Pharmacological evaluation of some new 2-substituted pyridine derivatives

Article abstract of DOI:10.1248/bpb.26.182

In the present study, a series of 2-substituted-pyridines were synthesized and characterized by IR, ¹H-NMR and Elemental Analysis. The compounds were assayed against seizures induced by maximal electro shock (MES) and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the rotarod test. The decrease in the elevated motor activity by introceptive chemical stimuli (amphetamine antagonistic activity) was studied at the dose level of 25 and 50 mg/kg, antihistaminic and cardiac activity were also studied. All the compounds exhibited significant anticonvulsant activity. Compounds 2-(2′-piperazino-ethanoxy)pyridine, 2-(3′-morpholino-2′- hydroxypropyloxy)pyridine, 2-(3′-piperidino-2′-hydroxypropyloxy) pyridine and 2-(3′-piperazino-2′-hydroxypropyloxy)pyridine were most active of the series against MES-induced seizures. Compounds 2-(2′-piperazino-ethanoxy)pyridine, 2-(2′-phenylamino-ethanoxy) pyridine, 2-(3′-imidazolo-2′-hydroxypropyloxy)pyridine, 2-(3′-methylamino-2′-hydroxypropyloxy)pyridine and 2-(3′-piperidino-2′-hydroxypropyloxy)pyridine exhibited significant decrease in the elevated motor activity at the dose of 50 mg/kg. Remarkable sympathetic blocking activity was observed with 2-(3′-piperazino-2′- hydroxypropyloxy)pyridine, 2-(3′-piperidino-2′-hydroxypropyloxy) pyridine and 2-(3′-imidazolo-2′-hydroxypropyloxy)pyridine only. Compounds 2-(2′-morpholino-ethanoxy)pyridine, 2-(2′-piperidino- ethanoxy)pyridine, 2-(2′-piperazino-ethanoxy)pyridine, 2-(2′-imidazolo-ethanoxy)pyridine, 2-(2′-diphenylamino-ethanoxy) pyridine, 2-(2′-diethanolamino-ethanoxy)pyridine, 2-(2′-phenylamino- ethanoxy)pyridine and 2-(2′-(4″-hydroxy)phenylamino-ethanoxy) pyridine exhibited significant blocking of histamine induced contraction on guinea pig ileum.

Full text of DOI:10.1248/bpb.26.182

182
Biol. Pharm. Bull. 26(2) 182—187 (2003)
Vol. 26, No. 2
Pharmacological Evaluation of Some New 2-Substituted Pyridine
Derivatives
Parasuraman NARENDAR,a Jeyaraman PARTHIBAN,a Navaneetharaman ANBALAGAN,b
a
,a
*
Vedachalam GUNASEKARAN, and Joseph THOMAS LEONARD
a Department of Pharmaceutical Chemistry and Pharmacology, Vel’s College of Pharmacy, Old Pallavaram; Chennai-600
117, India: and b Department of Pharmaceutical Chemistry, C. L. Baid Metha College of Pharmacy; Chennai-600 096,
India. Received August 30, 2002; accepted November 20, 2002
In the present study, a series of 2-substituted-pyridines were synthesized and characterized by IR, 1H-NMR
and Elemental Analysis. The compounds were assayed against seizures induced by maximal electro shock (MES)
and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the rotarod test. The decrease in the elevated
motor activity by introceptive chemical stimuli (amphetamine antagonistic activity) was studied at the dose level
of 25 and 50 mg/kg, antihistaminic and cardiac activity were also studied. All the compounds exhibited significant
anticonvulsant activity. Compounds 2-(2؅-piperazino-ethanoxy)pyridine, 2-(3؅-morpholino-2؅-hydroxypropyloxy)-
pyridine, 2-(3؅-piperidino-2؅-hydroxypropyloxy)pyridine and 2-(3؅-piperazino-2؅-hydroxypropyloxy)pyridine were
most active of the series against MES-induced seizures. Compounds 2-(2؅-piperazino-ethanoxy)pyridine, 2-(2؅-
phenylamino-ethanoxy)pyridine, 2-(3؅-imidazolo-2؅-hydroxypropyloxy)pyridine, 2-(3؅-methylamino-2؅-hydrox-
ypropyloxy)pyridine and 2-(3؅-piperidino-2؅-hydroxypropyloxy)pyridine exhibited significant decrease in the ele-
vated motor activity at the dose of 50 mg/kg. Remarkable sympathetic blocking activity was observed with 2-(3؅-
piperazino-2؅-hydroxypropyloxy)pyridine, 2-(3؅-piperidino-2؅-hydroxypropyloxy)pyridine and 2-(3؅-imidazolo-
2؅-hydroxypropyloxy)pyridine only. Compounds 2-(2؅-morpholino-ethanoxy)pyridine, 2-(2؅-piperidino-ethanoxy)-
pyridine, 2-(2؅-piperazino-ethanoxy)pyridine, 2-(2؅-imidazolo-ethanoxy)pyridine, 2-(2؅-diphenylamino-ethanoxy)-
pyridine, 2-(2؅-diethanolamino-ethanoxy)pyridine, 2-(2؅-phenylamino-ethanoxy)pyridine and 2-(2؅-(4؆-hydroxy)-
phenylamino-ethanoxy)pyridine exhibited significant blocking of histamine induced contraction on guinea pig
ileum.
