Substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones as hypoglycemic agents

Article abstract of DOI:10.1021/jm9803121

A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones was synthesized from amino alcohols or amino thiols and keto acids. A pharmacological model based on the results obtained with these compounds led to the synthesis and evaluation of a series of isoxazoles and other monocyclic compounds. These were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. The in vivo hypoglycemic efficacy and potency of these compounds were evaluated in a model of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus), the ob/ob mouse. 25a(2S) (SDZ PGU 693) was selected for further pharmacological studies.

Full text of DOI:10.1021/jm9803121

4556
J . Med. Chem. 1998, 41, 4556-4566
Su bstitu ted Tetr a h yd r op yr r olo[2,1-b]oxa zol-5(6H)-on es a n d
Tetr a h yd r op yr r olo[2,1-b]th ia zol-5(6H)-on es a s Hyp oglycem ic Agen ts1
Thomas D. Aicher,*,† Bork Balkan,‡ Philip A. Bell,§ Leonard J . Brand,† S. H. Cheon,† Rhonda O. Deems,‡
J ay B. Fell,† William S. Fillers,§ J ames D. Fraser,† J iaping Gao,‡ Douglas C. Knorr,† Gerald G. Kahle,†
Christina L. Leone,† J effrey Nadelson,† Ronald Simpson,† and Howard C. Smith†
Metabolic & Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, 556 Morris Avenue,
Summit, New J ersey 07901
Received May 18, 1998
A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-
b]thiazol-5(6H)-ones was synthesized from amino alcohols or amino thiols and keto acids. A
pharmacological model based on the results obtained with these compounds led to the synthesis
and evaluation of a series of isoxazoles and other monocyclic compounds. These were evaluated
for their ability to enhance glucose utilization in cultured L6 myocytes. The in vivo
hypoglycemic efficacy and potency of these compounds were evaluated in a model of type 2
diabetes mellitus (non-insulin-dependent diabetes mellitus), the ob/ ob mouse. 25a (2S) (SDZ
PGU 693) was selected for further pharmacological studies.
Ch a r t 1. Marketed Hypoglycemic Agents That
Enhance Glucose Utilization
In tr od u ction
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).2 Type 2 diabetes, diagnosed and undiag-
nosed, occurs in >5% of the U.S. population (affecting
16 million people in 1996).3 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.4,5
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
retinopathy, nephropathy, and neuropathy each by
>50% in insulin-dependent diabetes (IDDM).6 Evidence
is emerging that similar control of blood glucose levels
is also effective in type 2 diabetic patients in preventing
disease complications.7,8
recognized.9,10 Furthermore, the Whitehall study of
middle-aged men demonstrated that coronary heart
disease mortality was approximately doubled for sub-
jects with IGT.11 Since the major mortality, morbidity,
and cost associated with type 2 diabetes result from
these complications, reducing hyperglycemia and hy-
perinsulinemia concurrently should have a beneficial
effect in the treatment of this syndrome.12 The goal of
the studies reported here is the discovery of a novel
compound to enhance peripheral insulin sensitivity.
Metformin and troglitazone (Chart 1) are drugs
available in the clinic which enhance insulin sensitivity.
Metformin has been associated with serious lactic
acidosis; however patients at risk can be identified and
excluded from treatment with this drug.13 Gastrointes-
tinal side effects are common with metformin treatment
(∼one-quarter of patients drop from treatment proto-
cols), but most patients can tolerate 2-3 g daily (5%
have severe symptoms).14 The low efficacy and the side-
effect profile render metformin treatment suboptimal
in the majority of asymptomatic diabetic patients.
While metformin has been shown to decrease hepatic
glucose production and increase glucose utilization, its
biochemical mechanism of action is uncertain.15
While hyperglycemia has long been recognized as a
risk factor for microvascular disease (i.e., retinopathy,
nephropathy, neuropathy), a significant correlation
between hyperinsulinemia and coronary artery disease
(i.e., macrovascular complications) is now also generally
Troglitazone is the first member of a novel class of
compounds, the thiazolidinediones, to reach clinical
practice. Troglitazone induces preadipocyte differentia-
tion, probably via peroxisome-proliferator-activated
receptor-γ (PPARγ) receptors.16 While it is not clear
whether the hypoglycemic mechanism requires preadi-
† Department of Chemistry.
‡ Department of Diabetes Pharmacology.
§ Department of Molecular and Cellular Biology.
10.1021/jm9803121 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/02/1998

Oxazolones and Thiazolones as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4557
Sch em e 1. Lead Structures
Sch em e 2. Initial Strategy
pocyte differentiation, the maximum glucose-lowering
effect of troglitazone is similar to that seen with
metformin (about 40 mg/dL). Thiazolidinediones have
been shown to improve insulin sensitivity/glucose uti-
lization in rodents and to enhance insulin sensitivity
in humans.17 For these reasons, the title compounds’
efficacy was compared to that of metformin and/or
troglitazone as standards.
To discover novel compounds which have the ability
to increase cellular glucose uptake, an adipocyte glucose
transport assay was established. In this assay, clava-
mycin D (1) was found to increase [3H]glucose incorpo-
ration into lipids in adipocytes in the presence of
submaximal concentrations of insulin and to enhance
2-deoxyglucose uptake into 3T3L1 adipocytes using a
modification of the method described by Clancy and
Czech.18 This suggested that the compound increases
the sensitivity of the adipocyte to insulin. Substructure
and similarity searches of the compound collection of
Sandoz19 based on 1 led to the identification of (hy-
droxymethyl)clavam (2) and (+)-trans-2-[(4-chlorophe-
noxy)methyl]-7R-(4-chlorophenyl)tetrahydropyrrolo[2,1-
b]oxazol-5(6H)-one (3), which increased glucose utilization
by L6 myocytes (a muscle cell line) and lowered blood
glucose levels in vivo in the diabetic obese ob/ ob mouse
(Scheme 1). As a result of these findings, a synthetic
program was initiated based on these related structures.
Ch em istr y
The alcohols 6a and 6b were targeted for synthesis
as being ideal intermediates for this program (Scheme
2). However, attempts to prepare 6a and 6b directly
from 3-amino-1,2-propanediol and 3-(4-chlorobenzoyl)-
propionic acid led to the exclusive formation of 44a and
44b. The synthesis of 6a and 6b was accomplished from
1-amino-2-hydroxybut-3-ene. However, these com-

4558 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Aicher et al.
