Synthesis and In Vitro Pharmacological Evaluation of 5-(Alkoxymethyl)-2-(3-alkylamino-2-hydroxypropoxy)phenylethanones Related to Acebutolol and Celiprolol

Article abstract of DOI:10.1002/ardp.201600136

The structure–activity relationships of 13 analogs of aryloxyaminopropanol type derived from 2-hydroxyphenylethanone as potential β-blockers are described. The synthesized compounds possess an isopropyl or a tert-butyl group in the hydrophilic part of the

Full text of DOI:10.1002/ardp.201600136

RCHH HARM
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Arch. Pharm. Chem. Life Sci. 2016, 349, 1–8
Archiv der Pharmazie
Full Paper
Synthesis and In Vitro Pharmacological Evaluation of
5-(Alkoxymethyl)-2-(3-alkylamino-2-hydroxypropoxy)-
phenylethanones Related to Acebutolol and Celiprolol
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Katarına Bruchata , Andrej Nemethy , Ruzena Cizmarikova , Eva Racanska , and Ladislav Habala
1
Faculty of Pharmacy, Department of Chemical Theory of Drugs, Comenius University in Bratislava,
Bratislava, Slovakia
Faculty of Pharmacy, Department of Pharmacology and Toxicology, Comenius University in Bratislava,
Bratislava, Slovakia
2
The structure–activity relationships of 13 analogs of aryloxyaminopropanol type derived from
2-hydroxyphenylethanone as potential b-blockers are described. The synthesized compounds possess
an isopropyl or a tert-butyl group in the hydrophilic part of the molecule and an alkoxymethyl
substitution in the lipophilic moiety. The target compounds were prepared by an established four-
1
step method and their structures were confirmed by interpretation of their UV, IR, H NMR and
13C NMR spectra, and by elemental analysis. The b-adrenolytic efficacy of the prepared racemic
compounds was determined on isolated guinea pig atria (b1) and trachea (b2) and expressed as pA2
values against isoprenaline tachycardia. The assumed cardioselectivity was expressed as b1/b2 ratio
–
and the values of compounds with an alkoxy group (CH3O, iC3H5O, C5H11O, CH2 CHCH O,
–
2
CH3OCH2CH2O) in the lipophilic part and with tert-butyl in the hydrophilic part of the molecule were
found to be comparable or higher than those of the standards acebutolol and celiprolol. All
evaluated substances at a concentration of 10ꢀ7 mol/dm3 showed also negative chronotropic effects.
Keywords: 2-Hydroxyphenylethanone / Cardioselectivity / Isolated atria / Isolated trachea
Received: May 6, 2016; Revised: June 8, 2016; Accepted: June 22, 2016
DOI 10.1002/ardp.201600136
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
clinical utility, the classification of b-blockers is usually
based on their selectivity for different subtypes of the
Introduction
b-Adrenergic blocking agents (b-blockers) have been well
established in the therapy of various cardiovascular disorders
for more than four decades [1]. These agents also have
established therapeutic benefits beyond the original cardio-
vascular application, namely in the treatment of glaucoma [2],
anxiety [3], thyreotoxicosis [4], prophylaxis of migraine [5],
hemangioma [6], and osteoporosis [7]. With respect to their
b-adrenoceptor. While nonselective b-blockers (propranolol,
pindolol) antagonize both b1- and b2-adrenoreceptors,
selective drugs, i.e., acebutolol, celiprolol, and metoprolol,
have a much higher binding affinity for b1-adrenoceptors.
Selective b1-blockers are preferred for patients in whom
b2-adrenoceptor antagonism may be associated with an
increased risk of adverse effects (asthma, diabetes) [8–10].
The developmental history of b-adrenoceptor blockers
confirms that the pharmacological activity of these com-
pounds is based on an essential aryloxyaminopropanol
structure [11, 12]. Numerous derivatives have been synthe-
sized and the basic relationship between their chemical
structure and biological activity has been established [13, 14].
Our previous studies demonstrated that cardioselectivity can
be conferred to aryloxyaminopropanols by appropriate
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Correspondence: Ruzena Cizmarikova, Faculty of Pharmacy,
Department of Chemical Theory of Drugs, Comenius University in
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Bratislava, Kalinciakova 8, 83232 Bratislava, Slovakia.
E-mail: cizmarikova@fpharm.uniba.sk
Fax: þ421250117357
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substitution in the 4-position of the phenyl ring or on the
amino nitrogen [15–17]. In recent years, a number of selected
compounds have been evaluated for their basic b-adrenolytic
activities [18–21]. The pharmacological classification of
antagonists as selective is usually based on comparison of
their pA2 values in two tissues considered to possess b1- or
b2-adrenergic receptors. For this purpose, guinea pig atria and
trachea are frequently used. The obtained values show that
most of the compounds are very effective and their
pharmacological activity is similar to clinically used b-blockers,
i.e., acebutolol and celiprolol which have also acyl group. A
fraction of derivatives of 4-hydroxyacetophenones have also
been evaluated for their antidysrhythmic efficacy in guinea
pigs against ouabain-, calcium-, and barium-induced heart
rate disturbances [22–24].
reaction with chloromethyloxirane. This reaction can be
performed in water [27] or in the excess of chloromethyl-
oxirane [18]. In this case, the oxirane derivatives (3a–h)
were prepared in the third step (iii) by reaction of the
alkoxymethylderivatives with excess of chloromethyloxirane
in the nitrogen atmosphere to obtain better yield (iii). The
final bases (4a–l) were prepared in the final fourth step (iv) by
the reaction of oxirane derivatives with tert-butylamine
or isopropylamine. The compound 4 was prepared by the
same synthetic route except for the first and second steps
which were omitted because of absence of alkoxymethyl
substituent. For the pharmacological investigation, fumarate
and oxalate salts were prepared and used. The general
synthetic route to the target compounds is shown in
Scheme 1, the list of prepared structures in Table 1.
