Pharmacological evaluation of some new 1-substituted-4-hydroxy-phthalazines

Article abstract of DOI:10.1016/S0223-5234(02)01405-8

In the present study, a series of 1-substituted-4-hydroxyphthalazines were synthesized and characterized by IR, ¹H-NMR and Elemental analysis. The compounds were assayed against seizures induced by maximal electroshock (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^-1 and cardiac activity was also studied. All the compounds exhibited significant anticonvulsant activity. Compounds 4, 12, 13 and 17 were most active of the seriesagainst MES-induced seizures. Compounds 2, 4, 13 and 17 exhibited significant decrease in the elevated motor activity at the dose of 50 mg kg^-1. Remarkable sympathetic blocking activity was observed with 3, 5, 6, 7, 9 and 15 only.

Full text of DOI:10.1016/S0223-5234(02)01405-8

European Journal of Medicinal Chemistry 37 (2002) 793ꢁ801
/
www.elsevier.com/locate/ejmech
Original article
Pharmacological evaluation of some new 1-substituted-4-hydroxy-
phthalazines
Ramaiya Sivakumar, Sundararaj Kishore Gnanasam, Somasundaram Ramachandran,
Joseph Thomas Leonard *
Department of Pharmaceutical Chemistry and Pharmacology, Vel’s College of Pharmacy, Old Pallavaram, Chennai 600 117, India
Received 5 April 2002; received in revised form 7 July 2002; accepted 8 July 2002
Abstract
1
In the present study, a series of 1-substituted-4-hydroxyphthalazines were synthesized and characterized by IR, H-NMR and
Elemental analysis. The compounds were assayed against seizures induced by maximal electroshock (MES) and pentylenetetrazole
(
scMet). Neurologic deficit was evaluated by the rotarod test. The decrease in the elevated motor activity by introceptive chemical
ꢀ
1
stimuli (amphetamine antagonistic activity) was studied at the dose level of 25 and 50 mg kg and cardiac activity was also studied.
All the compounds exhibited significant anticonvulsant activity. Compounds 4, 12, 13 and 17 were most active of the seriesagainst
MES-induced seizures. Compounds 2, 4, 13 and 17 exhibited significant decrease in the elevated motor activity at the dose of 50 mg
ꢀ
1
kg . Remarkable sympathetic blocking activity was observed with 3, 5, 6, 7, 9 and 15 only.
#
´
2002 Editions scientifiques et m e´ dicales Elsevier SAS. All rights reserved.
Keywords: Amphetamine antagonism; Anticonvulsant; Aryloxypropanolamines; Aryloxyaminopropanes; Phthalazine; Sympatholytic
1
. Introduction
chemical entities with phthalazine, aryloxypropanola-
mine and aryloxyaminopropane moieties would result in
compounds of interesting biological activities.
Hydralazine is reported to be associated with drug
induced systemic lupus erythematous [1] because of the
presence of hydrazine group on phthalazine nucleus.
Phthalazine derivatives were reported to possess antic-
In this study, we report the synthesis, the pharmaco-
logical evaluation, and stuctureꢁactivity relationship of
/
1-(3?-substituted-2-hydroxy/unsubstituted-propyloxy)-4-
hydroxyphthalazine. The compounds were character-
1
ized by IR, H-NMR spectral and Elemental analysis.
onvulsant [2ꢁ/4], cardiotonic [5] and vasorelaxant [6,7]
anti-inflammatory [8,9] activities. Aryloxypropanola-
mines were reported to be associated with b-adrenergic
blocking [10,11], CNS depressant [12], hypotensive [13]
activities. Aryloxyaminopropanes were reported to pos-
sess CNS depressant [14], neuroleptic [15], antiarrythmic
The compounds were investigated for anticonvulsant
activity. The decrease in the elevated motor activity by
introceptive chemical stimuli (amphetamine antagonistic
ꢀ
1
activity) at the dose level of 25 and 50 mg kg
cardiac activity on isolated frog heart.
and
[
16], hypotensive [17] activities. In view of these poten-
tial nature of the compounds, it was thought worthwhile
to study the effects of two pharmacophoric moieties like
phthalazine and propanolamine/aminopropane in a
single molecule, on the biological activity. We have
reported the potential anticonvulsant activity of amino-
2
. Chemistry
In the present study, 1,4-dihydroxyphthalazine was
reacted with epichlorohydrine and 1-bromo-3-chloro-
propane in presence of silver chloride and sodium iodide
to yield 1-(2?,3?-epoxypropyloxy)-4-hydroxyphthalazine
and 1-(3?-chloropropyloxy)-4-hydroxyphthalazine, re-
spectively. These compounds were reacted with several
primary and secondary amines in the presence of 10%
propanes from our laboratory [18ꢁ/20], to continue our
work in the same direction it was envisaged that
* Correspondence and reprints
E-mail address: alabarae@yahoo.com (J. Thomas Leonard).
´
0
223-5234/02/$ - see front matter # 2002 Editions scientifiques et m e´ dicales Elsevier SAS. All rights reserved.
PII: S 0 2 2 3 - 5 2 3 4 ( 0 2 ) 0 1 4 0 5 - 8

794
R. Sivakumar et al. / European Journal of Medicinal Chemistry 37 (2002) 793ꢁ
/801
Fig. 1. Synthetic scheme.
methanolic potassium hydroxide to yield compounds 1ꢁ
/
contraction was observed and the effects of these
compounds with simultaneous administration of adre-
naline were also studied on isolated frog heart.
2
6 (Fig. 1).
3
. Pharmacology
4. Results and discussion
The protection offered by the synthesized compounds
against clonic and tonic convulsions in wistar albino
mice was screened at the dose levels of 30, 100 and 300
The compounds were tested for anticonvulsant activ-
ity by using the procedures described previously [21,22].
The initial evaluation (phase I) of anticonvulsant
activity of synthesized compounds presented in Table
1. The compounds were administered intraperitoneally
ꢀ
1
mg kg . The decrease in the elevated motor activity
induced by amphetamine (amphetamine antagonism)
was also studied for the synthesized compounds at the
ꢀ
1
ꢀ1
dose levels of 25 and 50 mg kg . The effects of the
synthesized compounds on the rate and force of
at three doses (30, 100 and 300 mg kg ). Three tests
were performed for each compound; maximal electro-

R. Sivakumar et al. / European Journal of Medicinal Chemistry 37 (2002) 793ꢁ
/801
795
Table 1
Anticonvulsant and toxicity screening data in mice (i.p.)
