.4 (m, 1H), 2.6 (m, 2H), 2.8 (m, 2H), 6.88 (m, 1H,
vinyl-CH), 6.67 (d, 2H, H-3), 7.0 (d, 2H, H-2).
CHCl3. Chromatography on silica gel with EtOAc containing
20% hexane and 2.5% MeOH gave 1.09
g (33%) of
[3-(4-chlorophenyl)-2-(4-isopropylphenoxy)-2-methylpropanoyl]-
guanidine: MS (CI) m/e 374 (M + H); NMR (CDCl3) δ 1.2 (d,
6H, Me), 1.3 (s, 3H, R-Me), 2.8 (m, 1H, CH), 3.1 (ABq, 2H,
benzylic CH2), 4.1 (bs, 1H, NH), 6.7 (m, 3H, H-2, NH), 6.9-
7.1 (m, 4H, H-3, NH), 7.2 (ABq, 4H, aromatic H′). This
material was converted to its hydrochloride by treatment with
HCl gas in Et2O and recrystallized from EtOAc/hexane.
P r ep a r a tion of Ca lciu m Mon o-3-(4-ch lor op h en yl)-2-(4-
isop r op ylp h en oxy)-2-m eth ylp r op yl P h osp h a te (75).
A
solution of 500 mg (1.57 mmol) of 3-(4-chlorophenyl)-2-(4-
isopropylphenoxy)-2-methylpropanol (70) and 0.219 mL (158
mg, 1.57 mmol) of triethylamine in 6 mL of CH2Cl2 was cooled
to 0 °C, treated dropwise with 0.144 mL (241 mg, 1.57 mmol)
of POCl3, and stirred at room temperature for 2h. The solvent
was stripped; the residue was dissolved in THF, treated with
1 mL of 6 N HCl, and stirred for 3 days at room temperature.
The solvent was then stripped, and the crude product [559 mg,
89%; MS (CI) m/e 301 (M - PO4H2); NMR (CDCl3) δ 1.1 (bs,
3H, R-Me), 1.2 (d, 6H, Me), 2.8 (m, 1H, CH), 3.0 (bs, 2H,
benzylic CH2), 3.6 (t, 2H, O-CH2), 3.9 (bs, 1H, OH), 4.04 (bs,
1H, OH), 6.8 (bd, 2H, H-2), 7.1 (bd, 2H, H-3), 7.2 (bs, 4H,
aromatic H′)] was dissolved in 20 mL of THF and added
dropwise to a suspension of 59 mg (1 equiv) of CaH2 in THF.
After stirring at room temperature for 4h, the solvent was
stripped and the residue recrystallized from MeOH to give a
first crop of 50 mg of calcium mono-3-(4-chlorophenyl)-2-(4-
isopropylphenoxy)-2-methylpropyl phosphate: NMR MeOH-
d4) δ 1.1 (bs, 3H, R-Me), 1.28 (d, 6H, Me), 2.9 (m, 1H, CH), 3.1
(bs, 2H, benzylic CH2), 3.9 (bd, 2H, O-CH2), 7.0 (bs, 2H, H-2),
7.2 (bs, 2H, H-3), 7.4 (d, 4H, aromatic H′).
P r ep a r a tion of 4-(4-Hyd r oxyp h en yl)-4H-2,3-d ih yd r o-
ben zoth iop yr a n (Sta r tin g Ma ter ia l for 56 a n d 60).
A
20.99 g (73 mmol) sample of 4-bromo[(tert-butyldimethylsilyl)-
oxy]benzene (prepared as described above) was allowed to react
with 1.77 g (73 mmol) of Mg in THF and then with 10 g (60
mmol) of thiochroman-4-one. The crude reaction product was
isolated and stirred at room temperature with 150 mL of
MeOH and 12 mL of 12 N HCl to give after chromatography
on silica gel with CH2Cl2 containing 2% MeOH 10.25 g (70%)
of 4-(4-hydroxyphenyl)-2H-benzothiopyran: MS (EI) m/e 240
(M); NMR (CDCl3) δ 3.4 (d, 2H, CH2-S), 4.94 (d, 1H, OH), 6.0
(t, 1H, vinyl-CH), 6.7 (d, 2H), 6.8 (d, 2H), 7.0 (m, 1H), 7.12 (m,
1H), 7.3 (d, 2H).
A 7.3 g (30 mmol) sample of this material was hydrogenated
in a Parr shaker at 46 psi over 5% Pd/BaSO4 in THF for 3
days with three changes of fresh catalyst to give, after
chromatography on silica gel with hexane containing 20% THF
and 2% AcOH, 3.93 g (53%) of 4-(4-hydroxyphenyl)-4H-2,3-
dihydrobenzothiopyran: MS (EI) m/e 242 (M); NMR (CDCl3)
δ 2.22 (m, 2H, CH2), 2.82 (m, 2H, CH2-S), 4.10 (t, 1H, CH),
6.68 (d, 2H), 6.8-6.9 (m, 3H, 7.0 t, 1H), 7.08 (m, 1H), 7.14 (d,
1H).
P r ep a r a tion of 3-(4-Ch lor op h en yl)-2-(4-isop r op ylp h e-
n oxy)-2-m eth ylp r op a n ol (70). To a solution of 3.07 g (9.24
mmol) of 26 in 30 mL of THF was added dropwise 18.48 mL
(2 equiv) of 1 M BH3 in THF. After stirring overnight, the
THF was stripped, the residue was treated with 6 N HCl at 0
°C, and the product was extracted with EtOAc. The organic
layer was washed with water, concentrated, and chromato-
graphed on silica gel with EtOAc/hexane (1:4) to give 1.87 g
(63%) of 3-(4-chlorophenyl)-2-(4-isopropylphenoxy)-2-methyl-
propanol as an oil: MS (CI) m/e 336 (M + NH4); NMR (CDCl3)
δ 1.0 (s, 3H, R-Me), 1.2 (d, 6H, Me), 2.9 (m, 1H, CH), 3.2 (ABq,
2H, benzylic CH2), 6.8 (d, 2H, H-2), 7.1 (d, 2H, H-3), 7.2 (ABq,
4H, aromatic H′).