This study describes the synthesis of 13 new derivatives of
aryloxyaminopropanol with an acyl group in the 2-position
next to the aminopropanol group. The synthesized com-
pounds possess isopropyl or tert-butyl group in the
hydrophilic part of the molecule and alkoxymethyl substitu-
tion in the lipophilic moiety. The antiisoprenaline activity of
these newly synthesized derivatives was studied on isolated
guinea pig atria and trachea. The results were expressed as
pA2 values and the cardioselectivity ratio was calculated as
b1/b2.
Pharmacological activity
The structure–activity relationship of prepared compounds
was evaluated on the basis of basic pharmacological
evaluation in vitro. The basic pharmacological property of
all b-blockers is negative chronotropic effect or antiisoprena-
line activity. The evaluated compounds at a concentration
10ꢀ7 mol/dm3 decreased heart frequency of spontaneous
beating isolated guinea pigs atria and this effect was
increasing during next 20 min after application (Tables 2
and 3). The derivatives with tert-butylamino group were
compared with celiprolol, since it also contains tert-
butylamino group, and the derivatives with isopropyl group
were compared with acebutolol.
Results and discussion
Chemistry
The capacity of evaluated compounds to influence
b2-adrenergic receptors of tracheal smooth muscle was tested
on histamine-contracted isolated guinea pig trachea. The
relaxation of tracheal smooth muscle was expressed as pA2 for
the b2-adrenergic receptor (Tables 4 and 5).
To determine the selectivity of b-blockers, it was necessary
to compare their effects in tissues bearing two basic subtypes
of b-adrenoceptors. The most suitable way to examine b1- and
b2-adrenergic effects was to study the inhibition of the
positive chronotropic effect of isoprenaline on the isolated
atria and on the relaxation of the tracheal smooth muscle of
The compounds were prepared by a four-step synthesis
using 2-hydroxyphenylethanone as the starting material
(Scheme 1). In the first step (i), the chloromethyl derivative
(1) was prepared by the reaction of the starting ketone with
concentrated HCl and paraformaldehyde according to the
published procedure [25]. In the second step (ii), alkoxyme-
thylderivatives (2a–h) were obtained by reaction of the
chloromethyl intermediate with the appropriate alcohol in
the presence of NaHCO3 [26]. The most difficult step, which is
common in the syntheses of various b-blockers, is the
Scheme 1. Synthesis of the target compounds. Reagents and conditions: (i) 36% HCl, (CH2O)n.nH2O, 30°C, 7 h; yield 69%
(ii) appropriate alcohol, NaHCO3, 4 h room temp., 30–40°C, 4 h; yield 60–83% (iii) chloromethyloxirane, 85% KOH, N2, 50–55°C, 4 h;
yield 64–84% (iv) EtOH (CH3)3CNH2 or (CH3)2CHNH2, reflux, 4–5 h, yield 40–84%.
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Pharmacological Evaluation of Celiprolol Analogs
Archiv der Pharmazie
Table 1. The prepared compounds.
moiety, antiisoprenaline activity depends on the type and
length of alkoxymethyl chain as follows:
methoxyethoxymethyl < allyloxymethyl < pentyloxymethyl <
isopropyloxymethyl < butyloxymethyl < propoxymethyl <
ethoxymethyl < methoxymethyl
Higher number of carbon atoms in alkoxymethyl chain and
isosteric replacement by oxygen decrease antiisoprenaline
activity. The compounds with longer alkoxymethyl chain and
tert-butyl moiety have lower antiisoprenaline activity but
their cardioselectivity rises in comparison with standard
celiprolol. The results show that the cardioselectivity of the
tert-butyl derivatives decreases from the methoxymethyl (4a)
to propoxymethyl (4e) substitution from 13.8 to 2.10. With
increasing length or branching of the alkoxymethyl chain or
replacement of the methylene group by oxygen, cardiose-
lectivity increases up to 13.5. In the case of compound 4
without alkoxymethyl chain there was no cardioselectivity.
The antiisoprenaline activity of derivatives related to
acebutolol with N-isopropyl moiety was nearly ten times lower
than antiisoprenaline activity of tert-butyl derivatives but
within the same group the activity was very similar for all
compounds. Structure–activity relationship suggests that anti-
isoprenaline activity is determined particularly by the isopropyl
moiety while cardioselectivity depends on the type and length
of alkoxymethyl chain. The most cardioselective compound
seems to be 4f bearing propoxymethyl chain, the value
expressed cardioselectivity was identical with acebutolol.
