Perhydroquinolylbenzamides as novel inhibitors of 11β-hydroxysteroid dehydrogenase type 1

Article abstract of DOI:10.1021/jm058228q

High-throughput screening identified 5 as a weak inhibitor of 11β-HSD1. Optimization of the structure led to a series of perhydroquinolylbenzamides, some with low nanomolar inhibitory potency. A tertiary benzamide is required for biological activity and substitution of the terminal benzamide with either electron-donating or -withdrawing groups is tolerated. The majority of the compounds show selectivity of >20 to > 700-fold over 11β-HSD2. Analogues which showed >50% inhibition of 11β-HSD1 at 1 μM in an cellular assay were screened in an ADX mouse model. A maximal response of >70% reduction of liver corticosterone levels was observed for three compounds; 9m, 25 and 49.

Full text of DOI:10.1021/jm058228q

6696
J. Med. Chem. 2005, 48, 6696-6712
Perhydroquinolylbenzamides as Novel Inhibitors of 11â-Hydroxysteroid
Dehydrogenase Type 1
Gary M. Coppola,*,† Paivi J. Kukkola,† James L. Stanton,† Alan D. Neubert,† Nicholas Marcopulos,‡
Natalie A. Bilci,† Hua Wang,† Hollis C. Tomaselli,† Jenny Tan,‡ Thomas D. Aicher,§ Douglas C. Knorr,†
Arco Y. Jeng,† Beatriz Dardik,† and Ricardo E. Chatelain†
Department of Metabolic and Cardiovascular Diseases, Novartis Institutes for Biomedical Research, 100 Technology Square,
Cambridge, Massachusetts 02139, Hoffmann-La Roche, 340 Kingsland Street, Nutley, New Jersey 07110, and Array
BioPharma, 3200 Walnut Street, Boulder, Colorado 80301
Received May 9, 2005
High-throughput screening identified 5 as a weak inhibitor of 11â-HSD1. Optimization of the
structure led to a series of perhydroquinolylbenzamides, some with low nanomolar inhibitory
potency. A tertiary benzamide is required for biological activity and substitution of the terminal
benzamide with either electron-donating or -withdrawing groups is tolerated. The majority of
the compounds show selectivity of >20 to >700-fold over 11â-HSD2. Analogues which showed
>50% inhibition of 11â-HSD1 at 1 µM in an cellular assay were screened in an ADX mouse
model. A maximal response of >70% reduction of liver corticosterone levels was observed for
three compounds; 9m, 25 and 49.
Introduction
people yearly and is the seventh leading cause of death
(sixth-leading cause of death by disease) in the United
States.1
Diabetes is a disease in which the body does not
produce or properly use insulin, a hormone that is
needed to convert glucose, starches and other food into
energy needed for daily life. While the cause of diabetes
is not clearly understood, both genetics and environ-
mental factors such as obesity and lack of exercise
appear to play roles. There are 18.2 million people or
6.3% of the population in the United States who have
diabetes. While an estimated 13 million have been
diagnosed, unfortunately, 5.2 million people are not
aware that they have the disease primarily due to the
lack of symptoms during the early stages of the disease.
According to the American Diabetes Association, each
day approximately 3600 people are diagnosed with
diabetes. About 1.3 million people will be diagnosed this
year.1 The more prevalent form of diabetes (type 2)
accounts for more than 90% of these cases. The patho-
genesis of type 2 diabetes is characterized by high
plasma glucose levels resulting from peripheral insulin
resistance, insufficient insulin secretion from pancreatic
â-cells and increased hepatic glucose production.2-4
Microvascular complications associated with diabetes
are responsible for a substantial portion of related
morbidity and mortality. Each year as many as 24 000
people lose their sight due to diabetic retinopathy.1,5 Ten
to 21% of all people with diabetes develop kidney disease
due to nephropathy, and 56 200 people require foot or
leg amputations each year as a result of diabetic
neuropathy.1,6,7 Dyslipidemia with its associated car-
diovascular risk factors accounts for approximately 80%
of all diabetic mortality.8,9 Diabetes with its associated
complications results in the death of at least 190 000
A variety of mechanistic approaches have been taken
to normalize the levels of blood glucose in the diabetic
state.10,11 These include the sulfonylurea receptor/ATP-
K+ channel,12,13 carnitine palmitoyltranferase (CPT),14
glucokinase (GK),15,16 peroxisome-proliferator activated
receptorγ (PPARγ),17-19 dipeptidylpeptidase 4 (DPP-
4),20,21 R-glucosidase,22 and glycogen phosphorylase.23
A conceptually different approach is to target the
enzyme 11â-hydroxysteroid dehydrogenase (11â-HSD).24
This microsomal membrane-bound enzyme controls the
interconversion of the receptor active hormone cortisol
(1a) and its inactive keto-form cortisone (2a, in man)
as well as corticosterone (1b) and dehydrocorticosterone
(2b, in rodents).25 The significance of the glucocorticoids
in glucose homeostasis is exemplified in the clinical
condition known as Cushing’s syndrome where cortisol
excess is characterized by impaired glucose tolerance,
obesity and hypertension.26,27 Cortisol from the liver
together with plasma cortisol derived from the adrenal
gland stimulates gluconeogenesis by enhancing the
activity of enzymes such as PEPCK and glucose 6-phos-
phatase. It also promotes adipogenesis and induces
lipolysis and the release of free fatty acids in the
adipocytes.
Two isoforms of the enzyme have been identified. The
type I isoform (11â-HSD1), located primarily in the liver
and adipose tissue, is a low-affinity, NADPH-dependent
bidirectional enzyme which acts predominantly as an
* To whom correspondence should be addressed. E-mail:
gary.coppola@novartis.com.
† Novartis Institutes for Biomedical Research.
‡ Hoffmann-La Roche.
§ Array BioPharma.
10.1021/jm058228q CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/16/2005

Perhydroquinolylbenzamides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6697
Table 1. Initial Modifications of 5. In Vitro Data.
a 13% Inhibition at 1 µM. NA ) not active.
oxidoreductase to form the active glucocorticoids, whereas
the type II isoform (11â-HSD2), located primarily in the
kidney, is a high-affinity, unidirectional enzyme func-
tioning exclusively as a NAD-dependent dehydrogenase
producing inactive 11-keto metabolites.28-32 It has been
demonstrated that the anti-ulcer drug carbenoxolone
(4), a nonselective inhibitor of 11â-HSD1, increases
hepatic insulin sensitivity in man.33,34 Furthermore,
11â-HSD1 knockout mice are resistant to hyperglycemia
provoked by a high-fat fed diet or stress and have
reduced PEPCK activity.35 11â-HSD2 plays an impor-
tant role in mineralocorticoid target tissues by allowing
aldosterone access to the mineralocorticoid receptors
(MR) which binds cortisol with equal affinity.29 Over-
stimulation of the MR by cortisol leads to sodium
retention, severe hypertension and hypokalemia.29,36-40
Indeed, it has been shown that adult 11â-HSD2 knock-
out mice are markedly hypertensive.28 Therefore, se-

6698 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21
Coppola et al.
Scheme 1a
lectively inhibiting 11â-HSD1 should reduce hepatic
glucose production and decrease lipolysis in adipose
tissue without the risk of adverse hypertension effects.
Glycyrrhetinic acid (3), the active pharmacological
component of licorice root (Glycyrrhiza glabra;
Glycyrrhiza uralensis Fisch.)41-44 and carbenoxolone45,46
(4), the synthetic succinyl ester47-49 of glycyrrhetinic
acid, have been reported to be low nanomolar inhibitors
of 11â-HSD50,51 and were used as reference compounds
in the present work. Both are nonselective inhibitors
actually favoring 11â-HSD2 over 11â-HSD152 (see Table
2. Recently, arylsulfonamidothiazoles were reported to
be selective inhibitors of 11â-HSD1.53 High-capacity
screening of 300 000 in-house compounds identified the
nonsteroidal CGP013289 (5) as a hit (IC50 ) 9.7 µM)54
and provided a starting point for structural optimiza-
tion.
a Reagents: (a) R1NHR2, i-Pr2NEt; (b) H2, Pd/C; (c) R3PhCOCl,
base; (d) 2,4-dichlorobenzoyl chloride, i-Pr2NEt; (e) NaOH; (f)
(COCl)2, DMF (cat.).
Chemistry
The initial compounds 9 listed in Table 1 were
synthesized via key intermediates 8 and 12 as outlined
in Scheme 1. Two approaches were employed. The first
method constructs the product by initially forming the
tertiary amide bond then the benzamide linkage. This
is accomplished by acylation of an appropriate amine
(e.g., piperidine) with 4-nitrobenzoyl chloride followed
by catalytic reduction of the nitro group to the corre-
sponding aniline 8. Reaction with a benzoyl chloride
furnishes the product. The second method reverses the
bond-forming steps. Ethyl 4-aminobenzoate (10) was
acylated with 2,4-dichlorobenzoyl chloride to provide
amide 11. Base hydrolysis of the ester followed by
treatment with oxalyl chloride furnished the acid chlo-
ride 12 in high yield. Reaction of 12 with a variety of
amines gave the desired product 9. Both of these
methods are amenable to multiparallel solution-phase
synthesis using scavenger resins to sequester HCl and
excess reagents or intermediates.
Scheme 2a
Derivatives of 9 based on noncommercially available
secondary amines were prepared according to Scheme
2 but similar to Method A. Acylation of exo-2-amino-
norbornane (13) with 4-nitrobenzoyl chloride gave the
amide 14 in good yield. Methylation of the nitrogen with
methyl iodide and sodium hydride yielded tertiary
amide 15 in high yield. Catalytic reduction of the nitro
group followed by acylation with 2,4-dichlorobenzoyl
chloride proceeded smoothly to give analogue 9k. Like-
wise, trans-2-methylcyclohexylamine was converted to
9l using an analogous series of steps.
a Reagents: (a) 4-nitrobenzoyl chloride, Et3N; (b) NaH, Mel; (c)
H2 (40 psi), 10% Pd/C; (d) 2,4-dichlorobenzoyl chloride, Et3N.
Compounds 24-55 listed in Table 2 are based on
trans-decahydroquinoline and the synthesis of these
derivatives is outlined in Scheme 3. Commercially
available trans-decahydroquinoline (containing 5-15%
cis isomer) was acylated with 4-nitrobenzoyl chloride

Perhydroquinolylbenzamides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6699
Scheme 3a
Table 2. Decahydroquinoline Analogues: Benzene Ring
Modifications. In Vitro Data
11â-HSD2
11â-HSD1 % inhib at
no. R2 R3
R4
R5
R6
IC50 (µM)
10 µM
24
25
26
27
28
29
30
31
32
33
34
35
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
Cl
OMe
Me
CN
COOH
SO2Me
SO2NH2
SO2NPr2
H
H
H
H
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
0.60
0.56
1.09
0.41
0.49
0.58
0.53
0.50
0.39
0.16
0.58
0.55
0.15
1.59
0.48
0.52
0.36
0.79
0.28
0.59
1.14
0.32
0.10
0.12
0.12
0.10
0
2
0
0
23
0
4
9
0
33
70
47
51
8
a Reagents: (a) 4-nitrobenzoyl chloride, i-Pr2NEt; (b) H2, Pd/C;
(c) RCOCl, i-Pr2NEt or RCOOH, EDCl, HOBt.
of the nitro group to the desired aniline. Conversion of
commercially available 2-methoxy-4-nitrobenzoic acid to
its corresponding acid chloride was accomplished with
oxalyl chloride in the presence of a catalytic amount of
DMF. Subsequent reaction with 21 gave the intermedi-
ate nitrobenzamide which was catalytically reduced to
59 in moderate yield. The 2-propoxy intermediate 60
was prepared in four steps from 2-hydroxy-4-nitro-
benzoic acid. Treatment of the starting material with
sodium hydride followed by allyl bromide produced the
2-allyloxy-4-nitrobenzoic acid allyl ester. Hydrolysis of
the ester with sodium hydroxide and subsequent reac-
tion with oxalyl chloride gave the acid chloride in good
yield. Direct reaction with 21 furnished the 2-allyloxy-
4-nitrobenzamide which was reduced under catalytic
conditions to give the desired intermediate.
36 OMe
37 Cl
38
F
2
39 Me
40 OMe
41 Cl
42 Cl
43 Cl
44 Cl
45 Cl
46 Cl
47 Cl
48 Cl
49 Cl
13
71
60
6
62
33
12
37
81
17
22
OMe
NH2
NHAc
(N)a
H
H
H
OMe
OPr
CHdCH-CHdCH
R1
50 4-pyridyl
51 2-furyl
52 1- methyl-2-pyrrolyl
53 cyclohexyl
54 isopropyl
0.43
0.44
0.32
2.21
2.7
34
30
26
58
47
55 1-adamantyl
3
4
1.45
0.011
0.110
7
0.006b
0.010b
a Central ring is derived from 2-aminopyridine-5-carboxylic acid.
b IC50 (µM) (in-house data).
to give 22. Separation of the cis and trans isomers was
possible at this stage either by multiple crystallizations
from ether/hexane (51% yield of the trans isomer) or
alternatively, by multiple flash chromatographies using
60:40 hexane/ethyl acetate (82% yield of the trans
isomer). Reduction of the nitro group furnished 23, then
acylation with various acid chlorides or condensation
with acids under peptide-coupling conditions provided
the desired products. This method was also amenable
to multiparallel solution-phase synthesis.
Substitution on the central aromatic ring required the
preparation of intermediates 56-60 and 62. Acylation
of 21 with 3-methyl-4-nitrobenzoyl chloride furnished
the corresponding nitrobenzamide in 48% yield. Reduc-
tion of the nitro group yielded the 4-aminobenzamide
56 in quantitative yield. Compound 57 was prepared
in good yield by direct coupling of 21 with 4-amino-3-
nitrobenzoic acid in the presence of HOBt/EDCI. Simi-
larly, 58 was synthesized by the coupling of 21 with
2-chloro-4-nitrobenzoic acid followed by the reduction
Synthesis of the pyridine analogue 45 is outlined in
Scheme 4. Acylation of 6-aminonicotinic acid methyl
ester (67) with 2,4-dichlorobenzoyl chloride gave amide
68. Hydrolysis of the ester with 4 N sodium hydroxide
gave the acid 69 which was directly coupled with 21 in
the presence of EDCI/DMAP to give the desired product
in low yield.
Replacement of the trans-decahydroquinoline hetero-
cycle with the isomeric trans-decahydroisoquinoline was

