Synthesis and anticonvulsant activity of novel 1-substituted-1,2-dihydro-pyridazine-3,6-diones.

Article abstract of DOI:10.1248/bpb.26.1407

The synthesis and pharmacological evaluation of novel 1-substituted-1,2-dihydro-pyridazine-3,6-diones (4a--l, 5a--j) as potential anticonvulsant agents are described. The compounds were tested in vivo for the anticonvulsant activity. The compound which have maximum protection against MES induced seizures is 1-[3-(2-aminophenylamino)-2-hydroxypropyl)-1,2-dihydro-pyridazine-3,6-dione 4h (ED(50)=44.7 mg x kg(-1) i.p.) 1-[2-hydroxy-3-piperazin1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4c (ED(50)=72 mg x kg(-1) i.p.) and 1-[2-hydroxy-3-imidazol-1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4d (ED(50)=79 mg x kg(-1) i.p.) were also found to have maximum protection against MES induced seizures. Whereas all these compounds failed to protect the animals from subcutaneous pentylenetetrazole (Metrozol) seizure threshold test (sc-Met).

Full text of DOI:10.1248/bpb.26.1407

October 2003
Biol. Pharm. Bull. 26(10) 1407—1411 (2003)
1407
Synthesis and Anticonvulsant Activity of Novel 1-Substituted-1,2-dihydro-
pyridazine-3,6-diones
Ramaiah SIVAKUMAR,a Navaneetharaman ANBALAGAN,b Vedachalam GUNASEKARAN,a and
,a
*
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; Thorapakkam,
Chennai-600 096, India. Received March 17, 2003; accepted July 18, 2003
The synthesis and pharmacological evaluation of novel 1-substituted-1,2-dihydro-pyridazine-3,6-diones
(4a—l, 5a—j) as potential anticonvulsant agents are described. The compounds were tested in vivo for the anti-
convulsant activity. The compound which have maximum protection against MES induced seizures is 1-[3-(2-
aminophenylamino)-2-hydroxypropyl)-1,2-dihydro-pyridazine-3,6-dione 4h (ED50؍44.7 mg·kg؊1 i.p.) 1-[2-hy-
droxy-3-piperazin1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4c (ED50؍72 mg·kg؊1 i.p.) and 1-[2-hydroxy-3-
imidazol-1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4d (ED50؍79 mg·kg؊1 i.p.) were also found to have maxi-
mum protection against MES induced seizures. Whereas all these compounds failed to protect the animals from
subcutaneous pentylenetetrazole (Metrozol) seizure threshold test (sc-Met).
Key words aminopropane; anticonvulsant; propanolamine; pyridazine-3,6-dione
Pyridazine derivatives were reported to possess anti-in- maleic anhydride (0.1 mol) with hydrazine monohydrate
flammatory,1) antioxidant,2) vasorelaxant,3) anticonvulsant4,5,6) (0.1 mol) in ethanol 25 (ml) and 30% acetic acid (15 ml) for
and antihypertensive7,8) activities. Propanolamines were re- 30 min. The reaction mixture was cooled and washed with
ported to be associated with b-adrenergic blocking,9,10) CNS pet. ether 40—60 °C (3ϫ40 ml) and recrystallized with
depressant,11) hypotensive,12) diurtetic13) and antiarrhyth- methanol–ether (1 : 1) mp 299—300 °C. 1H-HMR (CDCl3, d,
mic14) activities. Aminopropane were reported to possess ppm): 9.3—9.5 (s, 2H, (NH)2), 6.48—6.66 (s, 2H, 4, 5-CH).
CNS depressant11) and neuroleptic15) properties. In view of IR (KBr) cmϪ1: 3240, 1406, 1240, 1120. Anal. Calcd for
these new biodynamic agents from heterocyclic compounds, C4H4N2O2. Found (calculated): C, 42.97 (42.85); H, 3.69
it was thought worthwhile to study the effects of two pharma- (3.57); N, 24.72 (25.0).
cophoric moieties like pyridazine and propanolamine/amino-
Synthesis of 1-(2؅,3؅-Epoxypropyl)1,2-dihydro-pyri-
propane in a single molecule, on the biological activity. We dazine-3,6-dione (2) 1-(2Ј,3Ј-Epoxypropyl)-1,2-dihydro-
have reported the potential anticonvulsant activity of substi- pyridazine-3,6-dione was prepared by refluxing 1,2-dihydro-
tuted aminopropanes and propanol amines from our lab16—21) pyridazine-3,6-dione (0.1 mol) with epichlorohydrine (0.1
to continue our work in the same direction, it was envisaged mol) in the presence of silver chloride (0.0007 mol), sodium
that the chemical entities with pyridazine, and propanol- iodide (0.0006 mol) and methanol (50 ml) for about 20 h.The
amine/aminopropane moieties would result in compounds of resultant product was purified by recrystallization with chlo-
interesting biological activities.
