Hypoglycemic prodrugs of 4-(2,2-dimethyl-1-oxopropyl)benzoic acid

Article abstract of DOI:10.1021/jm980438y

SAH 51-641 (1) is a potent hypoglycemic agent, which acts by inhibiting hepatic gluconeogenesis. It is a prodrug of 4-(2,2-dimethyl-1- oxopropyl)benzoic acid (2) and 4-(2,2-dimethyl-1-hydroxypropyl)benzoic acid (3), which sequester coenzyme A (CoA) in the

Full text of DOI:10.1021/jm980438y

J . Med. Chem. 1999, 42, 153-163
153
Hyp oglycem ic P r od r u gs of 4-(2,2-Dim eth yl-1-oxop r op yl)ben zoic Acid
Thomas D. Aicher,*,† Gregory R. Bebernitz,† Philip A. Bell,‡ Leonard J . Brand,† J eremy G. Dain,§
Rhonda Deems,∇ William S. Fillers,‡ J ames E. Foley,∇ Douglas C. Knorr,† J effrey Nadelson,† Dario A. Otero,†
Ronald Simpson,† Robert J . Strohschein,† and Douglas A. Young∇
Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, New J ersey 07901
Received J uly 27, 1998
SAH 51-641 (1) is a potent hypoglycemic agent, which acts by inhibiting hepatic gluconeogenesis.
It is a prodrug of 4-(2,2-dimethyl-1-oxopropyl)benzoic acid (2) and 4-(2,2-dimethyl-1-hydroxy-
propyl)benzoic acid (3), which sequester coenzyme A (CoA) in the mitochondria, and inhibits
medium-chain acyltransferase. 1-3 and 4-tert-butylbenzoic acid all cause testicular degenera-
tion in rats at pharmacologically active doses. 14b (FOX 988) is a prodrug of 3, which is
metabolized in the liver at a rate sufficient enough to have hypoglycemic potency (an ED50 of
65 µmol/kg, 28 mg/kg/day, for glucose lowering), yet by avoiding significant escape of the
metabolite 3 to the systemic circulation, it avoids the testicular toxicity at doses up to 1500
µmol/kg/day. 14b was selected for clinical studies.
In tr od ction
in IGT) is resistance to the peripheral biological effects
of insulin. In patients with fasting blood glucose of
under 200 mg/dL, such peripheral insulin resistance is
primarily manifested as a defect in the uptake and
storage of glucose in skeletal muscle.8 The impaired
ability of insulin to clear glucose from the blood leads
to a compensatory hyperinsulinemia, which in turn
characteristically leads to an increase in insulin resis-
tance. Hyperglycemia, and eventually type 2 diabetes,
results in those patients unable to secrete sufficient
insulin to overcome this reflexive cycle. When fasting
blood sugars rise to greater than 200 mg/dL, further
changes in metabolism occur, driven by an elevation in
the flux of free fatty acids (FFAs) from adipocytes. The
increased oxidation of free fatty acids directly increases
the rate of gluconeogenesis and significantly exacerbates
the hyperglycemia. Clinical studies have demonstrated
that decreasing free fatty acid levels or inhibiting their
oxidation results in a reduction in this fatty-acid-driven
gluconeogenesis and, importantly, in the prevailing
hyperglycemic state.
Type 2 diabetes is a chronic, progressive metabolic
disease, typically characterized by hyperglycemia, hy-
perlipidemia, and insulin resistance. Diabetes is most
frequently diagnosed by the presentation of fasting
hyperglycemia, severely impaired oral glucose tolerance,
or the classical symptoms (polydipsia, polyphagia, and
polyuria).1 Type 2 diabetes, diagnosed and undiagnosed,
occurs in >5% of the U.S. population (affecting 16
million people in 1996).2 In addition, the prediabetic
state of impaired glucose tolerance (IGT, normal basal
glycemia with impaired glucose tolerance) is even more
prevalent affecting approximately 35-40 million adults
in the United States, and many of these subjects will
progress into overt type 2 diabetes.
As type 2 diabetic patients are frequently overweight,
and since weight loss and exercise lessen insulin
resistance, diet and exercise are usually the first pre-
scribed treatments for most type 2 diabetic patients.3,4
The rapid reversal of the positive effects of exercise and
weight loss after noncompliance leaves a large number
of patients in need of medication to help restore eugly-
cemia. The importance of such treatments was recently
emphasized when the Diabetes Control and Complica-
tions Trial (DCCT) conclusively demonstrated that tight
control of blood glucose reduced the development of reti-
nopathy, nephropathy and neuropathy, each by >50%
in type 1 diabetes (insulin-dependent diabetes, IDDM).5
The magnitude of these findings, together with the
similarity of the pathologies seen in type 1 and type 2
diabetes, strongly suggests that a similar control of
blood glucose levels in type 2 diabetic patients is equally
important.6 Indeed, virtually the same results as those
seen in the DCCT were reported in a prospective 6-year
study in J apan with type 2 diabetic patients.7
SAH 51-641 (1) is a potent hypoglycemic agent, which
acts by inhibiting gluconeogenesis via an inhibition of
fatty acid oxidation.9 1 is metabolized via sequential
oxidation/reduction to 4-(2,2-dimethyl-1-oxopropyl)ben-
zoic acid (2) and 4-(2,2-dimethyl-1-hydroxypropyl)ben-
zoic acid (3) which, as a substrate for the medium-chain
fatty acyl CoA ligase, is transformed to the correspond-
ing CoA ester (Figure 1). Such an esterification is
common with many benzoic acids, which are then
typically subjected to glycine conjugation to afford the
corresponding hippurates, which are in turn excreted.10
To the extent that this second step is rate-limiting, the
net effect is to lower intramitochondrial CoA levels.
Because of the integration of control of metabolic
pathways, this diminution of CoA in turn would be
expected to elicit several effects (Figure 2). Initially a
decrease in carnitine palmitoyltransferase II (CPT II)
activity and thus a lessening of fatty acid oxidation
would be expected, while the resultant lower levels of
acetyl CoA would result in increased pyruvate dehy-
A major factor in the impaired ability to dispose of
an oral glucose load (as occurs in type 2 diabetes and
* Author to whom correspondence should be addressed.
† Department of Chemistry.
‡ Department of Molecular and Cellular Biology.
§ DMPK Biotransformation.
∇ Department of Diabetes Pharmacology.
10.1021/jm980438y CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/19/1998

154 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
Aicher et al.
F igu r e 1. Metabolism of SAH 51-461 (1).
F igu r e 2. Metabolic consequences of lower CoA/AcCoA levels elicited by 3.
drogenase activity, leading to lower gluconeogenic con-
version of lactate, pyruvate, and alanine. Furthermore,
lower levels of acetyl CoA would lead to a diminished
acetyl CoA-mediated allosteric activation of the rate-
limiting gluconeogenic enzyme pyruvate carboxylase.
This mechanism of action is similar to that proposed
for 4-tert-butylbenzoic acid.11 Unfortunately, like 4-tert-
butylbenzoic acid, 1-3 caused a marked reduction in
testis weights.12 This effect was observed at all doses
where hypoglycemic activity was seen in a low-dose
streptozotocin (STZ)-treated diabetic animal model. As
such, these testicular effects were clearly development-
limiting.
3 at concentrations which would be sufficient to lower
gluconeogenesis, yet not lead to undesirably high con-
centrations of 3 in the systemic circulation (i.e., in the
blood supply to the testessFigure 3). If the prodrug did
not produce 3 at a sufficient rate to lower CoA levels,
then it would be ineffective as a hypoglycemic agent. If
3 is formed at too great a rate, it would “spill” into the
general circulation leading to unacceptable effects on
the testes.
To pursue this goal, a large number of potential pro-
drugs of 3 were synthesized, the title compounds being
illustrative examples. Four general conceptual ap-
proaches toward limiting the effect of 3 to the liver were
attempted. One was to replace the ketal of 1 with a
different chemical moiety which only slowly would
Our goal was to design a prodrug of 3 which would
be targeted only to the liver and which would produce

Hypoglycemic Prodrugs of Benzoic Acid
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 155
F igu r e 3. Design concept: make metabolic production of 3 rate-limiting.
Sch em e 1. Synthesis of Ketal and Ether Prodrugsa
Ch em istr y
SAH 51-641 (1) was prepared via condensation of
2,2,4′-trimethylpropiophenone with ethylene glycol with
a catalytic amount of acid. Oxidation of 2,2,4′-trimeth-
ylpropiophenone with aqueous KMnO4 afforded 2. Re-
duction of 2 with NaBH4 in alcohol afforded 3. Ketals
4a and 4b were prepared via treatment of 2 with the
appropriate diol and a catalytic amount of acid. Alky-
lation of 3 with methyl iodide or allyl bromide yielded
5a and 5b (Scheme 1).