6700 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21
Coppola et al.
Scheme 4a
Scheme 6a
a Reagents: (a) 2,4-dichlorobenzoyl chloride, Et3N; (b) NaOH;
(c) trans-decahydroquinoline, EDCl, DMAP.
Scheme 5a
a Reagents: (a) trans-decahydroquinoline, Et3N; (b) H2, Pd/C;
(c) 4-fluorobenzoyl chloride, i-Pr2NEt; (d) 4-fluorophenylacetyl
chloride, i-Pr2NEt.
Scheme 7a
a Reagents: (a) 3-nitrobenzoyl chloride, Et3N; (b) H2, Pd/C;
benzoyl chloride, PS-DIEA resin.
easily accomplished by acylation of the commercially
available trans-decahydroisoquinoline with 4-nitroben-
zoyl chloride to furnish 63 followed by reduction of the
nitro group to the anilino intermediate 64. Synthesis
of the oxazino intermediate 66 required the preparation
of the corresponding trans-decahydro-1,4-benzoxazine.
This was readily accomplished by epoxide ring opening
of cyclohexene oxide with ethanolamine followed by
dehydrative cyclization with 70% sulfuric acid.55 Analo-
gous reaction with 4-nitrobenzoyl chloride followed by
reduction of the nitro group furnished 66.
The isomeric meta analogue of 24, compound 72, was
prepared from 21 and 3-nitrobenzoyl chloride as shown
in Scheme 5. The amide 71 was acylated with benzoyl
chloride following Method C using PS-DIEA and PS-
trisamine resins as capturing agents for excess reagents
and byproducts.
a Reagents: (a) 4-nitrobenzenesulfonyl chloride, Et3N; (b) H2,
PtO2; (c) 4-fluorobenzoyl chloride, PS-DIEA resin; (d) 4-fluoro-
benzenesulfonyl chloride, Et3N.
Homologated analogues of 25, compounds 76 and 77,
were synthesized as outlined in Scheme 6. Treatment
of 21 with 4-nitrophenylacetyl chloride provided 74 in
modest yield. Reduction of the nitro group followed by
acylation of the anilino nitrogen with 4-fluorobenzoyl
chloride afforded the phenylacetamide 76. Condensation
of 23 with 4-fluorophenylacetyl chloride directly fur-
nished amide 77.
Replacement of each of the amide carbonyl groups
with sulfonyl groups was accomplished according to the
route shown in Scheme 7. Reaction of 21 with 4-nitro-
benzenesulfonyl chloride furnished sulfonamide 78 in
moderate yield. Reduction of the nitro group and acyl-
ation of the amine with 4-fluorobenzoyl chloride gave
the desired product 80. Conversely, the secondary
sulfonamide 81 was obtained from 23 by condensation
with 4-fluorobenzenesulfonyl chloride in the presence
of triethylamine. Replacement of the tertiary amide
carbonyl group by a thiocarbonyl was accomplished by
treating 22 with Lawesson’s reagent in toluene (Scheme
8) to give thioamide 82. Reduction of the nitro group
followed by acylation of the amine with 4-fluorobenzoyl
chloride gave the desired 84.
The reduced version of 25, compound 85, was easily
prepared as shown in Scheme 9 by reductive amination

Perhydroquinolylbenzamides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6701
Scheme 8a
shown in Table 1. Removal of the aromatic hydroxy
group from compound 5 (9a) nearly doubled its biologi-
cal activity. Simultaneous investigation of the benz-
amide substituents and tertiary amide further increased
11â-HSD1 inhibition to low micromolar values. A 2,4-
dichlorobenzamide group in conjunction with a methyl
group at the 2 position of the piperidine ring (i.e., 9d)
improved activity to less than 10 µM. Increasing the
length of the alkyl group (i.e., ethyl, 9e) further im-
proved activity to 1 µM. N,N-Disubstituted amides are
tolerated. For example, replacement of the piperidine
ring with an N-cyclohexyl-N-methylamide (9g) retained
activity. However, changing the cyclohexyl to aryl (9h)
or changing methyl to a larger alkyl group (cyclohexyl,
9i) resulted in considerable loss of activity. Addition of
a methyl group to the cyclohexane ring of 9g trans to
the amide nitrogen (9l) nearly doubled the 11â-HSD1
activity. This observation, in conjunction with the fact
that the 2-alkylpiperidine derivatives such as 9e are
favorable, suggested that combining the two rings in a
trans fashion might further enhance activity. In fact,
the trans-decahydroquinoline analogue 9m gained a
factor of 4-5 over either 9e or 9l. The corresponding
decahydroisoquinoline analogue 9o lost 3 to 4-fold activ-
ity relative to 9m and was not as selective against 11â-
HSD2. Incorporation of an oxygen into the hetero ring
(i.e., 9n) resulted in nearly complete loss of activity.
a Reagents: (a) Lawesson’s Reagent; (b) H2, Pd/C; (c) i-Pr2NEt,
4-fluorobenzoyl chloride.
Scheme 9a
At this point it was decided that any further SAR
would be performed on derivatives possessing the trans-
decahydroquinoline heterocycle. Furthermore, we de-
fined criteria for moving compounds along the develop-
mental pathway. Those analogues with IC50 values less
than 1 µM were screened for 11â-HSD2 inhibition.56
Compounds which showed less than 50% inhibition at
10 µM were further screened in primary rat hepatocytes
to ascertain relative cell permeability. Only those
compounds which produced greater than 50% inhibition
of cellular 11â-HSD1 at 1 µM were tested in vivo in the
adrenalectomized (ADX) mouse to determine liver cor-
ticosterone concentrations relative to untreated controls.
a Reagents: (a) i. 4-fluorobenzaldehyde, p-TsOH, ii. NaBH4; (b)
4-fluorobenzoyl chloride, i-Pr2NEt.
of 23 with 4-fluorobenzaldehyde. The N-methyl ana-
logue 87 was prepared by coupling 4-methylamino-
benzoic acid with 21 in the presence of EDCI/HOBt to
give 86 followed by reaction with 4-fluorobenzoyl chlo-
ride.
A series of compounds where the secondary amide
carbonyl and nitrogen atom are reversed are shown in
Table 4. These terephthalate derivatives 92-100 were
synthesized according to the route outlined in Scheme
10. Acylation of 21 with 4-carbomethoxymethylbenzoyl
chloride provided ester 89 in good yield. Hydrolysis of
the ester function with 1 N NaOH afforded the corre-
sponding benzoic acid 90. This intermediate was either
converted to acid chloride 91 with thionyl chloride and
reacted with an appropriate amine to produce the amide
or was coupled directly with an amine using EDCI/
HOBt.
Modifications were continued around the new core
structure 24 and the results are listed in Tables 2 and
3. We initially investigated substituent effects on the
secondary benzamide phenyl ring. Within a series of
4-substituted derivatives (25-33) it was found that
nearly all inhibited 11â-HSD1 equally, with IC50’s of
approximately 0.5 µM, independent of the electronic
nature of the substituent. In fact, there was little
difference between the 4-substituted analogues and the
unsubstituted derivative 24. In general, these com-
pounds showed selectivities of >20 against 11â-HSD2.
The most active compound in the series was 33 which
was marginally more active than 9m with respect to
11â-HSD1 and had a selectivity of >60 against 11â-
HSD2. One of the most selective analogues (compound
25) was tested at a higher concentration of 11â-HSD2.
At 50 µM it showed an inhibition of 24% which is a
factor of >90 relative to 11â-HSD1. This concentration
is bordering on the limit of solubility of the compound
in the testing medium.
Results and Discussion
The 4-aminobenzamide derivative 5 was identified
(IC50 ) 9.7 µM, pig 11â-HSD1; 128 µM, human 11â-
HSD1)54 as a potentially interesting target during high-
capacity screening of 300,000 in-house compounds. The
results of initial modifications of this structure are
It appears that the position of the substituents on the
phenyl ring does not have a dramatic effect on activity.
For example, the ortho-, meta-, and para-fluoro ana-
logues (35, 34, and 25) are equipotent. Both 4-chloro

6702 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21
Table 3. In Vitro Data of Other Decahydroquinoline Analoguesa
Coppola et al.
a NA ) not active.

Perhydroquinolylbenzamides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6703
Table 5. Cellular and Animal Data
Table 4. In Vitro Data of Terephthalate Analogues
primary
rat hepatocytes
(% inhib at 1 µM)
ADX mouse liver
corticosterone
no.
concentration (%)b
9e
9g
9m
24
25
26
29
30
31
32
33
39
42
45
46
48
49
52
54
55
72
81
87
92
94
95
96
97
98
99
4
55
61
81
84
86
81
79
23
75
57
76
82
74
68
50
17
59
100
79
74
19
47
45
74
34
42
70
57
79
1
NAc
NA
-70
-57
-73
-69
-18
-34
NA
-37
-50
ndd
-20
-15
-73
-67
NA
-21
-23
-22
-47
NA
Scheme 10a
66a
-98
a 2.5 µM (IC50 ) 2 µM). b Dosed at 50 mg/kg. c NA ) not active.
d nd ) not determined.
Replacing the phenyl ring with alkyl groups (i.e., 53,
54, 55) resulted in consistent loss of 11â-HSD1 activity.
Therefore, an aromatic ring at the secondary benzamide
location seems to be important for high potency.
Substitution on the central phenyl ring (compounds
41-49) produced mixed results. Those compounds with
functional groups on the carbon adjacent to the amide
nitrogen (41-44) were generally less active than 9m.
Only the methoxy derivative 42 retained similar potency
compared to 9m and exhibited a selectivity of >36
against 11â-HSD2. Substitution at the carbon adjacent
to the amide carbonyl (46-48) produced consistent 11â-
HSD1 inhibitions roughly twice that of 9m. Comparison
of methoxy-substituted analogues 42 and 47 revealed
that even though 47 was twice as active as 42, it was
significantly less 11â-HSD2-selective than 42. Replacing
methoxy with n-propoxy (48) retained 11â-HSD1 activ-
ity and increased 11â-HSD2 selectivity to >80. The
naphthalene derivative 49 was as potent as the chloro
analogue 46 and both exhibited selectivities of >100
over 11â-HSD2.
Moving the secondary benzamide from the 4- to the
3-position (72) resulted in a dramatic increase in activity
(IC50 ) 14 nM), nearly 50 times the potency of 24 and
with a selectivity of >700 over 11â-HSD2 (Table 3).
Unfortunately, 72 did not inhibit cellular 11â-HSD1
enough (see Table 5) to warrant further investigation.
The tertiary benzamide portion of the molecule is
sensitive to structural changes. Insertion of a methylene
between the carbonyl and phenyl ring (compound 76)
to form a homologated version of 25 resulted in complete
loss of activity. Replacing the amide carbonyl with
a Reagents: (a) trans-decahydroquinoline, i-Pr2NEt; (b) NaOH;
(c) SOCl2; (d) R-NH2, EDCl, HOBt.
and 2-chloro analogues 26 and 37 have IC50’s greater
than 1 µM for 11â-HSD1, however, the combined 2,4-
dichloro derivative 9m increased inhibition by a factor
of 5 relative to either compound. The corresponding 2,4-
difluoro analogue 38 was about half as active as 9m.
Since the ortho-methoxy derivative 36 increased 11â-
HSD1 inhibition by an order of magnitude over the
corresponding chloro analogue 37, the 4-chloro-2-meth-
oxy analogue 40 was prepared. Unfortunately this
combination did not result in enhanced activity. Ad-
ditionally, selectivity against 11â-HSD2 dropped dra-
matically. Replacing the phenyl ring with heterocycles
(i.e., 50, 51, 52) retained 11â-HSD1 activity relative to
24, although, 11â-HSD2 selectivity decreased slightly.

6704 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21
Coppola et al.
sulfonyl (80) loses nearly an order of magnitude potency
relative to 25. Conversion of the amide to thioamide (84)
also resulted in complete loss of activity.
for these studies because even if very low glucocorticoid
levels are present, these levels represent a uniformly
low background between animals (not as those produced
by the stress of sacrifice in normal animals) thus
allowing the accurate determination of small changes
in glucocorticoid production. Also, it has been suggested
that it is possible that the availability of very disparate
amounts of substrate within the tissue (as those present
in stressed animals with intact adrenals) may impart
large variations in the activity of the enzyme. In ADX
animals, despite the reduction in liver corticosterone,
11â-HSD1 activity was unchanged compared to normal
animals. Although liver corticosterone levels were sig-
nificantly reduced, enough remained to be useful in
determining the 11â-HSD1 inhibitory activity of test
compounds. In the ADX mouse model, the known 11â-
HSD inhibitor carbenoxolone (4) reduced the liver
corticosterone level by about 98% relative to untreated
controls. Carbenoxolone was administered orally at 50
mg/kg.
The secondary amide is not as sensitive to structural
manipulations. Insertion of a methylene between the
amide carbonyl and phenyl ring (compound 77) resulted
in a slight increase in 11â-HSD1 activity relative to 25,
however, 11â-HSD2 selectivity dropped considerably.
Replacing the amide carbonyl with sulfonyl (81) in-
creased 11â-HSD1 inhibition by an order of magnitude
relative to 25 and with a selectivity of >166 over 11â-
HSD2. Removal of the amide carbonyl oxygen (85) or
N-methylation of the amide nitrogen (87) also increased
activity by a factor of 10 relative to 25, however, 85 was
less selective against 11â-HSD2. The only deleterious
change associated with the secondary amide is the
transposition of the amide nitrogen and carbonyl to form
a terephthalate (compounds 92-100) and the results
are listed in Table 4. The data indicate that, with the
exception of isoquinoline amide 100, all of the com-
pounds were less active than their 4-aminobenzamide
counterparts (i.e., 93 vs 53, 94 vs 54, and 98 vs 25).
Although compound 100, which can be considered a
conformationally restricted analogue of 96, exhibited a
potency enhancement of 15 over the N-benzylamide 96,
it did not meet the 11â-HSD2 selectivity requirement.
Of the 64 synthetic analogues discussed in this paper
30 compounds were screened further for cellular 11â-
HSD1 inhibition (Table 5) and of these 30 compounds,
22 met the criteria for in vivo testing in the ADX mouse
model.
It is well-known that the adrenal gland is the main
source of circulating glucorticoids and, under normal
circumstances, most of the glucocorticoid concentration
within various tissues and organs is also adrenal-
derived. Glucocorticoid, a class of steroid hormones,
performs an important role in regulating many meta-
bolic and homeostatic processes. It stimulates transcrip-
tion of the hepatic gluconeogenic enzyme and plays a
major role in the enhancement of liver glucose output.57
Increased gluconeogenesis is a major source of increased
glucose production in type 2 diabetes.58
Conclusion
Optimization of the 11â-HSD1 screening hit 5 has led
to a series of perhydroquinolylbenzamides. In general,
substitution on the benzamide phenyl did not adversely
affect potency, whereas, substitution on the central
phenyl ring produced mixed results. Alkylation on
nitrogen, removal of the amide carbonyl or replacing the
benzamide with benzenesulfonamide is tolerated. The
best 11â-HSD1 inhibitors of the series (IC50’s between
0.6 and 0.014 µM) are about 200-9000 times more
potent than initial compound 5. The majority of these
compounds show selectivity of >20 to >700-fold over
11â-HSD2. Thirty of these compounds were screened in
a cellular 11â-HSD1 assay and 22 analogues which
showed >50% inhibition at 1 µM were tested in vivo in
the ADX mouse model. A maximal response of >70%
decrease in liver corticosterone levels was observed for
three compounds; 9m, 25 and 49. These compounds can
serve as useful tools to study the effects of 11â-HSD1
inhibition in animal models of diabetes, dyslipidemia
and obesity.
To isolate and ascertain the relative contribution of
liver 11â-HSD1 to liver glucocorticoid concentration,
ADX mice were used to avoid the confounding influence
of adrenal-derived steroids which, under the stress of
sacrifice, usually increase above normal levels by several-
fold. ADX mice were studied 10 days after adrenalec-
tomy. It was found that in ADX mice circulating
corticosterone was reduced to only 3% of the values
measured in animals with intact adrenals. There was
also a concomitant reduction in corticosterone concen-
tration in the liver to 19% of normal values. The low
levels of plasma and tissue corticosterone in the ADX
mice are considered to be produced by 11â-HSD1 in
liver, lung and adipose stores. These low levels are not
caused by imperfectly removed adrenals because the
absence of adrenal remnants was ascertained after
sacrifice in all the ADX animals. Furthermore, adrenal
remnants in rodents have a very high rate of cell
proliferation, rapidly leading to abnormally elevated
plasma steroid levels (the basis for the experimental
model called “Adrenal regeneration hypertension”).
Therefore, there are advantages in using ADX animals
Experimental Section
Human 11â-HSD1 Assay. Recombinant human 11â-HSD1
is expressed in yeast Pichia pastoris as reported by Hult.34
Cultures are grown at 30 °C for 3 days in the presence of
methanol to induce enzyme expression. The microsomal frac-
tion overexpressing 11â-HSD1 is prepared from the cell
homogenate and used as the enzyme source for primary
screening. A test compound at the desired concentration is
preincubated for 10 min at room temperature with 3 µg of the
microsomal protein in 50 mM sodium phosphate, pH 7.5, in a
total volume of 80 µL. The enzyme reaction is initiated by
adding 20 µL of a mixture containing 5 mM NADPH, 500 nM
cortisone, and 80 000 dpm of [3H]cortisone in the same buffer
and is terminated by ethyl acetate after incubation for 90 min
at 37 °C. The production of [3H]cortisol is quantitated upon
separation from [3H]cortisone by a C18 column on HPLC
equipped with a radioactivity detector. Glycerrhetinic acid, a
known inhibitor of 11â-HSD1, is used as a standard.
Human 11â-HSD2 Assay. The SW-620 human colon
carcinoma cell line is obtained from the American Type
Culture Collection (ATCC). Cells are plated at a density of
8-10 × 104 cells/cm2 in DMEM/F12 containing 5% BCS, 100
U/mL penicillin, 100 µg/mL streptomycin and 0.25 µg/L
amphotericin B. Cultures are grown to 80-90% confluence in

