Synthesis and neurotropic activity of (heterylphenylmethyl)-amines and -ureas

Full text of DOI:10.1023/A:1012735616975

Pharmaceutical Chemistry Journal
Vol. 35, No. 7, 2001
SEARCH FOR NEW DRUGS
SYNTHESIS AND NEUROTROPIC ACTIVITY
OF (HETERYLPHENYLMETHYL)-AMINES AND -UREAS
V. P. Shamshin,1 V. A. Aleshina,1 S. A. Sukhanova,1 and T. I. Kabanova1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 7, pp. 3 – 6, July, 2001.
Original article submitted November 21, 2000.
The antiepileptic drugs widely used in clinical practice,
such as diphenin, phenobarbital, and benzonal, belong to the
cyclic derivatives of urea [1]. Opening of the hydantoin ring
between carbon in position 5 and nitrogen leads to a noncyc-
lic urea derivative (a-diphenylacetylurea, known as the drug
fenuron) still retaining the anticonvulsant properties [2].
In the search for new substances possessing neurotropic
activity in the series of benzohydrylamines and benzohydry-
lureas, it was of interest to substitute a heterocyclic residue
for one of the phenyl fragments. We have studied the phar-
macological activity of a series of (heterylphenylmethyl)ami-
nes (IIIa – IIIe) and (heterylphenylmethyl)ureas (IVa – IVe)
synthesized by the following scheme:
The initial compounds (Ia – Ie) were prepared by acyla-
ting benzene with chloroanhydrides of the corresponding he-
terocyclic acids by a conventional method [3] under Frie-
del – Crafts reaction conditions. The synthesis of new com-
pounds proceeded by interaction of ketones
I with
ammonium formate under modified Leuckart reaction condi-
tions [4], followed by acid hydrolysis of the intermediate for-
mamides II to amines III. Finally, compounds IV were obtai-
ned using the condensation of compounds III with urea by
the known method described in [5, 6].
In addition, we synthesized a series of amine IIIa ana-
logs, including N-methyl, piperidine, and acetyl derivatives
(compounds V – VII, respectively), and N-[(4-pyridyl)phe-
nylmethyl]-N¢-methylurea (VIII) representing an analog of
compound IVa. [(4-Pyridyl)phenylmethyl]aminomethane di-
hydrochloride (compound V) was obtained using the interac-
tion of ketone Ia with methylamine and formic acid under
Leuckart reaction conditions [4], followed by hydrolysis of
the reaction mass with hydrochloric acid without isolation of
the intermediate formyl derivative. Compound VI was synt-
hesized by reducing ketone Ia with aluminum isopropylate to
the corresponding alcohol [7], followed by chlorine substitu-
tion for the oxy group with the aid of thionyl chloride, and
condensation with piperidine by analogy with the method
described in [8]. The acylation of amine IIIa with acetic an-
hydride using a procedure analogous to that described in [6]
led to N-[(4-pyridyl)phenylmethyl]acetamide (compound
VII), while interaction of the same amine IIIa with methyl
isocyanate by analogy with the reaction described in [9] yiel-
ded compound VIII.
O
HC
R
R
NH2
HCl H2O
H
C
HCOOH
NH
O
O
Ià – Ie
H
IIà – IIe
R
H
R
H2NCONH2
n HCl
H
C
C
HN
NH2
O
IIIà – IIIe
NH2
IVà – IVe
R: (à)
(c)
(b)
N
N
N
Br
(d)
(e)
The yields and some physicochemical characteristics of
the synthesized compounds are presented in Table 1.
N
N
n = 1, 2
H3C
O
EXPERIMENTAL CHEMICAL PART
1
The IR absorption spectra were measured on an UR-10
spectrophotometer (Germany) using samples prepared as nu-
jol mulls. The mass spectra were obtained using an
All-Russia Scientific Center for Safety Testing of Biologically Active
Substances, Ministry of Public Health of the Russian Federation, Staraya
Kupavna, Moscow Region, Russia.
349
0091-150X/01/3507-0349$25.00 © 2001 Plenum Publishing Corporation