Treatment of 2 with thionyl chloride afforded 4-(2,2-
dimethyl-1-oxopropyl)benzoyl chloride which when added
to the appropriate amine, hydroxylamine, or alkoxy-
lamine afforded 6a , 6c, 6d , 12, 13a , and 13g (Schemes
2 and 3). 6a , when treated with a 2-fold excess of KH
and of 4-(2,2-dimethyl-1-oxopropyl)benzoyl chloride, af-
forded 7a . In a similar manner acylation of 4-fluoroben-
zamide afforded 10. More extensive acylation of nicoti-
namide afforded 11. Dehydration of 6c via a modification
of Desneuelle’s procedure16 afforded 8, and cyclization
of 6d in analogy to Suda’s procedure17 yielded 9.
a
Conditions: (a) p-TsOH, diol, toluene; (b) KOH, aq EtOH; (c)
KH, alkyl halide, THF; (d) KOH, aq EtOH.
Hydroxamates 13c-f and 13h were prepared via
alkylation of the hydroxamic acid 12 with the appropri-
ate halide. Acylation of 13a -g with 4-(2,2-dimethyl-1-
oxopropyl)benzoyl chloride to yield 14a -g could be
effected with either triethylamine or KH as the base.
The stereochemistries of the resulting products were
initially assigned via analogy to literature examples.18
In the case of 14b, this assignment was subsequently
proven correct by X-ray analysis. Preparation of the
chiral enantiomers of 3 was accomplished by utilizing
the CBS chiral reducing agent developed in Corey’s
laboratory (Scheme 4).19 Interestingly, while the reduc-
tion of 15 to afford 16a and 16b proceeded at 0 °C with
high enantiomeric excess, the reduction of 14b did not
produce 17a in high optical purity at 0 °C. However,
when the reaction was done at room temperature, the
percentage of 17a in the crude product significantly
increased. Isolation of pure 17a and 17b was then
effected via crystallization of the major diastereomer
from the crude product.
undergo a transformation to an eventual alcohol and
which would thus produce 3 in a time-limited fashion.
The second approach was to limit the rate of metabolism
of a carboxylic acid prodrug. Clearly, a methyl group
was too rapidly converted into the acid. Would a
carboxylic acid prodrug, which was designed to be a poor
substrate for metabolizing enzymes, be successful?
Several amides, esters, ethers, and imides were syn-
thesized as compounds which potentially would produce
the carboxylic acid more slowly. A third approach was
to produce the chiral enantiomers of 3 in the expectation
that the pharmacodynamics of the enantiomers would
be different. The fourth approach was to target 3 to the
liver as an ester of glycerol.13-15 Our initial criteria of
success would be a compound which lowered the glu-
coneogenic capacity of freshly isolated hepatocytes,
which lowered fatty acid oxidation and glucose produc-
tion in vivo in the STZ diabetic animal model, and which
produced minimal circulating levels of 3.

156 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
Sch em e 2. Synthesis of Amide and Imide Prodrugsa
Aicher et al.
screening pool. The selection procedure resulted in a rat
model of type 2 diabetes in which animals exhibited
hyperglycemia in the fed (175-260 mg/dL) and fasted
states (160-230 mg/dL) with normal insulin levels (for
details, see Chronic Study in STZ-Treated Rats Fed a
High-Fat Diet in the Experimental Section). The results
presented in Table 1 are 6 h postdose on days 8 and 11
and are presented as percent efficacy (where 100%
efficacy is equal to a normalization of blood glucose
levels to 60 mg/dL).21
As stated in the Introduction, our goal was to design
a prodrug of 3 which would produce 3 at concentrations
in the liver sufficient to lower gluconeogenesis yet not
lead to high concentrations of 3 in the systemic circula-
tion. To pursue this aim, an assay to measure the
concentration of 3 in the plasma was developed as a
screening tool. Blood samples were centrifuged after
collection at each time point. Plasma from each group
was pooled to provide sufficient sample for analysis by
HPLC. The AUC0-48h of 3 in plasma was measured by
HPLC at time points of 2, 4, 7, 8, 24, 36, and 48 h post-
oral-dosing. The results are summarized (in µg‚h/mL)
in Table 1.
To preselect potential development compounds, those
which had an AUC0-48h of less than 500 µg‚h/mL (this
criterion was chosen as 4 times the AUC0-48h of 7a ,
which was the first compound which did not lower testes
weights) and a hypoglycemic percent efficacy of greater
than 60% in the STZ diabetic animal model were
evaluated in a 28-day rat testicular toxicity assay. From
the data produced by 1, 7a , 10, 11, 14a , 14b, and 14f
(discussed below), it became apparent that there existed
a useful trend between the incidence and severity of
testicular toxicity observed in a 28-day safety study and
the AUC0-48h of 3 in the blood observed following a
single oral dose. The AUC0-48h of 3, however, did not
correlate with the hypoglycemic efficacy of the com-
pounds (i.e., 14a , 14b, and 14f are all efficacious in the
STZ-treated diabetic animal model yet afford a low
AUC0-48h of 3 in blood plasma). This useful trend was
also utilized in the selection and evaluation of a different
series of prodrugs of 3.
Compounds which markedly decreased â-hydroxybu-
tyrate without markedly decreasing glucose levels in the
acute assay in some cases had an equivalent hypogly-
cemic effect as 1 in the chronically STZ-treated diabetic
animal model (i.e., compare 7a , 14b, and 14f to 1 and
10 in Table 1). Also compounds which inhibited fatty
acid oxidation while not immediately lowering glucose
levels tended to afford a lower area under the curve
(AUC0-48h) and to have lesser effects on the testes (i.e.,
compare 7a , 14a , 14b, and 14f to 1, 2, 3, 6a , and 10 in
Table 1; data discussed further below).
a
Conditions: (a) KH, 4-(2,2-dimethyl-1-oxopropyl)benzoyl chlo-
ride, THF; (b) KH, tert-butyl bromoacetate, THF; (c) TFA; (d)
SOCl2; (e) NaOH, EtOH; (f) DCC, dioxane.
Resu lts a n d Discu ssion
The compounds described were first evaluated for
their ability to inhibit oleate-dependent gluconeogenesis
in hepatocytes which had been freshly prepared from
18-h fasted rats according to the procedure of Berry and
Friend,20 with minor modifications as described by
Young et al.9 All compounds which significantly de-
creased glucose production at a concentration of less
than or equal to 100 µM were evaluated in vivo. All
compounds listed in Table 1 had IC50 values of less than
100 µM (data not shown).
Compounds were first tested in an acute in vivo study
for inhibition of gluconeogenesis in normal male Spra-
gue-Dawley rats (for details, see Acute Screen in the
Experimental Section). In this test, glycogen stores in
normal rats were exhausted by fasting for 18 h, and
consequently glucose levels were maintained via gluco-
neogenesis stimulated by free fatty acid oxidation, which
in turn directly elevated â-hydroxybutyrate levels. Both
â-hydroxybutyrate levels and glucose were measured as
percent of control values 3 h after dosing (see Table 1).
Compounds which decrease â-hydroxybutyrate and/or
glucose levels in the acute in vivo assay were subse-
quently tested in the streptozotocin (STZ)-treated dia-
betic animal model according to the procedure of Young
et al.9 with the modification that the animals were fed
a high-fat diet. The doses of streptozotocin dosed were
sufficient to significantly impair insulin secretion but
generally not high enough to induce a type 1 diabetic
state. However, even at this relatively low dose of
streptozotocin, some animals lost nearly all ability to
secrete insulin and consequently were removed from the
The chiral acid 16a has an approximately 4-fold lower
IC50 (7 µM vs 32 µM) than exhibited by its enantiomer
16b for the inhibition of oleate-derived gluconeogenesis
in the hepatocyte assay. When these compounds were
tested orally, it was demonstrated by chiral HPLC with
a Chiracel column (see Experimental Section) that the
two compounds did not interconvert. Therefore a chiral
version of 14b was prepared.
The testis was shown to be an organ adversely
affected by 1, 2, 3, 6a , and 10. These compounds caused
severe testicular toxicity as measured by decreased

Hypoglycemic Prodrugs of Benzoic Acid
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 157
Sch em e 3. Synthesis of Hydroxylamine-Derived Prodrugsa
a
Conditions: (a) NaOH, RX, THF; (b) NH2OR, 4-(2,2-dimethyl-1-oxopropyl)benzoyl chloride, aq THF; (c) KH, 4-(2,2-dimethyl-1-
oxopropyl)benzoyl chloride, THF; (d) OsO4, NMMO, aq acetone.
Sch em e 4. Synthesis of the Chiral Enantiomers of 3 and Prodrugs of 3a
a
Conditions: (a) BH3‚TMS, CBS catalyst, 0 °C, THF; (b) BH3‚TMS, CBS catalyst, rt, THF.
testicular weights (greater than 25% decrease each)
after chronic treatment for 28 days in normal rats. In
addition, there was an absence of mature sperm cells
similar to that reported for 4-tert-butylbenzoic acid.12
The first compounds which afforded hope that tes-
ticular toxicity could indeed be reduced while simulta-
neously maintaining the desired hypoglycemic effect
were the imides 7a and 11. These compounds afforded
a relatively low AUC0-48h of 3 and had a less severe
effect on the testis in chronic dosing. Our initial
enthusiasm for these compounds, based upon the ob-
servation that weights of testes from rats treated with
7a and 11 were not changed significantly upon chronic
dosing, was dampened when it was observed that there
still remained significant histological changes in tes-
ticular tissue upon dosing at 700 µmol/kg for 28 days
(sloughing/degeneration of germinal epithelium with
giant cell formation to a much lower extent, however,
than with 1).22
significantly higher systemic exposure (AUC0-48h) to the
metabolite 3.