Key words antihistaminic; anticonvulsant; aminoethane; aryloxypropanolamine; pyridine; sympatholytic
Pyridines were reported to possess anticonvulsant,1,2) car-
chemical shifts are reported as parts per million downfield
diotonic,3) antihypertensive,4) b-adrenergic blocking activ-
from tetra methyl silane(Me4Si). Microanalyses for C, H, N
ity.5) Aryloxypropanolamines were reported to be associated
were performed in Heraeus CHN Rapid Analyzer. Analyses
with b-adrenergic blocking,6,7) CNS depressant8) and hy-
indicated by the symbols of the elements are within Ϯ0.4%
potensive9) activities. In view of the potential nature of these
1
of the theoretical values. H-NMR and IR spectra were con-
moieties, it was thought worthwhile to study the effects of
two pharmacophoric moieties like pyridine and aryl-
oxypropanolamine/aminoethane in a single molecule. We
have reported the potential anticonvulsant activity of aryl-
oxypropanolamine from our laboratory10—13) to continue our
work in the same direction, it was envisaged that chemical
entities with both pyridine and aryloxypropanolamine/
aminoethane moieties would result in compounds of interest-
ing biological activities.
In the present study, we report the synthesis, the pharma-
cological evaluation, and structure–activity relationship of 2-
(3Ј-substituted-2Ј-hydroxypropyloxy/2Ј-substituted-ethoxy)-
pyridine. The compounds were characterized by IR, 1H-NMR
spectral and Elemental analysis. The compounds were inves-
tigated for anticonvulsant activity, the decrease in the ele-
vated motor activity by introceptive chemical stimuli (am-
phetamine antagonistic activity) at the dose level of 25 and
50 mg/kg, cardiac activity on isolated frog heart and antihist-
aminic on guinea pig ileum.
sistent with the assigned structures.
Synthesis of 2-(2؅-Chloro-ethanoxy)pyridine 2-Hy-
droxy pyridine (0.1 mol) was added to 1,2-dichloro ethane
(0.1 mol) and refluxed with potassium carbonate (0.02 mol)
in methanol for about 40 h. On cooling the reaction mixture,
the product was separated out, filtered, dried under vacuum
and recrystallized by using chloroform–ether (1 : 1). Yieldϭ
56%, mp 213—214 °C. 1H-NMR (CDCl3) d: 7.22—7.56 (m,
4H, 3, 5, 4, 6H), 3.89—4.02 (s, 4H, CH2–CH2). IR (KBr)
cmϪ1: 1413 (C–H), 1134 (C–O), 745, 723 (Ar–H). Anal.
Calcd for C7H8NOCl: C, 53.33; H, 5.08; N, 8.88. Found: C,
53.08; H, 5.29; N, 8.52.
General Method of Synthesis of 1 to 10 One hundredth
moles of the corresponding 2-(2Ј-chloro-ethaneoxy)-pyridine
was added to 0.01 mol of the appropriate amine in the pres-
ence of 20 ml of 5% alcoholic potassium hydroxide and re-
fluxed for 10 h. On cooling, the products were separated, fil-
tered, dried under vacuum and recrystallized using 1 : 1 ace-
tone–diethyl ether (1, 2, 4), 1 : 1 ethanol–diethyl ether (3, 5,
7), 1 : 1 chloroform–diethyl ether (8, 10) and 1 : 1 methanol–
diethyl ether (6, 9).
CHEMISTRY
2-(2Ј-Morpholino-ethanoxy)pyridine 1: Yieldϭ45%, mp
150 °C. H-NMR (CDCl3) d: 6.94—7.15 (m, 4H, 3, 4, 5,
6H), 4.14—4.25 (m, 4H, 2CH2), 2.82—3.01 (m, 8H, 2Љ, 3Љ,
5Љ, 6Љ-CH2). IR (KBr) cmϪ1: 3125 (C–H), 1425 (C–N), 1325
(N–H), 1109 (C–O), 850, 790 (Ar–H). Anal. Calcd for
1
Melting points were determined in open capillary tubes
and are uncorrected. IR spectra were recorded (in KBr) on
Bomem FT-IR spectrophotometer M.B Serial II. H-NMR
1
spectra were recorded on 300 MHz Bruker DPX 200. The
* To whom correspondence should be addressed. e-mail: alabarae@yahoo.com
© 2003 Pharmaceutical Society of Japan

February 2003
183
C11H16N2O2: C, 63.46; H, 7.69; N, 13.46. Found: C, 63.22; 4, 5, 6H), 5.57—5.72 (m, 1H, NH), 5.23—5.44 (m, 4H,
H, 7.41; N, 13.28.
C6H4), 4.14—4.25 (m, 4H, 2CH2). IR (KBr) cmϪ1: 3162
2-(2Ј-Piperidino-ethanoxy)pyridine 2: Yieldϭ42%, mp (C–H), 1434 (C–N), 1377 (N–H), 1143 (C–O), 823, 754
1
148 °C. H-NMR (CDCl3) d: 7.39—7.55 (m, 4H, 3, 4, 5, (Ar–H). Anal. Calcd for C13H13N3O3: C, 60.23; H, 5.01; N,
6H), 4.23—4.46 (m, 4H, 2CH2), 2.65—2.92 (m, 10H, 2Љ, 3Љ, 16.21. Found: C, 60.54; H, 4.92; N, 16.03.
