Synthesis of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4- benzoxazine, β-adrenergic affinity, inotropic, chronotropic and coronary vasodilating activities

Article abstract of DOI:10.1016/S0223-5234(99)00109-9

A series of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4- benzoxazine were synthesized and evaluated for inotropic, chronotropic and coronary vasodilating activities in the canine heart, affinity to β₁- adrenergic receptor in turkey erythrocytes and affinity to the β₂- adrenergic receptor in the rat lung. Among these compounds, 4-acetyl-6-(3- tert-butylamino-2-hydroxy)propoxy-3,4-dihydro-2H-1,4-benzoxazine showed 2.1- fold more potent affinity to the β₁ receptor than propranolol and 7-(3- tert-butylamino-2-hydroxy)propoxy-N-butyryl-3,4-dihydro-2H-1,4-benzoxazine showed 2.5-fold more potent affinity to the β₂ receptor and furthermore 4 386-fold more potent selectivity to the β₂ receptor than propranolol. In addition, 4-acetyl-6-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4- dihydro-2H-1,4-benzoxazine showed 1.1-fold more potent affinity to the β₁ receptor than propranolol and also 1 147-fold more potent selectivity to the β₁ receptor. With a few exceptions, negative inotropic and chronotropic actions of these compounds were dependent on the size of the 4-substituent obeying the order: unsubstituted < acetyl < propanoyl < butanoyl, while the benzoyl substituent conferred even stronger negative actions in the 6- oxypropanolamine derivatives. Neither negative inotropic and chronotropic actions related with affinity to β₁-adrenoceptor nor coronary vasodilator action related with affinity to β₂-adrenoceptor were observed. 4-acetyl-7- [3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4- benzoxazine exerted potent positive inotropic, chronotropic and coronary vasodilating actions. The inotropic and chronotropic actions of the latter compound may be attributed to the release of intrinsic catecholamines, as concluded by the absence of β₁-adrenoceptor affinity and disappearance of activity in the presence of a β-blocker.

Full text of DOI:10.1016/S0223-5234(99)00109-9

Eur. J. Med. Chem. 34 (1999) 903−917
© 1999 Éditions scientifiques et médicales Elsevier SAS. All rights reserved
903
Original article
Synthesis of oxypropanolamine derivatives
of 3,4-dihydro-2H-1,4-benzoxazine, â-adrenergic affinity, inotropic,
chronotropic and coronary vasodilating activities
Kriton Iakovoua*, Michalis Kazanisa, Andreas Vavayannisa,
Giancarlo Brunib, Maria Raffaella Romeob, Paola Massarellib,
Shuji Teramotoc, Hiroyuki Fujikic, Toyoki Moric
aDepartment of Pharmacy, Division of Pharmaceutical Chemistry,
University of Athens, Panepistimiopolis Zografou, GR-157 71 Athens, Greece
bIstituto di Farmacologia, Universita di Siena, 53100 Siena, Italy
c2nd Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co. Ltd.,
463-10 Kagasuno, Kawauchi-cho, Tokushima 771-01, Japan
(Received 18 January 1999; accepted 26 April 1999)
Abstract – A series of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine were synthesized and evaluated for inotropic,
chronotropic and coronary vasodilating activities in the canine heart, affinity to â1-adrenergic receptor in turkey erythrocytes and affinity to
the â2-adrenergic receptor in the rat lung. Among these compounds, 4-acetyl-6-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydro-2H-1,4-
benzoxazine showed 2.1-fold more potent affinity to the â1 receptor than propranolol and 7-(3-tert-butylamino-2-hydroxy)propoxy-N-butyryl-
3,4-dihydro-2H-1,4-benzoxazine showed 2.5-fold more potent affinity to the â2 receptor and furthermore 4 386-fold more potent selectivity
to the â2 receptor than propranolol. In addition, 4-acetyl-6-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-
benzoxazine showed 1.1-fold more potent affinity to the â1 receptor than propranolol and also 1 147-fold more potent selectivity to the â1
receptor. With a few exceptions, negative inotropic and chronotropic actions of these compounds were dependent on the size of the
4-substituent obeying the order: unsubstituted < acetyl < propanoyl < butanoyl, while the benzoyl substituent conferred even stronger negative
actions in the 6-oxypropanolamine derivatives. Neither negative inotropic and chronotropic actions related with affinity to â1-adrenoceptor nor
coronary vasodilator action related with affinity to â2-adrenoceptor were observed. 4-acetyl-7-[3-(3,4-dimethoxybenzyl)amino-2-
hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxazine exerted potent positive inotropic, chronotropic and coronary vasodilating actions. The
inotropic and chronotropic actions of the latter compound may be attributed to the release of intrinsic catecholamines, as concluded by the
absence of â1-adrenoceptor affinity and disappearance of activity in the presence of a â-blocker. © 1999 Éditions scientifiques et médicales
Elsevier SAS
1,4-benzoxazine / oxypropanolamines / â-adrenoceptor affinity / cardiovascular effects
1. Introduction
[11, 12]. Among the carbostyril derivatives, 5-(3-tert-
butylamino-2-hydroxypropoxy)-3,4-dihydro-2(1H)-qui-
nolinone (carteolol) [13, 14] is a â-blocker more potent
than propranolol and is apparently devoid of the side
effects which are usually associated with â-blocking
therapy as it retains an intrinsic sympathomimetic acti-
vity. Oxypropanolamine derivatives of 1,4-benzo-
dioxin [15, 16], which are analogues of 1,4-benzoxazine,
have been recently synthesized. The 4-acyl derivatives of
7-oxypropanolamine-3,4-dihydro-2H-1,4-benzoxazines
which are included in the present work may be consid-
A number of 1,4-benzoxazine derivatives [1–4] have
been synthesized so far and various pharmacological
activities have been reported with this class of molecules.
Ethanolamine and oxypropanolamine derivatives of 1,4-
benzothiazine active on the adrenergic system are already
known [5, 6], as well as of the isoster nuclei 1,4-
benzoxazine [7–10] and 3,4-dihydro-2(1H)-quinolinone
*Correspondence and reprints

904
Figure 1. Structure of the synthesized 4-acyl derivatives of 7-oxypropanolamine-3,4-dihydro-2H-1,4-benzoxazines compared to
practolol.
ered as dicyclic analogues of practolol, a prototype
cardioselective blocking agent, as shown in figure 1 [9,
17, 18].
1,4-benzoxazine in aqueous medium with the appropriate
anhydrides. The reaction of 6- or 7-hydroxy-3,4-dihydro-
2H-1,4-benzoxazine with benzoic or chloroacetic anhy-
dride was not successful in water and therefore ethyl
acetate was used instead. The intermediates 12 and 13
(table III) were synthesized via the corresponding
4-chloroacetyl compounds 10 and 11 (table III) which
were condensed with diethylamine in ethanol. The gen-
eral synthetic procedure for the hydroxy derivatives 2–13
is shown in figure 2.
The 7-hydroxy-3,4-dihydro-2H-1,4-benzoxazine was
synthesized by a method which is presented in figure 3.
Initially 7-methoxy-3,4-dihydro-2H-1,4-benzoxazin-3-
one [27–29] was converted into 1 through reduction with
lithium aluminium hydride in anhydrous tetrahydrofu-
ran [30]. The intermediate 1 was demethylated by means
of concentrated hydrobromic acid to give 7-hydroxy-3,4-
dihydro-2H-1,4-benzoxazine hydrobromide, which was
alkalized by concentrated ammonium hydroxide to afford
the free base [31].
The synthetic route of 6-hydroxy-3,4-dihydro-2H-1,4-
benzoxazine, as shown in figure 4, was achieved as
follows: 2,5-dimethoxyaniline was refluxed with 2-bromo-
ethanol in the presence of calcium carbonate in water to
yield 2,5-dimethoxy-N-(2-hydroxyethyl)aniline [32]
which was isolated in pure form by distillation in vacuo.
The latter was refluxed with concentrated hydrobromic
acid leading to 6-hydroxy-3,4-dihydro-2H-1,4-benzo-
xazine hydrobromide [32], which in turn, was alkalized
by concentrated ammonium hydroxide to provide the free
base.
It is well known that the catecholamine â-stimulants
(arylethanolamines and aryloxypropanolamines) have
been used as cardiotonic agents in the management of
heart failure. Unfortunately these compounds have some
disadvantages, such as powerful vasodilating effects,
which cause a reflex rise in heart rate, lack of oral
absorption and short half-life [19]. On the other hand,
some non-oxypropanolamine [20] or oxypropanolamine
derivatives of 2(1H)-quinolinone [21, 22], have demon-
strated remarkable positive inotropic activities, the latter
in some cases without having â-agonistic action. Further-
more, a series of non-oxypropanolamine derivatives of
3,4-dihydro-1,4-benzoxazine [23] have exhibited potent,
long-acting positive inotropic and peripheral vasodilating
activities.
In order to extend the investigation on inotropic,
chronotropic and vasodilating activities of non-catechol
derivatives with possible affinity to the â-adrenergic
receptors, we prepared molecules structurally similar to
the above. The synthesized compounds are novel 4-acyl
substituted 3,4-dihydro-2H-1,4-benzoxazines bearing the
typical oxypropanolamine chain at positions 6- and 7- of
the aromatic ring.
2. Chemistry
The target compounds 24–49 (tables I and II) were
prepared in a standard three-step procedure, shown in
figure 2, which involves: a) synthesis of the 6-
and 7-hydroxy-4-acyl-3,4-dihydro-2H-1,4-benzoxazines
[24], b) reaction thereof with epichlorhydrin in the
presence of potassium carbonate [25] and c) treatment of
the resulting 1-aryloxy-2,3-epoxypropanes with the ap-
propriate amines [26].
The 4-unsubstituted products 44–47 (table II) were
prepared, as shown in figure 2, by hydrolysis of the
corresponding 4-acetyl derivatives 24–27 with potassium
hydroxide in aqueous methanol [33].
IR absorption and NMR spectra were in conformity
with the structures expected. However, we observed that
the resonance of the aromatic proton 5 either appears as
a broad peak or disappears completely, depending on the
temperature. This is possibly due to stereochemical
The derivatives 2–7 (table III) were synthesized
through the reaction of 6- or 7-hydroxy-3,4-dihydro-2H-

