Synthesis and Pharmacology of Some Aryloxypropanolamine Derivatives
S. B. Jadhav1* and P. Y. Shirodkar2
1Department of Pharmaceutical Chemistry, P.E.S.’s Modern College of Pharmacy, Nigdi, Pune – 411 044
2Konkan Gyanpeeth Rahul Dharkar College of Pharmacy and Research Institute, Karjat, Maharashtra
*Corresponding Author E-mail: sbjadhav_pharma@yahoo.co.in
ABSTRACT:
4-hydroxy-3-methoxy benzaldehyde on reaction with substituted anilines gave imine compounds (2a-d) which on reaction with epichlorhydrin gave epoxides (3a-d). These compounds on reaction with amines gave 1-(2-methoxy-4-arylimino phenoxy)-3-(substituted amino)-propan-2-ol (4a-h). All newly synthesized compounds were characterized on the basis of spectral analysis and evaluated for β-blocking activity. Compound (4e) was found to be most potent compound of this series and was compared with the reference drug, propranolol. Other compounds in this series were found to possess varied degree of β-blocking activity.
KEYWORDS: Aryloxypropanolamines, β-blocking activity
INTRODUCTION:
Aryloxypropanolamines constitute an important class of bioactive compounds exhibiting β-blocking1,2,3, antihypertensive4,5, antihyperglycemic6, lipolytic and hypolipidemic activity7. This has prompted us to undertake the present work of synthesis of newer aryloxypropanolamines.
β-blocking activity:
The newly synthesized compounds were analysed for β-blocking activity using spontaneously beating guinea pig atrial preparations8,9. The atria of guinea pigs were removed after killing it with a blow to the head and the atria was mounted in organ bath with one end fixed and other end connected to force-displacement transducer. Krebs solution was used for the experiments. The activity of test compounds was expressed as pA2 value10 and the results were presented in Table-II.
The compounds – 4a and 4e have shown significant activity and remaining compounds have shown moderate to low activity. Propranolol was used as reference standard for comparison.
MATERIAL AND METHODS:
The melting points of the compounds were determined in open capillaries on Veego – VMP-I melting point apparatus and are uncorrected.
The purity of the synthesized compounds was routinely checked by thin layer chromatography on silica gel-G plates. The Infra Red spectra were recorded on Jasco FT-IR 4100 (vmax in cm-1). The 1H NMR spectra were recorded on Mercury YH-300 instrument using CDCl3/DMSO as solvent and tetramethylsilane (TMS) as an internal reference standard. Elemental analysis (C, H, N) of these newly synthesized compounds were obtained from SAIF, IIT Powai, Mumbai.
Synthesis of 2-methoxy-4-((substituted phenylimino) methyl)phenol (2a-d)
To a solution of substituted anilines in methanol, added drop wise a solution of equimolar quantity of 4-hydroxy-3-methoxy-benzaldehyde in methanol. The reaction mixture was refluxed for 45 minutes. It was immediately cooled on ice. The resulting product was filtered, dried and recrystallized with appropriate solvents (methanol / acetone) to get compounds (2a-d). The physical and analytical data of the derivatives are given in Table I.
The IR (KBr) γ cm-1: 3300-3410 (O-H str), 3050-3100 (C-H str of aromatic ring), 1600-1615 (C=N str), 1580-1595 (C=C str of aromatic ring), 1524 (NO2 str). 1H NMR: 3.89 - 3.98 (-OCH3), 6.40 - 6.52 (-OH), 6.85-7.64, (-Ar H), 8.34 - 8.65 (-CH).
Synthesis of N-(4-((oxyran-2yl)methoxy)-3-methoxybenzylidene)-substituted benzeneamine (3a-d)
To 2-methoxy-4-((substituted phenylimino) methyl) phenol (0.05 mol) in dry DMF (160 ml) was added NaH (0.05 mol) at 0-5ºC with stirring. Added excess of epichlorhydrin (0.15 mol) with stirring at room temperature and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under pressure, diluted with water and extracted with chloroform. The combined organic layers were dried using Na2SO4, filtered and evaporated to obtain the epoxides. The physical and analytical data of the derivatives are given in Table I.
The IR (KBr) γ cm-1: 3300-3400 (O-H str), 3046-3105 (C-H str of aromatic ring), 1602-1618 (C=N str), 1585-1600 (C=C str of aromatic ring), 1518 (NO2 str). 1H NMR: 2.32-2.40 (-CH3), 2.78-2.91 (CH2 epoxide), 3.49-3.57(-CH epoxide), 3.90-3.98 (-OCH3), 6.78-7.65 (-Ar H), 8.32-8.37 (-CH).
1-(4-((substituted phenylimino)methyl)-2methoxy phenoxy)-3-(substituted amino)propan-2-ol (4a-h)
Solution of epoxide (0.05 mol) in methanol (80 ml) was prepared. To this solution, added required amount of amine (0.05 mol, and in case of primary amine ≈ 4 times i.e. 0.2 mol) and stirred at room temperature approximately for 8 hours. Methanol was removed under vacuum and the product purified by column when necessary. The physical, analytical and activity data of the compounds are given in Table II.