4Љ, 5Љ, 6Љ-CH2). IR (KBr) cmϪ1: 1433 (C–H), 1384 (C–N),
Synthesis of 2-(2؅,3؅-Epoxypropyloxy)-pyridine 2-Hy-
1124, 1046 (C–O), 810, 762 (Ar–H). Anal. Calcd for droxy pyridine (0.1 mol) was added to epichlorhydrine (0.1
C12H18N2O: C, 69.90; H, 8.73; N, 13.59. Found: C, 69.71; H, mol, 9.3 g; 7.8 ml) refluxed with potassium carbonate (0.02
8.99; N, 13.73.
mol) in methanol for about 40 h. On cooling the reaction
2-(2Ј-Piperazino-ethanoxy)pyridine 3: Yieldϭ49%, mp mixture, On cooling the product was separated, filtered, dried
1
196 °C. H-NMR (CDCl3) d: 6.94—7.15 (m, 4H, 3, 4, 5, under vacuum and recrystallized using ethanol–ether (1 : 1).
1
6H), 5.57—5.72 (m, 1H, NH), 4.14—4.25 (m, 4H, 2CH2), Yieldϭ41%, mp 214 °C. H-NMR (CDCl3) d: 7.32—7.55
2.82—3.01(m, 8H, 2Љ, 3Љ, 5Љ, 6Љ-CH2). IR (KBr) cmϪ1: 1421 (m, 4H, 3, 4, 5, 6H), 3.66—3.83 (d, Jϭ4.5 Hz, 2H, 3Ј-CH2),
(C–H), 1350 (C–N), 1132 (C–O), 806, 791 (Ar–H). Anal. 3.37—3.51 (d, Jϭ5.7 Hz, 2H, 1Ј-CH2), 2.54—2.67 (m, 1H,
Calcd for C11H17N3O: C, 63.76; H, 8.21; N, 20.28. Found: C, 2Ј-CH). IR (KBr) cmϪ1: 1410 (C–H), 1253 (epoxide C–O),
63.92; H, 8.44; N, 20.04.
1144 (ether C–O) 833, 785 (Ar–H). Anal. Calcd for
2-(2Ј-Imidazolo-ethanoxy)pyridine 4: Yieldϭ37%, mp C8H9NO2: C, 61.93; H, 5.8; N, 9.03. Found: C, 61.67; H,
1
Ͼ300 °C. H-NMR (CDCl3) d: 6.85—7.03 (m, 4H, 3, 4, 5, 5.55; N, 8.89.
6H), 5.6—5.84 (m, 1H, 2ЈCH), 5.27—5.43 (m, 1H, 4Љ, 5Љ(-
General Method of Synthesis of 11 to 20 One hun-
CH)), 3.92—4.13 (m, 4H, 2CH2). IR (KBr) cmϪ1: 1435 dredth moles of the corresponding 2-(2Ј,3Ј-epoxypropyloxy)-
(C–H), 1361 (C–N), 1118 (C–O), 812, 790 (Ar–H). Anal. pyridine was added to 0.01 mol of the appropriate amine in
Calcd for C10H11N3O: C, 63.49; H, 5.82; N, 22.22. Found: C, the presence of 20 ml of 5% alcoholic potassium hydroxide
63.72; H, 5.98; N, 22.04.
and refluxed for 4 h. On cooling, the products were separated,
2-(2Ј-Diethylamino-ethanoxy)pyridine 5: Yieldϭ47%, mp filtered, dried under vacuum and recrystallized using 1 : 1
1
183 °C. H-NMR (CDCl3) d: 6.73—6.96 (m, 4H, 3, 4, 5, acetone–diethyl ether (13, 14, 20), 1 : 1 ethanol–diethyl ether
6H), 4.36—4.47 (m, 4H, 2CH2), 1.45—1.79 (s, 10H, (12, 15, 16, 19), 1 : 1 chloroform–diethyl ether (18) and 1 : 1
(C2H5)2). IR (KBr) cmϪ1: 3125 (C–H), 1445 (C–N), 1346 methanol–diethyl ether (11, 17).
(N–H), 1186 (C–O), 856, 778 (Ar–H). Anal. Calcd for
C11H18N2O: C, 68.04; H, 9.27; N, 14.43. Found: C, 68.31; H, Yieldϭ29%, mp 178 °C. H-NMR (CDCl3) d: 7.02—7.24
8.92; N, 14.13. (m, 4H, 3, 4, 5, 6H), 3.72—3.95 (m, 4H, 1Ј ,3Ј-CH2), 3.33—
2-(3Ј-Morpholino-2Ј-hydroxypropyloxy)-pyridine 11:
1
2-(2Ј-Diphenylamino-ethanoxy)pyridine 6: Yieldϭ54%, 3.49 (s, 1H, 2Ј-OH), 2.41—2.68 (m, 4H, 2Љ, 3Љ, 5Љ, 6ЉH),
1
mp 59 °C. H-NMR (CDCl3) d: 7.33—7.57 (m, 4H, 3, 4, 5, 1.24—1.43 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1425 (C–H),
6H), 6.24—6.45 (m, 10H, (C6H5)2), 4.37—4.60 (m, 4H, 1389 (C–N), 1144, 1042 (C–O) 833, 785 (Ar–H). Anal.
