Synthesis and bronchodilatory activity of some nitrogen bridgehead compounds

Article abstract of DOI:10.1016/S0223-5234(02)01345-4

A series of tricyclic nitrogen bridgehead compounds 7-22 have been synthesised and evaluated for their in vitro bronchodilatory activity using isolated guinea pig tracheal chain, precontracted with acetylcholine. The relaxant effect of 2,3,4,5-tetrahydroazepino[2,1-b]-8,9-dimethoxyquinazolin-11(1H)-one (7) (DPJ-386) was greater than that of theophylline, aminophylline and quinazoline derivative 3, which lacks methoxy groups at positions 8 and 9. Various nitrogen containing functionalities such as benzylamino, acetamido, benzamido and phthalimido were also introduced at 9 position of 3. This resulted in loss of relaxation activity in precontracted guinea pig tracheal chain. These results show that the better relaxation property possessed by compound 7 hydrochloride is due to methoxy groups at 8 and 9 positions.

Full text of DOI:10.1016/S0223-5234(02)01345-4

Eur. J. Med. Chem. 37 (2002) 419–425
www.elsevier.com/locate/ejmech
Short communication
Synthesis and bronchodilatory activity of some nitrogen
bridgehead compounds
Dharam Paul Jindal *, Ravinder Singh Bhatti, Seema Ahlawat, Ranju Gupta
Uni6ersity Institute of Pharmaceutical Sciences ( formerly Department of Pharmaceutical Sciences), Panjab Uni6ersity, Chandigarh 160 014, India
Received 18 May 2001; received in revised form 29 January 2002; accepted 29 January 2002
Abstract
A series of tricyclic nitrogen bridgehead compounds 7–22 have been synthesised and evaluated for their in vitro bronchodila-
tory activity using isolated guinea pig tracheal chain, precontracted with acetylcholine. The relaxant effect of 2,3,4,5-tetrahy-
droazepino[2,1-b]-8,9-dimethoxyquinazolin-11(1H)-one (7) (DPJ-386) was greater than that of theophylline, aminophylline and
quinazoline derivative 3, which lacks methoxy groups at positions 8 and 9. Various nitrogen containing functionalities such as
benzylamino, acetamido, benzamido and phthalimido were also introduced at 9 position of 3. This resulted in loss of relaxation
activity in precontracted guinea pig tracheal chain. These results show that the better relaxation property possessed by compound
´
7 hydrochloride is due to methoxy groups at 8 and 9 positions. © 2002 Published by Editions scientifiques et me´dicales Elsevier
SAS.
Keywords: Quinazoline; Bronchodilators; Vasaka alkaloids; Nitrogen bridgehead compounds; Guinea pig tracheal chains; Theophylline
1. Introduction
medical therapies and also involvement of asthmatic
patients [12]. Our aim with this study was to search a
new chemical entity possessing better bronchodilatory
effects. The findings are reported in this
communication.
There are various factors such as exercise, allergen
exposure, viral infections, irritants, environmental
chemicals, etc. which are responsible for inducing
symptoms of asthma. It is a complex and chronic
disease characterised by reversible airway obstruction,
airways inflammation and bronchial hyperresponsive-
ness. The first and the second reports of the national
asthma education and prevention programme expert
panel in US [1,2] and similar reports from other coun-
tries [3,4] have been beneficial in the management of
asthma. Many classes of drugs namely bronchodilators
such as b2-adrenoceptor agonists [5,6], methylxanthines
[7,8], anticholinergics [6], antihistaminics [9] and anti-
inflammatory agents such as glucocorticoids [10],
leukotriene receptor antagonists [6], adenosine antago-
nists [11], 5-lipoxygenase inhibitors [10] cromolyn
sodium [12], phosphodiesetrase inhibitors [13,14] have
resulted in substantial improvement in survival and
quality of life of asthmatic patients. The treatment of
asthma is complex and necessitates aggressive newer
Vasicine (1) and its oxidised product vasicinone (2)
[15–17] (Fig. 1) are the alkaloids obtained from the
leaves of plant Adhatoda 6asica Nees family
Acanthaceae. Both possess in vitro and in vivo bron-
chodilatory activity [16,18]. Vasicinone (2) has been
reported to possess antiasthmatic activity comparable
to sodium chromoglycate. Several modifications on va-
sicine (1) and vasicinone (2) have been made to get
better uterotonic or bronchodilatory effects [16]. This
resulted in the development of a compound 2,3,4,5-te-
trahydroazepino[2,1-b]quinazolin-11(1H)-one (3), RLX
(Fig. 1) which has been reported to be six to 10 times
more potent than aminophylline [19,20]. On the basis of
these observations, SAR studies have also been re-
ported [21].