position showed higher protection than the other
heterocyclic substitution like morpholino, piperidino
and piperazino compounds. Among the secondary
amines methyl amine substituted at 3? position offered
more protection than substituted (p-hydroxy phenyla-
mino, p-bromo phenylamino, p-nitro phenylamino, o-
amino phenylamino) and unsubstituted (phenyl amino,
phenyl hydrazino) aromatic compounds. In the propane
a,b
c
d
Compound
MES
scMet
Rotarod toxicity
30 min 4 h 30 min 4 h 30 min
4 h
1
2
3
4
5
6
7
8
9
ꢀ
ꢀ
ꢂ
ꢀ
ꢂ
ꢂ
ꢀ
ꢂ
ꢀ
ꢀ
ꢂ
ꢀ
ꢂ
ꢂ
ꢀ
ꢀ
ꢂ
ꢂ
ꢀ
ꢂ
ꢂ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢂꢂ
ꢂ
ꢂꢂ
ꢂ
ꢂ
ꢂꢂ
ꢂ
ꢀ
ꢂ
ꢂ
ꢂ
ꢂꢂ
ꢀ
ꢂ
ꢂ
ꢂꢂ
ꢂ
ꢂꢂ
ꢂꢂ
ꢂ
ꢀ
ꢂ
ꢀ
ꢂ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢂ
ꢀ
ꢀ
ꢂ
ꢂ
ꢀ
ꢂ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢂ
ꢂꢂ
ꢂ
ꢂꢂ
ꢂꢂ
ꢂ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢂꢂ
ꢂꢂ
ꢂꢂꢂ
ꢂꢂ
ꢂ
ꢂꢂ
ꢂ
ꢂ
ꢂꢂ
ꢂ
ꢂꢂꢂ
ꢂꢂ
ꢂ
series (18ꢁ26), compounds 19 and 20 were found to
/
have high degree of protection against MES-induced
seizures. Only heterocyclic (piperidino and piperazino)
groups substituted at the 3? position showed more
protection than the other substitution. It may be
ꢂꢂ
ꢀ
ꢂ
ꢂ
ꢀ
ꢀ
ꢀ
ꢂ
ꢀ
ꢂ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢂ
ꢂ
ꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢂꢂ
ꢀ
ꢂ
ꢂ
ꢂꢂ
ꢂ
ꢂꢂ
ꢂ
ꢀ
ꢂ
ꢀ
ꢂ
ꢀ
ꢂꢂ
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
suggested that the anticonvulsnat activity exerted by
2ꢂ
some of the compounds by blocking Ca
2ꢂ
channels.
Calcium influx via voltage-activated Ca channels also
plays a role in epileptogenesis and neurodegenerative
2
ꢂ
ꢂ
events, raising the possibility that the blockade of Ca
channels may represent the mechanism of action of these
compounds.
ꢂꢂ
ꢂꢂꢂ
ꢂ
ꢂꢂ
ꢂꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
Compounds 2, 3, 4, 9, 10, 13, 16, 17, 19 and 20
exhibited significant decrease motor activity. The de-
crease in motor activity by the compounds with respect
ꢀ
ꢀ
ꢀ
ꢀ
to propanol series (1ꢁ/17) was found to be in the order of
1
7ꢀ4ꢀ2ꢀ13ꢀ3ꢀ
/
/
/
/
/
10ꢀ16ꢀ9. Among the hetero-
/
/
cyclic groups substituted at the 3? position imidazolo
substituted compound is more active than piperidino
and piperazino substituted compounds. Morpholino
substituted compound was found to be very much less
potent than all the heterocyclic substituted compounds.
Among the secondary amines substituted at the 3?
position, substituted phenyl amino compounds showed
better activity. Among these compounds 2-amino sub-
stituted is more active than 4-hydroxy, 4-bromo and the
unsubstituted compounds. The decrease in motor activ-
ity by the compounds with respect to propane series
ꢂ
ꢀ
a
ꢀ1
Key: ꢂꢂꢂ, activity at 30 mg kg ; ꢂꢂ, activity at 100 mg
ꢀ
1
ꢀ1
ꢀ1
kg ; ꢂ, activity at 300 mg kg ; ꢀ, no activity at 300 mg kg
Maximal electroshock seizure test.
.
b
c
Subcutaneous pentylenetetrazole seizure test.
Neurologic toxicity (rotarod) test.
d
shock (MES)-induced convulsions, subcutaneous Me-
trozol (scMet)-induced convulsions and rotarod neuro-
toxicity test (Tox).
(
18ꢁ
/
26) was found to be in the order of 20ꢀ19. It was
/
As result of preliminary screening, compounds 2ꢁ
/5, 7,
also observed that 2-OH substitution in the propane side
chain plays a significant role in decrease of motor
activity since hydroxyl group substituted compound 2
and 3 exhibited higher protection than the correspond-
ing unsubstituted compounds 19 and 20.
1
0, 12, 13, 16, 17, 19 and 20 were considered for the
phase II trails. This provides an evaluation of the
median effective dose (ED ) and median neurotoxic
dose (TD ). The slope of the regression line and the SE
5
0
5
0
of the slope were then calculated. These data’s are
shown in Table 2. Some of these derivatives showed high
degree of protection against MES-induced seizures. But
they were found to be less effective aginast scMet-
induced seizures. Compound 4 was the best in the MES
Compounds 3, 5, 7, 8, 9, 13 and 15 exhibited potential
cardiac activity. Piperazino substituted compound
showed better blocking activity than the other hetero-
cyclic compounds where as all other compounds are less
active than piperazino compound. Among the tertiary
amines substituted diethyl and dimethyl amino com-
pounds are more active than the other compounds. p-
Hydroxyphenylamino, phenylamino and phenylhydra-
zino compounds are more active among secondary
amines. Electron pumping groups have a prominent
role in this effect. Proton pumping groups significantly
downplayed the effect of blocking adrenaline in the
entire series. None of the propane series compounds
were found to be active. The cardiac activity exhibited
ꢀ
1
test having ED50 of 23.8 mg kg . In the MES test, the
ꢀ
1
ED50 of compounds 12 (30.9 mg kg ), 13 (35 mg kg
ꢀ1
)
and 17 (37 mg kg ) were compared favourably with
phenytoin.
ꢀ
1
The following stuctureꢁ
observed. In the propanol series (1ꢁ
pounds 2ꢁ5, 7, 10, 12, 13, 16 and 17 were found to have
a high degree of protection against MES-induced
convulsions. Imidazolo substituted compound at the 3?
/activity relationships were
/17), only com-
/

796
R. Sivakumar et al. / European Journal of Medicinal Chemistry 37 (2002) 793ꢁ801
/
Table 2
Quantitative anticonvulsant data in mice (test drug administered i.p.)
a
b
Compound
ED50
MES
TD50
ScMet
2
3
4
5
7
85.2 (75ꢁ
98.1 (78ꢁ
23.8 (20ꢁ
51.6 (63ꢁ
42.2 (36ꢁ
59.7 (49ꢁ
30.9 (26ꢁ
35.8 (30ꢁ
112.2 (94ꢁ
37.5 (32ꢁ
63.4 (48ꢁ
71.8 (60ꢁ
9.9 (6.3ꢁ
9.2 (6.9ꢁ
297)
/
95)
118)
26)
74)
48)
69)
35)
41)
130)
44)
78)
84)
186 (168ꢁ
ꢀ250
/
202)
224 (195ꢁ
256 (215ꢁ
132 (114ꢁ
154 (130ꢁ
129 (105ꢁ
184 (164ꢁ
96 (71ꢁ
122 (107ꢁ
318 (293ꢁ
152 (130ꢁ
144 (124ꢁ
170 (145ꢁ
/
252)
288)
151)
180)
155)
204)
111)
137)
343)
174)
162)
195)
/
/
/
78 (63ꢁ/93)
/
/
ꢀ100
/
/
92 (73ꢁ
ꢀ150
ꢀ150
/114)
/
1
1
1
1
1
1
2
0
2
3
6
7
9
0
/
/
/
/
/
62 (52ꢁ/72)
/
/
144 (124ꢁ
/
164)
/
/
78 (65ꢁ
67 (52ꢁ
96 (76ꢁ
/
91)
/
/
/82)
/
/
/116)
/
Phenytoin
Carbamazepine
Valporate
/13.1)
ꢀ300
ꢀ125
69.8 (57.2ꢁ
74.4 (59.1ꢁ
437)
/
80.7)
/11.7)
/
87.5)
264 (236ꢁ
/
157 (133ꢁ
/
185)
408 (364ꢁ
/
a
Doses measured in mg kgꢀ1 at the peak effect.
b
ꢀ1
Doses (mg kg ) determined by rotarod test at the time of peak neuro toxic effect.
by these compounds may be correlated to the presence
of the pharmacophore similarity to the chemical func-
tionality present in b-adrenergic blocking agents. When
administered concurrently with adrenaline, the com-
pounds exhibited significant sympatholytic action. The
compounds were able to block the effects of adrenaline
2H, (phenolic OH)2). Anal. Found (Calc.) for
C H N O : C, 59.43 (59.25); H, 3.82 (3.70); N, 17.09%
(17.28).
