Pharmacological evaluation of some new 6-amino/methyl pyridine derivatives

Article abstract of DOI:10.1248/cpb.51.162

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-hydroxy-3-piperazinopropylamino)-6-aminopyridine, 2-[2-hydroxy-3-(1- imidazolyl)propylamino]-6-aminopyridine, 2-[2-(1-imidazolyl)ethylamino]-6- methylpyridine and 2-[2-(methylamino)ethylamino]-6-methylpyridine were most active of the series against MES-induced seizures. Compounds 2-[2-(phenylamino)ethylamino]-6-aminopyridine, 2-[2-[bis(2-hydroxyethyl)amino] ethylamino]-6-aminopyridine, 2-[2-(diethylamino)ethylamino]-6-methylpyridine and 2-[2-hydroxy-3-(1-imidazolyl)propylamino]-6-methylpyridine exhibited significant decrease in the elevated motor activity at the dose of 50 mg/kg. Remarkable sympathetic blocking activity was observed with 2-(2-hydroxy-3- piperazinopropylamino)-6-aminopyridine, 2-(2-hydroxy-3-morpholinopropylamino)-6- methylpyridine and 2-(2-hydroxy-3-piperazinopropylamino)-6-methylpyridine only. Compounds 2-[2-(diethylamino)ethylamino]-6-aminopyridine, 2-[2-[bis(2- hydroxyethyl)amino]ethylamino]-6-aminopyridine, and 2-[2-(diethylamino) ethylamino]-6-methylpyridine exhibited significant blocking of histamine induced contraction on guinea pig ileum.

Full text of DOI:10.1248/cpb.51.162

162
Chem. Pharm. Bull. 51(2) 162—170 (2003)
Vol. 51, No. 2
Pharmacological Evaluation of Some New 6-Amino/Methyl Pyridine
Derivatives
Inguva RAVLEE,b Ramaiah SIVAKUMAR,b Nithyanantham MURUGANANTHAM,b
Navaneetharaman ANBALAGAN, Vedachalam GUNASEKARAN, and Joseph THOMAS LEONARD
a
b
,b
*
a Department of Pharmaceutical Chemistry, C. L. Baid Metha College of Pharmacy; Chennai-600 096, India: and
b Department of Pharmaceutical Chemistry and Pharmacology, Vel’s College of Pharmacy, Old Pallavaram; Chennai-600
117, India. Received September 19, 2002; accepted November 21, 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 signifi-
cant anticonvulsant activity. Compounds 2-(2-hydroxy-3-piperazinopropylamino)-6-aminopyridine, 2-[2-hy-
droxy-3-(1-imidazolyl)propylamino]-6-aminopyridine, 2-[2-(1-imidazolyl)ethylamino]-6-methylpyridine and 2-[2-
(methylamino)ethylamino]-6-methylpyridine were most active of the series against MES-induced seizures. Com-
pounds 2-[2-(phenylamino)ethylamino]-6-aminopyridine, 2-[2-[bis(2-hydroxyethyl)amino]ethylamino]-6-amino-
pyridine, 2-[2-(diethylamino)ethylamino]-6-methylpyridine and 2-[2-hydroxy-3-(1-imidazolyl)propylamino]-6-
methylpyridine exhibited significant decrease in the elevated motor activity at the dose of 50 mg/kg. Remarkable
sympathetic blocking activity was observed with 2-(2-hydroxy-3-piperazinopropylamino)-6-aminopyridine, 2-(2-
hydroxy-3-morpholinopropylamino)-6-methylpyridine and 2-(2-hydroxy-3-piperazinopropylamino)-6-methyl-
pyridine only. Compounds 2-[2-(diethylamino)ethylamino]-6-aminopyridine, 2-[2-[bis(2-hydroxyethyl)amino]eth-
ylamino]-6-aminopyridine, and 2-[2-(diethylamino)ethylamino]-6-methylpyridine exhibited significant blocking
of histamine induced contraction on guinea pig ileum.
Key words antihistaminic; anticonvulsant; ethanediamine; arylaminopropanolamine; pyridine; sympatholytic
Pyridines were reported to possess anticonvulsant,1,2) car-
tra were consistent with the assigned structures.
Synthesis of 2-(2-Chloroethylamino)-6-aminopyridine 2,6-Diamino-
diotonic,3) antihypertensive,4) b-adrenergic blocking activ-
pyridine was reacted with 1,2-dichloroethane, using the previously reported
ity.5) Aryloxypropanolamines were reported to be associated
with b-adrenergic blocking,6,7) CNS depressant8) and hy-
potensive9) activities. In view of this potential nature of these
moieties, it was thought worthwhile to study the effects of
two pharmacophoric moieties like pyridine and pro-
panolamine/ethanediamine in a single molecule. We have re-
procedure.10) A solution of sodium methoxide (0.113 mol of sodium and
75 ml of methanol) was added to 0.113 mol of 2,6-diaminopyridine and re-
fluxed for 1 h. Then the methanol was completely removed from the medium
and 10 ml of anhydrous dimethyl formamide (DMF) was added to the dry
residue. A solution of 1,2-dichloroethane (0.113 mol) in 10 ml anhydrous di-
methyl formamide was then added dropwise to the reaction mixture with
continuous stirring. The mixture was stirred for 1 h at room temperature.
ported the potential anticonvulsant activity of arylamino- The product was filtered, dried in vacuum and recrystallised by using chloro-
form–diethylether (1 : 1). Yieldϭ56%, mp 175 °C. 1H-NMR (CDCl3) d:
7.22—7.56 (m, 3H, 3, 4, 5H), 5.82—5.91 (m, 1H, NH), 5.15—5.28 (s, 2H,
6-NH2), 3.89—4.09 (s, 4H, CH2–CH2). IR (KBr) cmϪ1: 1413 (C–H), 1134
(C–O), 745, 723 (Ar–H). Anal. Calcd for C7H10N3Cl: C, 49.12; H, 5.84; N,
24.56. Found: C, 49.36; H, 5.58; N, 24.34.
General Method of Synthesis of 1a to m 2-(2-Chloroethylamino)-6-
aminopyridine was reacted with various amines, using the previously re-
ported procedure.10) A solution of 2-(2-chloroethylamino)-6-aminopyridine
(0.013 mol) and the appropriate amine (0.013 mol) in 40 ml of methanol was
refluxed for 24 h. The product obtained was filtered, vacuum dried and re-
crystallized using 1 : 1 acetone–diethylether (1c, 1e, 1f, 1l), 1 : 1 ethanol–di-
ethylether (1a, 1h, 1k, 1m), 1 : 1 chloroform–diethylether (1b, 1g) and 1 : 1
methanol–diethylether (1d, 1i, 1j).
propanolamine10) of pyridine and arylaminopropanolamine/
aryloxyaminopropane,11—13) to continue our work with the
same intention, it was envisaged that, chemical entities with
both pyridine and arylaminopropanolamine/ethanediamine
moieties would result in compounds of interesting biological
activities.
In the present study, we report the synthesis, the pharma-
cological evaluation, and structure-activity relationship of 2-
(3Ј-substituted-2Ј-hydroxypropylamino/2Ј-substituted-ethyl-
amino)-pyridine. The compounds were characterized by IR,
1H-NMR spectral and elemental analysis. The compounds
were investigated for anticonvulsant activity, the decrease in
the elevated motor activity by introceptive chemical stimuli
(amphetamine antagonistic activity) at the dose level of 25
and 50 mg/kg, cardiac activity on isolated frog heart and anti-
histaminic on guinea pig ileum.
2-(2-Morpholinoethylamino)-6-aminopyridine 1a: Yieldϭ45%, mp
1
250 °C. H-NMR (CDCl3) d: 6.94—7.15 (m, 3H, 3, 4, 5H), 5.58—5.67 (m,
1H, NH), 5.15—5.28 (s, 2H, 6-NH2), 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 C11H18N4O: C,
59.45; H, 8.1; N, 25.22. Found: C, 59.13; H, 8.33; N, 25.51.
2-(2-Piperidinoethylamino)-6-aminopyridine 1b: Yieldϭ42%, mp 234 °C.
