Synthesis and antinociceptive activity of 4,4'-bis(1-substituted- semicarbazidyl)diphenylmethane and 4,4-bis(5-substituted-2,4-dihydro-3-oxo-3H-1, 2,4- triazol-4-yl)diphenylmethane derivatives

Article abstract of DOI:10.1007/s00706-009-0242-3

In the reaction of 4,4'-diphenylmethane diiso-cyanate with carboxylic acid hydrazides, 4,4'-bis(1- substituted-semicarbazidyl)diphenylmethane derivatives were obtained. Depending on their chemical nature, cyclization of these compounds in alkaline medium led to the formation of two groups of compounds: bis(2,4-dihy- dro-3H-1,2,4-triazol-3-one) derivatives or carboxylic acids. The pharmacological effects of the selected compounds on the central nervous system in mice were investigated. Strong antinociceptive properties of some derivatives, at a wide range of doses, were observed. Springer-Verlag 2010.

Full text of DOI:10.1007/s00706-009-0242-3

Monatsh Chem (2010) 141:199–203
DOI 10.1007/s00706-009-0242-3
ORIGINAL PAPER
Synthesis and antinociceptive activity
of 4,40-bis(1-substituted-semicarbazidyl)diphenylmethane
and 4,40-bis(5-substituted-2,4-dihydro-3-oxo-3H-1,2,4-
triazol-4-yl)diphenylmethane derivatives
•
Monika Pitucha Anna Chodkowska
•
•
Mariusz Maciejewski Ewa Jagiello-Wojtowicz
•
´
Anna Pachuta-Stec
Received: 6 January 2009 / Accepted: 21 December 2009 / Published online: 12 February 2010
Ó Springer-Verlag 2010
Abstract In the reaction of 4,40-diphenylmethane diiso-
cyanate with carboxylic acid hydrazides, 4,40-bis(1-
substituted-semicarbazidyl)diphenylmethane derivatives
were obtained. Depending on their chemical nature,
cyclization of these compounds in alkaline medium led to
the formation of two groups of compounds: bis(2,4-dihy-
dro-3H-1,2,4-triazol-3-one) derivatives or carboxylic acids.
The pharmacological effects of the selected compounds on
the central nervous system in mice were investigated.
Strong antinociceptive properties of some derivatives, at a
wide range of doses, were observed.
were tested for antinociceptive activity and showed
promising results [11, 12]. The 1,2,4-triazole system is a
structural element of many drugs that have anticonvulsant
or antidepressant activity such as nefazodone hydrochlo-
ride [13] or amdatezole [14].
One of the methods of preparing compounds containing
this nucleus is a cyclization reaction of acylsemicarbazide
derivatives in alkaline medium [15, 16]. In a previous
paper some 4,40-bis(5-substituted-2,4-dihydro-3-oxo-3H-
1,2,4-triazol-4-yl)diphenylmethane derivatives (3a–3d)
were synthesized in the reaction of the corresponding bis-
semicarbazide derivatives 2a–2d. The X-ray structure
analysis of 3a revealed that the asymmetric part of the unit
cell contains two independent molecules, both existing in
the keto tautomeric form [17].
Keywords CNS activity ꢀ Semicarbazide ꢀ
1,2,4-Triazol-3-one
In this paper, an investigation of the cyclization reaction of
new 4,40-bis(1-substituted-semicarbazidyl)diphenylmethanes
is presented. Depending on the chemical nature of the sub-
stituent in the starting compounds, the reaction led to the
formation of different derivatives. One of them is composed
of two 1,2,4-triazol-3-one systems connected by a diphe-
nylmethylene group. Additionally, we propose an alternative
method for synthesis of these compounds through the reaction
of appropriate amidrazone hydrochlorides with 4,40-di-
phenylmethane diisocyanate. Selected compounds were
investigated pharmacologically to determine their effect on
the central nervous system (CNS) in mice.
Introduction
Many compounds containing five-membered heterocyclic
rings, such as triazoles, oxadiazoles, thiadiazoles, and
imidazoles, have been intensively synthesized and evalu-
ated for their biological activities [1–4]. During the last few
decades, considerable attention has been devoted to the
synthesis of 1,2,4-triazole derivatives possessing diverse
pharmacological properties such as antimicrobial [5, 6],
anti-inflammatory [7], analgesic [8], antitumor [9], anti-
convulsant, and antiviral activities [10]. Some of them
M. Pitucha (&) ꢀ A. Pachuta-Stec
Results and discussion
Department of Organic Chemistry,
Medical University of Lublin, Lublin, Poland
e-mail: monika.pitucha@am.lublin.pl
Semicarbazides 2a–2d were synthesized in the reaction of
appropriate carboxylic acid hydrazides with 4,40-di-
phenylmethane diisocyanate (MDI) in anhydrous diethyl ether
at room temperature [15]. New semicarbazides 2e–2g were
´
A. Chodkowska ꢀ M. Maciejewski ꢀ E. Jagiello-Wojtowicz
Department of Toxicology, Medical University of Lublin,
Lublin, Poland
123

