Identification of cyclicsulfonamide derivatives with an acetamide group as 11β-hydroxysteroid dehydrogenase 1 inhibitors

Article abstract of DOI:10.1248/cpb.59.46

In the continuation of our 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor research, cyclic sulfonamide derivatives with an acetamide group at the 2-position were synthesized and evaluated for their abilities to inhibit 11β-HSD1. Among this s

Full text of DOI:10.1248/cpb.59.46

46
Regular Article
Chem. Pharm. Bull. 59(1) 46—52 (2011)
Vol. 59, No. 1
Identification of Cyclicsulfonamide Derivatives with an Acetamide Group
b
as 11 -Hydroxysteroid Dehydrogenase 1 Inhibitors
Se Hoan KIM,a Sung Wook KWON,a So Young CHU,b Jae Hong LEE,a Banda NARSAIAH,b
Chi Hyun KIM,b Seung Kyu KANG,b Nam Sook KANG,b Sang Dal RHEE,b Myung Ae BAE,b
Sung Hoon AHN,b Duck Chan HA,a Ki Young KIM,b and Jin Hee AHN*,b
a Department of Chemistry, Korea University; Seoul 136–701, Korea: and b Drug Discovery Division, Korea Research
Institute of Chemical Technology; Yuseong-gu, Daejeon 305–600, Korea.
Received July 6, 2010; accepted October 3, 2010
In the continuation of our 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) inhibitor research, cyclic
sulfonamide derivatives with an acetamide group at the 2-position were synthesized and evaluated for their abili-
ties to inhibit 11b-HSD1. Among this series, Compound 34 showed good in vitro activity toward human 11b-
HSD1, selectivity against 11b-HSD2, microsomal stability, good pharmacokinetic and safety profiles human
ether-a-go-go related gene (hERG and cytochrome P450 (CYP)). Also, a docking study explained the activity dif-
ference between human and mouse 11b-HSD1.
Key words diabetes; anti-diabetic agent; 11b-hydroxysteroid dehydrogenase type 1; cyclic sulfonamide
11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) is as type 2 diabetes. During the last few years, small molecule
an endoplasmic reticulum-associated enzyme that acts pre- 11b-HSD1 inhibitors have been reported,8—13) and several
dominantly as an reduced nicotinamide adenine dinucleotide candidates including Incyte’s compound are in clinical trials.
phosphate (NADPH)-dependent reductase in vivo and con-
verts inactive cortisone to the active glucocorticoid corti- ical evaluation of a new series of cyclic sulfonamide deriva-
sol1—3) (Fig. 1). tives.14) Among the cyclic sulfonamide derivatives, com-
In an earlier report, we described the synthesis and biolog-
The relation between 11b-HSD1 and type 2 diabetes has pound A showed good potency, selectivity, reasonable meta-
been demonstrated in mouse genetic models. Mice overex- bolic stability and pharmacokinetic (PK) profiles. Therefore,
pressing 11b-HSD1 in adipose showed metabolic syndrome- we have further evaluated toxicity related tests with com-
like phenotypes such as central obesity, glucose intolerance, pound A, which was found to inhibit cytochrome P450
and insulin resistance.4,5) In contrast, 11b-HSD1 deficient (CYP) subtypes (2C19, 2D6, 3A4) as shown in Table 1. CYP
mice were resistant to the development of high-fat diet-in- enzymes play a major role in metabolizing drug molecules.
duced obesity and exhibited improved insulin sensitivity and Many lead candidate molecules in pharmaceutical develop-
lipid profiles.6,7) These data suggest that 11b-HSD1 could be ment fail due to inhibition of one or more isozymic forms of
a drug target for the treatment of metabolic syndrome as well CYP enzymes.
In order to overcome CYP inhibition, a series of new
cyclicsulfonamide derivatives with an acetamide group was
developed (Fig. 2). We now wish to report here the synthesis
and biological evaluation of cyclicsulfonamide derivatives
with an acetamide group as 11b-hydroxysteroid dehydroge-
nase 1 inhibitors.