Ta ble 1. Physical and in Vitro Properties of Tetrahydropyrrolo[2,1-b]oxazol-5(6H)-one Analogues
entry
m, n
R1
R2
% yield (method)
mp (°C)
formula
anal.a
140% at (µM)b
metformin
troglitazone
1
1000
30
10
2
30
30
>1000
>300
>300
300
3a
1, 1
4-ClPh
CH2O(4-ClPh)
H
51 (A)
45 (A)
34 (A)
11 (B)
39 (A)
47 (A)
68 (C)
45 (C)
31 (A)
42 (A)
31 (A)
37 (D)
80 (A)
32 (A)
32 (A)
38 (A)
76 (A)
35 (A)
25 (A)
26 (A)
47 (A)
35 (A)
44 (A)
19 (A)
24 (A)
52 (A)
34 (A)
55 (A)
36 (A)
52 (A)
49 (A)
54 (A)
38 (A)
32 (A)
28 (A)
26 (A)
50 (A)
78 (A)
73 (A)
13 (A)
23 (B)
20 (A)
5 (A)
99-100
C19H17NO3Cl2
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
4
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
2, 1
2, 1
2, 1
1, 2
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
4-ClPh
83-84
oil
C
24H19NO3Cl2
5a
4-ClPh
CH2CH2Ph
C20H20NO2Cl
C13H14NO3Cl
C17H22NO3Cl
C16H18NO3Cl
C16H18NO5Cl
C15H18NO4Cl
C20H20NO4Cl
6a
4-ClPh
CH2OH
CH2Ot-Bu
CH2Oallyl
115-117
92-94
oil
7a
4-ClPh
8a
4-ClPh
>300
>300
>300
100
9a
4-ClPh
CH2OCH2COOMe
CH2OCH2CH2OH
CH2O(4-MeOPh)
CH2S(4-ClPh)
CH2NH(4-ClPh)
CH2NAc(4-ClPh)
H
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
H
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
oil
10a
11a
12a
13a
14a
15
4-ClPh
91-93
104-106
80-83
133-139
65-67
68
4-ClPh
3,4-diClPh
4-ClPh
C19H16NO2SCl3 C, H, N, Cl, S
C19H18N2O2Cl2 C, H, N, Cl
C22H20N2O3Cl2 C, H, N
100
>300
>300
300
4-ClPh
4-(PhO)Ph
4-(PhO)Ph
Ph
C
18H17NO3
C, H, N
C, H, N, Cl
C, H, N
C, H, N, Cl
C, H, N
C, H, N
C, H, N
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
16a
17a
18a
19
81-82
124-126
127
115-116
128-129
118-120
119-121
94-96
95-97
C25H22NO4Cl
C20H20NO3Cl
C26H24NO4Cl
10
30
100
30
4-(PhO)Ph
4-(PhO)Ph
4-ClPh
Me
t-Bu
c-hexyl
Ph
3,4-diClPh
3,4-diClPh
3,4-diClPh
4-(MeO)Ph
C
19H19NO3
20a
21a
22a
23a
24a
25a
25a (2R)
25a (2S)
26a
27a
28a
29a
30a
31a
32a
33a
34a
35a
36a
37a
38a
39a
5b
C20H19NO3Cl2
C14H16NO3Cl
C17H22NO3Cl
C19H24NO3Cl
C19H18NO3Cl
>300
>300
>300
100
100
126-127.5 C19H16NO3Cl3
10
102-104
102-104
128
C13H14NO3Cl
C19H16NO3Cl3
C20H20NO4Cl
30
10
30
4-Cl-3-CF3Ph CH2O(4-ClPh)
4-FPh
101.5-103.5 C20H16NO3Cl2F3 C, H, N, Cl
99-100
137
10
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
H
CH2O(4-ClPh)
CH2CH2Ph
CH2OH
CH2S(4-ClPh)
CH2NH(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
C19H17NO3ClF C, H, N, Cl
30
2-naphthyl
1-naphthyl
4-biphenyl
c
C23H20NO3Cl
C23H20NO3Cl
C25H22NO3Cl
C27H24NO3Cl
C25H20NO3Cl
C18H17N2O3Cl
C18H17N2O3Cl
C21H19N2O3Cl
C21H21NO3Cl2
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N
30
166-167
141-142
142-144
145-147
131-133
83-85
168-170
124-126
oil
120-121
oil
144-146
76-79
96-98
>300
10
30
d
30
4-pyridyl
3-pyridyl
3-indolyl
30
300
>300
1, 1 (diMe) 4-ClPh
1, 1 (diMe) 4-(PhO)Ph
1, 1 (diMe) 4-(PhO)Ph
30
C
20H21NO3
10
C27H26NO4Cl
C20H20NO2Cl
C13H14NO3Cl
C, H, N, Cl
C, H, N, Cl
C, H, N
30
1, 1
1, 1
1, 1
1, 1
2, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
1, 1
4-ClPh
4-ClPh
3,4-diClPh
4-ClPh
Ph
>300
>300
100
6b
12b
13b
17b
22b
23b
25b
26b
27b
28b
29b
31b
32b
33b
34b
35b
37b
40
C19H16NO2SCl3 C, H, N, Cl, S
C19H18N2O2Cl2 C, H, N, Cl
C20H20NO3Cl
C17H22NO3Cl
C19H24NO3Cl
C19H16NO3Cl3
C20H20NO4Cl
>300
>300
>300
>300
>300
>300
300
7 (A)
144-145
109-111
128-130
106-108
117
C, H, N
t-Bu
24 (A)
22 (A)
14 (A)
10 (A)
27 (A)
13 (A)
16 (A)
20 (A)
24 (A)
13 (A)
11 (A)
13 (A)
13 (A)
99 (E)
85 (E)
18 (F)
13 (F)
41 (A)
37 (A)
C, H, N, Cl
C, H, N, Cl
C, H, N
c-hexyl
3,4-diClPh
4-(MeO)Ph
C, H, N, Cl
4-Cl-3-CF3Ph CH2O(4-ClPh)
4-FPh
88.5-90.5
C20H16NO3Cl2F3 C, H, N, Cl
C19H17NO3ClF C, H, N, Cl
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
H
76-78
>300
>300
>300
>300
>300
100
2-naphthyl
4-biphenyl
c
145
C23H20NO3Cl
C25H22NO3Cl
C27H24NO3Cl
C25H20NO3Cl
C18H17N2O3Cl
C18H17N2O3Cl
C21H21NO3Cl2
C, H, N
157-158
118-120
137-139
140-143
138-140
117-119
91-92
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, S, Cl
C, H, N, S, Cl
d
4-pyridyl
3-pyridyl
300
1, 1 (diMe) 4-ClPh
100
1, 1
2, 1
1, 1
1, 1
4-ClPh
4-ClPh
4-ClPh
4-ClPh
OH
C
C
12H12NOSCl
13H14NOSCl
300
41
H
97-99
>300
>300
10
42
CH2O(4-ClPh)
CH2O(4-ClPh)
H
132-132.5 C19H17NOSCl2 C, H, N, Cl
43
100-102
C19H17NOSCl2 C, H, N, Cl
44a
44b
162
C
C
13H15NO3
13H15NO3
C, H, N
C, H, N
>300
>300
H
OH
175
a
b
Analytical results were within (0.4% of the theoretical value. Lowest concentration (µM) tested in the L6 myocyte in vitro assay at
which glucose utilized was greater than or equal to 140% of control (see Biological Methods). c R ) 2-(9,10-dihydrophenanthrenyl). R )
2-dibenzofuranyl.
d

Oxazolones and Thiazolones as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4559
Sch em e 3. General Synthesis of Tetrahydropyrrolo[2,1-b]oxa(thia)zol-5(6H)-ones
Sch em e 4. General Synthesis of 3-Oxa(thia)zolidinyl Analoguesa
a
Conditions: (a) EtOH or CH3CN or benzene and concentrate; (b) R1COCl or R1NCO or R1NCS or R1SO2Cl, Et3N or pyridine; (c) for
hydrochloride, Et3N, EtOH; (d) Boc-protected amide, TFA, aldehyde, CH3CN.
pounds in mild acid readily converted to 44a and 44b;
in fact the trace of acid in commercial CDCl3 readily
effected these conversions in less than 3 h. Therefore,
6a and 6b could not practically be utilized as a general
intermediate.
jugating the unpurified imine of the appropriate amino
alcohol or amino thiol with an aldehyde and the ap-
propriate acid chloride, isocyanate, isothiocyanate, or
sulfonyl chloride (Scheme 4). All of the derivatives in
Tables 1 and 2 are racemates with the exception of 25a -
(2R) and 25a (2S) which were prepared from optically
pure 1,2-amino alcohols.
The isoxazole derivatives 62a -k , 63a -b, and 64a
were synthesized via a cyclization of hydroximinoyl
chloride with a propargylic alcohol (Scheme 5).20 Isox-
azole 65 was synthesized via a Mitsunobu coupling of
p-chlorophenol with 62a . Isoxazole 66 was synthesized
via alkylation of 62a with methyl iodide. Isoxazole 67
was prepared via hydrolysis of isoxazole 62d (Scheme
6).