roform–ether (1 : 1) Yieldϭ57%, mp Ͼ325 °C. 1H-HMR
In the present study, we report the synthesis, the pharma- (CDCl3, d, ppm): 9.7—9.9 (s, 1H, NH), 6.92—7.09 (s, 2H,
cological evaluation and structure–activity relationship of 1- 4, 5-CH), 3.42—3.67 (d, Jϭ5.2 Hz, 2H, 3Ј-CH2), 3.21.4 (d,
substituted-1,2-dihydro-pyridazine-3,6-dione derivatives. The Jϭ6.3 Hz, 2H, 1Ј-CH2), 2.67—2.91 (m, 1H, 2Ј-CH). IR
1
compounds were characterized by IR, H-NMR spectral and (KBr) cmϪ1: 3214, 1429, 1254, 1153. Anal. Calcd for
Elemental analysis. The compounds were also investigated C14H8N4O2. Found (calculated): C, 49.71 (50.0); H, 4.63
for anticonvulsant activity.
CHEMISTRY
(4.76); N, 16.84 (16.66).
General Procedure for the Synthesis of 1-Substituted-
1,2-dihydro-pyridazine-3,6-dione (4a—l) A mixture of 1-
(2Ј,3Ј-epoxypropyl)-1,2-dihydro-pyridazine-3,6-dione (0.005
Solvents for reaction under anhydrous conditions were mol) and amine (0.005 mol) were refluxed with 10% methano-
dried according to standard procedures. Melting points were lic potassium hydroxide (25 ml). The reaction mixture was
determined in open capillary tubes and are uncorrected. IR filtered and the filterate on concentration yielded the product.
spectra were recorded (in KBr) on Perkin-Elmer IR spec- The products were dried under vacuum and recrystallized
trophotometer 298. 1H-NMR spectra were recorded on using 1 : 1 acetone–ether (4a, f, g, h, l), 1 : 1 ethanol–ether
300 MHz Bruker DPX 200. The chemical shifts are reported (4b, e, i), 1 : 1 methanol–ether (4c, d, j) and 1 : 1 chloroform–
as parts per million downfield from tetramethylsilane ether (4k).
(Me4Si). Microanalyses for C, H, N were performed in Her-
1-[2Ј-Hydroxy-3Ј-(1Љ-morpholino)propyl]-1,2-dihydro-
aeus CHN Rapid Analyzer. Analyses indicated by the sym- pyridazine-3,6-dione (4a): Yieldϭ72%, mp Ͼ325 °C. IR
1
bols of the elements are within Ϯ0.4% of the theoretical val- (KBr) cmϪ1: 1455, 1375, 1071. H-HMR (CDCl3, d, ppm):
1
ues. H-NMR and IR spectra were consistent with the as- 9.3—9.5 (s, 1H, NH), 6.67—6.9 (s, 2H, 4, 5-CH), 3.68—3.8
signed structures.
(m, 1H, 2Ј-CH), 3.27—3.3 (m, 4H, 1Ј, 3Ј-CH2), 2.4—2.62
Synthesis of Pyridazine-3,6-dione (1) Pyridazine-3,6- (m, 8H, 2Љ, 3Љ, 5Љ, 6Љ-CH2), 0.84—1.06 (s, 1H, 2Ј-OH). Anal.
dione was prepared with procedure of Hedaya22) by refluxing Calcd for C11H17N3O4. Found (calculated): C, 51.54 (51.76);
To whom correspondence should be addressed. e-mail: alabarae@yahoo.com
© 2003 Pharmaceutical Society of Japan

1408
Vol. 26, No. 10
Fig. 1. Synthesis of 4a—l and 5a—j
1
319 °C. IR (KBr) cmϪ1: 1455, 1368, 1324, 1161. H-HMR
H, 6.41 (6.66); N, 16.22 (16.47).
(CDCl3, d, ppm): 9.39—9.52 (s, 1H, NH), 6.46—6.67 (s,
2H, 4, 5-CH), 3.56—3.78 (m, 4H, 1Ј, 3Ј-CH2), 3.4—3.62 (m,
1H, 2Ј-CH), 2.84—3.05 (m, 8H, 1Љ, 2Љ-(C2H4)2), 2.26—2.84
(s, 1H, 2Ј-OH), 0.98—1.26 (s, 2H, 2Љ-OH). Anal. Calcd for
C11H19N3O5. Found (calculated): C, 48.13 (48.35); H, 6.79
(6.95); N, 15.16 (15.38).
1-[2Ј-Hydroxy-3Ј-(1Љ-piperidino)propyl]-1,2-dihydro-pyri-
dazine-3,6-dione (4b): Yieldϭ79%, mp 291 °C. IR (KBr)
1
cmϪ1: 1454, 1372, 1156. H-HMR (CDCl3, d): 9.72—9.91
(s, 1H, NH), 6.98—7.13 (s, 2H, 4, 5-CH), 3.8—3.92 (m, 1H,
2Ј-CH), 3.52—3.62 (m, 4H, 1Ј, 3Ј-CH2), 2.9—3.35 (m, 10H,
2Љ, 3Љ, 4Љ, 5Љ, 6Љ-CH2), 0.92—1.12 (s, 1H, 2Ј-OH). Anal.