905
Table I. 4-Acyl-6- and 7-(3-isopropylamino- and 3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydro-2H-1,4-benzoxazines and 4-acetyl-6-
and 7-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy-propoxy]-3,4-dihydro-2H-1,4-benzoxazines.
Compound Position
R1
R2
M.p. (°C)
Yield (%)
Formula
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
48
49
7
7
6
6
7
7
6
6
7
7
6
6
7
7
6
6
7
7
6
6
7
6
CH3
CH3
CH3
CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
Ph
iPr
tBu
iPr
tBu
iPr
tBu
iPr
tBu
iPr
tBu
iPr
tBu
iPr
tBu
iPr
tBu
176–179a
161–164a
134a
24
25
20
25
26
25
27
23
25
24
26
23
57
54
17
21
15
13
16
14
31
33
C16H24N2O4. 0.5 C4H4O4
C17H26N2O4. 0.5 C4H4O4
C16H24N2O4. 0.5 C4H4O4
C17H26N2O4. 0.5 C4H4O4
C17H26N2O4. 0.5 C4H4O4
C18H28N2O4. 0.5 C4H4O4
C17H26N2O4. 0.5 C4H4O4
C18H28N2O4. C4H4O4
C18H28N2O4. 0.5 C4H4O4
C19H30N2O4. 0.5 C4H4O4. 0.5 H2O
C18H28N2O4. 0.5 C4H4O4
C19H30N2O4. 0.5 C4H4O4
C21H26N2O4
169–171a
120a
203a
129–131a
140–142a
175–178a
171–172a
117–120a
142–145a
96–98
Ph
Ph
Ph
83–85
C22H28N2O4
176–180a
112–115b
54–56
C21H26N2O4. 0.5 C4H4O4
C22H28N2O4. C4H4O4. 0.5 H2O
C20H33N3O4. 0.5 H2O
C21H35N3O4. H2O
C20H33N3O4. 0.5 H2O
C21H35N3O4. 0.5 H2O
C22H28N2O6. C4H4O4. 2H2O
C22H28N2O6. C4H4O4. 2H2O
CH2N(C2H5)2
CH2N(C2H5)2
CH2N(C2H5)2
CH2N(C2H5)2
CH3
iPr
tBu
iPr
tBu
85–90
68–70
70–73
3,4-dimethoxybenzyl
3,4-dimethoxybenzyl
140–142b
138–140b
CH3
b
a: fumarate, : maleate.
effects caused by the equilibrium between two extreme
conformations of the morpholine ring. A further study of
this effect is still under investigation and will be pub-
lished elsewhere.
3. Pharmacology
The biological profiles of the compounds listed in
table IV on â1 and â2 adrenoceptors were respectively
Table II. 6- and 7-(3-Isopropylamino- and 3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydro-2H-1,4-benzoxazines.
Compound
Position
R2
M.p. (°C )
Yield (%)
Formula
44
45
46
47
7
7
6
6
iPr
tBu
iPr
130–134a
76–80b
19
17
20
22
C14H22N2O3. C4H4O4. 0.5 H2O
C15H24N2O3. 2 C4H4O4
C14H22N2O3. 2 C2H2O4
C15H24N2O3. C4H4O4
128–130c
138–140a
tBu
b
c
a: fumarate, : maleate, : oxalate.

906
Figure 2. General synthetic procedure of the target 6- and 7-(alkylamino-2-hydroxypropoxy)-3,4-dihydro-2H-1,4-benzoxazines.

907
Table III. 4-Acyl-6- and 7-hydroxy-3,4-dihydro-2H-1,4-benzoxazines.
Compound
Position
R1
M.p (°C )
Yield (%)
Solvents of crystalliza-
tion
2
3
4
5
6
7
8
9
10
11
12
13
7
6
7
6
7
6
7
6
7
6
7
6
CH3
CH3
152–154
185–188
104–106
146–148
123–125
102–103
190–193
155
120–122
128–130
110–113
124–125
72
65
79
84
80
79
65
61
82
57
57
63
a
a
a
a
a
a
a
a
a
a
b
b
CH2CH3
CH2CH3
CH2CH2CH3
CH2CH2CH3
Ph
Ph
CH2CI
CH2CI
CH2N(C2H5)2
CH2N(C2H5)2
a: benzene-pentane, b: cyclohexane.
assessed on turkey erythrocytes and on rat lung. The
inotropic (changes in contractile force, CF), chronotropic
(changes in sinus rate, SR) and coronary vasodilator
(changes in coronary blood flow, CBF) effects of the
synthesized products were evaluated in the isolated
blood-perfused preparations of canine heart.
4. Results and discussion
4.1. â1-Adrenenoceptor binding
The affinities of the 4-acetyl substituted 6-oxypro-
panolamines obeyed the order: 27 > 49 > 26. The
Figure 3. Preparation of 7-hydroxy-3,4-dihydro-2H-1,4-benzoxazine.
Figure 4. Preparation of 6-hydroxy-3,4-dihydro-2H-1,4-benzoxazine.

