Chemo- and stereoselective synthesis of benzocycloheptene and 1-benzoxepin derivatives as α-sympathomimetic and anorexigenic agents

Article abstract of DOI:10.1016/j.bmcl.2004.03.064

The synthesis and pharmacological evaluation of cis- and trans-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ols 4a-c and 5a-c and cis- and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ols 4d-f and 5d-f were carried out. Chemo- and stereoselective synthesis of 5a-f was achieved by reduction of corresponding α-amino ketones 3a-f with LiAl(t-BuO) ₃H. cis-4-Amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 4d and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 5d exhibited marked anorexigenic activity in mice at a dose of LD₅₀ 800 and 500mg/kg and ED₅₀ 75 and 55mg/kg, respectively, while the analog cis-2,3-dihydroxy-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol 8 showed typical α-sympathomimetic activity.

Full text of DOI:10.1016/j.bmcl.2004.03.064

Bioorganic & Medicinal Chemistry Letters 14 (2004) 2867–2870
Chemo- and stereoselective synthesis of benzocycloheptene and
-benzoxepin derivatives as a-sympathomimetic and anorexigenic
agents
1
a,
Vishnu K. Tandon, Kunwar A. Singh, Anoop K. Awasthi, J. M. Khanna, Bansi Lal
a
a
b
c
*
d
and Nitya Anand
a
Department of Chemistry, Lucknow University, Lucknow 226007, India
b
Ranbaxy Laboratories, New Delhi, India
c
Nicholas Piramal Laboratories, Mumbai, India
Central Drug Research Institute, Lucknow, India
d
Received 4 February 2004; accepted 15 March 2004
Abstract—The synthesis and pharmacological evaluation of cis- and trans-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ols
a–c and 5a–c and cis- and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ols 4d–f and 5d–f were carried out. Chemo- and
stereoselective synthesis of 5a–f was achieved by reduction of corresponding a-amino ketones 3a–f with LiAl(t-BuO) H. cis-4-
4
3
Amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 4d and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 5d exhibited marked
anorexigenic activity in mice at a dose of LD50 800 and 500 mg/kg and ED50 75 and 55 mg/kg, respectively, while the analog cis-2,3-
dihydroxy-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol 8 showed typical a-sympathomimetic activity.
ꢀ
2004 Elsevier Ltd. All rights reserved.
Obesity and its associated diseases are an increasing
1
tion of cis- and trans-4-amino-2,3,4,5-tetrahydro-1-
benzoxepin-5-ols 4d–f and 5d–f. These amino alcohols
have been found to possess marked anorexigenic activ-
ity. The results of anorexigenic activity of 4d–f and 5d–f
are shown in Table 1. Effect on blood pressure and
interaction with adrenaline, histamine, and acetylcholine
was studied in anesthetized (pentobarbitone 35.0 mg/kg
iv) cats using 2.5 mg/kg of each compound. The
anorexigenic activity was tested by measuring the
reduction of milk intake in overnight fasted mice. Gross
behavioral effects and acute toxicity (ALD50) of the
compounds 4d–f and 5d–f was studied in albino mice by
intraperitoneal administration of these compounds sus-
pended in gum acacia using five animals per dose.
challenge in medicine. Obesity is a worldwide health
problem. It has been estimated that nearly 300,000
2
deaths/annually in U.S.A. are attributed to obesity.
Anorexigenic drug, sibutramine is being recently used in
addition to fluoxetine, phentermine, and dexfenflur-
3
amine. a-Sympathomimetic drugs constitute pheneth-
ylamines, catecholamines, and related adrenergic
4
amines, which can assume a number of permissible
conformations at the receptor site. Rigid analogs with
severely limited permissible conformations can prove
helpful in this analysis. In connection with the study of
agents acting on adrenergic receptor, a new route
describing chemo- and stereoselective synthesis of
cis- and trans-6-amino-6,7,8,9-tetrahydro-5H-benzocyclo-
hepten-5-ols 4a–c and 5a–c and cis- and trans-4-amino-
Thecompounds 4d–f and 5d–f in general exhibited a
weak stimulant action and marked anorexigenic activity.
The most marked anorexigenic activity was shown by
cis- and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-
5-ols 4d and 5d. Their LD50 in miceis 800 and 500 mg/kg
and ED50 is 75 and 55 mg/kg, respectively. Replacement
2
,3,4,5-tetrahydro-1-benzoxepin-5-ols 4d–f and 5d–f is
being reported. Compounds 4a–c and 5a–c have been
shown to possess typical a-sympathomimetic activity.
We have carried out detailed pharmacological evalua-
1
of R by methyl group did not show any anorexigenic
1
activity. Replacement of R by methoxy group also did
not cause any anorexigenic activity in both cis-
and trans-isomers. The marked anorexigenic activity
*
0
Corresponding author. Tel.: +91-522-2684388; fax: +91-522-23266-
5; e-mail: vishnutandon@yahoo.co.in
6
960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.03.064