P r ep a r a t ion of 5-[2-(4-Ch lor op h en yl)-1-(4-isop r op yl-
p h en oxy)-1-m eth yleth yl]tetr a zole (73). A mixture of 745
mg (2.38 mmol) of 3-(4-chlorophenyl)-2-(4-isopropylphenoxy)-
2-methylpropionitrile (see general method G), 170 mg (2.62
mmol) of NaN3, 140 mg (2.62 mmol) of NH4Cl, and 7.5 mL of
DMF was heated to 110 °C for 16 h. Another 80 mg of NH4Cl
was added in 20 mg portions every few hours. The reaction
mixture was cooled to room temperature, treated with water,
and extracted several times with EtOAc. The organic extracts
were washed with water and brine, dried, and stripped to give
230 mg (27%) of crude product. After preparative TLC
chromatography on silica gel with CH2Cl2 containing 5% AcOH
and 2% MeOH and crystallization from cyclohexane was
obtained 50 mg (6%) of pure 5-[2-(4-chlorophenyl)-1-(4-iso-
propylphenoxy)-1-methylethyl]tetrazole: MS (CI) m/e 374 (M
+ NH4); NMR (CDCl3) δ 1.2 (d, 6H, Me), 1.8 (s, 3H, R-Me), 2.8
(m, 1H, CH), 3.35 (ABq, 2H, benzylic CH2), 6.55 (d, 2H, H-2),
7.05 (ABq, 4H, aromatic H′), 7.15 (d, 2H, H-3).
P r ep a r a tion of 3-(4-Ch lor op h en yl)-2-(4-isop r op ylp h e-
n oxy)-2-m eth ylp r op a n oic Acid Am id oxim e (76). This
compound was prepared by the method of Ellingboe et al.23
To a solution of 104 mg (1.5 mmol) of hydroxylamine hydro-
chloride in 2.5 mL of MeOH was added 1.28 mL of a 1.17 M
solution of NaOMe in MeOH at 0 °C followed by dropwise
addition of 470 mg (1.5 mmol) of 3-(4-chlorophenyl)-2-(4-
isopropylphenoxy)-2-methylpropionitrile (see general method
G). The mixture was stirred at room temperature for 48 h
and filtered and the filtrate evaporated to give after flash
chromatography on silica gel with CH2Cl2 containing 2%
MeOH 250 mg (48%) of 3-(4-chlorophenyl)-2-(4-isopropylphe-
noxy)-2-methylpropanoic acid amidoxime as a foam: MS (EI)
m/e 287 (M - C(NOH)NH2); NMR (CDCl3) δ 1.25 (dd, 6H, Me),
1.4 (s, 3H, R-Me), 2.85 (m, 1H, CH), 3.0-3.3 (m, 2H, benzylic
CH2), 4.82 (bs, 1H), 5.65 (bs, 0.35H), 6.45 (bs, 0.5H), 6.75 (d,
2H, H-2), 7.05 (d, 2H, H-3), 7.24 (ABq, 4H, aromatic H′), 7.35
(bs, 0.5H); 3:1 mixture of Z and E isomers.
P r ep a r a tion of Hyd r oxym eth yl 2-(4-Ch lor op h en yl)-1-
(4-isop r op ylp h en oxy)-1-m eth yleth yl Keton e (77). A 1.2
g sample of 26 was converted to its acid chloride by refluxing
with 1.3 mL (2.12 g, 18 mmol) of SOCl2 and 20 mL of CHCl3
for 4 h. The solvent was stripped and the residue azeotroped
three times with benzene. The residue was dissolved in 25
mL of Et2O and added in portions to a solution of diazo-
methane in Et2O (obtained from 1.6 g (10.8 mmol) of 1-methyl-
3-nitro-1-nitrosoguanidine, 100 mL of 1 N NaOH, and 100 mL
of Et2O; dried with K2CO3). After 10 min the solvent was
evaporated and the residue flash-chromatographed on silica
gel with CH2Cl2/hexane (1:1) to give 0.75 g (64%) of the diazo
ketone: MS (EI) m/e 356 (M); NMR (CDCl3) δ 1.2 (d, 6H, Me),
1.3 (s, 3H, R-Me), 2.85 (m, 1H, CH), 3.0 and 3.1 (ABq, 2H,
benzylic CH2), 5.3 (s, 0.5H), 5.7, (s, 0.5H), 6.78 (d, 2H, H-2),
7.1 (d, 2H, H-3), 7.25 (ABq, 4H aromatic H′).
A 495 mg (1.39 mmol) sample of this material was dissolved
in 40 mL of Et2O and treated with 16 mL of HBr-saturated
Et2O. After nitrogen evolution ceased, the solvent was stripped
and the residue azeotroped with benzene to give the bromo-
methyl ketone as a pale yellow syrup: MS (EI) m/e 408, 410
(M); NMR (CDCl3) δ 1.2 (d, 6H, Me), 1.4 (s, 3H, R-Me), 2.85
(m, 1H, CH), 3.0 and 3.25 (ABq, 2H, benzylic CH2), 4.05 and
4.35 (ABq, 2H, CH2-Br), 6.75 (d, 2H, H-2), 7.15 (ABq, 4H,
aromatic H′), 7.25 (d, 2H, H-3).
P r ep a r a tion of 3-(4-ch lor op h en yl)-2-(4-isop r op ylp h e-
n oxy)-2-m eth ylp r op a n oyl]gu a n id in e (74). A 1 g (43 mmol)
sample of Na was dissolved in 50 mL of absolute EtOH, 4.19
g (43 mmol) of guanidine hydrochloride was added, and the
mixture was stirred at room temperature for 30 min. After
addition of 3.17 g (8.8 mmol) of ethyl 3-(4-chlorophenyl)-2-(4-
isopropylphenoxy)-2-methylpropionate (see general method E),
the mixture was heated to 60 °C overnight. The solvent was
stripped and the residue treated with water and extracted with

Phenoxyphenylpropanoic Acids as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4799
This material was combined with 136 mg (1.38 mmol) of
KOAc in 5 mL of EtOH and heated to 80 °C overnight. The
solvent was stripped and the residue flash-chromatographed
on silica gel with CH2Cl2/hexane to give 250 mg (46%) of the
acetoxymethyl ketone: MS (EI) m/e 388 (M); NMR (CDCl3) δ
1.2 (d, 6H, Me), 1.35 (s, 3H, R-Me), 2.15 (s, 3H, Me-CO), 2.85
(m, 1H, CH), 3.05 and 3.25 (ABq, 2H, benzylic CH2), 5.35 and
5.65 (ABq, 2H, CH2-O), 6.75 (d, 2H, H-2), 7.15 (ABq, 4H,
aromatic H′), 7.35 (d, 2H, H-3).
A 137 mg (0.35 mmol) sample of this material was dissolved
in 7 mL of MeOH, cooled to 0 °C, and treated with 23 mg (0.35
mmol) of KCN. After stirring for 30 min at 0 °C, 12 drops of
AcOH was added followed by 100 mL of CH2Cl2 and 50 mL of
water. The organic phase was collected, dried (MgSO4), and
evaporated. The residue was purified by preparative TLC on
silica gel with Et2O/hexane (1:1) to give 70 mg (57%) of
hydroxymethyl 2-(4-chlorophenyl)-1-(4-isopropylphenoxy)-1-
methylethyl) ketone as a syrup: MS (CI) m/e 364 (M + NH4);
NMR (CDCl3) δ 1.25 (d, 6H, Me), 1.35 (s, 3H, R-Me), 2.7-2.9
(m, 2H, CH, OH), 3.05 and 3.25 (ABq, 2H, benzylic CH2), 4.3-
4.75 (m, 2H, CH2-O), 6.75 (d, 2H, H-2), 7.15 (d, 4H, aromatic
H′), 7.25 (d, 2H, H-3).