2CH2). IR (KBr) cmϪ1: 3067 (C–H), 1443 (C–N), 1355 Calcd for C12H18N2O3: C, 60.50; H, 7.56; N, 11.76. Found:
(N–H), 1167 (C–O), 882, 767 (Ar–H). Anal. Calcd for C, 60.68; H, 7.69; N, 11.52.
C19H18N2O: C, 78.62; H, 6.20; N, 9.65. Found: C, 78.34; H,
6.32; N, 9.78.
2-(3Ј-Piperidino-2Ј-hydroxypropyloxy)-pyridine 12: Yieldϭ
35%, mp 169 °C. 1H-NMR (CDCl3) d: 7.18—7.34 (m, 4H, 3,
2-(2Ј-Diethanolamino-ethanoxy)pyridine 7: Yieldϭ56%, 4, 5, 6H), 3.58—3.81 (m, 4H, 1Ј, 3Ј-CH2), 3.37—3.51 (s,
mp 175 °C. 1H-NMR (CDCl3) d: 6.28—6.59 (m, 4H, 3, 4, 5, 1H, 2Ј-OH), 2.45—2.61 (m, 10H, 2Љ, 3Љ, 4Љ, 5Љ, 6ЉH), 1.29—
6H), 4.23—4.46 (m, 4H, 2CH2), 3.22—3.43 (s, 2H; 2Љ(- 1.41 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1429 (C–H), 1372
OH)2), 2.98—3.12 (m, 8H, (C2H4)2). IR (KBr) cmϪ1: 3455 (C–N), 1141 (C–O), 842, 765 (Ar–H). Anal. Calcd for
(O–H), 3125 (C–H), 1425 (C–N), 1144 (C–O), 876, 783 C13H20N2O2: C, 66.10; H, 8.47; N, 11.86. Found: C, 66.32;
(Ar–H). Anal. Calcd for C11H18N2O3: C, 58.40; H, 7.96; N, H, 8.58; N, 11.72.
12.38. Found: C, 58.19; H, 7.80; N, 12.15.
2-(3Ј-Piperazino-2Ј-hydroxypropyloxy)-pyridine 13: Yieldϭ
2-(2Ј-Phenylamino-ethanoxy)pyridine 8: Yieldϭ44%, mp 48%, mp 132 °C. 1H-NMR (CDCl3) d: 7.46—7.63 (m, 4H, 3,
1
180 °C. H-NMR (CDCl3) d: 6.44—6.67 (m, 4H, 3, 4, 5, 4, 5, 6H), 6.35—6.5(s, 1H, –NH), 3.98—4.2 (m, 4H, 1Ј, 3Ј-
6H), 5.57—5.72 (m, 1H, NH), 5.23—5.44 (m, 1H, C6H5), CH2), 3.41—3.56 (s, 1H, 2Ј-OH), 2.35—2.54 (m, 8H, 2Љ, 3Љ,
3.77—3.97 (m, 4H, 2CH2). IR (KBr) cmϪ1: 3125 (C–H), 5Љ, 6ЉCH2), 1.23—1.39 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1:
1463 (C–N), 1325 (N–H), 1109 (C–O), 888, 745 (Ar–H). 1456 (C–H), 1329 (C–N), 1163 (C–O), 824, 735 (Ar–H).
Anal. Calcd for C13H14N2O: C, 72.89; H, 6.54; N, 13.08. Anal. Calcd for C12H19N3O2: C, 59.75; H, 7.88; N, 17.42.
Found: C, 72.98; H, 6.48; N, 12.92.
Found: C, 60.03; H, 7.61; N, 17.23.
2-(2Ј-(4Љ-Hydroxyphenylamino)-ethanoxy)pyridine 9:
2-(3Ј-Imidazolo-2Ј-hydroxypropyloxy)-pyridine 14: Yieldϭ
1
Yieldϭ49%, mp 210 °C. H-NMR (CDCl3) d: 6.94—7.15 34%, mp Ͼ300 °C. 1H-NMR (CDCl3) d: 7.25—7.42 (m, 4H,
(m, 4H, 3, 4, 5, 6H), 6.43—6.65 (m, 1H, OH), 5.57—5.72 3, 4, 5, 6H), 6.67—6.89 (m, 2H, 2Љ-CH), 6.23—6.47(m, 2H,
(m, 1H, NH), 5.23—5.44 (m, 1H, C6H5), 4.35—4.51 (m, 4H, 4 Љ, 5Љ-CH), 3.71—3.87 (m, 4H, 1Ј, 3Ј-CH2), 3.34—3.47 (s,
2CH2). IR (KBr) cmϪ1: 3455 (O–H), 3341 (Ar–NH2), 3145 1H, 2Ј-OH), 1.56—1.77 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1:
(C–H), 1473 (C–N), 1354 (N–H), 1166 (C–O), 867, 736 1424 (C–H), 1347 (C–N), 1137 (C–O), 845, 763 (Ar–H).
(Ar–H). Anal. Calcd for C13H14N2O2: C, 67.82; H, 6.08; N, Anal. Calcd for C11H13N3O2: C, 60.27; H, 5.93; N, 19.17.