Synthesis A series of cyclic sulfonamide derivatives was
synthesized according to Chart 1. Saccharin sodium salt 1
was reacted with alpha-bromo ketones in N,N-dimethylform-
amide (DMF) to provide the N-alkylated product 2. Com-
Fig. 1. The Role of 11b-HSD1 between Cortisone and Cortisol
pound 2 on refluxing in sodium–ethanol resulted in ring ex-
pansion and formed cyclic sulfonamide 3. It was further
alkylated with ethyl bromoaceate resulting in the correspon-
Table 1. In Vitro CYP Inhibitions of Compound A
A
CYP subtype
Inhibition at 10 mM (%)
1A2
2C19
2D6
3A4
7.9
90.5
79.8
73.0
Fig. 2. Structural Modification
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: jhahn@krict.re.kr

January 2011
47
Table 2. In Vitro 11b-HSD1 Inhibitory Activity of Cyclic Sulfonamide
Derivatives
a)
Compound
Structure
IC50, mM
Not active
34%
5
at 10 mM
6
3.5
Reagents and conditions: (a) BrCH2COR1 (R1ꢀmethyl, phenyl), DMF, 100 °C,
4 h; (b) Na, EtOH, reflux, 4 h; (c) 1 M NaOH, ethyl bromoacetate, room tempera-
ture, 12 h; (d) LiOH, THF/MeOH/H2O, room temperature, 5 h; (e) Amines, EDCI,
DMAP, CH2Cl2 (or DMF), room temperature, 5 h.
Chart 1
7
8
0.9
ding coupled product 4. Alkaline hydrolysis then provided
acid 5, which was further derivatized with diverse amines to
obtain the final amides 6—34.
Results and Discussion
Not active
45%
In vitro inhibition activity of 11b-HSD1 was assessed by a
Homogeneous Time Resolved Fluorescence (HTRF) cortisol
assay. Human microsomes were incubated with cortisone,
NADPH and compound. The IC50 values of the compounds
were determined from concentration-dependent inhibition
curves. Carbenoxolone was used as a standard 11b-HSD1 in-
hibitor.15)
First, acid 5 was inactive toward 11b-HSD1, but
adamantyl amide 6 was modestly potent with an IC50 of 3.5
mM as shown in Table 2. Also, cyclohexyl amide 7 showed
submicromolar activity (0.9 mM). Therefore, we further de-
rivatized with aliphatic amines, however, their activities (8—
10) were detrimental.
at 10 mM
Not active
4%
at 10 mM
9
Not active
44%
10
We then focused our attention on aromatic amides as
shown in Table 3. Benzyl amide (11) showed a good in vitro
activity with an IC50 value of 174 nM. Whereas, heteroaryl
amides (12, 13) were found to be less potent. Other substi-
tuted benzyl amide derivatives (14—18) exhibited weak to
moderate inhibitory activities (0.264—8.06 mM).
at 10 mM
Carbenoxolone
0.5
a) IC50 values were determined by GraphPad Prism software.
Among the aromatic amides, anilides were synthesized
and evaluated for their in vitro activity. As shown in Table 4,
compound 19, which is a simple aromatic anilide, showed a (122—272 nM), unsubstituted anilide 19 was still more po-
good inhibitory activity with an IC50 value of 102 nM. There- tent. Compound 31 is the first compound to improve on 19’s
fore, we chose 19 as a prototype compound for further de- activity with an IC50 value of 83 nM. Furthermore, compound
rivatization. The substituent effect of 19 at the 3-postion was 34, which is the most potent in this series, showed better in
investigated. The acetyl (20) and oxime (21) derivatives re- vitro activity with an IC50 value of 41 nM.
sulted in loss of in vitro activity. N-Methylanilide (22) and
heteroaryl amide (23) also showed poor activities.
Based on the above data, we chose three representative
compounds (31, 32, 34) for further biological evaluations
Compound 19 was evaluated for its CYP inhibition. Fortu- which include mouse 11b-HSD1 inhibition potency, selectiv-
nately, 19 was found to show no CYP inhibitions as shown in ity, metabolic stability, human ether a-go-go related gene
Table 5. Based on these results, we further synthesized (hERG), CYP assay and PK study in rat (Table 7). All com-
anilide derivatives having phenyl ring substituents.
pounds showed good in vitro activities toward human 11b-
The substituent effect of anilide derivatives was evaluated HSD1 and no significant CYP inhibition as we wished. How-
as shown in Table 6. Methyl substituents at ortho, meta and ever, in vitro activities toward mouse 11b-HSD1 were at mi-
para positions (24—26) were similar or less potent than un- cromolar levels with IC50 values in the range of 3—7 mM. In
substituted anilide 19 with IC50 values in the range of 129— order to better understand the activity difference between
795 nM. Also, although methoxy and fluoro substituted human and mouse 11b-HSD1, we investigated a binding
anilide derivatives (27—30) showed good in vitro potencies mode of compound 34 in both human and mouse 11b-HSD1

48
Vol. 59, No. 1
Table 3. In Vitro 11b-HSD1 Inhibitory Activity of Cyclic Sulfonamide
Derivatives
Table 4. In Vitro 11b-HSD1 Inhibitory Activity of Cyclic Sulfonamide
Derivatives
a)
a)
Compound
Structure
IC50, mM
Compound
Structure
IC50, mM
11
0.174
19
0.102
12
13
0.978
2.58
Not active
25%
at 10 mM
20
21
Not active
5%
at 10 mM
14
1.61
22
10.6
15
16
17
8.06
1.61
2.20
23
0.342
0.5
Carbenoxolone
a) IC50 values were determined by GraphPad Prism software.