Most of the substituted tetrahydropyrrolo[2,1-b]ox-
azol-5(6H)-ones (3a -39) and tetrahydropyrrolo[2,1-b]-
thiazol-5(6H)-ones (40-43) in Table 1 were readily
synthesized from appropriate amino alcohols or amino
thiols and keto acids in one step via a condensation as
shown in Scheme 3, usually in excellent yields. All
amino alcohols and keto acids utilized in this paper are
either commercially available or were prepared by
known literature methods. In most cases, near-quan-
titative yields of 1,2-amino alcohols resulted from the
stirring of a methanolic solution of the appropriate epox-
ide with an excess of ammonia in a steel bomb over-
night. The keto acids were prepared either via Friedel-
Crafts acylation or via decarboxylation of an alkylation
product of malonic acid. To prepare the tetrahydro-
pyrrolo[2,1-b]thiazol-5(6H)-ones, optimal yields were
obtained if the free base of the relevant amino thiol was
freshly prepared or the amino thiol was prepared in situ
via a deprotection of a t-BOC-protected amino thiol.
The monocyclic tetrahydrooxazoles 47a -56b and
tetrahydrothiazoles 57-61b were synthesized by con-
Resu lts a n d Discu ssion
Clavamycin D (1), (hydroxymethyl)clavam (2), and
(+)-trans-2-[(4-chlorophenoxy)methyl]-7R-(4-chlorophen-
yl)tetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (3) increased
glucose utilization by L6 myocytes (see Table 1) and
lowered blood glucose levels in vivo in diabetic obese
ob/ ob mice (see Table 4). As the â-lactams 1 and 2 and
the γ-lactam 3 each have an oxidized 2-methyl substitu-
ent attached to the ring, the requirement of this substi-
tuent for activity was explored. In the tetrahydropyrrolo-

4560 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Aicher et al.
Ta ble 2. Physical and in Vitro Properties of Tetrahydrooxa(thia)zole Analogues
entry
R1
R2
R3
% yield (method G) mp (°C)
formula
anal.a
140% at (µM)b
45
46
C(dS)NHMe
C(dO)NHMe
4-ClPh
H
H
31
62
29
26
53
29
39
33
33
24
36
37
39
25
21
29
23
20
32
12
27
33
62
94
44
68
26
42
138-140
97
C11H13N2OSCl
C, H, N, Cl, S
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
C, H, N, Cl
>300
>300
100
100
>300
>300
30
4-ClPh
C11H13N2O2Cl
47a C(dO)CH3
47b C(dO)CH3
48a C(dO)CH3
48b C(dO)CH3
49a C(dO)CH3
49b C(dO)CH3
50a C(dO)CH3
50b C(dO)CH3
4-ClPh
4-ClPh
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
104-106
80-83
115-117
104-106
84-88
oil
75-78
85-87
139-141
(oil)
oil
oil
140-142
85-7
88-90
89-92
94-96
99-101
oil
oil
oil
117-118
138-140
73-74
126-128
C18H17NO3Cl2
C18H17NO3Cl2
C19H20NO4Cl
C19H20NO4Cl
C18H16NO3Cl3
C18H16NO3Cl3
C19H16NO3Cl2F3 C, H, N
C19H16NO3Cl2F3 C, H, N
C20H20NO3Cl3
C20H20NO3Cl3
C23H18NO3Cl3
C23H18NO3Cl3
C17H17NO4SCl2 C, H, N, Cl, S
C17H17NO4SCl2 C, H, N, Cl, S
C18H16NO4Cl3
C18H16NO4Cl3
C23H19N2O3Cl3 C, H, N
4-MeOPh
4-MeOPh
3,4-diClPh
3,4-diClPh
3-CF3, 4-ClPh CH2O(4-ClPh)
3-CF3, 4-ClPh CH2O(4-ClPh)
30
30
30
51a C(dO)CH(CH3)2 3,4-diClPh
51b C(dO)CH(CH3)2 3,4-diClPh
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
CH2O(4-ClPh)
H
C, H, N, Cl
C, H, N
C, H, N, Cl
C, H, N, Cl
30
30
52a C(dO)Ph
52b C(dO)Ph
53a SO2CH3
3,4-diClPh
3,4-diClPh
4-ClPh
>300
300
30
53b SO2CH3
4-ClPh
100
300
30
54a C(dO)OCH3
54b C(dO)OCH3
55a C(dO)NHPh
55b C(dO)NHPh
56a SO2CH3
3,4-diClPh
3,4-diClPh
3,4-diClPh
3,4-diClPh
3,4-diClPh
3,4-diClPh
4-ClPh
C, H, N, Cl
C, H, N, Cl
30
C23H19N2O3Cl3 C, H, N, Cl
C18H17N2O3Cl3 C, H, N, Cl
C17H16NO4SCl3 C, H, N, Cl, S
30
30
56b SO2CH3
30
57
58
59
60
C(dO)Me
C
C
C
11H12NOSCl
11H13N2OSCl
11H13N2S2Cl
C, H, N
C, H, N, Cl, S
C, H, N
>300
300
300
300
300
30
C(dO)NHMe
C(dS)NHMe
SO2CH3
4-ClPh
H
4-ClPh
H
4-ClPh
H
C10H12NO2S2Cl C, H, N, Cl, S
C18H17NO2SCl2 C, H, N, S
61a C(dO)CH3
61b C(dO)CH3
4-ClPh
CH2O(4-ClPh)
CH2O(4-ClPh)
4-ClPh
105-106.5 C18H17NO2SCl2 C, H, N, Cl, S
a
b
Analytical results were within (0.4% of the theoretical value. Lowest concentration (µM) tested in the L6 myocyte in vitro assay at
which glucose utilized was greater than or equal to 140% of control (see Biological Methods).
Sch em e 5. General Synthesis of the Isoxazolesa
a
Conditions: (a) Et3N, CH2Cl2, propargylic alcohol; (b) Et3N, CH2Cl2, 2-methyl-3-butyn-2-ol; (c) Et3N, CH2Cl2, 3-butyn-1-ol.
[2,1-b]oxazol-5(6H)-ones, the 2-substituent CH2XAr,
where X is either oxygen or sulfur, increased the in vitro
potency of this series in effecting glucose utilization
(compare 3, 11a , and 12a to 4-10 in Table 1).
Sch em e 6. Synthesis of Other Isoxazolesa
Although the 2-substituent in 3a is trans to the 8-(4-
chlorophenyl) group, whereas the corresponding sub-
stituents in 1, 2, and 43 are cis-disposed, the global
minimal structures of these biologically active molecules
are predicted by molecular modeling to be quite simi-
lar.21 In each, the 2-aryloxymethyl (or hydroxymethyl)
substituent was predicted to be nearly coplanar to the
tetrahydrooxa(thia)zole ring and the 2-hydrogens to be
perpendicular to this ring. In the inactive isomers 3b
and 42, the 2-aryloxymethyl (or hydroxymethyl) sub-
stituent was predicted to be nearly perpendicular to the
tetrahydrooxa(thia)zole ring and the 2-hydrogens to be
approximately planar to this ring. To examine the
validity of these predictions, X-ray structures of 25a -
a
Conditions: (a) DIAD, Ph3P, THF, 4-chlorophenol; (b) NaH,
DMF, MeI; (c) 1 N NaOH, EtOH.

Oxazolones and Thiazolones as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4561
Ta ble 3. Physical and in Vitro Properties of Isoxazole Analogues
entry
R1
R2
% yield (method)
mp (°C)
formula
anal.a
140% at (µM)b
62a
62b
62c
62d
62e
62f
62g
62h
62i
62j
62k
63a
63b
64a
65
4-ClPh
4-(PhO)Ph
COMe
COOMe
Ph
2,4-diClPh
3,4-diClPh
4-(CF3)Ph
Me
CH2OH
97 (H)
75 (H)
6 (H)
99
C10H8NO2Cl
C16H13NO3
C6H7NO3
C, H, N, Cl
C, H, N
100
30
>300
>300
>300
300
30
100
>300
>300
>300
100
CH2OH
95
CH2OH
oil
oil
52-53.5
114
CH2OH
68 (H)
52 (H)
45 (H)
50 (H)
38 (H)
27 (H)
11 (H)
63 (H)
54 (H)
58 (H)
63 (H)
83 (I)
C7H9NO4
CH2OH
C10H9NO2
CH2OH
C10H7NO2Cl2
C10H7NO2Cl2
C11H8NO2F3
C5H7NO2
C, H, N, Cl
C, H, N
CH2OH
106-108
98-100
oil
CH2OH
CH2OH
Bn
t-Bu
CH2OH
oil
C11H11NO2
C8H13NO2
CH2OH
35-37.5
4-ClPh
4-(PhO)Ph
4-ClPh
4-ClPh
4-ClPh
CO2H
C(Me)2OH
C(Me)2OH
CH2CH2OH
CH2O(4-ClPh)
CH2OMe
CH2OH
98
C12H12NO2Cl
C18H17NO3
C11H10NO2Cl
C16H11NO2Cl2
C11H10NO2Cl
C5H5NO4
82-83
65
C, H, N
30
100
>300
100
C, H, N
143
C, H, N
66
67 (J )
73 (H)
54-55
C, H, N, Cl
67
135-136.5
>300
a
b
Analytical results were within (0.4% of the theoretical value. Lowest concentration (µM) tested in the L6 myocyte in vitro assay at
which glucose utilized was greater than or equal to 140% of control (see Biological Methods).