8
6
2
2
5
.1.2. Synthesis of 1-(2?,3?-epoxy-propyloxy)-4-
hydroxyphthalazine
-(2?,3?-Epoxy-proploxy)-4-hydroxyphthalazine was
(
100, 200 and 400 mg).
1
prepared according to the procedure given by JCE
Simpson [24]. A quantity of 1,4-dihydroxyphthalazine
5
. Experimental
(
0.1 mol) and epicholorohydrine (0.1 moles) were
refluxed in the presence of AgCl (0.0007 mol) NaI
0.0006 mol) and MeOH (150 mL) for 20 h. The
resultant product was purified by recrystallisation with
CHCl ꢁether (1:1). Yield: 62%, m.p.: 206 8C. IR (KBr,
(
5
.1. Chemistry
/
M.p. were determined in open capillary tubes and are
uncorrected. IR spectra were recorded (in KBr) on
Perkinꢁ
Spectra was recorded on 300 MHz Bruker DPX 200
using tetra methylsilane as internal standard. Elemental
analysis was performed on Heraeus CHN rapid analy-
ser. Analyses indicated by the symbols of the elements
3
ꢀ
1
cm ): 3240 (Oꢀ
120 (ether CꢀO), 812, 790 (Arꢀ
d, ppm): 8.3ꢁ8.5 (m, 4H, Benzo protons of phthalazine),
.38ꢁ7.16 (s, 1H, phenolic OH), 3.42ꢁ3.67 (d, Jꢄ5.2
Hz, 2H, 3?-CH ), 3.21ꢁ3.40 (d, Jꢄ
3.21 (s, 3H, 4-CH ), 2.67ꢁ2.91 (m, 1H, 2?-CH).
/
H), 1406 (Cꢀ
/
H), 1240 (epoxide Cꢀ
/
O),
1
1
Elmer IR spectrophotometer 298. H-NMR
1
/
/
H). H-NMR (CDCl ,
/
3
/
7
/
/
/
/
/
6.3 Hz, 2H; 1?-CH2),
2
2
.98ꢁ
/
/
3
Anal. Found (Calc.) for C H N O : C, 60.21 (60.55);
H, 4.34 (4.58); N, 12.62% (12.84).
are within 9
/
0.4% of the theoretical values.
11 10
2
3
5
.1.1. Synthesis of 1,4-dihydroxyphthalazine
In the present study 1,4-dihydroxyphthalazine was
prepared according to the procedure given by Fitton
23]. Phthalic anhydride (0.02 mol) was refluxed with
5.1.3. Synthesis of 1-(3?-chloropropyloxy)-4-
hydroxyphthalazine
[
1-(3?-Chloropropyloxy)-4-hydroxyphthalazine
was
hydrazine monohydrate (0.02 mol) in EtOH (25 mL) for
half an hour. The reaction mixture was cooled and
prepared according to the procedure given by JCE
Simpson [24]. A quantity of 1,4-dihydroxyphthalazine
(0.1 mol) and 1-bromo-3-chloropropane (0.1 mol) were
refluxed in the presence of AgCl (0.0007 mol), NaI
(0.0006 mol) and MeOH (150 mL) for 20 h.The
resultant product was purified by recrystallisation with
washed with petroleum ether 40ꢁ
/
60 8C (3ꢃ/40 mL) and
recrystallised with MeOHꢁether (1:1). Yield: 77%, m.p.:
/
ꢀ
1
3
8
(
34 8C. IR (KBr, cm ): 3240 (Oꢀ
/
H), 1406 (Cꢀ
/
H),
1
12, 790 (Arꢀ
/
H). H-NMR (CDCl , d, ppm): 8.3ꢁ
m, 4H, Benzo protons of phthalazine), 7.41ꢁ
/
8.5
7.29 (s,
3
/
CHCl3ꢁ
/
ether(1:1). Yield: 66%, m.p.: ꢀ375 8C. IR
/

R. Sivakumar et al. / European Journal of Medicinal Chemistry 37 (2002) 793ꢁ
/801
797
1
1
(
KBr, cmꢀ ): 1409 (Cꢀ
/
H), 1142 (Cꢀ
/
O), 811, 792 (Arꢀ
7.68
6.73 (s,
3.90 (m, 4H, 1?,3?-CH ), 1.15ꢁ
/
1142 (Cꢀ
ppm): 7.79ꢁ
7.18ꢁ7.39 (s, 1H, phenolic OH), 6.7ꢁ
6.23ꢁ6.47 (m, 2H, 4ƒ,5ƒ(ꢀCH)), 3.58ꢁ
OH), 3.35ꢁ3.42 (m, 4H, 1?,3?-CH ), 1.26ꢁ
/
O), 877, 745 (Arꢀ
7.92 (m, 4H, Benzo protons of phthalazine),
6.9 (m, 1H, 2?-CH),
3.76 (s, 1H, 2?-
1.38 (m, 1H,
/
H). H-NMR (CDCl , d,
3
1
H), 742 (Cꢀ
/
Cl). H-NMR (CDCl , d, ppm): 7.45ꢁ
/
/
3
(
1
m, 4H, benzo protons of phthalazine), 6.92ꢁ
/
/
/
H, phenolic OH), 3.42ꢁ
/
/
/
/
/
2
1
C H ClN O : C, 55.12 (55.46); H, 4.73 (4.62); N,
.23 (m, 2H, 2?-CH ). Anal. Found (Calc.) for
/
/
2
2
2?-CH). Anal. Found (Calc.) for C H N O : C, 58.55
1
1
11
2
2
14 14
5
3
1
1.47% (11.76).
(58.74); H, 4.65 (4.89); N, 19.49% (19.58)
5
.1.4. General method synthesis of 1ꢁ
A mixture of 1-(3?-chloropropyloxy)-4-hydroxyphtha-
lazine/1-(2?,3?-epoxypropyloxy)-4-hydroxyphthalazine
0.005 mol), amine (0.005 mol) were refluxed with 10%
/
26
5.1.4.5. 1-(3?-Diethylamino-2?-hydroxypropyloxy)-4-
hydroxyphthalazine (5). Yield: 82%, m.p. 264ꢁ265 8C.
H), 1372 (Cꢀ
H). H-NMR (CDCl , d,
/
ꢀ
1
IR (KBr, cm ): 3010 (Oꢀ
N), 1156 (CꢀO), 879, 840 (Arꢀ
ppm): 7.81ꢁ8.02 (m, 4H, Benzo protons of phthalazine),
7.09ꢁ6.84 (s, 1H, phenolic OH), 3.72ꢁ3.88 (s, 1H, 2?-
OH), 3.43ꢁ3.59 (m, 4H, 1?,3?-CH ), 1.64ꢁ1.83 (m, 1H,
2?-CH), 1.04ꢁ1.23 (s, 10H, (C H ) ). Anal. Found
(Calc.) for C H N O : C, 61.65 (61.85); H, 7.35
/
H), 1459 (Cꢀ
/
/
1
(
/
/
3
methanolic KOH (15 mL) for 5 h. The reaction mixture
was filtered and the filtrate on concentration yielded the
product. The product was dried under vacuum. The
/
/
/
/
/
2
products were recrystallised using 1:1 MeOHꢁ
/
ether (1,
ether (2, 9, 10, 11,
ether (4, 6, 8, 12, 18,
ether (17).