Perhydroquinolylbenzamides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6705
a humidified atmosphere of 5% CO2 at 37 °C. The medium is
changed to serum-free, phenol red-free DMEM/F12 twenty 4
h before harvesting the cells.
After 24 h, in serum-free medium, cultured SW-620 cells
are rinsed and scraped in Kreb’s-Ringer buffer, pH 7.4,
containing 1 mM EDTA, 2 µg/mL aprotinin, 10 µM leupeptin
and 1 µM pepstatin. After sonication (30 s) and low speed
centrifugation (2000 rpm, 5 min) to remove cellular debris, the
supernatant is collected and used to determine enzyme activity
and protein concentration (BCA, Pierce, Rockford, IL).
administered orally at 25 mg/kg each at 4 and 2 h before
sacrifice (total dose: 50 mg/kg). A second group of animals
received carbenoxolone administered in the same fashion (two
25 mg/kg doses at 4 and 2 h before sacrifice), and a third group
received the vehicle (cornstarch). Homogenized liver samples
were used to measure corticosterone concentration which was
determined by radioimmunoassay and is expressed as pg of
corticosterone per mg of liver protein. The coefficient of
variance for the inhibition of corticosterone production by
carbenoxolone was 22% (83 ( 18% inhibition [SDM]; n ) 28).
Chemistry. All melting points (mp) were obtained on a
Thomas-Hoover Unimelt capillary melting point apparatus
and are uncorrected. Proton magnetic resonance spectra were
recorded on a Bruker AC 300-MHz spectrometer. Chemical
shifts in ppm (δ) are reported relative to TMS. Mass spectra
were run on a Finnigan Mat 4600 spectrometer. Elemental
analyses were performed by Robertson Microlit Laboratories,
Inc. and 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 purifications were performed on a Biotage Flash
40 apparatus or employing standard flash chromatography
techniques59 using Merck silica gel (230-400 mesh) in glass
columns. Reagents and solvents were purchased from common
suppliers and were utilized as received. All reactions were
conducted under a nitrogen or argon atmosphere. Yields stated
are of purified product and were not optimized.
Preparation of Aminobenzamides 9. Method A. To a
solution of 1 mmol of the appropriate amine and 1.5 mmol of
triethylamine in 2 mL of methylene chloride was added
dropwise a solution of 1.1 mmol of 4-nitrobenzoyl chloride. The
mixture was stirred at room temperature for 18 h then was
washed with 2 N HCl followed by 10% NaHCO3. The organic
phase was dried over sodium sulfate and the solvent was
removed under reduced pressure. The product was purified
by crystallization or flash chromatography to give 7.
A solution of 7 in 10 mL of ethanol was hydrogenated over
10% Pd/C for 3-5 h. The catalyst was filtered through Celite
and the solvent removed under reduced pressure to furnish
the desired product 8. This generally was used without further
purification.
To a solution of 1 mmol of 8 and 1.5 mmol of triethylamine
or diisopropylethylamine in 10 mL of methylene chloride was
added dropwise a solution of 1 mmol of the appropriately
substituted benzoyl chloride in 5 mL methylene chloride. The
solution was stirred at room temperature for 4-18 h then was
washed with 2 N HCl followed by 10% NaHCO3. The organic
phase was dried over sodium sulfate and the solvent was
removed under reduced pressure. The product was purified
by crystallization or flash chromatography to give 9.
Method A (Multiparallel Synthesis Using Autochem).
Automated parallel solution-phase synthesis/HPLC purifica-
tion was performed according to the method described by
Tommasi.60 Stock solutions (0.5 M) of 8 (R1, R2 ) piperidine61
and R1 ) CH2C6H11, R2 ) Me), 58, 59 or 60 in DMF,
N-methylmorpholine (1.0 M in THF) and the appropriate
acid chloride (1.0 M in THF) were used and the ratio of
reactants was 1:1.5:1.5 equivalents. The chemistry was per-
formed directly on the HPLC setup and the reaction mixtures
were quenched and purified automatically after the pre-
programmed reaction time had elapsed (typically 18 h). The
product from each reaction was collected as a single component
in one easily traceable fraction using dual wavelength UV
detection at 210 and 254 nm. The molecular weight of each
compound was confirmed by API-MS. Using this method, the
following compounds were obtained; 9a, MS (ES+) m/z 399 (M
+ 1)+; 9b, MS (ES+) m/z 327 (M + 1)+; 9c, MS (ES+) m/z 377
(M + 1)+; 9j, MS (ES+) m/z 419 (M + 1)+; 46, (ES+) m/z 465
(M + 1)+; 47, (ES+) m/z 461 (M + 1)+; 48, (ES+) m/z 489 (M +
1)+.
Dehydrogenase activity is quantified by measuring the
conversion of radiolabeled cortisol to cortisone using lysates
of SW-620 cells as the enzyme source. The assay is performed
in tubes containing Kreb’s-Ringer buffer pH 7.4, with 0.20 mM
NAD and 200 000 dpm of [3H]cortisol and a test compound in
a total volume of 1 mL. The tubes are preincubated for 10 min
at 37 °C before adding 200 µg of cell lysates to start the
reaction. After incubation for 1 h at 37 °C in a shaking water
bath, the mixture is extracted with 2 volumes of ethyl acetate
and centrifuged for 10 min at 2000 rpm. The organic layer is
collected, dried under vacuum and resuspended in methanol.
The dissolved residues are quantitatively transferred to thin
layer plates and developed in chloroform-methanol (90:10).
Unlabeled cortisol and cortisone were used as reference
markers. The TLC plates are scanned on a Bioscan radio-
imaging detector (Bioscan, Washington, DC), and the fractional
conversion of cortisol to cortisone is calculated. Enzyme activity
is expressed as pmoles of product formed per mg protein per
hour. Carbenoxolone and glycyrrhetinic acid are used as
standards.
Cellular Primary Rat Hepatocyte 11â-HSD1 Assay.
Male Sprague-Dawley rats weighing 180-200 g are anesthe-
tized with sodium pentobarbital (65 mg/kg). The liver is
perfused in situ with calcium-free Earl’s Balanced Salt Solu-
tion (EBSS) followed by EBSS containing 100-150 U/mL of
collagenase, 1.8 mM CaCl2 and 10 mM HEPES, pH 7.4. The
perfused liver is removed and aseptically placed in warm
William’s Medium E containing 10% BCS. After decapsulation,
the organ is transferred to fresh medium and gently shaken
to facilitate tissue dissociation and cell release. Hepatocytes
are separated from nonparenchymal and dead cells by repeated
low speed centrifugation. Cell viability is determined by trypan
blue exclusion.
Hepatocytes are plated on collagen coated dishes at a
density of 1 × 105 cells/cm2 in William’s medium E containing
10% BCS, 100 U/mL penicillin, 100 µg/mL streptomycin, 0.25
µg/mL amphotericin B, 2 mM L-glutamine, 10 mM HEPES,
100 nM insulin and 1 nM dexamethasone. After 1 h the
medium is changed to serum-free William’s medium E supple-
mented as described above. Thereafter, the medium is replaced
every 24 h. The cultures are maintained in a humidified
atmosphere of 5% CO2 at 37 °C.
Enzyme activity is measured in the medium of primary
cultures of rat hepatocytes 48 h after plating the cells. The
medium is aspirated and replaced with serum-free William’s
medium E containing 2 nM [3H]11-dehydrocorticosterone and
a test compound and is incubated for 2 h. An aliquot of culture
medium is removed at the end of the incubation and the
mixture is extracted with 2 volumes of ethyl acetate, dried
under vacuum and resuspended in methanol. The dissolved
residues are quantitatively transferred to thin layer plates and
developed in chloroform-methanol (90:10). The TLC plates are
scanned on a Bioscan imaging detector and the fractional
conversion of 11-dehydrocorticosterone to corticosterone is
calculated. The cell layer is rinsed with cold phosphate-
buffered saline and dissolved in 0.1 N NaOH/5% SDS for the
determination of cellular protein (BCA, Pierce, Rockford, IL).
Enzyme activity is expressed as pmoles of product formed per
mg protein per hour.
Inhibition of Corticosterone Production in Adrena-
lectomized (ADX) Mice. Bilateral adrenalectomy was per-
formed in male mice of the CD1 strain (6 to 8 weeks of age,
25-30 g body weight) through a lumbar laparotomy. After 10
days the animals were fasted for 24 h. Compounds were
4-(2,4-Dichlorobenzoylamino)benzoic Acid Ethyl Es-
ter (11). To a solution of 2.5 g (15.1 mmol) of ethyl 4-amino-
benzoate (10) and 1.97 g (15.1 mmol) of diisopropylethylamine
in 75 mL of methylene chloride was added dropwise a solution