Ta ble 4. In Vivo Activity of Selected Compounds in a Model
resulted in loss of activity in the analogues tested
(compare 3 and 20). Whether the lack of activity of 20
of Diabetes, the ob/ob Mousea
% efficacy
2 h
is due to the nonplanarity of the 2-substituent or due
to an unfavorable steric interaction resulting from the
extra ring atom has not been established.
day 1
day 3
4 h
entry
2 h
4 h
8 h
These data suggest that a pharmacophore of a five-
atom heterocyclic ring with an aryloxy(or hydroxy)-
methyl group is required for in vitro activity. As a
consequence, compounds with a five-atom heteroaro-
matic ring substituted with an oxidized methyl group
were investigated for activity in the L6 myocyte screen
and in the ob/ ob mouse. The compounds initially
investigated for activity were 5-substituted-3-alkoxy(or
hydroxymethyl)isoxazoles. The isoxazoles 62c and 62d
were expected to be the most potent. However, 5-aryl-
substituted-3-(hydroxymethyl)isoxazoles, exemplified by
62a , 62b, and 62g, proved to be superior in enhancing
glucose utilization in L6 myocytes (see Table 3). The
effects of the aryl substituent on the SAR of the
isoxazoles were similar to those seen within the tetra-
hydropyrrolo[2,1-b]oxaxol-5(6H)-ones (discussed below).
The in vivo profile of the isoxazoles was improved by
adding two methyl groups to the hydroxymethyl side
chain, as exemplified by 63b (see Table 4).
It appeared likely that the conformation necessary for
biological activity of the lactam ring was quite flexible
as â-lactams (1 and 2), γ-lactams (e.g., 3), and δ-lactams
all possessed in vitro activity. As a consequence,
monocyclic derivatives, exemplified by 45-61, were
prepared (see Table 2) as a mixture of two readily
separable isomers. Molecular modeling suggested that
in each isomer, the aryl(R) group would be perpendicu-
lar to the plane of the tetrahydrooxazole ring to relieve
allylic strain with the N-acetyl moiety, whereas the
2-substituent would lie approximately within this plane
(X-ray structures of 49a and 49b were obtainedstheir
experimental structures are consistent with those pre-
dicted). Thus, both isomers would fit our minimal model
for activity, and indeed in many cases both isomers
increased glucose utilization in L6 myocytes. Replace-
ment of the acyl moiety of 49a and 49b presented an
opportunity to quickly explore diverse substituents in
similar proximity to the position of the methyls of 37a -
1b
2c
63**
66**
31*
21
63*
86**
46*
7
53*
14
23
-19
-3
2
10
45**
18
70**
-5
67**
49**
20
51*
8
13
1
55*
13
57*
-11
44
23
-15
28
44*
3a c
4
-26
11
-28
-4
11a
15
16a
17a
19
24a
25a
26a
28a
29a
31a
32a
33a
34
35a
39
29b
40
42
43
47b
49a
51
-17
-20
-8
-8
11
-6
29
29
45*
36
3
19
37*
17
38**
-1
-29
-25
-3
42*
50
54*
25
3
0
-12
-2
21
16
50**
-16
80**
-27
60*
62**
35*
56*
16
3
-28
78*
12
38
39
7
31*
45*
7
25
35
-25
-18
22
9
-6
16
28
9
-43
-2
20
31
22
-3
7
64**
9
48
-18
-11
2
-37
8
68**
11
14
3
0
35
10
8
42*
69**
25
54**
70**
6
54**
61**
1
26
15
32
-10
-12
13
-3
14
14
6
-11
51b
53a
53b
54b
62a
62b
62h
63b
21
18
-4
40
-1
15
52*
-2
20
24
6
11
55**
59**
19
22
35
29
25
-9
61*
56**
6
53
14
48**
60
34
24
50*
55*
61*
a
All compounds dosed orally with a dose of 300 µmol/kg, except
where noted. b Orally dosed at 15.86 µmol/kg. c Orally dosed at 200
µmol/kg. *p < 0.05; **p < 0.01.
(2R) and 42 were obtained, and these experimental
structures are consistent with those postulated.
Simultaneously, the effect of changing the ring sizes
of the bicyclic system was explored. Although the
lactam ring can contain four, five, or six atoms and
retain in vitro activity (compare compounds 2, 3, and
17), expansion of the tetrahydrooxazole ring to six atoms

4562 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Aicher et al.
39a . The reported compounds (45-61a ) are examples
of structural diversity in this region. As in the tetrahy-
dropyrrolo[2,1-b]oxazol-5(6H)-ones, it was necessary to
have a 2-substituent CH2XAr (where X is either oxygen
or sulfur) for optimal in vitro potency of this series in
affecting glucose utilization. If this substituent is
present, all compounds have similar potency in the L6
myocyte assay (see 49a , 49b, 53a , 53b, 55a , 55b).
Collectively these data suggest that the acetyl of 49a
does not interact with the compound’s unknown target
site.
To further the SAR of the tetrahydropyrrolo[2,1-b]-
oxazol-5(6H)-ones, the effect of different substituents at
the 7R-position was explored. Of the compounds tested,
the presence of a six-membered ring, especially a
substituted aromatic ring, was desirable for enhance-
ment of glucose utilization. Substitution of an aromatic
group in the para or meta-position afforded compounds
with slightly increased in vitro and in vivo potency
(compare 24a to 3a , 16a , 25a , and others). The addition
of a phenoxy group at the para-position allowed in vitro
and in vivo activity to be seen without a 2-substituent
CH2XAr (compare 4 to 15 and 19). It was disappointing
that 16a was not hypoglycemic orally, although it was
very efficacious via ip administration (data not shown).
The clog P values of the aromatic substituted tetrahy-
dropyrrolo[2,1-b]oxazol-5(6H)-ones were in the range of
4.0-6.5. It has been noted by Lipinski and others that
clog P values of above 5.0 may lead to problems of
absorption.22,23 However, the in vivo potency of this
series is not simply correlated to clog P, as 32a has a
higher clog P than 16a (6.5 vs 6.2) and is hypoglycemic
upon oral dosing.
Although the in vitro potency of this series of com-
pounds was not markedly affected by electronic effects,
the in vivo potency was significantly affected. Com-
pounds in which the aromatic ring was substituted with
electron-donating substituents were less efficacious in
vivo than those substituted with electron-withdrawing
substituents (i.e., compare 25a and 28a with 26a ).
Without a 2-substituent, the tetrahydrothiazole de-
rivatives were more potent in vitro and more efficacious
in vivo than the tetrahydrooxazole derivatives (compare
3 and 40). However, the addition of a C2-oxidized
methyl substituent, while causing an increase in in vitro
potency, did not have a significant effect on in vivo
potency (compare 40 to 43).