/
2
5 2
3
1
2
, 5, 7, 14, 15, 19, 21, 22), 1:1 EtOHꢁ
/
1
5
21
3
3
3, 16, 20, 23, 24, 25), 1:1 C H Oꢁ
/
(7.21); N, 14.55% (14.43).
3
6
6) and 1:1 petroleum etherꢁ
/
5
.1.4.6. 1-(3?-Diethanolamino-2?-hydroxypropyloxy)-4-
hydroxyphthalazine (6). Yield: 87%, m.p. 294ꢁ295 8C.
H), 1368 (Cꢀ
5
.1.4.1. 1-(3?-Morpholino-2?-hydroxypropyloxy)-4-
/
ꢀ
1
hydroxyphthalazine (1). Yield: 72%, m.p. 351 8C. IR
IR (KBr, cm ): 3118 (Oꢀ
N), 1324 (NꢀH), 1161 (Cꢀ
NMR (CDCl , d, ppm): 7.89ꢁ
/
H), 1455 (Cꢀ
/
/
ꢀ
1
1
(
8
(
1
(
0
KBr, cm ): 1455 (Cꢀ
/
H), 1375 (Cꢀ
/
N), 1071 (Cꢀ
/
O),
/
/
O), 834, 789 (Arꢀ
/
H). H-
1
34, 789 (Arꢀ
/
H). H-NMR (CDCl , d, ppm): 8.3ꢁ
/
8.54
/8.11 (m, 4H, Benzo
3
3
m, 4H, Benzo protons of phthalazine), 6.91ꢁ
H, phenolic OH), 3.68ꢁ
m, 4H, 1?,3?-CH ), 2.40ꢁ2.62 (m, 8H, 2ƒ,3ƒ,5ƒ,6ƒ-CH2),
1.1 (m, 1H, 2?-CH). Anal. Found (Calc.) for
/
7.14 (s,
protons of phthalazine), 6.34ꢁ
OH), 3.84ꢁ
2ƒ-(OH) ), 2.94ꢁ
/
6.67 (s, 1H, phenolic
/
3.8 (s, 1H, 2?-OH), 3.27ꢁ
/
3.3
/
3.97 (m, 4H, 1?,3?-CH ), 3.44ꢁ
/
3.58 (s, 2H,
3.05 (m, 8H, (C H ) ), 2.23ꢁ2.54 (s,
1.62 (m, 1H, 2?-CH). Anal. Found
2
/
/
/
2
2
2
4 2
.9ꢁ
/
1H, 2?-OH)), 1.48ꢁ
/
C H N O : C, 58.92 (59.01); H, 6.31 (6.22); N,
1
(Calc.) for C H N O : C, 55.9 (55.72); H, 6.35 (6.5);
N, 13.20% (13.00).
1
5
19
3
4
15 21 3 5
3.83% (13.77).
5
.1.4.2. 1-(3?-Piperidino-2?-hydroxypropyloxy)-4-
5.1.4.7. 1-(3?-Dimethylamino-2?-hydroxypropyloxy)-4-
hydroxyphthalazine (7). Yield: 83%, m.p. 287ꢁ288 8C.
H), 1373 (Cꢀ
H). H-NMR (CDCl , d,
hydroxyphthalazine (2). Yield: 79%, m.p. 316ꢁ
IR (KBr, cm ): 1454 (Cꢀ
/
317 8C.
/
ꢀ
1
ꢀ1
/
H), 1372 (Cꢀ
/
N), 1156 (Cꢀ
/
O),
8.15
IR (KBr, cm ): 3321 (Oꢀ
N), 1327 (NꢀH), 879, 840 (Arꢀ
ppm): 8.29ꢁ8.84 (m, 4H, Benzo protons of phthalazine),
7.29ꢁ7.56 (s, 1H, phenolic OH), 3.74ꢁ3.86 (s, 1H, 2?-
OH), 3.34ꢁ3.47 (m, 4H, 1?,3?-CH ), 2.26ꢁ2.42 (m, 1H,
2?-CH), 1.39ꢁ1.63 (s, 6H, (CH ) ). Anal. Found (Calc.)
for C H N O : C, 59.50 (59.31); H, 6.56 (6.46); N,
/
H), 1475 (Cꢀ
/
/
1
1
8
(
79, 840 (Arꢀ
m, 4H, Benzo protons of phthalazine), 7.16ꢁ
H, phenolic OH), 3.76ꢁ
m, 4H, 1?,3?-CH ), 2.9ꢁ
/
H). H-NMR (CDCl , d, ppm): 7.94ꢁ
/
/
/
3
3
/
7.48 (s,
/
1
/
3.92 (s, 1H, 2?-OH), 3.47ꢁ
3.35 (m, 10H, 2ƒ,3ƒ,4ƒ,5ƒ,6ƒ-
1.42 (m, 1H, 2?-CH). Anal. Found (Calc.)
for C H N O : C, 63.50 (63.36); H, 6.97 (6.93); N,
/
3.68
/
/
(
/
/
/
2
2
CH ), 1.22ꢁ
/
/
2
3 2
1
6
21
3
3
13 17
3
3
1
3.65% (13.86).
15.79% (15.96).
5
.1.4.3. 1-(3?-Piperazino-2?-hydroxypropyloxy)-4-
219 8C.
H), 1161 (Cꢀ
H). H-NMR (CDCl , d, ppm): 7.91ꢁ
5.1.4.8. 1-(3?-Phenylamino-2?-hydroxypropyloxy)-4-
hydroxyphthalazine (8). Yield: 77%, m.p. 248ꢁ249 8C.
H), 1356 (Cꢀ
H). H-NMR (CDCl , d,
hydroxyphthalazine (3). Yield: 80%, m.p. 218ꢁ
IR (KBr, cm ): 1373 (Cꢀ
/
/
ꢀ
1
ꢀ1
/
N), 1305 (Nꢀ
/
/
IR (KBr, cm ): 3017 (Oꢀ
N), 1149 (CꢀO), 854, 767 (Arꢀ
ppm): 7.75ꢁ8.39 (m, 4H, Benzo protons of phthalazine),
7.11ꢁ7.29 (s, 1H, phenolic OH), 6.64ꢁ6.75 (s, 1H, ꢀ
NH), 5.4ꢁ5.9 (m, 5H, C H ), 3.87ꢁ3.98 (s, 1H, 2?-
OH), 3.35ꢁ CH ) ), 1.32ꢁ1.52 (m,
1H; 2?-CH). Anal. Found (Calc.) for C H N O : C,
/
H), 1445 (Cꢀ
/
/
1
1
O), 763, 689 (Arꢀ
.17 (m, 4H, Benzo protons of phthalazine), 7.24ꢁ
s, 1H, phenolic OH), 6.9ꢁ6.4 (m, 1H, NH), 3.78ꢁ
s, 1H, 2?-OH), 3.45ꢁ
m, 8H, 2ƒ,3ƒ,5ƒ,6ƒ-CH ), 1.32ꢁ
/
/
/
/
3
3
8
/
7.41
/
(
(
(
/
/
3.92
3.3
/
/
/
/
3.6 (m, 4H, 1?,3?-CH ), 3.13ꢁ
/
/
/
2
6
5
/
1.44 (m, 1H, 2?-CH).