Calcd for C12H19N3O3. Found (calculated): C, 56.77 (56.91);
H, 7.38 (7.5); N, 16.91 (16.6).
1-[2Ј-Hydroxy-3Ј-(dimethylamino)-propyl]-1,2-dihydro-
pyridazine-3,6-dione (4f): Yieldϭ83%, mp 256 °C. IR (KBr)
1
cmϪ1: 1475, 1373, 1327. H-HMR (CDCl3, d, ppm): 9.67—
1-[2Ј-Hydroxy-3Ј-(1Љ-piperazino)propyl]-1,2-dihydro-pyri-
dazine-3,6-dione (4c): Yieldϭ80%, mp Ͼ325 °C. IR (KBr)
9.81 (s, 1H, NH), 6.41—6.52 (s, 2H, 4, 5-CH), 3.63—3.88
(m, 1H, 2Ј-CH), 3.45—3.68 (m, 4H, 1Ј, 3Ј-CH2), 2.16—2.66
(s, 1H, 2Ј-OH), 1.24—1.45 (s, 6H, (CH3)2). Anal. Calcd for
C9H5N3O3. Found (calculated): C, 50.52 (50.7); H, 7.13
(7.04); N, 19.83 (19.71).
1
cmϪ1: 1379, 1305, 1161. H-HMR (CDCl3, d): 9.69—9.83
(s, 1H, NH), 8.7—8.9 (m, 1H, NH), 6.46—6.7 (s, 2H, 4, 5-
CH), 3.72—3.86 (m, 1H, 2Ј-CH), 3.35—3.56 (m, 4H, 1Ј, 3Ј-
CH2), 3.0—3.37 (m, 8H, 2Љ, 3Љ, 5Љ, 6Љ-CH2), 0.96—1.24 (s,
1H, 2Ј-OH). Anal. Calcd for C11H17N3O4. Found (calculated):
C, 52.11 (51.96); H, 7.17 (7.08); N, 21.88 (22.04).
1-[2Ј-Hydroxy-3Ј-(diphenylamino)propyl]-1,2-dihydro-
pyridazine-3,6-dione (4g): Yieldϭ62%, mp Ͼ325 °C. IR
1
(KBr) cmϪ1: 1459, 1345, 1134. H-HMR (CDCl3, d, ppm):
1-[2Ј-Hydroxy-3Ј-(1Љ-imidazolo)propyl]-1,2-dihydro-pyri-
dazine-3,6-dione (4d): Yieldϭ82%, mp 268 °C. IR (KBr)
9.42—9.56 (s, 1H, NH), 6.58—6.7 (s, 2H, 4, 5-CH), 6.23—
6.48 (m, 10H, (C6H5)2), 3.64—3.77 (m, 1H, 2Ј-CH), 3.24—
3.46 (m, 4H, 1Ј, 3Ј-CH2), 0.98—1.24 (s, 1H, 2Ј-OH). Anal.
Calcd for C19H19N3O3. Found (calculated): C, 67.43 (67.65);
H, 5.35 (5.63); N, 12.27 (12.46).
1
cmϪ1: 1459, 1372, 1156. H-HMR (CDCl3, d): 9.34—9.47
(s, 1H, NH), 7.2—7.31 (s, 2H, 4, 5-CH), 6.7—6.9(m, 1H, 2Љ-
CH) 6.23—6.47 (m, 2H, 4Љ, 5Љ-CH), 3.8—3.92 (m, 1H, 2Ј-
CH), 3.5—3.6 (m, 4H, 1Ј, 3Ј-CH2), 0.92—1.12 (s, 1H, 2Ј-
OH). Anal. Calcd for C10H12N4O3. Found (calculated): C,
50.56 (50.84); H, 4.92 (5.08); N, 23.97 (23.72).
1-[2Ј-Hydroxy-3Ј-(2Љ-aminophenylamino)propyl]-1,2-di-
hydro-pyridazine-3,6-dione (4h): Yieldϭ77%, mp Ͼ325 °C.