F igu r e 1. Efficacy of glucose lowering by 25a (2S) (SDZ PGU
693; squares), troglitazone (circles), or metformin (triangles)
in ob/ ob mice. Compounds were given orally for 3 days. Data
depicted represent blood glucose concentrations at 2 h postdose
on day 3 (N ) 6-18 mice/group).
cytes in vitro, 25a (2S) stimulated glucose utilization
with an EC50 value of 6.8 µM. 25a (2S) enhanced
2-deoxyglucose uptake in 3T3-L1 adipocytes under both
basal and insulin-stimulated conditions. In vivo, 25a -
(2S) significantly improved glucose metabolism in dia-
betic and insulin-resistant animals. In obese, hyper-
glycemic ob/ ob mice, oral administration of 25a (2S) for
3 days effectively reduced glucose levels with a dose of
4 mg/kg/day producing 50% efficacy. The efficacy and
potency of 25a (2S) in this model was equal to or greater
than that of troglitazone and metformin (Figure 1). The
duration of action of 25a (2S) was at least 8 h (see Table
4). In obese, insulin-resistant cynomolgus monkeys, 21-
day treatment with 25a (2S) substantially increased
insulin sensitivity (SI, +71 ( 21%, p < 0.05) as
determined by the Bergman minimal model24 while
reducing basal (-36 ( 11%, p < 0.05) and glucose-
stimulated (-35 ( 11%, p < 0.05) insulin levels during
an intravenous glucose tolerance test.25 The results of
these pharmacological studies suggest that 25a (2S) may
provide a novel approach to improving glucose disposal
in type 2 diabetic patients.
Exp er im en ta l Section
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 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
Of the insulin-sensitizing agents described above, five
compounds (25a (2S), 40, 49a , 62a , and 63b) were
selected initially for further pharmacological profiling.
25a (2S), 40, 49a , 62a , and 63b enhanced insulin
sensitivity in vitro by a mechanism distinct from that
of the thiazolidinediones. Troglitazone induces pre-
adipocyte differentiation and is an agonist of PPARγ
receptors,16 whereas 25a (2S), 40, 49a , 62a , and 63b had
no affect on this process or receptor. The in vivo
mechanism of 25a (2S), 40, 49a , 62a , 63b, and other
members of this novel class of insulin-sensitizing agents
is unknown. The isoxazoles 62a and 63b were less
potent (ED50 values greater than 200 µmol/kg) in the
ob/ ob diabetic animal model than the other candidates.
spectrometer. Elemental analyses were performed on
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 chromatography 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 were of purified product and were
not optimized. All starting materials were commercially
available unless otherwise indicated. All keto acids and amino
alcohols which were not commercially available were made by
the methods reported in the literature, and were consistent
with the reported physical properties.
On the basis of both in vivo efficacy and preliminary
toxicity evaluation, 25a (2S) (SDZ PGU 693) was se-
lected for further pharmacological study. In L6 myo-

Oxazolones and Thiazolones as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4563
Gen er a l P r oced u r es for th e P r ep a r a tion of 3-67:
Meth od A. (+)-tr a n s-2-[(4-Ch lor op h en oxy)m eth yl]-7r-
(3,4-dich lor oph en yl)tetr ah ydr opyr r olo[2,1-b]oxazol-5(6H)-
on e (25a ) a n d (+)-cis-2-[(4-Ch lor op h en oxy)m et h yl]-7r-
(3,4-dich lor oph en yl)tetr ah ydr opyr r olo[2,1-b]oxazol-5(6H)-
on e (25b). In a round-bottom flask equipped with a Dean-
water and brine, dried over MgSO4, and concentrated. The
residue was filtered through silica gel eluting with 20% methyl
tert-butyl ether in CH2Cl2. The major fraction was concen-
trated to afford 9a (1.74 g, 68%) as a colorless oil: 1H NMR
(C6D6) δ 1.78 (m, 1H), 2.30-2.43 (m, 3H), 2.78 (m, 1H), 3.43
(s, 2H), 3.44 (s, 3H), 3.90-3.96 (m, 3H), 4.09 (m, 1H), 7.19 (d,
J ) 8.5 Hz, 2H), 7.24 (d, J ) 8.5 Hz, 2H). Anal. (C16H18NO5-
Cl) C, H, N, Cl.
2-tr a n s-7r-(4-Ch lor op h en yl)tetr a h yd r o-2-[(2-h yd r oxy-
eth oxy)m eth yl]p yr r olo[2,1-b]oxa zol-5(6H)-on e (10a ). To
a solution of the ester 9a (1.17 g, 3.45 mmol) in MeOH (50
mL) at 0 °C was added an excess of NaBH4 (600 mg). The
mixture was stirred overnight and then concentrated to a
paste. The residue was partitioned between water (20 mL)
and ethyl acetate (30 mL). The organic layer was separated,
washed with brine, dried (MgSO4), and concentrated. The
residue was subjected to chromatography, eluting with a 19:1
mixture of CH2Cl2-MeOH, to afford after concentration of the
major fraction and recrystallization from ethyl acetate/hexanes
10a (560 mg, 45%) as white crystals: mp 91-93 °C; 1H NMR
(CDCl3) δ 2.20 (m, 1H), 2.58-2.66 (m, 2H), 2.78 (m, 1H), 3.01
(dd, J ) 11.3, 8.1 Hz, 1H), 3.38 (dd, J ) 11.3, 3.0 Hz, 1H),
3.53 (m, 1H), 3.59-3.79 (m, 3H), 4.05 (dd, J ) 11.3, 3.5 Hz,
1H), 4.17 (m, 1H), 7.39 (m, 4H); MS (DCI, NH3) m/z (rel
Stark water separator,
a mixture of 3-(3,4-dichloroben-
zoyl)propionic acid (24.5 g, 99.5 mmol), 3-(4-chlorophenoxy)-
2-hydroxypropylamine (20.0 g, 99.5 mmol), and a catalytic
amount of p-toluenesulfonic acid monohydrate (0.1 g) in
toluene (1 L) was heated to reflux for 16 h. The mixture was
cooled and concentrated in vacuo. The crude residue was
separated via column chromatography on silica gel (∼750 g)
eluting with CH2Cl2-methanol (99.5:0.5, ∼5 L) to afford two
products. The first product to elute from the column was
concentrated in vacuo and recrystallized from CH2Cl2/diethyl
ether to yield 25a (18.1 g, 44%) as white crystals: mp 126-
127.5 °C; 1H NMR (CDCl3) δ 2.09 (m, 1H), 2.51-2.64 (m, 2H),
2.80 (m, 1H), 3.15 (dd, J ) 11.5, 8.2 Hz, 1H), 3.91 (dd, J )
10.2, 4.2 Hz, 1H), 4.05 (m, 2H), 4.37 (m, 1H), 6.83 (d, J ) 9.0
Hz, 2H), 7.22 (d, J ) 9.0 Hz, 2H), 7.33 (dd, J ) 8.3, 2.0 Hz,
1H), 7.44 (d, J ) 8.3 Hz, 1H), 7.61 (d, J ) 2.0 Hz, 1H); MS
(DCI, NH3) m/z (rel intensity) 416 (26), 415 (19), 414 (79), 413
(27), 412 (100), 380 (31), 378 (60). Anal. (C19H16NO3Cl3) C,
H, N, Cl.
intensity) 331 (20), 329 (65), 314 (33), 312 (100). Anal. (C15H18
NO4Cl) C, H, N, Cl.
-
The second product to elute was concentrated in vacuo and
recrystallized from CH2Cl2/diethyl ether to yield 25b (5.60 g,
14%) as white crystals: mp 106-108 °C; H NMR (CDCl3) δ
2.24 (m, 1H), 2.50-2.68 (m, 2H), 2.80 (m, 1H), 2.96 (dd, 1H),
3.75-3.85 (m, 2H), 4.37 (dd, 1H), 4.46 (m, 1H), 6.62 (d, 2H),
7.20 (d, 2H), 7.33 (dd, 1H), 7.40 (d, 1H), 7.55 (d, 1H); MS (DCI,
NH3) m/z (rel intensity) 416 (29), 415 (21), 414 (89), 413 (27),
412 (100). Anal. (C19H16NO3Cl3) C, H, N, Cl.