Chemistry
1H-NMR (CDCl3) d: 7.39—7.55 (m, 3H, 3, 4, 5H), 5.71—5.8 (m, 1H, NH),
Melting points were determined in open capillary tubes and are uncor- 5.49—5.62 (s, 2H, 7-NH2), 4.23—4.46 (m, 4H, 2CH2), 2.65—2.92(m, 10H,
rected. IR spectra were recorded (in KBr) on Bomem FT-IR spectropho- 2Љ, 3Љ, 4Љ, 5Љ, 6Љ-CH2). IR (KBr) cmϪ1: 1433 (C–H), 1384 (C–N), 1124, 1046
1
tometer M.B Serial II. H-NMR spectra were recorded on 300 MHz Bruker (C–O), 810, 762 (Ar–H). Anal. Calcd for C12H20N4: C, 65.45; H, 9.09; N,
DPX 200. The chemical shifts are reported as parts per million downfield 25.45. Found: C, 65.71; H, 8.81; N, 25.68.
from tetra methyl silane (Me4Si). Microanalyses for C, H, N were performed
2-(2-Piperazinoethylamino)-6-aminopyridine 1c: Yieldϭ49%, mp 190 °C.
in Heraeus CHN Rapid Analyzer. Analyses indicated by the symbols of the 1H-NMR (CDCl3) d: 7.02—7.25 (m, 3H, 3, 4, 5H), 5.8—5.91 (m, 1H, NH),
elements are within Ϯ0.4% of the theoretical values. 1H-NMR and IR spec- 5.3—5.51 (s, 2H, 7-NH2), 4.14—4.25 (m, 4H, 2CH2), 2.82—3.01 (m, 8H,
* To whom correspondence should be addressed. e-mail: alabarae@yahoo.com
© 2003 Pharmaceutical Society of Japan

February 2003
163
2Љ, 3Љ, 5Љ, 6Љ-CH2). IR (KBr) cmϪ1: 1421 (C–H), 1350 (C–N), 1132 (C–O),
806, 791 (Ar–H). Anal. Calcd for C11H19N5: C, 59.72; H, 8.59; N, 31.67.
Found: C, 59.99; H, 8.39; N, 31.25.
then added dropwise to the reaction mixture with continuous stirring. The
mixture was stirred for 1 h at room temperature. The product was filtered,
dried in vacuum and recrystallised by using ethanol–diethylether (1 : 1).
Yieldϭ41%, mp 205 °C. 1H-NMR (CDCl3) d: 7.32—7.55 (m, 3H, 3, 4, 5H),
5.72—5.85 (s, 2H, 7-NH2), 3.66—3.83 (d, Jϭ4.5 Hz, 2H, 3Ј-CH2), 3.37—
3.51 (d, Jϭ5.7 Hz, 2H, 1Ј-CH2), 2.54—2.67 (m, 1H, 2Ј-CH). IR (KBr)
cmϪ1: 1410 (C–H), 1253 (epoxide C–O), 1144 (ether C–O) 833, 785
(Ar–H). Anal. Calcd for C8H11N3O: C, 58.18; H, 6.66; N, 25.45. Found: C,
57.82; H, 6.35; N, 25.8.
General Method of Synthesis of 2a to j A solution of 2-(2,3-
epoxypropylamino)-6-aminopyridine (0.013 mol) and the appropriate amine
(0.013 mol) in 40 ml of methanol was refluxed for 24 h. The product ob-
tained was filtered, vacuum dried and recrystallized using 1 : 1 acetone–di-
ethylether (2b, 2d, 2j), 1 : 1 ethanol–diethylether (2c, 2f, 2g, 2i), 1 : 1 chloro-
form–diethylether (2a) and 1 : 1 methanol–diethylether (2e, 2h).
2-[2-(1-Imidazolyl)ethylamino]-6-aminopyridine 1d: Yieldϭ37%, mp
1
270 °C. H-NMR (CDCl3) d: 6.85—7.03 (m, 3H, 3, 4, 5H), 5.82—5.94 (m,
1H, NH), 5.52—5.61 (s, 2H, 7-NH2), 5.1—5.24 (m, 1H, 2ЈCH), 5.17—5.33
(m, 1H, 4Љ, 5Љ(-CH)), 3.92—4.13 (m, 4H, 2CH2). IR (KBr) cmϪ1: 1435
(C–H), 1361 (C–N), 1118 (C–O), 812, 790 (Ar–H). Anal. Calcd for
C10H13N5: C, 59.11; H, 6.4; N, 34.48. Found: C, 59.35; H, 6.16; N, 34.21.
2-[2-(Diethylamino)ethylamino]-6-aminopyridine 1e: Yieldϭ47%, mp
1
65 °C. H-NMR (CDCl3) d: 6.73—6.96 (m, 3H, 3, 4, 5H), 5.67—5.84 (m,
1H, NH), 5.3—5.51 (s, 2H, 7-NH2), 4.36—4.47 (m, 4H, 2CH2), 1.45—1.79
(s, 10H, (C2H5)2). IR (KBr) cmϪ1: 3125 (C–H), 1445 (C–N), 1346 (N–H),
1186 (C–O), 856, 778 (Ar–H). Anal. Calcd for C11H20N4: C, 63.46; H, 9.61;
N, 26.92. Found: C, 63.17; H, 9.97; N, 26.58.
2-[2-(Diphenylamino)ethylamino]-6-aminopyridine 1f: Yieldϭ54%, mp
75 °C. H-NMR (CDCl3) d: 7.33—7.57 (m, 3H, 3, 4, 5H), 6.24—6.45 (m,
10H, (C6H5)2), 5.8—5.91 (m, 1H, NH), 5.12—5.29 (s, 2H, 7-NH2), 4.37—
4.60 (m, 4H, 2CH2). IR (KBr) cmϪ1: 3067 (C–H), 1443 (C–N), 1355 (N–H),
1167 (C–O), 882, 767 (Ar–H). Anal. Calcd for C19H20N4: C, 75.0; H, 6.57;
N, 18.42. Found: C, 75.28; H, 6.37; N, 18.72.
2-(2-Hydroxy-3-morpholinopropylamino)-6-aminopyridine 2a: Yieldϭ
29%, mp Ͼ300 °C. 1H-NMR (CDCl3) d: 7.18—7.34 (m, 3H, 3, 4, 5H),
5.78—5.94 (m, 1H, NH), 5.3—5.51 (s, 2H, 7-NH2), 3.84—4.06 (m, 4H, 1Ј,
3Ј-CH2), 3.37—3.51 (s, 1H, 2Ј-OH), 2.41—2.68 (m, 4H, 2Љ, 3Љ, 5Љ, 6ЉH),
1.24—1.43 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1425 (C–H), 1389 (C–N),
1144, 1042 (C–O) 833, 785 (Ar–H). Anal. Calcd for C12H20N4O2: C, 57.14;
H, 7.93; N, 22.22. Found: C, 57.48; H, 7.61; N, 22.01.
2-(2-Hydroxy-3-piperidinopropylamino)-6-aminopyridine 2b: Yieldϭ
35%, mp Ͼ300 °C. 1H-NMR (CDCl3) d: 7.11—7.21 (m, 3H, 3, 4, 5H),
5.82—5.9 (m, 1H, NH), 5.23—5.46 (s, 2H, 7-NH2), 3.82—3.98 (m, 4H, 1Ј,
3Ј-CH2), 3.31—3.43 (s, 1H, 2Ј-OH), 2.11—2.2 (m, 10H, 2Љ, 3Љ, 4Љ, 5Љ, 6ЉH),
1.28—1.39 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1477 (C–H), 1383 (C–N), 1141
(C–O), 854, 757 (Ar–H). Anal. Calcd for C13H22N4O: C, 62.4; H, 8.8; N,
22.4. Found: C, 62.12; H, 8.51; N, 22.69.
1
2-[2-[Bis(2-hydroxyethyl)amino]ethylamino]-6-aminopyridine 1g: Yieldϭ
1
56%, mp 85 °C. H-NMR (CDCl3) d: 6.28—6.59 (m, 3H, 3, 4, 5H), 5.69—
5.78 (m, 1H, NH), 5.27—5.43 (s, 2H, 7-NH2), 4.23—4.46 (m, 4H, 2CH2),
3.22—3.43 (s, 2H, 2Љ(-OH)2), 2.98—3.12 (m, 8H, (C2H4)2). IR (KBr) cmϪ1
:
3455 (O–H), 3125 (C–H), 1425 (C–N), 1144 (C–O), 876, 783 (Ar–H). Anal.
Calcd for C11H20N4O2: C, 55.0; H, 8.33; N, 23.33. Found: C, 55.28; H, 8.58;
N, 23.61.
2-[2-(Phenylamino)ethylamino]-6-aminopyridine 1h: Yieldϭ44%, mp
Ͼ300 °C. 1H-NMR (CDCl3) d: 6.44—6.67 (m, 3H, 3, 4, 5H), 5.81—5.9 (m,
1H, NH), 5.69—5.78 (m, 1H, NH), 5.4—5.53 (s, 2H, 7-NH2), 5.03—5.18
(m, 1H, C6H5), 3.77—3.97 (m, 4H, 2CH2). IR (KBr) cmϪ1: 3125 (C–H),
1463 (C–N), 1325 (N–H), 1109 (C–O), 888, 745 (Ar–H). Anal. Calcd for
C13H16N4: C, 68.42; H, 7.01; N, 24.56. Found: C, 68.71; H, 6.87; N, 24.83.