Table 5. In Vitro CYP Inhibition of Compound 19
CYP subtype
Inhibition at 10 mM (%)
1A2
2C19
2D6
3A4
5
0
8
10
18
0.263
0.5
Compound 34 was the most potent in vitro toward both
human and mouse 11b-HSD1. Also 34 showed a good selec-
tivity, metabolic stability and no binding with hERG. The rat
PK profiles of compound 34 showed good systemic exposure
and oral bioavailability with an acceptable clearance and
half-life.
Carbenoxolone
a) IC50 values were determined by GraphPad Prism software.
(Fig. 3). Our model suggests that compound 34 interacts
through H-bonding with S170 and Y183 residues in the ac- Conclusion
tive sites in 11b-HSD1, and also shows the hydrophobic in-
We have developed a series of cyclic sulfonamide deriva-
teraction with Y177 in human form. However, in mouse ster- tive with an acetamide group as 11b-HSD1 inhibitors. Com-
ically unfavorable ineraction with Y284 residues in the B- pound 34 showed good in vitro activity toward human 11b-
chain resulted in lowering activity.
HSD1, selectivity toward 11b-HSD2, metabolic stability,

January 2011
49
Table 6. In Vitro 11b-HSD1 Inhibitory Activity of Cyclic Sulfonamide
Table 6. (Continue)
Compound
Derivatives
hHSD1
IC50, mM
Structure
a)
hHSD1
Compound
Structure
a)
IC50, mM
31
0.083
19
0.102
32
33
0.092
0.079
24
25
0.278
0.129
34
0.041
26
27
0.795
0.124
Carbenoxolone
0.5
a) IC50 values were determined by GraphPad Prism software.
Experimental
Chemistry All reported yields are isolated yields after column chro-
1
matography or crystallization. H-NMR spectra were obtained on FT-NMR
Bruker AVANCE-300 with tetramethylsilane (TMS) as an internal reference.
High-resolution mass spectra were obtained on the Autospec magnetic sec-
tor mass spectrometer (Micromass, Manchester, U.K.). Low-resolution mass
spectra were obtained on the liquid chromtography-mass spectrometer (LC-
MS, Waters, U.S.A.). General Procedure for the Synthesis of compound 34.
2-(2-Oxo-2-phenylethyl)benzo[d]isothiazol-3(2H)-one-1,1-dioxide (2)
Saccharin sodium salt (10 g, 0.049 mol) was dissolved in DMF (100 ml) and
was treated with 2-bromoacetophenone (0.059 mol) at room temperature.
The mixture was stirred for 4 h at 100 °C. The solution was poured into
ice/water, and the resulting solid was collected and dried in vacuo to give
28
29
30
0.256
0.122
0.272
1
compound 2 (12.98 g, 88%). H-NMR (300 MHz, CDCl3) d: 8.12 (d, Jꢀ6.6
Hz, 1H), 8.01 (m, 5H), 7.65 (t, Jꢀ7.8 Hz, 1H), 7.53 (t, Jꢀ7.8 Hz, 2H), 5.15
(s, 2H).
(4-Hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-3-yl)(phenyl)metha-
none (3) A solution of NaOEt, prepared from 2.3 g (33.18 mmol) of
sodium in 100 ml of ethanol was heated to 40 °C and 5.0 g (16.59 mmol) of
compound 2 was added all at once as the powder. The mixture was quickly
heated to 50—55 °C and maintained at this temperature for 3 h. It was then
quickly cooled to 25 °C and 10 ml of 9% HCl was added as rapidly as possi-
ble while maintaining the temperature at 30—35 °C. The crystals which sep-
arated from solution were collected by filtration, washed with 50% aq.
EtOH, and dried in vacuo at 60 °C for 1 h to yield compound 3 (3.9 g, 80%).
1H-NMR (300 MHz, CDCl3) d: 8.25 (d, Jꢀ7.8 Hz, 1H), 8.05 (d, Jꢀ6.9 Hz,
2H), 7.94 (m, 1H), 7.82 (m, 2H), 7.58 (m, 3H), 5.82 (brs, 1H).