Compound
R1
R2
4
–
-C(CH3)3
-C(CH3)3
-CH(CH3)2
-C(CH3)3
-CH(CH3)2
-C(CH3)3
-CH(CH3)2
-C(CH3)3
-C(CH3)3
-C(CH3)3
-CH(CH3)2
-C(CH3)3
-C(CH3)3
4a
4b
4c
4d
4e
4f
4g
4h
4i
-CH2OCH3
-CH2OCH3
-CH2OC2H5
-CH2OC2H5
-CH2OC3H7
-CH2OC3H7
-CH2OiC3H7
-CH2OC4H9
-CH2OC5H11
-CH2OC5H11
-CH2OC2H4OCH3
4j
4k
4l
–
–
-CH OCH CH
2
2
CH2
the guinea pig [27]. Cardioselectivity is a very important
pharmacological property of b-blockers in clinical use due to
better therapeutic utilization and elimination of side effects.
From the point of view of structure–activity relationship,
the substitution on the aromatic ring affects specific
antiisoprenaline activity and cardioselectivity. Generally, the
antiisoprenaline activity of compounds bearing tert-butyl
moiety is higher than in the group of compounds bearing
isopropyl moiety. In the group of compounds with tert-butyl
Conclusion
The aim of this work was the study of the relationship
between structure and activity of 13 racemic analogs as
potential b-blockers of the aryloxyaminopropanol type
Table 2. Negative chronotropic effect in spontaneously beating isolated guinea pig atria of the evaluated compounds
bearing a tert-butyl moiety at a concentration of 10ꢀ7 mol/dm3.
Heart rate (%)
Compound
5th min
10th min
15th min
20th min
4
4a
4c
4e
4g
4h
4i
4k
94.2 ꢁ 1.8
92.9 ꢁ 1.7
88.8 ꢁ 3.7
91.4 ꢁ 3.2
92.6 ꢁ 2.7
98.3 ꢁ 0.7
96.9 ꢁ 2.2
96.9 ꢁ 1.0
88.6 ꢁ 5.1
101.8 ꢁ 0.4
98.5 ꢁ 10
90.7 ꢁ 2.6
85.8 ꢁ 0.4
85.8 ꢁ 2.0
86.3 ꢁ 3.2
89.6 ꢁ 2.9
94.9 ꢁ 0.8
92.3 ꢁ 1.8
92.2 ꢁ 1.4
86.8 ꢁ 5.3
101.2 ꢁ 0.5
95.4 ꢁ 1.1
85.8 ꢁ 3.1
83.3 ꢁ 3.1
84.4 ꢁ 3.2
83.9 ꢁ 2.7
86.4 ꢁ 3.0
91.8 ꢁ 1.1
87.8 ꢁ 3.2
89.8 ꢁ 1.4
81.5 ꢁ 4.3
100.8 ꢁ 0.4
90.6 ꢁ 1.3
82.3 ꢁ 3.3
82.2 ꢁ 2.7
84.0 ꢁ 2.7
80.6 ꢁ 2.5
84.7 ꢁ 4.1
90.1 ꢁ 1.4
85.9 ꢁ 2.5
88.0 ꢁ 1.8
78.1 ꢁ 4.2
100.6 ꢁ 0.4
86.6 ꢁ 0.9
4l
Saline
Celiprolol
Each value represents the mean ꢁ SEM from 5 to 7 experiments.
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Table 3. Negative chronotropic effect in spontaneously beating isolated guinea pig atria of evaluated compounds
bearing isopropylamine moiety at a concentration of 10ꢀ7 mol/dm3.
Heart rate (%)
Compound
5th min
10th min
15th min
20th min
4b
4d
4f
4j
96.4 ꢁ 1.4
98.3 ꢁ 1.9
97.1 ꢁ 1.1
99.1 ꢁ 0.9
101.8 ꢁ 0.4
96.8 ꢁ 0.8
94.2 ꢁ 1.1
95.2 ꢁ 1.7
95.0 ꢁ 2.8
97.0 ꢁ 1.1
101.2 ꢁ 0.5
95.0 ꢁ 1.1
91.6 ꢁ 1.2
93.5 ꢁ 1.6
92.8 ꢁ 2.0
94.9 ꢁ 1.3
100.8 ꢁ 0.4
88.3 ꢁ 2.5
90.7 ꢁ 1.3
92.2 ꢁ 1.7
92.0 ꢁ 1.7
94.9 ꢁ 1.3
100.6 ꢁ 0.4
84.5 ꢁ 1.8
Saline
Acebutolol
Each value represents the mean ꢁ SEM from 6 to 7 experiments.
derived from 2-hydroxyphenylethanone. The b-antiadrener-
gic activity of synthesized compounds was tested on isolated
guinea pig atria (b1) and trachea (b2) and expressed as pA2
values against tachycardia induced by isoprenaline. The
cardioselectivity was expressed as b1/b2 ratio. Compounds
containing tert-butylamino group in the hydrophilic part of
molecule and with an alkoxy group (CH3O, iC3H5O, C5H11O,
assessed using TLC silica gel plates UV 254 (Merck) and the
solvent system of ethyl acetate/diethylamine (9:1 v/v) was
used. The melting point was determined using a Kofler hot
stage microscope and was quoted uncorrected.
Elemental analysis was performed using a Flash 2000
Organic Elemental Analyzer (Thermo Scientific). Ultraviolet
spectra were recorded on a Hewlett-Packard 8452 spectro-
photometer. IR spectra were recorded using an IMPACT 400D
(Nicolet) FTIR spectrophotometer in KBr. NMR spectra were
recorded with Varian Gemini 2000 spectrometer, 300 MHz for
1H NMR and 75 MHz for 13C NMR, using Si(CH3)4 as the
reference. Chemical shifts are reported in ppm (d). In
reporting the NMR multiplicities, we used the following
abbreviations: s, singlet; d, doublet; dd, doublet of doublets; t,
triplet; q, quartet; m, multiplet.
