Synthesis and biological evaluation of novel tetracyclic benzothiazepines

Article abstract of DOI:10.1080/10426500902922917

6-Arylidene-2,3-dimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-one 2a-l were obtained by the condensation of 2,3-dimethyl/3-methyl benzocyclohepten-5- one 1 with appropriate aromatic aldehydes, and upon condensation with 2-aminothiophenol in ethyl alcohol yielded 1,5-benzothiazepine derivatives 3a-l, respectively. Compounds 3d and 3h were found to possess antimicrobial activity when tested against B. Subtilis. Compounds 3i and 3j were found to possess moderate anti-inflammatory activity. Compound 3b was found to possess comparable antifungal activity when compared to clotrimazole against Trichomonas species. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426500902922917

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Synthesis and Biological Evaluation of
Novel Tetracyclic Benzothiazepines
T. Apparao a , V. Peesapati a , G. Rupavani b & S. Ramakrishna c
a Industrial Chemistry Laboratory, Centre for Environment, Institute
of Science Technology , JNT University , Hyderabad, India
b Postgraduate College of Sciences , Palamur University , Mehaboob
Nagar, A.P., India
c Pharmacology Division , Indian Institute of Chemical Technology ,
Hyderabad, India
Published online: 23 Mar 2010.
To cite this article: T. Apparao , V. Peesapati , G. Rupavani & S. Ramakrishna (2010) Synthesis and
Biological Evaluation of Novel Tetracyclic Benzothiazepines, Phosphorus, Sulfur, and Silicon and the
Related Elements, 185:4, 697-704, DOI: 10.1080/10426500902922917
To link to this article: http://dx.doi.org/10.1080/10426500902922917
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Phosphorus, Sulfur, and Silicon, 185:697–704, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902922917
SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL
TETRACYCLIC BENZOTHIAZEPINES
T. Apparao,1 V. Peesapati,1 G. Rupavani,2 and S. Ramakrishna3
1Industrial Chemistry Laboratory, Centre for Environment, Institute of Science
Technology, JNT University, Hyderabad, India
2Postgraduate College of Sciences, Palamur University, Mehaboob Nagar,
A.P. India
3Pharmacology Division, Indian Institute of Chemical Technology,
Hyderabad, India
6-Arylidene-2,3-dimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-one 2a–l were obtained by
the condensation of 2,3-dimethyl/3-methyl benzocyclohepten-5-one 1 with appropriate aro-
matic aldehydes, and upon condensation with 2-aminothiophenol in ethyl alcohol yielded
1,5-benzothiazepine derivatives 3a–l, respectively. Compounds 3d and 3h were found to
possess antimicrobial activity when tested against B. Subtilis. Compounds 3i and 3j were
found to possess moderate anti-inflammatory activity. Compound 3b was found to possess
comparable antifungal activity when compared to clotrimazole against Trichomonas species.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Antibacterial, anti-inflammatory, and antifungal activities; aromatic aldehydes;
benzocyclohepten-5-one; 1,5-benzothiazepines
INTRODUCTION
The synthesis of benzothiazepines constitutes an important area of research with
a large number of 1,5-benzothiazepines1 exhibiting a variety of pharmacological activi-
ties. However, their derivatives belong to the most frequently studied moieties. The 1,5-
benzothiazepine derivatives are of particular interest for lead discovery because they have
been found to be active against different families of targets.2 The 1,5-benzothiazepine scaf-
fold has been used as cardiovascular modulator3 such as vasodilator4,5 and antiarrythmic,6
protease inhibitors,7 elastase8/ACE inhibitors,9 antagonists of several G-protein coupled
receptors such as cholecystokinin (CCK) receptor,10 and as interleukin-1b converting en-
zyme inhibitors7/the angiotensin II receptor (ACE) inhibitors.11 Recently, anticancer ac-
tivity,12,13 hemodynamic effects,14 antihypertensive activity,15,16 antiulcer activity,17,18 and
spasmolytic activities19–23 have also been reported. The first molecule used clinically was
diltiazem, followed by clentiazem, for their cardiovascular action.4,24,25 Some of the 1,5-
benzothiazepine derivatives, which includes thiazesim and quetiapine fumarate,26,27 have
Received 9 January 2009; accepted 24 March 2009.
Address correspondence to Venkateshwaralu Peesapati, Industrial Chemistry Laboratory, Centre for Environ-
ment, Institute of Science Technology, JNT University, Hyderabad–500085, India. E-mail: vpeesapati@yahoo.com
697