Meth od D. 2-tr a n s-N-(4-Ch lor op h en yl)-N-[[7r-(4-ch lo-
r oph en yl)h exah ydr o-5-oxopyr r olo[2,1-b]oxazol-2-yl]m eth -
yl]a ceta m id e (14a ). To a solution of 2-trans-7R-(4-chloro-
phenyl)tetrahydro-2-[[(4-chlorophenyl)amino]methyl]pyrrolo-
[2,1-b]oxazol-5(6H)-one (13a ) (0.42 g, 1.1 mmol) in THF (10
mL) was added triethylamine (16 µL, 1.1 mmol) followed by
acetyl chloride (8 µL, 1.1 mmol). The mixture was stirred at
room temperature for 72 h and was partitioned between ethyl
acetate (15 mL) and water (15 mL). After separation, the
organic layer was dried (MgSO4) and concentrated. The
residue was subjected to column chromatography, eluting with
ethyl acetate-hexanes (2:1) to afford after concentration of the
lower Rf major component 14a (170 mg, 37%): mp 65-67 °C;
1H NMR (CDCl3) δ 1.86 (s, 3H), 2.06 (m, 1H), 2.33 (m, 1H),
2.44 (m, 1H), 2.75 (m, 1H), 3.02 (dd, J ) 11.5, 7.9 Hz, 1H),
3.63 (dd, J ) 11.5, 5.4 Hz, 1H), 3.70-3.92 (m, 2H), 4.21 (m,
1H), 7.16-7.43 (m, 8H); MS (DCI, NH3) m/z (rel intensity) 438
(25), 437 (11), 436 (40), 422 (15), 421 (62), 420 (26), 419 (100).
Anal. (C22H20N2O3Cl2) C, H, N, Cl.
Meth od E. (()-7r-(4-Ch lor oph en yl)tetr a h yd r op yr r olo-
[2,1-b]th ia zol-5(6H)-on e (40). Sodium hydroxide (8.8 g) in
methanol (20 mL) was added to a saturated solution of
cystamine hydrochloride (25.0 g, 220 mmol) in anhydrous
methanol (75 mL). The mixture was stirred for 15 min,
filtered, and concentrated. A mixture of the residue, toluene
(500 mL), 3-(4-chlorobenzoyl)propionic acid (30.0 g, 141 mmol),
and p-toluenesulfonic acid (1.25 g) was refluxed for 1 h using
a Dean-Stark trap. The solution was cooled to room temper-
ature, and then diethyl ether was added (300 mL). The
solution was decanted. The solution was washed with water
(200 mL), 0.2 N HCl (200 mL), and water (200 mL) and then
dried (MgSO4) and concentrated under reduced pressure to
approximately 50 mL. To the mixture was added hexane (30
mL). Crystallization occurred, and the filtered crystals were
dried in vacuo to yield 40 (35.6 g, 99.5% theoretical yield) as
white crystals: mp 91-92 °C; 1H NMR (CDCl3) δ 2.30 (m, 1H),
2.61-2.78 (m, 3H), 2.93-3.06 (m, 2H), 3.21 (m, 1H), 4.40 (m,
1H), 7.31 (d, J ) 8.8 Hz, 2H), 7.38 (d, J ) 8.6 Hz, 2H); MS
(DCI, NH3) m/z (rel intensity) 273 (36), 271 (100), 256 (18),
254 (52). Anal. (C12H12NSOCl) C, H, N.
1
Meth od B. (+)-tr a n s-2-(Hyd r oxym eth yl)-7r-4-(ch lo-
r op h en yl)tetr a h yd r op yr r olo[2,1-b]oxa zol-5(6H)-on e (6a )
a n d (+)-cis-2-(Hyd r oxym eth yl)-7r-4-(ch lor op h en yl)tet-
r a h yd r op yr r olo[2,1-b]oxa zol-5(6H)-on e (6b). Following
the general procedure of method A from 1-amino-2-hydroxybut-
3-ene (0.91 g, 10.5 mmol) and 3-(4-chlorobenzoyl)propionic acid
(2.12 g, 10 mmol) was obtained 1.13 g of a mixture of bicyclic
alkenes which were used as they were. Ozone was passed
through a solution of the alkenes (1.49 g, 5.66 mmol) in CH2-
Cl2 (15 mL) and 4.5 mL of a 2.5 N solution of NaOH in MeOH
at -78 °C until the solution became blue (∼0.5 h). The
mixture was diluted with diethyl ether (50 mL), washed with
water and brine, dried (MgSO4), and concentrated. The
residue was filtered through silica gel eluting with 5% methyl
tert-butyl ether in CH2Cl2. The filtrate was concentrated to
afford 1.28 g of a mixture of two esters.
To a mixture of the esters (1.88 g, 6.38 mmol) in MeOH (50
mL) at 0 °C was added an excess of NaBH4 (600 mg). The
mixture was stirred overnight and then concentrated to a
paste. The residue was partitioned between water (20 mL)
and ethyl acetate (30 mL). The organic layer was washed with
brine, dried (MgSO4), and concentrated. The residue was
subjected to chromatography, eluting with a 19:1 mixture of
CH2Cl2-2-propanol, to afford after concentration 183 mg (11%)
of 6a : mp 115-117 °C; 1H NMR (C6D6) δ 1.76 (m, 1H), 2.09-
2.47 (m, 4H), 3.16-3.38 (m, 3H), 3.95 (dd, 1H), 4.22 (1H, m),
7.15 (d, 2H), 7.22 (d, 2H); MS (DCI, NH3) m/z (rel intensity)
270 (30), 269 (16), 268 (100). Anal. (C13H14NO3Cl) C, H, N.
Also eluted was 6b (385 mg, 23%): mp 144-146 °C; 1H NMR
(C6D6) δ 1.72 (m, 1H), 2.17-2.47 (m, 4H), 3.15 (m, 1H), 3.20
(m, 1H), 3.27 (m, 1H), 3.88 (dd, 1H), 4.19 (m, 1H), 7.17 (d, 2H),
7.21 (d, 2H); MS (DCI, NH3) m/z (rel intensity) 285 (29), 270
(30), 268 (100). Anal. (C13H14NO3Cl) C, H, N.
Meth od C. 2-tr a n s-2-[[7r-(4-Ch lor op h en yl)h exa h yd r o-
5-oxopyr r olo[2,1-b]oxazol-2-yl]m eth oxy]acetic Acid, Meth -
yl Ester (9a ). Ozone was passed through a solution of 2-trans-
7R-(4-chlorophenyl)tetrahydro-2-[(2-propenyloxy)methyl]pyr-
rolo[2,1-b]oxazol-5(6H)-one (8a ) (2.33 g, 7.59 mmol) in CH2-
Cl2 (15 mL) and 4.5 mL of a 2.5 N solution of NaOH in MeOH
at -78 °C until the solution became blue (∼0.5 h). The
mixture was diluted with diethyl ether (50 mL), washed with
Meth od F . (+)-cis-2-[(4-Ch lor op h en oxy)m eth yl]-7r-
(3,4-d ich lor op h en yl)t et r a h yd r op yr r olo[2,1-b]t h ia zol-5-
(6H)-on e (42) a n d (+)-tr a n s-2-[(4-Ch lor op h en oxy)m eth -
yl]-7r-(3,4-d ich lor op h en yl)tetr a h yd r op yr r olo[2,1-b]th i-
a zol-5(6H)-on e (43). To a stirred mixture of di-tert-butyl
dicarbonate (35.1 g, 161 mmol) in CH2Cl2 (320 mL) was added
aqueous 2 N NaOH (161 mL, 322 mmol) followed by 3-(4-
chlorophenoxy)-2-hydroxypropylamine (32.4 g, 161 mmol). The

4564 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Aicher et al.
mixture was stirred until clear (2 h), washed with water (200
mL), 2 N HCl (150 mL), 10% NaHCO3 (150 mL), and brine
(150 mL), dried (MgSO4), and concentrated in vacuo to yield
N-(tert-butoxycarbonyl)-3-(4-chlorophenoxy)-2-hydroxypropyl-
amine as a white solid which was used without additional
purification.