Hermecz et al. [21] have reported the synthesis and
bronchodilator activity of bis- and tricyclic nitrogen
bridgehead derivatives with a pyrimidine-4(3H)-one
ring against serotonin-, histamine- and acetylcholine-in-
duced spasms in guinea pig Konzett–Ro¨ssler test.
* Correspondence and reprints.
E-mail address: dharampjindal@yahoo.co.in (D.P. Jindal).
´
0223-5234/02/$ - see front matter © 2002 Published by Editions scientifiques et me´dicales Elsevier SAS.
PII: S0223-5234(02)01345-4

420
D.P. Jindal et al. / European Journal of Medicinal Chemistry 37 (2002) 419–425
Among the various synthesised compounds, 2,3,4,5-te-
trahydroazepino[2,1-b]-7,8,9,10-tetrahydroquinazolin-
11(1H)-one (4) and cyclopenta[d]tetrahydroazepino[1,2-
a]pyrimidine (5) (Fig. 1) were found to be 28 and 10
times more potent than theophylline anisate in carba-
chol-induced contractions of isolated human bronchus.
Papaverine (6) (Fig. 1) also has a direct relaxant
effect on smooth muscles (a non-selective PDE in-
hibitor). It possesses a dimethoxy group in heteroaro-
matic nucleus [22].
Taking into account all these considerations, we in-
troduced dimethoxy functions in tricyclic nitrogen
bridgehead compound through the synthesis of 2,3,4,5-
tetrahydroazepino[2,1 - b] - 8,9 - dimethoxyquinazolin-
11(1H)-one (7) (Fig. 2). In addition, a number of
nitrogenous functions were introduced at position 9 of
compound 3. The synthesised compounds were studied
for their bronchodilatory activity using isolated guinea
pig tracheal chain.
2. Chemistry
Compounds have been synthesised according to Figs.
2–5. The target compound 7 was prepared by conden-
sing 2-amino-4,5-dimethoxy benzoic acid with 1-aza-2-
methoxy-1-cycloheptene(O-methylcaprolactim), which,
in turn, was prepared by treating o-caprolactam with
dimethyl sulphate at 80 °C (Fig. 2).
As a part of the programme, number of functionali-
ties were introduced at position 9 of compound 3. For
this purpose structure 3 was subjected to nitration using
a concentrated nitric acid–sulphuric acid mixture at
80 °C to obtain 9-nitro derivative 8 [19], which, after
reduction with tin–concentrated hydrochloric acid af-
forded the 9-amino congener 9 [19]. Various functio-
nalities were introduced by treating
9 with tri-
methoxybenzaldehyde, veratraldehyde, p-anisaldehyde,
p-nitrobenzaldehyde, p-cyanobenzaldehyde, pyridine-2-
carboxaldehyde, pyridine-4-carboxaldehyde, p-iso-
propylbenzaldehyde, indole-2-carboxaldehyde at room
temperature. Subsequent reduction with sodium boro-
hydride under chilled conditions gave amino derivatives
10–18 (Fig. 3); among these products 9-(4%-isopropyl-
benzylamino) derivative 15 was characterised as a hy-
drochloride salt.
Amide derivatives 19 and 20 were prepared by trea-
ting 9-amino congener 9 with isobutyryl chloride and
trimethoxybenzoylchloride at room temperature (Fig.
4).
Fig. 1. Structures of vasicine (1), vasicinone (2), RLX (3), tricyclic
nitrogen bridgehead compounds (4, 5) and papaverine (6).
It was thought worthwhile to introduce imide func-
tionality to observe its effect on biological activity.
Fusion of phthalic anhydride and dimethoxyphathlic
anhydride with 9-amino derivative 9 at 160–180 °C for
2 h resulted in the formation of 9-phthalimido deriva-
tives 21 and 22 (Fig. 5).
Structures of the synthesised compounds were esta-
blished with the help of the spectral and elemental
analyses.