698
T. APPARAO ET AL.
also been used clinically for CNS disorders, Prompted by these observations and in con-
tinuation of our interest in the synthesis of biologically active fused heterocyclics,28–31 we
report in this article the synthesis, structure determination, and primary biological screening
of new benzothiazepines 3a–l. This method is a most satisfactory simple, one-pot operation
and provides consistently with moderate yields.
RESULTS AND DISCUSSION
6-Arylidene-2,3-dimethyl/3-methyl-6,7,8,9-tetrahydro-benzocyclohepten-5-one 2a
is a useful intermediate for the formation of into new heterocycles. 6-Arylidene-2,3-
dimethyl/3-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ones 2a were obtained
by the condensation of 2,3-dimethylbenzocyclohepten-5-one32 1a with appropriate
O
6a
8
O
R3
4
R1
R2
3
2
R1
R2
alc KOH
5
6
7
+
R3-CHO
1
9
1a,b
2a-l
2-Aminothiophenol
HCl gas
11
12
10
13
14
9
8
S
N
1
7a
R3
R1
2
NH2 H2N
7
+
R2
3
6
S
S
4
5
3a-l
4
1a) R1 & R2 = CH3
1b) R1= CH3, R2 = H
2a&3a) R1 & R2 = CH3, R3
=
Br
Br
2g&3g) R1 & R2 = CH3, R3
=
OCH3
OCH3
2b&3b) R1 = CH3, R2 = H, R3
=
2h&3h) R1 = CH3, R2 = H, R3
=
2c&3c) R1 & R2 = CH3, R3
=
2i&3i) R1& R2 = CH3, R3
=
S
S
2d&3d) R1 = CH3, R2 = H, R3
=
2j&3j) R1 = CH3, R2 = H, R3
=
=
=
2e&3e) R1 & R2 =CH3, R3
=
CH3 2k&3k) R1 & R2 =CH3, , R3
O
O
CH3
2f&3f) R1 = CH3, R2 = H, R3
=
2l&3l) R1 = CH3, R2 = H, R3
Scheme 1 Synthesis of 1,5-benzothiazepine derivatives.