–
CH2 CHCH O, CH OCH CH O) on the aromatic ring show
–
2
3
2
2
higher cardioselectivity than standard celiprolol. Compounds
with isopropylamino group show lower activity than standard
acebutolol.
Experimental
Chemistry
The InChI codes of the investigated compounds are
provided as Supporting Information.
All reactions were carried out using commercial grade
reagents and solvents. Diethylether was dried by refluxing
over potassium hydroxide and sodium followed by distilla-
tion. The purity of the newly prepared compounds was
Generalprocedureforthepreparationof[5-(chloromethyl)-
2-(hydroxy)phenyl]ethanone (1)
To the mixture of (2-hydroxyphenyl)ethanone (24g, 20 mmol),
150mL of concentrated hydrochloric acid and paraformalde-
hyde (6 g, 20 mmol) were added during 30min at 30°C. The
mixture was kept at 30°C for 7 h under stirring. Subsequently,
themixturewaspouredinto2000 mLofcoldwaterandfiltered.
Table 4. pA2 values in atria and trachea of guinea pigs and
b1/b2 selectivity ratio calculated as the antilog (pA2 b1–
pA2 b2) of derivatives bearing tert-butyl moiety at a
concentration of 10ꢀ7 mol/dm3.
pA2
pA2
Table 5. pA2 values in atria and trachea of guinea pigs and
b1/b2 selectivity ratios calculated as antilog (pA2 b1–pA2
b2) of derivatives bearing isopropylamine moiety at a
concentration of 10ꢀ7 mol/dm3.
Compound
b1 (atria)
b2 (trachea)
b1/b2
4
4a
4c
4e
4g
4h
4i
4k
8.16 ꢁ 0.21
9.01 ꢁ 0.11
8.82 ꢁ 0.34
8.47 ꢁ 0.22
8.22 ꢁ 0.10
8.36 ꢁ 0.17
8.21 ꢁ 0.21
7.94 ꢁ 0.19
8.04 ꢁ 0.28
8.62 ꢁ 0.11
8.72 ꢁ 0.15
7.01 ꢁ 0.13
8.04 ꢁ 0.21
8.15 ꢁ 0.11
7.41 ꢁ 0.07
7.79 ꢁ 0.44
7.20 ꢁ 0.12
6.81 ꢁ 0.26
7.01 ꢁ 0.17
7.84 ꢁ 0.10
0.3
13.8
6.0
2.1
10.2
3.7
10.2
13.5
11.2
6.00
pA2
pA2
Compound
b1 (atria)
b2 (trachea)
b1/b2
4b
4d
4f
4j
7.73 ꢁ 0.17
7.99 ꢁ 0.07
7.96 ꢁ 0.38
7.73 ꢁ 0.23
7.55 ꢁ 0.66
7.05 ꢁ 1.63
7.15 ꢁ 0.10
7.01 ꢁ 0.10
7.97 ꢁ 0.30
6.58 ꢁ 0.24
4.8
6.9
9.3
0.6
9.3
4l
Celiprolol
Acebutolol
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Pharmacological Evaluation of Celiprolol Analogs
Archiv der Pharmazie
The remaining substance was crystallized from methanol to
afford yellow solid. C9H9ClO2, yield 16.6 g (69%). Mp 90–92°C.
1H NMR (CDCl3): d 2.65 (s, 3H, COCH3); 4.57 (s, 2H, ClCH2); 6.99–
7.02 (d J ¼ 9 Hz, 1H, Ar3H); 7.47–7.50 (d J ¼ 9 Hz, 1H, Ar4H); 7.73
(s,1H, Ar6H); 12.31 (s, 1H, OH). 13C NMR (CDCl3): d 29.7, 45.7,
128.1, 130.8, 131.1, 136.8, 137.0, 162.4, 204.1.
to afford the final base. The salts were prepared by
quantitative reaction of anhydrous ether solution of base
and anhydrous ether solution of fumaric acid. The crystals
were collected by filtration and recrystallized from ethyl
acetate to give fumarate salt as a white solid.
[2-(3-tert-Butylamino)-2-hydroxypropoxy-5-
General procedure for the preparation of [(5-(alkoxymethyl)-
2-(hydroxyphenyl)]ethanones 2a–h
(methoxymethyl)phenyl]ethanone (4a)
Yield: 70%, mp: 83–85°C. IR (cmꢀ1): 3200 (n, OH, NH), 1661 (n,
1
–
–
NaHCO3 (24 g, 290 mmol) was added continually to the
mixture of the chloromethyl derivative (26.7 g, 145 mmol)
and 150 mL of appropriate alcohol. The mixture was stirred
for 4 h at room temperature and then for an additional 4 h at
30–40°C. After filtration of the mixture, the remaining alcohol
was removed under reduced pressure. Distilled water (50 mL)
was added and the residue was extracted three times with
diethylether (3 ꢂ 100 mL). The combined organic layers were
dried with anhydrous MgSO4 and evaporated to dryness. The
product was used in the next reaction step without any
further purification. Yields 60–83%, 2a: 1H NMR (CDCl3): d
2.55 (s, 3H, COCH3); 3.50 (s, 3H, OCH3); 4.30 (s, 2H, Ar-CH2-O-);
6.90–6.93 (d J ¼ 9 Hz, 1H, Ar3H); 7.11–7.15 (d J ¼ 12 Hz, 1H,
Ar4H); 7.50 (s, 1H, Ar6H); 12.25 (s, 1H, ArOH).