P r ep a r a tion of 3-(4-Ch lor op h en yl)-2-eth yl-2-(4-isop r o-
p ylp h en oxy)p r op a n oic Acid (81). This compound was
prepared in analogy to General Method E, using ethyl R-bro-
mobutyrate as starting material. In the final saponification
step, NaOH or LiOH failed to hydrolyze the ester. However,
when a 1.5 g (4 mmol) sample of ethyl 3-(4-chlorophenyl)-2-
ethyl-2-(4-isopropylphenoxy)propanoate was dissolved in 40
mL of EtOH and treated with 8 of mL 2 N KOH and kept at
reflux for 48 h, 865 mg (56%) of 3-(4-chlorophenyl)-2-ethyl-2-
(4-isopropylphenoxy)propanoic acid was obtained after the
usual workup and flash chromatography with Et2O/hexane (1:
1): MS (CI) m/e 364 (M + NH4); NMR (DMSO-d6): δ 0.75 (t,
3H, Me), 1.15 (d, 6H, Me), 1.5 (q, 2H, R-CH2), 2.8 (m, 2H, CH),
3.2 (ABq, 2H, benzylic CH2), 6.8 (d, 2H, H-2), 7.0 (d, 2H, H-3),
7.1 and 7.2 (ABq, 4H, aromatic H′). This material was
converted to the Na salt with NaOH in MeOH.
P r ep a r a tion of 3-(4-Ch lor op h en yl)-2-(4-isop r op ylp h e-
n oxy)bu ta n oic Acid (82, 83). A 26.7 g (0.17 mol) batch of
R-methyl-4-chlorobenzyl alcohol was dissolved in benzene,
cooled to 0 °C, and treated with HBr gas for 40 min. The upper
phase was collected, dried over MgSO4, and evaporated to give
28.31 g (76%) of R-methyl-4-chlorobenzyl bromide. A 18.83 g
(81 mmol) batch of this material was used to alkylate 6 g (27
mmol) of ethyl 2-(4-isopropylphenoxy)acetate according to
general method E to give after chromatography on silica gel
with hexane and rechromatography with hexane/THF (10:1)
593 mg (6%) of ethyl 3-(4-chlorophenyl)-2-(4-isopropyl-
phenoxy)butanoate: MS (EI) m/e 360 (M); NMR (CDCl3) δ 1.1-
1.25 (m, 9H, Me), 1.38 (d) and 1.42 (d, 3H) (â-Me), 2.8 (m, 1H,
CH), 3.36 (m, 1H, â-CH), 4.0-4.2 (m, 2H, O-CH2), 4.51 (d) and
4.56 (d, 1H) (R-CH), 6.7 (d, 2H, H-2), 7.05 (d, 2H, H-3), 7.24
(s, 4H, aromatic H′).
After saponification with NaOH in EtOH according to
general method E was obtained 455 mg (83%) of crude product.
Purification by preparative TLC with EtOAc/hexane (1:1) gave
196 mg of pure 3-(4-chlorophenyl)-2-(4-isopropylphenoxy)-
butanoic acid as a mixture of diastereomers. Crystallization
from pentane gave 81 mg of diastereomer A (82): MS (CI) m/e
350 (M + NH4); NMR (CDCl3) δ 1.18 (d, 6H, Me), 1.42 (d, 3H,
â-Me), 2.83 (m, 1H, CH), 3.4 (m, 1H, â-CH), 4.65 (d, 1H, R-CH),
6.76 (d, 2H, H-2), 7.1 (d, 2H, H-3), 7.26 (s, 4H, aromatic H′).
The mother liquor of this crop [96 mg; MS (CI) m/e 350 (M +
NH4); NMR (CDCl3) δ 1.18 (d, 6H, Me), 1.46 (d, 3H, â-Me),
2.83 (m, 1H, CH), 3.4 (m, 1H, â-CH), 4.62 (d, 1H, (R-CH), 6.71
(d, 2H, H-2), 7.1 (d, 2H, H-3), 7.26, (s, 4H, aromatic H′)] was
converted to the Na salt of 83 with NaOMe in MeOH.
P r ep a r a tion of 3-(4-Ch lor op h en yl)-2-(4-isop r op ylp h e-
n oxy)-2-m eth ylbu ta n oic Acid (84, 85). A 14.2 g (64.7
mmol) sample of R-methyl-4-chlorobenzyl bromide (see prepa-
ration of 82, 83 above) was used to alkylate 5.12 g (21.7 mmol)
of ethyl 2-(4-isopropylphenoxy)propanoate with 1.05 equiv of
LICA according to general method E to give after chromatog-
raphy on silica gel with hexane followed by hexane/CH2Cl2 (1:
1) 4.89 g (60%) of ethyl 3-(4-chlorophenyl)-2-(4-isopropyl-
phenoxy)-2-methylbutanoate: GC/MS 41:56 mixture of dia-
stereomers; MS (EI) m/e 374 (M); NMR (CDCl3) δ 1.18 (d, 6H,
Me), 1.2 (t) and 1.25 (t, 3H) Me), 1.21 (s) and 1.31 (s, 3H) R-Me),
1.37 (d) and 1.43 (d, 3H) (â-Me), 2.83 (m, 1H, CH), 3.26 (d)
and 3.36 (d, 1H) (â-CH), 4.11 (q) and 4.2 (q, 2H) (O-CH2), 6.68
(d) and 6.75 (d, 2H) H-2), 7.01 (d, 2H, H-3), 7.25 (ABq, 4H,
aromatic H′).