3. Pharmacology
Hydrochlorides of the compounds 7–22 were eval-
uated for their in vitro bronchodilator activity using
Fig. 2. Synthesis of 8,9-dimethoxy derivative (7). Reagents and condi-
tions: (a) benzene/reflux.

D.P. Jindal et al. / European Journal of Medicinal Chemistry 37 (2002) 419–425
421
Fig. 3. Synthetic procedure to 8–18. Reagents and conditions: (a) concentrated HNO3–H2SO4; (b) Sn–concentrated HCl; (c) (i) RꢀCHO–MeOH;
and (ii) NaBH4/ice cold.
isolated guinea pig tracheal chain precontracted with
acetylcholine (1 mg ml−1). Aminophylline and
theophylline were used as the standard drugs.
5. Experimental
5.1. Chemistry
All m.p.s were obtained on a Veego melting point
apparatus and were uncorrected. IR spectra were
recorded as KBr pellets on Perkin–Elmer 882 spec-
trophotometer model. Proton (1H) nuclear magnetic
resonance spectroscopy was performed using Varian
EM-360L, 60 MHz and Brucker AC-300F, 300 MHz
spectrometers using Me4Si as an internal standard.
Plates for TLC were prepared using silica gel G
4. Results and discussion
The results of bronchodilatory activity for com-
pounds 7–22 are reported in Tables 1 and 2.
The compound 7, having structural resemblance to
papaverine, has been found more potent than 3,
theophylline and aminophylline (Table 1). The intro-
duction of dimethoxy functionality at positions 8 and 9
of tricyclic nitrogen bridgehead compound looks re-
sponsible for increased potency.
A dose dependent relaxation of acetylcholine induced
contractions in guinea pig tracheal chain were also
observed with dimethoxy derivative 7 and it showed
much more potential towards bronchodilation than 3
(Table 2).
9-Substituted derivatives did not show significant
bronchodilatory effects. These results suggest that
dimethoxy group at 8- and 9-positions of heteroaro-
matic nucleus is significant for activity whereas substi-
tution at 9 position by amino functionalities results in
loss of bronchodilatory activity (Table 1).
Fig. 4. Synthetic procedure to 19 and 20. Reagents and conditions:
(a) CH2Cl2–RCOCl.

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D.P. Jindal et al. / European Journal of Medicinal Chemistry 37 (2002) 419–425
5.1.1. 2,3,4,5-Tetrahydroazepino[2,1-b]-8,9-di-
methoxyquinazolin-11(1H)-one (7)
Dimethyl sulfate (0.3 mL) was added to 2-oxo-hexa-
methyleneamine (o-caprolactam) (1.0 g, 8.8 mmol) in a
two necked flask to get clear solution at room tempera-
ture (r.t.) and then heated at 80 °C. Additional quan-
tity of dimethyl sulfate (0.6 mL) was added dropwise
while maintaining the temperature at 80 °C. The mix-
ture was then stirred for 3 h at 80–90 °C, cooled to r.t.,
diluted with thiophene-free-C6H6 and washed with 40%
NaOH (10 mL) to remove the excess of dimethyl
sulfate. The NaOH solution was then extracted with
C6H6. The combined C6H6 layer was dried. 2-Amino-
4,5-dimethoxybenzoic acid (1.0 g, 5.1 mmol) was added
in small portions to the solution of 1-aza-2-methoxy-1-
caprolactim(O-methylcaprolactim) at r.t. with constant
stirring. The reaction mixture was refluxed for 5 h and
solvent removed. The residue so obtained was picked
up in CHCl3 and washed with 5% NaOH (2×20 mL)
and then with distilled water and dried. Chloroform
was removed under reduced pressure and residue ob-
tained was crystallised from MeOH to give 7 (0.7 g,
28.86%): m.p. 186–190 °C. IR (KBr, cm−1): wmax 1701,
Fig. 5. Synthetic procedure to 21 and 22. Reagents and conditions:
(a) fusion/160–180 °C/phthalic anhydride–dimethoxy phthalic anhy-
dride.