C O), 1594 (n, C Car.), 1296 (n, C-O-Car.), 763 (d, Ar). H NMR
–
–
(CDCl3) d: 1.12 (s, 9H, C(CH3)3); 2.63 (s, 3H, COCH3); 2.70–2.90
(m, 2H, CH2N); 3.36 (s, 3H, OCH3); 3.96–4.01 (m, 2H, ArOCH2);
4.08–4.11 (m, 1H, CHOH); 4.44 (s, 2H, ArCH2); 6.98–7,01 (d
J ¼ 9 Hz, 1H, Ar3H); 7.44–7.49 (d J ¼ 15 Hz, 1H, Ar4H); 7.71 (s,
1H, Ar6H). 13C NMR (CDCl3) d: 22.9, 26.7, 49.3, 52.7, 59.0, 69.2,
73.0, 73.3, 117.2, 128.4, 129.9, 130.2, 133.7, 162.0, 199.6. UV
(MeOH) lmax 306 (e 363), 246 (e 812), 214 (e 2398). Anal. calcd.
for C34H54N2O8.C4H4O4, Mr 734.9; % C 62.11, % H 7.96, % N
3.81. Found % C 61.91, % H 7.86, % N 3.61.
[2-(2-Hydroxy-3-(isopropylamino)propoxy)-5-
(methoxymethyl)phenyl]ethanone (4b), oxalate salt
Yield: 77%, mp: 94–97°C. IR (cmꢀ1): 3308 (n, OH, NH), 1675 (n,
1
–
–
C O), 1574 (n, C Car.), 1295 (n, C-O-Car.), 793 (d, Ar). H NMR
–
–
General procedure for the preparation of [(5-(alkoxymethyl)-
2-(oxirane-2-ylmethoxy)phenyl]ethanones 3a–h
(CD3OD) d 1.37–1.40 (m, 6H, (CH3)2), 2.64 (s, 3H, COCH3), 3.19–
3.26 (m, 2H, CH2N), 3.42 (s, 3H, OCH3), 3.47–3.52 (m, 1H, CH
(CH3)2), 4.16–4.25 (m, 2H, ArOCH2), 4.31–4.35 (m, 1H, CHOH),
4.57 (s, 2H, ArCH2), 7.12–7.15 (m, 1H, Ar3H), 7.50–7.54 (m, 1H,
Ar4H), 7.73 (m, 1H, Ar6H). 13C NMR (CD3OD): d 17.36, 29.97,
50.73, 56.87, 57.12, 68.92, 73.21, 77.14, 112.83, 124.10, 127.07,
130.51, 134.22, 157.19, 200.35. UV (MeOH) lmax 306 (e 524),
246 (e 1412), 212 (e 4897). Anal. calcd. for C34H54N2O8.C2H2O4,
Mr 708.9; % C 61.00, % H 7.96, % N 3.96. Found % C 61.21, %
H 7.96, % N 3.71.
To a stirred solution of the appropriate substituted phenol
(150 mmol) in 3 mol of (ꢁ)-chloromethyloxirane 170 mmol of
85% KOH was added. The mixture was stirred at 50–55°C
under nitrogen for 4 h. The inorganic salts were filtered off
and the (ꢁ)-chloromethyloxirane was distilled off under
reduced pressure. Distilled water (50 mL) was added and the
residue was extracted three times with diethylether
(3 ꢂ 100 mL). The organic phase was separated and dried
with anhydrous Na2SO4. The filtered solution was concen-
trated under reduced pressure and the remaining oil was used
without previous purification in the next reaction step. Yields:
64–84%. 3a: 1H NMR (CDCl3): d 2.54 (s, 3H, COCH3); 2.76–2.79
(d J ¼ 9 Hz, 1H, CH2oxirane); 2.94–2.98 (t, 1H, CH2oxirane); 3.03–
3.08 (m, 1H, CHoxirane); 3.32 (s, 3H, OCH3); 3.98–4.01 (d J ¼ 9 Hz,
1H, CH2CH); 4.07–4.10 (d J ¼ 9 Hz, 1H, CH2CH); 4.51 (s, 2H,
ArCH2); 6.96–6.99 (d J ¼ 9 Hz, 1H, Ar3H); 7.42–7.47 (t, 1H,
Ar4H); 7.63–7.66 (d J ¼ 9 Hz, 1H, Ar6H).
[2-(3-tert-Butylamino)-2-hydroxypropoxy)-5-(ethoxymethyl)-
phenyl]ethanone (4c)
Yield: 64%, mp: 97–100°C. IR (cmꢀ1): 3400 (n, OH, NH), 1660 (n,
1
–
–
C O), 1594 (n, C Car.), 1298 (n, C-O-Car.), 875 (d, Ar). H NMR
–
–
(CDCl3) d 1.12–1.17 (t, 3H, CH2CH3); 1.25 (s, 9H, (CH3)3); 2.64 (s,
3H, COCH3); 2.70–2.90 (m, 2H, CH2N); 3.57–3.66 (q, 2H,
CH2CH3); 3.97–4.01 (m, 2H, CH2CH); 4.09–4.12 (m, 1H, CHOH);
4.45 (s, 2H, ArCH2); 6.99–7.03 (d J ¼ 12 Hz, 1H, Ar3H); 7.46–7,48
(d J ¼ 6 Hz, 1H, Ar4H); 7.73 (s, 1H, Ar6H). UV (MeOH) lmax 306 (e
363), 246 (e 1000), 214 (e 2884). Anal. calcd. for C36H58N2O8.