908
Table IV. Inhibition of [3H]DHA binding on â1 and â2 adrenoreceptors.
Compound
â1
â2
â1/â2
Ki (± s.e.)
Ki (± s.e.)
selectivity ratio
(M)
(M)
Propranolol
24a
25a
26a
27a
28a
29a
30a
31a
32a
33a
34a
35a
36
1.6 × 10–9 ± 0.132
6.0 × 10–6 ± 0.116
2.9 × 10–6 ± 0.327
7.4 × 10–8 ± 0.684
8.01 × 10–10 ± 0.782
2.7 × 10–6 ± 0.296
1.3 × 10–6 ± 0.131
1.2 × 10–6 ± 0.214
1.1 × 10–5 ± 0.121
2.0 × 10–9 ± 0.188
2.9 × 10–6 ± 0.282
inactive
2.5 × 10–9 ± 0.171
6.4 × 10–7 ± 0.201
3.6 × 10–5 ± 0.319
2.8 × 10–9 ± 0.267
1.0 × 10–9 ± 0.326
3.3 × 10–8 ± 0.715
1.6 × 10–8 ± 0.220
inactive
1.520
0.106
12.290
0.350
1.280
0.012
0.013
1.6 × 10–7 ± 0.359
1.3 × 10–6 ± 0.264
1.0 × 10–9 ± 0.136
5.6 × 10–6 ± 0.454
5.5 × 10–6 ± 0.481
8.2 × 10–6 ± 2.720
2.3 × 10–7 ± 0.234
4.5 × 10–6 ± 0.459
1.2 × 10–7 ± 0.169
inactive
0.014
555
0.0003
8.1 × 10–9 ± 0.849
1.3 × 10–7 ± 0.121
5.6 × 10–7 ± 0.628
inactive
681
61
4.13
37
39b
40
inactive
41
42
43
6.1 × 10–7 ± 0.606
7.1 × 10–5 ± 0.684
3.1 × 10–6 ± 0.306
1.9 × 10–8 ± 0.186
inactive
inactive
2.5 × 10–5 ± 0.651
5.3 × 10–6 ± 0.386
1.2 × 10–6 ± 0.172
3.4 × 10–7 ± 0.238
4.5 × 10–8 ± 0.185
inactive
7.95
280
44a
45b
46c
47a
48b
49b
inactive
2.7 × 10–8 ± 0.296
inactive
1.70
1.4 × 10–9 ± 0.106
2.5 × 10–6 ± 0.306
1 744
b
c
a: fumarate, : maleate, : oxalate.
observed affinity order of the side-chain amino substitu-
ents was tert-Bu > 3,4-dimethoxybenzyl > iPr. The
highest affinities observed with derivatives 27 and 49,
were respectively 2.1- and 1.1-fold higher than that of
propranolol. For the 6-iPr derivatives the elongation from
the acetyl to the propanoyl chain led to a significant drop
in affinity (30). Additional lengthening of the chain by a
methylene group led to a loss in affinity (34). In the case
of the corresponding 6-tert-Bu-derivatives, the presence
of the propanoyl group (31) reduced the affinity, whereas
the replacement thereof with butanoyl (35) led to in-
creased activity. In the group of the 4-unsubstituted
derivatives, 44 and 47 showed affinities ca. 10-fold lower
than that of propranolol, while 45 and 46 had no affinity
to the â1 adrenoceptor. The 4-acetyl substituted 7-
oxypropanolamine compounds (24 and 25) showed a low
degree of affinity. For the 7-oxypropanolamine deriva-
tives, the elongation from the acetyl to the propanoyl
chain led to little increase in affinity (28 and 29). The
observed affinity order for the amino substituents follows
the order tert-Bu > iPr. Additional lengthening of the
chain by a methylene group increased the affinity (32).
The replacement of the iPr group of 32 with tert-Bu led
to a drastic decrease in affinity (33). Among the
4-benzoyl and 4-diethylaminoacetyl derivatives (36, 37,
39, and 40–43) only compound 36 showed an EC50 in the
10–7 range.
4.2. â2-Adrenenoceptor binding
The high affinities for the â2-adrenenoceptor were
observed with the 4-acetyl substituted 6-oxypro-
panolamine derivatives. The affinities of 26 and 27 were
1.1-fold lower and 2.5-fold higher than that of propra-
nolol, respectively. On the contrary, the 7-isomers 24 and
25 had low affinities to the â2-adrenenoceptor. As to the
4-acetyl substituted 6-oxypropanolamine derivatives, the
change of the amino substituent from iPr or tBu into
3,4-dimethoxybenzyl dramatically decreased the affinity
(49), whereas it led to a loss of affinity of the correspond-

909
ing 7-isomer (48). For the 6-derivatives the elongation
from the acetyl to the propanoyl or butanoyl chain led to
a substantial reduction, up to deletion, of affinity (30, 31,
34, and 35). On the contrary, the lengthening of the acyl
chain of the 7-isomers, led to considerable increase in
affinity, except for compound 32. The 4-unsubstituted
derivatives 44–47 showed low affinity to the â2-
adrenoceptor. The 4-benzoyl (36, 37, and 39) and
4-diethylaminoacetyl derivatives (40–43) showed practi-
cally no affinity.
4.3. â1/â2 selectivity
Compound 32 showed considerable â1-adrenergic af-
finity with a high â1/â2 selectivity ratio (365 times more
than that of propranolol). Compound 35 was 5-fold less
â1-affinitive than propranolol, but 448-fold more â1-
selective. Compound 44 was 11-fold less â1-affinitive
than propranolol, but 185-fold more â1-selective. Com-
pound 49 was 1.1-fold more â1-affinitive than propra-
nolol and also 1 147-fold more â1-selective. Compounds
28 and 29 exhibited a moderate â2-affinity, but consider-
able â2-selectivity (about 120-fold more than that of
propranolol). It is noteworthy that compound 33 was
2.5-fold more â2-affinitive and furthermore 4 386-fold
more â2-selective than propranolol.
The results discussed in the preceding paragraphs 4.1
to 4.3 and presented in table IV, have shown that it is
impossible to draw any straightforward conclusions re-
garding structure-activity relationships. For example, al-
though compound 24 has the closest structure to practolol
(figure 1), it did not show the expected activity, which in
fact was much lower than its 6-substituted isomer 26. It is
possible that other parameters, such as the difference in
steric configuration or the absence of amidic hydrogen,
affect the biological activity of these cyclic analogues of
practolol. Another example lies in the group of N-acyl
7-substituted compounds, where each additional methyl-
ene in the acyl chain may have a drastic effect on receptor
affinity and selectivity. Although this fact is obvious in
the cases of compounds 25 vs. 29 and 28 vs. 32 it cannot
serve as a general rule.
Figure 5. Structure-inotropic activity relationships of 6- and
7-oxypropanolamine-3,4-dihydro-2H-1,4-benzoxazine deriva-
tives in canine isolated blood-perfused heart preparations.
Effects of test compounds on right ventricular papillary muscle
contractile force (CF) were expressed by the % changes from
basal CF. Test compounds were dissolved in DMSO and the
action of the solvent itself was subtracted for compensation.
tive actions. Similar structure-activity relationships were
observed in the series of 7-oxypropanolamine deriva-
tives, i.e. unsubstituted (44 and 45) < acetyl (24 and 25)
< propanoyl (28 and 29) < butanoyl (32 and 33), but no
further negative action was observed in the benzoyl
subsutituted compounds 36 and 37. The negative inotro-
pic and chronotropic actions of these compounds were
difficult to explain by the â1-adrenoceptor antagonistic
actions because of inconsistency with the â1-
adrenoceptor affinity as described earlier.
In general, coronary vasodilator actions of the
6-oxypropanolamine derivatives were more potent than
those of their 7-substituted counterparts (figure 7). It was
also difficult to explain the coronary vasodilator action of
these compounds in relation to their â2-adrenoceptor
agonistic actions.
The 4-diethylaminoacetyl substituted 6-oxypro-
panolamine derivatives with iPr (42) and tert-Bu (43)
functions, as well as the 4-acetyl substituted compound
bearing a 3,4-dimethoxybenzyl group (49), exerted weak
positive inotropic and chronotropic actions. The same
was true for the isomer of 42 bearing the side chain at
position 7 (40). The 4-unsubstituted compounds 44 and
45 showed moderate positive actions (figure 8).
4.4. Inotropic, chronotropic and coronary vasodilating
activities
As shown in figures 5–7, negative inotropic and chro-
notropic actions of the tested compounds were dependent
on the size of the 4-substituent. In the series of the
6-oxypropanolamine derivatives the actions followed the
order: unsubstituted (46 and 47) < acetyl (26 and 27) <
propanoyl (30 and 31) < butanoyl (34 and 35). The
benzoyl compounds (38 and 39) exerted stronger nega-
The 3,4-dimethoxybenzyl derivative 48 exerted potent
positive inotropic, chronotropic and coronary vasodila-
tory actions (figure 8). It should be noted that the inotro-