Table 1
In vitro bronchodilatory activity of compounds 7–22
Compound
Concentration
In vitro guinea pig tracheal
% relaxation
(mg ml−1
)
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
20
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
82.14
0.00
0.00
2.13
10.19
5.16
4.28
0.00
3.21
1.10
0.00
0.00
3.20
6.50
0.00
2.24
67.14
40.00
50.00
1
1645, 1377, 1328, 1253, 1026. H-NMR (CDCl3): l 1.85
(m, 6H, 2,3, and 4-CH2), 3.05 (t, 2H, 5-CH2), 3.99 (s,
6H, 8 and 9-OCH3), 4.39 (t, 2H, 1-CH2), 7.01 (s, 1H,
7-CH), 7.57 (s, 1H, 10-CH) ppm; 13C-NMR (CDCl3): l
25.5 (C-3), 28.1 (C-4), 29.6 (C-2), 37.7 (C-1), 42.8 (C-5),
56.2 (ꢀOCH3), 56.3 (ꢀOCH3), 106.0 (C-7), 107.2 (C-10),
113.5 (C-10a), 143.7 (C-9), 148.8 (C-8), 154.9 (C-6a),
158.5 (C-5a), 161.3 (C-11) ppm. MS: m/z 274 [M+].
Anal. Calc. for C15H18N2O3: C, 65.67; H, 6.61; N,
10.21. Found: C, 66.08; H, 6.34; N, 10.60%.
5.1.2. General procedure for the synthesis of
benzylamines 10–18
3
To a solution of 9-amino-2,3,4,5-tetrahydroazepino-
[2,1-b]quinazolin-1(1H)-one (9) [19] (0.4 g, 1.75 mmol)
in MeOH (8.0 mL) was added a solution of aldehyde
(4.0 mmol) in MeOH (8.0 mL) with constant stirring.
The reaction mixture was allowed to stand overnight at
r.t. Sodium borohydride (0.8 g, 21.1 mmol) was added
in small portions to the chilled and stirred reaction
mixture over a period of 2 h. The reaction mixture was
further stirred for 2 h. Crushed ice was added to the
reaction mixture and precipitate was filtered, washed
with water, dried and recrystallised to give the desired
amines 10–18.
Theophylline
Aminophylline
Table 2
Comparative % relaxation produced by (3) HCl and (7) HCl in
acetylcholine-induced bronchoconstriction
Concentration
% relaxation produced in mg ml−1
acetylchloine-induced bronchoconstriction
(mg ml−1
)
(3) HCl
(7) HCl
(DPJ-386)
3
–
20.00
10
20
30
21.74
58.33
67.14
43.40
82.14
not accessed
5.1.2.1.
9-(3%,4%,5%-Trimethoxybenzylamino)-2,3,4,5-
tetrahydroazepino[2,1-b]quinazolin-11(1H)-one
(10).
Yield: 36%, m.p. 170–172 °C. IR (KBr, cm−1): wmax
1
3367, 1662, 1226, 1035, 842, 789. H-NMR (CDCl3): l
1.82 (m, 6H, 2,3,4-CH2), 3.02 (t, 2H, 5-CH2), 3.83 (s,
9H, 3%,4%,5%-OCH3), 4.33 (m, 4H, 1-CH2, NHꢀCH2),
4.37 (b, 1H, ꢀNH), 6.59 (s, 2H, 2% and 5%-CH), 7.06 (dd,
according to Stahl (E. Merck) using EtOAc as solvent
and activated at 110 °C for 30 min.

D.P. Jindal et al. / European Journal of Medicinal Chemistry 37 (2002) 419–425
423
1H, 7-CH), 7.34 (d, 1H, 8-CH), 7.45 (d, 1H, 10-CH)
ppm. MS: m/z 409 [M+]. Anal. Calc. for C23H27N3O4:
C, 67.46; H, 6.29; N, 10.26. Found: C, 67.09; H, 6.29;
N, 10.60%.
3300, 3010, 2900, 1695, 1615, 1525, 1380, 1350. 1H-
NMR (CDCl3–DMSO-d6): l 1.22 (d, 6H, J=6.6 Hz,
ꢀCH(CH3)2), 1.86 (m, 6H, 2,3 and 4-CH2), 2.89 (sept,
1H, J=6 Hz, ꢀCH(CH3)2), 3.50 (m, 2H, 5-CH2), 4.35
(s, 2H, ꢀNHꢀCH2), 4.46 (m, 2H, 1-CH2), 7.17 (m, 3H,
2%-CH, 6%-CH and 7-CH, aromatic), 7.30 (m, 3H, 3%,5%-
and 8-CH, aromatic), 7.89 (d, 1H, J=9.0 Hz, 10-CH,
aromatic) ppm. Anal. Calc. for C23H28ClN3O: C, 69.41;
H, 7.09; N, 10.56. Found: C, 69.75; H, 6.79; N, 10.24%.