C4H4O4, Mr 762.9; % C 62.99, % H 8.14, % N 3.69. Found % C
63.11, % H 7.96, % N 3.81.
General procedure for the preparation of [(5-(alkoxymethyl)-
2-(2-hydroxy-3-alkylaminopropoxy)phenyl]ethanones 4a–l
The solution of the oxirane derivative (80 mmol) and tert-
butylamine (180 mmol) or isopropylamine (180 mmol) in
ethanol was kept at 30°C for 2 h and then was heated for
additional 5 h at reflux temperature. The solvent was distilled
off. To the residue distilled water (50 mL) was added and the
residue was washed three times with diethylether
(3 ꢂ 100 mL). The combined organic layers were washed with
brine (100 mL), then with water, separated and dried with
K2CO3. The filtered solution was concentrated under reduced
pressure and the remaining oil was crystallized from n-hexane
[(5-(Ethoxymethyl)-2-(2-hydroxy-3-isopropylaminopropoxy)-
phenyl]ethanone (4d)
Yield: 74%, mp: 80–82°C. IR (cmꢀ1): 3414 (n, OH, NH), 1674 (n,
1
–
–
C O), 1578 (n, C Car.), 1357 (n, C-O-Car.), 720 (d, Ar). H NMR
–
–
(fumarate) (CD3OD): d 1.15–1.24 (m, 3H,CH2CH3), 1.34–1.37 (d
J ¼ 9 Hz, 6H, (CH3)2), 2.64 (s, 3H, COCH3), 3.13–3.20 (m, 2H,
CH2N), 3.24–3.26 (m, 1H, CH(CH3)2), 3.52–3.59 (m, 2H, CH2CH3),
4.17–4.21 (m, 2H, CH2CH), 4.24–4.30 (m, 1H, CHOH), 4.47 (s, 2H,
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K. Bruchata et al.
ꢀ
Archiv der Pharmazie
Ar-CH2), 6.65 (s, 2H, fum), 7.12–7.15 (d J ¼ 9 Hz, 1H, Ar3H),
7.51–5.54 (d J ¼ 9 Hz, 1H, Ar4H), 7.73 (s, 1H, Ar6H). 13C NMR
(fumarate) (CD3OD): d 14.00, 17.57, 18.17, 29.95, 50.47, 65.33,
65.39, 71.09, 71.25, 112.82, 129.95, 131.29, 133.57, 135.66,
157.15, 172.89. UV (MeOH) lmax 306 (e 309), 246 (e 741), 214
(e 2290). Anal. calcd. for C34H54N2O8.C4H4O4, Mr 734.9; % C
62.11, % H 7.96, % N 3.81. Found % C 62.31, % H 8.15, % N
3.95.
(CD3OD): d 0.90–0.95 (t, 3H, CH2CH3), 1.36–1.43 (m, 11H,
CH2CH3, C(CH3)3), 1.56–1.60 (m, 2H, CH2CH2CH3), 2.64 (s, 3H,
COCH3), 3.15–3.18 (m, 2H, CH2NH), 3.46–3.51 (m, 2H,
OCH2CH2), 4.17–4.28 (m, 3H, CH2CHOH), 4.46 (s, 2H, Ar-CH2),
6.66 (s, 2H, fum), 7.12–7.15 (d J ¼ 9 Hz, 1H, Ar3H), 7.50–7.53 (d
J ¼ 9 Hz, 1H, Ar4H), 7.71 (s, 1H, Ar6H). 13C NMR (CD3OD): d
12.78, 18.97, 24.54, 30.09, 31.45, 44.56, 56.42, 65.56, 69.77,
70.91, 71.44, 112.88, 127.28, 129.76, 131.37, 133.47, 135.77,
157.16, 173.17, 200.26. UV (MeOH) lmax 308 (e 616), 246
(e 1698), 216 (e 6760). Anal. calcd. for C40H66N2O8.C4H4O4, Mr
819.06; % C 64.52, % H 8.61, % N 3.42. Found % C 64.40, % H
8.78, % N 3.65.
[2-(2-Hydroxy-3-tert-butylamino)propoxy)-5-
(propoxymethyl)phenyl]ethanone (4e)
Yield: 52%, mp: 148–150°C. IR (cmꢀ1): 3300 (n, OH), 1670 (n,
1
–
–
C O), 1567 (n, C Car.), 1235 (n, C-O-Car.), 728 (d, Ar). H NMR
–
–
(CD3OD): d 0.92–0.97 (t, 3H, CH2CH3), 1.41 (s, 9H, C(CH3)3),
1.59–1.66 (m, 2H, CH2CH3), 2.64 (s, 3H, COCH3), 3.14–3.18 (m,
2H, CH2CH2CH3), 3.47–3.50 (m, 2H, CH2NH), 4.16–4.25 (m, 3H,
CH2CHOH), 4.47 (s, 2H, Ar-CH2), 6.66 (s, 2H, fum), 7.12–7.15 (d
J ¼ 9 Hz, 1H, Ar3H), 7.50–7.54 (d J ¼ 12 Hz, 1H, Ar4H), 7.72 (s,
1H, Ar6H). 13C NMR (CD3OD): d 9.52, 22.48, 24.59, 30.01, 44.58,
56.29, 65.64, 70.93, 71.40, 71.74, 109.99, 112.87, 129.78,
131.39, 133.45, 157.13. UV (MeOH) 308 (e 566), 246 (e 1595),
215 (e 7302). Anal. calcd. for C38H62N2O12.C4H4O4, Mr 791.0; %
C 63.78, % H 8.41, % N 3.54. Found % C 63.65, % H 8.20, % N
3.75.