Attempts to saponify this material with NaOH or LiOH or
under acidic conditions with H2SO4 or AcOH/HCl failed, giving
little or no product and side reactions. However, a 1.8 g (4.8
mmol) sample of this material was saponified successfully by
the method of Gassman and Schenk24 by adding a solution in
10 mL of Et2O to a slurry of 8.68 g of KOt-Bu in 70 mL of
Et2O and 0.2 mL of water and stirring at room temperature
overnight. The mixture was cooled to 0 °C, 150 mL of water
was added, and the phases were separated. The aqueous
phase was acidified with 12 N HCl and extracted twice with
CH2Cl2 to give 930 mg (56%) of 3-(4-chlorophenyl)-2-(4-
isopropylphenoxy)-2-methylbutanoic acid as a 60:40 mixture
of diastereomers: GC/MS (CI) m/e 364 (M + NH4). Fractional
crystallization from benzene/hexane gave 200 mg (12%) of
diastereomer A (84): MS (CI) m/e 364 (M + NH4); NMR
(CDCl3) δ 1.2 (d, 6H, Me), 1.23 (s, 3H, R-Me), 1.49 (d, 3H,
â-Me), 2.83 (m, 1H, CH), 3.27 (d, 1H, â-CH), 6.78 (d, 2H, H-2),
7.06 (d, 2H, H-3), 7.3 (ABq, 4H, aromatic H′); X-ray analysis
showed this compound to have the RS/SR configuration.
Crystallization of the mother liquor from Et2O/hexane gave
281 mg (17%) of the other diastereomer (B, 85): MS (CI) m/e
364 (M + NH4); NMR (CDCl3) δ 1.2 (d, 6H, Me), 1.32 (s, 3H,
R-Me), 1.42 (d, 3H, â-Me), 2.8 (m, 1H, CH), 3.26 (d, 1H, â-CH),
6.74 (d, 2H, H-2), 7.03 (d, 2H, H-3), 7.2 (ABq, 4H, aromatic
H′).
P r ep a r a tion of 3-(4-Ch lor op h en yl)-2-(4-isop r op ylp h e-
n oxy)-2-m eth ylp en ta n oic Acid (86, 87). A sample of 4-chlo-
ropropiophenone was reduced with NaBH4 in MeOH and
converted with HBr gas into the bromide in analogy to the
method described above in the preparation of 82, 83. This
material was used to prepare ethyl 3-(4-chlorophenyl)-2-(4-
isopropylphenoxy)-2-methylpentanoate by general method E.
Saponification was carried out with KOt-Bu as described above
for 84, 85 to give 824 mg of a mixture of diastereomers: GC/
MS (CI) m/e 378 (M + NH4). Fractional crystallization from
hexane gave 93 mg of diastereomer A (86): MS (CI) m/e 378
(M + NH4); NMR (CDCl3) δ 0.75 (t, 3H, Me), 1.2 (m, 9H, i-Pr-
Me, R-Me), 1.9-2.2 (m, 2H, CH2), 2.85 (m, 1H, CH), 3.0 (dd,
1H, â-CH), 6.85 (d, 2H, H-2), 7.1 (d, 2H, H-3), 7.33 (s, 4H,
aromatic H′); tentatively assigned the RS/SR configuration in
analogy with 84. Also obtained was 568 mg of diastereomer
B (87): MS (CI) m/e 378 (M + NH4); NMR (CDCl3) δ 0.8 (t,
3H, Me), 1.2 (d, 6H, i-Pr-Me), 1.4 (s, 3H, R-Me) 1.9-2.0 (m,
2H, CH2), 2.85 (m, 1H, CH), 3.0 (dd, 1H, â-CH), 6.8 (d, 2H,
H-2), 7.1 (d, 2H, H-3), 7.28 (s, 4H, aromatic H′).
P r ep a r a tion of 3-(4-Ch lor op h en yl)-2-(4-isop r op ylben -
zyl)-2-m eth ylp r op a n oic Acid (93). A 2.5 g (24.5 mmol)
sample of ethyl propanoate was alkylated with LICA and
4-chlorobenzyl bromide according to general method E to give
2.54 g (46%) of ethyl 3-(4-chlorophenyl)-2-methylpropanoate:
MS (EI) m/e 226 (M); NMR (CDCl3) δ 1.1-1.3 (m, 6H, Me),
2.6-2.75 (m, 2H, benzylic CH2), 2.9-3.1 (m, 1H, R-CH), 4.15
(q, 2H, O-CH2), 7.1 (d, 2H, H-2), 7.22 (d, 2H, H-3).
This material was alkylated according to general method E
with LICA and 4-isopropylbenzyl bromide to give in 63% yield
ethyl 3-(4-chlorophenyl)-2-(4-isopropylbenzyl)-2-methylpro-
panoate: MS (EI) m/e 358 (M); NMR (CDCl3) δ 1.05 (s, 3H,
R-Me), 1.1-1.3 (m, 9H, Me), 2.65 (dd, 2H, benzylic CH2), 2.85
(m, 1H, CH), 3.15 (t, 2H, benzylic CH2), 4.05 (q, 2H, O-CH2),
6.95-7.15 m, 6H), 7.2-7.3 (m, 2H).
This material proved very resistant to saponification. The
only conditions which gave a 12% yield of the desired product
involved refluxing an EtOH solution with 4 equiv of 1 N NaOH
overnight to give 3-(4-chlorophenyl)-2-(4-isopropylbenzyl)-2-
methylpropanoic acid: MS (CI) m/e 348 (M + NH4); NMR
(CDCl3) δ 1.05 (s, 3H, R-Me), 1.25 (d, 6H, Me), 2.65-2.75 (dd,
2H, benzylic CH2), 2.85 (m, 1H, CH), 3.2-3.35 (dd, 2H, benzylic
CH2), 7.15 (m, 6H), 7.25 (m, 2H).

4800 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Sarges et al.
P r ep a r a t ion of 2-(4-Ch lor ob en zyl)-3-flu or o-3-(4-iso-
p r op ylp h en yl)-2-m eth ylp r op a n oic Acid (94, 95). A 1.2 g
(5.3 mmol) sample of ethyl 3-(4-chlorophenyl)-2-methylpro-
panoate (see preparation of 93) was treated according to
general method E with 1 equiv of LICA and 1 equiv of
4-isopropylbenzaldehyde to give after chromatography on silica
gel with hexane/Et2O (3:1) 1.01 g (51%) of ethyl 2-(4-chloro-
ben zyl)-3-h ydr oxy-3-(4-isopr opylph en yl)-2-m et h ylpr o-
panoate: MS (CI) m/e 375 (M + H); NMR (CDCl3) δ 1.0 (s,
3H, R-Me), 1.15 (t, 3H, Me), 1.25 (d, 6H, Me), 2.55 and 3.2
(ABq, 2H, benzylic CH2), 2.9 (m, 1H, CH), 3.2 (d, 2H, OH), 4.1
(q, 2H, O-CH2), 4.8 (d, 1H, CH), 7.05 (d, 2H), 7.2-7.3 (m, 6H).