2868
V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2867–2870
Table 1. Anorexigenic activity of compounds 4d–f and 5d–f
1
Compounds
R
R
ALD50 mg/kg ip
in mice)
Gross effect (mice) ip
Effect on blood
pressure, change in mm
Anorexigenic activity in
mice, ED50 mg/kg, ip
(
(
duration in minutes)
a
4
5
4
5
4
5
d
d
e
e
f
H
H
H
H
H
H
H
800
500
Stimulation
Stimulation
44 fl (transient)
32 fl 40
75
55
H
Me300
Me150
OMe150
OMe150
Stimulation
10
38
fl (transient)
fl 160
fl (transient)
fl (transient)
NE
NE
NE
NE
Stimulation
Stimulation
Stimulation
20
40
f
NE ¼ No effect.
a
Increase in spontaneous motor activity, respiration, reactivity, tremors, and convulsions.
Table 2. Pharmacological activity of compounds 4a–c, 4g, and 5a
1
Compounds
R
R
ALD50 mg/kg ip
in mice)
Gross effect (mice) ip
Protection against
amphetamine toxicity
ED50 mg/kg, pc
Effect on blood pressure,
changein mm Hg
(duration in minutes)
(
4
4
4
4
5
a
b
c
H
MeMe150
OMeOMe150
H
150
Tranquilizer
NE
73
NE
NE
NE
NE
NE
NE
NE
NE
0
g
a
OH
H
OH
H
150
150
Depression
NE
51 (13 )
NE
NE ¼ No effect.
exhibited by cis- and trans-amino alcohols 4d and 5d
refers these as lead compounds of the series.
R
R
X
X
(
)n
a
( )n
R1
R1
NOH
Thecompounds 4a–c and 5a–c were evaluated for their
pharmacological activity by standard methods and these
2
O
O
1
b
are reported in Table 2. cis-6-Amino-6,7,8,9-tetrahydro-
5
5
H-benzocyclohepten-5-ol 4a has LD50 150 mg/kg, ip in
mice. It gave protection against amphetamine toxicity
ED50 73 mg/kg, po). It showed typical effects of a
R
R
X
X
(
)n
NH2
( )n
NH .HCl
d
(
R1
tranquilizer in the EEG in rabbits. The corresponding
trans-isomer 5a did not show any tranquilizing activity.
Ther ea son for theactivity of cis-isomer 4a compared to
the trans-isomer 5a indicates that ephedrine configura-
tion is necessary for activity of these compounds (Fig.
R1
2
3
5
OH
X
O
c
1
). cis-2,3-Dihydroxy-6-amino-6,7,8,9-tetrahydro-5H-
R
R
X
(
)n
benzocyclohepten-5-ol 4g in gross observation studies in
miceLD 50 150 mg/kg ip showed only slight depression
and no other prominent effect. In normal anesthetized
cats at a doseof 1 mg/kg iv, it caus ed 51 mm Hg fall of
BP for 13 min. The responses to epinephrine, norepi-
nephrine, and tyramine were potentiated by pretreat-
ment with the compound. It showed stimulant effect on
rabbit heart in vitro, which could be blocked by a b-
blocker (DCI). Thus 4d has a direct sympathomimetic
effect, stimulating the a-adrenergic receptors. The
corresponding trans-isomer 5g did not show any
( )n
+
R1
NH2
R1
NH2
OH
5
OH
4
X = O or CH , n = 2
2
Scheme 1. Reagents and conditions: (a) KOEt, n-BuONO; (b) 10% Pd/
C, H ; (c) LiAlH , NaBH or 10% Pd/C, H ; (d) LiAl(t-BuO) H.
2
4
4
2
3
sympathomimetic activity. The synthesis of trans-
6-amino-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-5-ols
5a–c and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxe-
pin-5-ols 5d–f and corresponding cis-isomer is shown in
Schemes 1 and 2.
H
Ph
OH
C
Oximino ketones 2a–f obtained by nitrosation of the
ketones 1, on catalytic reduction in presence of 10% Pd/
C gave a-amino ketones, which were converted into
hydrochlorides 3a–f by treatment with ethereal HCl.
Thesynth et ic data for compounds 2 and 3 aregiv en in
Tables 3 and 4, respectively. We have devised a new
routefor thesynth es is of cis- or trans-amino alcohols by
NH2
C
H
HO
Me
NHMe
4a
(
-)-Ephedrine
Figure 1.