1
IR (KBr) cmϪ1: 1445, 1356, 1149. H-HMR (CDCl3, d,
1-{3Ј-[Bis-(2Љ-hydroxyethyl)amino]-2Ј-hydroxypropyl}-
1,2-dihydro-pyridazine-3,6-dione (4e): Yieldϭ87%, mp
ppm): 9.22—9.39 (s, 1H, NH), 6.84—6.95 (s, 2H, 4, 5-CH),

October 2003
1409
6.48—6.66 (m, 4H, C6H4), 5.54—5.66 (s, 2H, NH2), 4.41— dione (5a): Yieldϭ72%, mp 273 °C. IR (KBr) cmϪ1: 1434,
1
4.56 (m, 1H, NH), 3.73—3.89 (m, 1H, 2Ј-CH), 3.33—3.48 1383, 1123. H-HMR (CDCl3, d, ppm): 9.14—9.25 (s, 1H,
(m, 4H, 1Ј, 3Ј-CH2), 0.86—1.04 (s, 1H, 2Ј-OH). Anal. Calcd NH), 6.34—6.5 (s, 2H, 4, 5-CH), 3.52—3.69 (m, 4H, 1Ј, 3Ј-
for C13H16N4O3. Found (calculated): C, 56.33 (56.52); H, CH2), 2.57—2.69 (m, 8H; 2Љ, 3Љ, 5Љ, 6Љ-CH2), 1.13—1.27 (m,
5.86 (5.79); N, 20.04 (20.28).
2H, 2Ј-CH2). Anal. Calcd for C11H17N3O3. Found (calcu-
1-[2Ј-Hydroxy-3Ј-(4Љ-hydroxyphenylamino)propyl]-1,2- lated): C, 54.92 (55.23); H, 6.84 (7.11); N, 17.91 (17.57).
dihydro-pyridazine-3,6-dione (4i): Yieldϭ68%, mp 274 °C.
1-[3Ј-(1Љ-Piperidino)propyl]-1,2-dihydro-pyridazine-3,6-
1
IR (KBr) cmϪ1: 3310, 1478, 1394, 1176. H-HMR (CDCl3, dione (5b): Yieldϭ55%, mp 235 °C. IR (KBr) cmϪ1: 1432,
1
d, ppm): 9.14—9.3 (s, 1H, NH), 8.64—8.83 (s, 1H, NH), 1356, 1178. H-HMR (CDCl3, d, ppm): 9.35—9.48 (s, 1H,
6.93—7.08 (s, 2H, 4, 5-CH), 6.23—6.57 (m, 4H, C6H4), NH), 6.73—6.87 (s, 2H, 4, 5-CH), 3.45—3.59 (m, 4H, 1Ј,
3.72—3.88 (m, 1H, 2Ј-CH), 3.45—3.56 (m, 4H, 1Ј, 3Ј-CH2), 3Ј-CH2), 2.78—2.97 (m, 10H, 2Љ, 3Љ, 4Љ, 5Љ, 6Љ-CH2), 1.49—
0.85—1.04 (s, 1H, 2Ј-OH). Anal. Calcd for C13H15N3O4. 1.62 (m, 1H, 2Ј-CH2). Anal. Calcd for C12H19N3O2. Found
Found (calculated): C, 55.29 (55.12); H, 5.18 (5.3); N, 17.12 (calculated): C, 60.43 (60.75); H, 8.32 (8.01); N, 17.53
(16.96).
(17.72).
1-[2Ј-Hydroxy-3Ј-(4Љ-nitrophenylamino)propyl]-1,2-dihy-
1-[3Ј-(1Љ-Piperazino)propyl]-1,2-dihydro-pyridazine-3,6-
dro-pyridazine-3,6-dione (4j): Yieldϭ80%, mp 297 °C. IR dione (5c): Yieldϭ67%, mp 279 °C. IR (KBr) cmϪ1: 1389,
(KBr) cmϪ1: 1493, 1375, 1112. 1H-HMR (CDCl3, d): 9.49— 1334, 1176. H-HMR (CDCl3, d, ppm): 9.75—9.87 (s, 1H,
1
9.62 (s, 1H, NH), 6.87—6.98 (s, 2H, 4, 5-CH), 6.34—6.66 NH), 8.81—8.94 (m, 1H, NH), 6.56—6.71 (s, 2H, 4, 5-CH),
(m, 4H, C6H4), 4.26—4.43 (m, 1H, NH), 3.74—3.87 (m, 1H, 3.48—3.59 (m, 4H, 1Ј, 3Ј-CH2), 3.21—3.39 (m, 8H, 2Љ, 3Љ,
2Ј-CH), 3.45—3.62 (m, 4H, 1Ј, 3Ј-CH2), 0.76—0.94 (s, 1H, 5Љ, 6Љ-CH2), 1.26—1.44 (s, 1H, 2Ј-CH2). Anal. Calcd for
2Ј-OH). Anal. Calcd for C13H14N4O5. Found (calculated): C, C11H18N4O2. Found (calculated): C, 55.13 (55.46); H, 7.21
51.07 (50.98); H, 4.51 (4.57); N, 18.17 (18.3).
(7.56); N, 23.84 (23.52).