2-[2-(4-Hydroxyphenylamino)ethylamino]-6-aminopyridine 1i: Yieldϭ
2-(2-Hydroxy-3-piperazinopropylamino)-6-aminopyridine 2c: Yieldϭ
48%, mp 290 °C. 1H-NMR (CDCl3) d: 7.02—7.14 (m, 3H, 3, 4, 5H), 6.27—
6.41 (s, 1H, –NH), 5.71—5.87 (s, 1H, –NH), 5.34—5.52 (s, 2H, 7-NH2),
3.81—3.96 (m, 4H, 1Ј, 3Ј-CH2), 3.67—3.82 (s, 1H, 2Ј-OH), 2.3—2.39 (m,
8H, 2Љ, 3Љ, 5Љ, 6ЉCH2), 1.89—1.99 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1453
(C–H), 1347 (C–N), 1124 (C–O), 836, 745 (Ar–H). Anal. Calcd for
C12H21N5O: C, 57.37; H, 8.36; N, 27.88. Found: C, 57.6; H, 8.65; N, 27.54.
2-(2-Hydroxy-3-(1-imidazolyl)propylamino)-6-aminopyridine 2d]: Yieldϭ
1
49%, mp 70 °C. H-NMR (CDCl3) d: 6.94—7.15 (m, 3H, 3, 4, 5H), 6.43—
6.65 (m, 1H, OH), 5.79—5.91(m, 1H, NH), 5.63—5.76 (m, 1H, NH),
5.36—5.51 (s, 2H, 7-NH2), 5.03—5.14 (m, 1H, C6H5), 4.35—4.51 (m, 4H,
2CH2). IR (KBr) cmϪ1: 3455 (O–H), 3341 (Ar–NH2), 3145 (C–H), 1473
(C–N), 1354 (N–H), 1166 (C–O), 867, 736 (Ar–H). Anal. Calcd for
C13H16N4O: C, 63.93; H, 6.55; N, 22.95. Found: C, 63.68; H, 6.83; N, 22.52.
2-[2-(Methylamino)ethylamino)-6-aminopyridine 1j: Yieldϭ52%, mp
1
34%, mp 85 °C. H-NMR (CDCl3) d: 7.11—7.25 (m, 3H, 3, 4, 5H), 6.67—
6.81 (m, 2H, 2Љ-CH), 6.49—6.58 (s, 1H, –NH), 6.29—6.41 (m, 2H, 4Љ, 5Љ-
CH), 5.79—5.91 (s, 2H, 7-NH2), 3.89—4.01 (m, 4H, 1Ј, 3Ј-CH2), 3.31—
3.46 (s, 1H, 2Ј-OH), 1.12—1.27 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1436
(C–H), 1338 (C–N), 1165 (C–O), 846, 757 (Ar–H). Anal. Calcd for
C11H15N5O: C, 56.65; H, 6.43; N, 30.04. Found: C, 56.83; H, 6.64; N, 30.35.
2-[3-(Diethylamino)-2-hydroxypropylamino]-6-aminopyridine 2e: Yieldϭ
47%, mp 128 °C. 1H-NMR (CDCl3) d: 7.02—7.15 (m, 3H, 3, 4, 5H), 6.13—
6.24 (s, 1H, –NH), 5.81—5.92 (s, 2H, 7-NH2), 3.89—3.98 (m, 4H, 1Ј, 3Ј-
CH2), 3.31—3.43 (s, 1H, 2Ј-OH), 1.02—1.11 (s, 10H, (C2H5)2). IR (KBr)
cmϪ1: 1434 (C–H), 1343 (C–N), 1154 (C–O), 845, 745 (Ar–H). Anal. Calcd
for C12H22N4O: C, 60.5; H, 9.24; N, 23.52. Found: C, 60.24; H, 9.58; N,
23.21.
1
210 °C. H-NMR (CDCl3) d: 6.79—6.91 (m, 3H, 3, 4, 5H), 5.83—5.98 (m,
1H, NH), 5.66—5.75 (m, 1H, NH), 5.3—5.51 (s, 2H, 7-NH2), 5.03—5.14
(m, 3H, CH3), 4.14—4.25 (m, 4H, 2CH2). IR (KBr) cmϪ1: 3162 (C–H),
1434 (C–N), 1377 (N–H), 1143 (C–O), 823, 754 (Ar–H). Anal. Calcd for
C8H14N4: C, 57.83; H, 8.43; N, 33.73. Found: C, 57.52; H, 8.71; N, 33.48.
2-[2-(2-Aminophenylamino)ethylamino]-6-aminopyridine 1k: Yieldϭ
49%, mp 200 °C. 1H-NMR (CDCl3) d: 6.94—7.15 (m, 3H, 3, 4, 5H), 5.72—
5.82 (m, 4H, C6H4), 5.57—5.67 (m, 1H, NH), 5.36—5.51 (m, 1H, NH),
5.13—5.24 (s, 2H, 7-NH2), 4.35—4.51 (m, 4H, 2CH2). IR (KBr) cmϪ1
:
2-[3-(Diphenylamino)-2-hydroxypropylamino]-6-aminopyridine 2f:
1
3455 (O–H), 3341 (Ar–NH2), 3145 (C–H), 1473 (C–N), 1354 (N–H), 1166
(C–O), 867, 736 (Ar–H). Anal. Calcd for C11H17N5: C, 60.27; H, 7.76; N,
31.96. Found: C, 60.59; H, 7.99; N, 31.63.
Yieldϭ34%, mp 42 °C. H-NMR (CDCl3) d: 7.56—7.69 (m, 3H, 3, 4, 5H),
6.29—6.37(s, 1H, –NH), 6.03—6.14 (m, 10H, (C6H5)2, 5.57—5.89 (s, 2H,
7-NH2), 3.69—3.83 (m, 4H, 1Ј, 3Ј-CH2), 3.32—3.43 (s, 1H, 2Ј-OH), 1.44—
1.53 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1456 (C–H), 1334 (C–N), 1147
(C–O), 846, 789 (Ar–H). Anal. Calcd for C20H22N4O: C, 71.85; H, 6.58; N,
16.76. Found: C, 71.62; H, 6.41; N, 16.46.
2-[2-(4-Nitrophenylamino)ethylamino]-6-aminopyridine 1l: Yieldϭ52%,
1
mp 125 °C. H-NMR (CDCl3) d: 6.94—7.15 (m, 3H, 3, 4, 5H), 5.82—5.94
(m, 4H, C6H4), 5.57—5.72 (m, 1H, NH), 5.3—5.51 (m, 1H, NH), 5.23—
5.44 (s, 2H, 7-NH2), 4.14—4.25 (m, 4H, 2CH2). IR (KBr) cmϪ1: 3162
(C–H), 1434 (C–N), 1377 (N–H), 1143 (C–O), 823, 754 (Ar–H). Anal.
Calcd for C11H15N5O2: C, 53.01; H, 6.02; N, 28.11. Found: C, 53.37; H,
6.33; N, 27.88.
2-[3-[Bis(2-hydroxyethyl)amino]-2-hydroxypropylamino)-6-aminopyri-
1
dine 2g: Yieldϭ43%, mp 240 °C. H-NMR (CDCl3) d: 7.02—7.17 (m, 3H,
3, 4, 5H), 6.11—6.2 (s, 1H, –NH), 5.68—5.81 (s, 2H, 7-NH2), 3.81—3.94
(m, 4H, 1Ј, 3Ј-CH2), 3.43—3.52 (s, 1H, 2Ј-OH), 2.49—2.63 (m, 4H, 2Љ, 3Љ,
5Љ, 6ЉH), 1.47—1.54 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1434 (C–H), 1357
(C–N), 1176 (C–O) 858, 755 (Ar–H). Anal. Calcd for C12H22N4O3: C, 53.33;
H, 8.14; N, 20.74. Found: C, 53.63; H, 7.93; N, 20.44.