12.17. Found: C, 67.71; H, 5.92; N, 12.41.
Found: C, 60.01; H, 5.99; N, 19.31.
2-(2Ј-(4Љ-Nitrophenylamino)-ethanoxy)pyridine 10: Yieldϭ
2-(3Ј-Diethylamino-2Ј-hydroxypropyloxy)-pyridine 15:
1
52%, mp 135 °C. 1H-NMR (CDCl3) d: 6.94—7.15 (m, 4H, 3, Yieldϭ47%, mp 225 °C. H-NMR (CDCl3) d: 7.25—7.42

184
Vol. 26, No. 2
(m, 4H, 3, 4, 5, 6H), 3.71—3.92 (m, 4H, 1Ј, 3Ј-CH2), 3.23—
3.41 (s, 1H, 2Ј-OH), 1.12—1.25 (m, 1H, 2Ј-CH), 0.92—1.1
(s, 10H, (C2H5)2). IR (KBr) cmϪ1: 1463 (C–H), 1343 (C–N),
1146 (C–O), 854, 798 (Ar–H). Anal. Calcd for C12H20N2O2:
C, 64.28; H, 8.92; N, 12.5. Found: C, 64.42; H, 8.73; N,
12.25.
2-(3Ј-Diphenylamino-2Ј-hydroxypropyloxy)-pyridine 16:
Yieldϭ34%, mp 48 °C. 1H-NMR (CDCl3) d: 7.31—7.46 (m,
4H, 3, 4, 5, 6H), 6.35—6.63 (s, 1H, –NH), 5.93—6.08 (m,
10H, (C6H5)2, 3.81—3.97 (m, 4H, 1Ј, 3Ј-CH2), 3.31—3.44
(s, 1H, 2Ј-OH), 1.36—1.52 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1:
1436 (C–H), 1355 (C–N), 1167 (C–O), 825, 745 (Ar–H).
Anal. Calcd for C20H20N2O2: C, 75.0; H, 6.25; N, 8.75.
Found: C, 75.31; H, 6.04; N, 8.52.
2-(3Ј-Diethanolamino-2Ј-hydroxypropyloxy)-pyridine 17:
1
Yieldϭ43%, mp 246 °C. H-NMR (CDCl3) d: 7.54—7.73
(m, 4H, 3, 4, 5, 6H), 3.81—4.03 (m, 4H, 1Ј, 3Ј-CH2), 3.32—
3.47 (s, 1H, 2Ј-OH), 2.34—2.55 (m, 4H, 2Љ, 3Љ, 5Љ, 6ЉH),
1.65—1.81 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1434 (C–H),
1365 (C–N), 1156 (C–O), 845, 756 (Ar–H). Anal. Calcd for
C12H20N2O4: C, 56.25; H, 7.81; N, 10.93. Found: C, 56.04;
H, 7.63; N, 10.71.
2-(3Ј-Phenylamino-2Ј-hydroxypropyloxy)-pyridine 18:
Yieldϭ49%, mp 224 °C. 1H-NMR (CDCl3) d: 7.34—7.5 (m,
4H, 3, 4, 5, 6H), 6.05—6.19 (s, 1H, –NH), 5.91—6.04 (m,
4H, C6H4), 3.76—3.98 (m, 4H, 1Ј, 3Ј-CH2), 3.43—3.59 (s,
1H, 2Ј-OH), 1.65—1.84 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1:
1443 (C–H), 1336 (C–N), 1158 (C–O), 865, 746 (Ar–H).
Anal. Calcd for C14H16N2O2: C, 68.85; H, 6.55; N, 11.47.
Found: C, 68.57; H, 6.32; N, 11.28.
Fig. 1. Synthetic Scheme
2-(3Ј-(4Љ-HydroxyPhenylamino)-2Ј-hydroxypropyloxy)-
1
pyridine 19: YieldЈ41%, mp Ͼ300 °C. H-NMR (CDCl3) d:
7.45—7.61 (m, 4H, 3, 4, 5, 6H), 6.45—6.67 (s, 1H, –OH),
6.15—6.29 (s, 1H, –NH), 5.94—6.02 (m, 4H, C6H4), 3.95—
4.22 (m, 4H, 1Ј, 3Ј-CH2), 3.33—3.47 (s, 1H, 2Ј-OH), 1.56—
1.72 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1434 (C–H), 1358
(C–N), 1176 (C–O), 856, 787 (Ar–H). Anal. Calcd for
C14H16N2O3: C, 64.61; H, 6.15; N, 10.76. Found: C, 64.37;
H, 6.32; N, 10.52.
2-(3Ј-Methylamino-2Ј-hydroxypropyloxy)-pyridine
20:
1
Yieldϭ47%, mp Ͼ300 °C. H-NMR (CDCl3) d: 7.11—7.29
(m, 4H, 3, 4, 5, 6H), 3.91—4.2 (m, 4H, 1Ј, 3Ј-CH2), 3.48—
3.59 (s, 1H, 2Ј-OH), 1.67—1.81 (m, 1H, 2Ј-CH), 1.39—1.51
(s, 3H, CH3). IR (KBr) cmϪ1: 1465 (C–H), 1354 (C–N),
1176 (C–O), 856, 787 (Ar–H). Anal. Calcd for C9H14N2O2:
C, 59.34; H, 7.69; N, 15.38. Found: C, 59.49; H, 7.87; N,
15.50.