/
3.49 (m, 4H, 1?,3?(ꢀ
/
/
2
2 2
Anal. Found (Calc.) for C H N O : C, 59.35 (59.21);
1
5
20
4
3
17 17
3
3
H, 6.69 (6.57); N, 18.6% (18.42).
65.7 (65.59); H, 5.60 (5.46); N, 13.7% (13.5).
5
.1.4.4. 1-(3?-Imidazolo-2?-hydroxypropyloxy)-4-
5.1.4.9. 1-(3?-(4ƒ-Hydroxyphenylamino)-2?-
hydroxypropyloxy)-4-hydroxyphthalazine (9). Yield:
hydroxyphthalazine (4). Yield: 77%, m.p. 326 8C. IR
ꢀ
1
ꢀ1
(
KBr, cm ): 3213 (Oꢀ
/
H), 1473 (Cꢀ
/
H), 1385 (Cꢀ
/N),
80%, m.p. 344 8C. IR (KBr, cm ): 3231 (Oꢀ
/
H),

798
R. Sivakumar et al. / European Journal of Medicinal Chemistry 37 (2002) 793ꢁ801
/
1
493 (Cꢀ
/
H), 1375 (Cꢀ
/
N), 1112 (Cꢀ
/
O), 812, 736 (Arꢀ
8.29 (m, 4H,
7.58 (s, 2H,
7.23 (m, 1H, NH), 6.4ꢁ6.7 (m,
4.12 (s, 1H, 2?-OH), 3.73ꢁ3.88 (m, 4H,
CH ) ), 1.4ꢁ1.52 (m, 1H, 2?-CH). Anal. Found
/
5.1.4.14. 1-(3?-Diphenylamino-2?-hydroxypropyloxy)-4-
hydroxyphthalazine (14). Yield: 62%, m.p. 213 8C. IR
1
H). H-NMR (CDCl , d, ppm): 8.06ꢁ
Benzo protons of phthalazine), 7.32ꢁ
/
3
ꢀ
1
/
(KBr, cm ): 3211 (Oꢀ
1134 (CꢀO), 858, 792 (Arꢀ
ppm): 7.86ꢁ8.06 (m, 4H, Benzo protons of phthalazine),
6.76ꢁ6.92 (s, 1H, phenolic OH), 6.3ꢁ6.54 (m, 10H,
(C H ) ), 4.40ꢁ4.64 (s, 1H, 2?-OH), 3.4ꢁ3.58 (m, 4H,
1?,3?-CH ), 1.42ꢁ1.52 (m, 1H, 2?-CH). Anal. Found
Calc.) for C H N O : C, 71.42 (71.31); H, 5.60 (5.42);
/
H), 1459 (Cꢀ
/
H), 1345 (Cꢀ
/
N),
1
(
phenolic OH) ), 7.12ꢁ
/
/
/
/
H). H-NMR (CDCl , d,
2
3
4
1
H, C H ), 3.98ꢁ
/
/
/
6
4
?,3?(ꢀ
/
/
/
/
2
2
(
Calc.) for C H N O : C, 62.50 (62.38); H, 5.25 (5.19);
/
/
1
7
17
3
4
6
5 2
N, 12.79% (12.84).
/
2
(
2
3
21
3
3
N, 10.69% (10.85).
5
hydroxypropyloxy)-4-hydroxyphthalazine (10). Yield:
.1.4.10. 1-(3?-(4ƒ-Bromophenylamino)-2?-
ꢀ
1
6
1
8%, m.p. 301 8C. IR (KBr, cm ): 3035 (Oꢀ
478 (CꢀH), 1394 (CꢀN), 1176 (CꢀO), 889, 778 (Arꢀ
8.37 (m, 4H,
7.48 (s, 1H,
6.7 (m,
3.48 (m, 4H,
1.62 (m, 1H, 2?-CH). Anal. Found
/
H),
5.1.4.15. 1-(3?-(6ƒ-Aminopyridyl-2ƒ-amino)-2?-
hydroxypropyloxy)-4-hydroxyphthalazine (15). Yield:
67%, m.p. 336 8C. IR (KBr, cm ): 3160 (Oꢀ
/
/
/
/
1
ꢀ1
H). H-NMR (CDCl , d, ppm): 7.87ꢁ
Benzo protons of phthalazine), 7.26ꢁ
phenolic OH), 6.92ꢁ
/
/
H),
3
/
1454 (Cꢀ
/
H), 1385 (Cꢀ
/
N), 1174 (Cꢀ
/
O), 814, 756 (Arꢀ
/
1
/
7.13 (s, 1H, ꢀ
3.92 (s, 1H, 2?-OH), 3.34ꢁ
CH ) ), 1.43ꢁ
/
NH), 6.3ꢁ
/
H). H-NMR (CDCl , d, ppm): 7.2ꢁ
/
7.7 (m, 4H, Benzo
3
4
H, C H ), 3.78ꢁ
/
/
protons of phthalazine), 6.72ꢁ
OH), 5.34ꢁ
3.78ꢁ3.89 (s, 1H, 2?-OH), 3.28ꢁ
1.34ꢁ
C H N O : C, 58.55 (58.71); H, 5.3 (5.19); N, 21.55%
/
6.87 (s, 1H, phenolic
6
4
1
?,3?(ꢀ
/
/
/
6.13 (m, 2H, NH ), 4.9ꢁ
/
5.1 (m, 1H, NH),
2
2
2
(Calc.) for C H N O Br: C, 52.36 (52.3); H, 4.23 (4.1);
N, 10.81% (10.76).
/
/
3.42 (m, 4H, 1?,3?-CH2),
1
7
16
3
3
/
1.56 (m, 1H, 2?-CH). Anal. Found (Calc.) for
1
6
17
5
3
(
21.4).
5
hydroxypropyloxy)-4-hydroxyphthalazine (11). Yield:
.1.4.11. 1-(3?-(4ƒ-Nitrophenylamino)-2?-
ꢀ
1
6
1
7%, m.p. 198 8C. IR (KBr, cm ): 3201 (Oꢀ
447 (CꢀH), 1395 (CꢀN), 1146 (CꢀO), 843, 756 (Arꢀ
8.28 (m, 4H,
7.88 (s, 1H,
6.45 (m,
3.82 (m, 4H,
1.48 (m, 1H, 2?-CH). Anal. Found
/
H),
5.1.4.16. 1-(3?-(6ƒ-Methylpyridyl-2ƒ-amino)-2?-
hydroxypropyloxy)-4-hydroxyphthalazine (16). Yield:
73%, m.p. 308ꢁ
1494 (CꢀH), 1334 (Cꢀ
H). H-NMR (CDCl , d, ppm): 8.65ꢁ
/
/
/
/
1
ꢀ1
H). H-NMR (CDCl , d, ppm): 8.05ꢁ
Benzo protons of phthalazine), 7.61ꢁ
phenolic OH), 7.11ꢁ
/
/
309 8C. IR (KBr, cm ): 3270 (Oꢀ
/
H),
3
/
/
/
N), 1176 (Cꢀ
/
O), 837, 783 (Arꢀ
8.41 (m, 4H,
7.56 (s, 1H,
CH)), 4.09ꢁ
/
1
/
7.32 (m, 1H, NH), 6.32ꢁ
4.34 (s, 1H, 2?-OH), 3.65ꢁ
?,3?-CH ), 1.32ꢁ
/
/
3
4
H, C H ), 4.12ꢁ
/
/
Benzo protons of phthalazine), 7.22ꢁ
/
6
4
1
/
phenolic OH), 6.5ꢁ
3.98 (s, 1H, 2?-OH), 3.72ꢁ
2.65 (s, 3H, CH ), 1.45ꢁ
/
6.9 (m, 3H, 3ƒ,4ƒ,5ƒ(ꢀ
/
/
2
(
N, 15.85% (15.73).