To a solution of triphenylphosphine (84.5 g, 322 mmol) in
THF (320 mL) at 0 °C was added diisopropyl azodicarboxylate
(63.4 mL, 322 mmol), and the mixture was stirred for 30 min.
Crude N-(tert-butoxycarbonyl)-3-(4-chlorophenoxy)-2-hydroxy-
propylamine and thioacetic acid (23.0 mL, 322 mmol) in THF
(160 mL) was added dropwise, and the mixture was allowed
to warm to room temperature overnight. The mixture was
concentrated, and the residue was extracted with diethyl ether
(2 × 100 mL). The combined ether layer was dried and
concentrated, and the residue was subjected to column chro-
matography with 20% methyl tert-butyl ether-hexanes as the
eluant. The major fraction was concentrated to yield (19.8 g,
34%) the N-(tert-butoxycarbonyl)-3-(4-chlorophenoxy)-2-mer-
captopropylamine, acetic acid thioester as an oil.
two products were separated via column chromatography
eluting with ethyl acetate-hexanes (3:1). The first product
to elute was concentrated and crystallized from hexanes-CH2-
Cl2 to afford 49a as white crystals (1.30 g, 39%): mp 84-8 °C;
1H NMR (CD3SOCD3, 100 °C) δ 2.01 (s, 3H), 3.80 (m, 1H), 3.88
(m, 1H), 4.13-4.19 (m, 2H), 4.64 (m, 1H), 6.32 (s, 1H), 6.97
(d, J ) 9.0 Hz, 2H), 7.30 (d, J ) 9.0 Hz, 2H), 7.39 (d, J ) 8.3
Hz, 1H), 7.59-7.61 (m, 2H); MS (DCI, NH3) m/z (rel intensity)
421 (27), 420 (19), 419 (75), 418 (31), 417 (100), 402 (26), 400
(35), 385 (29). Anal. (C18H16NO3Cl3) C, H, N, Cl.
The second product to elute was concentrated and crystal-
lized from hexanes-CH2Cl2 to afford 49b as an oil (1.10 g,
33%): 1H NMR (CD3SOCD3, 100 °C) δ 1.98 (s, 3H), 3.58 (m,
1H), 4.13 (m, 1H), 4.17 (dd, J ) 11.0, 5.1 Hz, 1H), 4.25 (dd, J
) 11.0, 3.6 Hz, 1H), 4.55 (m, 1H), 6.15 (s, 1H), 6.96 (d, J ) 9.0
Hz, 2H), 7.28 (d, J ) 9.0 Hz, 2H), 7.40 (dd, J ) 8.3, 2.0 Hz,
1H), 7.56 (d, J ) 8.3 Hz, 1H), 7.63 (d, J ) 2.0 Hz, 1H); MS
(DCI, NH3) m/z (rel intensity) 421 (27), 420 (20), 419 (85), 418
(26), 417 (100), 402 (34), 401 (12), 400 (43), 385 (29), 383 (51),
365 (31). Anal. (C18H16NO3Cl3) C, H, N, Cl.
NH4OH (15 N) (7.3 mL, 110 mmol) was added to a solution
of N-(tert-butoxycarbonyl)-3-(4-chlorophenoxy)-2-mercaptopro-
pylamine, acetic acid thioester (19.7 g, 54.9 mmol) in methanol
(500 mL); the mixture was stirred for 16 h. The reaction
mixture was concentrated to a paste, poured into a cold
solution of 3 N HCl (13 mL), and extracted with diethyl ether
(2 × 150 mL). The combined organic extracts were washed
with brine (10 mL), dried (MgSO4), and concentrated in vacuo.
The N-(tert-butoxycarbonyl)-3-(4-chlorophenoxy)-2-mercapto-
propylamine was purified by column chromatography on silica
gel (150 g) using ethyl acetate-hexane (15:85) yielding (17.5
g, ∼100%) a clear oil.
Meth od I. 3-(4-Ch lor op h en yl)-5-(h yd r oxym eth yl)isox-
a zole (62a ). N-Chlorosuccinimide (51.2 g, 383 mmol) was
added to a solution of 4-chlorobenzaldoxime (52.1 g, 335 mmol)
in dimethylformamide (800 mL) at 0-5 °C. After stirring
overnight at room temperature, the solution was added to ethyl
acetate (800 mL). The solution was washed with 1:1 saturated
sodium chloride-water (2 × 800 mL) and water (2 × 800 mL),
dried (MgSO4), and concentrated to yield the hydoximinoyl
chloride as a white solid.
Triethylamine (51 mL, 370 mmol) was added to a mixture
of the crude chloride and propargyl alcohol (25 mL, 430 mmol)
in CH2Cl2 (800 mL) at 0 °C at a rate such that the temperature
did not rise (30 min). The mixture warmed to room temper-
ature overnight. The mixture was washed with water, dried
(MgSO4), and concentrated. The residue was recrystallized
twice from CH2Cl2-hexane (4:1, 800 mL of solution each time)
to afford 62a as white crystals (42.4 g, 60% based on oxime).
Recrystallization of the mother liquor afforded another crop
In a round-bottom flask equipped with a Dean-Stark water
separator, a mixture of N-(tert-butoxycarbonyl)-3-(4-chlorophe-
noxy)-2-mercaptopropylamine (5.00 g, 15.7 mmol), 3-(4-chlo-
robenzoyl)propionic acid (3.35 g, 15.7 mmol), and trifluoroacetic
acid (30 mL) in toluene (100 mL) was stirred for 30 min at
room temperature and then heated to reflux for 1 h. The
mixture was cooled, diluted with CH2Cl2 (100 mL), washed
with saturated aqueous NaHCO3 (50 mL), dried (MgSO4), and
concentrated in vacuo. The crude residue was purified via
column chromatography on silica gel eluting with 20% diethyl
ether-hexane (1:5) to afford two products. After concentration
and recrystallization of the first product to elute, 42 was
isolated as white crystals (1.15 g, 18%): mp 132-132.5 °C;
1H NMR (CDCl3) δ 2.34 (m, 1H), 2.70 (m, 2H), 2.79 (m, 1H),
3.13 (dd, J ) 12.4, 6.0 Hz, 1H), 3.90 (m, 3H), 4.52 (dd, J )
12.6, 0.6 Hz, 1H), 4.37 (m, 1H), 6.83 (d, 2H), 7.22 (d, 2H), 7.39
(m, 4H); MS (DCI, NH3) m/z (rel intensity) 413 (70), 412 (21),
411 (100), 396 (26), 394 (33). Anal. (C19H16NOCl2) C, H, N,
Cl.
The second fraction was concentrated and also recrystallized
from hexanes-diethyl ether to afford 43 as white crystals (0.85
g, 13%): mp 100-102 °C; 1H NMR (CDCl3) δ 2.26 (m, 1H),
2.64-2.75 (m, 3H), 2.84 (dd, J ) 12.4, 7.4 Hz, 1H), 3.65 (dd, J
) 9.5, 7.8 Hz, 1H), 3.89 (dd, J ) 9.5, 5.7 Hz, 1H), 4.16 (m,
1H), 4.73 (dd, J ) 12.4, 7.9 Hz, 1H), 6.62 (d, 2H), 7.18 (d, 2H),
7.34-7.43 (m, 4H); MS (DCI, NH3) m/z (rel intensity) 413 (72),
412 (24), 411 (100), 396 (74), 395 (22), 394(99), 136 (28). Anal.
(C19H16NOCl2) C, H, N, Cl
1
of crystals (26.7 g, 37%): mp 99 °C; H NMR (CDCl3) δ 2.33
(bs, 1H), 4.83 (s, 2H), 6.55 (s, 1H), 7.43 (d, J ) 8.6 Hz, 2H),
7.72 (d, J ) 8.6 Hz, 2H); MS (DCI, NH3) m/z (rel intensity)
229 (33), 227 (100), 212 (20), 210 (55). Anal. (C10H8NO2Cl)
C, H, N, Cl.