Fig. 2. Depiction of the Presence of Pharmacophore in 13 Similar to Sym-
patholytic Drugs
PHARMACOLOGY
All the synthesized compounds were screened for anticon-
vulsant activity. The amphetamine antagonism was done at
the dose of 25 mg and 50 mg/kg. The experimental dose for
the amphetamine antagonism was selected between the mini-
mal effective and maximal non-lethal dose. The compounds
were also screened for the cardiac activity on isolated frog
heart. All the compounds were soluble in water and adminis-
tered to the animals as a solution in water for injection and
triple glass distilled water. Wistar albino mice (18—25 g) and
hartely guinea pig of either sex were procured from King In-
Fig. 3. Depiction of the Presence of Pharmacophore in 5 Similar to Anti-
stitute, Guindy, Chennai. They were kept in colony cages at histaminic Drugs

February 2003
185
Table 1. Anticonvulsant and Toxicity Screening Data in Micea)
MESb,c) scMetb,d) Rotarod toxicityb,e)
25Ϯ2 °C, relative humidity 45—55% under 12 h light and
dark cycle (0600 to 1800 h-light; 1800 to 0600 h-dark). All
the animals were acclimatized for a week before use. Small
frogs (Rana trigana, 80—120 g) were procured locally and
used on the same day. Unpaired Student t-test14) was per-
formed to ascertain the significance of the exhibited activity.
Anticonvulsant Activity The compounds were tested
for anticonvulsant activity by using the procedures described
previously.15) All compounds were tested for anticonvulsant
activity with wistar albino mice (nϭ5) in the 18—25 g
weight range. Each compound was administered intraperi-
toneally at three dose levels (30100 and 300 mg/kg). Three
tests were performed for each compound; maximal elec-
troshock (MES) induced convulsions, subcutaneous Metro-
zol (sc-Met) induced convulsions and rotarod neurotoxicity
test (Tox). The compounds were made solution with water
for injection.
Maximal electroshock seizures (MES) were induced
30 min after drug treatment by the application of 50 mA cur-
rent for 0.2 s via corneal electrodes into the eyes. The protec-
tion was defined as the abolition of hind leg and tonic maxi-
mal extension component of the seizure. The subcutaneous
pentylenetetrazole (Metrozol) seizure threshold test (sc-Met)
was carried out by the subcutaneous administration of
pentylenetetrazole (85 mg/kg). Animals were observed for
over 30 min. Failure to observe the generalised clonic seizure
is defined as protection.
Compd
30 min
4 h
30 min
4 h
30 min
4 h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
ϩϩ
Ϫ
ϩϩ
ϩϩ
Ϫ
ϩ
ϩϩ
ϩ
ϩϩ
ϩ
ϩϩ
ϩϩϩ
ϩϩϩ
ϩ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
ϩ
Ϫ
Ϫ
ϩ
Ϫ
ϩ
ϩ
Ϫ
Ϫ
Ϫ
ϩ
ϩ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
ϩ
ϩ
ϩ
Ϫ
ϩ
ϩ
ϩ
ϩ
Ϫ
ϩ
ϩ
ϩ
ϩ
Ϫ
ϩ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
ϩ
Ϫ
Ϫ
Ϫ
Ϫ
ϩ
Ϫ
Ϫ
ϩϩ
ϩϩ
ϩ
ϩ
Ϫ
Ϫ
ϩ
Ϫ
ϩ
ϩ
ϩ
ϩ
ϩ
Ϫ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
ϩ
Ϫ
ϩ
ϩ
Ϫ
Ϫ
Ϫ
ϩ
Ϫ
ϩ
Ϫ
Ϫ
ϩ
Ϫ
ϩ
ϩ
ϩϩ
ϩϩ
ϩ
ϩϩ
ϩ
a) All the compounds were administered intraperitoneally. b) Key: ϩϩϩϭactiv-
ity at 30 mg/kg, ϩϩϭactivity at 100 mg/kg, ϩϭactivity at 300 mg/kg, Ϫϭno activity
at 300 mg/kg. c) Maximal electroshock seizure test. d) Subcutaneous pentylenete-
trazole seizure test. e) Neurologic toxicity (rotarod) test.
Table 2. Quantitative Anticonvulsant Data in Micea)
Minimal neurotoxicity16) (TD50) was measured by the ro-
tarod test (Tox) in mice. Wistar albino mice (nϭ4) were
placed in 1-in. diameter knurled plastic rod rotating 6 rpm
after administration of the drug, and their ability to maintain
their balance was tested. Neurological deficit was indicated
by the inability of the animal to maintain the equilibrium for
1 min on the rotating rod in each of three trials. The results
are tabulated in Tables 1 and 2.