NOVEL TETRACYCLIC BENZOTHIAZEPINES
699
aldehydes. In the enone 2a, the olefinic proton CH Ar appeared at δ 7.85–7.95 in the
1H NMR spectra. The 6-aryl methylene derivatives 2a–l reacted with 2-aminothiophenol
in dry ethanol and dry HCl gas was passed with the reaction mixture until it was saturated.
The usual workup gave 2,3-dimethyl-8-phenyl-6,7,7a,8-tetrahydro-5H-9-thia-14-aza-
dibenzo[a,i]heptalenes 3a–l along with a small amount of a dimer 4 as a side product
(Scheme 1). One can control or minimize the formation of disulfide (dimer) 4 by saturating
the reaction mixture with HCl gas before adding the 2-aminothiophenol. The mass spectra
1
and H NMR spectral data gave strong substantiation for the structure of 3a. The mass
spectrum of 3a (taken as a representative example) had the molecular ion peaks at m/z 463
(4%), 420 (22%), 418 (20%), 292 (11%), 266 (38%), 253 (100%), 251 (22%), 128 (12%),
1
115 (18%), 91 (13%), consistent with the molecular formula. The H NMR spectrum of
3a showed the presence of a doublet and a multiplet at δ 4.30–4.34 (J = 7.25 Hz) and
δ 3.00–3.15, respectively, integrating for one proton each, assigned to C8 H proton and
C7a H proton, respectively. Further, the spectrum had signals for 3-methylene groups
between 1.45 and 2.95. The aromatic protons appeared as a multiplet at 6.90–7.60. The
13C NMR spectrum is also in agreement with proposed structure 3a. The IR spectrum also
showed the disappearance of the carbonyl absorption band and the presence of C N
group in the region 1618 cm−1, indicating the cyclization had taken place (Tables I and II).
Table I IR (cm−1), 1H NMR (δ ppm), and mass of the compounds 2a–l
C
C
MS(EI):
m/z (M+)
Compd. stretch
1H NMR (CDCl3)
2a
2b
2c
2d
2e
2f
1601
1595
1616
1601
1595
1593
1590
1588
1610
1590
1580
1593
δ 1.95–2.10 (2H, m, 8-CH2), 2.38 (6H, s, 2-CH3). 2.70 (2H, t, 7-CH2). 2.85
(2H, t, 9-CH2).7.00–7.75 (6H, m), 7.85–7.95 (1H, s, C CH).
δ 1.80–2.00 (2H, m, 8-CH2), 2.40 (3H, s, CH3). 2.30 (2H, t, 7-CH2). 2.80
(2H, t, 9-CH2).7.00–7.70 (7H, m), 7.75 (1H, s, C CH).
δ 1.90–2.00 (2H, m, 8-CH2), 2.30 (6H, s, 2CH3). 2.20 (2H, t, 7-CH2). 2.80
(2H, t, 9-CH2).7.00–7.65 (7H, m), 7.70 (1H, s, C CH).
δ 1.80–2.00 (2H, m, 8-CH2), 2.35 (3H, s, 2CH3). 2.25 (2H, t, 7-CH2). 2.60
(2H, t, 9-CH2).7.00–7.70 (8H, m), 7.75 (1H, s, C CH).
δ 1.90–2.00 (2H, m, 8-CH2), 2.40 (9H, s, 3CH3). 2.40 (2H, t, 7-CH2). 2.50
(2H, t, 9-CH2).6.95–7.60 (8H, m, aromatic), 7.65 (1H, s, C CH).
δ 1.78–2.00 (2H, m, 8-CH2), 2.30 (6H, s, 2CH3). 2.20 (2H, t, 7-CH2). 2.70
(2H, t, 9-CH2), 6.90–7.50 (8H, m), 7.70 (1H, s, C CH).
δ 1.75–2. 00 (2H, m, 8-CH2), 2.40 (6H, s, 2CH3). 3.5 (H, s, OCH3) 2.70 (2H,
t, 7-CH2). 2.85 (2H, t, 9-CH2).7.00–7.75 (8H, m,), 7.80 (1H, s, C CH).
δ 1.70–2.00 (2H, m, 8-CH2), 2.40 (3H, s, CH3). 2.24 (2H, t, 7-CH2). 2.60
(2H, t, 9-CH2). 3.6 (H, s, OCH3) 6.80–7.40 (7H, m,), 7.70 (1H, s, C CH).
δ 1.65–2.00 (2H, m, 8-CH2), 2.30 (6H, s, 2CH3). 2.40 (2H, t, 7-CH2). 2.60
(2H, t, 9-CH2). 6.60–7.30 (5H, m,), 7.60 (1H, s, C CH).
δ 1.70–2.00 (2H, m, 8-CH2), 2.40 (3H, s, CH3), 2.40 (2H, t, 7-CH2), 2.60
(2H, t, 9-CH2), 6.65–7.35 (6H, m), 7.60 (1H, s, C CH).
δ 1.80–2.00 (2H, m, 8-CH2), 2.30 (6H, s, 2CH3). 2.40 (2H, t, 7-CH2). 2.50
(2H, t, 9-CH2).6.70–7.60 (5H, m), 7.70 (1H, s, C CH).
355
342
276
262
276
262
290
276
282
268
266
252
2g
2h
2i
2j
2k
2l
δ 1.80–2.20 (2H, m, 8-CH2), 2.30 (3H, s, CH3). 2.50 (2H, t, 7-CH2), 2.70
(2H, t, 9-CH2), 6.80–7.50 (6H, m), 7.70 (1H, s, C CH).
13C NMR of compound 2a
19.2, 23.7 (C-8), 28.3 (C-7), 32.4 (C-9), 124.2–136.8 (Aromatic protons)
133.4 (C-6) 135.2 C-6a), 194.5 (C O)
2a