[2-(3-tert-Butylamino)-2-hydroxypropoxy)-5-
(pentyloxymethyl)phenyl]ethanone (4i), fumarate salt
Yield: 63%, mp: 127–128°C. IR (cmꢀ1): 3432 (n, OH), 1672 (n,
ꢀ
–
–
C O), 1574 (n, C Car.), 1580 (n , COO ), 1236 (n, C-O-Car.),
–
–
as
824 (d, Ar). 1H NMR (DMSO-d6): d 0.88–0.93 (t, 3H, CH2CH3),
1.29–1.61 (m, 17H (CH3)3, CH2CH2CH2CH3, CH2N), 2.62 (s, 1H,
COCH3), 3.42–3.51 (m, 2H, OCH2CH2), 4.05–4.16 (m, 3H,
CH2CHOH), 4.41 (s, 2H, ArCH2), 6.66 (s, 2H, fum), 6.92–6.95
(d J ¼ 9 Hz, 1H, Ar3H), 7.40–7.43 (d J ¼ 9 Hz, 1H, Ar4H), 7.63 (s,
1H, Ar6H). UV (MeOH) lmax 308 (e 380), 246 (e 1071), 214
(e 5248). Anal. calcd. for C42H70N2O8.C4H4O4, Mr 847,10; % C
65.22, % H 8.81, % N 3.31. Found % C 64.91, % H 8.61, % N
3.39.
[2-(2-Hydroxy-3-(isopropylamino)propoxy)-5-
(propoxymethyl)phenyl]ethanone (4f)
Yield: 60%, mp: 84–86°C. IR (cmꢀ1): 3426 (n, OH,NH), 1664 (n,
[2-(2-Hydroxy-3-(isopropylamino)propoxy)-5-
1
–
–
C O), 1495 (n, C Car.), 1274 (n, C-O-Car.), 814 (d, Ar). H NMR
(pentyloxymethyl)phenyl]ethanone (4j), oxalate salt
–
–
(CDCl3): d 0.94–1.03 (t, 3H, CH2CH3), 1.10–1.13 (d J ¼ 9 Hz, 6H
(CH3)2), 1.62–1.69 (m, 2H, CH2CH3), 2.56 (s, 3H, COCH3),
2.86–2.93 (m, 4H, CH2N, CH(CH3)2), 3.96–4.04 (m, 2H,
OCH2CH2), 4.07–4.12 (m, 3H, CH2CHOH), 4.80 (s, 2H, ArCH2),
6.99–7.02 (d J ¼ 9 Hz, 1H, Ar3H), 7.46–7.50 (d J ¼ 12 Hz, 1H,
Ar4H), 7.73 (s, 1H, Ar6H). UV (MeOH) lmax 310 (e 756), 248 (e
1034), 216 (e 2334). Anal. calcd. for C34H54N2O8.C4H4O4, Mr
734.9; % C 62.11, % H 7.96, % N 3.81. Found % C 62.31, % H
8.15, % N 3.95.
Yield: 84%, mp: yellow oil. IR (cmꢀ1): 3415 (n, OH, NH), 1676 (n,
1
–
–
C O), 1610 (n, C Car.), 1248 (n, C-O-Car.), 816 (d, Ar). H NMR
–
–
(CDCl3) 0.88–0.93 (t, 3H, CH2CH3), 1.27–1.58 (m, 14H, (CH3)2,
CH2CH2CH2CH3, CH2N), 2.62 (s, 1H, COCH3), 3.42–3.51 (m, 2H,
OCH2CH2), 4.05–4.16 (m, 3H, CH2CHOH), 4.41 (s, 2H, ArCH2),
6.66 (s, 2H, fum), 6.92–6.95 (d J ¼ 9 Hz, 1H, Ar3H), 7.40–7.43 (d
J ¼ 9 Hz, 1H, Ar4H), 7.63 (s, 1H, Ar6H). UV (MeOH) lmax 320
(e 52), 252 (e 182), 218 (e 173). Anal. calcd. for C40H66N2O8.
C2H2O4, Mr 793,02; % C 63.55, % H 8.32, % N 3.53. Found % C
60.31, % H 8.24, % N 3.90.
[2-(3-tert-Butylamino)-2-hydroxypropoxy)-5-
(isopropoxymethyl)phenyl]ethanone (4g)
[2-(3-tert-Butylamino)-2-hydroxypropoxy)-5-((2-
methoxyethoxy)methyl)phenyl]ethanone (4k), fumarate
salt
Yield: 62%, mp: 72–75°C. IR (cmꢀ1): 3424 (n, OH, NH), 1662 (n,
1
–
–
C O), 1594 (n, C Car.), 1247 (n, C-O-Car.), 812 (d, Ar). H NMR
–
–
(CDCl3): d 1.12–1.17 (d J ¼ 15 Hz, 6H, (CH3)2), 1.21 (s, 9H (CH3)3),
2.64 (s, 3H, COCH3), 2.60–2.71 (m, 2H, CH2N), 3.67–3.71 (m, 1H,
CH(CH3)2), 3.95–3.99 (m, 2H, CH2CH); 4.07 (m, 1H, CHOH); 4.80
(s, 2H, ArCH2), 6.95–6.99 (d J ¼ 12 Hz, 1H, Ar3H), 7.45–7.48 (d
J ¼ 9 Hz, 1H, Ar4H), 7.67 (s, 1H, Ar6H). UV (MeOH) lmax 310 (e
758), 250 (e 1023), 216 (e 2344). Anal. calcd. for C38H62N2O8.