910
Figure 6. Structure-chrononotropic activity relationships of 6-
and 7-oxypropanolamine-3,4-dihydro-2H-1,4-benzoxazine de-
rivatives in canine isolated blood-perfused heart preparations.
Effects of test compounds on right atrial sinus rate (SR) were
expressed by changes from basal SR. Test compounds were
dissolved in DMSO and the action of the solvent itself was
subtracted for compensation.
Figure 8. Effects of 6- and 7-oxypropanolamine-3,4-dihydro-
2H-1,4-benzoxazine derivatives on inotropic, chronotropic, and
coronary vasodilator actions in canine isolated blood-perfused
heart preparations. Effects of test compounds on the right
ventricular papillary muscle contractile force (CF) were ex-
pressed by the % changes from basal CF, on the right atrial
sinus rate (SR) were expressed by changes from basal SR and
coronary blood flow (CBF) through anterior septal arteries were
expressed by the mL/min changes from basal CBF. Test
compounds were dissolved in DMSO and the action of the
solvent itself was subtracted for compensation.
pic and chronotropic actions of this compound were
inhibited by pretreatment with the â-blocker carteolol
(figure 9).
5. Experimental protocols
5.1. Chemistry
Melting points were determined on a Büchi micro
melting point apparatus without correction. 1H-NMR and
13C-NMR spectra were recorded on a 200 MHz Bruker
AC 200 spectrometer in CDCl3 or DMSO-d6 using
tetramethylsilane as internal standard. All target com-
pounds were analysed for C, H and some additionally
analysed for N. Elemental analyses indicated by the
symbols of the elements or functions were within ± 0.4%
of the theoretical values.
Figure 7. Structure-coronary vasodilator activity relationships
of 6- and 7-oxypropanolamine-3,4-dihydro-2H-1,4-benzo-
xazine derivatives in canine isolated blood-perfused heart
preparations. Effects of test compounds on coronary blood flow
(CBF) through anterior septal arteries were expressed by the
mL/min changes from basal CBF. Test compounds were dis-
solved in DMSO and the action of the solvent itself was
subtracted for compensation.
5.1.1. 7-Methoxy-3,4-dihydro-2H-1,4-benzoxazine 1
A
solution of 7-methoxy-3,4-dihydro-2H-1,4-
benzoxazin-3-one (0.028 mol) in dry tetrahydrofuran
(95 mL) was added dropwise to a suspension of lithium
aluminum hydride (0.066 mol) in dry tetrahydrofuran

911
Figure 9. Effects of â-blocker carteolol on the positive inotropic and chronotropic response induced by compound 48 (4-acetyl-7-
[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxa-zine) in canine isolated blood-perfused prepara-
tions. The atrial and papillary muscle preparations were preloaded with 2 g and 1 g respectively.
(75 mL). The mixture was stirred and refluxed for 3 h and
cooled. Aq. sodium hydroxide 5% (40 mL) was added
dropwise under cooling and continuous stirring. The
mixture was stirred at room temperature for 1 h and the
liquid part separated through a filter. The solution was
dried over anhydrous sodium sulfate and evaporated in
5.1.3. 2,5-Dimethoxy-N-(2≠-hydroxyethyl)aniline
A mixture of 2,5-dimethoxy-aniline (0.19 mol), cal-
cium carbonate (0.0135 mol), water (150 mL) and
2-bromoethanol (0.24 mol) was refluxed for 4 h. The
reaction mixture was cooled, then extracted with ethyl
acetate (300 mL) and evaporated in vacuo. The oily
residue was fractionated in vacuo (160 °C, 2 mm Hg).
Yield: 41%, m.p.: 43–47 °C. 1H-NMR (CDCl3, 200
MHz) δ 2.15 (s, 1H, NH), 3.25 (t, 2H, NHCH2, J = 5.5
Hz), 3.71–3.84 (m, 9H, 2CH3O, CH2OH and OH), 6.15
(dd, 1H, arom, J = 8.5 Hz, 2.9 Hz), 6.24 (d, 1H, arom, J
= 2.8 Hz), 6.65 (d, 1H, arom, J = 8.6 Hz).
1
vacuo to give an oil. Yield 85%. H-NMR (CDCl3, 200
MHz) δ 3.00 (brs, 1H, NH), 3.35 (brs, 2H, CH2NH), 3.7
(s, 3H, CH3O), 4.22 (t, 2H, OCH2, J = 4.3Hz), 6.38–6.58
(m, 3H, arom).
5.1.2. 7-Hydroxy-3,4-dihydro-2H-1,4-benzoxazine
A solution of 1 (0.04 mol) in 25 mL concentrated
hydrobromic acid 62% (0.528 mol) was stirred and re-
fluxed for 2 h. The reaction mixture was then basified
with concentrated ammonium hydroxide 28% (32 mL)
and evaporated in vacuo. Ethyl acetate (250 mL) was
added to the residue and the resulting mixture was stirred
for 1 h and filtered. The filtrate was dried over anhydrous
sodium sulfate and evaporated in vacuo to give 0.031 mol
of 7-hydroxy-3,4-dihydro-2H-1,4-benzoxazine. Yield:
85%, m.p.: 95–97 °C (benzene-hexane). 1H-NMR
(DMSO-d6, 200 MHz) δ 2.07 (s, 1H, NH), 3.17 (t, 2H,
CH2NH, J = 4.3 Hz), 4.06 (t, 2H, OCH2, J = 4.3 Hz),
6.11–6.16 (m, 2H, arom), 6.41 (d, 1H, arom, J = 8.8 Hz),
8.62 (s, 1H, OH).
5.1.4. 6-Hydroxy-3,4-dihydro-2H-1,4-benzoxazine
A solution of 2,5-dimethoxy-N-(2≠-hydroxyethyl)-
aniline (0.02 mol) in 20 mL of concentrated hydrobromic
acid 62% (0.44 mol) was stirred and refluxed for 2 h. The
reaction mixture was basified with concentrated ammo-
nium hydroxide 28% (22 mL) and evaporated in vacuo.
Ethyl acetate (120 mL) was added to the residue and the
resultant mixture was stirred for 1 h and filtered. The
filtrate was dried over anhydrous sodium sulfate and
evaporated in vacuo to give 0.015 mol of 6-hydroxy-3,4-
dihydro-2H-1,4-benzoxazine.
108–109 °C (benzene). H-NMR (DMSO-d6, 200 MHz)
δ 3.19 (t, 2H, CH2NH, J = 3.9 Hz), 3.97 (t, 2H, OCH2, J
Yield:
76%,
m.p.:
1