6706 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21
Coppola et al.
of 3.17 g (15.1 mmol) of 2,4-dichlorobenzoyl chloride in 5 mL
of methylene chloride. The mixture was stirred at room
temperature for 16 h then was washed successively with 50
mL portions of H2O, 1 N HCl, H2O and saturated NaCl
solution. The organic phase was dried over sodium sulfate and
the solvent was removed under reduced pressure. The result-
ing solid was triturated with ether to give 4.09 g (80%) of 11;
MS (ES+) m/z 405 (M + 1)+; 9g, MS (ES+) m/z 405 (M + 1)+;
9h, MS (ES+) m/z 399 (M + 1)+; 9i, MS (ES+) m/z 473 (M +
1)+.
Method B (Preparative). The following procedure is an
illustrative example of using Method B for the preparation of
2,4-Dichloro-N-[4-((4aR*,8aS*)-octahydroquinoline-1-car-
bonyl)phenyl]benzamide (9m). To a solution of 1.39 g (10
mmol) of trans-decahydroquinoline and 1.2 g (9 mmol) of
diisopropylethylamine in 45 mL of methylene chloride was
added dropwise a solution of 3.0 g (9 mmol) of 12a in 10 mL
of methylene chloride. After stirring the mixture at room
temperature for 18 h, it was washed with H2O and the organic
phase was dried over sodium sulfate. The solvent was removed
under reduced pressure and the residual solid was crystallized
from EtOH to give 2.73 g (69%) of 9m, mp ) 213-214 °C; IR
(KBr), ν (cm-1): 1740, 1707; 1H NMR (DMSO-d6): δ 10.69 (s,
1H), 7.79 (d, 1H, J ) 1.8 Hz), 7.73 (d, 2H, J ) 8.4 Hz), 7.65 (d,
1H, J ) 8.4 Hz), 7.57 (m, 1H), 7.36 (d, 2H, J ) 8.40 Hz), 3.34
(m, 3H), 2.10 (m, 1H), 1.77-0.98 (m, 12H); MS (ES+) m/z 431
(M + 1)+; Anal. (C23H24N2O2Cl2) C, H, N.
N-Bicyclo[2.2.1]hept-2-yl-4-nitrobenzamide (14). To a
solution of 1.0 g (9 mmol) of exo-norbornylamine and 1.4 g (14
mmol) of triethylamine in 20 mL of methylene chloride was
added dropwise a solution of 1.7 g (9.2 mmol) of 4-nitrobenzoyl
chloride in 5 mL methylene chloride. The mixture was stirred
at room temperature for 18 h then was washed with 2 N HCl
followed by 10% NaHCO3. The organic phase was dried over
sodium sulfate and the solvent was concentrated to ap-
proximately one-fourth volume at which point crystallization
occurred. Some MTBE was added and the solid was filtered
to give 1.55 gm (66%) of 14, mp ) 163-165 °C; 1H NMR
(CDCl3): δ 8.27 (d, J ) 8.8, 2H), 7.89 (d, J ) 8.8 Hz, 2H), 6.00
(m, broad, 1H), 3.94 (m, 1H), 2.36 (s, 2H), 1.98-1.88 (m, 1H),
1.66-1.45 (m, 2H), 1.44-1.14 (m, 5H); Anal. (C14H16N2O3) C,
H, N.
N-Bicyclo[2.2.1]hept-2-yl-N-methyl-4-nitrobenz-
amide (15). To a solution of 1.5 g (5.8 mmol) of 14 in 25 mL
of DMF was added 0.22 g (5.8 mmol) of sodium hydride (60%
in mineral oil). The mixture was stirred at room temperature
for 90 min. To the resulting orange solution was added 1.3 g
(9.2 mmol) of methyl iodide. The mixture was stirred at room
temperature for 18 h then an additional 100 mg of sodium
hydride and 400 mg of methyl iodide were added. After stirring
the mixture for 24 h the solvent was removed under reduced
pressure. Water was added and the mixture was extracted
with methylene chloride. The organic phase was dried over
sodium sulfate and the solvent was removed under reduced
pressure. The resulting oil was passed through a plug of silica
gel using 2% MeOH/methylene chloride to elute the product,
1.5 g (95%) of 15 as an oil; MS (ES+) m/z 275 (M + 1)+. This
material was used directly in the next step.
4-Amino-N-bicyclo[2.2.1]hept-2-yl-N-methylbenz-
amide (16). A solution of 1.5 g (5.5 mmol) of 15 in 50 mL of
ethanol was hydrogenated over 150 mg of 10% Pd/C at 40 psi
for 3 h. The catalyst was filtered through Celite and the solvent
was evaporated. The residue was filtered through a pad of
silica gel using 2% MeOH/methylene chloride to elute the
product, 1.3 g (99%) of 16 as an off-white solid, mp ) 178-
181 °C; IR (CH2Cl2), ν (cm-1): 3682, 3596, 1610; 1H NMR
(CDCl3): δ 8.27 (d, J ) 8.8 Hz, 2H), 7.52 (d, J ) 8.8 Hz, 2H),
2.98 (s, broad, 3H), 2.33 (d, broad, J ) 12.5 Hz, 2H), 1.74-
0.77 (m, 11H); MS (ES+) m/z 245 (M + 1)+; Anal. (C15H20N2O?0.4
H2O) C, H, N.
1
mp ) 133-134 °C; IR (KBr), ν (cm-1): 3349, 1710; H NMR
(DMSO-d6): δ 10.90 (s, 1H), 7.97 (d, J ) 8.46 Hz, 2H), 7.88-
7.77 (m, 3H), 7.67 (d, J ) 8.09 Hz, 1H), 7.61-7.55 (m, 1H),
4.30 (q, 2H), 1.32 (t, 3H); MS (ES-) m/z 336 (M - 1)-. Anal.
(C16H13Cl2NO3) C, H, N.
4-(2,4-Dichlorobenzoylamino)benzoic Acid. To a sus-
pension of 4.9 g (14.5 mmol) of 11 in 200 mL of H2O/EtOH
(1:1) was added 15 mL of 1 N NaOH. The mixture was refluxed
for 1 h then the solvent was removed until precipitation
occurred. Water was added and the resulting solution was
washed with ether and the aqueous phase acidified with 1 N
HCl. The resulting precipitate was filtered, washed with H2O
and dried to give 3.6 g (97%) of product as a white solid; mp )
274-275 °C; IR (KBr), ν (cm-1): 1665, 1592, 769; 1H NMR
(DMSO-d6): δ 12.80 (s, 1H), 10.87 (s, 1H), 7.94 (d, J ) 8.67
Hz, 2H), 7.86-7.78 (m, 3H), 7.67 (d, J ) 8.29 Hz, 1H), 7.62-
7.55 (m, 1H); MS (ES-) m/z 308 (M - 1)-. Anal. (C14H9NO3-
Cl2) C, H, N.
4-(2,4-Dichlorobenzoylamino)benzoyl Chloride (12a).
A mixture of 250 mg (0.81 mmol) of the above acid, 407 mg
(3.2 mmol) of oxalyl chloride and 2 drops of DMF in 5 mL of
methylene chloride was stirred at room temperature for 90
min. The solvent was removed under reduced pressure.
Methylene chloride was added and the solvent was removed
under reduced pressure (3x) to give 260 mg (97%) of 12a as a
white solid, mp ) 95-99 °C; IR (KBr), ν (cm-1): 3230, 3095,
1770, 1743, 1672; 1H NMR (CDCl3): δ 8.49 (s, broad, 1H), 8.13
(d, J ) 8.82 Hz, 2H), 7.82 (d, J ) 8.82, 2H), 7.71 (d, J ) 8.45
Hz, 1H), 7.48 (m, 1H), 7.43-7.34 (m, 1H); Anal. (C14H8NO2Cl3)
C, H, N.
4-(2,4-Dichlorobenzoylamino)-3-methoxybenzoyl Chlo-
ride (12b). To a solution of 270 mg (1.49 mmol) of 4-amino-
3-methoxybenzoic acid methyl ester and 386 mg (2.99 mmol)
of diisopropylethylamine in 10 mL of methylene chloride was
added 312 mg (1.49 mmol) of 2,4,-dichlorobenzoyl chloride. The
mixture was stirred at room temperature for 18 h then was
washed with 1 N HCl followed by 8% NaHCO3 solution. The
organic phase was dried over sodium sulfate and the solvent
was removed under reduced pressure to give 385 mg (72%) of
4-(2,4-dichlorobenzoylamino)-3-methoxybenzoic acid methyl
ester. This ester was dissolved in 30 mL of THF/H2O (2:1) and
91 mg of LiOH was added. The mixture was stirred at room
temperature for 18 h then was poured into EtOAc. The mixture
was acidified with 1 N HCl and any insoluble material was
filtered. The organic phase was dried over sodium sulfate and
the solvent evaporated to give 295 mg (81%) of 4-(2,4-
dichlorobenzoylamino)-3-methoxybenzoic acid. A mixture of the
benzoic acid and 441 mg of oxalyl chloride and one drop of
DMF in 10 mL of methylene chloride was stirred at room
temperature for 18 h. The solvent was removed under reduced
pressure then methylene chloride was added and the solvent
was removed again. This process was repeated three times to
give 311 mg (100%) of 12b. This material was used directly in
subsequent steps.
Method B (Multiparallel Synthesis). On an argonaut
Quest 210 apparatus, each tube was charged with 0.5 mmol
of the appropriate amine (R1NHR2), 200 mg of PS-DIEA resin
(3.75 mmol/g) and 10 mL of methylene chloride. To this was
added 182 mg (0.55 mmol) of 12a. After agitation for 18 h,
100 mg of PS-Trisamine resin (3.75 mmol/g) was added and
agitation was continued for an additional 3 h. The tubes were
drained and the resin was washed with methylene chloride.
The solvent was removed to afford the desired product. The
following compounds were prepared by this method: 9d, MS
(ES+) m/z 391 (M + 1)+; 9e, MS (ES+) m/z 405 (M + 1)+; 9f,
N-((1S*,2S*)-2-Methyl-cyclohexyl)-4-nitrobenzamide
(18). To a solution of 2.26 g (20 mmol) of 2-methylcyclohexyl-
amine and 2.2 g (22 mmol) of triethylamine in 70 mL of
methylene chloride was added dropwise a solution of 3.72 g
(20 mmol) of 4-nitrobenzoyl chloride in 5 mL methylene
chloride. The mixture was stirred at room temperature for 4
h then the solvent was removed under reduced pressure. Water
was added to the residue and the mixture was extracted with
ethyl acetate. The organic phase was dried over sodium sulfate
and the solvent was removed under reduced pressure. The
residual solid was crystallized from methylene chloride/MTBE

Perhydroquinolylbenzamides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6707
to give 2.4 g (46%) of 18, mp ) 172-174 °C; 1H NMR (CDCl3):
δ 8.28 (d, J ) 9 Hz, 2H), 7.91 (d, J ) 9.2 Hz, 2H), 5.91 (d,
broad, J ) 8.8 Hz, 1H), 3.80-3.65 (m, 1H), 2.13-2.02 (m, 1H),
1.86-1.68 (m, 3H), 1.39 (m, 2H), 1.29-1.13 (m, 3H), 1.00 (d,
J ) 6.5 Hz, 3H); Anal. (C14H18N2O3) C, H, N.
NaHCO3 and saturated NaCl. The organic phase was dried
over sodium sulfate and the solvent was removed under
reduced pressure. The crude product was purified either by
crystallization or flash chromatography.
N-[4-((4aR*,8aS*)-Octahydroquinoline-1-carbonyl)phen-
yl]-4-sulfamoylbenzamide (32). To a solution of 100 mg
(0.39 mmol) of 23 and 78 mg (0.39 mmol) of 4-sulfamoylbenzoic
acid and 75 mg (0.39 mmol) of EDCI in 10 mL of DMF was
added 58 mg 0.43 mmol) of HOBt. The mixture was stirred at
50 °C for 18 h. After cooling the mixture to room temperature,
EtOAc was added then the mixture was washed with 1 N HCl
and 8% NaHCO3 solution. The organic phase was dried over
sodium sulfate and the solvent was removed under reduced
pressure. The residual solid was crystallized from EtOH to give
65 mg (38%) of 32, mp ) >250 °C; 1H NMR (DMSO-d6): δ
10.57 (s, 1H), 8.11 (d, J ) 8.46 Hz, 2H), 7.97 (d, J ) 8.45 Hz,
2H), 7.83 Hz (d, J ) 8.83 Hz, 2H), 7.54 (s, 2H), 7.37 (d, J )
8.45 Hz, 2H), 3.49-3.25 (m, 3H), 2.15-2.04 (m, 1H), 1.78-
0.96 (m, 12H); MS (ES+) m/z 442 (M + 1)+; Anal. (C23H27N3O4S)
C, H, N.
N-Methyl-N-((1S*,2S*)-2-methyl-cyclohexyl)-4-nitro-
benzamide (19). To a solution of 1.7 g (6.5 mmol) of 18 in 25
mL of DMF was added 0.25 g (6.6 mmol) of sodium hydride
(60% in mineral oil). The mixture was stirred at room tem-
perature for 90 min. To the resulting orange solution was
added 1.2 g (8.4 mmol) of methyl iodide. The mixture was
stirred at room temperature for 18 h then an additional 100
mg of sodium hydride and 500 mg of methyl iodide were added.
After stirring the mixture for 24 h the solvent was removed
under reduced pressure. Water was added and the mixture
was extracted with methylene chloride. The organic phase was
dried over sodium sulfate and the solvent was removed under
reduced pressure. The resulting oil was passed through a plug
of silica gel using 2% MeOH/methylene chloride to elute the
product, 1.7 g (95%) of 19 as an oil which solidifies to a waxy
1
solid on standing, mp ) 75-79 °C; H NMR (CDCl3): δ 8.27
2-Fluoro-N-[4-((4aR*,8aS*)-octahydroquinoline-1-car-
bonyl)phenyl]benzamide (35). Prepared in 99% yield from
23 and 2-fluorobenzoyl chloride according to Method A (step
(d, J ) 8.8 Hz, 2H), 7.53 (d, J ) 8.8 Hz, 0.75H), 7.49 (d, J )
8.8 Hz, 1.25 H), 2.97 (s, 2H), 2.96-2.86 (m, 1H), 2.74 (s, 1H),
1.90-1.44 (m, 7H), 1.30-1.00 (m, 2H), 0.96 (d, J ) 6.6 Hz,
1H), 0.80 (d, J ) 6.6 Hz, 2H); MS (ES+) m/z 277 (M + 1)+;
Anal. (C15H20N2O3) C, H, N.
1
c), mp ) 198-204 °C; H NMR (CDCl3): δ 8.57 (d, J ) 15.44
Hz, 1H), 8.17 (t, 1H), 7.70 (d, J ) 8.46 Hz, 2H), 7.60-7.50 (m,
1H), 7.43 (d, J ) 8.46 Hz, 1H), 7.37-7.14 (m, 3H), 3.58-3.30
(m, 3H), 2.37-2.19 (m, 1H), 1.86-1.01 (m, 12H); MS (ES+)
m/z 381 (M + 1)+; Anal. (C23H25N2O2F) C, H, N.
4-Amino-N-methyl-N-((1S*,2S*)-2-methylcyclohexyl)-
benzamide (20). A solution of 1.6 g (5.8 mmol) of 19 in 40
mL of ethanol was hydrogenated over 160 mg of 10% Pd/C at
50 psi for 18 h. The catalyst was filtered through Celite and
the solvent evaporated to give 1.2 g (85%) of 20, mp ) 151-
153 °C; MS (ES+) m/z 247 (M + 1)+. The material was used
directly in the next step.
Preparation of 4-Aminobenzamide Derivatives 24-
55 (Method C). (4-Nitrophenyl)-(4aR*,8aS*)-octahydro-
quinolin-1-yl-methanone (22). To a solution of 10.0 g (71.8
mmol) of trans-decahydroquinoline (21) and 18.6 g (144 mmol)
of diisopropylethylamine in 150 mL of methylene chloride
cooled in an ice bath was added dropwise a solution of 13.33
g (71.8 mmol) of 4-nitrobenzoyl chloride in 25 mL of methylene
chloride. The mixture was stirred at room temperature for 18
h then was washed twice with 1 N HCl. The organic phase
was dried over sodium sulfate and the solvent was removed
under reduced pressure. The residue was crystallized three
times from ether/hexane and once from ether to give 10.47 g
(51%) of 22; mp ) 84-87 °C; 1H NMR (CDCl3): δ 8.26 (d, 2H,
J ) 7 Hz), 7.55 (d, 2H, J ) 7 Hz), 3.55-3.45 (m, 1H), 3.43-
3.24 (m, 2H), 2.27 (m, 1H), 1.87-1.04 (m, 12H); MS (ES+) m/z
289 (M + 1)+; Anal. (C16H20N2O3) C, H, N.
4-Aminophenyl)-(4aR*,8aS*)-octahydroquinolin-1-yl-
methanone (23). A mixture of 2.0 g of 22 and 200 mg of 10%
Pd/C in 100 mL ethanol was hydrogenated at 1 atm for 18 h.
The catalyst was filtered through Celite and the filtrate was
evaporated to give 1.8 g (100%) of 23. This material was used
directly in subsequent steps.
Method C (Multiparallel Synthesis). On an argonaut
Quest 210 apparatus, each tube was charged with 0.25 mmol
of 23, 100 mg of PS-DIEA resin (3.75 mmol/g) and 4 mL of
methylene chloride. To this was added 0.28 mmol of the
appropriate acid chloride. After agitation for 18 h, 75 mg of
PS-Trisamine resin (3.75 mmol/g) was added and agitation was
continued for an additional 3 h. The tubes were drained and
the resin was washed with methylene chloride. The solvent
was removed to afford the desired product. The following
compounds were prepared by this method: 24, mp ) 216-
219 °C; MS (ES+) m/z 363 (M + 1)+; 26, mp ) 269-270 °C;
MS (ES+) m/z 397 (M + 1)+; 36, MS (ES+) m/z 393 (M + 1)+;
72 (from 71), MS (ES+) m/z 363 (M + 1)+.
2-Chloro-N-[4-((4aR*,8aS*)-octahydroquinoline-1-car-
bonyl)phenyl]benzamide (37). Prepared in 42% yield from
23 and 2-chlorobenzoyl chloride according to Method A (step
c), mp ) 204-205 °C; 1H NMR (CDCl3): δ 8.02 (s, broad, 1H),
7.81-7.75 (m, 1H), 7.65 (d, J ) 8.66 Hz, 2H), 7.50-7.36 (m,
5H), 3.56-3.29 (m, 3H), 2.32-2.23 (m, 1H), 1.86-1.02 (m,
12H); MS (ES+) m/z 397 (M + 1)+; Anal. (C23H25N2O2Cl) C, H,
N.
2,4-Difluoro-N-[4-((4aR*,8aS*)-octahydroquinoline-1-
carbonyl)phenyl]benzamide (38). Prepared in 79% yield
from 23 and 2,4-difluorobenzoyl chloride according to Method
A (step c), mp ) 226-228 °C; IR (KBr), ν (cm-1): 3448, 3308,
3190, 3119, 1677, 1603; 1H NMR (DMSO-d6): δ 10.57 (s, 1H),
7.82-7.71 (m, 2H), 7.74 (d, J ) 8.45 Hz, 1H), 7.49-7.39 (m,
1H), 7.35 (d, J ) 8.46 Hz, 2H), 7.29-7.21 (m, 1H), 3.45-3.25
(m, 3H), 2.14-2.04 (m, 1H), 1.77-0.96 (m, 12H); MS (ES+)
m/z 399 (M + 1)+; Anal. (C23H24N2O2F2) C, H, N.
4-Chloro-2-methyl-N-[4-((4aR*,8aS*)-octahydroquino-
line-1-carbonyl)phenyl]benzamide (39). Prepared in 64%
yield from 23 and 4-chloro-2-methylbenzoyl chloride according
to Method A (step c), mp ) 204-207 °C; IR (KBr), ν (cm-1):
3433, 3308, 1675, 1596; 1H NMR (CDCl3): δ 8.02 (s, 1H), 7.56
(d, J ) 8.09 Hz, 2H), 7.44 (d, J ) 8.09 Hz, 1H), 7.34 (d, J )
8.09 Hz, 2H), 7.26-7.21 (m, 2H), 3.51-3.30 (m, 3H), 2.49 (s,
3H), 2.27-2.18 (m, 1H), 1.83-1.53 (m, 6H), 1.47-1.00 (m, 6H);
MS (ES+) m/z 411 (M + 1)+; Anal. (C24H27N2O2Cl) C, H, N.
4-Chloro-2-methoxy-N-[4-((4aR*,8aS*)-octahydro-
quinoline-1-carbonyl)phenyl]benzamide (40). Prepared in
67% yield from 23 and 4-chloro-2-methoxybenzoyl chloride
1
according to Method A (step c), mp ) 145-153 °C; H NMR
(CDCl3): δ 9.72 (s, 1H), 8.22 (d, J ) 8.45 Hz, 1H), 7.67 (d, J )
8.46 Hz, 2H), 7.42 (d, J ) 8.46 Hz, 2H), 7.13 (dd, J ) 8.46 and
1.84 Hz, 1H), 7.04 (m, 1H), 4.08 (s, 3H), 3.57-3.33 (m, 3H),
2.35-2.24 (m, 1H), 1.87-1.56 (m, 6H), 1.52-1.04 (m, 6H); MS
(ES+) m/z 427 (M + 1)+; Anal. (C24H27N2O3Cl) C, H, N.
N-[2-Amino-4-((4aR*,8aS*)-octahydroquinoline-1-car-
bonyl)phenyl]-2,4-dichlorobenzamide (43). To a solution
of 6.06 g (20 mmol) of 57 and 700 mg (5.7 mmol) of DMAP in
70 mL of pyridine was added 4.5 g (21 mmol) of 2,4-
dichlorobenzoyl chloride. The mixture was stirred at 85 °C for
16 h then the pyridine was removed under reduced pressure.
The resulting solid was washed with H2O and dried. This was
purified by flash chromatography (CH2Cl2 as eluent) and the
product crystallized from ether/hexane to give 5.0 g (52%) of
2,4-dichloro-N-[2-nitro-4-((4aR*,8aS*)-octahydroquinoline-1-
carbonyl)phenyl]benzamide as a pale-yellow solid, mp ) 165-
Method C (Preparative, General Procedure). To a
solution of 1 mmol of 23 and 1.5 mmol of diisopropylethylamine
in 10 mL of methylene chloride was added dropwise a solution
of 1 mmol of the appropriate acid chloride in 5 mL of methylene
chloride. After stirring the mixture at room temperature for
18 h, it was washed sequentially with 1 N HCl, 8% aqueous