V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2867–2870
2869
Table 6. Synthetic data for compounds 5
R
R
X
X
(
)n
( )n
1
Compounds
X
n
R
R
Mp ꢁC
Yield %
+
R1
NH2
R1
NH2
2
2
2
5a
5b
CH
CH
CH
O
2
2
2
2
2
2
H
H
147–48
87
OH
5
OH
MeM e1 78–180 90
OMeOM e1 35 89
4
5c
5d
a
H
H
H
H
Me148–149 92
153–154
3
5
e
O
R
X
(
R
X
5f
O
OMe143–144 85
)n
( )n
+
R1
NHAc
R1
NHAc
OH
OH
6
7
useof LiAl( t-BuO) H or conversion into acetamido
3
alcohols 6 as shown in Schemes 1 and 2. It seemed
essential to devise method for exclusive synthesis of cis-
and trans-isomers as reduction of a-amino ketones 3a–f
b
R
X
(
)n
4 4
with LiAlH , NaBH , or 10% Pd/C,H led to mixture of
cis- and trans-amino alcohols 4a–f and 5a–f in varied
proportions, which were difficult to separate. a-Amino
ketones 3 on reduction with LiAl(t-BuO) H in THF
3
R1
NHAc
OH
c
6
gave exclusively trans-amino alcohols 5 (Table5). cis-
Amino alcohols 4 were synthesized by conversion of
mixtureof 4 and 5 obtained by reduction of a-amino
ketones 3 into acetamido alcohols 6a–f and 7a–f. cis-
Acetamido alcohols 6 could beisolat ed as insolublepart
by fractional crystallization with benzene from mixture
of 6a–f and 7a–f. Compound 6 on hydrolysis with
aqueous NaOH resulted in isolation of cis-amino alco-
R
X
(
)n
R1
NH2
OH
4
X = O or CH , n = 2
2
5
hols 4a–f (Table6). Thus both cis- and trans- isomers
can be synthesized in pure form according to Schemes 1
and 2. The structures of these compounds were eluci-
Scheme 2. Reagents and conditions: (a) Ac
2
O, MeOH; (b) benzene,
fractional crystallization; (c) 10% aq NaOH.
1
dated on the basis of H NMR spectra.
Table 3. Synthetic data for compounds 2
In conclusion we have devised new route for synthesis of
6;7
1
Compounds
X
n
R
R
Mp ꢁC
Yield %
60
cis- and trans-amino alcohols 4a–f and 5a–f having
marked pharmacological activity. Both compounds 4d
and 5d are lead compounds for anorexigenic activity in
mice whereas 4a is a lead compound as tranquilizer and
4g has a-sympathomimetic activity.
2a
2b
2c
2d
2e
2f
CH
CH
CH
O
2
2
2
2
2
2
2
2
2
H
H
MeMe 192
127–128
70
73
OMeOMe 173
H
H
H
H
Me123–124
125–127
69
O
88
82
O
OMe118–119
Acknowledgements
The authors are thankful to the Regional Sophisticated
Instrumentation Centre, CDRI, Lucknow for elemental
analysis, spectral data, and pharmacological activity.
This work was supported by a research grant from
University Grants Commission of India.
Table 4. Synthetic data for compounds 3
1
Compounds
X
n
R
R
Mp ꢁC
183
Yield %
90
3a
3b
3c
3d
3e
3f
CH
CH
CH
O
2
2
2
2
2
2
2
2
2
H
H
MeMe 205–207 85
OMeOMe 168–170 88
H
H
H
H
Me198–200 53
208–210 62
O
O
OMe189–190 72
References and notes
1
. Nisoli, E.; Carruba, M. O. J. Endocrinol. Invest. 2002, 25,
05.
. James, W. P. T.; Astrup, A.; Finer, N. Lancet 2000, 356,
119.
9
2
Table 5. Synthetic data for compounds 4
2
1
3. Welman, P. J.; Jones, S. L.; Miller, D. K. Pharmacol.
Biochem. Behav. 2003, 75, 103.
Compounds
X
n
R
R
Mp ꢁC Yield %
HCl
4
. Hoffmann, B. B.; Lefkowitz, R. J. In The Pharmacological
Basis of Therapeutics, 9th ed.; Goodman, Gilman, Eds.; Mc
Graw-Hill: U.S.A., 1996; pp 232–233.
. Khanna, J. M.; Bolger, J.; Anand, N. Indian J. Chem. 1969,
7
4a
4b
4c
4d
4e
4f
CH
CH
CH
O
2
2
2
2
2
2
2
2
2
H
MeMe292
H
278
90
78
88
OMeOMe230
45
260
5
6
H
H
H
H
, 550.
. General procedure for stereoselective synthesis of 5: LiAl
t-BuO) H (0.47 g, 15 mmol) was added to a solution of
O
Me252
OMe240
73
88
O
(
3