700
T. APPARAO ET AL.
Table II IR (cm−1), 1H NMR (δ ppm), and mass of the compounds
MS (EI):
m/z (M+)
Compd.
C
N
1HNMR (CDCl3)
3a
1618
1621
1660
1690
1695
1688
1680
1695
1688
1682
1670
1685
3400
δ 1.45–1.60 (2H, m, 6-CH2), 2.15 & 2.30 (6H, 2s, CH3), 2.70–2.80 (2H, m,
7-CH2), 2.85–2.95 (2H, t, 5-CH2), 3.00–3.15 (1H, m, 7a-CH), 4.30 (1H,
d, 8-CH, J = 7.25 Hz), 6.90–7.60 (10H, m).
463
447
369
383
397
383
413
399
389
375
373
359
248
3b
3c
3d
3e
3f
δ 1.60–1.80 (1H, m, 6-CH2), 2.40 (3H, s, CH3), 2.65–2.75 (2H, t, 7-CH2),
2.80–2.95 (2H, t, 5-CH2), 3.05–3.12 (1H, m, 7a-CH), 4.30 (1H, d, 8-CH,
J = 7.25 Hz), 6.90–7.60 (11H, m).
δ 1.45–1.60 (2H, m, 6-CH2), 2.45 (6H, 2s, 2CH3), 2.70–2.80 (2H, m,
7-CH2), 2.85–2.95 (2H, t, 5-CH2), 3.10–3.20 (1H, m, 7a-CH), 4.30 (1H,
d, 8-CH, J = 7.25 Hz), 7.00–7.85 (11H, m).
δ 1.50–1.80 (2H, m, 6-CH2), 2.45 (3H, s-CH3), 2.62–2.85 (2H, m, 7-CH2),
2.90–3.00 (2H, t, 5-CH2), 3.00–3.15 (1H, m, 7a-CH), 4.40 (1H, d, 8-CH,
J = 7.30 Hz), 6.95–7.60 (12H, m):
δ 1.56–1.70 (2H, m, 6-CH2), 2.26–2.30 (9H, 3s, 3x, CH3), 2.72–2.74 (2H,
m, 7-CH2), 2.78–2.88 (2H, t, 5-CH2), 3.12–3.30 (1H, m, 7a-CH),
4.31–4.34 (1H, d, 8-CH, J = 7.28, Hz), 6.70–7.53 (10H, m).
δ 1.50–1.75 (2H, m, 6-CH2), 2.20–2.45 (6H, 2s, 2x-CH3), 2.65–2.75 (2H, m,
7-CH2), 2.80–2.95 (2H, t, 5-CH2), 3.02–3.15 (1H, m, 7a-CH), 4.35 (1H,
d, 8-CH, J = 7.26 Hz), 6.90–7.75 (11H, m).
3g
3h
3i
δ 1.60–1.80 (2H, m, 6-CH2), 2.29 (6H, 2s, 2-CH3), 2.88–2.95 (2H, m,
5-CH2), 3.10–3.20 (1H, m, 7a-CH), 3.80 (3H, s, -OCH3), 4.40 (1H, d,
8-CH, J = 7.30 Hz); 6.90–7.70 (10H, m).
δ 1.70–1.90 (2H, m, 6-CH2), 2.40 (3H, s, -CH3), 2.65–2.75 (2H, m, 7-CH2),
2.80–2.95 (2H, t, 5-CH2), 3.05–3.20 (1H, m, 7a-CH), 3.80(3H, s,
-OCH3), 4.55 (1H, d, 8-CH J = 7.28 Hz), 6.90–7.70 (11H, m).
δ 1.75–1.90 (2H, m, 6-CH2), 2.30 (6H, s, 2-CH3), 2.65–2.75 (2H, t, 7-CH2),
2.80–2.95 (2H, t, 5-CH2), 3.15–3.25 (1H, m, 7a-CH), 4.45 (1H, d, 8-CH,
J = 7.32 Hz); 6.95–7.50 (9H, m).
3j
δ 1.65–1.90 (2H, m, 6-CH2), 2.35 (3H, s, -CH3), 2.65–2.80 (2H, m, 7-CH2),
2.80–2.90 (2H, t, 5-CH2), 3.00–3.12 (1H, m, 7a-CH), 4.60 (1H, d, 8CH,
J = 7.32 Hz); 6.95–7.50 (10H, m).
3k
3l
δ 1.30–1.75 (2H, m, 6-CH2), 2.32 (3H, s, -CH3), 2.60–2.70 (2H, m, 7-CH2),
2.75–2.85 (2H, t, 5-CH2), 3.00–3.15 (1H, m, 7a-CH), 4.35 (1H, d, 8CH,
J = 7.30 Hz), 6.90–7.50 (9H, m).
1.50–1.75 (2H, m, 6-CH2), 2.35 (3H, s, -CH3), 2.60–2.80 (2H, m, 7-CH2),
2.85–2.95 (2H, t, 5-CH2), 3.10–3.20 (1H, m, 7a-CH), 4.70 (1H, d, 8-CH,
J = 7.32 Hz), 6.90–7.50 (10H, m).
4
δ 4.70 (4H, s, 6–2x-NH2), 6.40–6.70 (4H, m), 7.00–7.20 (4H, m).
C13 NMR of compound 3a
δ 19.6, 26.2 (C-6), 29.2 (C-7), 33.4 (C-5), 41.6 (C-7a), 53.6 (C-8),
118.2–136.5 (Aromatic protons), 160.2 (C N).
3a
Under analogous conditions, the reaction of 6-arylidene-2,3-dimethyl/3-methyl-
6,7,8,9-tetrahydrobenzocyclohepten-5-one 2b–l with 2-aminothiophenol in ethyl alcohol
afforded 1,5-benzothiazepine derivatives 3b-l, respectively.
CONCLUSION
In summary, this work demonstrates an efficient and convenient method for synthesis
of 1,5-benzothiazepines and their biological activities evaluated. The results showed that