The O-acylation of the hydroxamates 13a -h afforded
the prodrugs 14a -h . Such mixed esters are known in
the literature to be resistant to hydrolysis by aqueous
base.18 14a -h inhibited fatty-acid-driven gluconeogen-
esis in hepatocytes, inhibited fatty acid oxidation in the
acute in vivo model, and lowered glucose levels in the
STZ-treated diabetic animal model. Based upon the
AUC0-48h of 3 produced by dosing of 14a , 14b, 14f, and
14g, it was predicted that the severity of testicular
toxicity induced by these compounds would be lower
than that of 1. Indeed none of these compounds caused
changes in testicular weights in rats upon chronic
treatment. It was encouraging that the methyl imide
14b at doses up to 1500 µmol/kg/day also failed to cause
any significant histological changes in the testes of rats
or dogs (in which it also lowered free fatty oxidation)
after 4 weeks of dosing.22,23
It was hypothesized that the imide 7a was not as
easily metabolized to 3 as were previously synthesized
amide or ester prodrugs, presumably because there
existed no lipase or amidase which would easily recog-
nize the imide functionality for hydrolysis. Consequent-
ly, other imides and other constrained amide motifs
were prepared for evaluation. Substitution of the imide
of 7a with polar moieties, such as 7b, afforded a
Overall 14b had an EC50 of 9.2 µM in lowering oleate-
stimulated glucose production in hepatocytes from 18-h
fasted normal rats, an ED50 of 47 µmol/kg for lowering
â-hydroxybutyrate levels in 18-h fasted normal rats, and
an ED50 of 65 µmol/kg (28 mg/kg/day) for glucose
lowering in the STZ-treated diabetic animal model.24 In
addition to lowering glucose levels, 14b also causes
significant decreases in serum triglyceride (g60% de-

158 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
Ta ble 1. In Vivo Properties of Prodrugs of 3
Aicher et al.
a
AUC0-48h (µg‚h/mL)
in vivo chronic assayc
testes weightd
in vivo acute assayb (% of control)
150
300
µmol/kg
700
% efficacy
(day 8.25)
% efficacy
(day 11.25)
% of control
(dose µmol/kg/day)
compd
µmol/kg
µmol/kg
ketones
12***
glucose
58**
1
1
1513
1465
3562
52***
64***
52 (700)***
2
3
4a
4b
5a
5a
47 (700)***
74 (350)***
50***
111
105
1402
263
1015
775
15***
18***
17***
41**
na
23*
65***
na
59**
81*
5b
941
29***
107
na
na
6a
6d
7a
7b
8
9
10
11
14a
14b
14c
14d
14e
14f
14g
14h
16a
16b
17a
17b
48 (700)***
101 (700)
964
122
1083
886
413
588
64
2928
2669
4***
21***
6***
92
56***
74**
90*
65**
95
70**
98
98
53**
na
na
57**
73***
80***
64***
92***
109***
47**
na
na
54**
74***
98***
59***
92***
108***
20***
21***
13***
46***
50***
30***
15***
19***
15***
41***
43***
19***
23***
80*
2568
325
63 (700)***
95 (350)
102 (700)
96 (700)
0
55
85
122
565
1849
1629
155
158
2033
49***
70**
94
94
80***
53**
90***
64**
na
98***
85***
102***
63**
105
1001
63***
42***
94
59 (350)***
62 (350)***
na
2370
17***
61***
a
b
Area under the curve of the active metabolite 3 in blood plasma, after dosing orally at the dose indicated. In vivo acute screen (see
Experimental Section). Data are reported as percent of control at 3 h postdosing (100 µmol/kg). c In vivo chronic study orally dosed at 70
µmol/kg in STZ-treated rats fed a high-fat diet (see Experimental Section). Data are reported as percent efficacy (where 100% efficacy is
d
lowering of blood glucose levels to 60 mg/dL) (na, no statistical significance to activity). [(Testes weight(treated)/body weight(treated)]/
[testes weight(control)/body weight(control)] × 100%. * p < 0.05; ** p < 0.01; *** p < 0.001.
crease at all doses > 70 µmol/kg/day, p < 0.001), serum
insulin levels (g40% decrease at all doses g 35 µmol/
kg/day, p < 0.01), serum free fatty acid levels (g25%
decrease at all doses g 35 µmol/kg/day, p < 0.05), and
cholesterol levels (g30% decrease at all doses g 35 µmol/
kg/day, p < 0.001) following multiple dose in the STZ-
treated diabetic animal model on day 11.24 On the basis
of these data, 14b was selected for clinical trials since
toxicity from systemic effects on the testes should no
longer be a limiting factor for dosing patients.
The authors recognize that the hypothesis that 7a and
14b cause less testicular lesions due to greater diffi-
culty in their metabolic activation may not be correct.
Indeed it is troubling for this hypothesis that the more
polar derivatives of 7a and 14b cause higher systemic
exposure to 3. Three possible explanations for this
divergence have been considered. First, it is possible
that the greater hydrolysis of 14c, 14h , and 7b and
other polar moieties could be due to intramolecular
assistance in the hydrolysis. Indeed, transacetylation
and decomposition of many of these compounds occur
slowly in solution (however 17a does not have this route
of decomposition available to it). A second possibility is
that 14b and 7a , although absorbed well, are not
delivered to the liver at the same rate as the more polar
analogues. A possible mechanism for such a pharma-
cokinetic effect is the incorporation of 7a and 14b into
lipid vesicles. Such a route of delivery could be highly
liver-selective.14 A future paper will address a different
compound series which was designed for such a route
of delivery.
Exp er im en ta l Section
P h a r m a cology. 1. Acu te Scr een . The acute screen is
conducted in normal male Sprague-Dawley rats (200-300 g)
which are fasted for 18 h prior to the experiment. Five animals
per group are dosed orally (po) by gavage with vehicle
(carboxymethylcellulose, CMC) or compound in vehicle. At 3
h postdose, animals are anesthetized briefly (approximately
30 s) with CO2 and a blood sample is obtained via cardiac
puncture. After the sample is obtained, animals are allowed
to recover from the CO2 and may potentially be used for up to
three times in studies spaced at weekly intervals. Serum levels
of â-hydroxybutyrate, glucose, and lactate are measured.
Comparisons between metabolite levels of control and treated
groups are made using Student’s t-tests. During a 6-month
period, mean ( SEM control values for po administration have
been 11.7 ( 0.3 mg/dL for ketones, 115 ( 1 mg/dL for serum
glucose, and 1.22 ( 0.05 mM for serum lactate.
2. Ch r on ic Stu d y in STZ-Tr ea ted Ra ts F ed a High -F a t
Diet. The selection procedure of the rats for this model is
similar to the previously described model, with the significant
modification that rats (250-300 g) were fed a high-fat purified
diet throughout the study (Purina 5814M-4).9,25 In short, 3
days after initiation of the diet, the rats were rendered diabetic
by injection of 40 mg/kg streptozotocin into the tail vein. Five
days later, animals with blood glucose levels greater than 200
mg/dL were excluded. Those remaining were fasted for 18 h
prior to an oral glucose load (1.35 g/kg dextrose). Three hours
later, animals with blood glucose levels between 40 and 100
mg/dL were retained. The screen began 4 days later, using
animals with blood glucose levels > 180 mg/dL. Animals were
dosed once per day (1 mL/100 g of body weight) with vehicle
(CMC) or compound in vehicle. Blood glucose levels were
checked at 0 and 6 h postdose on days 1, 4, 8, and 11 of the
11-day screen. Food was removed at the 0-h sample and
returned after the 6-h sample. The results are expressed as

Hypoglycemic Prodrugs of Benzoic Acid
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 159
percent efficacy, which is calculated with the assumption that
normal fasting blood glucose is 60 mg/dL in the rat. Therefore,
100% efficacy would indicate complete normalization of blood
glucose levels in STZ-treated rats. Total cholesterol and
triglycerides were analyzed by standard enzymatic assays
(Electro-Nucleonics, Fairfield, NJ ).
refluxed overnight using a Dean-Stark water separator,
cooled, and concentrated in vacuo. A solution of KOH (4.00 g,
71 mmol) in water (30 mL) and EtOH (50 mL) was added to
the crude residue, and the mixture was refluxed for 1 h.
Concentration in vacuo to 20 mL, dilution with water to 50
mL, and at 0 °C a careful acidification to pH 3 (with 2 N HCl)
afforded a mixture which was filtered. The solids were washed
several times with water and then hexanes and dried in vacuo
to yield 3.38 g of 4a (44%) as a white solid: mp 235-236 °C;
1H NMR (CDCl3) δ 0.89 (s, 9H), 1.19 (m, 1H), 2.09 (m, 1H),
3.65 (m, 2H), 3.89 (m, 2H), 7.49 (d, J ) 8.6 Hz, 2H), 8.13 (d, J
) 8.6 Hz, 2H); MS (DCI, isobutane) m/z (rel intensity) 266 (16),
265 (100). Anal. (C15H20O4) C, H.