Calc.) for C H N O : C, 57.49 (57.30); H, 4.55 (4.49);
/
3.83 (m, 4H, 1?,3?-CH ), 2.48ꢁ
/
1
7
16
4
5
2
/
1.66 (m, 1H, 2?-CH). Anal.
3
Found (Calc.) for C H N O : C, 62.7 (62.51); H, 5.65
(5.52); N, 17.35% (17.17).
1
7
18
4
3
5
.1.4.12. 1-(3?-Methylamino-2?-hydroxypropyloxy)-4-
hydroxyphthalazine (12). Yield: 88%, m.p. 362 8C. IR
ꢀ
1
(
1
KBr, cm ): 3120 (Oꢀ
134 (CꢀO), 812, 739 (Arꢀ
ppm): 8.43ꢁ8.62 (m, 4H, Benzo protons of phthalazine),
7.65 (s, 1H, phenolic OH), 6.37ꢁ6.45 (s, 1H, NH),
4.26 (s, 1H, 2?-OH), 3.23ꢁ3.41 (m, 4H, 1?,3?-CH2),
2.34 (m, 1H, 2?-CH), 1.23ꢁ1.34 (s, 3H, CH3).
/
H), 1474 (Cꢀ
/
H), 1332 (Cꢀ
/
N),
5.1.4.17. 1-(3?-(2ƒ-Aminophenylamino)-2?-hydroxy-
propyloxy)-4-hydroxyphthalazine (17). Yield: 80%, m.p.
1
/
/
H). H-NMR (CDCl , d,
3
ꢀ
1
/
109ꢁ
H), 1351 (Cꢀ
NMR (CDCl , d, ppm): 7.42ꢁ
/
110 8C. IR (KBr, cm ): 3102 (Oꢀ
/
H), 1478 (Cꢀ
/
1
H). H-
7
4
2
.44ꢁ
.10ꢁ
.12ꢁ
/
/
/
N), 1193 (CꢀO), 873, 729 (Arꢀ
/
/
/
/
/7.61 (m, 4H, Benzo
3
/
/
protons of phthalazine), 7.09ꢁ
OH), 6.7ꢁ
4.31ꢁ4.45 (m, 1H, NH), 3.80ꢁ
.6 (m, 4H, 1?,3?-CH ), 0.92ꢁ1.12 (m, 1H, 2?-CH). Anal.
/7.23 (s, 1H, phenolic
Anal. Found (Calc.) for C H N O : C, 57.95 (57.83);
H, 6.23 (6.02); N, 16.95% (16.86).
/
6.9 (m, 5H, C H ), 5.63ꢁ
/
5.76 (s, 2H, NH2),
1
2
15
3
3
6
5
/
/
3.92 (s, 1H, 2?-OH), 3.5ꢁ
/
3
/
2
Found (Calc.) for C H N O : C, 62.70 (62.51); H, 5.75
(5.52); N, 17.05% (17.17).
5
4
2
1
.1.4.13. 1-(3?-Hydrazinophenyl-2?-hydroxypropyloxy)-
-hydroxyphthalazine (13). Yield: 88%, m.p. 276ꢁ
17 18
4
3
/
ꢀ
1
77 8C. IR (KBr, cm ): 3212 (Oꢀ
392 (CꢀN), 1124 (CꢀO), 878, 745 (Arꢀ
8.36 (m, 4H, Benzo protons of
7.66 (s, 1H, phenolic OH), 6.4ꢁ6.9
m, 5H, C H ), 5.54ꢁ5.72 (m, 2H, NHꢀNH), 4.22ꢁ
.41 (s, 1H, 2?-OH), 3.78ꢁ3.92 (m, 4H, 1?,3?-CH2),
.06ꢁ1.24 (m, 1H, 2?-CH). Anal. Found (Calc.) for
/
H), 1487 (Cꢀ
/
H),
1
/
/
/
H). H-NMR
5.1.4.18. 1-(3?-Morpholinopropyloxy)-4-
(
CDCl , d, ppm): 8.13ꢁ
/
hydroxyphthalazine (18). Yield: 62%, m.p. 234 8C. IR
3
ꢀ
1
phthalazine), 7.37ꢁ
(
4
1
/
/
(KBr, cm ): 3207 (Oꢀ
1185 (CꢀO), 851, 730 (Arꢀ
ppm): 7.49ꢁ7.78 (m, 4H, Benzo protons of phthalazine),
6.59ꢁ6.87 (s, 1H, phenolic OH), 5.9ꢁ6.16 (m, 1H, NH),
3.23ꢁ3.42 (m, 4H, 1?,3?-CH ), 2.40ꢁ2.62 (m, 8H,
2ƒ,3ƒ,5ƒ,6ƒ-CH ), 1.36ꢁ1.47 (m, 2H, 2?-CH ). Anal.
/
H), 1456 (Cꢀ
/
H), 1349 (Cꢀ
/
N),
1
/
/
/
/
/
H). H-NMR (CDCl , d,
6
5
3
/
/
/
/
/
C H N O : C, 62.72 (62.57); H, 5.60 (5.52); N, 17.30%
/
/
1
7
18
4
3
2
(
17.17).
/
2
2

R. Sivakumar et al. / European Journal of Medicinal Chemistry 37 (2002) 793ꢁ
/801
799
Found (Calc.) for C H N O : C, 62.3 (62.28); H, 6.65
1
Table 3
Amphetamine antagonism of the compounds
5
19
3
3
(
6.57); N, 14.4% (14.53).
Dose (mg kgꢀ
1
)
% Reduction of motor activity
Compound
5
.1.4.19. 1-(3?-Piperidinopropyloxy)-4-
hydroxyphthalazine (19). Yield: 80%, m.p. 282 8C. IR
1
25
50
12.46*
23.78*
ꢀ
1
(
1
KBr, cm ): 3107 (Oꢀ
175 (CꢀO), 845, 775 (Arꢀ
ppm): 8.13ꢁ8.36 (m, 4H, Benzo protons of phthalazine),
7.38 (s, 1H, phenolic OH), 3.80ꢁ3.92 (s, 10H,
?,3?,4?,5?,6?-CH ), 3.73ꢁ3.88 (m, 6H, 1?,3?-CH ), 1.56ꢁ
/
H), 1423 (Cꢀ
/
H), 1343 (Cꢀ
/
N),
1
**
/
/
H). H-NMR (CDCl , d,
2
25
0
44.48
89.54*
3
5
/
7
2
1
.16ꢁ
/
/
3
25
5
43.26*
86.52*
0
/
/
2
2
4
25
5
45.76*
91.6*
.72 (m, 2H, 2?-CH ). Anal. Found (Calc.) for
2
0
C H N O : C, 66.6 (66.89); H, 7.37 (7.31); N, 14.5
(
1
6
21
3
2
**
14.63).