5.1.2.2. 9-(3%,4%-Dimethoxybenzylamino)-2,3,4,5-tetra-
hydroazepino[2,1-b]quinazolin-11(1H)-one (11). Yield:
67.43%, m.p. 206–210 °C. IR (KBr, cm−1): wmax 3380,
1
3010, 1658, 1620, 1580, 1260. H-NMR (CDCl3): l 1.82
(m, 6H, 2,3, and 4-CH2), 3.08 (m, 2H, 5-CH2), 3.87 (s,
6H, 3% and 4%-OCH3), 4.33 (m, 5H, 1-CH2, NHꢀCH2,
disappeared on deuterium exchange, ꢀNH), 6.83 (d,
1H, J=6.0 Hz, 7-CH, aromatic), 6.91 (m, 2H, 8-CH
and 6%-CH, aromatic), 7.04 (dd, 1H, J=3.0 and 9.0 Hz,
5%-CH, aromatic), 7.36 (d, 1H, J=3 Hz, 2%-CH, aro-
matic), 7.45 (d, 1H, J=9.0 Hz, 10-CH, aromatic) ppm.
Anal. Calc. for C22H25N3O3: C, 69.63; H, 6.64; N,
11.07. Found: C, 69.33; H, 6.36; N, 11.37%.
5.1.2.7. 9-(4-Picolylamino)-2,3,4,5-tetrahydroazepino-
[2,1-b]quinazolin-11(1H)-one (16). Yield: 71.51%, m.p.
144–148 °C. IR (KBr, cm−1): wmax 3240, 2930, 1650,
1
1585, 1350, 840. H-NMR (CDCl3): l 1.82 (s, 6H, 2,3,
and 4-CH2), 3.02 (m, 2H, 5-CH2), 4.36 (m, 2H, 1-CH2),
4.46 (s, 2H, NHꢀCH2), 4.58 (m, 1H, disappeared on
deuterium exchange, ꢀNH), 7.05 (dd, 1H, J=3.0 and
9.0 Hz, 7-CH, aromatic), 7.26–7.31 (m, 3H, pyridino
protons and 8-CH, aromatic), 7.46 (d, 1H, J=9.0 Hz,
10-CH, aromatic), 8.54 (d, 2H, J=5.8 Hz, pyridino
protons adjacent to nitrogen) ppm. Anal. Calc. for
C19H20N4O: C, 70.78; H, 6.25; N, 18.00. Found: C,
70.37; H, 6.50; N, 17.71%.
5.1.2.3. 9-(4%-Methoxybenzylamino)-2,3,4,5-tetrahydro-
azepino[2,1-b]quinazolin-11(1H)-one
(12).
Yield:
74.67%, m.p. 160–164 °C. IR (KBr, cm−1): wmax 3375,
1
3060, 2830, 1650, 1390, 1250, 1020. H-NMR (CDCl3):
l 1.80 (s, 6H, 2,3, and 4-CH2), 3.0 (s, 2H, 5-CH2), 3.76
(s, 3H, 4%-OCH3), 4.26 (m, 5H, 1-CH2, NHꢀCH2, disap-
peared on deuterium exchange, ꢀNH), 6.70–7.50 (m,
7H, aromatic protons) ppm. Anal. Calc. for
C21H23N3O2: C, 72.18; H, 6.68; N, 12.03. Found: C,
72.54; H, 6.73; N, 12.14%.
5.1.2.8. 9-(2-Picolylamino)-2,3,4,5-tetrahydroazepino-
[2,1-b]quinazolin-11(1H)-one (17). Yield: 74.90%, m.p.