912
= 4.2 Hz), 5.62 (brs, 1H, NH), 5.83 (dd, 1H, arom, J = 8.4
Hz, 2.8 Hz), 5.97 (d, 1H, arom, J = 2.2 Hz), 6.38 (d, 1H,
arom, J = 8.4 Hz), 8.52 (s, 1H, OH).
(0.02 mol) in ethyl acetate (50 mL) was refluxed for 1 h.
The mixture was then cooled, filtered, extracted with
ammonium hydroxide 14% (60 mL). The alkaline solu-
tion was discarded and the organic phase was washed
with water, shaken with hydrochloric acid 10% (25 mL)
and finally dried over anhydrous sodium sulfate and
5.1.5. 4-Acyl-6- and 7-hydroxy-3,4-dihydro-2H-1,4-
benzoxazines 2–7
1
concentrated in vacuo. H-NMR (DMSO-d6, 200 MHz)
To a suspension of 6- or 7-hydroxy-3,4-dihydro-2H-
1,4-benzoxazine (0.02 mol) in water (12 mL), acetic or
propanoic or butanoic anhydride (0.025 mol) was added.
The reaction mixture was heated in a water bath for
15 min. After cooling, ethyl acetate (130 mL) was added
and the resulting mixture was stirred, filtered and ex-
tracted with ammonium hydroxide 14% (24 mL). The
alkaline solution was discarded and the organic layer was
washed with water (100 mL). The organic layer was
separated, shaken with hydrochloric acid 5% (35 mL),
water (35 mL), dried over anhydrous sodium sulfate and
8: δ 3.80 (brs, 2H, CH2N), 4.24 (brs, 2H, OCH2),
6.10–6.30 (m, 2H, arom), 7.37–7.52 (m, 6H, arom), 9.37
(s, 1H, OH), IR (Nujol): νOH 3 389 cm–1, νC=O
1 710 cm–1. Anal. (C15H13NO3) C, H, N. 1H-NMR
(DMSO-d6, 200 MHz) 9: δ 3.77 (t, 2H, CH2N, J = 4.4
Hz), 4.18 (t, 2H, OCH2, J = 4.3 Hz), 6.43 (dd, 1H, arom,
J = 8.4 Hz, 2.0 Hz), 6.68 (d, 1H, arom, J = 8.4 Hz), 6.83
(brs, 1H, arom), 7.40–7.55 (m, 5H, arom), 8.9 (s, 1H,
OH), IR (Nujol): νOH: 3 406 cm–1, νC=O: 1 720 cm–1.
Anal. (C15H13NO3) C, H, N.
1
evaporated to dryness under reduced pressure. H-NMR
5.1.7. 4-Chloroacetyl-6- and 7-hydroxy-3,4-dihydro-2H-
1,4-benzoxazines 10 and 11
(DMSO-d6, 200 MHz) 2: δ 2.15 (s, 3H, NCOCH3), 3.75
(t, 2H, CH2N, J = 4.4 Hz), 4.16 (brs, 2H, OCH2),
6.24–6.30 (m, 2H, arom), 7.03 (brs, 1H, arom), 7.34 (s,
1H, OH). Anal. (C10H11NO3) C, H, N. 3: δ 2.21 (s, 3H,
NCOCH3), 3.77 (t, 2H, CH2N, J = 4.4 Hz), 4.14 (t, 2H,
OCH2, J = 4.5 Hz), 6.43 (dd, 1H, arom, J = 8.6 Hz, 2.2
Hz), 6.66 (d, 1H, arom, J = 8.7 Hz), 8.97 (brs, 1H, OH).
Anal. (C10H11NO3) C, H, N. 1H-NMR (CDCl3, 200
MHz) 4: δ 1.13 (t, 3H, CH3, J = 6.2 Hz), 2.56 (q, 2H,
NCOCH2, J = 6.8 Hz), 3.89 (s, 2H, CH2N), 4.24 (t, 2H,
OCH2, J = 4.8 Hz), 6.35–6.40 (m, 2H, arom), 6.93 (brs,
1H, arom), 7.34 (s, 1H, OH). Anal. (C11H13NO3) C, H, N.
1H-NMR (DMSO-d6, 200 MHz) 5: δ 1.03 (t, 3H, CH3, J
= 6.2 Hz), 2.50–2.57 (q, 2H, NCOCH2, J = 7.0 Hz), 3.79
(t, 2H, CH2N, J = 4.1 Hz), 4.13 (t, 2H, OCH2, J = 4.0 Hz),
6.46 (dd, 1H, arom, J = 8.6 Hz, 2.1 Hz), 6.67 (d, 1H,
arom, J = 8.6 Hz), 7.32 (brs, 1H, arom), 8.95 (brs, 1H,
OH). Anal. (C11H13NO3) C, H, N. 1H-NMR (CDCl3, 200
MHz) 6: δ 0.91 (t, 3H, CH3, J = 7.2 Hz), 1.6–1.8 (m, 2H,
COCH2CH2), 2.51 (t, 2H, COCH2CH2, J = 7.6 Hz), 3.9
(brs, 2H, CH2N), 4.24 (t, 2H, OCH2, J = 4.7 Hz), 5.3 (brs,
1H, OH), 6.35–6.45 (m, 2H, arom), 6.9 (brs, 1H, arom).
Anal. (C12H15NO3) C, H, N. 7: δ 0.94 (t, 3H, CH3, J =
7.3 Hz), 1.60–1.76 (m, 2H, COCH2CH2), 2.54 (t, 2H,
COCH2CH2, J = 7.4 Hz), 3.68 (brs, 1H, OH), 3.87 (brs,
2H, CH2N), 4.21 (t, 2H, OCH2, J = 4.7 Hz), 6.57 (dd, 1H,
arom, J = 8.9 Hz, 2.7 Hz), 6.75 (d, 1H, arom, J = 8.9 Hz),
7.34 (s, 1H, arom). Anal. (C12H15NO3) C, H, N.
Compounds 10 and 11 were synthesized through reac-
tion of 6- or 7-hydroxy-3,4-dihydro-2H-1,4-benzoxazine
with chloroacetic anhydride in ethyl acetate according to
1
the previous method. H-NMR (DMSO-d6, 200 MHz)
10: δ 3.79 (t, 2H, CH2N, J = 4.5 Hz), 4.22 (t, OCH2, J =
4.1 Hz), 4.55 (s, 2H, CH2CI), 6.25–6.33 (m, 2H, arom),
7.75 (brs, 1H, arom), 9.45 (brs, 1H, OH). IR (Nujol):
νOH
:
3 327 cm–1,
νC=O
:
1 688 cm–1.
Anal.
(C10H10ClNO3) C, H, N. 1H-NMR (DMSO-d6, 200
MHz) 11: δ 3.82 (t, 2H, CH2N, J = 4.4 Hz), 4.19 (t, 2H,
OCH2), 4.60 (s, 2H, CH2CI), 6.47 (dd, 1H, arom), 6.68
(d, 1H, arom), 7.35 (s, 1H, arom), 9.03 (s, 1H, OH). IR
(Nujol): νOH: 3 315 cm–1, νC=O: 1 679 cm–1 Anal.
.
(C10H10ClNO3) C, H, N.
5.1.8. 4-Diethylaminoacetyl-6- and 7-hydroxy-3,4-
dihydro-2H-1,4-benzoxazines 12 and 13
A mixture of 10 or 11 (0.012 mol) and diethylamine
(0.034 mol) in absolute ethanol (100 mL) was refluxed
for 3 h. The mixture was then cooled, filtered and
evaporated in vacuo. After addition of ethyl acetate
(70 mL) the mixture was stirred, filtered and the filtrate
was concentrated in vacuo. Water (20 mL) was added to
the obtained viscous oil and the resulting precipitate was
1
collected by filtration. H-NMR (DMSO-d6, 200 MHz)
12: δ 0.94 (t, 6H, N(CH2CH3)2, J = 6.7 Hz), 2.48–2.58
(m, 4H, N(CH2CH3)2), 3.44 (s, 2H, COCH2N), 3.84 (brs,
2H, CH2N), 4.19 (brs, 2H, OCH2), 6.22–6.30 (m, 2H,
arom), 7.75 (brs, 1H, arom), 9.34 (brs, 1H, OH). Anal.
(C14H20N2O3) C, H, N. 13: δ 0.95 (t, 6H, N(CH2CH3)2,
J = 7.0 Hz), 2.48–2.58 (m, 4H, N(CH2CH3)2), 3.41 (s,
2H, COCH2N), 3.86 (t, 2H, CH2N, J = 4.2 Hz), 4.15 (t,
5.1.6. 4-Benzoyl-6- and 7-hydroxy-3,4-dihydro-2H-1,4-
benzoxazines 8 and 9
A mixture of 6- or 7-hydroxy-3,4-dihydro-2H-1,4-
benzoxazine (0.02 mol) and benzoic anhydride