5
25
0
39.62
77.26*
5
5
.1.4.20. 1-(3?-Piperazinopropyloxy)-4-
6
25
5
39.38*
80.28*
0
hydroxyphthalazine (20). Yield: 76%, m.p. 210 8C. IR
ꢀ
1
(
KBr, cm ): 3087 (Oꢀ
142 (CꢀO), 835, 724 (Arꢀ
ppm): 7.93ꢁ8.21 (m, 4H, Benzo protons of phthalazine),
7.12 (s, 1H, phenolic OH), 6.13ꢁ6.47 (m, 1H, NH),
4.08 (m, 8H, 2ƒ,3ƒ,5ƒ,6?-CH ), 3.78ꢁ3.91 (m, 6H,
1.83 (m, 2H, 2?-CH ). Anal. Found
/
H), 1424 (Cꢀ
/
H), 1332 (Cꢀ
/
N),
7
25
50
39.62*
78.26*
1
1
/
/
H). H-NMR (CDCl , d,
3
*
*
8
25
5
24.62
49.58
/
***
0
6.89ꢁ
4.24ꢁ
1?,3?-CH ), 1.56ꢁ
/
/
9
25
5
39.62*
/
/
2
**
80.28
0
/
2
2
*
*
*
(Calc.) for C H N O : C, 62.4 (62.5); H, 6.89 (6.94);
N, 19.3% (19.44).
10
25
5
43.72
85.74
1
5
20
4
2
*
0
*
*
*
1
1
1
1
2
3
25
0
21.44
43.48
*
5
5
.1.4.21. 1-(3?-Imidazolopropyloxy)-4-
**
25
50
33.28
66.62*
hydroxyphthalazine (21). Yield: 66%, m.p. 313 8C. IR
ꢀ
1
(
KBr, cm ): 3176 (Oꢀ
169 (CꢀO), 845, 787 (Arꢀ
ppm): 8.19ꢁ8.34 (m, 4H, Benzo protons of phthalazine),
7.84 (s, 1H, phenolic OH), 4.5ꢁ4.9 (m, 1H, CH),
4.3 (m, 2H, (ꢀCH) ), 3.32ꢁ3.48 (m, 4H, 1?,3?-CH2),
.12ꢁ1.36 (m,1H, 2?-CH ). Anal. Found (Calc.) for
/
H), 1458 (Cꢀ
/
H), 1386 (Cꢀ
/N),
1
25
5
44.52*
1
/
/
H). H-NMR (CDCl , d,
3
**
87.48
0
/
7
4
1
.65ꢁ
/
/
14
15
25
5
8.14*
17.88*
0
.1ꢁ
/
/
/
2
/
25
38.82*
2
**
96.76
5
0
C H N O : C, 62.1 (62.22); H, 5.16 (5.18); N, 20.5%
20.74).
1
4
14
4
2
**
1
6
7
25
0
41.84
82.72*
46.64*
(
5
1
25
5
5
.1.4.22. 1-(3?-Diethylaminopropyloxy)-4-
***
93.88
0
hydroxyphthalazine (22). Yield: 72%, m.p. 147 8C. IR
ꢀ
1
**
(
KBr, cm ): 3198 (Oꢀ
191 (CꢀO), 829, 782 (Arꢀ
ppm): 8.21ꢁ8.37 (m, 4H, Benzo protons of phthalazine),
.65ꢁ7.91 (s, 1H, phenolic OH), 4.23ꢁ4.46 (m, 4H, 1?,3?-
CH ), 2.32ꢁ2.43 (m, 2H, 2?-CH ), 1.72ꢁ1.92 (m, 10H,
/
H), 1429 (Cꢀ
/
H), 1373 (Cꢀ
/N),
18
19
25
50
35.24
69.44*
1
1
/
/
H). H-NMR (CDCl , d,
3
/
25
5
41.24*
83.46*
0
7
/
/
2
2
0
1
25
5
42.66*
84.52*
/
/
2
2
0
(
(
C H ) ). Anal. Found (Calc.) for C H N O : C, 65.19
65.21); H, 7.91 (7.97); N, 15.1% (15.21).
2
5 2
15 22
3
2
**
25
5
23.82
49.34*
0
5
.1.4.23. 1-(3?-Diethanolaminopropyloxy)-4-
22
23
25
5
38.68*
**
0
75.52
hydroxyphthalazine (23). Yield: 58%, m.p. 187 8C. IR
ꢀ
1
(
KBr, cm ): 3061 (Oꢀ
134 (CꢀO), 859, 746 (Arꢀ
ppm): 8.08ꢁ8.21 (m, 4H, Benzo protons of phthalazine),
.48ꢁ7.69 (s, 1H, phenolic OH), 4.23ꢁ4.45 (m, 4H, 1?,3?-
CH ), 3.15ꢁ3.36 (s, 2H, 2ƒ-(OH) ), 2.94ꢁ3.05 (m, 8H,
1.53 (m, 2H, 2?-CH ). Anal. Found
/
H), 1484 (Cꢀ
/
H), 1335 (Cꢀ
/N),
25
50
13.12*
**
25.94
1
1
/
/
H). H-NMR (CDCl , d,
3
**
2
4
5
25
0
22.32
43.76*
23.82*
/
5
7
/
/
2
25
5
/
/
2
2
**
46.34
0
(
(
(
C H ) ), 1.32ꢁ
Calc.) for C H N O : C, 57.4 (57.32); H, 6.91
7.00); N, 15.3% (15.28).
/
2
4 2
2
**
26
25
0
32.34
63.76*
1
5
22
3
4
5

800
R. Sivakumar et al. / European Journal of Medicinal Chemistry 37 (2002) 793ꢁ801
/
Table 3 (Continued)
2
(Calc.) for C H N O : C, 63.1 (62.9); H, 7.3 (7.25);
?-CH ), 2.31ꢁ2.45 (m, 6H, (CH ) ). Anal. Found
/
2
3 2
Dose (mg kgꢀ1
1
3
18
3
2
Compound
)
% Reduction of motor activity
N, 16.8% (16.93).
Phenobarbitone 10
98.32*
5
.1.4.25. 1-(3?-Aminophenylpropyloxy)-4-
*
*
*
P B0.05.
* P B0.01.
** P B0.001 compared to control.
hydroxyphthalazine (25). Yield: 90%, m.p. 203 8C. IR
ꢀ1
(
KBr, cm ): 3190 (Oꢀ
187 (CꢀO), 836, 739 (Arꢀ
ppm): 7.67ꢁ7.84 (m, 4H, Benzo protons of phthalazine),
7.57 (s, 1H, phenolic OH), 7.13ꢁ7.27 (m, 1H, NH),
6.54 (m, 5H, C H ), 4.45ꢁ
/
H), 1438 (Cꢀ
/
H), 1332 (Cꢀ
/
N),
1
1
/
/
H). H-NMR (CDCl , d,
3
/
5
.1.4.24. 1-(3?-Dimethylaminopropyloxy)-4-
hydroxyphthalazine (24). Yield: 85%, m.p. 159 8C. IR
7.43ꢁ
6.18ꢁ
1.54ꢁ
/
/
/
/
4.69 (m, 4H, 1?,3?-CH2),
ꢀ
1
6
5
(
KBr, cm ): 3108 (Oꢀ
164 (CꢀO), 867, 739 (Arꢀ
ppm): 7.79ꢁ7.93 (m, 4H, Benzo protons of phthalazine),
.56ꢁ6.82 (s, 1H, phenolic OH), 4.35ꢁ4.49 (s, 1H, 2?-
OH), 3.67ꢁ3.88 (m, 4H, 1?,3?-CH ), 2.92ꢁ
/
H), 1454 (Cꢀ
/
H), 1396 (Cꢀ
/
N),
/
1.74 (m, 2H, 2?-CH ). Anal. Found (Calc.) for
1
2
1
/
/
H). H-NMR (CDCl , d,
3
C H N O : C, 69.24 (69.15); H, 5.65 (5.76); N, 14.31%
(14.23).