1-[2Ј-Hydroxy-3Ј-(methylamino)propyl]-1,2-dihydro-pyri-
1-[3Ј-(1Љ-Imidazolo)propyl]-1,2-dihydro-pyridazine-3,6-
dazine-3,6-dione (4k): Yieldϭ67%, mp 304 °C. IR (KBr) dione (5d): Yieldϭ49%, mp 239 °C. IR (KBr) cmϪ1: 1478,
1
1
cmϪ1: 1447, 1395, 1146. H-HMR (CDCl3, d, ppm): 9.59— 1345, 1189. H-HMR (CDCl3, d, ppm): 9.38—9.49 (s, 1H,
9.72 (s, 1H, NH), 6.86—6.91 (s, 2H, 4, 5-CH), 6.14—6.3 (s, NH), 7.17—7.32 (s, 2H, 4, 5-CH), 6.81—6.95 (m, 1H, 2Љ-
1H, NH), 3.68—3.84 (m, 1H, 2Ј-CH), 3.37—3.54 (m, 4H, CH), 6.36—6.51 (m, 2H, 4Љ, 5Љ-CH2), 3.32—3.46 (m, 4H, 1Ј,
1Ј, 3Ј-CH2), 2.42—2.65 (s, 1H, 2Ј-OH), 0.78—0.97 (s, 3H, 3Ј-CH2), 1.22—1.37 (m, 2H, 2Ј-CH2). Anal. Calcd for
CH3). Anal. Calcd for C8H13N3O3. Found (calculated): C, C10H12N4O2. Found (calculated): C, 51.54 (51.76); H, 6.41
48.13 (48.24); H, 6.48 (6.53); N, 21.22 (21.1).
(6.66); N, 16.22 (16.47).
1-[2Ј-Hydroxy-3Ј-(phenylamino)propyl]-1,2-dihydro-pyri-
1-{3Ј-[Bis-(2Љ-hydroxyethyl)amino]-2(-hydroxypropyl}-
dazine-3,6-dione (4l): Yieldϭ88%, mp 279 °C. IR (KBr) 1,2-dihydro-pyridazine-3,6-dione (5e): Yieldϭ68%, mp
1
1
cmϪ1: 1474, 1332, 1134. H-HMR (CDCl3, d): 9.58—9.7 (s, 269 °C. IR (KBr) cmϪ1: 1487, 1374, 1358, 1136. H-HMR
1H, NH), 6.96—7.24 (m, 5H, C6H5), 6.67—6.75 (s, 2H, 4, 5- (CDCl3, d, ppm): 9.22—9.38 (s, 1H, NH), 6.25—6.42 (s,
CH), 6.34—6.52 (s, 1H, H), 3.69—3.86 (m, 1H, 2Ј-CH), 2H, 4, 5-CH), 3.82—3.95 (m, 4H, 1Ј, 3Ј-CH2), 3.53—3.69
3.36—3.44 (m, 4H, 1Ј, 3Ј-CH2), 0.83—1.04 (s, 1H, 2Ј-OH). (s, 2H, 2Љ (–OH)2), 2.76—2.95 (m, 8H, (C2H4)2), 1.19—1.32
Anal. Calcd for C13H15N3O3. Found (calculated): C, 59.65 (m, 2H, 2Ј-CH2). Anal. Calcd for C11H19N3O4. Found (calcu-
(59.77); H, 5.63 (5.74); N, 16.36 (16.09).
lated): C, 51.04 (51.36); H, 7.72 (7.39); N, 16.73 (16.34).
Synthesis of 1-(3؅-Chloropropyl)-1,2-dihydro-pyri-
1-[3Ј-Dimethylaminopropyl]-1,2-dihydro-pyridazine-3,6-
dazine-3,6-dione (3) 1-(3Ј-Chloropropyl)-1,2-dihydro- dione (5f): Yieldϭ47%, mp 237 °C. IR (KBr) cmϪ1: 1434,
1
pyridazine-3,6-dione was prepared by refluxing 1,2-dihy- 1368, 1356. H-HMR (CDCl3, d, ppm): 9.28—9.39 (s, 1H,
dropyridazine-3,6-dione (0.1 mol) with 1-bromo-3-chloro NH), 6.17—6.31 (s, 2H, 4, 5-CH), 3.23—3.41 (m, 4H, 1Ј,
propane (0.1 mol) in the presence of silver chloride 3Ј-CH2), 2.63—2.83 (m, 2H, 2Ј-CH2), 1.49—1.63 (s, 6H, 1Ј,
(0.0007 mol), sodium iodide (0.0006 mol) and methanol 3Ј (CH3)2). Anal. Calcd for C9H15N3O2. Found (calculated):
(50 ml) for about 20 h. The resultant product was purified by C, 54.51 (54.82); H, 7.37 (7.61); N, 21.02 (21.31).
recrystallization with chloroform–ether (1 : 1) Yieldϭ61%,
1-[3Ј-Diphenylaminopropyl]-1,2-dihydro-pyridazine-3,6-
1
mp 298 °C. H-HMR (CDCl3) d: 9.35—9.52 (s, 1H, NH), dione (5g): Yieldϭ59%, mp 293 °C. IR (KBr) cmϪ1: 1465,
1
6.72—6.93 (s, 2H, 4, 5-CH), 3.29—3.43 (d, Jϭ4.9 Hz, 4H, 1387, 1186. H-HMR (CDCl3, d, ppm): 9.11—9.29 (s, 1H,
1Ј, 3Ј-CH2), 2.49—2.67 (m, 2H, 2Ј-CH2). IR (KBr) cmϪ1: NH), 6.69—6.87 (s, 2H, 4, 5-CH), 6.13—6.38 (m, 10H,
3210, 1432. Anal. Calcd for C7H9N2O2Cl. Found (calcu- (C6H5)2), 3.39—3.52 (m, 4H, 1Ј, 3Ј-CH2), 1.48—1.61 (m,
lated): C, 44.31 (44.68); H, 4.92 (4.78); N, 14.57 (14.89).