A 1 g (2.67 mmol) sample of this material was dissolved in
5 mL of CH2Cl2 and added at -78 °C to a solution of 430 mg
(2.67 mmol) of diethylaminosulfur trifluoride25 in 5 mL of
CH2Cl2. After 1 h at -78 °C the mixture was allowed to warm
to room temperature overnight, cold water was added, and the
organic layer was separated and washed with bicarbonate and
water. The solvent was stripped and the residue chromato-
graphed on silica gel with hexane/Et2O (4:1) to give 240 mg
(24%) of diastereomer A [LP fraction; MS (CI) m/e 394 (M +
NH4); NMR (CDCl3) δ 1.05 (s, 3H, R-Me), 1.15 (t, 3H, Me), 1.25
(d, 6H, Me), 2.9 (m, 1H, CH), 2.95 and 3.35 (ABq, 2H, benzylic
CH2), 4.0 (q, 2H, O-CH2), 5.7 (s) and 5.85 (s, 1H) (CHF), 7.1
(m, 2H), 7.2-7.3 (m, 6H)] and 466 mg (47%) of diastereomer
B [MP fraction; MS (CI) m/e 394 (M + NH4); NMR (CDCl3) δ
1.05 (s, 3H, R-Me), 1.20 (t, 3H, Me), 1.25 (d, 6H, Me), 2.3 and
3.15 (ABq, 2H, benzylic CH2), 2.95 (m, 1H, CH), 4.15 (q, 2H,
O-CH2), 5.65 (s) and 5.75 (s, 1H) (CHF), 6.95 (d, 2H), 7.2 (d,
2H), 7.25 (s, 4H)] of ethyl 2-(4-chlorobenzyl)-3-fluoro-3-(4-
isopropylphenyl)-2-methylpropanoate.
Diastereomer B was saponified with 1 equiv of KOt-Bu in
DMSO at 40 °C for 4 h to give 2-(4-chlorobenzyl)-3-fluoro-3-
(4-isopropylphenyl)-2-methylpropanoic acid (diastereomer B,
94): mp 143-5 °C; MS (CI) m/e 366 (M + NH4); NMR (CDCl3)
δ 1.05 (s, 3H, R-Me), 1.25 (d, 6H, Me), 2.35 and 3.15 (ABq,
2H, benzylic CH2), 2.95 (m, 1H, CH), 5.7 (s) and 5.9 (s, 1H)
(CHF), 7.0 (d, 2H), 7.2 (d, 2H), 7.25 (s, 4H). Diastereomer A
of the ester was saponified with 1 equiv of KOt-Bu in DMSO
at room temperature overnight to give 2-(4-chlorobenzyl)-3-
fluoro-3-(4-isopropylphenyl)-2-methylpropanoic acid (dia-
stereomer A, 95): MS (CI) m/e 366 (M + NH4); NMR (CDCl3)
δ 1.1 (s, 3H, R-Me), 1.15 (t, 3H, Me), 1.25 (d, 6H, Me), 2.9 (m,
1H, CH), 2.95 and 3.35 (ABq, 2H, benzylic CH2), 5.7 (s) and
5.85 (s, 1H) (CHF), 7.1 (d, 2H), 7.2-7.3 (m, 6H).
δ 1.2 (m, 9H, Me), 2.82 (m, 1H, CH), 3.24 (ABq, 2H, benzylic
CH2), 3.2 and 3.46 (ABq, 2H, 3-CH2), 4.16 (q, 2H, CH2-O), 6.8
(d, 1H, H-7), 6.98 (s, 1H, H-4), 7.0 (d, 1H, H-6), 7.24 (ABq,
4H, aromatic H′).
A 1.2 g (3.4 mmol) sample of this material was saponified
with 4 equiv of 1 N NaOH in EtOH at room temperature
overnight to give after gradient chromatography on silica gel
with hexane containing 10-40% EtOAc and 2% AcOH 520 mg
(46%) of 2-(4-chlorobenzyl)-2,3-dihydro-5-isopropylbenzofuran-
2-carboxylic acid: MS (CI) m/e 348 (M + NH4); NMR (CDCl3)
δ 1.2 (d, 6H, Me), 2.82 (m, 1H, CH), 3.16 and 3.33 (ABq, 2H,
benzylic CH2), 3.26 and 3.58 (ABq, 2H, 3-CH2), 6.8 (d, 1H, H-7),
7.0 (m, 2H, H-4, H-6), 7.2 (ABq, 4H, aromatic H′).
P r ep a r a tion of 3-(4-Ch lor op h en yl)-2,3-d ih yd r o-5-iso-
p r op ylben zofu r a n -2-ca r boxylic Acid (98). In analogy to
the method of Fuson et al.26 a 6.9 g (50.8 mmol) sample of
4-isopropylphenol was treated with 1 equiv of NaH and 1 equiv
of ethyl 2-bromo-2-(4-chlorobenzoyl)acetate as described in
general method A to give 15.37 g (84%) of ethyl 2-(4-chloro-
benzoyl)-2-(4-isopropylphenoxy)acetate: MS (CI) m/e 378 (M
+ NH4); NMR (CDCl3) δ 1.1-1.3 (m, 9H, Me), 2.8 (m, 1H, CH),
4.1 (q) and 4.3 (q, 2H) (CH2-O), 6.8 (d, 2H, H-2), 7.0-7.1 (m,
4H), 7.4 (d, 2H), 8.0 (d, 1H, R-CH).
A 7.37 g (20.4 mmol) sample of this material was cooled to
-40 °C and treated dropwise with 10 mL (9 equiv) of
concentrated H2SO4. The mixture was allowed to come slowly
to room temperature, stirred for 3 h, and poured over ice.
Extraction with EtOAc and chromatography on silica gel with
hexane/Et2O (10:1) gave 2.0 g (30%) of ethyl 3-(4-chloro-
phenyl)-5-isopropylbenzofuran-2-carboxylate: MS (EI) m/e 342
(M); NMR (CDCl3) δ 1.2-1.4 (m, 9H, Me), 3.0 (m, 1H, CH),
4.16 (q, 2H, CH2-O), 7.32-7.4 (m, 2H), 7.4-7.6 (m, 5H).
A 1.13 g (3.29 mmol) sample of this material was dissolved
in 15 mL of EtOH, treated with 0.489 g (2.25 equiv) of 85%
KOH in 3 mL of water, and stirred at room temperature
overnight. After workup we obtained 0.65 g (62%) of 3-(4-
chlorophenyl)-5-isopropylbenzofuran-2-carboxylic acid: MS
(CI) m/e 332 (M + NH4); NMR (CDCl3) δ 1.2 (d, 6H, Me), 3.0
(m, 1H, CH), 7.2-7.5 (m, 7H).