NOVEL TETRACYCLIC BENZOTHIAZEPINES
701
most of the compounds exhibited moderate to good activity against Trichomonas viginalis
and also displayed the anti-inflammatory activity and antibacterial activity.
BIOLOGICAL EVALUATION
The new compounds were characterized from their spectral data and elemental analy-
sis and were screened for their antibacterial activity, anti-inflammatory activity, and antifun-
gal activity (see the Supplemental Materials available online, Figures S1 and S2, Table S1).
Antibacterial Activity
The minimum inhibitory concentration was done by the broth dilution method ac-
cording to the method of Villanova 1982.33
Anti-Inflammatory Activity
The anti-inflammatory activity of the test compounds was evaluated in Wistar rats
employing the method of Winter et al.34
Antifungal Activity
The antifungal activity was tested against Trichmonas vaginalis.
EXPERIMENTAL
Melting points were determined using Gallenkamp apparatus and are uncorrected.
1
IR spectra were recorded on a FT-IR 1605 Perkin-Elmer. H NMR were taken in CDCl3
on a Varian FT-80A spectrometer with TMS as an internal standard and mass spectra on a
VG-Micro mass 7070H mass spectrometer. TLC was run on silica gel G coated plates and
iodine vapor as visualizing agent.
General Experimental Procedure (2a–l): Synthesis of
6-Arylidene-2,3-dimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-one (2a)
A
mixture of 2,3-dimethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one 1a
(0.35 g, 2 mmol) and bromobenzaldelyde (0.20 g, 2 mmol) in ethanolic potassium
hydroxide was stirred at room temperature for 30 min. During this time, the product was
formed. The reaction mixture was neutralized with aqueous acetic acid 5–6 mL. The solid
thus obtained was filtered and washed thoroughly with water and dried. Recrystallization
from methanol gave the product 2a (0.5 g, 92%) as colorless crystals (Table III).
Analogues 2b–l were similarly obtained using the same procedure. The structures of
all the compounds were established on the basis of spectral data and elemental analysis.
General Experimental Procedure (3a–l): Synthesis of 4-(2,3-Dimethyl-
6,7,7a,8-tetrahydro-5H-benzo[b]benzo[3,4]cyclo-hepta[e][1,4]thiazepin-
8-yl]-benzene (3a)
6-Arylidene-2,3-dimethyl-6,7,8,9-tetrahydrobenzocyclohepten-5-one 2a (0.52 g,
2 mmol) was dissolved in dry ethanol (8 mL) and was saturated with HCl gas followed

702

NOVEL TETRACYCLIC BENZOTHIAZEPINES
703
by adding 2-aminothiophenol (0.3 mL, 3 mmol) and then refluxed for a period of 3 h.
Removal of the excess of solvent under reduced pressure gave a crude solid, which was
subjected to column chromatography gave two major bands. The first band was obtained
in 65% yield from ethyl acetate to give light yellow crystals, and the second band was
identified as a dimer (4) (Table III).
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