1
7
17
3
2
/
6
/
/
/
/3.12 (m, 2H,
2
5
.1.4.26. 1-(3?-(4ƒ-Hydroxyphenylamino)propyloxy)-4-
hydroxyphthalazine (26). Yield: 82%, m.p. 255 8C. IR
ꢀ
1
(
KBr, cm ): 3047 (Oꢀ
1138 (CꢀO), 829, 735 (Arꢀ
ppm): 7.69ꢁ7.88 (m, 4H, Benzo protons of phthalazine),
.14ꢁ7.37 (s, 2H, (phenolic OH) ), 6.2ꢁ
C H ), 4.23ꢁ
/
H), 1457 (Cꢀ
/
H), 1378 (Cꢀ
/
N),
Table 4
1
Cardiac activity of the compounds
/
/
H). H-NMR (CDCl , d,
3
/
Compound Concentration
Effect on systole
7
/
/
6.67 (m, 4H,
2
1
1ꢁ
/
50 mg of 1
Normal
Negative ionotropic
6
4
/
4.4 (m, 1H, NH), 3.78ꢁ
/
3.92 (m, 4H, 1?,3?-
1
1
4
00 mg of 1
CH ), 1.92ꢁ2.12 (m, 2H, 2?-CH ). Anal. Found (Calc.)
for C H N O : C, 65.2 (65.59); H, 5.37 (5.46); N,
13.61% (13.50).
/
2
2
00 mg of 1ꢂ100 mg of adrenaline Positive ionotropic
00 mg of 1ꢂ100 mg of adrenaline Normal
1
7
17
3
3
3
4
1ꢁ
1
/
4 mg of 3
mg of 3ꢂ100 mg of adrenaline
mg of 3ꢂ100 mg of adrenaline
Negative ionotropic
Positive ionotropic
Normal
5.2. Pharmacology
2
1ꢁ
/
2 mg of 4
100 mg of 4
Normal
Negative ionotropic
All the synthesized compounds were screened for
4
1
4
ꢁ/
anticonvulsant activity. The amphetamine antagonism
was done at the dose of 25 mg and 50 mg kgꢀ . The
experimental dose for the amphetamine antagonism was
selected between the minimal 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 administered to
the animals as a solution in water for injection and triple
glass distilled water. Wistar albino mice (20ꢁ
either sex were procured from King Institute, Guindy,
Chennai. They were kept in colony cages at 92 8C,
relative humidity 45ꢁ55% under 12 h light and dark
cycle. All the animals were acclimatized for a week
before use. Small frogs (Rana trigana, 80ꢁ120 g) were
00 mg of 4ꢂ100 mg of adrenaline Positive ionotropic
00 mg of 4ꢂ100 mg of adrenaline Normal
1
5
7
1ꢁ
4
/
2 mg of 5
0 mg of 5ꢂ100 mg of adrenaline
0 mg of 5ꢂ100 mg of adrenaline
Negative ionotropic
Positive ionotropic
Normal
5
1ꢁ
/
8 mg of 7
0ꢁ20 mg of 7
0 mg of 7ꢂ100 mg of adrenaline
Normal
Negative ionotropic
Positive ionotropic
1
5
1
/
00 mg of 7ꢂ100 mg of adrenaline Normal
/
30 g) of
8
9
0
1ꢁ
/
40 mg of 8
Normal
Negative ionotropic
1
1
2
00 mg of 8
/
00 mg of 8ꢂ100 mg of adrenaline Positive ionotropic
00 mg of 8ꢂ100 mg of adrenaline Normal
/
1ꢁ
/
8 mg of 9
0ꢁ40 mg of 9
0 mg of 9ꢂ100 mg of adrenaline
Normal
Negative ionotropic
Positive ionotropic
/
1
2
1
/
procured locally and used on the same day. Unpaired
student’s t-test [25] was performed to ascertain the
significance of the exhibited activity.
00 mg of 9ꢂ100 mg of adrenaline Normal
1
1ꢁ
/
100 mg of 10
Normal
Negative ionotropic
2
2
4
00ꢁ400 mg of 10
00 mg of 10ꢂ100 mg of adrenaline Positive ionotropic
00 mg of 10ꢂ100 mg of adrenaline Normal
/
5
.2.1. Anticonvulsant activity
All compounds were tested for anticonvulsant activity
with Wistar albino mice. Each compound was adminis-
1
3
5
1ꢁ
5
/
40 mg of 13
Normal
Negative ionotropic
0ꢁ200 mg of 13
00 mg of 13ꢂ100 mg of adrenaline Normal
/
tered intraperitoneally at three dose levels (30, 100 and
ꢀ
2
1
00 mg kg ). The compounds were made solution with
3
water for injection.
1
2ꢁ
/
10 mg of 15
Normal
Negative ionotropic
2
1
2
0 mg of 15
Maximal electroshock seizures (MES) were induced
30 min after drug treatment by application of 50 mA
current for 0.2 s via corneal electrodes into the eyes. The
00 mg of 15ꢂ100 mg of adrenaline Positive ionotropic
00 mg of 15ꢂ100 mg of adrenaline Normal

R. Sivakumar et al. / European Journal of Medicinal Chemistry 37 (2002) 793ꢁ
/801
801
[
3] R. Soliman, M. Gabr, M.S. Abouzeit-Har, F.M. Sharabi, J.
protection was defined as the abolition of hind-leg tonic
maximal extension component of the seizure. The
subcutaneous pentylenetetrazole (Metrozol) seizure
threshold test (scMet) was carried out by an intraper-
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kg ). Animals were observed for over 30 min. Failure
to observe the generalised clonic seizure is defined as
protection.
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[
4] K. Go, K. Tsurumi, H. Fujimura, Jpn. J. Pharmacol. 28 (1978) 1.
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5
0
rotarod test (Tox). Mice were placed in 1-in diameter
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2
[
[
[
[
[
[
8
11] S.D. Samant, S.M. Gupte, R.A. Kulkarni, Indian J. Chem., Sect.
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5
.2.2. Amphetamine antagonistic activity
The decrease in the motor activity [26] induced by
(
1999) 33.
introceptine stimuli of the compounds was studied by
amphetamine antagonism. Wistar albino mice (nꢄ6) of
either sex were selected by random sampling technique.
14] S.K. Agarwal, A.K. Saxena, P.C. Jain, N. Anand, R.N. Sur, R.C.
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/
The compounds were administered at a dose level 25 mg
ꢀ
1
and 50 mg kg
of amphetamine (5 mg kg , i.p.). Phenobarbitone (10
i.p 30 min prior to the administration
ꢀ
[16] S.K. Starling, S.N. Rastogi, N. Anand, R.C. Srimal, K. Kar,
Indian J. Chem., Sect. B 15 (1977) 715.
1
ꢀ
1
[17] S.K. Agarwal, Y. Kumar, A. Saxena, P.C. Jain, N. Anand, Indian
J. Chem., Sect. B 21 (1982) 435.
mg kg , i.p) was used as the standard drug. The motor
activity of the compounds was observed for 15 min in an
octophotometer after 10 min of amphetamine adminis-
tration. The percentage reduction of motor activity by
the compounds is presented in Table 3.
[
18] L.J. Thomas, N. Anbalagan, K.S. Sadish, G.S. Kishore, S.K.
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5
.2.3. Cardiac activity
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locke solution. The effect of the compounds on the rate
and force of the contraction was observed from 1 to 100
mg. The effect of the compounds at different concentra-
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[
[
[
[
23] A.O. Fitton, R.K. Smalley (Eds.), Practical Heterocyclic Chem-
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adrenaline (100, 200 and 400 mg) was also studied (Table
).
/
800 mg) with simultaneous administration with
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Interscience Publishers, New York, 1953, p. 157.
4
25] M.R. Spiegel, R. Meddis, Probability and Statistics, McGraw-Hill
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