General Procedure for the Synthesis of 1-Substituted- lated): C, 71.34 (71.02); H, 5.63 (5.91); N, 13.38 (13.08).
1,2-dihydro-pyridazine-3,6-diones (5a—j) A mixture of
1-[3Ј-(2Љ-Aminophenylamino)propyl]-1,2-dihydro-pyri-
2H, 2Ј-CH2). Anal. Calcd for C19H19N3O2. Found (calcu-
1-(3Ј-chloropropyl)-1,2-dihydro-pyridazine-3,6-dione (0.005 dazine-3,6-dione (5h): Yieldϭ58%, mp 258 °C. IR (KBr)
1
mol) and amine (0.005 mol) were refluxed with 10% methano- cmϪ1: 1456, 1387, 1176. H-HMR (CDCl3, d, ppm): 9.08—
lic potassium hydroxide (25 ml). The reaction mixture was 9.29 (s, 1H, NH), 8.37—8.56 (m, 1H, NH), 6.82—6.91 (s,
filtered and the filterate on concentration yielded the product. 2H, 4, 5-CH), 6.46—6.62 (m, 4H, C6H4), 5.68—5.82 (s, 2H,
The products were dried under vacuum and recrystallized NH2), 3.49—3.61 (m, 4H, 1Ј, 3Ј-CH2), 1.17—1.3 (m, 2H, 2Ј-
using 1 : 1 acetone–ether (5a, g, i), 1 : 1 ethanol–ether (5c, d, CH2). Anal. Calcd for C13H16N4O2. Found (calculated): C,
h, j), 1 : 1 methanol–ether (5b, e, f).
60.34 (60.00); H, 6.42 (6.15); N, 21.29 (21.53).
1-[3Ј-(1Љ-Morpholino)propyl]-1,2-dihydro-pyridazine-3,6-
1-[3Ј-(4Љ-Hydroxyphenylamino)propyl]-1,2-dihydro-pyri-

1410
Vol. 26, No. 10
Table 1. Anticonvulsant and Toxicity Screening Data in Mice (i.p.)
MESa,b) Sc-Metc) Rotarod toxicityd)
dazine-3,6-dione (5i): Yieldϭ76%, mp 265 °C. IR (KBr)
cmϪ1: 3328, 1434, 1353, 1157. 1H-HMR (CDCl3, d): 9.26—
9.45 (s, 1H, NH), 8.35—8.48 (s, 1H, NH), 7.15—7.3 (s, 1H,
–OH), 6.55—6.71 (s, 2H, 4, 5-CH), 6.13—6.37 (m, 4H,
C6H4), 3.19—3.35 (m, 4H, 1Ј, 3Ј-CH2), 1.15—1.28 (m, 2H,
2Ј-CH2). Anal. Calcd for C13H15N3O3. Found (calculated): C,
59.43 (59.77); H, 5.48 (5.74); N, 16.37 (16.07).
Compd.
30 min
4 h
30 min
4 h
30 min
4 h
4a
4b
4c
4d
4e
4f
4g
4h
4i
ϩϩ
ϩ
ϩϩ
ϩϩ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
ϩ
ϩ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
ϩ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
ϩ
Ϫ
ϩ
ϩ
Ϫ
Ϫ
ϩ
ϩ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
ϩ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
ϩ
ϩϩ
ϩϩ
ϩϩ
Ϫ
ϩ
ϩ
Ϫ
ϩ
ϩ
ϩ
ϩ
ϩ
Ϫ
ϩ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
1-[3Ј-(4Љ-Nitrophenylamino)propyl]-1,2-dihydro-pyri-
dazine-3,6-dione (5j): Yieldϭ39%, mp 245 °C. IR (KBr)
1
cmϪ1: 1476, 1345, 1176. H-HMR (CDCl3, d): 9.23—9.42
ϩ
ϩϩ
ϩϩϩ
ϩ
ϩ
ϩϩ
ϩ
ϩ
ϩ
ϩϩ
ϩϩ
ϩ
ϩ
ϩ
ϩϩ
ϩ
ϩϩ
(s, 1H, NH), 6.79—6.96 (s, 2H, 4, 5-CH), 6.17—6.29 (m,
4H, C6H4), 4.59—4.69 (m, 1H, NH), 3.67—3.78 (m, 4H, 1Ј,
3Ј-CH2), 1.26—1.36 (m, 2H, 2Ј-CH2). Anal. Calcd for
C13H14N4O4. Found (calculated): C, 53.55 (53.79); H, 4.53
(4.82); N, 19.64 (19.31).