6708 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21
Coppola et al.
1
167 °C; H NMR (CDCl3): δ 10.95 (s, 1H), 8.96 (d, J ) 8.82
(4-Amino-3-nitrophenyl)-(4aR*,8aS*)-octahydroquino-
lin-1-yl-methanone (57). To a solution of 8.5 g (59.2 mmol)
of 21, 10.8 g (59.2 mmol) of 4-amino-3-nitrobenzoic acid and
8.0 g (59.2 mmol) of HOBt in 100 mL DMF was added 11.4 g
(59.2 mmol) of EDCI. After stirring the mixture at room
temperature for 18 h, H2O was added. The resulting solid was
filtered, washed with H2O, dried under reduced pressure and
recrystallized from MeOH/CH2Cl2 to give 11.7 g (65%) of 57
Hz, 1H), 8.33 (d, J ) 1.84 Hz, 1H), 7.76 (dd, J ) 8.45 and 1.83
Hz, 1H), 7.69 (d, J ) 8.09 Hz, 1H), 7.53 (d, J ) 1.84 Hz, 1H),
7.41 (dd, J ) 8.46 and 1.84 Hz, 1H), 3.55-3.33 (m, 3H), 2.32-
2.23 (m, 1H), 1.88-1.59 (m, 7H), 1.53-1.02 (m, 5H).
A solution of 2.4 g (5 mmol) of the above material in 150
mL of MeOH/CH2Cl2 (1:1) was hydrogenated at 50 psi over
700 mg of sulfided 5% Pt/C for 3.25 h. The catalyst was filtered
through Celite and the solvent was removed under reduced
pressure. The residual foam was crystallized from ether to give
1.94 g (86%) of 43 as an off-white solid, mp ) 208-210 °C; 1H
NMR (CDCl3): δ 9.56 (s, 1H), 7.67 (d, J ) 8.29 Hz, 1H), 7.46
(d, J ) 1.51 Hz, 1H), 7.35 (dd, J ) 8.29 and 1.88 Hz, 1H), 7.03
(d, J ) 8.29 Hz, 1H), 6.66 (s, 1H), 6.58-6.51 (m, 1H), 3.40-
3.15 (m, 3H, 2.03-1.92 (m, 1H), 1.82-1.49 (m, 9H), 1.35-0.99
(6H); MS (ES+) m/z 447 (M + 1)+; Anal. (C23H25N3O2Cl2) C, H,
N.
N-[2-Acetylamino-4-((4aR*,8aS*)-octahydroquinoline-
1-carbonyl)phenyl]-2,4-dichlorobenzamide (44). To a so-
lution of 178 mg (0.4 mmol) of 43 and 111 mg (1.1 mmol) of
triethylamine in 4 mL of CH2Cl2 was added 102 mg (1 mmol)
of acetic anhydride. After stirring the mixture for 16 h, it was
washed with H2O and the organic phase was dried over sodium
sulfate. The solvent was removed under reduced pressure and
the residue was purified by flash chromatography (2% MeOH/
CH2Cl2 as eluent). The product was crystallized from ether to
give 90 mg (46%) of 44 as an off-white solid, mp ) 187-188
°C; 1H NMR (CDCl3): δ 9.96 (s, 1H), 8.53 (s, 1H), 7.63 (d, J )
8.29 Hz, 1H), 7.50-7.45 (m, 2H), 7.37 (dd, J ) 8.29 and 1.88
Hz, 1H), 7.27 (d, J ) 7.92 Hz, 1H), 6.87 (dd, J ) 7.91 and 1.51
Hz, 1H), 3.36-3.17 (m, 3H), 2.17 (s, 3H), 2.05-1.94 (m, 1H),
1.85-1.48 (m, 7H), 1.37-0.97 (m, 5H); Anal. (C25H27N3O3Cl2)
C, H, N.
2,4-Dichloro-N-[5-((4aR*,8aS*)-octahydroquinoline-1-
carbonyl)-pyridin-2-yl]benzamide (45). To a stirred solu-
tion of 1.1 g (3.54 mmol) of 69 in 25 mL of methylene chloride
was added 545 mg (3.9 mmol) of 21 followed by 50 mg (0.41
mmol) of DMAP. To this was added 1.2 g (6.28 mmol) of EDCI.
After stirring the mixture at room temperature for 18 h, it
was poured into H2O. The aqueous phase was extracted with
EtOAc and the combined organic extracts were washed suc-
cessively with 1 N HCl, H2O, saturated aqueous NaHCO3
solution, H2O and brine. The organic layer was dried over
Na2SO4 and the solvent was removed under reduced pressure.
The residue is triturated with ether to give 230 mg (15%) of
45 as a white solid: mp 202-203 °C; IR (KBr), ν (cm-1): 2925,
1678, 1613, 1587, 1310, 855, 796;1H NMR (CDCl3) δ 8.75 (s,
1H), 8.38 (s, 2H), 7.86-7.69 (m, 2H), 7.51 (s, 1H), 7.42-7.36
(m, 1H), 3.56-3.36 (m, 3H), 2.33-2.21 (m,1H), 1.94-1.00 (m,
12H); MS (ES+) m/z 432 (M + 1)+; MS (ES+) m/z 489 (M +
1)+; Anal. (C22H23N3O2Cl2‚0.25 H2O) C, H, N.
1
as yellow crystals, mp ) 212-215 °C; H NMR (DMSO-d6) δ
7.97 (s, 1H), 7.69 (s, 2H), 7.43 (dd, J ) 8.67, 1.88 Hz, 1H),
7.03 (d, J ) 9.04 Hz, 1H), 3.53-3.14 (m, 3H), 2.12-2.01 (m,
1H), 1.78-0.93 (m, 12H); MS (ES+) m/z 304 (M + 1)+; Anal.
(C16H21N3O3‚0.2 H2O) C, H, N.
(4-Amino-2-chlorophenyl)-(4aR*,8aS*)-octahydro-
quinolin-1-yl-methanone (58). To a solution of 2.01 g (10
mmol) of 2-chloro-4-nitrobenzoic acid in 20 mL of DMF was
added 2.75 mL (25 mmol) of N-methylmorpholine and 5.56 g
(12 mmol) of TPTU. After stirring the reddish mixture for 15
min, 1.67 g (12 mmol) of 21 was added. The mixture was
stirred at room temperature for 18 h then was partitioned
between H2O and EtOAc. The organic phase was washed
sequentially with saturated aqueous lithium chloride and
brine, dried over Na2SO4, and the solvent was removed under
reduced pressure. Purification by flash chromatography (20%
EtOAc/hexane) afforded 1.1 g (34%) of (2-chloro-4-nitrophenyl)-
(4aR*,8aS*)-octahydroquinolin-1-yl-methanone as a pale yel-
1
low oil; H NMR (CDCl3) δ 8.19-8.16 (m,1H), 8.32-8.27 (m,
1H), 7.54-7.42 (m, 1H), 2.62-3.43 (m, 3H), 1.84-1.15 (m,
13H).
A solution of 844 mg (2.62 mmol) of the above compound in
40 mL of EtOAc/EtOH (1:3) was hydrogenated over 50 mg of
10% Pd/C at 1 atm for 16 h. The catalyst was removed by
vacuum filtration through Celite and the residue was purified
by flash chromatography (60% EtOAc/hexane) to afford 700
mg (92%) of 58 as a white solid: 1H NMR (CDCl3) δ 7.70-
6.93 (m, 1H), 6.56-6.52 (m, 1H), 6.69-6.62 (m, 1H), 3.84 (s,
broad, 2H), 3.54-3.15 (m, 3H), 1.81-1.04 (m, 13H).
(4-Amino-2-methoxyphenyl)-(4aR*,8aS*)-octahydro-
quinolin-1-yl-methanone (59). To a solution of 2.22 g (11.26
mmol) of 2-methoxy-4-nitrobenzoic acid and 0.5 mL of DMF
in 25 mL of methylene chloride was added dropwise 1.47 mL
(16.9 mmol) of oxalyl chloride. The mixture was stirred at room
temperature for 1 h, then 2.48 mL (22.54 mmol) of N-
methylmorpholine was added followed by a dropwise addition
of 2.35 g (16.9 mmol) of 21 in 10 mL of methylene chloride.
The mixture was stirred at room temperature for 18 h then
was quenched with 1 N HCl. The mixture was extracted with
ether and the organic phase was washed sequentially with 1
N NaOH, H2O and brine. The organic phase was dried over
sodium sulfate and the solvent was removed under reduced
pressure. The residue was flash chromatographed (20% EtOAc/
hexane) to give 2.35 g (44%) of (2-Methoxy-4-nitrophenyl)-
(4aR*,8aS*)-octahydroquinolin-1-yl-methanone: 1H NMR
(CDCl3) δ 7.87 (dd, J ) 8.29 and 1.88 Hz, 1H), 7.76 (s, 1H),
7.44-7.29 (m, 1H), 3.93 (s, 3H), 3.71-2.86 (m, 3H), 2.53-2.27
(m, 1H), 2.01-0.96 (m, 12H).
A solution of the above material in 75 mL of EtOH/EtOAc
(1:1) was hydrogenated over 150 mg of 10% Pd/C at 1 atm for
24 h. The catalyst was filtered through Celite and the filtrate
evaporated under reduced pressure to give 2.25 g (100%) of
59 as a foam: 1H NMR (DMSO-d6) δ 6.74 (s, 1H), 6.19 (s, 1H),
6.12 (dd, J ) 7.72 and 1.84 Hz, 1H), 5.31 (s, 2H), 3.66 (s, 3H),
3.50-3.08 (m, 3H), 2.14-1.93 (m, 1H), 1.80-1.43 (m, 7H),
1.38-0.92 (m, 5H).
(4-Amino-2-propoxyphenyl)-(4aR*,8aS*)-octahydro-
quinolin-1-yl-methanone (60). To a solution of 1.937 g (10.58
mmol) of 2-hydroxy-4-nitrobenzoic acid in 40 mL of DMF was
added 931 mg (23.28 mmol) of sodium hydride. After stirring
the mixture at room temperature for 20 min, 2.61 mL (23.28
mmol) of allyl bromide was added and the reaction was strirred
at room temperature for 16 h. The reaction was quenched with
1 N HCl and the mixture was extracted with EtOAc. The
organic layer was washed sequentially with saturated aqueous
lithium chloride and brine, dried over Na2SO4, and the solvent
(4-Amino-3-methylphenyl)-(4aR*,8aS*)-octahydro-
quinolin-1-yl-methanone (56). To a solution of 3.84 g (27.6
mmol) of trans-decahydroquinoline (21) and 7.1 g (55 mmol)
of diisopropylethylamine in 50 mL of methylene chloride was
added dropwise a solution of 5.5 g (27.6 mmol) of 3-methyl-4-
nitrobenzoyl chloride in 5 mL of methylene chloride. After
stirring at room temperature for 18 h, the mixture was poured
into EtOAc. The solution was washed with 1 N HCl (2x) and
saturated NaCl solution. The solution was dried over sodium
sulfate and the solvent was removed under reduced pressure.
The residue was stirred with ether for 18 h and the solid
filtered to give 4.0 g (48%) of (3-methyl-4-nitrophenyl)-
(4aR*,8aS*)-octahydroquinolin-1-yl-methanone, mp ) 93-95
°C; IR (KBr), ν (cm-1): 3435, 1633; H NMR (CDCl3): δ 7.99
(d, J ) 8.46 Hz, 1H), 7.40-7.26 (m, 2H), 3.57-3.23 (m,3H),
2.62 (s, 3H), 2.33-2.22 (m,1H), 1.91-1.00 (m, 12H); Anal.
(C17H22N2O3) C, H, N.
A solution of 500 mg (1.65 mmol) of the above compound in
50 mL of EtOH was hydrogenated over 50 mg of 10% Pd/C at
1 atm for 16 h. The catalyst was removed by vacuum filtration
through Celite and the solvent removed under reduced pres-
sure to give 450 mg (100%) of 56. This was used directly in
subsequent reactions.
1