4-[2-(1,1-Dim eth yleth yl)-5,5-d im eth yl-1,3-d ioxa n -2-yl]-
ben zoic Acid (4b). Prepared in a similar manner, substitut-
ing 2,2-dimethyl-1,3-propanediol for 1,3-propanediol, was 4b.
From the acid 2 (5.00 g, 24.3 mmol) was obtained 6.28 g (89%)
of 4b as a white solid: mp 239 °C; 1H NMR (CDCl3) δ 0.53 (s,
3H), 0.93 (s, 9H), 1.25 (s, 3H), 3.30 (d, J ) 11.1 Hz, 2H), 3.40
(d, J ) 11.1 Hz, 2H), 7.48 (d, J ) 8.5 Hz, 2H), 8.13 (d, J ) 8.5
Hz, 2H); MS (DCI, isobutane) m/z (rel intensity) 294 (21), 293
(100). Anal. (C17H24O4) C, H.
4-(1-Meth oxy-2,2-d im eth ylp r op yl)ben zoic Acid (5a ). A
slurry of potassium hydride (3.1 g, 77 mmol) in hexane (8 mL)
was added to a solution of 3 (4.80 g, 23 mmol) in DMF (10
mL) and THF (10 mL) at 0 °C. After the mixture stirred for
15 min, an excess of methyl iodide (4.3 mL, 69 mmol) was
added. This mixture was stirred overnight at room tempera-
ture and then quenched by the addition of MeOH (4 mL). The
mixture was concentrated in vacuo to a paste, which was
partitioned between CH2Cl2 and water. The organic layer was
dried and concentrated. A solution of potassium hydroxide
(4.00 g, 71 mmol) in water (20 mL), was added to the residue
dissolved in EtOH (20 mL) and the resulting mixture was
refluxed for 1 h, cooled, and concentrated to 20 mL. The
concentrate was acidified with 2 N HCl to pH 3 and filtered.
The solid was washed several times with water and dried in
vacuo to yield 2.54 g (50%) of 5a as a white solid: mp 171 °C;
1H NMR (CDCl3) δ 0.87 (s, 9H), 3.18 (s, 3H), 3.82 (s, 1H), 7.47
(d, J ) 8.4 Hz, 2H), 8.06 (d, J ) 8.4 Hz, 2H); MS (DCI, NH3)
m/z (rel intensity) 224 (14), 223 (100). Anal. (C13H18O3) C, H.
3. Sta tistics. Responses of treated animals were compared
to control responses using Student’s t-test.
Ch em istr y. All melting points (mp) were obtained on a
Thomas-Hoover capillary melting point apparatus and are
uncorrected. Proton magnetic resonance spectra were recorded
on a Bruker AC 300-MHz NMR or a J EOL 270-MHz NMR
spectrometer. Chemical shifts were recorded in ppm (δ) and
are reported relative to the solvent peak or TMS. Mass spectra
were run on a Finnigan Mat 4600 spectrometer. Elemental
analyses were performed with a CHNS-O EA 1108 elemental
analyzer produced by Carlo Erba, and the data for C, H, and
N are within 0.4% of theoretical values unless otherwise
indicated. Thin-layer chromatography (TLC) was carried out
on Macherey-Nagel Polygram Sil G/U254 plates. Column chro-
matography separations were carried out using Merck silica
gel 60 (mesh 230-400). Reagents and solvents were purchased
from common suppliers and were utilized as received. All
reactions were conducted under a nitrogen atmosphere. Yields
are of purified product and were not optimized. All starting
materials are commercially available unless otherwise indi-
cated.
2-(1,1-Dim et h ylet h yl)-2-(4-m et h ylp h en yl)-1,3-d ioxo-
la n e (1). A solution of 2,2,4′-trimethylpropiophenone (105 g,
595 mmol), ethylene glycol (43.4 g, 700 mmol), benzene (1400
mL), and a catalytic amount of p-toluenesulfonic acid mono-
hydrate (500 mg, 1.5 mmol) was refluxed overnight using a
Dean-Stark water separator. The mixture was cooled, washed
with water (3 × 600 mL) and brine (600 mL), dried (MgSO4),
and concentrated. The crude product was recrystallized from
ether to afford 66.2 g (50%) of 1 as white crystals: mp 65-67
°C; 1H NMR (CDCl3) δ 0.93 (s, 9H), 2.33 (s, 3H), 3.63-3.70
(m, 2H), 3.86-3.95 (m, 2H), 7.08 (d, J ) 8.1 Hz, 2H), 7.30 (d,
J ) 8.1 Hz, 2H); MS (DCI, isobutane) m/z (rel intensity) 222
(8), 221 (100). Anal. (C14H20O2) C, H.
4-(2,2-Dim eth yl-1-oxop r op yl)ben zoic Acid (2). 2,2,4′-
Trimethylpropiophenone (90 g, 510 mmol) was added to a
solution of KMnO4 (162 g, 1.03 mmol) in water (1.2 L). The
mixture was refluxed for 2 h; additional KMnO4 (154 g, 0.97
mmol) was added. The mixture was refluxed for an additional
2 h and filtered while hot, and the MnO2 was washed with
water. The combined filtrate was cooled in an ice bath and
acidified to pH 2 with concentrated HCl. The white solid
was filtered and washed several times with water. CH2Cl2
(190 mL) and MeOH (10 mL) were added, and the mixture
was filtered. The filtrate was concentrated and recrystallized
from ether to obtain 59 g (56%) of 2 as white crystals: mp
161-162 °C; 1H NMR (CD3OD) δ 1.31 (s, 9H), 7.67 (d, J )
8.6 Hz, 2H), 8.06 (d, J ) 8.6 Hz, 2H); MS (DCI, isobu-
tane) m/z (rel intensity) 208 (8), 207 (100), 189 (31). Anal.
(C12H14O3) C, H.
4-(1-Hyd r oxy-2,2-d im eth ylp r op yl)ben zoic Acid (3). So-
dium borohydride (8.0 g, 210 mmol) was added to a solution
of 2 (15 g, 73 mmol) in absolute EtOH (100 mL) at 0 °C. The
mixture was stirred at 0 °C for 1 h and then stirred an
additional 5 h at room temperature. The mixture was diluted
with water (300 mL) and concentrated in vacuo to 200 mL.
The mixture was washed with hexane. The aqueous layer was
acidified to pH 2 with 2 N HCl and filtered. The white solid
was recrystallized from aqueous ethanol to afford 14.1 g (93%)
of the monohydrate of the acid 3 as fine white crystals: mp
162-163 °C; 1H NMR (CD3OD) δ 0.89 (s, 9H), 4.49 (s, 1H),
7.41 (d, J ) 8.5 Hz, 2H), 8.13 (d, J ) 8.5 Hz, 2H); MS (DCI,
isobutane) m/z (rel intensity) 210 (8), 209 (100), 191 (35). Anal.
(C12H16O3‚H2O) C, H.
4-[2,2-Dim eth yl-1-(2-p r op en yloxy)p r op yl]ben zoic Acid
(5b). Prepared in
a similar fashion was 5b. The above
alkylation of 3 (4.00 g, 19.2 mmol) was repeated, using allyl
bromide rather than methyl iodide, and after recrystallization
of the crude product from CH2Cl2/hexane, there was obtained
1
3.32 g (70%) of 5b as white crystals: mp 86-88 °C; H NMR
(CDCl3) δ 0.91 (s, 9H), 3.71 (m, 1H), 3.92 (m, 1H), 4.04 (s, 1H),
5.13 (m, 1H), 5.26 (m, 1H), 5.90 (m, 1H), 7.40 (d, J ) 8.5 Hz,
2H), 8.11 (d, J ) 8.5 Hz, 2H); MS (DCI, NH3) m/z (rel intensity)
267 (16), 266 (100), 191 (50). Anal. (C15H20O3) C, H.
4-(2,2-Dim eth yl-1-oxop r op yl)ben za m id e (6a ). A mixture
of 2 (135 g, 655 mmol) and SOCl2 (135 mL, 1.85 mole) was
refluxed for 90 min. The excess SOCl2 was removed in vacuo,
and the residual oil was dissolved in hexane (1.2 L). The
solution was concentrated in vacuo to 300 mL, and the
resulting crystallization from the mixture yielded 4-(2,2-
dimethyl-1-oxopropyl)benzoyl chloride (146.6 g, 99%) as white
crystals: mp 39-40 °C.
4-(2,2-Dimethyl-1-oxopropyl)benzoyl chloride (5.62 g, 25
mmol) in ether (10 mL) was added dropwise to concentrated
aqueous ammonia (20 mL) at 0 °C. The mixture was stirred
for 1 h at 0 °C and stored overnight in the refrigerator. The
mixture was filtered and washed with water and then with
cold ether (2 × 50 mL) to afford 4.60 g (90%) as a white solid:
mp 137-139 °C.