913
2H, OCH2, J = 4.2 Hz), 6.42 (dd, 1H, arom, J = 8.7 Hz,
2.4 Hz), 6.65 (d, 1H, arom J = 8.7 Hz), 7.46 (brs, 1H,
arom), 8.92 (s, 1H, OH). Anal. (C14H20N2O3) C, H, N.
be crystallized, the bases were purified as follows: the
oily salts were diluted in water, made alkaline with
sodium hydroxide, extracted with chloroform and the
organic layer was dried over anhydrous sodium sulfate
1
and evaporated in vacuo. H-NMR (CDCl3, 200 MHz)
5.1.9. 4-Acyl-6- and 7-(2,3-epoxypropoxy)-3,4-dihydro-
2H-1,4-benzoxazines 14–23
24: δ 1.06 (d, 6H, CH(CH3)2, J = 6.3 Hz), 2.25 (s, 3H,
COCH3), 2.39 (brs, 2H, OH and NH), 2.62–2.89 (m, 3H,
CH(CH3)2 and OCH2CH(OH)CH2), 3.88–3.99 (m, 5H,
OCH2CH(OH)CH2, CH2CH2N), 4.24 (t, 3H, OCH2CH2,
J = 4.7 Hz), 6.43–6.49 (m, 2H, arom), 6.93 (brs, 1H,
arom). 1H-NMR (DMSO-d6, 200 MHz) 24 (fumarate): δ
1.15 (dd, 6H, CH(CH3)2, J = 6.2 Hz, 1.9 Hz), 2.18 (s, 3H,
COCH3), 2.75–3.19 (m, 3H, CH(CH3)2 and OCH2CH
A mixture of 2–9, 12 or 13 (0.013 mol), epichlorohy-
drin (0.11 mol) and potassium carbonate (0.026 mol) was
stirred at 90–95 °C for 3 h. After cooling, ethyl acetate
(50 mL) or chloroform was added and the mixture was
stirred, filtered and extracted with sodium hydroxide 5%
(40 mL). The organic phase was dried over anhydrous
sodium sulfate and evaporated in vacuo to give a viscous
oil. All epoxides were used in the next step without
purification, except for compounds 15 and 20 which were
purified as follows: the crude oily residue was worked up
with hot cyclohexane and filtered. After cooling the
filtrate, compound 15 separated as an oily layer which
was isolated after decantation and evaporation of the
remaining solvent (yield 59%), whereas compound 20
was isolated as a white crystalline solid (m.p. 75–77 °C,
(OH)CH2),
3.35–4.50
(m,
OCH2CH(OH)CH2,
CH2CH2N, OCH2CH2, NH, OH, HOOCCH=CHCOOH),
6.37 (s, 1H, HOOCCH=CHCOOH), 6.42–6.55 (m, 2H,
arom), 7.20, 7.90 (2brs, 1H, arom). Anal. C18H26N2O6
1
(C, H, N). H-NMR (CDCl3, 200 MHz). 25: δ 1.08 (s,
9H, C(CH3)3), 2.25–2.83 (m, 7H, COCH3, OH, NH and
OCH2CH(OH)CH2), 3.90 (s, 5H, OCH2CH(OH)CH2 and
CH2CH2N), 4.24 (t, 3H, CH(CH3)2 and OCH2CH
(OH)CH2) 3.88–3.99 (m, 5H, OCH2CH(OH)CH2,
CH2CH2N), 4.24 (t, 2H, OCH2CH2, J = 4.5 Hz),
6.44–6.49 (m, 2H, arom), 6.97 (brs, 1H, arom). 1H-NMR
(DMSO-d6, 200 MHz) 25 (fumarate): δ 1.2 (s, 9H,
C(CH3)3), 2.2 (s, 3H, COCH3), 2.7–3.1 (m, 2H,
OCH2CH(OH)CH2), 3.20–4.40 (m, OCH2CH(OH)CH2,
CH2CH2N, OCH2CH2, NH, OH, HOOCCH=CHCOOH),
6.37 (s, 1H, HOOCCH=CHCOOH), 6.42–6.55 (m, 2H,
arom), 7.20, 7.90 (2brs, 1H, arom). 13C-NMR (DMSO-
d6) δ 22.26, 25.47, 30.27, 43.81, 52.84, 53.63, 59.3,
65.62, 69.87, 101.76, 106.21, 121.01, 124.27, 135.29,
145, 167.94, 169. Anal. C19H28N2O6 (C, H, N). 1H-NMR
(CDCl3, 200 MHz) 26: δ 1.08 (d, 6H, CH(CH3)2, J = 6.3
Hz), 2.29 (s, 3H, COCH3), 2.64–2.91 (m, 3H, CH(CH3)2
and OCH2CH(OH)CH2), 3.14 (brs, 2H, NH and OH),
3.86–4.23 (m, 7H, OCH2CH(OH)CH2, CH2CH2N and
1
yield 65%). H-NMR (CDCl3, 200 MHz) 15: δ 2.32 (s,
3H, COCH3), 2.72 (dd, 1H, CH2-oxiranic, J = 4.7 Hz, 2.6
Hz), 2.88 (t, 1H, CH2-oxiranic, J = 4.5 Hz), 3.29–3.33
(m, 1H, CH-oxiranic), 3.80–3.89, 4.15–4.25 (2m, 6H,
CH2O, CH2CH2N, OCH2CH2), 6.66 (dd, 1H, arom, J =
8.9 Hz, 2.5 Hz), 6.8 (d, 1H, arom, J = 9.0 Hz), 6.95 (brs,
1H, arom). Anal. (C13H15NO4) C, H, N. 20: δ 2.7 (dd,
1H, CH2-oxiranic, J = 4.8 Hz, 2.6 Hz), 2.87 (t, 1H,
CH2-oxiranic, J = 4.5 Hz), 3.26–3.35 (m, 1H, CH-
oxiranic), 3.84 (dd, 1H, CH2O, J = 10.9 Hz, 5.6 Hz),
3.95–3.97 (m, 2H, CH2CH2N), 4.13 (dd, 1H, CH2O, J =
11.0 Hz, 3.0 Hz), 4.3–4.32 (m, 1H, OCH2CH2), 6.26 (d,
1H, arom, J = 6.9 Hz), 6.44 (d, 1H, arom, J = 2.8 Hz),
6.91 (brs, 1H, arom), 7.34–7.48 (m, 5H, arom). Anal.
(C18H17NO4) C, H, N.
1
5.1.10. 4-Acyl-6- and 7-(3-isopropylamino- and 3-tert-
butylamino-2-hydroxypropoxy)-3,4-dihydro-2H-1,4-ben-
zoxazines 24–43
OCH2CH2), 6.6–6.8 (m, 2H, arom). H-NMR (DMSO-
d6, 200 MHz) 26 (fumarate): δ 1.1 (d, 6H, CH(CH3)2, J
= 6.3 Hz), 2.24 (s, 3H, COCH3), 2.61–3.09 (m, 3H,
CH(CH3)2 and OCH2CH(OH)CH2), 3.20–4.20 (m,
OCH2CH (OH)CH2, CH2CH2N, OCH2CH2, NH, OH,
HOOCCH=CHCOOH), 6.37 (s, 1H, HOOCCH=
CHCOOH), 6.64 (dd, 1H, arom, J = 6.9 Hz), 6.79 (d, 1H,
arom, J = 7.1 Hz). Anal. C20H28N2O8 (C, H, N).
1H-NMR (CDCl3, 200 MHz) 27: δ 1.09 (s, 9H, C(CH3)3),
2.31 (s, 3H, COCH3), 2.57–2.84 (m, 2H,
OCH2CH(OH)CH2), 3.89 (brs, 5H, OCH2CH(OH)CH2
and CH2CH2N), 4.22 (t, 2H, OCH2CH2, J = 4.7 Hz), 6.65
(dd, 1H, arom, J = 8.9 Hz, 2.6 Hz), 6.79 (d, 1H, arom, J
= 9.0 Hz). Anal. C19H28N2O6 (C, H). 28: δ 1.09–1.26 (m,
9H, CH(CH3)2 and COCH2CH3), 2.50–2.92 (m, 5H,
A mixture of 14–23 (0.008 mol) and isopropylamine or
tert-butylamine (0.08 mol) in isopropyl alcohol (90 mL)
was refluxed for 3 h. The resulting solution was thor-
oughly evaporated in vacuo, the viscous oily residue was
worked up with hot cyclohexane, filtered immediately
and the solvent was evaporated. Compounds 40–43 were
insoluble in hot cyclohexane and were converted directly
into salts. With the exception of 36 and 37 which were
isolated as crystalline solids, the oily amines were con-
verted into the fumarates (dry acetone-diethyl ether),
except for 39 which was converted into the maleate (ethyl
acetate). Because the salts of the amines 40–43 could not