Ethyl 2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-
yl)acetate (4) Compound 3 (1 g, 3.32 mmol) was dissolved in ethanol
(25 ml) and was treated with 1 M aqueous NaOH (5 ml) followed by ethyl
bromoacetate (665 mg, 3.98 mmol) and was stirred at room temperature for
12 h. The resulting suspension was filtered, and the solid was washed with
water and dried in vacuo to give compound 4 (587 mg, 45%). 1H-NMR
(300 MHz, DMSO-d6) d: 8.13—8.08 (m, 1H), 7.88—7.81 (m, 5H), 7.60—
good PK and safety profile such as hERG and CYP. Also, a
docking study explained the activities difference between
human and mouse 11b-HSD1.

50
Vol. 59, No. 1
Table 7. In Vitro Inhibition, Metabolic Stability, hERG and PK Study of Cyclic Sulfonamide Derivatives
Microsomal
stability
30 min after
CYP
inhibition %
at 10 mM
hHSD1
IC50, mM
mHSD1
IC50, mM
hHSD2
IC50, mM
Entry
hERG
PK in rat
a)
a)
a)
1A2
0%
17%
20%
7%
PO Cmaxꢀ1.1 mg/ml
t1/2ꢀ5.5 h
CL (l/h/kg)ꢀ0.4
Fꢀ48.1%
20%
at 10 mM
85% (h)
69% (r)
2C19
2D6
3A4
34
0.041
3.0
ꢃ100 mM
1A2
2C19
2D6
3A4
0%
0%
0%
0%
63% (h)
66% (r)
33
0.079
6.3
7.0
NTb)
NT
26 mM
57 mM
Fꢀ84.6%
Fꢀ84.6%
1A2
2C19
2D6
3A4
0%
24%
35%
32%
85% (h)
68% (r)
31
0.083
0.5
Carben-oxolone
a) IC50 values were determined by GraphPad Prism software. b) Not tested.
7.48 (m, 3H), 3.92 (s, 2H), 3.69 (q, Jꢀ7.1 Hz, 2H), 0.78 (t, Jꢀ7.1 Hz, 3H);
LC-MS (m/z): 388 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2- Jꢀ7.2 Hz, 2H), 7.90—7.85 (m, 3H), 7.68—7.58 (m, 3H), 4.02 (s, 2H), 3.34
yl)acetic Acid (5) To a solution of 4 (340 mg, 0.878 mmol) in tetrahydro-
furan (THF)/MeOH (5 ml/5 ml), was added a solution of LiOH (185 mg,
4.39 mmol) in H2O (5 ml). The reaction mixture was stirred for 5 h, and then
the solvent was evaporated. Ice was poured into this residue, and acidified by
2 N HCl to adjust it to pH 3. The resulting solution was extracted with
EtOAc and the organic layer was separated, dried and evaporated under re-
duced pressure to give 5 (300 mg, 95%). mp 201—203 °C; IR (KBr): 1692,
morpholinoethanone (10) mp 134—136 °C; IR (KBr): 1662, 1718
(CꢀO) cmꢂ1 1H-NMR (300 MHz, CDCl3) d: 8.14 (m, 1H), 8.00 (d,
;
(s, 4H), 3.03 (s, 4H); LC-MS (m/z): 429 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
benzylacetamide (11) mp 233—235 °C; IR (KBr): 3358 (NH) cmꢂ1
,
1675, 1702 (CꢀO) cmꢂ1 1H-NMR (300 MHz, DMSO-d6) d: 7.85—7.83
;
(m, 1H), 7.67—7.59 (m, 3H), 7.31—7.21 (m, 10H); LC-MS (m/z): 449
(MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
1727 (CꢀO) cmꢂ1; 1H-NMR (300 MHz, DMSO-d6) d: 12.67 (s, 1H), 8.18— (pyridin-2-ylmethyl)acetamide (12) mp 176—178 °C; IR (KBr): 3377
8.15 (m, 1H), 8.00—7.98 (m, 2H), 7.93—7.90 (m, 3H), 7.72—7.58 (m, 3H), (NH) cmꢂ1, 1687, 1695 (CꢀO) cmꢂ1
;
1H-NMR (300 MHz, DMSO-d6) d:
3.80 (s, 2H); LC-MS (m/z): 360 (MHꢁ).