2-[2-(4-Bromophenylamino)ethylamino]-6-aminopyridine 1m: Yieldϭ
1
52%, mp 85 °C. H-NMR (CDCl3) d: 6.94—7.15 (m, 3H, 3, 4, 5H), 5.85—
5.98 (m, 4H, C6H4), 5.57—5.72 (m, 1H, NH), 5.3—5.51 (m, 1H, NH),
5.23—5.44 (s, 2H, 7-NH2), 4.14—4.25 (m, 4H, 2CH2). IR (KBr) cmϪ1
:
2-[2-Hydroxy-3-(phenylamino)propylamino]-6-aminopyridine 2h: Yieldϭ
49%, mp 153 °C. 1H-NMR (CDCl3) d: 7.03—7.14 (m, 3H, 3, 4, 5H), 6.45—
6.68 (s, 1H, –NH), 6.04—6.21 (m, 4H, C6H4), 5.45—5.61 (s, 2H, 7-NH2),
3.74—3.86 (m, 4H, 1Ј, 3Ј-CH2), 3.47—3.58 (s, 1H, 2Ј-OH), 1.65—1.82 (m,
1H, 2Ј-CH). IR (KBr) cmϪ1: 1445 (C–H), 1368 (C–N), 1187 (C–O), 863,
765 (Ar–H). Anal. Calcd for C14H18N4O: C, 65.11; H, 6.97; N, 21.7. Found:
C, 65.43; H, 6.67; N, 21.43.
2-[2-Hydroxy-3-(4-hydroxyphenylamino)propylamino]-6-aminopyridine
2i: Yieldϭ41%, mp 55 °C. 1H-NMR (CDCl3) d: 7.15—7.28 (m, 3H, 3, 4,
5H), 6.51—6.74 (s, 1H, –OH), 6.15—6.29 (s, 1H, –NH), 5.93—6.08 (m,
3162 (C–H), 1434 (C–N), 1377 (N–H), 1143 (C–O), 823, 754 (Ar–H). Anal.
Calcd for C11H15N4Br: C, 48.36; H, 5.49; N, 20.52. Found: C, 48.62; H,
5.61; N, 20.25.
Synthesis of 2-(2,3-Epoxypropylamino)-6-aminopyridine A solution
of sodium methoxide (0.113 mol of sodium and 75 ml of methanol) was
added to 0.113 mol of 2,6-diaminopyridine and refluxed for 1 h. Then the
methanol was completely removed from the medium and 10 ml of anhydrous
dimethyl formamide (DMF) was added to the dry residue. A solution of
epichlorohydrin (0.113 mol) in 10 ml anhydrous dimethyl formamide was

164
Vol. 51, No. 2
4H, C6H4), 5.78—5.94 (s, 2H, 7-NH2), 3.88—3.98 (m, 4H, 1Ј,3Ј-CH2),
2-[2-(Phenylamino)ethylamino]-6-methylpyridine 3h: Yieldϭ44%, mp
223—224 °C. 1H-NMR (CDCl3) d: 6.44—6.67 (m, 3H, 3, 4, 5H), 5.57—
3.37—3.51 (s, 1H, 2Ј-OH), 1.34—1.41 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1
:
1445 (C–H), 1356 (C–N), 1185 (C–O), 863, 768 (Ar–H). Anal. Calcd for 5.72 (m, 1H, NH), 5.23—5.44 (m, 1H, C6H5), 3.77—3.97 (m, 4H, 2CH2),
C14H18N4O2: C, 61.31; H, 6.56; N, 20.43. Found: C, 61.12; H, 6.28; N, 3.42—3.54 (s, 3H, 4-CH3). IR (KBr) cmϪ1: 3125 (C–H), 1463 (C–N), 1325
20.71.
(N–H), 1109 (C–O), 888, 745 (Ar–H). Anal. Calcd for C14H17N3: C, 74.0; H,
2-(2-Hydroxy-3-methylamino)propylamino)-6-amino pyridine 2j: Yieldϭ 7.48; N, 18.5. Found: C, 74.34; H, 7.18; N, 18.78.
1
47%, mp 220—221 °C. H-NMR (CDCl3) d: 7.09—7.24 (m, 3H, 3, 4, 5H),
2-[2-(4-Hydroxyphenylamino)ethylamino]-6-methylpyridine 3i: Yieldϭ
6.23—6.35 (s, 1H, –NH), 6.05—6.16 (s, 1H, –NH), 5.67—5.79 (s, 2H, 7- 49%, mp 79—80 °C. 1H-NMR (CDCl3) d: 6.94—7.15 (m, 3H, 3, 4, 5H),
NH2), 3.81—3.97 (m, 4H, 1Ј, 3Ј-CH2), 3.47—3.58 (s, 1H, 2Ј-OH), 1.98— 6.43—6.65 (m, 1H, OH), 5.57—5.72 (m, 1H, NH), 5.23—5.44 (m, 1H,
2.12 (m, 1H, 2Ј-CH), 1.29—1.42 (s, 3H, CH3). IR (KBr) cmϪ1: 1442 (C–H),
1378 (C–N), 1158 (C–O), 853, 754 (Ar–H). Anal. Calcd for C9H16N4O: C,
55.1; H, 8.16; N, 28.57. Found: C, 55.36; H, 8.46; N, 28.2.
C6H5), 4.35—4.51 (m, 4H, 2CH2), 3.13—3.25 (s, 3H, 4-CH3). IR (KBr)
cmϪ1: 3455 (O–H), 3341 (Ar–NH2), 3145 (C–H), 1473 (C–N), 1354 (N–H),
1166 (C–O), 867, 736 (Ar–H). Anal. Calcd for C14H17N3O: C, 69.13; H,
Synthesis of 2-(2-Chloroethylamino)-6-methylpyridine A solution of 6.99; N, 17.28. Found: C, 69.26; H, 6.63; N, 17.49.
sodium methoxide (0.113 mol of sodium and 75 ml of methanol) was added
2-[2-(Methylamino)ethylamino]-6-methylpyridine 3j: Yieldϭ52%, mp
to 0.113 mol of 2-amino-6-methylpyridine and refluxed for 1 h. Then the 281—282 °C. 1H-NMR (CDCl3) d: 6.99—7.11 (m, 3H, 3, 4, 5H), 5.67—
methanol was completely removed from the medium and 10 ml of anhydrous 5.79 (m, 1H, NH), 5.23—5.44 (m, 4H, C6H4), 4.24—4.35 (m, 4H, 2CH2),
dimethyl formamide (DMF) was added to the dry residue. A solution of 1,2- 3.32—3.68 (s, 3H, 4-CH3). IR (KBr) cmϪ1: 3162 (C–H), 1434 (C–N), 1377
dichloroethane (0.113 mol) in 10 ml anhydrous dimethyl formamide was (N–H), 1143 (C–O), 823, 754 (Ar–H). Anal. Calcd for C9H15N3: C, 65.45;
then added dropwise to the reaction mixture with continuous stirring. The H, 9.09; N, 25.45. Found: C, 65.69; H, 9.29; N, 25.29.
mixture was stirred for 1 h at room temperature. The product was filtered,
Synthesis of 2-(2,3-Epoxypropylamino)-6-methylpyridine A solution
dried in vacuum and recrystallised by using chloroform–diethylether (1 : 1). of sodium methoxide (0.113 mol of sodium and 75 ml of methanol) was
1
Yieldϭ56%, mp 78—79 °C. H-NMR (CDCl3) d: 7.22—7.56 (m, 3H, 3, 4, added to 0.113 mol of 2-amino-6-methylpyridine and refluxed for 1 h. Then
5H), 3.89—4.09 (s, 4H, CH2–CH2), 3.32—3.68 (s, 3H, 4-CH3). IR (KBr) the methanol was completely removed from the medium and 10 ml of anhy-
cmϪ1: 1413 (C–H), 1134 (C–O), 745, 723 (Ar–H). Anal. Calcd for drous dimethyl formamide (DMF) was added to the dry residue. A solution
C8H11N2Cl: C, 56.47; H, 6.47; N, 10.47. Found: C, 56.15; H, 6.72; N, 10.66.
of epichlorohydrin (0.113 mol) in 10 ml anhydrous dimethyl formamide was
General Method of Synthesis of 3a to j A solution of 2-(2-chloroeth- then added dropwise to the reaction mixture with continuous stirring. The
ylamino)-6-methylpyridine (0.013 mol) and the appropriate amine mixture was stirred for 1 h at room temperature. The product was filtered,
(0.013 mol) in 40 ml of methanol was refluxed for 24 h. The product ob- dried in vacuum and recrystallised by using ethanol–diethylether (1 : 1).
1
tained was filtered, vacuum dried and recrystallized using 1 : 1 acetone–di- Yieldϭ41%, mp 213—214 °C. H-NMR (CDCl3) d: 7.32—7.55 (m, 3H, 3,
ethylether (3a, 3d, 3g), 1 : 1 ethanol–diethylether (3c, 3e, 3i), 1 : 1 chloro- 4, 5H), 3.66—3.83 (d, Jϭ4.5 Hz, 2H, 3Ј-CH2), 3.73—3.88 (s, 3H, 4-CH3),
form–diethylether (3b, 3j) and 1 : 1 methanol–diethylether (3f, 3h).