90–94 °C. IR (KBr, cm−1): wmax 3300, 3090, 2850,
1
1650, 1630, 1590, 1500. H-NMR (CDCl3): l 1.82 (s,
6H, 2,3, and 4-CH2), 3.02 (m, 2H, 5-CH2), 4.38 (m, 2H,
1-CH2), 4.54 (d, 2H, J=3.6 Hz, NHꢀCH2), 5.26 (s, 1H,
disappeared on deuterium exchange, ꢀNH), 7.12–7.66
(m, 6H, aromatic and pyridino protons), 8.59 (d, 1H,
J=4.8 Hz, pyridino protons adjacent to nitrogen)
ppm. Anal. Calc. for C19H20N4O: C, 70.78; H, 6.25; N,
18.00. Found: C, 70.69; H, 6.09; N, 18.32%.
5.1.2.4. 9-(4%-Nitrobenzylamino)-2,3,4,5-tetrahydroaze-
pino[2,1-b]quinazolin-11(1H)-one (13). Yield: 68.84%,
m.p. 218–224 °C. IR (KBr, cm−1): wmax 3400, 3115,
3080, 2920, 2850, 1650, 1620, 1585, 1505, 1375, 1330,
1
840. H-NMR (CDCl3–DMSO-d6): l 1.80 (s, 6H, 2,3,
and 4-CH2), 3.00 (s, 2H, 5-CH2), 4.20–4.66 (m, 4H,
N-CH2, NHꢀCH2), 5.46 (br, disappeared on deuterium
exchange, ꢀNH), 7.00–7.70 (m, 5H, aromatic), 8.13 (d,
2H, J=9.0 Hz, aromatic) ppm. Anal. Calc. for
C20H20N4O3: C, 65.55; H, 5.50; N, 15.83. Found: C,
65.78; H, 5.55; N, 15.61%.
5.1.2.9. 9-(3-Indolylmethylamino)-2,3,4,5-tetrahydroaze-
pino[2,1-b]quinazolin-11(1H)-one (18). Yield: 70.52%,
m.p. 148–154 °C. IR (KBr, cm−1): wmax 3400, 3120,
1
3080, 1660, 1595, 1500. H-NMR (CDCl3): l 1.77 (s,
6H, 2,3, and 4-CH2), 2.98 (m, 2H, 5-CH2), 4.33 (m, 2H,
1-CH2), 4.48 (s, 2H, NHꢀCH2), 6.0 (br, 1H, NH,
disappeared on deuterium exchange), 6.97–7.64 (m,
8H, aromatic protons and indolic-CH), 10.69 (s, 1H,
disappeared on deuterium exchange, NH) ppm. Anal.
Calc. for C22H22N4O: C, 73.31; H, 6.15; N, 16.10.
Found: C, 73.03; H, 6.27; N, 16.38%.
5.1.2.5. 9-(4%-Cyanobenzylamino)-2,3,4,5-tetrahydroaze-
pino[2,1-b]quinazolin-11(1H)-one (14). Yield: 77.33%,
m.p. 188–194 °C. IR (KBr, cm−1): wmax 3220, 3060,
2910, 2200, 1640, 1590, 1510. 1H-NMR (CDCl3–
DMSO-d6): l 1.80 (s, 6H, 2,3, and 4-CH2), 3.00 (br,
2H, 5-CH2), 4.33 (m, 5H, 1-CH2, NHꢀCH2, disap-
peared on deuterium exchange, ꢀNH), 7.00–7.90 (m,
7H, aromatic) ppm. Anal. Calc. for C21H20N4O: C,
72.81; H, 5.82; N, 16.75. Found: C, 72.44; H, 5.51; N,
16.84%.
5.1.3. General procedure for the synthesis of amides 19
and 20
To a stirred solution of 9-amino-2,3,4,5-tetrahy-
droazepino[2,1-b]quinazolin-11(1H)-one (9) (0.4 g, 1.75
mmol) in CH2Cl2 (10 mL) was added respective acid
chlorides (5 mL) dropwise under anhydrous conditions.
The stirring was continued for 2 h at r.t. Solvent was
removed under vacuo and sticky residue so obtained
5.1.2.6. 9-(4%-Isopropylbenzylamino)-2,3,4,5-tetrahydro-
azepino[2,1-b]quinazolin-11(1H)-one (15) hydrochloride.
Yield: 77.57%, m.p. 212–218 °C. IR (KBr, cm−1): wmax

424
D.P. Jindal et al. / European Journal of Medicinal Chemistry 37 (2002) 419–425
was neutralised with Na2CO3 solution. The precipitate
obtained was filtered, washed, dried and crystallised to
afford the amides 19 and 20.