2-(4-((p-tolylimino)methyl)-2-methoxyphenoxy)-3-(isopropylamino)propan-2-ol (4a)
IR (KBr) γ cm-1: 3455 (N-H str), 3368 (O-H str), 3072 (C-H str of aromatic ring), 1617 (C=N str) 1583 (C=C str of aromatic ring),. 1H NMR: 1.25 (-CH3 isoprop.), 2.37 (-CH3), 2.95 (-CH2), 3.36 (-CH2), 3.52 (-NH), 3.92 (-OCH3), 4.28 (-OH), 6.84-7.61 (-Ar H), 8.36 (-CH=N).
2-(4-((p-tolylimino)methyl)-2-methoxyphenoxy)-3-(tert-butylamino)propan-2-ol (4b)
IR (KBr) γ cm-1: 3442 (N-H str), 3350 (O-H str), 3092 (C-H str of aromatic ring), 1620 (C=N str), 1588 (C=C str of aromatic ring). 1H NMR: 1.28 (-CH3 t.but), 2.24 (-CH2), 2.39 (CH3), 3.46 (-CH), 3.64 (-NH), 3.96 (-OCH3), 4.21 (-CH2), 4.36 (-OH), 6.58-7.62 (-Ar H), 8.36 (-CH=N).
2-(4-((o-tolylimino)methyl)-2-methoxyphenoxy)-3-(isopropylamino)propan-2-ol (4c)
IR (KBr) γ cm-1: 3447 (N-H str), 3386 (O-H str), 3066 (C-H str of aromatic ring), 1610 (C=N str), 1591 (C=C str of aromatic ring). 1H NMR: 1.25 (-CH3 isoprop.), 2.36 (-CH3), 3.20 (-CH), 3.52 (-CH2), 3.77 (-CH), 3.91 (-OCH3), 4.38 (-NH), 5.40 (-OH), 6.66-7.64 (-Ar H), 8.21 (-CH=N).
2-(4-((o-tolylimino)methyl)-2-methoxyphenoxy)-3-(tert-butylamino)propan-2-ol (4d)
IR (KBr) γ cm-1: 3445 (N-H str), 3362 (O-H str), 3087 (C-H str of aromatic ring), 1619 (C=N str), 1586 (C=C str of aromatic ring). 1H NMR: 1.29 (-CH3 t.but), 2.35 (-CH3), 2.94 (-CH2), 3.24 (-OH), 3.44 (-OCH3), 3.91 (-CH), 4.38 (-NH), 6.64-7.64 (-Ar H), 8.18 (-CH=N).
2-(4-((3-nitrophenylimino)methyl)-2-methoxyphenoxy)-3-(isopropylamino)propan-2-ol (4e)
IR (KBr) γ cm-1: 3450 (N-H str), 3378 (O-H str), 3081 (C-H str of aromatic ring), 1613 (C=N str), 1589 (C=C str of aromatic ring), 1524 (NO2 str). 1H NMR: 1.25 (-CH3 isoprop.), 2.91 (-CH2), 3.05 (-OH), 3.53 (CH), 3.91 (-OCH3), 3.51 (-CH2), 4.11 (-NH), 6.88-8.03 (-Ar H), 8.21 (-CH=N).
2-(4-((3-nitrophenylimino)methyl)-2-methoxyphenoxy)-3-(tert-butylamino)propan-2-ol (4f)
IR (KBr) γ cm-1: 3456 (N-H str), 3368 (O-H str), 3090 (C-H str of aromatic ring), 1613 (C=N str), 1584 (C=C str of aromatic ring), 1532 (NO2 str). 1H NMR: 1.20 (-CH3 t.but), 2.88 (-CH2), 3.03 (-CH2), 3.81 (-OH), 3.91 (-CH), 3.96 (-OCH3), 4.14 (-NH), 6.96-8.06 (-Ar H), 8.39 (-CH=N).
2-(4-((naphthalen-1-ylimino)methyl)-2-methoxyphenoxy)-3-(isopropylamino)propan-2-ol (4g)
IR (KBr) γ cm-1: 3448 (N-H str), 3352 (O-H str), 3072 (C-H str of aromatic ring), 1615 (C=N str), 1580 (C=C str of aromatic ring). 1H NMR: 1.27 (-CH3 isoprop.), 2.86 (-CH), 3.21 (-CH), 3.64 (-OH), 3.89 (-OCH3), 4.22 (-CH2), 4.84 (-NH), 6.68-7.74 (-Ar H), 8.35 (-CH=N).