A 200 mg (0.6 mmol) sample of this material was reduced
with 10 g (10 equiv) of 3% sodium amalgam in 25 mL of
saturated aqueous NaHCO3 under mechanical stirring at room
temperature overnight. After workup we obtained 83 mg
(41%) of 3-(4-chlorophenyl)-2,3-dihydro-5-isopropylbenzofuran-
2-carboxylic acid as a 2:1 mixture of Z and E isomers which
could not be separated by chromatography or crystallization:
MS (CI) m/e 334 (M + NH4); NMR (CDCl3) δ 1.16 (d, 6H, Me),
3.0 (m, 1H, CH), 4.75 (d) and 4.95 (d, 1H) H-3), 4.84 (d) and
5.02 (d, 1H) H-2), 6.8-6.9 (m, 1H, H-7), 7.0-7.2 (m, 2H, H-4,
H-6), 7.26 (ABq, 4H, aromatic H′).
P r ep a r a tion of 2-(4-Ch lor oben zyl)-2,3-d ih yd r o-6-iso-
p r op yl-4H-ben zop yr a n -2-ca r boxylic Acid (99). A 14.49 g
(41.77 mmol) sample of ethyl 3-(4-chlorophenyl)-2-(4-isopro-
pylphenoxy)propanoate (prepared according to general method
E) was alkylated with 1 equiv of LICA and 1 equiv of benzyl
2-bromoacetate according to general method E to give 6.1 g
(29%) of benzyl 4-(4-chlorophenyl)-3-(ethoxycarbonyl)-3-(4-
isopropylphenoxy)butanoate as an oil: MS (CI) m/e 512 (M +
NH4); NMR (CDCl3) δ 1.15 (m, 9H, Me), 2.7 and 2.9 (ABq, 2H,
benzylic CH2), 2.85 (m, 1H, CH), 3.4 and 3.55 (ABq, CO-CH2),
4.15 (q, O-CH2), 5.05 (ABq, 2H, O-CH2-benzyl), 6.75 (d, 2H
H-2), 7.05 (d, 2H, H-3), 7.2-7.4 (m, 9H).
This material (6.1 g, 12.32 mmol) was dissolved in 123 mL
of AcOH and hydrogenated at atmospheric pressure over 1.2
g of 5% Pd/C until H2 uptake ceased (1 h) to give 4.25 g (85%)
of 4-(4-chlorophenyl)-3-(ethoxycarbonyl)-3-(4-isopropylphe-
noxy)butanoic acid as an oil: MS (CI) m/e 422 (M + NH4);
NMR (CDCl3) δ 1.2 (m, 9H, Me), 2.7 and 2.9 (ABq, 2H, benzylic
CH2), 2.85 (m, 1H, CH), 3.4 and 3.55 (ABq, CO-CH2), 4.2 (q,
O-CH2), 6.8 (d, 2H, H-2), 7.05 (d, 2H, H-3), 7.25 (ABq, 4H,
aromatic H′).
A 4.23 g (10.45 mmol) sample of this material was dissolved
in 50 mL of CH2Cl2, cooled to 5 °C, and treated dropwise with
a solution of 2.22 mL (15.7 mmol) of trifluoroacetic anhydride
in 25 mL of CH2Cl2 (15 min) and then with a solution of 0.09
mL (1.05 mmol) of trifluoromethanesulfonic acid in 25 mL of
P r ep a r a tion of 2-(4-Ch lor oben zyl)-2,3-d ih yd r o-5-iso-
p r op ylben zofu r a n -2-ca r boxylic Acid (97). A 10 g (29
mmol) sample of ethyl 3-(4-chlorophenyl)-2-(4-isopropyl-
phenoxy)propanoate (prepared according to general method E),
dissolved in 80 mL of toluene, was added to 10.64 g of
paraformaldehyde followed by 80 mL of AcOH. The mixture
was cooled to 0 °C, perfused with HCl gas for 2 h, and then
allowed to stir at room temperature overnight. Since GC/MS
analysis indicated only 50% conversion, the mixture was cooled
again to 0 °C, treated with 5 g of paraformaldehyde, perfused
again with HCl gas for 2 h, and then allowed to stir at room
temperature overnight. After stripping the solvent and azeotro-
ping with hexane, the residue was dissolved in EtOAc and
washed with brine to give 10.52 g of crude product. This was
chromatographed on silica gel with CH2Cl2/hexane (1:1) to give
4.06
g
(35%) of ethyl 2-[2-(chloromethyl)-4-isopropyl-
phenoxy]-3-(4-chlorophenyl)propanoate: MS (EI) m/e 394 (M);
NMR (CDCl3) δ 1.2 (m, 9H, Me), 2.8 (m, 1H, CH), 3.2 (d, 2H,
benzylic CH2), 4.16 (q, 2H, CH2-O), 4.5 and 4.66 (ABq, 2H, CH2-
Cl), 4.8 (t, 1H, R-CH), 6.6 (d, 1H, H-6), 7.0 (m, 1H, H-3), 7.2
(m, 1H, H-5), 7.26 (s, 4H, aromatic H′).
A 3.47 g (8.77 mmol) sample of this material was dissolved
in 20 mL of THF, cooled to -78 °C, and treated dropwise with
1 equiv of LICA (prepared according to general method E from
1.44 mL (8.77 mmol) of N-isopropylcyclohexylamine). The
mixture was stirred overnight at -78 °C in a dry ice-acetone
bath and allowed to warm very slowly to room temperature.
After the usual workup and chromatography on silica gel with
hexane containing 10% CH2Cl2 and 5% THF, we obtained 1.37
g (44%) of ethyl 2-(4-chlorobenzyl)-2,3-dihydro-5-isopropyl-
benzofuran-2-carboxylate: MS (EI) m/e 358 (M); NMR (CDCl3)

Phenoxyphenylpropanoic Acids as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4801
CH2Cl2 (15 min). The mixture was stirred at 5 °C for 30 min
and then at room temperature for 1 h. After washing with
bicarbonate and brine, drying, evaporation, and flash chro-
matography on silica gel with hexane/CH2Cl2 (1:1) was ob-
tained 2.87 g (71%) of ethyl 2-(4-chlorobenzyl)-2,3-dihydro-6-
isopropyl-4-oxo-4H-benzopyran-2-carboxylate as an oil: MS
(CI) m/e 404 (M + NH4); NMR (CDCl3) δ 1.1 (t, 3H, Me), 1.2
(d, 6H, Me), 2.8 and 3.1 (ABq, 2H, benzylic CH2), 2.85 (m, 1H,
CH), 3.25 (ABq, 3-CH2), 4.05 (q, O-CH2), 7.0 (d, 1H, H-8), 7.2
(ABq, 4H, aromatic H′), 7.35 dd 1H, H-7), 7.65 (d, 1H, H-5).