2-(2-Morpholinoethylamino)-6-methylpyridine 3a: Yieldϭ45%, mp (KBr) cmϪ1: 1410 (C–H), 1253 (epoxide C–O), 1144 (ether C–O) 833, 785
Ͼ300 °C. 1H-NMR (CDCl3) d: 6.94—7.15 (m, 3H, 3, 4, 5H), 4.14—4.25
(Ar–H). Anal. Calcd for C9H12N2O: C, 65.85; H, 7.31; N, 17.07. Found: C,
3.37—3.51 (d, Jϭ5.7 Hz, 2H, 1Ј-CH2), 2.54—2.67 (m, 1H, 2Ј-CH). IR
(m, 4H, 2CH2), 3.22—3.41 (s, 3H, 4-CH3), 2.91—3.03 (m, 8H; 2Љ, 3Љ, 5Љ, 6Љ- 65.57; H, 7.58; N, 17.38.
CH2). IR (KBr) cmϪ1: 3122 (C–H), 1443 (C–N), 1345 (N–H), 1109 (C–O),
General Method of Synthesis of 4a to j A solution of 2-(2,3-
850, 790 (Ar–H). Anal. Calcd for C12H19N3O: C, 65.15; H, 8.59; N, 19.0. epoxypropylamino)-6-methylpyridine (0.013 mol) and the appropriate amine
Found: C, 65.47; H, 8.23; N, 19.31.
(0.013 mol) in 40 ml of methanol was refluxed for 24 h. The product ob-
2-(2-Piperidinoethylamino)-6-methylpyridine 3b: Yieldϭ42%, mp 268— tained was filtered, vacuum dried and recrystallized using 1 : 1 acetone–di-
1
269 °C. H-NMR (CDCl3) d: 7.39—7.55 (m, 3H, 3, 4, 5H), 4.23—4.46 (m, ethylether (4a, 4f, 4h), 1 : 1 ethanol–diethylether (4d, 4e, 4g, 4j), 1 : 1 chlo-
4H, 2CH2), 3.22—3.39 (s, 3H, 4-CH3), 2.65—2.92 (m, 10H, 2Љ, 3Љ, 4Љ, 5Љ,
roform–diethylether (4b) and 1 : 1 methanol–diethylether (4c, 4i).
6Љ-CH2). IR (KBr) cmϪ1: 1433 (C–H), 1384 (C–N), 1124, 1046 (C–O), 810,
2-(2-Hydroxy-3-morpholinopropylamino)-6-methylpyridine 4a: Yieldϭ
1
762 (Ar–H). Anal. Calcd for C13H21N3: C, 71.23; H, 9.58; N, 19.17. Found: 29%, mp 248—249 °C. H-NMR (CDCl3) d: 7.11—7.24 (m, 3H, 3, 4, 5H),
C, 71.55; H, 9.82; N, 19.45.
3.84—4.06 (m, 4H, 1Ј, 3Ј-CH2), 3.42—3.52 (s, 3H, 4-CH3), 3.37—3.51 (s,
1H, 2Ј-OH), 2.41—2.68 (m, 4H, 2Љ, 3Љ, 5Љ, 6ЉH), 1.29—1.39 (m, 1H, 2Ј-
CH). IR (KBr) cmϪ1: 1425 (C–H), 1345 (C–N), 1134 (C–O), 864, 756
(Ar–H). Anal. Calcd for C13H21N3O2: C, 62.15; H, 8.36; N, 16.73. Found: C,
2-(2-Piperazinoethylamino)-6-methylpyridine 3c: Yieldϭ49%, mp
Ͼ300 °C. 1H-NMR (CDCl3) d: 6.94—7.15 (m, 3H, 3, 4, 5H), 5.57—5.72
(m, 1H, NH), 4.14—4.25 (m, 4H, 2CH2), 3.49—3.53 (s, 3H, 4-CH3), 2.82—
3.01 (m, 8H, 2Љ, 3Љ, 5Љ, 6Љ-CH2). IR (KBr) cmϪ1: 1421 (C–H), 1350 (C–N), 62.42; H, 8.65; N, 16.51.
1132 (C–O), 806, 791 (Ar–H). Anal. Calcd for C12H20N4: C, 65.45; H, 9.09;
N, 25.45. Found: C, 65.71; H, 9.33; N, 25.08.
2-(2-Hydroxy-3-piperidinopropylamino)-6-methylpyridine 4b: Yieldϭ
35%, mp 224—225 °C. H-NMR (CDCl3) d: 7.57—7.82 (m, 3H, 3, 4, 5H),
3.73—3.89 (m, 4H, 1Ј, 3Ј-CH2), 3.32—3.46 (s, 3H, 4-CH3), 3.17—3.29 (s,
1
2-[2-(1-Imidazolyl)ethylamino]-6-methylpyridine 3d: Yieldϭ37%, mp
265—266 °C. 1H-NMR (CDCl3) d: 6.85—7.03 (m, 3H, 3, 4, 5H), 5.6—5.84 1H, 2Ј-OH), 2.49—2.58 (m, 10H, 2Љ, 3Љ, 4Љ, 5Љ, 6ЉH), 1.67—1.84 (m, 1H, 2Ј-
(m, 1H, 2ЈCH), 5.27—5.43 (m, 1H, 4Љ, 5Љ(-CH)), 3.92—4.13 (m, 4H, 2CH2),
CH). IR (KBr) cmϪ1: 1445 (C–H), 1343 (C–N), 1135 (C–O), 856, 745
3.5—3.69 (s, 3H, 4-CH3). IR (KBr) cmϪ1: 1435 (C–H), 1361 (C–N), 1118 (Ar–H). Anal. Calcd for C14H23N3O: C, 67.46; H, 9.23; N, 16.86. Found: C,
(C–O), 812, 790 (Ar–H). Anal. Calcd for C11H14N4: C, 65.34; H, 6.93; N, 67.19; H, 9.69; N, 16.51.
27.72. Found: C, 65.63; H, 6.77; N, 27.49.
2-(2-Hydroxy-3-piperazinopropylamino)-6-methylpyridine 4c: Yieldϭ
1
2-[2-(Diethylamino)ethylamino]-6-methylpyridine 3e: Yieldϭ47%, mp 48%, mp 198—199 °C. H-NMR (CDCl3) d: 7.34—7.44 (m, 3H, 3, 4, 5H),
278—279 °C. 1H-NMR (CDCl3) d: 6.73—6.96 (m, 3H, 3, 4, 5H), 4.36— 6.28—6.4 (s, 1H, –NH), 3.81—3.92 (m, 4H, 1Ј, 3Ј-CH2), 3.39—3.53 (s, 3H,
4.47 (m, 4H, 2CH2), 3.2—3.33 (s, 3H, 4-CH3), 1.45—1.79 (s, 10H,
4-CH3), 3.39—3.49 (s, 1H, 2Ј-OH), 2.49—2.68 (m, 8H, 2Љ, 3Љ, 5Љ, 6ЉCH2),
(C2H5)2). IR (KBr) cmϪ1: 3125 (C–H), 1445 (C–N), 1346 (N–H), 1186 1.68—1.92 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1434 (C–H), 1374 (C–N), 1179
(C–O), 856, 778 (Ar–H). Anal. Calcd for C12H21N3: C, 69.56; H, 10.14; N, (C–O), 857, 758 (Ar–H). Anal. Calcd for C13H22N4O: C, 62.4; H, 8.8; N,
27.72. Found: C, 69.36; H, 10.37; N, 27.56.
22.4. Found: C, 62.2; H, 8.58; N, 22.07.
2-[2(Diphenylamino)ethylamino]-6-methylpyridine 3f: Yieldϭ54%, mp
2-(2-Hydroxy-3-(1-imidazolyl)propylamino)-6-methylpyridine 4d: Yieldϭ
34%, mp 185—186 °C. H-NMR (CDCl3) d: 7.23—7.32 (m, 3H, 3, 4, 5H),
1
Ͼ300 °C. 1H-NMR (CDCl3) d: 7.33—7.57 (m, 3H, 3, 4, 5H), 6.24—6.45
(m, 10H, (C6H5)2), 4.37—4.60 (m, 4H, 2CH2), 3.39—3.53 (s, 3H, 4-CH3). 6.66—6.82 (m, 2H, 2Љ-CH), 6.36—6.51 (m, 2H, 4Љ, 5Љ-CH), 3.78—3.93 (m,
IR (KBr) cmϪ1: 3067 (C–H), 1443 (C–N), 1355 (N–H), 1167 (C–O), 882,
767 (Ar–H). Anal. Calcd for C20H21N3: C, 79.2; H, 6.93; N, 13.86. Found: C, 1.44—1.58 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1435 (C–H), 1356 (C–N), 1164
4H, 1Ј, 3Ј-CH2), 3.39—3.56 (s, 3H, 4-CH3), 3.17—3.26 (s, 1H, 2Ј-OH),
79.49; H, 6.68; N, 13.61.