8.50—8.40 (m, 2H), 8.13—8.09 (m, 1H), 8.02—7.99 (m, 2H), 7.87—7.86
(m, 3H), 7.72—7.59 (m, 4H), 7.23—7.19 (m, 1H), 7.00 (br d, 1H), 4.05 (d,
Jꢀ7.2 Hz, 2H), 3.86 (m, 2H); LC-MS (m/z): 450 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
[3-(trifluoromethyl)phenyl]acetamide (34) To a solution of 5 (50 mg,
0.139 mmol) and m-trifluoromethylaniline (26.9 mg, 0.167 mmol) in CH2Cl2,
were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (40 mg,
0.209 mmol) and 4-dimethylaminopyridine (DMAP) (cat). The reaction mix-
ture was stirred for 5 h at room temperature and then brine and CH2Cl2 were
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
(furan-2-ylmethyl)acetamide (13) IR (KBr): 3335 (NH) cmꢂ1, 1678,
1
1701 (CꢀO) cmꢂ1; H-NMR (300 MHz, DMSO-d6) d: 8.24 (s, 1H). 8.13—
8.09 (m, 1H), 8.00—7.97 (m, 2H), 7.89—7.81 (m, 3H), 7.69—7.57 (m, 3H),
added. The organic layer was separated, dried over anhydrous MgSO4, and 7.48—6.47 (m, 1H), 6.30—6.29 (m, 1H), 6.03—6.02 (m, 1H), 3.91 (d,
evaporated under reduced pressure. The residue was purified by silica gel
Jꢀ5.2 Hz, 2H), 3.76 (s, 2H); LC-MS (m/z): 439 (MHꢁ).
column chromatography to give 34 (21 mg, 30%). mp 292—294 °C; IR
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
(KBr): 3359 (NH) cmꢂ1, 1692, 1712 (CꢀO) cmꢂ1
;
1H-NMR (300 MHz, (4-fluorobenzyl)acetamide (14) IR (KBr): 3352 (NH) cmꢂ1, 1670, 1697
1
DMSO-d6) d: 15.07 (s, 1H), 10.17 (s, 1H), 8.19—7.18 (m, 13H), 4.00 (s, (CꢀO) cmꢂ1; H-NMR (300 MHz, DMSO-d6) d: 8.31 (s, 1H). 8.12—8.08
2H); high resolution-mass spectra (HR-MS) (C24H17F3N2O5S): Calcd (m, 1H), 8.01—7.99 (m, 2H), 7.90—7.82 (m, 3H), 7.70—7.57 (m, 3H),
502.0810, Found 502.0807.
7.09—6.98 (m, 4H), 3.92 (d, Jꢀ5.5 Hz, 2H), 3.79 (s, 2H); LC-MS (m/z):
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N- 467 (MHꢁ).
adamantylacetamide (6) mp 146—148 °C; IR (KBr): 3323 (NH) cmꢂ1
,
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
(1-(4-fluorophenyl)ethyl)acetamide (15) mp 162—164 °C; IR (KBr):
1
1667, 1680 (CꢀO) cmꢂ1; H-NMR (300 MHz, DMSO-d6) d: 12.67 (s, 1H),
8.18—8.15 (m, 1H), 8.00—7.98 (m, 2H), 7.93—7.90 (m, 3H), 7.72—7.58 3302 (NH) cmꢂ1, 1660, 1692 (CꢀO) cmꢂ1; 1H-NMR (300 MHz, DMSO-d6)
(m, 3H), 3.80 (s, 2H); LC-MS (m/z): 360 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
cyclohexylacetamide (7) mp 145—147 °C; H-NMR (300 MHz, CD3OD)
d: 8.27—8.24 (m, 1H), 8.07—7.99 (m, 3H), 7.85—7.80 (m, 3H), 7.70—
7.58 (m, 3H), 7.10—7.01 (m, 4H), 4.52—4.47 (m, 1H), 3.76 (s, 2H), 1.08
(d, Jꢀ6.9 Hz, 3H); LC-MS (m/z): 481 (MHꢁ).
1
d: 8.23—8.18 (m, 1H), 8.08—8.03 (m, 2H), 7.84—7.73 (m, 2H), 7.66—
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
7.54 (m, 4H), 3.68 (s, 2H), 3.18—3.12 (m, 1H), 1.62—0.85 (m, 10H); LC- (4-(trifluoromethyl)benzyl)acetamide (16) IR (KBr): 3288 (NH) cmꢂ1
,
1
MS (m/z): 441 (MHꢁ).
1672, 1700 (CꢀO) cmꢂ1; H-NMR (300 MHz, DMSO-d6) d: 8.42 (s, 1H).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N- 8.10—7.99 (m, 3H), 7.85—7.82 (m, 3H), 7.70—7.58 (m, 5H), 7.21—7.19
ethylacetamide (8) mp 155—157 °C; IR (KBr): 3273 (NH) cmꢂ1, 1685, (m, 2H), 4.03 (d, Jꢀ5.3 Hz, 2H), 3.82 (s, 2H); LC-MS (m/z): 517 (MHꢁ).