A 2.59 g (6.7 mmol) batch of this material was dissolved in
33 mL of MeOH, cooled to 5 °C, and treated in portions with
506 mg (13.4 mmol) of NaBH4. After workup and chromatog-
raphy on silica gel with CH2Cl2 was obtained 2.25 g (82%) of
ethyl 2-(4-chlorobenzyl)-2,3-dihydro-4-hydroxy-6-isopropyl-4H-
benzopyran-2-carboxylate as a mixture of diastereomers: MS
(CI) m/e 406 (M + NH4); NMR (CDCl3) δ 1.1-1.2 (m, 9H, Me),
1.7 (bs, 1H, OH), 1.75-1.85 (m, and 1.92 (dd) and 2.0 (dd, 1H)
H-3 axial), 2.60 and 2.75 (dd) and 2.60 and 2.65 (dd, 1H) H-3
equatorial), 2.85 (m, 1H, CH), 3.1 and 3.25 (ABq) and 3.1 and
3.3 (ABq, 2H) (benzylic CH2), 4.1 (q, O-CH2), 4.75 (m, 1H, H-4),
6.85 (d) and 6.9 (d, 1H) H-8), 7.05 (dd) and 7.1 (dd, 1H) H-7),
7.05 (d) and 7.25 (d, 1H) H-5), 7.25 (s, 4H, aromatic H′).
A 2.24 g (5.76 mmol) batch of this material was dissolved
in 25 mL of trifluoroacetic acid, cooled to 0 °C, and treated
dropwise with 1.84 mL (11.52 mmol) of triethylsilane (10 min).
The mixture was stirred at 0 °C for 2 h and then poured into
ice-water and EtOAc to give, after isolation and chromatog-
raphy on silica gel with hexane/CH2Cl2 (4:1), 920 mg (43%) of
ethyl 2-(4-chlorobenzyl)-2,3-dihydro-6-isopropyl-4H-benzo-
pyran-2-carboxylate as a syrup: MS (CI) m/e 390 (M + NH4);
NMR (CDCl3) δ 1.1-1.2 (m, 9H, Me), 1.7-1.9 (m, 1H, H-4
axial), 2.25 -2.4 (m, 1H, H-3 axial), 2.6-2.8 (m, 2H, H-3, H-4
equatorial), 2.7-2.85 (m, 1H, CH), 3.15 (ABq, 2H, benzylic
CH2), 4.1 (q, O-CH2), 6.75-7.0 (m, 3H, H-5,7,8), 7.25 (s, 4H,
aromatic H′).
A 910 mg (2.44 mmol) sample of this material was dissolved
in 50 mL of EtOH and saponified with 9.76 mL (4 equiv) of 1
N NaOH at room temperature overnight to give, after recrys-
tallization from cyclohexane, 330 mg (39%) of 2-(4-chloroben-
zyl)-2,3-dih ydr o-6-isopr opyl-4H -ben zopyr a n -2-ca r boxylic
acid: MS (CI) m/e 362 (M + NH4); NMR (CDCl3) δ 1.2 (d, 6H,
Me), 1.9-2.05 (m, 1H, H-4 axial), 2.3 -2.4 (m, 1H, H-3 axial),
2.7-2.85 (m, 3H, H-3, H-4 equatorial, CH), 3.15 (ABq, 2H,
benzylic CH2), 6.85 (d, 1H, H-8), 6.9 (d, 1H, H-5), 7.02 (dd,
1H, H-7), 7.20 (ABq, 4H, aromatic H′).
P r ep a r a tion of 2-(5-Ch lor oin d a n -1-yl)-2-(4-isop r op yl-
p h en oxy)-2-m eth yla cetic Acid (100, 101). A 4.726 g (20
mmol) sample of ethyl 2-(4-isopropylphenoxy)propanoate (pre-
pared according to general method E) was treated with 1 equiv
of LICA and 3.332 g (20 mmol) of 5-chloro-1-indanone accord-
ing to general method E to give, after flash chromatography
on silica gel with Et2O/hexane (1:1), 3.06 g (38%) of ethyl 2-(5-
ch lor o-1-h ydr oxyin da n -1-yl)-2-(4-isopr opylph en oxy)-2-
methylacetate: NMR (CDCl3) δ 1.05 (t) and 1.25 (t, 3H) Me),
1.2 (d, 6H, Me), 2.05-2.25 (m, 1H), 2.6-3.0 (m, 4H), 4.2 (q)
and 4.35 (q, 2H) (O-CH2), 6.65-6.80 (m, 3H), 7.0-7.1 (m, 2H),
7.15 (m, 1H), 7.55 (d) and 7.65 (d, 1H).
NH4); NMR (CDCl3) δ 1.1-1.3 (m, 9H, Me), 1.35 (s, 3H, R-Me),
2.3-2.4 (m, 2H, H-2, H-3 axial), 2.7-3.1 (m, 3H, H-2, H-3
equatorial, CH), 3.7 (t, H-1), 4.2 (q, 2H, O-CH2), 6.7 (d, 2H,
H-2′), 7.0-7.15 (m, 3H, H-3′, H-6), 7.2 (s, 1H, H-4), 7.25 (d,
1H, H-7).
A 230 mg (0.6 mmol) sample of this material was saponified
with KOt-Bu in Et2O/water as described in the preparation of
84, 85. The diastereomers were separated by preparative TLC
on silica gel with Et2O/hexane (1:1) containing 2% AcOH to
give 139 mg (65%) of diastereomer A [LP, 101; MS (CI) m/e
376 (M + NH4); NMR (DMSO-d6) δ 1.15 (d, 6H, Me), 1.22 (s,
3H, R-Me), 2.2-2.4 (m, 2H, H-2, H-3 axial), 2.7-3.1 (m, 3H,
H-2, H-3 equatorial, CH), 3.75 (t, H-1), 6.72 (d, 2H, H-2′), 7.09
(d, 2H, H-3′), 7.15 (m, 1H), 7.3 (m, 2H)], after recrystallization
from hexane 70 mg (mp 117-8 °C), and 53 mg (25%) of
diastereomer B (MP, 100) as an oil: MS (CI) m/e 376 (M +
NH4); NMR (DMSO-d6) δ 1.1 (s, 3H, R-Me), 1.15 (d, 6H, Me),
2.7-3.0 (m, 3H, H-2, H-3 axial, CH), 3.25-3.4 (bm, 2H, H-2,
H-3 equatorial), 3.75 (t, H-1), 6.8 (d, 2H, H-2′), 7.15 (d, 2H,
H-3′), 7.20 (d, 1H, H-6), 7.3 (s, 1H H-4), 7.55 (d, 1H, H-7). This
was converted to the Na salt with NaOEt in EtOH to give 18
mg.