Perhydroquinolylbenzamides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6709
was removed under reduced pressure. Purification by flash
chromatography (10% EtOAc/hexane) afforded 1.49 g (76%)
of 2-allyloxy-4-nitrobenzoic acid allyl ester as a yellow oil; 1H
NMR (CDCl3) δ 7.80-7.94 (m, 3H), 5.97-6.13 (m, 2H), 5.29-
5.57 (m, 4H), 4.83-4.86 (m, 2H), 4.72-4.74 (m, 2H).
A solution of 1.13 g (28.23 mmol) of sodium hydroxide
dissolved in 10 mL of H2O was added to a solution of 1.49 g
(5.65 mmol) of the above allyl ester in 40 mL THF. The
reaction was stirred at room temperature for 16 h then
acidified with 1 N HCl. The mixture was extracted with EtOAc
and the organic layer was washed with brine, dried over
anhydrous Na2SO4. The solvent was removed under reduced
pressure to afford 1.12 g (89%) of 2-allyloxy-4-nitrobenzoic acid
as a pale yellow solid. This was used directly in the following
step; 1H NMR (CDCl3) δ 8.29-8.33 (m, 1H), 7.84-7.98 (m, 2H),
6.05-6.18 (m, 1H), 5.48-5.61 (m, 2H), 4.89 (d, J ) 5.3 Hz,
2H).
(4-Nitrophenyl)-(4aR*,8aS*)-octahydroisoquinolin-2-
yl-methanone (63). To a solution of 695 mg (5 mmol) of trans-
decahydroisoquinoline and 750 mg (7.4 mmol) of triethyl-
ethylamine in 30 mL of methylene chloride was added drop-
wise a solution of 930 mg (5 mmol) of 4-nitrobenzoyl chloride
in 10 mL of methylene chloride. The mixture was stirred at
room temperature for 4 h then was washed with 2 N HCl
followed by 10% NaHCO3. The organic phase was dried over
sodium sulfate and the solvent was removed under reduced
pressure. The residual solid was crystallized from CH2Cl2/
MTBE to give 950 mg (66%) of 63 as a white solid, mp ) 137-
139 °C; IR (KBr), ν (cm-1): 1631; 1H NMR (CDCl3): δ 8.27 (d,
J ) 8.82 Hz, 2H), 7.55 (d, J ) 8.46 Hz, 2H), 4.79 (d, J ) 13.61
Hz, 0.5 H), 4.61 (d, J ) 12.50 Hz, 0.5H), 3.58 (d, J ) 12.50 Hz,
0.5H), 3.38 (d, J ) 13.97 Hz, 0.5H), 3.05 (t, 0.5H), 2.83-2.61
(m, 1H), 2.39 (t, 0.5H), 1.85-0.87 (m, 12H); Anal. (C16H20N2O3)
C, H, N.
(4-Aminophenyl)-(4aR*,8aS*)-octahydroisoquinolin-2-
yl-methanone (64). A mixture of 940 mg of 63 and 100 mg
of 10% Pd/C in 50 mL ethanol was hydrogenated at 50 psi For
18 h. The catalyst was filtered through Celite and the filtrate
was evaporated to give 810 mg (96%) of 64 as a gray solid, mp
) 143-146 °C; IR (KBr), ν (cm-1): 3459, 3359, 1607; 1H NMR
(CDCl3): δ 7.24 (d, J ) 8.46 Hz, 2H), 6.65 (d, J ) 8.46 Hz,
2H), 4.90-3.93 (m, broad, 1H), 3.85 (s, broad, 3H), 3.03-3.21
(m, 2H), 1.84-0.81 (m, 12H); MS (ES+) m/z 259 (M + 1)+. Anal.
(C16H22N2O) C, H, N.
(4-Nitrophenyl)-(4aS*,8aS*)-octahydrobenzo[1,4]oxazin-
4-yl-methanone (65). To a solution of 700 mg (5 mmol) of
(4aS*,8aS*)-octahydrobenzo[1,4]oxazine66 and 600 mg (6 mmol)
of triethylamine in 10 mL of methylene chloride was added
dropwise a solution of 930 mg (5 mmol) of 4-nitrobenzoyl
chloride in 10 mL of methylene chloride. After stirring the
mixture at room temperature for 18 h, the solvent was
removed under reduced pressure. Ethyl acetate was added to
the residue and the mixture was washed with H2O. The
organic phase was dried over sodium sulfate and the solvent
was removed under reduced pressure. The residual solid was
crystallized from MTBE/hexane to give 1.25 g (86%) of 65, mp
) 115-118 °C; 1H NMR (CDCl3): δ 8.27 (d, J ) 8.82 Hz, 2H),
7.62 (d, J ) 8.83 Hz, 2H), 3.95-3.49 (m, 5H), 3.44-3.33 (m,
1H), 2.47 (d, broad, J ) 15.44 Hz, 1H), 2.07-1.96 (m, 1H),
1.86-1.70 (m, 2H), 1.55-1.25 (m, 4H); MS (ES+) m/z 290 (M
+ 1)+; Anal. (C15H18N2O4) C, H, N.
Oxalyl chloride (0.65 mL, 7.47 mmol) was added dropwise
to a solution of 1.11 g (4.98 mmol) of the above benzoic acid in
40 mL CH2Cl2 and 0.5 mL DMF at 0 °C. The reaction was
stirred at 0 °C for 1 h then 1.37 mL (12.45 mmol) of
N-methylmorpholine and 832 mg (5.97 mmol) of trans-deca-
hydroquinoline (21) were added sequentially. The reaction was
warmed to room temperature and stirred for 3 h. The mixture
was partitioned between EtOAc and 1 N NaOH. The organic
layer was washed with brine, dried over anhydrous Na2SO4,
and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography (25% EtOAc/
hexane) to give 1.2 g (76%) of (2-allyloxy-4-nitrophenyl)-
(4aR*,8aS*)-octahydroquinolin-1-yl-methanone as a yellow oil;
1H NMR (CDCl3) δ 7.73-7.89 (m, 2H), 7.33-7.42 (m, 1H),
5.96-5.99 (m, 1H), 5.38 (dd, 2H), 4.64 (s, broad, 2H), 3.01-
3.58 (m, 2H), 2.42 (br s, 1H), 1.24-1.76 (m, 13H); MS (ES+)
m/z 345 (M + 1)+.
A solution of 1.15 g (3.43 mmol) of the above compound in
30 mL of EtOAc/EtOH (1:1) was hydrogenated over 50 mg of
10% Pd/C at 1 atm for 16 h. The catalyst was removed by
vacuum filtration through Celite and the residue was purified
by flash chromatography (50% EtOAc/hexane) to afford 730
mg (69%) of 60 as a yellow foam: 1H NMR (DMSO-d6) δ 6.71-
6.79 (m, 1H), 6.10-6.17 (m, 2H), 5.31 (s, broad, 2H), 3.80 (t,
2H), 3.20 s, broad, 3H), 1.15-1.72 (m, 15H), 0.95 (t, 3H): MS
(ES+) m/z 317 (M + 1)+.
(4-Nitronaphthalen-1-yl)-(4aR*,8aS*)-octahydroquino-
lin-1-yl-methanone (61). To a solution of 1.12 g (5.2 mmol)
of 4-nitronaphthalene-1-carboxylic acid64 and 1.45 g (10.4
mmol) of 21 in 40 mL of DMF was added 0.8 g (5.2 mmol) of
HOBt followed by 1.5 g (7.8 mmol) of EDCI. Within 5 min a
suspension formed. The mixture was stirred at room temper-
ature for 18 h then was poured into H2O. The mixture was
extracted with ether (3 × 120 mL) and the organic solution
was washed with H2O and saturated NaCl. The organic phase
was dried over magnesium sulfate and the solvent was re-
moved under reduced pressure and the residue was triturated
with hexane to give 1.32 g (75%) of 61 as a solid, mp ) 129-
(4-Aminophenyl)-(4aS*,8aS*)-octahydrobenzo[1,4]-
oxazin-4-yl-methanone (66). A mixture of 1.1 g of 65 and
100 mg of 10% Pd/C in 35 mL ethanol was hydrogenated at
50 psi for 4 h. Methylene chloride was added to dissolve some
precipitated product then the catalyst was filtered through
Celite. The solvent was concentrated until crystallization
occurred. On cooling, the solid was filtered and washed with
MTBE to give 840 mg (85%) of 66 as a white solid, mp ) 196-
1
198 °C; IR (KBr), ν (cm-1): 3434, 3349, 2936, 2863, 1619; H
NMR (CDCl3): δ 7.34 (d, J ) 8.83 Hz, 2H), 6.64 (d, J ) 8.46
Hz, 2H), 3.94-3.74 (m, 5H), 3.68-3.56 (m, 1H), 3.54-3.41 (m,
2H), 2.60-2.51 (m, 1H), 2.03-1.94 (m, 1H), 1.82-1.66 (m, 2H),
1.49-1.28 (m, 4H); MS (ES+) m/z 261 (M + 1)+.
1
135 °C; IR (KBr), ν (cm-1): 3439, 1630; H NMR (DMSO-d6):
δ 8.17 (d, J ) 8.09 Hz, 1H), 8.10 (d, J ) 7.72 Hz, 1H), 7.77-
7.62 (m, 3H), 7.48-7.29 (m, 1H), 3.42-2.93 (m, 3H), 2.25-
2.16 (m, 1H), 1.85-0.75 (m, 12H); MS (ES+) m/z 339 (M + 1)+;
Anal. (C20H22N2O3) C, H, N.
6-(2,4-Dichlorobenzoylamino)-nicotinic Acid methyl
ester (68). To a stirred solution of 1.0 g (5.31 mmol) of 6765
and 1.4 g (13.3 mmol) of triethylamine in 20 mL of methylene
chloride at 0 °C was added 1.67 g (7.97 mmol) of 2,4-
dichlorobenzoyl chloride. After the mixture was stirred at room
temperature for 4 h, 50 mL of ether was added. The solids
were filtered and the filtrate concentrated under reduced
pressure. The residue was purified by flash chromatography
using hexane/EtOAc (3:1) to provide1.65 g (96%) of 68. The
material was used directly in the next step; MS (ES+) m/z 325
(M + 1)+.
6-(2,4-Dichlorobenzoylamino)-nicotinic Acid (69). To
a solution of 1.2 g (3.68 mmol) of 68 in 6 mL THF/MeOH (2:1)
was added 3 mL of 4 N NaOH (12 mmol). After stirring the
mixture for 10 h, it was poured into 25 mL of H2O and the
mixture was washed with ether. The aqueous layer was
acidified with 6 N HCl and extracted with EtOAc. The organic
(4-Aminonaphthalen-1-yl)-(4aR*,8aS*)-octahydro-
quinolin-1-yl-methanone (62). To a solution of 340 mg (1
mmol) of 61 in 40 mL of EtOH (under nitrogen) was added
1.8 mL of hydrazine hydrate followed by 70 mg of 10% Pd/C.
The mixture was refluxed for 30 min then was allowed to cool.
The catalyst was filtered from the reaction mixture through
Celite and the solvent was removed under reduced pressure.
Hexane was added to the residue and was removed under
reduced pressure (3x) to give 335 mg (100%) of 62 as an orange
foam. This was used directly in subsequent reactions. 1H NMR
(DMSO-d6): δ 8.19 (d, J ) 8.09 Hz, 1H), 7.80-7.67 (m 1H),
7.60-7.41 (m, 2H), 7.26-7.11 (m, 1H), 6.72 (d, J ) 7.72 Hz,
1H), 6.06 (s, 2H), 3.65-3.09 (m, 3H), 2.39-2.16 (m, 1H), 2.03-
0.92 (m, 12H).