1716 (CꢀO) cmꢂ1; 1H-NMR (300 MHz, DMSO-d6) d: 8.13 (m, 1H), 8.00—
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
7.98 (m, 2H), 7.90—7.82 (m, 4H), 7.68—7.58 (m, 3H), 3.69 (s, 2H), 2.74 (4-(methoxy)benzyl)acetamide (17) IR (KBr): 3312 (NH) cmꢂ1, 1683,
1
(m, 2H), 0.76 (t, Jꢀ7.2 Hz, 3H); LC-MS (m/z): 387 (MHꢁ).
1711 (CꢀO) cmꢂ1; H-NMR (300 MHz, DMSO-d6) d: 9.74 (s, 1H), 8.18—
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)- 8.17 (m, 1H), 8.05—8.04 (m, 2H), 7.93—7.86 (m, 3H), 7.70—7.62 (m, 3H),
N,N-diethylacetamide (9) mp 163—165 °C; IR (KBr): 1654, 1697 7.12—7.10 (m, 2H), 6.76—6.74 (m, 2H), 3.95 (s, 2H), 3.65 (s, 3H); LC-MS
(CꢀO) cmꢂ1; H-NMR (300 MHz, CDCl3) d: 8.23 (d, Jꢀ6.6 Hz, 1H), 8.09 (m/z): 465 (MHꢁ).
1
(d, Jꢀ7.2 Hz, 2H), 7.85—7.82 (m, 1H), 7.80—7.71 (m, 3H), 7.62—7.50 (m,
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
3H), 4.22 (s, 1H), 3.53 (s, 1H), 2.95—2.88 (m, 4H), 0.90 (t, Jꢀ7.1 Hz, 3H), (4-ethylbenzyl)acetamide (18) IR (KBr): 3306 (NH) cmꢂ1, 1667, 1708
1
0.79 (t, Jꢀ7.1 Hz, 3H); LC-MS (m/z): 415 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-1-
(CꢀO) cmꢂ1; H-NMR (300 MHz, DMSO-d6) d: 9.76 (s, 1H), 8.17—8.14
(m, 1H), 8.04—8.01 (m, 2H), 7.90—7.84 (m, 4H), 7.68—7.58 (m, 3H),

January 2011
51
1
(CꢀO) cmꢂ1; H-NMR (300 MHz, CDCl3) d: 8.28—8.25 (m, 1H), 7.90—
7.85 (m, 3H), 7.80—7.75 (m, 2H), 7.47—7.34 (m, 3H), 7.26—7.22 (m, 3H),
6.85—6.82 (m, 3H), 2.94 (s, 3H); LC-MS (m/z): 448.96 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
(pyridin-4-yl)acetamide (23) mp 150—152 °C; IR (KBr): 3262 (NH)
1
cmꢂ1, 1660, 1726 (CꢀO) cmꢂ1; H-NMR (300 MHz, DMSO-d6) d: 8.36—
7.18 (m, 13H), 4.02 (s, 2H); LC-MS (m/z): 436 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
o-tolylacetamide (24) IR (KBr): 3293 (NH) cmꢂ1, 1670, 1692 (CꢀO)
cmꢂ1; 1H-NMR (300 MHz, DMSO-d6) d: 9.27 (s, 1H). 8.13—8.03 (m, 3H),
7.88—7.84 (m, 3H), 7.72—7.60 (m, 3H), 7.08—6.98 (m, 4H), 4.00 (s, 2H),
1.92 (s, 3H); LC-MS (m/z): 449 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
m-tolylacetamide (25) mp 134—136 °C; IR (KBr): 3257 (NH) cmꢂ1
,
1
1693, 1708 (CꢀO) cmꢂ1; H-NMR (300 MHz, DMSO-d6) d: 9.76 (s, 1H).