Met h od J . 5-(4-Ch lor op h en oxym et h yl)-3-(4-ch lor o-
p h en yl)isoxa zole (65). Diethyl azodicarboxylate (790 µL,
5.02 mmol) in THF (1 mL) was added over 15 min to a stirred
solution at 0 °C of the alcohol 62a (1.00 g, 4.78 mmol),
4-chlorophenol (615 mg, 4.78 mmol), and triphenylphosphine
(1.32 g, 5.02 mmol) in THF (10 mL). The mixture was allowed
to warm to room temperature overnight. To the mixture was
added hexane (15 mL), followed by filtration, and the solids
were washed with hexane. The combined filtrates was con-
centrated. The residue was filtered through silica (CH2Cl2
eluant), concentrated, and recrystallized from aqueous ethanol
to yield 65 as white crystals (1.28 g, 83%): mp 143 °C; 1H NMR
(CDCl3) δ 5.19 (s, 2H), 6.62 (s, 1H), 6.92 (d, J ) 9.0 Hz, 2H),
7.27 (d, J ) 9.0 Hz, 2H), 7.43 (d, J ) 8.5 Hz, 2H), 7.75 (d,
J ) 8.5 Hz, 2H); MS (DCI, NH3) m/z (rel intensity) 229 (33),
227 (100), 212 (20), 210 (55). Anal. (C16H11NO2Cl2) C, H,
N.
Met h od G. 1-[5-[(4-Ch lor op h en oxy)m et h yl]-2-(3,4-
dich lor oph en yl)-3-oxazolidin yl]-tr a n s-eth an on e (49a) an d
1-[5-[(4-Ch lor op h en oxy)m eth yl]-2-(3,4-d ich lor op h en yl)-
3-oxa zolid in yl]-cis-et h a n on e (49b ). A mixture of 3,4-
dichlorobenzaldehyde (10.0 g, 57 mmol) and 3-(4-chlorophenoxy)-
2-hydroxypropylamine (11.5 g, 57 mmol) in benzene (500 mL)
was heated at reflux with a Dean-Stark trap for 4 h. The
mixture was cooled and concentrated to afford a crude hy-
droxylimine (20.5 g, ∼100%) which was used as is in aliquots.
Met h od K. 3-(4-Ch lor op h en yl)-5-(m et h oxym et h yl)-
isoxa zole (66). NaH (60% in mineral oil) (1.20 g, 40 mmol)
was washed with hexane. DMF (15 mL) was carefully added.
To this mixture at 0 °C was added a solution of the alcohol
62a (3.20 g, 15 mmol) in DMF (5 mL). The mixture was stirred
at room temperature for 90 min, methyl iodide (4.26 g, 30
mmol) was added, and stirring was continued overnight. The
mixture was poured into water and extracted with ether (2 ×
40 mL). The combined organic layers were washed with brine,
dried (MgSO4), and concentrated in vacuo. Recrystallization
of the residue from petroleum ether afforded 66 as white
crystals (2.23 g, 67%): mp 54-55 °C; 1H NMR (CDCl3) δ 3.48
(s, 3H), 4.60 (s, 2H), 6.55 (s, 1H), 7.42 (d, J ) 8.5 Hz, 2H),
Acetyl chloride (0.60 mL, 84 mmol) was added to a solution
of the hydroxylimine (3.0 g, 84 mmol) and pyridine (0.70 mL,
84 mmol) in CH2Cl2 (50 mL). The mixture was stirred at room
temperature for 8 h, diluted in ethyl acetate (100 mL), washed
with water and brine, dried (MgSO4), and concentrated. The

Oxazolones and Thiazolones as Hypoglycemic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4565
(3) Roman, S. H.; Harris, M. I. Management of Diabetes Mellitus
From a Public Health Perspective. Endocrinol. Metab. Clin. N.
Am. 1997, 26.3, 443-474.
7.78 (d, J ) 8.5 Hz, 2H); MS (DCI, NH3) m/z (rel intensity)
243 (36), 241 (100), 226 (26), 224 (72). Anal. (C11H10NO2Cl)
C, H, N, Cl.
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Biologica l P r oced u r es. (1) In Vitr o Stim u la tion of
Glu cose Utiliza tion in L6 Myocytes. Rat L6 myoblasts
(American type Culture Collection) were maintained in Dul-
becco’s modified Eagle’s medium (DMEM, containing 5 mM
glucose and 10% calf serum supplement) and were plated in
96-well microtiter plates at a density of 3000 cells/well. Cells
were used in experiments once they had differentiated, on the
11th or 13th day following plating. L6 cells were treated with
the test compound and serum-free DMEM containing 15 mM
glucose for 20 h. The test compound was dissolved in DMSO
(the final concentration of DMSO in the serum-free testing
media (1%) had no effect on glucose utilization). The com-
pound was tested in quadruplicate in each experiment at a
final concentration of 3, 10, 30, 100, and 300 µM. Glucose
utilization was assessed by measurement of glucose remaining
in the media using a glucose oxidase assay (Ciba-Corning
#S1004B).
A statistical analysis of the screening of 1508 random
compounds of the Sandoz compound library19 determined that
an enhancement of glucose utilization of 40% was ∼2.33
standard deviations from the mean. In Tables 1-3 the lowest
concentrations at which compounds effected an enhancement
of glucose utilization of greater than or equal to 40% from the
control values are indicated. The maximum enhancement of
glucose utilization was approximately 80% over control. The
maximum efficacy of SDZ PGU 693 is the same as the maximal
effect of insulin, metformin, or troglitazone.
(2) In Vivo Hyp oglycem ic Activity. Adult male C57BL
ob/ ob mice (J ackson Lab., Bar Harbor, ME) were housed
4/cage in hanging wire-bottom cages with standard laboratory
conditions and a 12:12-h light-dark cycle (lights off 6 a.m.).
Food (Purina Rodent Chow) and water were available ad
libitum. For blood sampling the mice were placed in a
restrainer and a drop of blood was obtained by a nick in the
tip of the tail. Blood glucose concentrations were determined
in 10 µL of blood using a YSI 27 (Yellow Springs Instruments,
OH) analyzer. The protocol for compound evaluation was as
follows: Fed mice were distributed into groups of 6 and
matched for blood glucose levels on day 0. The animals were
dosed (po) in the morning of days 1-3 with vehicle (carboxy-
methylcellulose (CMC, 0.5%) with Tween-80 (0.2%)) or com-
pound. Blood glucose concentrations were monitored 2 and 4
h postdose on day 1 and at 2, 4, and 8 h postdose on day 3.
Results are expressed as absolute blood glucose concentrations
(in mg/dL) and as % efficacy, i.e., the ability of the compound
to normalize glycemia (100 mg/dL), calculated with the for-
mula: % efficacy ) {1 - ([glucose]compound - 100)/[glucose]vehicle
- 100)} × 100. Animals that displayed glycemia of less than
150 mg/dL on day 0 (basal) were considered not to be diabetic
and were excluded from the study. Statistical significance (*p
< 0.05, **p < 0.01) is given versus the appropriate condition
in vehicle-treated animals.
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(19) Sandoz merged with Ciba-Geigy to form Novartis on J an 1,
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(21) Modeling studies were performed with SYBYL 6.3 available from
TRIPOS Associates, St. Louis, MO, 1993, using Gasteiger-
Huckel charges and the consistent valence force field supplied
with the SYBYL package. A systematic search for local minima
was conducted. In each of the accessible local minima (<1.0 kcal
above the global minima), the nearly coplanar arrangement of
these seven atoms was observed.
Ack n ow led gm en t. The authors thank Dr. Hans
Peter Weber for conducting the X-ray cystallographic
analyses of 25a (2R), 42, 49a , and 49b. The authors also
thank Dr. Michael J . Shapiro and Bertha Owens for
help with NMR and MS analyses.
Su p p or tin g In for m a tion Ava ila ble: Complete X-ray
crystallographic data of 3a , 42, 49a , and 49b (37 pages).
Ordering information is given on any current masthead page.
Refer en ces
(1) Presented in part at the 214th American Chemical Society
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(2) The Expert Committee on the Diagnosis and Classification of
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J M9803121