(C–O), 858, 748 (Ar–H). Anal. Calcd for C12H16N4O: C, 62.06; H, 6.89; N,
24.13. Found: C, 62.35; H, 6.64; N, 24.42.
2-[3-(Diethylamino)-2-hydroxypropylamino]-6-methylpyridine 4e: Yieldϭ
47%, mp Ͼ300 °C. 1H-NMR (CDCl3) d: 7.28—7.39 (m, 3H, 3, 4, 5H),
3.82—3.95 (m, 4H, 1Ј, 3Ј-CH2), 3.49—3.62 (s, 3H, 4-CH3), 3.17—3.3 (s,
2-[2-[Bis(2-hydroxyethyl)amino]ethylamino)-6-methylpyridine 3g: Yieldϭ
56%, mp Ͼ300 °C. 1H-NMR (CDCl3) d: 6.28—6.59 (m, 3H, 3, 4, 5H),
4.23—4.46 (m, 4H, 2CH2), 3.45—3.52 (s, 3H, 4-CH3), 3.22—3.43 (s, 2H,
2Љ(–OH)2), 2.98—3.12 (m, 8H, (C2H4)2). IR (KBr) cmϪ1: 3455 (O–H), 3125
(C–H), 1425 (C–N), 1144 (C–O), 876, 783 (Ar–H). Anal. Calcd for 1H, 2Ј-OH), 1.44—1.56 (m, 1H, 2Ј-CH), 1.28—1.43 (s, 10H, (C2H5)2). IR
C12H21N3O2: C, 64.57; H, 9.41; N, 18.83. Found: C, 64.22; H, 9.53; N, (KBr) cmϪ1: 1435 (C–H), 1339 (C–N), 1136 (C–O), 845, 745 (Ar–H). Anal.
18.56.
Calcd for C13H23N3O: C, 65.82; H, 9.7; N, 17.72. Found: C, 65.57; H, 9.48;

February 2003
165
N, 17.46.
30 min after drug treatment by application of 50 mA current
for 0.2 s via corneal electrodes into the eyes. The protection
was defined as the abolition of hind leg and tonic maximal
extension component of the seizure. The subcutaneous
2-[3-(Diphenylamino)-2-hydroxypropylamino]-6-methylpyridine 4f:
Yieldϭ34%, mp 285—286 °C. H-NMR (CDCl3) d: 7.37—7.52 (m, 3H, 3,
4, 5H), 6.45—6.58 (s, 1H, –NH), 6.12—6.28 (m, 10H, (C6H5)2), 3.81—3.93
1
(m, 4H, 1Ј, 3Ј-CH2), 3.31—3.44 (s, 3H, 4-CH3), 3.06—3.21 (s, 1H, 2Ј-OH),
1.43—1.57 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1443 (C–H), 1394 (C–N), 1154 pentylenetetrazole (Metrozol) seizure threshold test (sc-Met)
(C–O), 873, 737 (Ar–H). Anal. Calcd for C21H23N3O: C, 75.67; H, 6.9; N,
12.61. Found: C, 75.37; H, 6.56; N, 12.75.
2-[3-[Bis(2-hydroxyethyl)amino]-2-hydroxypropylamino]-6-methylpyri-
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.
Minimal neurotoxicity (TD50) was measured by the rotarod
test (Tox). Wistar albino mice (nϭ4) were placed in 1-in. di-
ameter 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 rotat-
ing rod in each of three trials. The results are tabulated in Ta-
dine 4g: Yieldϭ43%, mp Ͼ300 °C. 1H-NMR (CDCl3) d: 7.28—7.4 (m, 3H,
3, 4, 5H), 3.81—3.93 (m, 4H, 1Ј, 3Ј-CH2), 3.53—3.67 (s, 3H, 4-CH3),
3.36—3.47 (s, 1H, 2Ј-OH), 2.43—2.56 (m, 4H, 2Љ, 3Љ, 5Љ, 6ЉH), 1.35—1.47
(m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1442 (C–H), 1353 (C–N), 1158 (C–O),
876, 756 (Ar–H). Anal. Calcd for C13H23N3O3: C, 57.99; H, 8.55; N, 15.61.
Found: C, 57.63; H, 8.79; N, 15.88.
2-[2-Hydroxy-3-(phenylamino)propylamino)-6-methylpyridine 4h: Yieldϭ
49%, mp Ͼ300 °C. 1H-NMR (CDCl3) d: 7.45—7.62 (m, 3H, 3, 4, 5H),
6.12—6.24 (s, 1H, –NH), 5.93—6.08 (m, 4H, C6H4), 3.69—3.82 (m, 4H, 1Ј,
3Ј-CH2), 3.48—3.67 (s, 3H, 4-CH3), 3.39—3.48 (s, 1H, 2Ј-OH), 1.45—1.67
(m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1475 (C–H), 1337 (C–N), 1187 (C–O),
843, 745 (Ar–H). Anal. Calcd for C15H19N3O: C, 70.03; H, 7.39; N, 16.34.
Found: C, 69.79; H, 7.51; N, 16.66.
Table 1. Anticonvulsant and Toxicity Screening Data in Mice (i.p.)
2-[2-Hydroxy-3-(4-hydroxyphenylamino)propylamino]-6-methylpyridine
4i: Yieldϭ41%, mp 202—203 °C. 1H-NMR (CDCl3) d: 7.31—7.48 (m, 3H,
3, 4, 5H), 6.53—6.67 (s, 1H, –OH), 6.35—6.47 (s, 1H, –NH), 5.91—6.04
(m, 4H, C6H4), 3.83—3.97 (m, 4H, 1Ј, 3Ј-CH2), 3.46—3.62 (s, 3H, 4-CH3),
3.13—3.25 (s, 1H, 2Ј-OH), 1.4—1.61 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 1452
(C–H), 1323 (C–N), 1136 (C–O), 853, 745 (Ar–H). Anal. Calcd for
C15H19N3O2: C, 65.93; H, 6.95; N, 15.38. Found: C, 65.59; H, 6.69; N,
15.61.
MESa,b)
30 min
scMeta,c)
30 min
Rotarod toxicitya,d)
Compd.
4 h
4 h
30 min
4 h
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1d
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ϩϩ
ϩ
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Ϫ
2-[2-Hydroxy-3-(methylamino)propylamino]-6-methylpyridine 4j: Yieldϭ
1
47%, mp 290—291 °C. H-NMR (CDCl3) d: 7.34—7.45 (m, 3H, 3, 4, 5H),
3.82—3.94 (m, 4H, 1Ј, 3Ј-CH2), 3.42—3.55 (s, 3H, 4-CH3), 3.22—3.41 (s,
1H, 2Ј-OH), 2.37—2.51 (m, 1H, 2Ј-CH), 1.63—1.74 (s, 3H, CH3). IR (KBr)
cmϪ1: 1453 (C–H), 1334 (C–N), 1134 (C–O), 858, 775 (Ar–H). Anal. Calcd
for C10H17N3O: C, 61.53; H, 8.71; N, 21.53. Found: C, 61.31; H, 8.95; N,
21.79.
1k
1l
Pharmacology
1m
2a
2b
2c
2d
2e
2f
2g
2h
2I
2j
3a
3b
3c
3d
3e
3f
3g
3h
3I
3j
4a
4b
4c
4d
4e
4f
4g
4h
4I
4j
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-
stitute, Guindy, Chennai. They were kept in colony cages at
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.15,16) All compounds were tested for anticonvulsant
activity with wistar albino mice (nϭ5). Each compound was
administered intraperitoneally at three dose levels (30, 100,
300 mg/kg). Three tests were performed for each compound;
maximal electroshock (MES) induced convulsions, subcuta-
neous Metrozol (sc-Met) induced convulsions and rotarod
neurotoxicity test (Tox). The compounds were made solution
with water for injection.