Amphetamine Antagonistic Activity The decrease in
the motor activity17) induced by introceptine stimuli of the
compounds was studied by amphetamine antagonism. Wistar
albino mice (nϭ3) of either sex were selected by random
sampling technique. The compounds were administered at a
dose level 25 mg and 50 mg/kg i.p 30 min prior to the admin-
istration of amphetamine (5 mg/kg, i.p.). Phenobarbital (10
mg/kg, i.p.) was used as the standard drug. The motor activ-
ity of the compounds was observed for 15 min in an octopho-
tometer (3 pair beam Photo Actometer; Inco Pvt. Ltd.; Mum-
bai; India) after 10 min of amphetamine administration. The
percentage reduction of motor activity by the compounds are
presented in Table 3.
b)
ED50
Compound
c)
MES
ScMet
Ͼ250
TD50
1
3
4
7
9
11
12
13
53.4 (39—68)
45.4 (32—48)
48.8 (35—61)
68.4 (56—80)
67.3 (53—81)
47.3 (35—59)
39.3 (30—41)
36.6 (25—46)
57.4 (44—70)
53.7 (41—65)
48.4 (37—59)
44.5 (34—53)
188 (156—219)
210 (177—253) 175 (143—205)
83 (64—102)
Ͼ150
164 (136—197)
127 (92—158)
122 (93—154) 145 (125—165)
Ͼ175 191 (174—203)
165 (146—188) 195 (177—224)
Ͼ175
96 (79—112)
Ͼ150
188 (162—215)
178 (158—198)
167 (143—188)
16
17
19
122 (103—142) 256 (225—279)
145 (125—165) 220 (194—258)
20
Phenytoin
9.9 (6.3—13.1) Ͼ300
69.8 (57.2—80.7)
74.4 (59.1—87.5)
Carbamazepine 9.2 (6.9—11.7) Ͼ125
Valproate
264 (236—297) 157 (133—185) 408 (364—437)
a) Test drugs administered intraperitoneally. b) Doses measured in mg/kg at the
peak effect. c) Doses (mg/kg) determined by rotarod test at the time of peak neuro-
toxic effect.
Cardiac Activity18) Frogs were selected by random sam-
pling technique. Isolated frog heart was mounted using nor-
mal amphibian ringer solution. Drugs may influence the rate
and force of contraction of the heart. An increase in the force
of contraction is called positive ionotropic and decrease in
the force of contraction is marked as negative ionotropic.
Force of the contraction was measured from the recordings
of the frontal lever and they are denoted as negative and posi-
tive ionotropic. The effect of the compounds on the force of
contraction was observed from 1 to 400 mg/dose. The effect
of the compounds at various concentration with simultaneous
administration of adrenaline (100, 200, 400 mg/dose) was
also studied (Table 4).
Evaluation of Antihistaminic Activity19) The terminal
portion of the guinea pig ileum was dissected out from
overnight fasted (water given ad libitum) healthy hartely
strain of guinea pigs. Antihistaminic activity is based on the
antagonism to the contraction of smooth muscle and the cap-
illary dilation produced by histamine. The ileum was
mounted by using tyrode solution bubbled with O2 (95%)
and CO2 (5%) mixture at 37Ϯ0.5 °C in the organ bath. Con-
centration dependent responses of histamine were recorded
using frontal lever. Contact time of 30 s, and 5 min time cycle
are kept for proper recording of the responses. The effect of
the compounds (250, 500, 1000 mg/dose) on histamine-in-
duced contractions was reported in Table 5. Contractile re-

186
Vol. 26, No. 2
sponses (given in table) are derived from the recordings of RESULTS AND DISCUSSION
frontal lever.
The initial evaluation (phase I) of anticonvulsant activity
of synthesized compounds presented in the Table I. The com-
pounds were administered intraperitoneally at three doses
(30, 100, 300 mg/kg).
Table 3. Amphetamine Antagonism of the Compounds
Compound
Dose (mg/kg)
% Reduction of motor activity
As result of preliminary screening, compounds 1, 3, 4, 7,
9, 11—13, 16, 17, 19 and 20 were considered for the phase II
trails. This provides an evaluation of the median effective
dose (ED50) and median neurotoxic dose (TD50). Most of the
compounds were active at 30 min but not at 4 h. These datas
are shown in the Table 2. Some of these derivatives showed
high degree of protection against MES-induced seizures. But
they were found to be less effective against scMet-induced
seizures. Compound 13 was the best in the MES test having
ED50 of 36.3 mg/kg. In the MES test, the ED50 of compounds
1
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
10
26.58*
52.88*
43.56**
86.72*
48.34*
96.48***
39.56**
80.86*
33.46**
66.52***
22.34***
44.42*
26.56*
52.46*
44.84**
88.64*
31.94*
62.44*
14.56**
28.72*
18.48*
35.56**
38.46**
76.68*
34.22*
68.82*
47.44**
94.46*
35.64**
70.42*
23.44**
46.68*
15.34*
31.24*
18.44**
36.64*
24.46*
48.26*
43.42*
86.88*
96.46*
2
3
4
5
6
Table 4. Cardiac Activity of the Compounds
7
Compound
Concentration
Effect on Systole
8
11
1—50 mg of 11
100 mg of 11
Normal
Negative ionotropic
9
100 mg of 11ϩ100 mg of adrenaline Positive ionotropic
400 mg of 11ϩ100 mg of adrenaline Normal
10
12
13
1—100 mg of 12
Negative ionotropic
100 mg of 12ϩ100 mg of adrenaline Positive ionotropic
200 mg of 12ϩ100 mg of adrenaline Normal
11
1—20 mg of 13
20—40 mg of 13
Normal
Negative ionotropic
Positive ionotropic
12
50 mg of 13ϩ100 mg of adrenaline
13
100 mg of 13ϩ100 mg of adrenaline Normal
14
16
1—50 mg of 14
Negative ionotropic
Positive ionotropic
14
60 mg of 14ϩ100 mg of adrenaline
200 mg of 14ϩ100 mg of adrenaline Normal
15
1—50 mg of 16
60—200 mg of 16
Normal
Negative ionotropic
16
200 mg of 16ϩ100 mg of adrenaline Positive ionotropic
400 mg of 16ϩ100 mg of adrenaline Normal
17
17
19
1—50 mg of 17
100 mg of 17
Normal
Negative ionotropic
18
200 mg of 17ϩ100 mg of adrenaline Positive ionotropic
400 mg of 17ϩ100 mg of adrenaline Normal
19
20
1—20 mg of 19
20—200 mg of 19
Normal
Negative ionotropic
200 mg of 19ϩ100 mg of adrenaline Positive ionotropic
400 mg of 19ϩ100 mg of adrenaline Normal
Phenobarbital
* pϽ0.05, ** pϽ0.01, *** pϽ0.001 compared to control.