2870
V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2867–2870
3
a–f (10 mmol) in anhydrous THF (5 mL) with stirring at
7. General procedure for synthesis of 4: A mixtureof cis-acetamido
alcohol 6a–f: (2.5 mmol) MeOH (30 mL) and 10% aqueous
NaOH (20mL) was re fluxe d on a ste am bath for 12h. The
solution was cooled and solvent MeOH removed under
reduced pressure. The solid product on cooling was filtered,
room temperature. The reaction mixture was stirred at
0 ꢁC for 12 h diluted with water and extracted with CHCl
TheCHCl extract was dried over Na SO and filtrate
concentrated in vacuo. The residue was crystallized from
CHCl –n-C 12 to givecrystalline 5a–f. For example,
trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol (5d)
yield 83%; mp 153–154 ꢁC; IR 3350 (OH) and 3300 (NH)/
3
3
.
3
2
4
3
6
H
2 3 6 12
washe d with HO, dried, and crystallized with CHCl –n-C H .
For example, cis-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol
hydrochloride( 4d) yield 90%; mp 278 ꢁC; IR (free base) 3335,
1
1
cm; H NMR d 2.02 (br h, 3H, OH, NH
O), 2.75 (m, 2H, C –H), 3.20 (br h, 1H, C
J ¼ 7:05 Hz, C –H), 4.47 (d, 1H, J4a;5a ¼ 8:0 Hz, C
.8–7.4 (m, 3H, Ar–H), 7.65 (m, 1H, Ar–H). Anal. Calcd
ꢀHCl (215.5): C, 67.03; H, 7.27; N, 7.82.
Found: C, 66.70; H, 7.34; N, 7.63.
2
exchangeable by
–H), 4.02 (t,
–H),
3275, 1000, 960, 950, and 660/cm; H NMR: d 2.08 (br h, 3H,
D
2
3
4
OH, NH
h, 1H, C
2
exchangeable by D
–H), 4.02 (t, J ¼ 7:05 Hz, C
–H), 6.8–7.5 (m, 4H, Ar–H). Anal. Calcd for
ꢀHCl (215.5): C, 67.03; H, 7.27; N, 7.82. Found: C,
66.70; H, 7.60; N, 7.54.
2
O), 2.78 (m, 2H, C
3
–H), 3.25 (br
2
5
4
2
–H), 4.82 (d, 1H,
6
J
C
4a;5e ¼ 1:5 Hz, C
5
for C10
H13NO
2
10
H
13NO
2