N-[4-(2,2-Dim eth yl-1-oxop r op yl)ben zoyl]-L-p h en yla la -
n in e (6d ). A solution of 4-(2,2-dimethyl-1-oxopropyl)benzoyl
chloride (1.68 g, 7.5 mmol) in acetone (5 mL) was added to a
solution of L-phenylalanine (3.30 g, 20 mmol) in 2 N NaOH
(10 mL, 20 mmol) and acetone (10 mL) at 0 °C, while
maintaining the pH at ∼11 by the dropwise addition of 2 N
NaOH. After 1 h, the mixture was allowed to warm to room
temperature. The mixture was acidified with 2 N HCl, diluted
4-[2-(1,1-Dim eth yleth yl)-1,3-d ioxa n -2-yl]ben zoic Acid
(4a ). A mixture of 2 (6.00 g, 29.1 mmol), 1,3-propanediol (12.6
mL, 175 mmol), toluene (100 mL), and a catalytic amount of
p-toluenesulfonic acid monohydrate (250 mg, 0.76 mmol) was

160 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
Aicher et al.
with water (30 mL), and concentrated to 40 mL. The mixture
was extracted with CH2Cl2, dried (MgSO4), and concentrated
in vacuo. The residue was recrystallized from ether/hexane to
yield 2.33 g (88%) of 6d as white crystals: mp 120-123 °C;
1H NMR (CDCl3) δ 1.18 (s, 9H), 3.00 (m, 1H), 3.25 (m, 1H),
4.69 (m, 1H), 7.00-7.10 (m, 5H), 7.34 (d, J ) 8.4 Hz, 2H), 7.51
(d, J ) 8.4 Hz, 2H); MS (DCI, NH3) m/z (rel intensity) 355
(20), 354 (100). Anal. (C21H23NO4) C, H, N.
4-(2,2-Dim eth yl-1-oxop r op yl)-N-(4-flu or oben zoyl)ben -
za m id e (10). A slurry of potassium hydride (1.32 g, 33 mmol)
in hexane (5 mL) was slowly added to 4-fluorobenzamide (1.53
g, 11.0 mmol) in THF (20 mL) at 0 °C. The mixture was
allowed to warm to room temperature over 1 h. A solution of
4-(2,2-dimethyl-1-oxopropyl)benzoyl chloride (1.35 g, 6.0 mmol),
cooled to 0 °C, was added, and the mixture was stirred for 1 h
at room temperature and poured onto ice. This mixture was
extracted twice with CH2Cl2, and the combined organic layers
were washed with brine, dried, and concentrated in vacuo. The
product was isolated by column chromatography (CH2Cl2/
MeOH, 99:1, as the elutant), followed by recrystallization
with ether/hexane to yield 1.73 g (48%) of 10 as white
crystals: mp 100-101 °C; 1H NMR (CDCl3) δ 1.31 (s, 9H), 7.13
(m, 2H), 7.59-7.94 (m, 6H), 9.05 (bs, 1H); MS (DCI, NH3) m/z
(rel intensity) 329 (17), 328 (100), 221 (38), 140 (18). Anal.
(C19H18FNO3) C, H, N.
4-(2,2-Dim eth yl-1-oxop r op yl)-N-[4-(2,2-d im eth yl-1-oxo-
p r op yl)ben zoyl]ben za m id e (7a ). Prepared in a similar
fashion from 4-pivaloylbenzamide was 7a . mp 131-132 °C; 1H
NMR (CDCl3) δ 1.34 (s, 18H), 7.68 (d, J ) 7.2 Hz, 4H), 7.81
(d, J ) 7.2 Hz, 4H), 9.08 (s, 1H); MS (DCI, isobutane) m/z (rel
intensity) 395 (20), 394 (100). Anal. (C24H27NO4) C, H, N.
2-[4-(2,2-Dim e t h yl-1-oxop r op yl)p h e n yl]-4-(p h e n yl-
m eth yl)-5(4H)-oxa zolon e (9). A mixture of l-phenylalanine-
4-pivaloylbenzamide (5.00 g, 14.2 mmol), DCC (2.92 g, 14.2
g), and dioxane (20 mL) was stirred for 2 days at room
temperature and filtered, and the filtrate was concentrated
in vacuo. The residue was recrystallized from CH2Cl2/hexane
to yield 3.91 g (82%) of 9 as white crystals: mp 61 °C; 1H NMR
(CDCl3) δ 0.85 (s, 9H), 3.25 (dd, J ) 14.0, 5.9 Hz, 1H), 3.37
(dd, J ) 14.0, 5.8 Hz, 1H), 5.10 (m, 1H), 6.57 (d, J ) 7.7 Hz,
1H), 7.15-7.38 (m, 4H), 7.63-7.75 (m, 4H); MS (DCI, NH3)
m/z (rel intensity) 337 (21), 336 (100). Anal. (C21H21NO3) C,
H, N.
4-(2,2-Dim eth yl-1-oxop r op yl)-N-[4-(2,2-d im eth yl-1-oxo-
p r op yl)ben zoyl]ben za m id e N-2-Acetic Acid (7b). A mix-
ture of potassium hydride (0.35 g, 8.75 mmol) in THF (2 mL)
was added to a stirred solution of 7a (3.14 g, 8.0 mmol) in THF
(15 mL). After 15 min, a solution of tert-butyl bromoacetate
(1.42 mL, 8.8 mmol) was added, and the mixture was refluxed
for 24 h. Ether (50 mL) was added, and the mixture was
filtered. The filtrate was concentrated and subjected to column
chromatography using CH2Cl2 as the elutant. The major
product was crystallized from ether/hexane to yield 4.50 g of
the tert-butyl ester as white crystals: mp 61 °C.
A solution of the tert-butyl ester in trifluoroacetic acid (10
mL) was stirred at 0 °C for 2 h. The mixture was concen-
trated and crystallized from ether/hexane to afford 3.75 g
(98%) of 7b as white crystals: mp 159-160 °C; 1H NMR
(CDCl3) 1.17 (s, 18H), 4.84 (s, 2H), 7.35 (d, J ) 8.4 Hz,
4H), 7.49 (d, J ) 8.4 Hz, 4H), 8.74 (bs, 1H); MS (DCI, NH3)
m/z (rel intensity) 470 (29), 469 (100), 246 (73), 223 (22). Anal.
(C26H29NO6) C, H, N.
1-[4-(4,5-Dih yd r o-2-oxa zolyl)p h en yl]-2,2-d im et h yl-1-
p r op a n on e (8). A solution of 4-(2,2-dimethyl-1-oxopropyl)-
benzoyl chloride (5.58 g, 24.8 mmol) in acetone (5 mL) was
added to a solution of ethanolamine (1.5 mL, 24.8 mmol) in 2
N NaOH (12.4 mL, 24.8 mmol) at 0 °C. The mixture was
stirred at room temperature and concentrated in vacuo, and
the residue was partitioned between CH2Cl2 and 2 N HCl. The
organic layer was washed with brine, dried (MgSO4), and
concentrated in vacuo. The residue, N-[(2,2-dimethyl-1,3-
dioxola n -4-yl)m et h yl]-4-(2,2-dim et h yl-1-oxopr opyl)ben z-
amide (6b), was dissolved in thionyl chloride (20 mL), heated
to 60 °C for 1 h, cooled, and poured onto saturated NaHCO3
solution. The mixture was extracted with ether, and the
organic layer was dried (MgSO4) and concentrated in vacuo.
The residue was crystallized from ether/hexane to yield 4.45
g (67%) of 4-(2,2-dimethyl-1-oxopropyl)-N-(2-chloroethyl)ben-
zamide.
A solution of NaOH (662 mg, 60.4 mmol) in water (2 mL)
was added to a solution of this product (4.42 g, 16.5 mmol) in
EtOH (20 mL), and the mixture was heated to 65 °C for 15
min, diluted in cold water, and extracted twice with CH2Cl2.
The combined organic layers were dried (MgSO4) and concen-
trated in vacuo. The residue was recrystallized from ether/
hexane to yield 2.56 g (67%) of 8 as white crystals: mp 84 °C;
1H NMR (CDCl3) δ 0.85 (s, 9H), 4.12 (t, J ) 9.6 Hz, 2H), 4.47
(t, J ) 9.6 Hz, 2H), 7.68 (d, J ) 8.1 Hz, 2H), 7.99 (d, J ) 8.1
Hz, 2H); MS (DCI, NH3) m/z (rel intensity) 233 (14), 232 (100).
Anal. (C14H17NO2) C, H, N.
N,N-Bis[4-(2,2-dim eth yl-1-oxopr opyl)ben zoyl]-3-pyr idi-
n eca r boxa m id e (11). A slurry of potassium hydride (1.06 g,
26 mmol) in THF (5 mL) was added to a solution of nicotina-
mide (1.46 g, 12 mmol) in THF (30 mL). After 20 min, the
mixture was cooled to 0 °C, and a solution of 4-(2,2-dimethyl-
1-oxopropyl)benzoyl chloride (5.39 g, 24 mmol) in THF (15 mL)
was added. The reaction mixture was stirred for 1 h, ether
(100 mL) was added, and the mixture was filtered. The filtrate
was concentrated; the major product was isolated via chro-
matography using MeOH/CH2Cl2 (1:99) as the elutant and
recrystallized from ether/hexane to afford 2.80 g (47%) of 11
1
as white crystals: mp 151-152 °C; H NMR (CDCl3) δ 1.32
(s, 18H), 7.44 (dd, J ) 8.1, 4.7 Hz, 1H), 7.64 (d, J ) 8.4 Hz,
4H), 7.88 (d,, J ) 8.4 Hz, 4H), 8.15 (ddd, J ) 8.1, 4.7, 2.3 Hz,
1H), 8.80 (dd, J ) 4.7, 1.5 Hz, 1H), 9.01 (d, J ) 2.3 Hz, 1H);
MS (DCI, NH3) m/z (rel intensity) 517 (32), 516 (100), 499 (30).