200
M. Pitucha et al.
obtained by heating the substrates in the melt. The reaction
conditions were established experimentally. Next, bis-semi-
carbazides 2a–2g were heated in 2% aqueous NaOH solution.
The products of these reactions depended on the substituent
in the starting material. In the case of 4,40-bis(1-substituted-
semicarbazidyl)diphenylmethanes 2a–2e, 4,40-bis(5-substi-
tuted-2,4-dihydro-3-oxo-3H-1,2,4-triazol-4-yl)diphenylmethane
derivatives 3a–3e were obtained (3a–3d were described
earlier [17]). The alkaline cyclization of semicarbazides
2f–2h afforded quite different products. From the reaction of
2f and 2g the corresponding carboxylic acids were formed.
In continuation of the experiments the reaction of
amidrazone salts with 4,40-diphenylmethane diisocyanate
was investigated. In this alternative synthetic method
amidrazone hydrochlorides were used as starting materials.
Appropriate amidrazones were prepared by a method
described earlier [19, 20].
The condensation of hydrochlorides of acetamidrazone
or N1-phenylbenzamidrazone with MDI was carried out by
heating the substrates in the melt for 20 h. The conditions
of the reaction were established experimentally. Based on
the results of elemental analysis and the spectral data (IR,
1H NMR) it was revealed that the reaction leads to for-
mation of a cyclic five-membered ring system by
instantaneous reaction on the N1 nitrogen atom of the
hydrazine moiety and the N3 nitrogen atom of the amide
moiety. Probably, the course of this reaction includes the
formation of intermediate semicarbazone derivatives which
cyclize spontaneously to the 1,2,4-triazole system.
1
The structures of these compounds were confirmed by H
NMR spectra in comparison with the Spectral Database for
Organic Compounds (SDBS) spectral library and MS,
and in case of benzoic acid additionally by X-ray analysis.
Similarly, in case of bis[(4-morpholinylpropionyl)semicarb-
azide] 2h, 4-(2-carboxyethyl)-4-morpholinium chloride was
obtained [18] (Scheme 1).
Scheme 1
O
NH
NCO
NH NH
O
NH2 NH
O
Ether
or T
R
NaOH
R
R
+
2
OH
O
R
,
3f 3g
O
-
1a 1h
NH NH
O
NCO
-
NH
2a 2h
NaOH
NaOH
O
H
N
H
N
O
N
N
O
N
N
N
COOH . HCl
R
R
3h
-
3a 3e
H3C
Ph2CH
R =
a
e
f
b
CH2
N
N
CH3
Ph
g
h
N
c
d
N
N
CH2
N
O
PhCH2
123