Table 5. Antihistaminic Activity
Contractile response of guinea pig ileum (in mm)
% Inhibition
of contraction
Compound
Histamine
(500 ng)ϩtest
Histamine
(500 ng)ϩtest
Histamine
(500 ng)ϩtest
Histamine (500 ng)
compound (250 mg)
compound (500 mg)
compound (1000 mg)
1
2
3
4
5
6
7
8
9
39
42
43
37
39
40
42
39
41
39
35
36
39
41
36
36
36
40
35
39
37
28
33
36
39
33
32
33
38
33
37
35
26
32
35
38
32
30
31
36
32
36
34
24
17.9
16.66
13.15
13.51
23.07
22.5
14.28
17.9
12.19
12.82
25.71
10
CPM
CPM: Chlopheniramine maleate.

February 2003
187
was found to be 12 (39.3 mg/kg), 3 (45.5 mg/kg) and 11 more active than the other compounds. 4-Hydroxyphenyl-
(47.3 mg/kg). amino, is more active among secondary amines. Electron
The following structure–activity relationships were ob- pumping groups have prominent role in this effect. Proton
served. In the propanol series (11—20), only compounds pumping groups significantly downplayed the effect of block-
11—13, 16, 17, 19 and 20 were found to have a high degree ing adrenaline in the entire series. The cardiac activity exhib-
of protection against MES-induced convulsions. Piperazino ited by these compounds may be correlated to the presence
substituted compound at the 3rd position showed higher pro- of the pharmacophore similarity to the chemical functionality
tection than the other heterocyclic substitution like mor- present in b-adrenergic blocking agents. When administered
pholino, piperidino and imidazolo compounds. Among the concurrently with adrenaline, the compounds exhibited sig-
tertiary amines, diethanolamino substituted at 3rd position nificant sympatholytic action. The compounds were able to
offered more protection than other tertiary amino compounds block the effects of adrenaline (100, 200, 400 mg).
(diethylamino, diphenylamino). Among the secondary amine
In the antihistaminic activity, almost all the ethane deriva-
substituted compounds methyl amino compound is more ac- tives showed promising activity, whereas propanol series
tive than other compounds (phenylamino, 4-hydroxyphenyl- compounds found to be inactive. The active compounds were
amino). In the ethane series (1—10), compounds 1, 3, 4, 7 1, 2, 4—6 and 8. Diethylamino and diphenylamino substi-
and 9 were found to have high degree of protection against tuted compounds found to be more active in the entire series.
MES-induced seizures. Only heterocyclic (piperazino and This promising activity may be because of similarity of the
imidazolo) groups substituted at the 2nd position showed functionality with other antihistaminic agents.
more protection than the other substitution.
Irrespective of the aromatic moiety involved all the aryl-
b-Blockers and aryloxypropanolamines20) inhibit adenylyl oxypropanolamines and aryloxyaminopropanes were found
cyclase, which reduces the production of c-AMP (adenosine to possess anticonvulsant activities. Earlier we have reported
mono phosphate). c-AMP activates the phosphorylation of the anticonvulsant activities and sympatholytic activities of
hydroxyl (HO-) group containing aminoacids such as tyro- b-pyridylaminopropanolamines.10) Substituting b-pyridyl-
sine, serine and threonine which causes the enzyme to amino with b-pyridyloxy does not influence both the activi-
change the shape, which causes the release of Ca2ϩ. Since b- ties much.
blockers reduce c-AMP, less Ca ions are released. The
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propanol series of compounds may be correlated to the pres-
ence of the pharmacophore similarity to the chemical func-
tionality present in b-adrenergic blocking agents. It may be
hypothesized that the anticonvulsant activity exerted by some
of the compounds by blocking Ca2ϩ channels. Calcium influx
via voltage-activated Ca2ϩ channels also plays a role in
epileptogenesis and neurodegenerative events, raising the
possibility that the blockade of Ca2ϩ channels may represent
the mechanism of action of these compounds.
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substituted diphenyl and diethanolamino compounds are
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