Anal. (C30H30N2O5) C, H, N.
4-[[[(2,2-Dim eth yl-1-oxopr opyl)ben zoyl]am in o]oxy]ace-
tic Acid (13h ). A solution of hydroxylamine hydrochloride
(4.90 g, 71 mmol) dissolved in 2 N NaOH (35.5 mL, 71 mmol)
was slowly added to a stirred solution of 4-(2,2-dimethyl-1-
oxopropyl)benzoyl chloride (8.00 g, 35.6 mmol) in ether (50 mL)
at 0 °C. The mixture was poured into 2 N HCl (30 mL) and
extracted twice with ether. The combined organic layers were
dried (MgSO4) and concentrated in vacuo. The residue was
recrystallized (hexane/ether, 4:1) to yield 6.5 g (82%) of 4-(2,2-
dimethyl-1-oxopropyl)-N-hydroxybenzamide (12) as white crys-
tals: mp 125-126 °C.
To a solution of NaOH (1.70 g, 42.5 mmol) in EtOH (80 mL)
was added bromoacetic acid (3.06 g, 22 mmol) followed by the
hydroxamic acid 12 (4.42 g, 20 mmol). The mixture was
refluxed for 2 h and concentrated in vacuo, and the residue
was washed with ether. The solids were dissolved in water,
and the solution was acidified with 2 N HCl. The precipitated
solids were filtered off and recrystallized from CH2Cl2/Et2O
to yield 2.93 g (72%) of 13h as white crystals: mp 145-146
1
°C; H NMR (CDCl3) δ 1.32 (s, 9H), 4.67 (s, 2H), 7.68 (d, J )
8.4 Hz, 2H), 7.84 (d, J ) 8.4 Hz, 2H); MS (DCI, NH3) m/z (rel
intensity) 297 (37), 280 (11), 224 (13), 223 (100), 206 (23). Anal.
(C14H17NO5) C, H, N.
Prepared in a similar manner, using the appropriate halide
and with the following reactions times, were 13c-g:
4-(2,2-Dim eth yl-1-oxopr opyl)-N-(2-h ydr oxyeth oxy)ben -
za m id e (13c). Hydroxamic acid 12 (12.6 g, 56.9 mmol) and
2-bromoethanol (5.26 mL, 74.2 mmol) were refluxed as above
for 1 day. Crystallization of the product from CH2Cl2/hexane
gave 9.50 g (63%) of 13c as a white solid: 1H NMR (CD3OD)
δ 1.33 (s, 9H), 3.78 (t, J ) 7.1 Hz, 2H), 4.07 (t, J ) 7.1 Hz,
2H), 7.71 (d, J ) 8.4 Hz, 2H), 7.83 (d, J ) 8.4 Hz, 2H); MS
(DCI, NH3) m/z (rel intensity) 283 (37), 266 (13), 224 (13), 223
(100).
4-(2,2-Dim eth yl-1-oxopr opyl)-N-(2-m eth oxyeth oxy)ben -
za m id e (13d ). Hydroxamic acid 12 (8.00 g, 36.2 mmol) and
2-bromoethyl methyl ether (4.40 mL, 46.8 mmol) were re-
fluxed as above for 1 day. Crystallization of the product from
CH2Cl2/MeOH yielded 6.41 g (63%) of 13d as a white solid:
1H NMR (CDCl3) δ 1.31 (s, 9H), 3.41 (s, 3H), 3.63 (t, J ) 5.0

Hypoglycemic Prodrugs of Benzoic Acid
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 161
Hz, 2H), 4.21 (t, J ) 5.0 Hz, 2H), 7.65-7.84 (m, 4H), 9.41 (bs,
1H); MS (DCI, NH3) m/z (rel intensity) 297 (34), 280 (55), 223
(100).
(4.16 g, 15.8 mmol) and Et3N (2.88 mL, 20.7 mmol) in THF
(20 mL). After the mixture stirred for 2 h at room temperature,
Et2O (100 mL) was added and the mixture was filtered. The
filtrate was concentrated in vacuo, and the residue was
purified via column chromatography. The major product was
recrystallized from hexane to yield 5.00 g (70%) of 14f as white
1,1-Dim eth yleth yl 4-[[[4-(2,2-Dim eth yl-1-oxop r op yl)-
ben zoyl]a m in o]oxy]bu ta n oa te (13e). Hydroxamic acid 12
and tert-butyl 4-bromobutanoate were refluxed for 5 h. Crys-
tallization of the product from CH2Cl2/MeOH yielded 13e as
1
crystals: mp 89-90 °C; H NMR (CDCl3) δ 1.24 (d, J ) 6.3
1
Hz, 6H), 1.31 (s, 9H), 1.35 (s, 9H), 4.49 (heptet, J ) 6.3 Hz,
1H), 7.70-7.88 (m, 6H), 8.23 (d, J ) 8.4 Hz, 2H); 13C NMR
(65 MHz, CDCl3) δ 21.3, 27.6, 27.9, 44.2, 44.4, 125.4, 127.5,
128.0, 129.7, 129.9, 130.1, 132,1, 139.9, 144.0, 146.2, 161.3,
208.4, 209.2; MS (DCI, NH3) m/z (rel intensity) 470 (13), 469
(47), 453 (27), 452 (100). Anal. (C27H33NO5) C, H, N.
white crystals (62%): mp 67-71 °C; H NMR (CDCl3) δ 1.33
(s, 9H), 1.48 (s, 9H), 2.11 (m, 2H), 2.47 (t, J ) 7.2 Hz, 2H),
4.08 (t, J ) 6.3 Hz, 2H), 7.67-7.84 (m, 4H), 9.49 (bs, 1H); MS
(DCI, isobutane) m/z (rel intensity) 364 (21), 309 (17), 308
(100).
4-(2,2-Dim eth yl-1-oxop r op yl)-N-(1-m eth yleth oxy)ben -
za m id e (13f). Hydroxamic acid 12 and isopropyl bromide were
refluxed for 21 h. Recrystallization of the product from CH2-
Cl2/MeOH afforded 13f as white crystals (46%): mp 80-83
4-(2,2-Dim eth yl-1-oxop r op yl)ben zoic Acid An h yd r id e
w ith 4-(2,2-Dim eth yl-1-oxop r op yl)-N-(2-h yd r oxyeth oxy)-
ben zen eca r boxim id ic Acid (14c). p-Anisylchlorodiphenyl-
methane (13.0 g, 42.2 mmol) was added to a stirred solution
of the hydroxamate ester 13c (9.41 g, 35.5 mmol) in CH2Cl2
(20 mL) and pyridine at 0 °C, and the temperature was allowed
to rise to room temperature over 2 h. The mixture was diluted
with CH2Cl2, washed with saturated aqueous NaHCO3 and
brine, dried (MgSO4), and concentrated. The major product was
purified via column chromatography using hexane/EtOAc (5:
1) as the elutant to afford 18.6 g of the trityl ether.
A slurry of potassium hydride (4.70 g, 120 mmol) in hexane
(15 mL) was added to a stirred solution of this ether (18.6 g)
in THF (100 mL) at 0 °C. After 30 min, a solution of 4-(2,2-
dimethyl-1-oxopropyl)benzoyl chloride (9.56 g, 42.6 mmol) in
THF (15 mL) was added. After stirring at room temperature
for 1 h, the mixture was poured onto a mixture of ice and
saturated aqueous NH4Cl. The mixture was extracted twice
with t-BuOMe (100 mL), and the combined organic layers were
washed with brine, dried, and concentrated. The crude product
was dissolved in THF (50 mL), and at 0 °C, 2 N HCl (2 mL)
was added. The mixture was stored at 0 °C for 2 days and
then poured onto saturated aqueous NaHCO3. The mixture
was extracted twice with t-BuOMe, and the combined organic
layers were washed with brine, dried, and concentrated. The
major product was first isolated via column chromatography
eluting with hexane/EtOAc (1:1) and then triturated from
hexane/CH2Cl2 (6:1) to afford 8.99 g (56%) of 14c as an
amorphous solid: mp 106 °C; 1H NMR (CDCl3) δ 1.29 (s, 9H),
1.31 (s, 9H), 2.46 (bs, 1H), 3.88 (t, J ) 4.5 Hz, 2H), 4.30 (t, J
) 4.5 Hz, 2H), 7.68-7.77 (m, 6H), 8.26 (d, J ) 8.5 Hz, 2H);
MS (DCI, NH3) m/z (rel intensity) 471 (26), 455 (25), 454 (100),
206 (18). Anal. (C26H31NO6) C, H, N.