914
COCH2CH3, CH(CH3)2 and OCH2CH(OH)CH2),
3.65–4.21 (m, 9H, OH, NH, OCH2CH(OH)CH2,
CH2CH2N and OCH2CH2), 6.35–6.44 (m, 2H, arom),
6.95 (brs, 1H, arom). Anal. C19H28N2O6 (C, H, N). 29: δ
1–1.25 (m, 12H, C(CH3)3 and COCH2CH3), 2.47–2.87
(m, 6H, COCH2CH3, OCH2CH(OH)CH2, OH and NH),
3.65–3.98 (m, 5H, OCH2CH(OH)CH2 and CH2CH2N),
4.17–4.27 (m, 2H, OCH2CH2), 6.4–6.5 (m, 2H, arom),
6.95 (brs, 1H, arom). Anal. C20H28N2O6 (C, H, N). 30: δ
1.07 (d, 6H, CH(CH3)2, J = 6.3 Hz), 1.17 (t, 3H,
COCH2CH3, J = 6.2), 2.52–2.88 (m, 7H, COCH2CH3,
CH(CH3)2, OCH2CH(OH)CH2, OH and NH), 3.84–4.05
(m, 5H, OCH2CH(OH)CH2 and CH2CH2N), 4.22 (t, 2H,
OCH2CH2, J = 4.0 Hz), 6.64 (dd, 1H, arom, J = 7.5 Hz,
2.0 Hz), 6.77 (d, 1H, arom, J = 8.7 Hz). Anal.
C19H28N2O6 (C, H). 31: δ 1.06 (s, 9H, C(CH3)3), 1.15 (t,
3H, COCH2CH3, J = 6.2), 2.4–2.85 (m, 6H, COCH2CH3,
OCH2CH(OH)CH2, OH and NH), 3.86 (brs, 5H,
OCH2CH(OH)CH2 and CH2CH2N), 4.19 (t, 2H,
OCH2CH2, J = 4.0 Hz), 6.64 (dd, 1H, arom, J = 7.5 Hz,
2 Hz), 6.77 (d, 1H, arom, J = 8.7 Hz). Anal. C22H30N2O8
(C, H). 32: δ 0.91 (t, 3H, COCH2CH2CH3, J = 7.2 Hz),
1.07 (d, 6H, CH(CH3)2, J = 6.2 Hz), 1.6–1.8 (m, 2H,
COCH2CH2CH3), 1.83 (brs, 2H, OH and NH), 2.51 (t,
2H, COCH2CH2CH3, J = 7.6 Hz), 2.63–2.9 (m, 3H,
CH(CH3)2 and OCH2CH(OH)CH2), 3.89–4.07 (m, 5H,
OCH2CH(OH)CH2 and CH2CH2N), 4.24 (t, 2H,
OCH2CH2, J = 4.7 Hz), 6.45–6.5 (m, 2H, arom), 6.97
(brs, 1H, arom). Anal. C20H30N2O6 (C, H). 33: δ
0.87–1.13 (m, 12H, COCH2CH2CH3 and C(CH3)3),
1.6–1.8 (m, 2H, COCH2CH2CH3), 1.86 (brs, 2H, OH and
NH), 2.45–2.89 (m, 4H, COCH2CH2CH3 and
OCH2CH(OH)CH2), 3.9 (brs, 5H, OCH2CH(OH)CH2
and CH2CH2N), 4.25 (brs, 2H, OCH2CH2), 6.4–6.5 (m,
2H, arom), 6.97 (brs, 1H, arom). Anal. C21H32N2O6 (C,
H). 34: δ 0.95 (t, 3H, COCH2CH2CH3, J = 7.2 Hz), 1.08
(d, 6H, CH(CH3)2, J = 6.2 Hz), 1.6–2 (m, 4H,
COCH2CH2CH3, OH and NH), 2.5–2.9 (m, 5H,
COCH2CH2CH3, CH(CH3)2, and OCH2CH(OH)CH2),
3.85–4.04 (m, 5H, OCH2CH(OH)CH2 and CH2CH2N),
4.22 (t, 2H, OCH2CH2, J = 4.7 Hz), 6.64 (dd, 1H, arom,
J = 7.5 Hz, 2.0 Hz), 6.8 (d, 1H, arom, J = 8.7 Hz). Anal.
C20H30N2O6 (C, H). 35: δ 0.95 (t, 3H, COCH2CH2CH3,
J = 7.2 Hz), 1.09 (s, 9H, C(CH3)3), 1.6–1.8 (m, 2H,
COCH2CH2CH3), 2 (brs, 2H, OH and NH), 2.5–2.88 (m,
4H, COCH2CH2CH3 and OCH2CH(OH)CH2), 3.87 (s,
5H, OCH2CH(OH)CH2 and CH2CH2N), 4.22 (t, 2H,
OCH2CH2, J = 4.7 Hz), 6.67 (dd, 1H, arom, J = 7.5 Hz,
2.0 Hz), 6.78 (d, 1H, arom, J = 8.7 Hz). Anal.
C21H32N2O6 (C, H). 36: δ 1.05 (d, 6H, CH(CH3)2, J = 6.2
Hz), 2.1 (brs, 2H, NH and OH), 2.6–2.86 (m, 3H,
CH(CH3)2 and OCH2CH(OH)CH2), 3.85–3.99 (m, 5H,
OCH2CH(OH)CH2 and CH2CH2N), 4.32 (t, 2H,
OCH2CH2, J = 4.4 Hz), 6.25 (d, 1H, arom, J = 7.5 Hz),
6.44 (d, 1H, arom, J = 2.7 Hz), 7.29–7.48 (m, 5H, arom).
Anal. C21H26N2O4 (C, H, N). 37: δ 1.20 (s, 9H,
C(CH3)3), 2.60–2.95 (m, 4H, OCH2CH(OH)CH2, OH
and NH), 3.87–4.00 (m, 5H, OCH2CH(OH)CH2 and
CH2CH2N), 4.30 (d, 2H, OCH2CH2, J = 3.7 Hz), 6.25 (d,
1H, arom, J = 6.9 Hz), 6.44 (d, 1H, arom, J = 2.8 Hz),
7.34–7.48 (m, 5H, arom). Anal. C22H28N2O4 (C, H, N).
38: δ 1.10 (d, 6H, CH(CH3)2, J = 6.2 Hz), 2.55–3.00 (m,
3H, CH(CH3)2 and OCH2CH(OH)CH2), 3.55–4.47 (m,
7H, OCH2CH(OH)CH2, CH2CH2N and OCH2CH2),
6.55–6.84 (m, 1H, arom), 7.30–7.57 (m, 6H, arom), 8.03
(d, 1H, arom, J = 8.2 Hz). Anal. C23H28N2O6 (C, H).
1H-NMR (DMSO-d6, 200 MHz) 39 (maleate): δ 1.27 (d,
9H, C(CH3)3), J = 4.5 Hz), 2.71–3.00 (m, 2H, OCH2CH
(OH)CH2), 3.65–4.29 (m, 7H, OCH2CH(OH)CH2,
CH2CH2N and OCH2CH2), 5.83–6.00 (m, 2H, CH=CH-
maleic), 6.64–6.90 (m, 1H, arom), 7.49–7.68 (m, 6H,
arom), 8.02 (d, 1H, arom, J = 8.2 Hz), 8.28 (brs, 1H,
1
COOH). Anal. C26H32N2O8 (C, H). H-NMR (CDCl3,
200 MHz) 40: δ 0.9–1.25 (m, 12H, CH(CH3)2, and
N(CH2CH3)2), 1.70–2.10 (m, 6H, N(CH2CH3)2, OH and
NH), 2.50–2.85 (m, 3H, CH(CH3)2 and OCH2CH
(OH)CH2), 3.15 (d, 2H, NCOCH2N, J = 5.7 Hz), 3.40
(brs, H2O), 3.71–3.91 (m, 5H, OCH2CH(OH)CH2 and
CH2CH2N), 4.19 (brs, 2H, OCH2CH2), 6.40 (d, 2H,
arom, J = 2.5 Hz), 6.63 (d, 1H, arom, J = 9.5 Hz). Anal.
C20H33N3O4 (C, H). 41: δ 0.85–1.30 (m, 15H, C(CH3)3
and N(CH2CH3)2), 1.70–2.10 (m, 6H, N(CH2CH3)2, OH
and NH), 2.50–2.85 (m, 2H, OCH2CH(OH)CH2), 3.13
(brs, 2H, NCOCH2N), 3.40 (brs, H2O), 3.7–4.2 (m, 7H,
OCH2CH(OH)CH2, CH2CH2N and OCH2CH2),
6.34–6.69 (m, 3H, arom). Anal. C21H35N3O4 (C, H). 42:
δ 0.9–1.27 (m, 12H, CH(CH3)2, and N(CH2CH3)2),
1.7–2.1 (m, 6H, N(CH2CH3)2), OH and NH), 2.5–2.85
(m, 3H, CH(CH3)2 and OCH2CH(OH)CH2), 3.20 (d, 2H,
NCOCH2N) 3.40 (brs, H2O), 3.8–4.2 (m, 7H,
OCH2CH(OH)CH2, CH2CH2N and OCH2CH2), 6.13 (dd,
1H, arom, J = 8.0 Hz, 2.8 Hz), 6.3 (d, 1H, arom, J = 2.8
Hz), 6.65 (d, 1H, arom, J = 8.5 Hz). 13C-NMR (CDCl3)
δ 22.58, 29.66, 49.08, 50.04, 55.88, 64.19, 65.83, 67.71,
68.27, 70.98, 100.01, 102.08, 116.25, 135.96, 138.44,
153.63, 163.58. Anal. C20H33N3O4 (C, H). 1H-NMR
(CDCl3, 200 MHz) 43: δ 0.85–1.27 (m, 15H, C(CH3)3
and N(CH2CH3)2), 1.65–2.06 (m, 6H, N(CH2CH3)2), OH
and NH), 2.45–2.8 (m, 2H, OCH2CH(OH)CH2), 3.20
(brs, 2H, NCOCH2N) 3.40 (brs, H2O), 3.7–4.2 (m, 7H,
OCH2CH(OH)CH2, CH2CH2N and OCH2CH2),), 6.13
(dd, 1H, arom, J = 8.0 Hz, 2.8 Hz), 6.3 (d, 1H, arom, J =
2.8 Hz), 6.65 (d, 1H, arom, J = 8.5 Hz). Anal.
C21H35N3O4 (C, H).