(CDCl3): l 2.05 (m, 6H, 2,3 and 4-CH2), 3.38 (m, 2H,
5-CH2), 4.08 (s, 6H, 5% and 6%-OCH3), 4.59 (m, 2H,
1-CH2), 7.54 (s, 2H, 4% and 7%-CH, phthalimido pro-
tons), 7.88 (d, 1H, J=8.7 Hz, 7-CH, aromatic), 8.13
(dd, 1H, J=2.2 and 8.7 Hz, 8-CH, aromatic), 8.50 (d,
1H, J=2.2 Hz, 10-CH, aromatic) ppm. Anal. Calc. for
C23H21N3O5: C, 65.85; H, 5.05; N, 10.02. Found: C,
65.66; H, 4.87; N, 10.30%.
5.1.3.1. 9-(Dimethylacetamido)-2,3,4,5-tetrahydroaze-
pino[2,1-b]quinazolin-11(1H)-one (19). Yield: 75.43%,
m.p. 190–194 °C. IR (KBr, cm−1): wmax 3325, 3100,
3060, 1698, 1650, 1530, 850. 1H-NMR (CDCl3–
DMSO-d6): l 1.24 (d, 6H, J=6.7 Hz, ꢀCH(CH3)2),
1.80 (m, 6H, 2,3, and 4-CH2), 2.61 [septet, 1H, J=6.7
Hz, ꢀCH(CH2)3], 3.06 (m, 2H, 5-CH2), 4.36 (m, 2H,
1-CH2), 7.53 (d, 1H, J=8.8 Hz, 7-CH, aromatic), 8.13
(d, 1H, J=2.4 Hz, 8-CH, aromatic); 8.38 (dd, 1H,
J=2.4 and 8.8 Hz, 10-CH, aromatic), 8.74 (br, 1H,
disappeared on deuterium exchange, ꢀNH) ppm. Anal.
Calc. for C17H21N3O2: C, 68.20; H, 7.07; N, 14.04.
Found: C, 68.08; H, 7.17; N, 14.24.
5.2. Pharmacology
Tracheal chain of the guinea pig was exposed by
giving a longitudinal incision in the neck then removed
from the body and transferred in the beaker containing
Kreb’s–Hanslet solution. Tracheal chain was prepared
according to the method of Akcasu [23]. A 2 g tension
was provided to the trachea by sticking plasticin on the
lever. The tissue was provided a rest for half an hour.
Dose dependent relaxant effect of the compound were
recorded on the kymograph tracings in the concentra-
tions of 1, 3, 10, 20 and 30 mg ml−1 on tracheal chain
precontracted with 1 mg ml−1 acetylcholine.
5.1.3.2. 9-(3%,4%,5%-Trimethoxybenzamido)-2,3,4,5-tetra-
hydroazepino[2,1-b]quinazolin-11(1H)-one (20). Yield:
65.70%, m.p. 148–152 °C. IR (KBr, cm−1): wmax 3350,
1
3100, 3060, 1680, 1650, 1585, 1500. H-NMR (CDCl3–
DMSO-d6): l 1.83 (m, 6H, 2,3 and 4-CH2), 3.06 (m,
2H, 5-CH2), 3.92 (s, 9H, 3%,4%, and 5%-OCH3), 4.32 (m,
2H, 1-CH2), 7.16 (s, 2H, 2% and 6%-CH, aromatic), 7.63
(d, 1H, J=8.7 Hz, 7-CH aromatic), 8.19 (d, 1H, J=2.2
Hz, 8-CH, aromatic), 8.43 (dd, 1H, J=2.2 and 8.7 Hz,
10-CH, aromatic), 8.58 (s, 1H, disappeared on deu-
terium exchange, ꢀNH) ppm. Anal. Calc. for
C23H25N3O5: C, 65.23; H, 5.95; N, 9.92. Found: C,
65.57; H, 5.87; N, 9.80%.
Acknowledgements
Authors are thankful to Regional Research Labora-
tory, Jammu Tawi, India for carrying out the biological
activity. This work was supported by University Grants
Commission, New Delhi, India and Haryana State
Council for Science and Technology, Chandigach,
India.
5.1.4. General procedure for the synthesis of
phthalimido deri6ati6es 21 and 22
9-Amino-2,3,4,5-tetrahydroazepino[2,1-b]quinazolin-
11(1H)-one (9) (0.5 g, 2.2 mmol) and phthalic anhy-
dride (3.3 mmol) were fused together at 160–180 °C
for 2 h. The fused mixture was refluxed in distilled
water for 1 h to remove the unreacted material and
filtered. The residue obtained was dried and crystallised
to afford 9-phthalimido derivatives 21 and 22.
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