1
°C; H NMR (CDCl3) δ 1.31 (d, J ) 6.3 Hz, 6H), 1.35 (s, 9H),
4.29 (heptet, J ) 6.3 Hz, 1H), 7.63-7.81 (m, 4H), 8.75 (bs, 1H);
MS (DCI, NH3) m/z (rel intensity) 280 (15), 279 (100), 221 (25).
4-(2,2-D im e t h y l-1-o x o p r o p y l)-N -(2-p r o p e n y lo x y )-
ben za m id e (13g). To a mixture of THF (50 mL) and aqueous
2 N NaOH (39 mL, 78 mmol) was added O-allylhydroxylamine
hydrochloride (5.0 g, 54.6 mmol), followed by a solution of
4-(2,2-dimethyl-1-oxopropyl)benzoyl chloride (6.90 g, 30.7 mmol)
in THF (10 mL). The mixture was stirred for an additional 30
min and was then partitioned between t-BuOMe and saturated
aqueous NaHCO3. The organic layer was washed with brine,
dried (MgSO4), and concentrated. The residue was crystallized
from hexane/CH2Cl2 to afford 7.82 g (97%) of 13g as white
crystals: 1H NMR (CDCl3) δ 1.33 (s, 9H), 4.50 (m, 2H), 5.25-
5.48 (m, 2H), 6.01 (m, 1H), 7.62 (d, J ) 8.5 Hz, 2H), 7.79 (d, J
) 8.5 Hz, 2H); MS (DCI, NH3) m/z (rel intensity) 280 (18), 279
(81), 263 (21), 262 (100), 223 (61).
N-(1,1-Dim eth yleth oxy)-4-(2,2-d im eth yl-1-oxop r op yl)-
ben za m id e (13a ). In a similar manner was prepared 13a .
From O-tert-butylhydroxylamine hydrochloride (5.00 g, 39.8
mmol) and 4-(2,2-dimethyl-1-oxopropyl)benzoyl chloride (5.96
g, 26.6 mmol) was obtained 7.05 g (96%) of 13a as white
crystals: 1H NMR (CDCl3) δ 1.32 (s, 9H), 1.34 (s, 9H), 7.66 (d,
J ) 8.4 Hz, 2H), 7.79 (d, J ) 8.4 Hz, 2H), 8.52 (bs, 1H); MS
(DCI, NH3) m/z (rel intensity) 279 (18), 278 (100).
4-(2,2-Dim eth yl-1-oxop r op yl)ben zoic Acid An h yd r id e
w ith N-(1,1-Dim eth yleth oxy)-4-(2,2-d im eth yl-1-oxop r o-
p yl)ben zen eca r boxim id ic Acid (14a ). A cooled solution of
O-tert-butylhydroxylamine hydrochloride (10.06 g, 80 mmol)
in aqueous 0.5 N NaOH (160 mL, 80 mmol), while being
vigorously stirred, was slowly added to a solution of 4-(2,2-
dimethyl-1-oxopropyl)benzoyl chloride (36.80 g, 164 mmol) and
Et3N (26 mL, 187 mmol) in toluene (400 mL) at 0 °C. After
the addition was complete (20 min), the mixture was allowed
to warm to room temperature overnight, diluted with EtOAc
(300 mL) and hexane (300 mL), and washed with water (400
mL). The organic layer was dried (MgSO4) and concentrated
in vacuo. The residue was purified via column chromatography
(CH2Cl2/hexane as elutant). The major component was recrys-
tallized from hexane to yield 33.45 g of 14a (89.8%) as white
crystals: mp 104.5-105.5 °C; 1H NMR (CDCl3) δ 1.31 (s, 9H),
1.33 (s, 9H), 1.36 (s, 9H), 7.65-7.85 (m, 6H), 8.23 (d, J ) 8.4
Hz, 2H); MS (DCI, isobutane) m/z (rel intensity) 467 (28), 466
(100), 260 (19). Anal. (C28H35NO5) C, H, N.
4-(2,2-Dim eth yl-1-oxop r op yl)ben zoic Acid An h yd r id e
w ith 4-(2,2-Dim eth yl-1-oxop r op yl)-N-m eth oxyben zen e-
ca r boxim id ic Acid (14b). Prepared in a similar manner was
14b. From O-methylhydroxylamine hydrochloride was ob-
tained 14b in 91% yield as white crystals: mp 104-104.8 °C;
1H NMR (CDCl3) δ 1.31 (s, 9H), 1.33 (s, 9H), 4.00 (s, 3H), 7.62-
7.82 (m, 6H), 8.23 (d, J ) 8.4 Hz, 2H); MS (DCI, isobutane)
m/z (rel intensity) 425 (27), 424 (100). Anal. (C25H29NO5) C,
H, N.
4-(2,2-Dim eth yl-1-oxop r op yl)ben zoic Acid An h yd r id e
w ith 4-(2,2-Dim eth yl-1-oxop r op yl)-N-(1-m eth yleth oxy)-
ben zen eca r boxim id ic Acid (14f). A solution of 4-(2,2-
dimethyl-1-oxopropyl)benzoyl chloride (4.11 g, 18.3 mmol) in
THF (15 mL) was added to a solution of the hydroxamate 13f
Prepared in a similar manner were 14d , 14e, and 14g:
4-(2,2-Dim eth yl-1-oxop r op yl)ben zoic Acid An h yd r id e
w ith 4-(2,2-Dim eth yl-1-oxop r op yl)-N-(2-m eth oxyeth oxy)-
ben zen eca r boxim id ic Acid (14d ). From hydroxamate ester
13d (6.40 g, 22.9 mmol) 4.32 g (40%) of 14d was obtained as
an oil: 1H NMR (CDCl3) δ 1.32 (s, 9H), 1.34 (s, 9H), 3.34 (s,
3H), 3.66 (t, J ) 5.0 Hz, 2H), 4.33 (t, J ) 5.0 Hz, 2H), 7.67-
7.83 (m, 6H), 8.23 (d, J ) 8.4 Hz, 2H); 13C NMR (65 MHz,
CDCl3) δ 27.6, 27.8, 44.2, 44.4, 59.0, 70.5, 125.5, 127.5, 128.0,
129.4, 130.2, 131.6, 140.3, 144.2, 147.2, 161.1, 208.4, 209.2;
MS (DCI, NH3) m/z (rel intensity) 485 (17), 469 (27), 468 (100).
Anal. (C27H33NO6) C, H, N.
4-(2,2-Dim eth yl-1-oxop r op yl)ben zoic Acid [(3-Ca r -
boxypr opoxy)im in o][4-(2,2-dim eth yl-1-oxopr opyl)ph en yl]-
m eth yl Ester (14e). From hydroxamate ester 13e (4.42 g, 20
mmol) was obtained 4.50 g (62%) of the tert-butyl ester as
white crystals: mp 65-67 °C; 1H NMR (CDCl3) δ 1.33 (s, 9H),
1.36 (s, 9H), 1.43 (s, 9H), 2.01 (m, 2H), 2.31 (t, J ) 7.3 Hz,
2H), 4.22 (t, J ) 6.1 Hz, 2H), 7.67-7.84 (m, 6H), 8.25 (d, J )
8.4 Hz, 2H); MS (DCI, NH3) m/z (rel intensity) 553 (28), 552
(87), 496 (30), 308 (32), 307 (86), 290 (78), 223 (58), 176 (50),
122 (100).
A solution of the tert-butyl ester (4.20 g, 7.61 mmol) in
trifluoroacetic acid (85 mL) was stirred for 20 h, concentrated
in vacuo, added to heptane (50 mL), and CH2Cl2 (50 mL) and
again concentrated in vacuo. The residue was purified via
column chromatography (CH2Cl2/MeOH, 98:2, as the elutant).
The major product was crystallized from ether/hexane to yield

162 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
Aicher et al.
2.10 g (56%) of 14e as white crystals: mp 125-126 °C; 1H
NMR (CDCl3) δ 1.33 (s, 9H), 1.36 (s, 9H), 2.03 (m, 2H), 2.41
(t, J ) 7.3 Hz, 2H), 4.24 (t, J ) 6.1 Hz, 2H), 7.64-7.82 (m,
6H), 8.22 (d, J ) 8.4 Hz, 2H); MS (DCI, NH3) m/z (rel intensity)
496 (8), 308 (59), 307 (100), 290 (47), 223 (62), 206 (27), 205
(32), 122 (16). Anal. (C28H33NO7) C, H, N.
4-(1-Hyd r oxy-2,2-d im eth ylp r op yl)ben zoic Acid An h y-
d r ide with [R-(R*,R*)]-4-(1-Hydr oxy-2,2-d im eth ylp r op yl)-
N-m eth oxyben zen eca r boxim id ic a cid (17a ). A solution of
the ketone 14b (5.00 g, 11.8 mmol) and (R)-5,5-diphenyl-2-
methyl-3,4-propano-1,3,2-oxazaborolidine (500 mg, 1.8 mmol)
in THF (20 mL) was added over 10 min to a solution of (R)-
5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (500
mg, 1.8 mmol) in THF (20 mL) and a 2 M solution of BH3-
dimethyl sulfide complex in THF (8 mL, 16 mmol) at 0 °C.