8.18—8.15 (m, 1H), 8.03—8.01 (m, 2H), 7.92—7.85 (m, 3H), 7.70—7.58
(m, 3H), 7.06—6.97 (m, 3H), 6.77—6.75 (m, 1H), 3.95 (s, 2H), 2.14 (s,
3H); LC-MS (m/z): 449 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
p-tolylacetamide (26) mp 133—135 °C; IR (KBr): 3342 (NH) cmꢂ1
,
1688, 1707 (CꢀO) cmꢂ1; H-NMR (300 MHz, CDCl3) d: 8.22 (dd, Jꢀ7.1,
2.0 Hz, 1H), 8.05 (dd, Jꢀ7.7, 1.7 Hz, 2H), 7.88 (dd, Jꢀ6.9, 1.8 Hz, 1H),
7.74 (p, Jꢀ7.4 Hz, 2H), 7.53—7.46 (m, 3H), 7.18 (s, 1H), 6.98 (d,
Jꢀ8.4 Hz, 2H), 6.91 (d, Jꢀ8.7 Hz, 2H), 3.76 (s, 2H), 2.26 (s, 3H); LC-MS
(m/z): 449 (MHꢁ).
1
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
(2-methoxyphenyl)acetamide (27) mp 212—214 °C; IR (KBr): 3335
1
(NH) cmꢂ1, 1673, 1702 (CꢀO) cmꢂ1; H-NMR (300 MHz, CDCl3) d: 8.21
(dd, Jꢀ7.2, 1.5 Hz, 1H), 8.07 (dd, Jꢀ8.1, 1.5 Hz, 2H), 7.84 (d, Jꢀ7.2 Hz,
1H), 7.77—7.64 (m, 4H), 7.50—7.42 (m, 3H), 6.98 (t, Jꢀ8.7 Hz, 1H), 6.77
(t, Jꢀ8.4 Hz, 2H), 3.86 (s, 5H); LC-MS (m/z): 465 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
(3-methoxyphenyl)acetamide (28) mp 153—155 °C; IR (KBr): 3298
1
(NH) cmꢂ1, 1678, 1712 (CꢀO) cmꢂ1; H-NMR (300 MHz, CDCl3) d: 8.22
(d, Jꢀ7.2 Hz, 1H), 8.05 (d, Jꢀ7.5 Hz, 2H), 7.89 (d, Jꢀ7.2 Hz, 1H), 7.75 (p,
Jꢀ7.5 Hz, 2H), 7.54—7.48 (m, 3H), 7.22 (s, 1H), 7.08 (t, Jꢀ8.4 Hz, 1H),
6.78 (s, 1H), 6.59 (t, Jꢀ8.4 Hz, 2H), 3.77 (s, 2H), 3.73 (s, 3H); LC-MS
(m/z): 465 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
(2-fluorophenyl)acetamide (29) IR (KBr): 3362 (NH) cmꢂ1, 1666, 1706
(CꢀO) cmꢂ1; 1H-NMR (DMSO-d6, 300 MHz) d: 9.72 (s, 1H), 8.17 (m. 1H),
8.04 (d, Jꢀ7.5 Hz, 2H), 7.97—7.85 (m, 3H), 7.73—7.61 (m, 3H), 7.52—
7.47 (m, 1H), 7.23—6.98 (m, 3H), 3.92 (s, 2H); LC-MS (m/z): 453 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
(3-fluorophenyl)acetamide (30) mp 180—182 °C; IR (KBr): 3287 (NH)
cmꢂ1, 1669, 1701 (CꢀO) cmꢂ1 1H-NMR (300 MHz, CDCl3) d: 8.23 (dd,
;
Fig. 3. The Binding Mode of 34 Was Shown for Human (a)16) and Mouse
(b) 11b-HSD1
The used reference structure for 11b-HSD1 complex was obtained from protein data
bank (pdb entry; 3FRJ for human, 1Y5M for mouse). The calculation for docking was
carried out using LigandFit17) interfaced with Accelrys DiscoveryStudio2.5.
Jꢀ7.1, 2.0 Hz, 1H), 8.05 (dd, Jꢀ6.0, 1.8 Hz, 2H), 7.89 (dd, Jꢀ7.4, 1.7 Hz,
1H), 7.78 (d, Jꢀ7.2 Hz, 2H), 7.54—7.46 (m, 3H), 7.32 (s, 1H), 7.19—7.11
(m, 1H), 6.99 (dt, Jꢀ10.7, 2.1, 1H), 6.79—6.72 (m, 2H), 3.78 (s, 2H); LC-
MS (m/z): 453 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
(2-chlorophenyl)acetamide (31) mp 169—171 °C; IR (KBr): 3253 (NH)
cmꢂ1, 1676, 1706 (CꢀO) cmꢂ1; 1H-NMR (300 MHz, DMSO-d6) d: 9.54 (s,
1H), 8.15—8.14 (m, 1H), 8.04 (m, 2H), 7.90—7.88 (m, 3H), 7.71—7.64 (m,
3H), 7.40—7.38 (m, 1H), 7.31 (m, 1H), 7.20—7.13 (m, 1H), 7.12—7.09 (m,
1H), 4.08 (s, 2H); HR-MS (C23H17ClN2O5S): Calcd 468.0547, Found
468.0512.