4j
4k
4l
5a
5b
5c
5d
5e
5f
5g
5h
5i
PHARMACOLOGY
All the synthesized compounds were screened for anticon-
vulsant activity. All the compounds were solubilized in water
and administered to the animals as a solution in water for in-
jection. Wistar albino mice (18—25 g) of either sex were
procured from king Institute, Guindy, Chennai. They were
kept in colony cages at 25Ϯ2 °C, relative humidity 45—55%
under 12 h light and dark cycle. All the animals were accli-
matized for a week before use.
ϩ
Ϫ
ϩ
Ϫ
5j
ϩ
a) Key: ϩϩϩϭprotection at 30 mg·kgϪ1
,
ϩϩϭprotection at 100 mg·kgϪ1
b) Maximal elec-
,
ϩϭprotection at 300 mg·kgϪ1, Ϫϭno protection at 300 mg·kgϪ1
.
troshock seizure test. c) Subcutaneous pentylenetetrazole seizure test. d) Neuro-
logic toxicity (rotarod) test.
Anticonvulsant Activity The compounds were tested
for anticonvulsant activity by using the procedures described
previously.23,24) All the compounds were tested for anticon-
vulsant activity with wistar albino mice. Each compound was
administered intraperitoneally at three dose levels (30, 100,
300 mg·kgϪ1). The compounds were made solution with
water for injection.
Table 2. Quantitative Anticonvulsant Data in Mice (Test Drug Adminis-
tered i.p.)
a)
ED50
b)
Compound
TD50
MES
Sc-Met
Maximal electroshock seizures (MES) were induced
30 min after drug treatment by application of 50 mA current
for 0.2 s via corneal electors in to the eyes. The protection
was defined as the abolition of hind leg and tonic maximal
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·kgϪ1). Animals were observed for
30 min. Failure to observe the generalized clonic seizure is
defined as protection.
4a
4c
4d
4e
4g
4h
4k
5c
5d
109 (90—132)
72 (55—89)
79 (64—95)
Ͼ200
Ͼ200
Ͼ250
221 (192—250)
177 (150—203)
226 (192—256)
111 (94—128) 193 (176—213) 204 (172—235)
84 (71—98)
44.7 (32—57)
92 (64—83)
85 (67—99)
106 (88—124) 206 (184—234) 255 (228—274)
82 (65—96) Ͼ200 200 (177—226)
94 (78—110) 169 (152—188) 225 (201—253)
9.9 (6.3—13.1)
9.2 (6.9—11.7)
264 (236—297) 157 (133—185) 408 (364—437)
142 (125—166) 232 (208—256)
225 (206—242) 156 (132—179)
250 (219—278) 203 (169—238)
154 (132—179) 222 (189—246)
5h
5j
Phenytoin
Carbama zepine
Valproate
Ͼ300
Ͼ200
69.8 (57.2—80.7)
74.4 (59.1—87.5)
Minimal neurotoxicity (TD50) was measured by the rotarod
test (Tox). Mice were placed in 1-in. diameter knurled plastic
rod rotating 6 rpm after administration of the drug, and their
a) Doses measured in mg·kgϪ1 at the peak effect. b) Doses (mg·kgϪ1) deter-
ability to maintain their balance was tested. Neurological mined by rotarod test at the time of peak effect.
deficit was indicated by the inability of the animal to main-
e, g, h, k, 5c, d, h and j were considered for the phase II tri-
tain the equilibrium for 1 min on the rotating rod in each of
three trials. The results are tabulated in Tables 1 and 2.
als. This provides an evaluation of the median effective dose
and median neurotoxic dose. The slope of the regression line
and the SE of the slope were then calculated. 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 sc-Met induced
seizures. Compound 4h was the best in the MES test having
ED50 of 44.7 mg·kgϪ1. In the MES test, the ED50 of
compounds were found to be 4c (72 mg·kgϪ1) and 4d
(79 mg·kgϪ1).
RESULTS AND DISCUSSION
The initial evaluation phase I of anticonvulsant activity of
synthesized compounds presented in the Table 1. The com-
pounds were administered intraperitoneally at three doses
(30, 100, 300 mg·kgϪ1). Three tests were performed for each
compound; maximal electroshock (MES)-induced convul-
sions, subcutaneous Metrozol (sc-Met)-induced convulsions
and rotarod neurotoxicity test (Tox).
The following structure-activity relationships were ob-
served. In the propanol series (4a—l), compounds 4a, c, d, e,
As a result of preliminary screening compounds 4a, c, d,

October 2003
1411
Orallo F., Calleja J. M., Arch. Pharm. (Weinheim), 324, 455—460
(1991).