After stirring 20 min, the mixture was poured onto MeOH (30
mL) and then concentrated to a paste. The residue was purified
via a column chromatography using 4:1 hexane/EtOAc as the
elutant. The crude product had a purity of 91% as determined
by chiral HPLC with a Chiracel OD column with hexanes/
EtOH as the elutant. The crude product was recrystallized
from hexane/Et2O (20:1, 100 mL) to afford 4.00 g (80%) of 17a
as white crystals: mp 93-95 °C; [R]D ) 18.5 ( 1.0 (c ) 1.00,
MeOH); 1H NMR (CDCl3) δ 0.91 (s, 9H), 0.97 (s, 9H), 1.92 (bs,
1H), 1.99 (bs, 1H), 3.98 (s, 3H), 4.42 (s, 1H), 4.50 (s, 1H), 7.33
(d, J ) 8.4 Hz, 2H), 7.49 (d, J ) 8.4 Hz, 2H), 7.73 (d, J ) 8.4
Hz, 2H), 8.16 (d, J ) 8.4 Hz, 2H); MS (DCI, NH3) m/z (rel
intensity) 429 (24), 428 (100). Anal. (C25H33NO5) C, H, N.
Prepared in a similar manner substituting (S)-5,5-diphenyl-
2-methyl-3,4-propano-1,3,2-oxazaborolidine for (R)-5,5-diphen-
yl-2-methyl-3,4-propano-1,3,2-oxazaborolidine was 17b: mp
93-95 °C; [R]D ) -19.1 ( 1.5 (c ) 1.00, MeOH).
4-(2,2-Dim eth yl-1-oxop r op yl)ben zoic Acid An h yd r id e
w it h 4-(2,2-Dim et h yl-1-oxop r op yl)-N-(2-p r op en yloxy)-
ben zen eca r boxim id ic Acid (14g). From the hydroxamate
ester 13g (6.64 g, 25.4 mmol) was obtained, after crystalliza-
tion with hexane/2-propanol, 7.52 g (66%) of 14g as white
1
crystals: mp 76 °C; H NMR (CDCl3) δ 1.34 (s, 9H), 1.36 (s,
9H), 4.72 (m, 1H), 5.31 (m, 1H), 6.02 (m, 1H), 7.70-7.89 (m,
6H), 8.28 (d, J ) 8.4 Hz, 2H); 13C NMR (65 MHz, CDCl3) δ
27.6, 27.8, 44.2, 44.4, 76.2, 118.0, 125.5, 127.5, 128.0, 129.4,
130.2, 131.6, 133.3, 140.2, 144.2, 146.9, 161.1, 208.4, 209.2;
MS (DCI, NH3) m/z (rel intensity) 451 (29), 450 (100), 205 (32).
Anal. (C27H31NO5) C, H, N.
4-(2,2-Dim eth yl-1-oxop r op yl)ben zoic Acid An h yd r id e
w it h N-(2,3-Dih yd r oxyp r op oxy)-4-(2,2-d im et h yl-1-oxo-
p r op yl)ben zen eca r boxim id ic Acid (14h ). A 1 N solution
of OsO4 in tert-butyl alcohol (1 mL) was added to a solution of
14g (4.00 g, 8.90 mmol) and N-methylmorpholine oxide (2.10
g, 17.9 mmol) in water (3 mL) and acetone (27 mL), and the
mixture was stirred for 1 day. Excess sodium m-bisulfite was
added, and the mixture was stirred for 30 min and concen-
trated in vacuo. The residue was purified via column chroma-
tography (hexane/EtOAc, 1:1, as the elutant). The major
product was crystallized from CH2Cl2:hexane to yield 2.74 g
(64%) of 14h as white crystals: mp 64 °C; 1H NMR (CDCl3) δ
1.33 (s, 9H), 1.36 (s, 9H), 2.17 (bs, 1H), 2.99 (bs, 1H), 3.60 (dd,
J ) 11.4, 5.3 Hz, 1H), 3.74 (dd, J ) 11.4, 3.7 Hz, 1H), 4.08 (m,
1H), 4.20 (dd, J ) 11.8, 7.3 Hz, 1H), 4.30 (dd, J ) 11.8, 7.6
Hz, 1H), 7.65-7.82 (m, 6H), 8.27 (d, J ) 8.8 Hz, 2H); MS (DCI,
NH3) m/z (rel intensity) 485 (23), 484 (80), 244 (37), 206 (60),
205 (77), 188 (100). Anal. (C27H33NO7) C, H, N.
Meth yl 4-(2,2-Dim eth yl-1-oxop r op yl)ben zoa te (15). HCl
gas was added to a solution of the acid 2 (41.0 g, 200 mmol) in
MeOH (300 mL) until saturated. The mixture was refluxed
for 3 h, stirred overnight, and concentrated to an oil. The
concentrate was diluted in ether (300 mL), washed with
saturated NaHCO3 and brine, dried, and concentrated. The
crude product was crystallized from hexane/CH2Cl2 to afford
39.6 g (90%) of 15.
(+)-(R)-4-(1-Hyd r oxy-2,2-d im eth ylp r op yl)ben zoic Acid
(16a ). A solution of the ketone 15 (10.0 g, 45.5 mmol) and (R)-
5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (630
mg, 2.3 mmol) was added to a solution of (R)-5,5-diphenyl-2-
methyl-3,4-propano-1,3,2-oxazaborolidine (630 mg, 2.3 mmol)
in THF (20 mL) and a 2 M solution of BH3-dimethyl sulfide
complex in THF (15 mL, 30 mmol) at -30 °C. After 5 min, the
mixture was quenched with MeOH (10 mL) and concentrated
to a paste. The crude product was crystallized from aqueous
ethanol (80:20 EtOH/H2O, 100 mL) to afford 9.6 g (95%) of
the methyl ester as white crystals. The optical purity of the
product was determined to be 98% by chiral HPLC analysis
using a Chiracel OD column with hexane/EtOH as elutant.
An identical run of the reaction afforded an additional 9.1 g
of the methyl ester.
A solution of the methyl ester (19.2 g, 86.5 mmol) in EtOH
(60 mL) was added to a solution of potassium hydroxide (5.23
g, 130 mmol) in water (10 mL) and EtOH (75 mL). The mixture
was heated to 80 °C for 5 h, cooled, and concentrated to 30
mL. The mixture was dissolved in water (100 mL) and washed
with Et2O (2 × 60 mL). The aqueous layer was acidified to pH
2 with 2 N HCl. The mixture was extracted with ether (3 ×
50 mL). The combined organic layers were dried and concen-
trated. The residue was recrystallized from aqueous ethanol
to afford 16.9 g (94%) of the acid 16a as fine white crystals:
mp 188 °C; [R]D ) 18.8 ( 1.5 (c ) 1.00, EtOH).
Ack n ow led gm en t. We thank Dr. Michael J . Sha-
piro and Bertha Owens for helpful NMR and MS
analyses.
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Hypoglycemic Prodrugs of Benzoic Acid
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groups. The percent efficacy so calculated was utilized as a tool
to be able to qualitatively compare two different experiments in
which the diabetic nontreated control groups had blood values
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of 220 or 170 mg/dL after
a 6-h fast. In a representative
experiment with FOX 988, the glucose of the untreated diabetic
animals was 200 ( 10 mg/dL. The treated animals (140 mmol/
kg) displayed a glucose level of 100 ( 20 mg/dL (p < 0.001). This
may actually represent a normalization of glucose. In our table,
we represent these data as displaying a 70% efficacy.
(22) Histological changes were measured as described in references
in ref 12.
(23) Lau, D. T.-W.; K., G.; Aun, R. L.; Tse, F. L. S. The Effect of the
Fat Content of Food on the Pharmacokinetics and Pharmaco-
dynamics of SDZ FOX 988, an Antidiabetic Agent, in the Dog.
Biopharm. Drug Dispos. 1995, 16, 137-150.
(24) The STZ-treated diabetic animal model, as described in the
Experimental Section, on day 11 following a 6-h fast. The doses
in the study were 35, 70, 100, and 140 µmol/kg/day with 9 rats/
group.
(25) With our normal chow-fed model (see ref 9), blood glucose was
often variable and the model was not stable for more than a few
days. The addition of a high-fat diet has significantly improved
each of these parameters, allowing testing of compounds for up
to 15 days.
(16) Desneuelle, P.; Naudet, M.; Sambuc, E. Sur la Transposition des
R-Oxyethylamides Gras en les R-Amino-Esters Correspondants.
(On the Transposition of R-Oxyethylamides into the Correspond-
ing R-Amino-Esters.) Bull. Soc. Chim. Fr. 1949, 650-654.
(17) Suda, K.; Hino, F.; Yijima, C. An Efficient Transformation of
N-Acyl-R-Amino Acids into Diacylamines Via 2,4-Disubstituted
Oxazol-5(4H)-ones. Chem. Pharm. Bull. 1985, 33, 882-885.
(18) McCarthy, D. G.; Hegarty, A. E. Acylation of O-Alkylbenzohy-
droxamic Acids; Configurational Assignment, Interconversion,
and Rearrangement of the E- and Z-Isomers of a New Group of
J M980438Y