6710 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21
Coppola et al.
phase was dried over MgSO4, and solvent was removed under
reduced pressure. The resulting solid is collected and dried
from 79 and 4-fluorobenzoyl chloride according to Method B
(multiparallel); product isolated as a foam; IR (KBr), ν (cm-1):
3373, 1682, 1505, 1320, 1150; 1H NMR (CDCl3): δ 7.94 (s, 1H),
7.96-7.88 (m, 2H), 7.78 (s, 4H), 7.20 (t, 2H), 4.14-4.03 (m,
1H), 2.84-2.69 (m, 1H), 2.28-2.17 (m, 1H), 1.81-0.85 (m,
12H); MS (ES-) m/z 415 (M-1)-; Anal. (C22H25N2O3SF) C, H,
N, S.
1
under high vaccum to give 81% of 69; H NMR (DMSO-d6) δ
11.47 (s, 1H), 8.86 (s, 1H), 8.31 (q, 2H), 7.83-7.72 (m, 2H),
7.64 (d, J ) 8.29 Hz, 1H), 7.57-7.49 (m, 2H); MS (ES+) m/z
311 (M + 1)+.
(3-Nitrophenyl)-(4aR*,8aS*)-octahydroquinolin-1-yl-
methanone (70). To a solution of 1.39 g (10 mmol) of trans-
decahydroquinoline (21) and 1.5 g (15 mmol) of triethylamine
in 50 mL of methylene chloride was added dropwise a solution
of 1.85 g (10 mmol) of 3-nitrobenzoyl chloride in 20 mL of
methylene chloride. The mixture was stirred at room temper-
ature for 18 h then was washed with 2 N HCl followed by 10%
NaHCO3. The organic phase was dried over sodium sulfate
and the solvent was removed under reduced pressure to give
4-Fluoro-N-[4-((4aR*,8aS*)-octahydroquinoline-1-car-
bonyl)phenyl]benzenesulfonamide (81). To a solution of
258 mg (1 mmol) of 23 and 150 mg (1.5 mmol) of triethylamine
in 15 mL of CH2Cl2 was added 210 mg (1.07 mmol) of
4-fluorobenzenesulfonyl chloride. The mixture was stirred at
room temperature for 48 h then 100 mg of PS-Trisamine resin
was added and stirring was continued for 18 h. The resin was
filtered and the organic solution was washed with 2 N HCl.
The organic phase was dried over sodium sulfate and the
solvent was removed under reduced pressure. The residual oil
was flash chromatographed using 2% MeOH/CH2Cl2 to give
1
2.3 g (80%) of 70 as a thick oil; H NMR (CDCl3): δ 8.25 (s,
2H), 7.74 (d, J ) 7.53 Hz, 1H),7.65-7.57 (m, 1H), 3.57-3.28
(m, 3H), 2.33-2.23 (m, 1H), 1.91-0.86 (m, 12H); MS (ES+)
m/z 289 (M + 1)+.
1
259 mg (62%) of 81 as a gum; H NMR (CDCl3): δ 7.84-7.76
(m, 2H), 7.46 (s, 1H), 7.26 (d, J ) 8.45 Hz, 2H), 7.14-7.02 (m,
4H), 3.52-3.41 (m, 1H), 3.40-3.31 (m, 2H), 2.27-2.18 (m, 1H),
1.83-1.00 (m, 12H); MS (ES+) m/z 417 (M + 1)+.
(3-Aminophenyl)-(4aR*,8aS*)-octahydroquinolin-1-yl-
methanone (71). A mixture of 0.9 g of 70 and 100 mg of 10%
Pd/C in 200 mL ethanol was hydrogenated at 50 psi For 18 h.
The catalyst was filtered through Celite and the filtrate was
evaporated to give 0.71 g (88%) of 71. mp ) 108-109 °C; MS
(ES+) m/z 259 (M + 1)+; Anal. (C16H22N2O) C, H, N.
2-(4-Nitrophenyl)-1-(4aR*,8aS*)-octahydroquinolin-1-
yl-ethanone (74). To a solution of 7.7 g (55 mmol) of of trans-
decahydroquinoline (21) and 8.4 g (83 mmol) of triethylethyl-
amine in 200 mL of methylene chloride was added dropwise a
solution of 10.9 g (55 mmol) of 4-nitrophenylacetyl chloride
(73) in 50 mL of methylene chloride. The mixture was stirred
at room temperature for 18 h then was washed with 1 N HCl
followed by 10% NaHCO3. The organic phase was dried over
sodium sulfate and the solvent was removed under reduced
pressure. The residue was purified by flash chromatography
to give 6.5 g (39%) of 74; 1H NMR (CDCl3): δ 8.19 (d, J ) 8.29
Hz, 2H), 7.43 (d, J ) 8.67 Hz, 2H), 3.84-3.73 (m, 1H), 3.78 (d,
J ) 3.39 Hz, 2H), 3.44-3.13 (m, 2H), 2.18-2.07 (m, 1H), 1.84-
0.97 (m, 12H).
(4-Nitrophenyl)-(4aR*,8aS*)-octahydroquinolin-1-yl-
methanethione (82). A mixture of 200 mg (0.69 mmol) of 22
and 140 mg (0.35 mmol) of Lawesson’s reagent in 25 mL of
toluene was refluxed for 2.5 h. The solvent was removed under
reduced pressure and the residue was dissolved in methylene
chloride. The solution was washed with 8% aqueous NaHCO3
and was dried over magnesium sulfate. The solvent was
removed under reduced pressure and the residue flash chro-
matographed using hexane/ethyl acetate (75:25) to furnish 200
1
mg (95%) of 82; mp ) 147-150 °C; H NMR (CDCl3): δ 8.26
(d, J ) 9.2 Hz, 2H), 7.53-7.23 (m, 2H), 4.47-4.19 (m, 1H),
3.61-3.34 (m, 2H), 2.84-2.57 (m, 1H), 1.94-1.60 (m, 7H),
1.45-1.08 (m, 5H); MS (ES+) m/z 305 (M + 1)+; Anal.
(C16H20N2O2S) C, H, N.
(4-Aminophenyl)-(4aR*,8aS*)-octahydroquinolin-1-yl-
methanethione (83). A solution of 190 mg (0.62 mmol) of 82
in 100 mL of ethanol was hydrogenated at 50 psi over 50 mg
of 10% Pd/C for 24 h. The catalyst was filtered through Celite
and the solvent removed under reduced pressure. The residue
was filtered through a pad of silica gel using ethyl acetate to
elute the product, 135 mg (79%) of 83 as a solid, mp ) 197-
200 °C; 1H NMR (CDCl3): δ 7.09 (d, J ) 8.09 Hz, 2H), 6.61 (d,
J ) 7.73 Hz, 2H), 4.33 (t, 1H), 4.04-3.91 (m, 1H), 3.76 (s,
broad, 2H), 3.43-3.29 (m, 1H), 2.69 (d, broad, J ) 11.4 Hz,
1H), 1.91-1.11 (m, 12H); MS (ES+) m/z 275 (M + 1)+, 316
(base, MH+MeCN); Anal. (C16H22N2S?0.2 EtOAc) C, H, N.
2-(4-Aminophenyl)-1-(4aR*,8aS*)-octahydroquinolin-
1-yl-ethanone (75). A mixture of 6.5 g of 74 and 650 mg of
10% Pd/C in 300 mL ethanol was hydrogenated at 50 psi For
18 h. The catalyst was filtered through Celite and the filtrate
1
was evaporated to give 5.7 g (97%) of 75 as an oil; H NMR
(CDCl3): δ 7.03 (d, J ) 7.92 Hz, 2H), 6.63 (d, J ) 8.29 Hz,
2H), 3.68-3.53 (m, 1H), 3.58 (s, 2H), 3.43-3.30 (m, 1H), 3.19-
3.02 (m, 1H), 2.20-2.09 (m, 1H), 1.83-0.94 (m, 12H); MS (ES+)
m/z 273 (M + 1)+.
(4aR*,8aS*)-1-(4-Nitrobenzenesulfonyl)-decahydro-
quinoline (78). To a solution of 1.4 g (10 mmol) of 21 and 1.3
g (13 mmol) of triethylamine in 15 mL of methylene chloride
was added dropwise a solution of 2.2 g (10 mmol) of 4-nitro-
benzenesulfonyl chloride in 15 mL of methylene chloride. A
precipitate initially formed and after stirring the mixture for
18 h a solution resulted. The solvent was removed under
reduced pressure and the residue was partitioned between
EtOAc and H2O. The organic phase was washed twice with
H2O and was dried over sodium sulfate. The solvent was
removed under reduced pressure and the residue was crystal-
lized from MTBE/hexane to give 1.9 g (59%) of 78 as a tan
solid; mp ) 106-109 °C; 1H NMR (CDCl3): δ 8.34 (d, J ) 8.82
Hz, 2H), 7.98 (d, J ) 9.19 Hz, 2H), 4.19-4.09 (m, 1H), 2.94-
2.84 (m, 1H), 2.69-2.55 (m, 1H), 2.11-2.00 (m, 1H), 1.83-
0.88 (m, 12H); Anal. (C15H20N2O4S) C, H, N, S.
4-[(4aR*,8aS*)-(Octahydroquinolin-1-yl)sulfonyl]-phen-
ylamine (79). A mixture of 1.5 g (4.6 mmol) of 78 and 150
mg of PtO2 in 150 mL of EtOH was hydrogenated at 50 psi for
4 h. The catalyst was filtered through Celite and the filtrate
evaporated under reduced pressure to give an oil. This was
filtered through a pad of silica gel (CH2Cl2 as eluent) to give
1.3 g (96%) of 79 as a glass; MS (ES+) m/z 295 (M + 1)+. This
material was used directly in the next step.
4-Fluoro-N-[4-((4aR*,8aS*)-octahydroquinoline-1-car-
bothioyl)phenyl]benzamide (84). To a mixture of 107 mg
(0.39 mmol) of 83 and 100 mg (0.78 mmol) of diisopropylethyl-
amine in 9 mL of methylene chloride was added dropwise a
solution of 62 mg (0.39 mmol) of 4-fluorobenzoyl chloride in 1
mL of methylene chloride. The mixture was stirred at room
temperature for 18 h then the solvent was removed under
reduced pressure. The residue was dissolved in ethyl acetate
and was washed with 1 N HCl and saturated sodium chloride
solution. The solution was filtered through a pad of silica gel
and the solvent was removed under reduced pressure. The
residual solid was triturated with ether to give 128 mg (82%)
1
of 84, mp ) 239-243 °C; H NMR (CDCl3): δ 10.38 (s, 1H),
8.09-8.00 (m, 2H), 7.76 (d, J ) 8.82 Hz, 2H), 7.38 (t, 2H), 7.20
(d, broad, J ) 7.72 Hz, 2H), 4.20-4.04 (m, 1H), 3.55-3.27 (m,
3H), 1.92-1.54 (m, 7H), 1.44-1.01 (m, 5H); MS (ES+) m/z 397
(M + 1)+; Anal. (C23H25N2OFS) C, H, N.
[4-(4-Fluoro-benzylamino)phenyl]-(4aR*,8aS*)-octa-
hydroquinolin-1-yl-methanone (85). A mixture of 150 mg
(0.58 mmol) of 23, 73 mg (0.59 mmol) of 4-fluorobenzaldehyde
and 5 mg of p-toluenesulfonic acid in 40 mL of toluene was
refluxed under Dean-Stark conditions for 16 h. The solvent
was removed under reduced pressure and the residue dissolved
in 20 mL of EtOH. To this was added 22 mg (0.58 mmol) of
NaBH4 and the mixture was stirred at room temperature for
16 h. Water was added and the mixture was extracted with
4-Fluoro-N-{4-[(4aR*,8aS*)-(octahydroquinolin-1-yl)-
sulfonyl]-phenyl}-benzamide (80). Prepared in 55% yield

Perhydroquinolylbenzamides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6711
EtOAc. The organic phase was washed with brine and was
dried over MgSO4. The solvent was removed under reduced
pressure and the residue was purified by flash chromatography
using CH2Cl2/EtOH (99:1) to elute the product, 154 mg (72%)
The residual solid was purified by crystallization or flash
chromatography to furnish the product.
Method E. To a solution of 1 mmol of 90, 1 mmol of EDCI
and 1.1 mmol HOBt in 10 mL of methylene chloride was added
1 mmol of the appropriate amine and the resultant mixture
was stirred at room temperature for 18 h. Ethyl acetate was
added then the mixture was washed with 1 N HCl. The organic
phase was dried over magnesium sulfate, the solvent was
removed under reduced pressure and the residue was purified
by flash chromatography.
4-((4aR*,8aS*)-Octahydroquinoline-1-carbonyl)-N-pen-
tylbenzamide (92). Prepared in 46% yield from 90 and
n-hexylamine according to Method E, mp ) 94-95 °C; 1H NMR
(CDCl3): δ 7.76 (d, J ) 8.29 Hz, 2H), 7.42 (d, J ) 8.29 Hz,
2H), 6.16 (s, broad, 1H), 3.55-3.39 (m, 3H), 3.38-3.29 (m, 2H),
2.33-2.19 (m, 1H), 1.84-1.02 (m, 20H), 0.90 (t, 3H); MS (ES+)
m/z 371 (M + 1)+; Anal. (C23H34N2O2) C, H, N.
1
of 85, mp ) 161-164 °C; H NMR (CDCl3): δ 7.39-7.22 (m,
5H), 7.02 (t, 2H), 6.57 (d, J ) 8.45 Hz, 2H), 4.32 (s, 2H), 3.59-
3.34 (m, 3H), 2.30-2.20 (m, 1H), 1.84-0.98 (m, 12H); MS (ES+)
m/z 367 (M + 1)+; Anal. (C23H27N2OF) C, H, N.
(4-Methylamino-phenyl)-(4aR*,8aS*)-octahydroquino-
lin-1-yl-methanone (86). Reaction using 21, 4-methylamino-
benzoic acid, HOBt and EDCI was performed similar to the
1
preparation of 32 to give 86 in 8% yield. H NMR (CDCl3): δ
7.30 (d, J ) 8.67 Hz, 2H), 6.56 (d, J ) 8.67 Hz, 2H), 3.96-
3.87 (m, 1H), 3.59-3.38 (m 3H), 2.85 (d, J ) 4.90 Hz, 3H),
2.31-2.22 (m, 1H), 1.81-1.00 (m, 12H).
4-Fluoro-N-methyl-N-[4-((4aR*,8aS*)-octahydroquino-
line-1-carbonyl)phenyl]benzamide (87). To a solution of
130 mg (0.48 mmol) of 86 and 180 mg (0.96 mmol) of
diisopropylethylamine in 5 mL of methylene chloride was
added 60 mg (0.048 mmol) of 4-fluorobenzoyl chloride. The
mixture was stirred at room temperature for 18 h then was
washed with water. The organic phase was dried over mag-
nesium sulfate and the solvent was removed under reduced
pressure. The residue was flash chromatographed using hex-
ane/EtOAc (3:2) to elute the product, 70 mg (37%) of 87 as a
Supporting Information Available: Spectral data for
compounds 9k, 9l, 9n, 25, 27-31, 33, 34, 41, 42, 49-55, 76,
77, 93-100 and table of elemental analyses for purified
products described in this paper. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) CDC.; http://www.cdc.gov/diabetes/pubs/estimates.htm.
(2) DeFronzo, R. A. The Triumvirate: â-Cell, Muscle, Liver; A
Collusion Responsible for NIDDM. Diabetes 1988, 37, 667-687.
(3) Evans, A. J.; Krentz, A. J. Recent Developments and Emerging
Therapies for Type 2 Diabetes Mellitus. Drugs R&D 1999, Aug
2 (2), 75-94.
(4) Horton, E. S. NIDDM - The Devastating Disease. Diabetes Res.
Clin. Pract. 1995, Aug 28 Suppl S3-11.
(5) Kikkawa, R. Chronic Complications in Diabetes Mellitus. Br.
J. Nutr. 2000, 84 (Suppl 2), S183-185.
(6) Scheen, A. J. Diabetic Neuropathy: Epidemiologic and Predictive
Data. Diabetes Metab. 1998, 24, Nov Suppl 3, 45-49.
(7) Constantino, L.; Rastelli, G.; Gamberini, M. C.; Barlocco, D.
Pharmacological Approaches to the Treatment of Diabetic
Complications. Expert Opin. Ther. Pat. 2000, 10, 1245-1262.
(8) Stern, M. P.; Haffner, S. M. Dyslipidemia in Type II Diabetes.
Implications for Therapeutic Intervention. Diabetes Care 1991,
14, 1144-1159.
(9) Goldberg, R. B. Hyperlipidemia and Cardiovascular Risk Factors
in Patients with Type 2 Diabetes. Am. J. Managed Care 2000,
6 (13 Suppl), S682-691.
(10) Cobb, J.; Dukes, I. Recent Advances in the Development of
Agents for the Treatment of Type 2 Diabetes. Annu. Rep. Med.
Chem. 1998, 33, 213-222.
1
colorless oil; H NMR (CDCl3): δ 7.36-7.24 (m, 4H), 7.04 (d,
J ) 8.29 Hz, 2H), 6.86 (t, 2H), 3.50 (s, 3H), 3.49-3.38 (m, 1H),
3.36-3.27 (m, 2H), 2.24-2.15 (m, 1H), 1.82-1.02 (m, 12H);
MS (ES+) m/z 395 (M + 1)+.
4-((4aR*,8aS*)-Octahydroquinoline-1-carbonyl)benz-
oic Acid Methyl Ester (89). To a solution of 2.8 g (20 mmol)
of 21 and 2.25 g (22 mmol) of triethylamine in 100 mL of
methylene chloride was added dropwise a solution of 4.0 g (20
mmol) of 4-carbomethoxybenzoyl chloride (88) in 10 mL
methylene chloride. After stirring the mixture at room tem-
perature for 18 h, it was washed sequentially with 1 N HCl, 1
N NaOH, and water. The organic phase was dried over sodium
sulfate and the solvent was removed under reduced pressure.
The residue was flash chromatographed using hexane/ethyl
acetate (3:2) to elute the product, 4.1 gm (68%) of 89 as a white
solid, mp ) 109-110 °C; 1H NMR (CDCl3): δ 8.06 (d, 2H, J )
8.4 Hz), 7.45 (d, 2H, J ) 8.4 Hz), 3.93 (s, 3H), 3.49 (m, 1H),
3.36-3.30 (m, 2H), 2.28 (m, 1H), 1.87-1.00 (m,12H); Anal.
(C18H23NO3) C, H, N.
4-((4aR*,8aS*)-Octahydroquinoline-1-carbonyl)benz-
oic Acid (90). To a solution of 3.0 g (10 mmol) of 89 in 50 mL
of methanol was added 30 mL (30 mmol) of 1 N NaOH. After
stirring the mixture at room temperature for 18 h, the
methanol was removed under reduced pressure. The aqueous
solution was acidified with 1 N HCl and was extracted with
ethyl acetate. The organic phase was dried over sodium sulfate
and the solvent was removed under reduced pressure to give
(11) Zhang, B. B.; Moller, D. E. New Approaches in the Treatment
of Type 2 Diabetes. Curr. Opin. Chem. Biol. 2000, 4, 461-467.
(12) Babenko, A. P.; Aguliar-Bryan, L.; Bryan, J. A View of SUR/
KIR6.X, KATP Channels. Annu. Rev. Physiol. 1998, 60, 667-
687.
(13) Aguliar-Bryan, L.; Clement, J. P., IV; Gonzalez, G.; Kunjilwar,
K.; Babenko, A.; Bryan, J. Toward Understanding the Assembly
and Structure of KATP Channels. Physiol. Rev. 1998, 78, 227-
245.
(14) Anderson, R. C. Carnitine Palmitoyltransferase: A Viable Target
for the Treatment of NIDDM?. Curr. Pharm. Des. 1998, 4, 1-15.
(15) Matschinsky, F. M.; Davis, E.; Cuesta-Munoz, A.; Buettger, C.;
Sweet, I.; Moates, M.; Magnuson, M. A. The Glucokinase System
and the Regulation of Blood Sugar. Front. Diabetes 2000, 15,
99-108.
(16) Slosberg, E. D.; Desai, U. J.; Fanelli, B.; St. Denny, I.; Connelly,
S.; Kaleko, M.; Boettcher, B. R.; Caplan, S. L. Treatment of Type
2 Diabetes by Adenoviral-Mediated Overexpression of the Glu-
cokinase Regulatory Protein. Diabetes 2001, 50, 1813-1820.
(17) Rose, M. L.; Paulik, M. A.; Lenhard, J. M. Therapeutic Ap-
proaches to Type 2 Diabetes Mellitus. Exp. Opin. Ther. Pat.
1999, 9, 1223-1236.
(18) Martin, G.; Schoonjans, K.; Staels, B.; Auwerx, J. PPARγ
Activators Improve Glucose Homeostasis by Stimulating Fatty
Acid Uptake in the Adipocytes. Atherosclerosis 1998, 137, S75-
80.
(19) Spiegelman, B. M. PPARγ: Adipogenic Regulator and Thiazo-
lidinedione Receptor. Diabetes 1998, 47, 507-514.
(20) Villhauer, E. B.; Coppola, G. M.; Hughes, T. E. DPP-IV
Inhibition and Therapeutic Potential. Annu. Rep. Med. Chem.
2001, 36, 191-200.
(21) Coppola, G. M.; Zhang, Y. L.; Schuster, H. F.; Russell, M. E.;
Hughes, T. E. 1-Aminomethylisoquinoline-4-carboxylates as
Novel Dipeptidylpeptidase IV Inhibitors. Bioorg. Med. Chem.
Lett. 2000, 10, 1555-1558.
1
2.4 g (84%) of 90, mp ) 194-195°; H NMR (CDCl3): δ 8.12
(d, 2H, J ) 8.1 Hz), 7.48 (d, 2H, J ) 8.1 Hz), 4.29 (s, 1H, broad),
3.52 (m, 1H), 3.40-3.30 (m, 2H), 2.30 (m, 1H), 1.85-1.00 (m,
12H); MS (ES-) m/z 286 (M-1)-; Anal. (C17H21NO3) C, H, N.
4-((4aR*,8aS*)-Octahydroquinoline-1-carbonyl)benz-
oyl chloride (91). To a solution of 2.0 g (6.96 mmol) of 90 in
100 mL of methylene chloride was added 3.3 g (28 mmol) of
oxalyl chloride and 4 drops of DMF. The mixture was stirred
at room temperature for 18 h then the solvent was removed
under reduced pressure. Methylene chloride was added to the
residue and the solvent was removed under reduced pressure.
This was repeated three times. The resulting material was
used directly in the next reaction.
Preparation of Terephthalate Derivatives 92-100.
Method D. To a solution of 1 mmol of the appropriate amine
and 2 mmol of diisopropylethylamine in 10 mL of methylene
chloride was added dropwise a solution of 1 mmol of 91 in 2
mL of methylene chloride. After stirring the mixture at room
temperature for 18 h, it was washed with 1 N HCl followed
by aqueous NaHCO3. The organic phase was dried over sodium
sulfate and the solvent was removed under reduced pressure.