9) Nathanson J. A., Hunnicutt E. J., J. Pharm. Pharmacol., 40, 803—805
(1998).
10) Samant S. D., Gupte S. M., Kulkarni R. A., Indian J. Chem., 19B,
524—525 (1980).
11) Agarwal S. K., Saxena A. K., Jain P. C., Anand N., Sur R. N., Srimal
R. C., Dhawan B. N., Indian J. Chem., 30B, 413—416 (1991).
12) Ahmed B., Siddiqui A. A., Agarwal M., Indian J. Pharmacol., 31,
33—35 (1999).
13) Cecchetti V., Fravolini A., Schiaffella F., Tabarrini O., Bruni G., Segre
G., J. Med. Chem., 36, 157—161 (1993).
14) Butera J. A., Spinelli W., Anantharaman V., Marcopulos N., Parsons R.
W., Moubarak I. F., Cullinan C., Bagli J. F., J. Med. Chem., 34. 3212—
3228 (1991).
15) Sur R. N., Shanker G., Rathore R. K. S., Chak I. M., Agarwal S. K.,
Jain P. C., Indian J. Exp. Bio., 18, 1190—1195 (1980).
16) Leonard J. T., Anbalagan N., Kumar S. S., Gnanasam S. K., Sridhar S.
K., Biol. Pharm. Bull., 25, 215—217 (2002).
g, h and k were found to have high degree of protection
against MES-induced seizures. Among the heterocyclic sub-
stituted compounds, piperazino and imidazolo groups substi-
tuted at the 3 position showed more protection than the other
substitution. Among the tertiary amine substituted com-
pounds, diphenyl substituted compound is more potent than
the other (dimethyl, diethanol) substitutions. Among the sec-
ondary amine substitutions, 2-aminophenylamine, methyl-
amino substituted compounds are more active than the other
(4-bromophenylamine, 4-nitrophenylamine and phenyl-
amino) substitutions.
REFERENCES
1) Tewari A. K., Mishra A., Bioorg. Med. Chem., 11, 715—718 (2001).
2) Ostby O. B., Gundersen L. L., Rise F., Aantonsen O., Ffosnes K.,
Larsen V., Bast A., Custers I., Haenen G. R., Arch. Pharm. (Wein- 17) Leonard J. T., Sivakumar R., Anbalagan N., Kumar S. K., Sridhar S.
heim), 334, 21—24 (2001).
K., Boll. Chim. Farm., 141, 357—360 (2002).
3) Kots A. Y., Grafov M. A., Khropov Y. V., Betin V. L., Belushkina N. 18) Leonard J. T., Gangadhar R., Gnanasam S. K., Ramachandran S., Sara-
N., Busygina O. G., Yazykova M. Y., Ovchinnikov I. V., Kulikov A. S.,
vanan M., Sridhar S. K., Biol. Pharm. Bull., 25, 798—802 (2002).
Makhova N. N., Medvedeva N. A., Bulargina T. V., Severina I. S., Br. 19) Sivakumar R., Gnanasam S. K., Ramachandran S., Leonard J. T., Eur.
J. Pharmacol., 129, 1163—1177 (2000).
J. Med. Chem., 37, 793—801 (2002).
4) Moreau S., Coudert P., Rubat C., Vallee-Goyet D., Gardette D., Gra- 20) Ravlee I., Sivakumar R., Muruganantham N., Anbalagan N., Gu-
main J. C., Couquelet J., Bioorg. Med. Chem., 8, 983—991 (1998).
nasekaran V., Leonard J. T., Chem. Pharm. Bull., 51, 162—170 (2003).
5) Moreau S., Coudert P., Rubat C., Gardette D., Vallee-Goyet D., 21) Narendar P., Parthiban J., Anbalagan N., Gunasekaran V., Leonard J.
Couquelet J., Bastide P., Tronche P., J. Med. Chem., 37, 2153—2160
(1994).
6) Altomare C., Campagna F., Carta V., Cellamare S., Carotti A., Genchi
G., De Sarro G., Farmaco., 49, 313—323 (1994).
T., Biol. Pharm. Bull., 26, 182—187 (2003).
22) Hedaya E., Hinman R. L., Theodoroopulos S., J. Org. Chem., 31,
1317—1326 (1966).
23) Krall R. L., Penry J. K., White B. G., Kupferberg H. J., Swinyard E.
A., Epilepsia, 19, 409—428 (1978).
7) Gil-Longo J., De los Reyes Laguna M., Verde I., Castro M. E., Orallo
F., Fontenla J. A., Calleja J. M., Ravina E., Teran C., J. Pharma. Sci., 24) Porter R. J., Cereghino J. J., Gladding G. D., Hessis B. J., Kupferberg
82, 286—290 (1993).
H. J., Scoville B., White B. G., Cleveland Clin. Q., 51, 293—305
8) Ravina E., Teran C., Dominguez N. G., Masaguer C. F., Gil-Longo J.,
(1984).