Synthesis and antinociceptive activity
201
In the reaction of acetamidrazone hydrochloride and MDI,
4,40-(methylenedi-4,1-phenylene)bis(2,4-dihydro-5-methyl-
3H-1,2,4-triazol-3-one) (3a) was obtained in 71% yield. This
is an alternative method because this compound was also
obtained by the cyclization of 4,40-bis(semicarbazidyl)di-
phenylmethane 2a in alkaline medium [17]. Mixed melting
points have not shown any depression. The IR and 1H NMR
spectra of these compounds were also identical. When we used
N1-phenylbenzamidrazone hydrochloride, 4,40-(methylenedi-
4,1-phenylene)bis(2,4-dihydro-2,5-diphenyl-3H-1,2,4-tria-
zol-3-one) (4) was obtained (Scheme 2).
In conclusion, it was shown that the tested compounds
have antinociceptive properties, which deserve further
investigation of the action in rodents.
Experimental
Melting points were determined in a Fisher-Johns block.
Elemental analyses (C, H, N) were conducted using the
Elemental Analyser CHN, and results were found to be in
good agreement with calculated values. IR spectra were
recorded from KBr discs using a Specord IR-75 spectro-
Selected compounds were screened for their influence
on the central nervous system. The pharmacological
behavioral tests showed that both 4,40-bis(1-substituted-
semicarbazidyl)diphenylmethanes 2a–2d and 4,40-bis-
(5-substituted-2,4-dihydro-3-oxo-3H-1,2,4-triazol-4-yl)di-
phenylmethanes 3a and 3b displayed antinociceptive
activity (Table 1). A significant decrease in the number of
writhing episodes was observed at a wide range of doses.
Compound 2c at a dose of 1.5625 mg/kg i.p. significantly
decreased the number of writhing episodes induced in
mice. A similar activity was observed by compound 2d
having a benzyl substituent. Among the cyclic derivatives,
4,40-(methylenedi-4,1-phenylene)bis[2,4-dihydro-5-[(1-
methyl-2-pyrrolyl)methyl]-3H-1,2,4-triazol-3-one] (3a)
significantly decreased the number of writhing episodes
induced in mice, whereas for 4,40-(methylenedi-4,1-phe-
nylene)bis(2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one)
(3a) a relation between dose and effect could be seen. In
the remaining pharmacological tests none of the com-
pounds 2a–2d, 3a, and 3b at a dose of 0.1 of their LD50
produced significant effects on the CNS of mice. In other
behavioral tests the investigated compounds had no effect
on the central nervous system of mice.
1
photometer. H and 13C NMR spectra were recorded on a
Bruker AC 300F instrument (300 MHz) in DMSO-d6 with
TMS as an internal standard. The mass spectra were
obtained with an AMD-604 mass spectrometer using a
70-eV electron beam. Chemicals were purchased from
Lancaster or Fluka Ltd. The purity of obtained compounds
was checked by TLC on aluminium oxide 60 F254 plates
(Merck) in a CHCl3/C2H5OH (10:1 and 10:2) solvent
system with UV or iodine visualization.
The hydrazides were synthesized by a published method
[21]. Compounds 2a–2d and 3a–3d were synthesized and
characterized earlier [17].
Diphenylacetic acid 1,10-[2,20-[methylenebis(4,1-phenyle-
neiminocarbonyl)]dihydrazide] (2e, C43H38N6O4)
A mixture of 4.52 g diphenylacetic acid hydrazide (1e,
20 mmol) and 2.5 g 4,40-diphenylmethane diisocyanate
(10 mmol) was heated in an oil bath at 120 °C for 15 h.
The formed product was washed first with diethyl ether,
then with hot water. Subsequently it was dried and
crystallized from ethanol to give 4.98 g 2e (71%). M.p.:
250-252 °C; IR (KBr): v = 3,216, 3,028, 2,930, 1,667,
1,411 cm-1; 1H NMR (300 MHz, DMSO-d6): d = 3.78
Scheme 2
NCO
R
R
R1
R1
N
NH2
NH
N
N
NH
180 °C
2R
+
NH
NH
NH
HN
NH
R1
O
O
. HCl
NCO
R1
R1
O
O
N
N
N
N
N
N
R
R
3a, R = CH3, R1 = H
4, R = Ph, R1 = Ph
123