6712 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21
Coppola et al.
(22) Lebovitz, H. E. R-Glucosidase Inhibitors. Endocrin. Metabol.
Clin. North Amer. 1997, 26, 539-551.
(23) Treadway, J. L.; Mendys, P.; Hoover, D. J. Glycogen Phosphoryl-
ase Inhibitors for Treatment of Type 2 Diabetes Mellitus. Exp.
Opin. Invest. Drugs 2001, 10, 439-454.
(24) (a) Barf, T. Intervention of Hepatic Glucose Production. Small
Molecule Regulators of Potential Targets for Type 2 Diabetes
Therapy. Mini-Reviews in Medicinal Chemistry 2004, 4, 897-
908. (b) Fotsch, C.; Askew, B. C.; Jian, J. 11â-Hydroxysteroid
Dehydrogenase-1 as a Therapeutic Target for Metabolic Dis-
eases. Expert Opin. Ther. Pat. 2005, 15, 289-303.
(25) (a) Krozowski, Z. 11â-Hydroxysteroid Dehydrogenase and the
Short-chain Alcohol Dehydrogenase (SCAD) Superfamily. Mol.
Cell. Endocrin. 1992, 84, C25-C31. (b) Stewart, P. M.; Whor-
wood, C. B.; Walker, B. R. Steroid Hormones and Hyperten-
sion: The Cortisol-Cortisone Shuttle. Steroids 1993, 58, 614-
620.
(26) Andrews, R. C.; Walker, B. R. Glucocorticoids and Insulin
Resistance: Old Hormones, New Targets. Clin. Sci. 1999, 96,
513-523.
(27) Wajchenberg, B. L. Subcutaneous and Visceral Adipose Tissue:
Their Relation to the Metabolic Syndrome. Endocr. Rev. 2000,
21, 697-738.
(28) Kotelevtsev, Y.; Seckl, J. R.; Mullins, J. 11â-Hydroxysteroid
Dehydrogenases: Key Modulators of Glucocorticoid Action In
Vivo. Curr. Opin. Endocrinol. Diabetes 1999, 6, 191-198.
(29) Krozowski, Z.; Li, K. X. Z.; Koyama, K.; Smith, R. E.;
Obeyesekere, V. R.; Stein-Oakley, A.; Sasano, H.; Coulter, C.;
Cole, T.; Sheppard, K. E. The Type I and Type II 11â-Hydroxy-
steroid Dehydrogenase Enzymes. J. Steroid Biochem. Mol. Biol.
1999, 69, 391-401.
(30) Edwards, C. R.; Benediktsson, R.; Lindsay, R. S.; Seckl, J. R.
11â-Hydroxysteroid Dehydrogenases: Key Enzymes in Deter-
mining Tissue-specific Glucocorticoid Effects. Steroids 1996, 61,
263-269.
(45) Pinder, R. M.; Brogden, R. N.; Sawyer, P. R.; Speight, T. M.;
Spencer, R.; Avery, G. S. Carbenoxolone: A Review of its
Pharmacological Properties and Therapeutic Efficacy in Peptic
Ulcer Disease. Drugs 1976, 11, 245-307.
(46) Pindado, S.; Corrigan, O.; O’Driscoll, C. M. Carbenoxolone
Sodium. Anal. Profiles Drug Subst. Excipients 1996, 24, 1-43.
(47) Nakamura, Y. Carbenoxolone and its Sodium Salt. Japanese
Patent 61165348 1986; Chem. Abstr. 106, 5278.
(48) Martinez, R.; Arellano-Garcia, M.; Martinez-Vazquez, M.;
Gallegos, J. A. Synthesis of Carbenoxolone Analogues From
Argentatin B. Org. Prep. Proced. Int. 1993, 25, 698-703.
(49) Peng, Y.; Han, Y.; Wang, C.; Feng, R. Synthesis of Carbenoxolone
Sodium. Zhongguo Yiyao Gongye Zazhi 1994, 25, 106-107;
Chem. Abstr. 121, 109395.
(50) Monder, C.; Stewart, P. M.; Lakshmi, V.; Valentino, R.; Burt,
D.; Edwards, C. R. W. Licorice Inhibits Corticosteroid 11â-
Dehydrogenase of Rat Kidney and Liver: In Vivo and In Vitro
Studies. Endocrinol. 1989, 125, 1046-1053.
(51) Buhler, H.; Perschel, F. H.; Hierholzer, K. Inhibition of Rat Renal
11â-hydroxysteroid Dehydrogenase by Steroidal Compounds and
Triterpenoids: Structure/Function Relationship. Biochim. Bio-
phys. Acta 1991, 1075, 206-212.
(52) Diederich, S.; Grossmann, C.; Hanke, B.; Quinkler, M.; Herr-
mann, M.; Ba¨hr, V.; Oelkers, W. In the Search for Specific
Inhibitors of Human 11â-Hydroxysteroid-dehydrogenases (11â-
HSDs): Chenodeoxycholic Acid Selectively Inhibits 11â-HSD-I.
Eur. J. Endocrin. 2000, 142, 200-207.
(53) Barf, T.; Vallgarda, J.; Emond, R.; Ha¨ggstro¨m, C.; Kurz, G.;
Nygren, A.; Larwood, V.; Mosialou, E.; Axelsson, K.; Olsson, R.;
Engblom, L.; Edling, N.; Ro¨nquist-Nii, Y.; O¨ hman, B.; Alberts,
P.; Abrahmsen, L. Arylsulfonamidothiazoles as a New Class of
Potential Antidiabetic Drugs. Discovery of Potent and Selective
Inhibitors of the 11â-Hydroxysteroid Dehydrogenase Type 1. J.
Med. Chem. 2002, 45, 3813.
(54) In the initial phases of this program compounds were screened
using pig liver 11â-HSD1 due to the large amounts of enzyme
required for the high-capacity screening and preliminary multi-
parallel synthetic efforts. We subsequently replaced the porcine
enzyme with the more relevant human 11â-HSD1 and found that
the class of compounds described in this paper tended to be much
less active (e.g. the IC50 for 5 is 128 µM). In addition, the IC50’s
of 106 compounds of different structural classes were compared
in both pig and human enzymes and there was little correlation
between them. Consequently, all 11â-HSD1 data reported in this
paper is based on the human enzyme.
(55) Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis
and Absolute Configuration of Substituted Morpholines Tetra-
hedron 1980, 36, 409-415.
(56) Some compounds were screened for HSD2 prior to setting the
selection criteria, therefore a few HSD1 values of >1 µM are
reported.
(57) Pilkis, S. J.; Granner, D. K. Molecular Physiology of the
Regulation of Hepatic Gluconeogenesis and Glycolysis. Annu.
Rev. Physiol. 1992, 54, 888-909.
(58) Consoli, A.; Nurjhan, N.; Capani, F.; Gerich, J. Predominant Role
of Gluconeogenisis in Increased Hepatic Glucose Production in
NIDDM. Diabetes 1989, 38, 550-557.
(59) Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic
Technique for Preparative Separations with Moderate Resolu-
tion. J. Org. Chem. 1978, 43, 2923-2925.
(60) Tommasi, R. A.; Whaley, L. W.; Marepalli, H. R. Autochem:
Automated Solution-Phase Oarallel Synthesis and Purification
via HPLC. J. Comb. Chem. 2000, 2, 447-449.
(31) Seckl, J. R.; Walker, B. R. Minireview: 11â-Hydroxysteroid
Dehydrogenase Type 1 - A Tissue-Specific Amplifier of Gluco-
corticoid Action. Endocrinology 2001, 142, 1371-1376.
(32) Sandeep, T. C.; Walker, B. R. Pathophysiology of Modulation of
Local Glucocorticoid Levels by 11â-Hydroxysteroid Dehydro-
genases. Trends Endocrinol. Metab. 2001, 12, 446-453.
(33) Walker, B. R.; Connacher, A. A.; Lindsay, R. M.; Webb, D. J.;
Edwards, C. R. W. Carbenoxolone Increases Hepatic Insulin
Sensitivity in Man: A Novel Role for 11-Oxosteroid Reductase
in Enhancing Glucocorticoid Receptor Activation. J. Clin. En-
dicrinol. Metab. 1995, 80, 3155-3159.
(34) Hult, M.; Jornvall, H.; Oppermann, U. C. T. Selective Inhibition
of Human Type 1 11â-Hydroxysteroid Dehydrogenase by Syn-
thetic Steroids and Xenobiotics. FEBS Lett. 1998, 441, 25-28.
(35) Kotelevtsev, Y.; Holmes, M. C.; Burchell, A.; Houston, P. M.;
Schmoll, D.; Jamieson, P.; Best, R.; Brown, R.; Edwards, C. R.
W.; Seckl, J. R.; Mullins, J. J. 11â-Hydroxysteroid Dehydro-
genase Type 1 Knockout Mice Show Attenuated Glucocorticoid-
inducible Responses and Resist Hyperglycemia on Obesity or
Stress. Proc. Nat. Acad. Sci. U.S.A. 1997, 94, 14924-14929.
(36) Wilson, R. C.; Krozowski, Z. S.; Lee, K.; Obeyesekere, V. R.;
Razzaghy-Azar, M.; Harbison, M. D.; Wei, J. Q.; Shackleton, C.
H. L.; Funder, J. W.; New, M. I. A Mutation in the HSD11â2
Gene in a Family with Apparent Mineralocorticoid Excess. J.
Clin. Endocrinol. Metab. 1995, 80, 2263-2266.
(37) Mune, T.; Rogerson, F. M.; Nikkila, H.; Agarwal, A. K.; White,
P. C. Human Hypertension Caused by Mutations in the Kidney
Isozyme of 11â-Hydroxysteroid Dehydrogenase. Nat. Genet.
1995, 10, 394-399.
(38) Stewart, P. M.; Krozowski, Z. S.; Gupta, A.; Milford, D. V.; Howie,
A. J.; Sheppard, M. C.; Whorwood, C. B. Hypertension in the
Syndrome of Apparent Mineralocorticoid Excess Due to Mutation
of the 11â-Hydroxysteroid Dehydrogenase Type 2 Gene. Lancet
1996, 347, 88-91.
(39) Li, K. X. Z.; Obeyesekere, V. R.; Zygmunt, S.; Ferrari, P.
Oxoreductase and Dehydrogenase Activities ot the Human and
Rat 11â-Hydroxysteroid Dehydrogenase Type 2 Enzyme. Endo-
crinology 1997, 138, 2948-2952.
(40) Stewart, P. M. Cortisol as a Mineralocorticoid in Human Disease.
J. Steroid Biochem. Mol. Biol. 1999, 69, 403-408.
(61) Varma, R. S.; Kapoor, A. 1-(4′-Benzazolylmethylaminobenzoyl)-
morpholines and Piperidines as Antimicrobial Agents. Ind. J.
Chem. 1979, 18B, 200-202.
(62) Kruse, C. H.; Holden, K. G.; Pritchard, M. L.; Field, J. A.;
Rieman, D. J.; Greig, R. G.; Poste, G. Synthesis and Evaluation
of Multisubstrate Inhibitors of an Oncogene-Encoded Tyrosine-
Specific Protein Kinase. 1. J. Med. Chem. 1988, 31, 1762-1767.
(63) Munakata, K.; Tanaka, S.; Toyoshima, S. Therapy for Uro-
lithiasis with Hydroxamic Acids. I. Synthesis of New N-(Aroyl)-
glycinohydroxamic Acid Derivatives and Related Compounds.
Chem. Pharm. Bull. 1980, 28, 2045-2051.
(64) Leuck, G. J.; Perkins, R. P.; Whitmore, F. C. The Mercuration
of Naphthalic Acids. J. Am. Chem. Soc. 1929, 51, 1831-1836.
(65) Dunbar, P. G.; Durant, G. J.; Hoss, W. P.; Messer, W. S., Jr.
Preparation of Pyridine and Pyrimidine Derivatives as Musca-
rinic Agents. US Patent 1992, 5, 175, 166; Chem. Abstr. 118,
139862.
(41) Murav’ev, I. A. Chemical Composition and Technology of Licorice
and its Preparations. Farm. Pol. 1967, 23, 559-566; Chem.
Abstr. 68:117104.
(42) Murav’ev, I. A.; Savchenko, L. N. Preparation of Glycyrrhetinic
Acid from Licorice Root Extracts. Khim.-Farm. Zh. 1979, 13, 97-
102; Chem. Abstr. 91, 71699.
(43) Sobotka-Wierzbowicz, J.; Adamczyk, H.; Smulkowska, H. Den-
sitometric Determination of Glycyrrhizic Acid in Dried Licorice
Extract. Farm. Pol. 1984, 40, 527-529; Chem. Abstr. 103, 3762.
(44) Tsai, T.; Chen, C. Determination of Three Active Principles in
Licorice Extract by Reverse-phase High-performance Liquid
Chromatography. J. Chromatog. 1991, 542, 521-525.
(66) Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis
and Absolute Configuration of Substituted Morpholines. Tetra-
hedron 1980, 36, 409-415.
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