C4H4O4, Mr 791.00; % C 63.78, % H 8.41, % N 3.54. Found % C
63.31, % H 7.94, % N 3.95.
Yield: 69%, mp: 121–124°C. IR (cmꢀ1): 3425 (n, OH), 1671 (n,
ꢀ
–
–
C O), 1497 (n, C Car.), 1578 (n , COO ), 1241 (n, C-O-Car.), 810
–
–
as
(d, Ar). 1H NMR (CD3OD): d 1.40s (s, 9H, C(CH3)3), 2.63 (s, 3H,
COCH3), 3.15–3.18 (m, 2H, CH2NH), 3.35 (s, 3H, CH2OCH3), 3.54–
3.58 (m, 2H, CH3OCH2CH2), 3.61–3.64 (m, 2H, CH3OCH2CH2),
4.16–4.28 (m, 3H, CH2CHOH), 4.51 (s, 2H, ArCH2), 6.65 (s, 2H,
fum), 7.11–7.14 (d J ¼ 9 Hz, 1H, Ar3H), 7.51–7.54 (d J ¼ 9 Hz, 1H,
Ar4H), 7.73 (s, 1H, Ar6H). 13C NMR(CD3OD): d 24.56, 30.04, 44.57,
57.69, 62.83, 65.57, 69.02, 70.93, 71.54, 71.73, 112.88, 127.28,
129.00, 129.9, 131.06, 133.54,135.78, 157.19, 173.19,200.26. UV
(MeOH)lmax 308(e616),248(e1445),214(e724).Anal.calcd.for
[(5-(Butoxymethyl)-2-(3-tert-butylamino)-2-
hydroxypropoxy)phenyl]ethanone (4h)
Yield: 76%, mp: 57–59°C. IR (cmꢀ1): 3367 (n, OH,NH), 1672 (n,
C38H62N2O8.C4H4O4, Mr 791.00; % C 63.78, % H 8.41, % N 3.54.
Found % C 63.41, % H 8.15, % N 3.71.
1
–
–
C O), 1599 (n, C Car.), 1237 (n, C-O-Car.), 824 (d, Ar). H NMR
–
–
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Arch. Pharm. Chem. Life Sci. 2016, 349, 1–8
Pharmacological Evaluation of Celiprolol Analogs
Archiv der Pharmazie
[(5-(Allyloxymethyl)-2-(3-tert-butylamino)-2-
applied and allowed to equilibrate for 30 min before the IPN
curve was re-established. The EC50 and pA2 values from the
shift in CRC of IPN were then calculated according to the
method described above.
hydroxypropoxy)phenyl]ethanone (4l)
Yield: 50%, mp: yellow oil. IR (cmꢀ1): 3422 (n, OH,NH), 1670 (n,
1
–
–
C O), 1605 (n, C Car.), 1247 (n, C-O-Car.), 810 (d, Ar). H NMR
–
–
(CD3OD): d 1.40 (s, 9H, C(CH3)3), 2.64 (s, 3H, COCH3), 3.10–3.16
–
(m, 2H, CH NH), 4.02–4.04 (d J ¼ 6 Hz, 2H, CH CH CH ),
Data analysis
–
2
2
2
4.04–4.26 (m, 3H, CH2CHOH), 4.28 (s, 2H, Ar-CH2), 5.17–5.33
Values presented are the means ꢁ SEM of 5–7 experiments.
Comparison between the two data was made by Student’s
t-test for paired or unpaired data. In this test, p < 0.05 was
considered indicative of a significant difference.
Experiments involving isolated tissues were performed in
accordance with the European Guidelines for the use of
animals in research.
–
–
(m, 2H, CH CH CH ), 5.88–5.99 (m, 1H, CH CH CH ), 6.66 (s,
–
–
2
2
2
2
2H, fum), 7.12–7.15 (d J ¼ 9 Hz, 1H, Ar3H), 7.51–7.55 (d J ¼ 12,
1H, Ar4H), 7.72–7.73 (s, 1H, Ar6H). 13C NMR (CD3OD): d 24.64,
44.58, 56.21, 63.07, 65.70, 70.75, 70.96, 112.91, 116.06, 129.92,
131.12, 133.57, 134.52, 135.67, 172.92. UV (MeOH) lmax 308 (e
489), 248 (e 549), 218 (e 2290). Anal. calcd. for C38H58N2O8.
C4H4O4, Mr 786.96; % C 64.10, % H 7,94, % N 3.56. Found % C
64.31, % H 8.15, % N 3.65.
This study was supported by the Slovak Research and
Development Agency under contract No. APVV-0516-12.
Pharmacology
Experiments involving isolated tissues were performed in
accordance with the European Guidelines for the use of
animals. The isolated guinea pig atria and trachea prepara-
tions were used, known to preferentially express b1- and
b2-adrenoreceptor mediated responses, respectively.
The authors have declared no conflicts of interest.
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