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
(3-chlorophenyl)acetamide (32) IR (KBr): 3266 (NH) cmꢂ1, 1674, 1714
(CꢀO) cmꢂ1; 1H-NMR (300 MHz, CDCl3) d: 8.23 (dd, Jꢀ7.7, 1.4 Hz, 1H),
8.04 (dd, Jꢀ7.8, 1.7 Hz, 2H), 7.90 (dd, Jꢀ7.4, 1.4 Hz, 1H), 7.78 (p,
Jꢀ7.5 Hz, 2H), 7.56—7.47 (m, 3H), 7.29 (s, 1H), 7.20—7.17 (m, 2H),
7.09—7.04 (m, 2H), 3.77 (s, 2H); LC-MS (m/z): 469 (MHꢁ).
7.09—6.96 (m, 4H), 3.95 (s, 2H), 2.44 (q, Jꢀ7.5 Hz, 2H), 1.05 (t, Jꢀ7.5 Hz,
3H); LC-MS (m/z): 463 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
phenylacetamide (19) mp 128—130 °C; IR (KBr): 3280 (NH) cmꢂ1
,
1660, 1680 (CꢀO) cmꢂ1; 1H-NMR (300 MHz, DMSO-d6) d: 9.85 (br s, 1H),
9.13—7.85 (m, 6H), 7.85 (m, 3H), 7.18—7.16 (m, 4H), 6.96—6.92 (m, 1H),
3.95 (s, 2H); HR-MS (C23H18N2O5S): Calcd 434.0936, Found 434.0936.
2-(3-Acetyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
phenylacetamide (20) mp 188—190 °C; IR (KBr): 3345 (NH) cmꢂ1
,
1620, 1671 (CꢀO) cmꢂ1 1H-NMR (300 MHz, DMSO-d6) d: 8.04—7.99
;
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
(3,4-difluorophenyl)acetamide (33) mp 194—196 °C; IR (KBr): 3475
(m, 1H), 7.81—7.66 (m, 3H), 7.48—7.40 (m, 2H), 7.29—7.21 (m, 2H),
7.03—6.97 (m, 1H), 4.13—3.89 (m, 2H), 2.48—2.47 (m, 3H); LC-MS
(m/z): 373 (MHꢁ).
(NH) cmꢂ1, 1631, 1710 (CꢀO) cmꢂ1 1H-NMR (300 MHz, CD3OD) d:
;
8.17—8.13 (m, 1H), 7.99—7.96 (m, 2H), 7.77—7.71 (m, 3H), 7.54—7.42
(m, 3H), 7.33—7.27 (m, 1H), 6.97—6.89 (m, 1H), 6.68—6.61 (m, 1H), 3.89
(s, 2H); HR-MS (C23H16F2N2O5S): Calcd 470.0748, Found 470.0749.
Biological Evaluation. in Vitro Study Human 11b-HSD1: To assay mi-
crosomal 11b-HSD1 activity, 10 mg of human microsome was added in an
assay buffer (100 ml) containing 250 mM NADPH, 160 nM cortisone, 20 mM
Tris–HCl, and 5 mM ethylenediaminetetraacetic acid (EDTA, pH 6.0) with or
without compounds (in dimethyl sulfoxide (DMSO), final 1%) and allowed
(E)-2-{1,1-Dioxo-4-hydroxy-3-[(hydroxyimino)(phenyl)methyl]-2H-
benzo[e][1,2]thiazin-2-yl}-N-phenylacetamide (21) mp 214—216 °C; IR
1
(KBr): 3375 (NH) cmꢂ1, 1651 (CꢀO) cmꢂ1, 1604 (CꢀN) cmꢂ1; H-NMR
(300 MHz, CD3OD) d: 8.08—8.06 (m, 1H), 7.91—7.89 (m, 3H), 7.84—7.79
(m, 1H), 7.67—7.62 (m, 1H), 7.43—7.37 (m, 3H), 7.28—7.20 (m, 4H),
7.09—7.05 (m, 1H), 3.85 (s, 2H); LC-MS (m/z): 450 (MHꢁ).
2-(3-Benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-
methyl-N-phenylacetamide (22) mp 186—188 °C; IR (KBr): 1668, 1744

52
Vol. 59, No. 1
References
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Acknowledgment This research was supported by the Center for Bio-
logical Modulators of the 21st Century Frontier R&D Program, Ministry of
Education, Science and Technology, Korea.