Biology. 1. In Vitr o Ch ar acter ization . Glu cose Tr an s-
p or t Activity. Acute glucose transport modulation in vitro
was assessed by measuring 2-deoxyglucose transport in 3T3-
L1 adipocytes or L6 myocytes. 3T3-L1 or L6 fibroblasts were
grown to confluency in 6-well cluster dishes. Adipocyte
differentiation was induced by supplementing the media with
a combination of 1 µM insulin, 250 nM dexamethasone, and
500 µM 3-isobutyl-1-methylxanthine for 48 h followed by
insulin alone for an additional 48 h. L6 cells were grown in
2% fetal bovine serum in R-MEM and differentiated into
myocytes without further medium supplementation. Trans-
port experiments were performed 7-11 days postinduction of
differentiation. The test compounds were prepared in 100%
DMSO (final concentration 0.1%, v/v) and then added to fresh
media 1 h prior to measuring glucose transport activity.
Glucose uptake was measured in Krebs-Ringer phosphate
buffer, pH 7.4, using 0.5 µCi/mL [14
C]-2-deoxy-D-glucose (50
µM; DuPont-NEN) for 10 min at 37 °C. The assay was
terminated by aspiration and washing the cells with ice-cold
PBS. Samples were extracted with 1% Triton X-100 and
counted in a scintillation counter. Data are expressed as the
mean percent increase of triplicate determinations of glucose
transport rate over the basal (unstimulated) rate.
Chronic 48 h glucose transport modulation in vitro was
assessed in the 3T3-L1 cell line prepared as described above.
Seven days postinduction of differentiation, the test compounds
prepared in 100% DMSO (final concentration 0.1%, v/v) were
added to fresh media at 48 and 24 h prior to measuring glucose
transport activity as described above. Data are expressed as
described above for the acute treatments.
Glu con eogen esis In h ibition Activity. Hepatocytes were
isolated by collagenase digestion of livers from fed male
Sprague-Dawley rats (∼200 g of body weight) as previously
described.27 Cells were suspended (∼40 mg of weight/mL) in
Krebs-Henseleit bicarbonate buffer, pH 7.4, containing 1.5%
(w/v) gelatin (Difco, Detroit, MI) and continuously gassed with
O2/CO2 (19:1). Hepatocyte suspensions of 1.5 mL were incu-
bated in 25 mL of polypropylene Erlenmeyer flasks and placed
in a shaking water bath maintained at 37 °C. Stock solutions
of compounds were prepared in 100% DMSO; final concentra-
tion of DMSO did not exceed 0.5%. The isolated rat hepato-
cytes were incubated in the absence or presence of compounds
at a final concentration of 100 µM for 20 min; then [U14C]lactic
acid (NEC-599, DuPont-NEN; 2 mM, 0.625 µCi) ( 0.3 nM
glucagon were added, and the incubation was continued for
an additional 20 min. The conversion of [14C]lactic acid to [14C]-
glucose was then determined as described.15,28
2. In Vivo Ch a r a cter iza tion . Or a l Hyp oglycem ic
Activity. The blood glucose-lowering activities of the test
compounds were measured with 6-8 week old C57BL/6J -ob/
ob mice (obtained from J ackson Laboratories, Bar Harbor,
ME). Animals were housed 5/cage under standard animal care
practices. After a 5 day acclimation period, the animals were
weighed, and 25 µL of blood was collected via the retro-orbital
A 1.76 g (4.37 mmol) sample of this material was dissolved
in 40 mL EtOH and treated with 4.4 of mL 12 N HCl. The
mixture was heated at reflux for 30 min, the solvent was
stripped, and the residue was dissolved in Et2O and washed
with water. After drying (MgSO4) and stripping, the residue
was chromatographed on silica gel with CH2Cl2/hexane (1:1)
to give 1.1 g (66%) of ethyl (5-chloroinden-1-yl)-2-(4-isopropyl-
phenoxy)-2-methylacetate: MS (EI) 384 (M); NMR (CDCl3) δ
1.25 (t) and 1.35 (t, 3H) Me), 1.25 (d, 6H, Me), 1.85 (s, 3H,
R-Me), 2.8 (m, 1H, CH), 3.4 (d, 2H, 3-CH2), 4.2 (q, 2H, O-CH2),
6.65 (m, 1H, H-2), 6.8 (d, 2H, H-2′), 7.0 (d, 2H, H-3′), 7.25 (d,
1H, H-6), 7.4 (d, 1H, H-4), 7.7 (d, 1H, H-7).
A 0.817 g (2.12 mmol) sample of this material was dissolved
in 10 mL of AcOH and hydrogenated over 0.3 g of 5% Pd/C at
atmospheric pressure for 3 h to give, after flash chromatog-
raphy on silica gel with CH2Cl2/hexane (3:1), 533 mg (65%) of
ethyl 2-(5-chloroindan-1-yl)-2-(4-isopropylphenoxy)-2-methyl-
acetate as a mixture of diastereomers: MS (CI) m/e 404 (M +

4802 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Sarges et al.
sinus prior to any treatment. The blood sample was im-
mediately diluted 1:5 with heparinized saline and held on ice
for subsequent centrifugation and glucose analysis of the
supernatant. Animals were grouped 5/cage with equal mean
blood glucose concentrations in each group and then dosed
(oral gavage) daily for 4 days with drug in vehicle or vehicle
alone (0.25% (w/v) methyl cellulose in water with no pH
adjustment). Animals were bled 20-24 h after the fourth
administration of drug or vehicle for blood glucose levels. The
weight of each animal was recorded on days 1 and 5; net food
intake (grams per cage of five animals) was also measured over
the 5 day period. The diluted plasma sample was analyzed
for glucose with the VP Super System Auto analyzer (Abbott
Laboratories, Irving, TX). Racemic englitazone was dosed at
50 mg/kg as a positive control.
The results are reported in the tables as glucose normaliza-
tion as percent of glucose lowering achieved by the standard
(racemic englitazone) at 50 mg/kg. As a rule, this dose of
racemic englitazone was sufficient to lower plasma glucose
levels of the ob/ ob mice to that of their lean litter mates (∼170
mg/dL). In data from 23 separate representative experiments,
the mean of the average day 5 glucose value in the vehicle-
treated control mice was 315 mg/dL (range 213-379 mg/dL)
and the mean coefficient of variation (CV%) was 26% (range
13-41%). In these same experiments the mean of the average
day 5 glucose value in the mice treated with racemic englita-
zone (the positive control) was 171 mg/dL (range 144-219 mg/
dL) and the mean CV% was 22% (range 8-64%). For
statistical analysis of the data the glucose values of drug-
treated and vehicle-treated animals were compared by an
unpaired two-tailed Student’s t-test.
A. Martin, Ernest S. Paight, and J oseph F. Russo for
excellent technical assistance, Drs. David A. Clark,
Bernard Hulin, and Ralph W. Stevenson for helpful
discussions, and Dr. Scott F. Sneddon for initial energy
minimizations.
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