ϩ
ϩ
ϩϩ
ϩϩ
ϩ
ϩϩ
ϩ
ϩ
ϩϩϩ
ϩ
ϩϩ
ϩϩ
ϩϩ
ϩϩ
ϩ
ϩ
ϩ
ϩ
ϩϩ
ϩ
a) Key: ϩϩϩϭactivity at 30 mg/kg, ϩϩϭactivity at 100 mg/kg, ϩϭactivity at
300 mg/kg, Ϫϭno activity at 300 mg/kg. b) Maximal electroshock seizure test. c)
Maximal electroshock seizures (MES) were induced Subcutaneous pentylenetetrazole seizure test. d) Neurologic toxicity (rotarod) test.

166
Vol. 51, No. 2
Table 2. Quantitative Anticonvulsant Data in Mice (Test Drug Adminis- Table 3. Amphetamine Antagonism of the Compounds
tered i.p.)
% Reduction of
motor activity
Compound
Dose (mg/kg)
a)
ED50
b)
Compound
TD50
MES
ScMet
1a
1b
1c
1d
1e
1f
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
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
34.26*
68.48*
30.34*
60.22*
42.24*
84.56*
33.44*
66.82*
32.34*
64.24*
26.28*
52.66*
25.46*
50.84*
46.52**
92.48*
36.46*
72.84*
22.6**
44.42*
16.46*
32.62**
33.44**
66.48*
39.42*
68.68*
41.24**
82.48*
28.44**
56.28*
21.68**
42.46*
43.56*
86.84*
25.34**
50.36*
32.54*
64.46*
52.48*
98.88*
36.2**
72.66*
19.58*
38.46*
32.24**
64.48*
22.36**
44.48*
41.48*
82.82*
29.54**
58.42*
33.36*
66.48**
48.2*
1c
1d
1g
2a
2c
2d
2I
3c
3d
3f
3I
4a
4b
4c
4d
115.9 (95—135)c)
102.6 (92—124)
135 (110—163)
111 (93—129)
89 (74—104)
95 (78—114)
126 (104—145) 155 (134—173) 188 (168—208)
145 (122—163)
98 (81—114)
123 (105—145) 159 (141—179) 220 (194—258)
41.9 (31—53) Ͼ200 188 (156—219)
Ͼ200
250 (231—272)
150 (135—165) 175 (152—203)
Ͼ100 227 (209—244)
159 (137—180) 245 (225—266)
Ͼ190 206 (178—234)
172 (153—190) 288 (258—314)
Ͼ170
177 (153—198)
182 (165—203) 256 (225—279)
1g
1h
1I
1j
142 (120—165) 179 (157—197) 225 (193—255)
130 (112—153) 156 (138—174) 184 (156—207)
105 (86—124)
Ͼ175
227 (192—258)
125 (102—148) 156 (135—174) 175 (155—197)
4I
129 (101—153)
9.9 (6.3—13.1)
9.2 (6.9—11.7)
Ͼ250
Ͼ300
Ͼ125
195 (177—224)
69.8 (57.2—80.7)
74.4 (59.1—87.5)
Phenytoin
Carbamazepine
Valproate
264 (236—297) 157 (133—185) 408 (364—437)
1k
1l
a) Doses measured in mg/kg at the peak effect. b) Doses (mg/kg) determined by
rotarod test at the time of peak neuro toxic effect. c) 95% confidence limits.
1m
2a
2b
2c
2d
2e
2f
bles 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 (nϭ6) 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 ad-
ministration of amphetamine (5 mg/kg, i.p.). Phenobarbital
(10 mg/kg, i.p.) was used as the standard drug. The motor ac-
tivity of the animals (groupwise) was observed for 15 min in
an octophotometer after 10 min of amphetamine administra-
tion. 70% decrease in motor activity is defined as significant
decrease in motor activity. The percentage reduction of
motor activity by the compounds are presented in Table 3.
Cardiac Activity18) Isolated frog heart was mounted
using normal amphibian ringer solution. The effect of the
compounds on the rate and force of contraction was observed
from 1 to 400 mg/animal. The effect of the compounds at var-
ious concentration with simultaneous administration of
adrenaline (100, 200, 400 mg/dose) was also studied (Table
4).
2g
2h
2I
2j
3a
3b
3c
3d
3e
3f
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 based on the an-
tagonism to the contraction of smooth muscle and the capil-
lary dilation produced by histamine. The ileum was mounted
by using tyrode solution bubbled with O2 (95%) and CO2
(5%) mixture at 37Ϯ0.5 °C. The effect of the compounds
(250, 500, 1000 mg/dose) on histamine-induced contractions
was reported in Table 5.
96.28*
22.48*
44.66*
11.36*
22.28*
31.54*
62.64*
43.56*
86.42*
41.46*
82.24*
21.48*
42.24*
3g
3h
3I
3j
Results and Discussion
The initial evaluation (phase I) of anticonvulsant activity
of synthesized compounds were presented in the Table 1. The
compounds were administered intraperitoneally at three
4a

February 2003
167
Table 3. Continued
Table 4. Cardiac Activity of the Compounds
% Reduction of
motor activity
Compound
Concentration
Effect on systole
Compound
Dose (mg/kg)
2a
1—100 mg of 2a
200 mg of 2a
Normal
Negative ionotropic
4b
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
10
39.54*
78.58*
34.34*
68.46*
46.44*
92.84*
39.44*
78.56*
42.32*
84.64*
42.48*
84.82*
22.48*
44.36*
23.52*
46.34*
45.44*
90.14*
98.44*
200 mg of 2aϩ100 mg of adrenaline Positive ionotropic
400 mg of 2aϩ100 mg of adrenaline Normal
4c
2b
2c
1—50 mg of 2b
100 mg of 2b
Normal
Negative ionotropic
4d
200 mg of 2bϩ100 mg of adrenaline Positive ionotropic
400 mg of 2bϩ100 mg of adrenaline Normal
4e
1—50 mg of 2c
50—80 mg of 2c
Normal
Negative ionotropic
Positive ionotropic
4f
80 mg of 2cϩ100 mg of adrenaline
4g
100 mg of 2cϩ100 mg of adrenaline Normal
2d
2e
1—80 mg of 2d
Negative ionotropic
4h
100 mg of 2dϩ100 mg of adrenaline Positive ionotropic
200 mg of 2dϩ100 mg of adrenaline Normal
4I
4j
1—50 mg of 2e
60—100 mg of 2e
Normal
Negative ionotropic
200 mg of 2eϩ100 mg of adrenaline Positive ionotropic
400 mg of 2eϩ100 mg of adrenaline Normal
Phenobarbitone
2f
1—100 mg of 2f
200 mg of 2f
Normal
Negative ionotropic
* pϽ0.05, ** pϽ0.01, compared to control.
400 mg of 2fϩ100 mg of adrenaline Positive ionotropic
800 mg of 2fϩ100 mg of adrenaline Normal
2g
2h
1—50 mg of 2g
60—100 mg of 2g
Normal
Negative ionotropic
doses (30, 100, 300 mg/kg).
200 mg of 2gϩ100 mg of adrenaline Positive ionotropic
400 mg of 2gϩ100 mg of adrenaline Normal
As result of preliminary screening, compounds 1c, 1d, 1g,
2a, 2c, 2d, 2I, 3c, 3d, 3f, 3I, 4a, 4b, 4c, 4d and 4I were con-
sidered for the phase II trails. The estimation of ED50 and
TD50 values for the protection and their confidence limits are
calculated by probit analysis of the data using the number of
dosed vs. the number of surviving animals. This provides an
evaluation of the median ED50 and median neurotoxic dose
(TD50). These datas are shown in the Table 2. Most of the
compounds were active at 30 min but not at 4 h. Some of
these derivatives showed high degree of protection against
MES-induced seizures. But they were found to be less effec-
tive against scMet-induced seizures. Compound 3i was the
best in the MES test having ED50 of 41.9 mg/kg. In the MES
test, the ED50 of compounds was found to be 2c (89 mg/kg),
2d (95 mg/kg) and 3d (98 mg/kg).
The following structure–activity relationships were ob-
served. In the entire series of propanol, 6-amino substituted
compounds are more active than the corresponding 6-methyl
substituted compounds. In the propanol series of 6-amino
(2a—j), only compounds 2a, 2c, 2d and 2i were found to
have a high degree of protection against MES-induced con-
vulsions. Imidazolo substituted compound at the 3rd position
showed higher protection than the other heterocyclic substi-
tution like morpholino, piperidino and piperazino com-
pounds. Among the secondary amines, 4-hydroxyphenyl-
amino substituted at 3rd position offered more protection
than other secondary amino compounds (phenylamino,
methylamino). In the propanol series of 6-methyl (4a—j),
only compounds 4a, 4b, 4c, 4d and 4i were found to have a
high degree of protection against MES-induced convulsions.