202
M. Pitucha et al.
3-Pyridinecarboxylic acid 1,10-[2,20-[methylenebis
(4,1-phenyleneiminocarbonyl)]dihydrazide]
(2f, C22H20N7O4)
Table 1 Antinociceptive activity of investigated compounds in the
writhing syndrome test in mice (n = 10)
Compound Treatment (mg/kg i.p.) Fraction of LD50 Inhibition (%)
To 2.74 g 3-pyridinecarboxylic acid hydrazide (1f,
20 mmol) dissolved in 40 cm3 N,N-dimethylacetamide,
2.5 g 4,40-diphenylmethane diisocyanate (10 mmol) was
added. The mixture was refluxed in a water bath for 20 h.
The solvent was evaporated under reduced pressure. The
residue was extracted with anhydrous ethanol and recrys-
tallized from ethanol to give 3.46 g 2f (71%). M.p.: 285–
286 °C; IR (KBr): v = 3,206, 3,015, 2,959, 1,672,
1,419 cm-1; 1H NMR (300 MHz, DMSO-d6): d = 3.80
(s, 2H), 7.08–7.57 (m, phenyl-H), 8.25–9.07 (m, 3-pyridyl),
8.25 (s, 2H, NH), 8.81 (s, 2H, NH), 10.47 (s, 2H, NH) ppm;
13C NMR (75 MHz, DMSO-d6): d = 59.53 (CH2), 113.77,
117.08, 117.63, 133.35, 133.96, 146.77, 147.27, 150.39,
154.30 (229 Carom), 163.37 (C=O), 163.83 (C=O) ppm.
Control
–
–
0
17
2a
6.25
12.5
25.0
50.0
100.0
6.25
12.5
25.0
50.0
100.0
1.5625
3.125
6.25
12.5
25.0
50.0
100.0
1.5625
3.125
6.25
12.5
25.0
50.0
100.0
3.125
6.25
12.5
25.0
50.0
100.0
3.125
6.25
12.5
25.0
50.0
100.0
0.00625
0.0125
0.025
0.05
71**
76**
95**
89**
21
0.1
2b
2c
0.00625
0.0125
0.025
0.05
66*
91**
80**
99**
47**
19**
34**
61**
72**
88**
87**
9
0.1
0.00156
0.003125
0.00625
0.0125
0.025
0.05
Benzoic acid 1,10-[2,20-[methylenebis(4,1-
phenyleneiminocarbonyl)]dihydrazide]
(2g, C23H21N6O4)
To 2.72 g benzoic acid hydrazide (20 mmol) dissolved in
40 cm3 N,N-dimethylacetamide, 2.5 g 4,40-diphenylme-
thane diisocyanate (10 mmol) was added. The mixture
was kept at room temperature at 24 h. Then 50 cm3 water
was added. The precipitate was filtered and crystallized from
ethanol to give 3.02 g 2g (68%). M.p.: 329–330 °C; IR
(KBr): v = 3,299, 3,028, 2,360, 1,410, 1,659 cm-1; 1H NMR
(300 MHz, DMSO-d6): d = 3.78 (s, 2H), 7.07-8.06 (m,
phenyl-H), 8.12 (s, 2H, NH), 8.85 (s, 2H, NH), 10.26 (s, 2H,
NH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 50.19
(CH2), 112.79, 117.31, 126.13, 126.88, 127.44, 127.73,
145.16 (249 Carom), 154.25 (C=O), 164.33 (C=O) ppm.
0.1
2d
0.00156
0.003125
0.00625
0.0125
0.025
0.05
44**
47**
71*
96**
93**
94*
0.1
3a
0.003125
0.00625
0.0125
0.025
0.05
10
27*
45**
84**
72**
88**
36*
4,40-(Methylenedi-4,1-phenylene)bis[5-(diphenylmethyl)-
2,4-dihydro-3H-1,2,4-triazol-3-one] (3e, C43H34N6O2)
A mixture of 5.5 g bis-semicarbazide 2e (10 mmol) and
50 cm3 2% aqueous sodium hydroxide solution was refluxed
for 20 h. After cooling, the solution was neutralized with
dilute hydrochloric acid. The precipitate was filtered off and
then crystallized from ethanol. Yield 4.33 g (65%); m.p.:
95–97 °C; IR (KBr): v = 3,312, 3,027, 2,361, 1,674,
0.1
3b
0.003125
0.00625
0.0125
0.025
0.05
38*
70**
72**
84**
97**
0.1
1
1,452 cm-1; H NMR (300 MHz, DMSO-d6): d = 3.93 (s,
Percentage inhibition obtained compared with control group
2H), 5.22 (s, 2H), 7.02–7.32 (m, phenyl-H), 11.78 (s, 2H,
NH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 53.47
(CH2), 105.48, 112.90, 126.91, 138.89, 145.22, 154.07,
163.01 (389 Carom), 169.41 (C=O), 169.86 (C=O) ppm.
* p \ 0.05 versus control group, ** p \ 0.01 versus control group
(s, 2H), 4.18 (s, 2CH), 6.83–7.39 (m, phenyl-H), 8.05 (s,
2H, NH), 8.58 (s, 2H, NH), 9.79 (s, 2H, NH) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 48.60 (CH2), 117.18,
126.92, 127.14, 127.29, 127.52, 133.75, 136.14, 138.48,
138.85, 153.92 (389 Carom), 169.21 (C=O), 169.71
(C=O) ppm.
General procedure for the synthesis of bis(1,2,4-triazol-
3-one)s 3a and 4 from amidrazone hydrochlorides
A
mixture of 2.18 g acetamidrazone hydrochloride
(20 mmol) or 4.94 g N1-phenylbenzamidrazonehydrochloride
123

Synthesis and antinociceptive activity
203
(20 mmol) and 2.5 g 4,40-diphenylmethane diisocyanate
(10 mmol) was heated in an oil bath at 180 °C for 20 h.
After cooling, the mixture was refluxed with 15 cm3
anhydrous ethanol for 1 h. Next, the solid was filtered off.
The solvent was cooled and the precipitated compound was
filtered off and dried.
swimming test [24]. Pain reactivity was measured by the
writhing syndrome test [25]. Antiepileptic effects were
tested by reduction of pentetrazole (90 mg/kg sc)-induced
seizures. Antiserotoninergic effects were determined by the
Corne test [26].
4,40-(Methylenedi-4,1-phenylene)bis(2,4-dihydro-5-methyl-
3H-1,2,4-triazol-3-one)(3a)
References
Yield 2.56 g (71%); m.p.: 307–309 °C (Ref. [17] 308–
310 °C).
ˇ
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123