Scheme
Table I: Physical and analytical data of compounds (2a-3d)
|
Comp. No. |
R |
m.p. (0C) |
Yield % |
Elemental analysis |
|||||
|
%C |
%H |
%N |
|||||||
|
Calcd |
(Found) |
Calcd |
(Found) |
Calcd |
(Found) |
||||
|
2a |
4-CH3 |
112 |
85 |
74.69 |
74.78 |
6.22 |
6.30 |
5.81 |
5.75 |
|
2b |
2-CH3 |
78 |
81 |
74.69 |
74.53 |
6.22 |
6.28 |
5.81 |
5.87 |
|
2c |
3-NO2 |
125 |
89 |
61.76 |
61.65 |
4.41 |
4.51 |
10.29 |
10.21 |
|
2d |
-napthyl |
68 |
72 |
77.61 |
77.75 |
7.18 |
7.11 |
6.70 |
6.62 |
|
3a |
4-CH3 |
<30 |
74 |
72.72 |
72.60 |
6.40 |
6.48 |
4.71 |
4.78 |
|
3b |
2-CH3 |
<30 |
64 |
72.72 |
72.82 |
6.40 |
6.32 |
4.71 |
4.66 |
|
3c |
3-NO2 |
<30 |
78 |
62.20 |
62.34 |
4.88 |
4.80 |
8.54 |
8.63 |
|
3d |
-naphthyl |
<30 |
61 |
75.68 |
75.79 |
5.71 |
5.63 |
4.20 |
4.28 |
Table II: Physical, analytical and activity data of compounds (4a-h)
|
Comp No. |
R |
R1 |
m.p. (0C) |
Yield % |
Elemental analysis |
pA2 value |
|||||
|
%C |
%H |
%N |
|||||||||
|
Calcd |
(Found) |
Calcd |
(Found) |
Calcd |
(Found) |
||||||
|
4a |
4-CH3 |
|
126 |
75 |
70.79 |
70.64 |
7.87 |
7.81 |
7.87 |
7.79 |
4.64±0.09 |
|
4b |
4-CH3 |
|
117 |
71 |
71.35 |
71.43 |
8.11 |
8.02 |
7.57 |
7.44 |
3.95±0.18 |
|
4c |
2-CH3 |
|
131 |
69 |
70.79 |
70.64 |
7.87 |
7.79 |
7.87 |
7.81 |
3.52±0.08 |
|
4d |
2-CH3 |
|
104 |
62 |
71.35 |
71.49 |
8.11 |
8.19 |
7.57 |
7.70 |
3.79±0.21 |
|
4e |
3-NO2 |
|
118 |
73 |
61.86 |
61.73 |
6.44 |
6.36 |
10.82 |
10.75 |
5.16±0.12 |
|
4f |
3-NO2 |
|
105 |
65 |
62.84 |
62.69 |
6.73 |
6.64 |
10.47 |
10.35 |
3.93±0.14 |
|
4g |
naphthyl |
|
109 |
60 |
73.45 |
73.58 |
7.14 |
7.23 |
7.14 |
7.20 |
2.17±0.11 |
|
4h |
naphthyl |
|
112 |
54 |
73.89 |
73.72 |
7.39 |
7.30 |
6.90 |
6.78 |
2.54±0.17 |
|
# propranolol |
8.36±0.12 |
||||||||||
2-(4-((naphthlen-1-ylimino)methyl)-2-methoxyphenoxy)-3-(tert-butylamino)propan-2-ol (4h)
IR (KBr) γ cm-1: 3445 (N-H str), 3370 (O-H str), 3068 (C-H str of aromatic ring), 1610 (C=N str), 1586 (C=C str of aromatic ring). 1H NMR: 1.19 (-CH3 t.but), 2.72 (-CH2), 3.26 (-CH2), 3.91 (-OCH3), 3.98 (-CH), 4.08 (-OH), 4.78 (-NH), 6.54-7.62 (-Ar H), 8.19 (-CH=N).
RESULTS:
Aryloxypropanolamines have been associated with various biological and pharmacological activities. 4-hydroxy-3-methoxy-benzaldehyde on reaction with substituted anilines gave various imines which on further reaction with epichlorhydrin gave epoxides which were treated with isopropyl/tertbutyl amine to give various aryloxypropanolamines. These compounds were screened for β-blocking activity. Compound 4e was found to be the most active amongst the present series of compounds. The pharmacological data of all the compounds in this series have been reported in Table II. The characteristic feature of this series is the substitution of different moieties on iminophenyl ring and isopropyl or tertbutyl group substitution on the oxypropanolamine side chain.
DISCUSSION:
While evaluating the β-blocking activity, it was observed that compound 4g having –iminonaphthyl group showed least activity (2.17 ± 0.11) while compound 4e having 3-NO2-iminophenyl group exhibited maximum response (5.16 ±0.12) in comparison with the other substituted compounds. Other compounds exhibited low to moderate β-blocking activity.
ACKNOWLEDGEMENTS:
SAIF IIT Powai, Mumbai for elemental analysis and University of Pune for spectral analysis.
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Received on 29.01.2011 Modified on 27.02.2011
Accepted on 08.03.2011 © AJRC All right reserved
Asian J. Research Chem. 4(5): May, 2011; Page757-760