Piperazino substituted compound at the 3rd position showed
higher protection than the other heterocyclic substitution like
morpholino, piperidino and imidazolo compounds. Among
the secondary amines, 4-hydroxyphenylamino substituted at
3rd position offered more protection than other secondary
amino compounds (phenylamino, methylamino).
1—50 mg of 2h
100 mg of 2h
Normal
Negative ionotropic
200 mg of 2hϩ100 mg of adrenaline Positive ionotropic
400 mg of 2hϩ100 mg of adrenaline Normal
2I
2j
1—100 mg of 2I
Negative ionotropic
100 mg of 2Iϩ100 mg of adrenaline Positive ionotropic
200 mg of 2Iϩ100 mg of adrenaline Normal
1—100 mg of 2j
200 mg of 2j
Normal
Negative ionotropic
200 mg of 2jϩ100 mg of adrenaline Positive ionotropic
400 mg of 2jϩ100 mg of adrenaline Normal
4a
4b
1—50 mg of 4a
Negative ionotropic
Positive ionotropic
50 mg of 4aϩ100 mg of adrenaline
100 mg of 4aϩ100 mg of adrenaline Normal
1—50 mg of 4b
50—100 mg of 4b
Normal
Negative ionotropic
100 mg of 4bϩ100 mg of adrenaline Positive ionotropic
200 mg of 4bϩ100 mg of adrenaline Normal
4c
4d
4e
4f
1—20 mg of 4c
20—40 mg of 4c
Normal
Negative ionotropic
Positive ionotropic
50 mg of 4cϩ100 mg of adrenaline
100 mg of 4cϩ100 mg of adrenaline Normal
1—60 mg of 4d
70—200 mg of 4d
Normal
Negative ionotropic
200 mg of 4dϩ100 mg of adrenaline Positive ionotropic
400 mg of 4dϩ100 mg of adrenaline Normal
1—100 mg of 14
Normal
200 mg of 14ϩ100 mg of adrenaline Negative ionotropic
400 mg of 14ϩ100 mg of adrenaline Positive ionotropic
800 mg of 14ϩ100 mg of adrenaline Normal
1—40 mg of 4f
50—100 mg of 4f
Normal
Negative ionotropic
200 mg of 4fϩ100 mg of adrenaline Positive ionotropic
400 mg of 4fϩ100 mg of adrenaline Normal
4g
4h
1—40 mg of 4g
50—100 mg of 4g
Normal
Negative ionotropic
100 mg of 4gϩ100 mg of adrenaline Positive ionotropic
200 mg of 4gϩ100 mg of adrenaline Normal
1—50 mg of 4h
60—200 mg of 4h
Normal
Negative ionotropic
200 mg of 4hϩ100 mg of adrenaline Positive ionotropic
400 mg of 4hϩ100 mg of adrenaline Normal
In the ethane series of 6-amino (1a—m), compounds 1c,

168
Vol. 51, No. 2
Table 5. Antihistaminic Activity
Contractile response of guinea pig ileum (in mm)
Treatment
Compound
Histamine
Histamine
(500 ng)ϩtest
Histamine
% inhibition
Histamine (500 ng)
(500 ng)ϩtest
(500 ng)ϩtest
of contraction
compound (250 mg)
compound (500 mg)
compound (1000 mg)
1a
1b
1c
1d
1e
1f
1g
1h
1I
39
46
41
39
40
42
37
39
39
41
44
38
39
40
42
38
41
38
39
39
41
39
39
38
36
43
38
38
37
40
34
37
36
39
41
36
37
38
39
36
39
35
36
35
39
37
36
35
33
40
36
35
34
37
31
35
34
37
39
35
35
36
38
33
37
32
33
32
37
35
34
32
32
39
34
34
31
34
28
33
32
35
38
34
33
34
36
31
35
29
31
30
35
33
32
28
17.94
15.21
17.07
12.82
22.5
19.04
24.32
15.38
17.94
14.63
13.63
10.52
15.38
15
14.28
18.42
14.63
23.68
17.94
23.07
14.63
15.38
17.94
26.31
1j
1k
1l
1m
3a
3b
3c
3d
3e
3f
3g
3h
3I
3j
CPM
CPM, chlopheniramine maleate.
Fig. 2. Depiction of the Presence of the Pharmacophore in 2c Similar to
Sympatholytic Drugs
found to have high degree of protection against MES-in-
duced seizures. Piperazino and imidazolo groups substituted
at the 2nd position showed more protection than the other
substitutions. 4-Hydroxyphenylamino substituted compound
Fig. 1. Synthetic Scheme
1d and 1g were found to have high degree of protection is more active among all the substitutions.
against MES-induced seizures. Only heterocyclic (piperazino
b-Blockers and aryloxypropanolamines20) inhibit adenylyl
and imidazolo) groups substituted at the 2nd position showed cyclase, which reduces the production of c-AMP (adenosine
more protection than the other substitution. In the ethane se- mono phosphate). c-AMP activates the phosphorylation of
ries of 6-methyl (3a—j), compounds 3c, 3d, 3f and 3i were hydroxyl group containing aminoacids such as tyrosine, ser-

February 2003
169
with respect to propanol series (4a—j) was found to be in the
order of 4dϾ4jϾ4f. Among the heterocyclic groups substi-
tuted at the 3rd position imidazolo substituted compound is
more active than piperidino and piperazino substituted com-
pounds. Among the tertiary amines diphenylamino com-
pound showed promising activity, whereas secondary amine
substituted at the 3rd position methylamino showed better ac-
tivity.
2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2I, 2j, 4a, 4b, 4c, 4d, 4e, 4f,
4g and 4h exhibited potential cardiac activity. None of ethane
series compounds found to be active. Among the propanol
series piperazino substituted compound showed better block-
ing activity than the other heterocyclic compounds where as
all other compounds are less active than piperazino substi-
tuted compound. Among the tertiary amines substituted
amino compounds is more active than the other compounds.
4-hydroxyphenylamino is more active among secondary
amines. Electron pumping groups have prominent role in this
effect. Proton pumping groups significantly downplayed the
effect of blocking adrenaline in the entire series. The cardiac
activity exhibited by these compounds may be correlated to
the presence of the pharmacophore similarity to the chemical
functionality present in b-adrenergic blocking agents. When
administered concurrently with adrenaline, the compounds
exhibited significant sympatholytic action. The compounds
were able to block the effects of adrenaline (100, 200,
400 mg).
In the antihistaminic activity, almost all the ethane deriva-
tives showed promising activity, whereas propanol series of
compounds found to be inactive. The active compounds were
1c, 1e, 1f, 1g, 3c, 3e, 3f, 3g and 3j. Diethanolamino and di-
ethylamino substituted compounds found to be more active
in the entire series. This promising activity may be because
of similarity of the functionality with other antihistaminic
agents.
Fig. 3. Depiction of the Presence of the Pharmacophore in 1e Similar to
Antihistaminic Drugs
ine and threonine which causes the enzyme to change the
shape, which causes the release of Ca2ϩ. Since b-blockers re-
duce c-AMP, less Ca ions are released. The propanol series
of compounds may be correlated to the presence of the phar-
macophore similarity to the chemical functionality present in
b-adrenergic blocking agents. It may be hypothesized that
the anticonvulsant activity exerted by some of the com-
pounds by blocking Ca2ϩ channels. Calcium influx via volt-
age-activated Ca2ϩ channels also plays a role in epileptogen-
esis and neurodegenerative events, raising the possibility that
the blockade of Ca2ϩ channels may represent the mechanism
of action of these compounds.
1c, 1h, 1I, 2a, 2d, 2g, 2h, 3b, 3e, 3I, 3j, 4b, 4d, 4e, 4f, 4g
and 4j compounds exhibited significant decrease (70%)
motor activity.
With respect to the 6-amino derivatives, the decrease in
motor activity by the compounds in ethane series (1a—m)
was found to be in the order of 1hϾ1cϾ1i. Among the hete-
rocyclic groups substituted at the 2nd position piperazino
substituted compound is more active than piperidino and imi-
dazolo substituted compounds. None of the tertiary amines
showed promising activity, whereas secondary amine substi-
tuted at the 2nd position, (phenylamino) showed better activ-
ity. The decrease in motor activity by the compounds with re-
spect to propanol series (2a—j) was found to be in the order
of 2gϾ2dϾ2aϾ2h. Among the heterocyclic groups substi-
tuted at the 3rd position imidazolo substituted compound is
more active than piperidino and piperazino substituted com-
pounds. Among the tertiary amines diethanolamino com-
pound showed promising activity, whereas secondary amine
substituted at the 3rd position, phenylamino, showed better
activity.
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