915
5.1.11. 6- and 7-(3-Isopropylamino- and 3-tert-butyl-
amino-2-hydroxypropoxy)-3,4-dihydro-2H-1,4-benzoxa-
zines 44–47
6.40–6.50 (m, 2H, arom), 6.72–6.87 (m, 3H, arom), 7.75
(s, 1H, arom). Anal. C26H32N2O10 (C, H). 49: δ 2 (brs,
2H, OH and NH), 2.30 (s, 3H, NCOCH3), 2.67–2.92 (m,
2H, OCH2CH(OH)CH2), 3.70–3.95 (m, 13H, CH2CH2N,
CH2NHCH2CH(OH), 2CH3O and OCH2CH(OH)CH2),
4.23 (t, 2H, OCH2CH2, J = 4.3 Hz), 6.60–6.88 (m, 5H,
arom), 7.35 (s, 1H, arom). Anal. C26H32N2O10 (C, H).
A mixture of 24–27 (0.0031 mol), potassium hydrox-
ide (0.0372 mol), water (2.5 mL) and methanol (6 mL)
was stirred at 65–70 °C for 3 h. The methanol was
removed in vacuo and the residue was extracted succes-
sively with ethyl acetate (50 mL) and water (20 mL). The
aqueous layer was discarded, the organic phase was dried
over anhydrous sodium sulfate and evaporated in vacuo
to give a viscous dark-coloured oil. The amines were
taken up from the crude product with warm cyclohexane
and the light-coloured oils which remained after evapo-
ration, were converted into fumarates or maleates. Com-
pound 46 was converted into the oxalate from ethyl
5.2. Pharmacological methods
5.2.1. â1-Adrenoceptor binding assay
Pellets containing â1 type adrenergic receptors were
obtained from turkey erythrocyte membranes as de-
scribed in the literature [34]. [3H]Dihydroalprenolol
([3H]DHA) (NEN), having a specific activity of 99.9
Ci/mmol and radiochemical purity > 98.5%, was used as
ligand.
1
acetate. H-NMR (CDCl3, 200 MHz) 44: δ 1.05 (d, 6H,
CH(CH3)2, J = 6.3 Hz), 2.34 (brs, 3H, OH and 2NH),
2.60–2.86 (m, 3H, CH(CH3)2 and OCH2CH(OH)CH2),
3.34 (t, 2H, CH2CH2N, J = 4.4 Hz), 3.83–3.98 (m, 3H,
OCH2CH(OH)CH2), 4.21 (t, 2H, OCH2CH2, J = 4.3 Hz),
6.32–6.40 (m, 2H, arom), 6.51 (d, 1H, arom, J = 8.2 Hz).
Anal. C18H26N2O7 (C, H). 45: δ 1.09 (s, 9H, C(CH3)3),
2.2 (brs, 3H, OH and 2NH), 2.60–2.85 (m, 2H,
OCH2CH(OH)CH2), 3.35 (t, 2H, CH2CH2N, J = 4.4 Hz),
3.80–3.95 (m, 3H, OCH2CH(OH)CH2), 4.20 (t, 2H,
OCH2CH2, J = 4.3 Hz), 6.30–6.40 (m, 2H, arom), 6.52
(d, 1H, arom, J = 8.2 Hz). Anal. C23H32N2O11 (C, H, N).
46: δ 1.12 (s, 6H, CH(CH3)2), 2.55–2.87 (m, 6H, OH,
2NH, CH(CH3)2 and OCH2CH(OH)CH2), 3.70–4.04 (m,
5H, CH2CH2N and OCH2CH(OH)CH2), 4.22 (t, 2H,
OCH2CH2, J = 4.3 Hz), 6.65 (dd, 1H, arom, J = 8.4 Hz,
2.8 Hz), 6.80 (d, 1H, arom, J = 8.5 Hz). Anal.
C18H26N2O11 (C, H). 47: δ 1.10 (s, 9H, C(CH3)3), 2.35
(brs, 3H, OH and 2NH), 2.57–2.85 (m, 2H,
OCH2CH(OH)CH2), 3.38 (t, 2H, CH2CH2N, J = 4.3 Hz),
3.70–3.87 (m, 3H, OCH2CH(OH)CH2), 4.17 (t, 2H,
OCH2CH2, J = 4.3 Hz), 6.15–6.23 (m, 2H, arom), 6.66
(dd, 1H, arom, J = 8.4 Hz, 2.8 Hz). Anal. C19H28N2O7 (C,
H).
â1-adrenergic receptor binding assays were determined
as follows: 100 µL of membrane (≈ 431 µg/mL of protein
diluted 1:8 v/v) were incubated for 15 min at 37 °C with
100 µL of 6 nM [3H]DHA and 100 µL of various con-
centrations of the test compounds (dissolved in saline
with DMSO 2.5%) and 12 mM Tris-HCI, pH = 7.5 (total
vol. 1 mL). The incubations were stopped by adding
4 mL of cold buffer (12 mM Tris-HCI) followed by rapid
filtration through glass fibre filter disks (Whatman GF/B).
The samples were subsequently washed 3 times with
4.5 mL of the same buffer and placed into scintillation
vials, 10 mL of Filter-Count (Packard) liquid scintillation
cocktail was then added to each vial and counting was
carried out by scintillation spectrometer (Packard TRI-
CARB 300C). Non-specific binding was defined as non-
displaceable binding in the presence of 100 µL of 10 µM
propranolol. Blank experiments were carried out to de-
termine the effect of the solvent (2.5%) on the binding.
The concentrations of the test compounds that inhib-
ited [3H]DHA binding by 50% (IC50) were determined by
log-probit analysis with six concentrations of the displac-
ers, each performed in triplicate. The IC50 values ob-
tained were used to calculate apparent inhibition con-
stants (Ki) by the method of Cheng and Prussoff [35],
from the following equation: Ki = IC50/(1 + S/KD) where
S represents the concentration of the ligand used and KD
its receptor dissociation constant (KD values, obtained by
Scatchard analysis [36], for [3H]DHA is 3.6 × 10–9 M).
5.1.12. 4-Acetyl-6- and 7-[3-(3,4-dimethoxybenzyl)
amino-2-hydroxypropoxy]-3,4-dihydro-2H-1,4-benzoxa-
zines 48 and 49
A mixture of 14 or 15 (0.0025 mol) and 3,4-
dimethoxybenzylamine (0.025 mol) in isopropyl alcohol
(30 mL) was refluxed for 3 h. The solvent was evaporated
in vacuo and the residue was purified by crystallization
5.2.2. â2-Adrenoceptor binding assay
Preparation of lung homogenate: male Sprague-
Dawley rats were sacrificed by decapitation. The right
lung was removed free of the major bronchi. Lungs were
homogenized with a Brinkman Polytron (setting 5 for
15 s) in 50 volumes of buffer, 75 mM Tris-HCI (pH 7.65),
25 mM MgCl2 and then centrifuged at 30 000 g for
1
from diethyl ether. H-NMR (CDCl3, 200 MHz) 48: δ
1.60 (brs, 2H, OH and NH), 2.25 (s, 3H, NCOCH3),
2.6–2.85 (m, 2H, OCH2CH(OH)CH2), 3.70–3.92 (m,
13H, CH2CH2N, CH2NHCH2CH(OH), 2CH3O and
OCH2CH(OH)CH2), 4.20–4.30 (m, 2H, OCH2CH2),

916
10 min twice. The resulting pellets were resuspended in
100 volumes of buffer, 75 mM Tris-HCI (pH 7.65),
25 mM MgCl2, then were frozen at –80 °C before being
assayed [37, 38]. [3H]Dihydroalprenolol was used as
ligand. 300 µL of lung membrane were incubated for
30 min at 37 °C with 50 µL of 6 nM [3H]DHA, 50 µL of
ketanserine 10–7 M 5HT antagonist, 50 µL of practolol
10–6 M as â2 antagonist and 50 µL of various concentra-
tions of the test compounds (dissolved in saline with
DMSO 5%, or H2O) and 75 mM Tris-HCI (pH 7.65),
25 mM MgCl2 (total volume 0.5 mL). The samples were
subsequently washed with 4.5 mL of the same buffer and
placed into scintillation vials. 10 mL of Filter-Count
(Packard) liquid scintillation cocktail was then added to
each vial and counting was carried out by scintillation
spectrometer (Packard Tricarb 300C). Non-specific bind-
ing was defined as non-displaceable binding in the
presence of 50 µL of 10 µM ICI 118551.
Sanei, Recti-Horiz 8K). The compounds were injected
intra-arterially with microsyringes.
Acknowledgements
The authors thank Sig. Michele Guerrini for technical
assistance. Financial support from MURST (60%) and
LAVIFARM S.A. is gratefully acknowledged.
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