350
V. P. Shamshin et al.
MKh-1303 spectrometer (Russia) equipped with a system of
direct sample injection into the ion source operated at an
electron impact energy of 30 eV. The chemical purity of the
synthesized compounds was checked by TLC using Silufol
UV-254 plates (Czech Republic) eluted in the chloro-
form – ethanol – NH4OH (20 : 2 : 1) solvent system with
Rf ~ 0.45 (for compound I), 0.6 (II), 0.5 (III), 0.05 (IV), 0.55
(V), 0.7 (VI), 0.3 (VII), and 0.2 (VIII).
The molecular masses of all compounds determined by
mess spectrometry coincide with the calculated values, and
the character of fragmentation is consistent with the propo-
sed structures. The melting points (uncorrected) were deter-
mined using a Koefler heating stage. The data of elemental
analyses correspond to the results of calculations using the
empirical formulas.
N-(Heterylphenylmethyl)formamides (IIa – IIe). Ge-
neral method. To 422 mmole of a 25% aqueous ammonia is
slowly added with stirring 422 mmole of formic acid 99,5%.
The mixture is gradually (over 1.5 – 2 h) heated up to 160°C
(while water and formic acid are simultaneously distilled off)
and cooled to 90°C. Then 81.9 mmole of ketone I is added
and the mixture is stirred for 15 min. After that, the pH of the
medium, checked by a universal indicator, must not exceed
6.5. If the reaction mass shows an alkaline or neutral reacti-
on, formic acid (~16 ml) is added to pH 4 – 4.5 and the reac-
tion mixture is again heated to 160°C and kept at this tempe-
rature for ~6 h (until water is completely distilled off and ga-
seous carbon dioxide ceases to evolve). Then the reaction
mass is cooled to 140°C and poured at this temperature into
90 ml of water, after which the mixture is cooled to 25°C and
kept for 1 h at 0 – 5°C. The oil and aqueous layers are sepa-
rated and the the latter is treated with 4 ´ 30 ml of chloro-
form. The extract is evaporated and the residue combined
with the main oil fraction. Then 100 ml of benzene is added
and the mixture is boiled in the presence of 1 g of activated
charcoal. The charcoal is separated by filtration and washed
with 20 ml of benzene. The total filtrate is mixed with 25 ml
of hexane, cooled to 10°C, and filtered. The residue is was-
hed with benzene (2 ´ 5 ml) and dried to obtain the target
compound IIa – IIe (Table 1).
(Heterylphenylmethyl)amine hydrochlorides (IIIa – IIIe).
General method. A mixture of 36 mmole of compound II,
20 ml of anhydrous isopropyl alcohol, and 7.8 ml of concent-
rated hydrochloric acid is boiled for ~3 h until the initial for-
mamide II is fully consumed (TLC monitoring). Upon coo-
ling down to room temperature, the mixture is neutralized
with a 40% aqueous sodium hydroxide solution to pH 9 – 10
and amine III is extracted with ether (2 ´ 25 ml). The ether
extracts are combined, dried over magnesium sulfate, and fil-
tered. To this ether solution is added a solution of hydrogen
chloride in isopropyl alcohol to pH 1 – 2, after which the re-
sulting suspension is poured into 200 ml of acetone. The pre-
cipitate is filtered and dried to obtain dihydrochlorides of
compounds IIIa and IIIb or hydrochlorides of compounds
IIIc – IIIe (Table 1).
TABLE 1. Yields and Some Physicochemical Characteristics of (Heterylphenylmethyl)-formamides (IIa – IIe), -amines (IIIa – IIIe, V – VII),
and -ureas (IVa – IVe)
Mass spectrum
Compound
Yield, %
M.p., °C
Empirical formula
C13H12N2O
IR spectrum: n, cm – 1
3160 (NH), 1670(C=O)
(M + H)
IIa
IIb
IIc
IId
IIe
66
81
70
86
85
92
51
60
59
58
78
68
61
68
50
102.5 – 103.5
104.0 – 105.5
107.0 – 109.0
134.5 – 136.0
123.5 – 125.0
230*
213
C13H12N2O
3170(NH), 1670(C=O)
3165(NH), 1675(C=O)
3160 (NH), 1670(C=O)
3150(NH), 1690(C=N)
213
C13H12N2O
213
C13H11BrN2O
C18H16N2O
291, 292
292
3455 (NH3 ), 2580 (NH+)
185
+
IIIa
IIIb
IIIc
IIId
IIIe
IVa
IVb
IVc
IVd
IVe
V
C12H12N2 · 2HCl
C12H12N2 · 2HCl
C12H12IN2 · HCl
C12H11BrN2 · HCl
C17H16IN2 · HCl
C13H13N3O
3450 (NH3 ), 2600 (NH+)
185
+
250 – 260*
224.5*
+
3450 (NH3 )
185
+
243.5 – 244.5*
136 – 138*
226.5 – 227
165.5 – 167
197.5 (decomp.)
223.5 – 225
181 – 182
3445 (NH3 )
264, 265
264
+
3400 (NH3 ), 1690 (C = N)
3420, 3285, 3150 (NH, NH2), 1650 (C=O)
3420, 3300, 3160 (NH, NH2), 1650 (C=O)
3470.3310 (NH, NH2), 1640 (C=O)
3420, 3255 (NH2), 3200 (NH), 1660 (C=O)
3490, 3440, 3350 (NH, NH2), 1650 (C=O)
3420 (NH2+), 2650 (NH+)
227
C13H13N3O · H2O
C13H13N3O
227
227
C13H11N2BrO
C18H17N3O2
306
307
39**
38**
82
217 – 219*
170 – 172*
131 – 132.5*
192 (decomp.)
C13H14IN2 · 2HCl
C17H20N2 · 2HCl
C14H14N2O
198
VI
2600 (NH+)
252
VII
VIII
3300 (NH), 1635 (C=O)
2325, 3270 (NH+), 1670 (C=O)
226
80
C14H15IN3O · HCl
242
*
Amine salts melt with decomposition.
Yields of compounds V and VI are calculated with respect to the initial ketone and carbinol, respectively.
**

Synthesis and Neurotropic Activity of (Heterylphenylmethyl)-amines
351
(Heterylphenylmethyl)ureas (IVa – IVe). General
method. To a thoroughly stirred mixture of 126 mmole of
urea and 8.5 ml of water are added 21 mmole of amine III
and 2.25 ml of concentrated hydrochloric acid. The reaction
mass is slowly (over 1 h) heated from 20°C up to
104 – 105°C, boiled at this temperature for 3 h, and cooled
down to ~20°C. The precipitate is filtered, washed with wa-
ter until neutral reaction, dried, and recrystallized from met-
hyl, ethyl, or isopropyl alcohol to obtain compounds
IVa – IVe (Table 1).
the filtrate is evaporated in vacuum to dryness and the resi-
due (7 g) is dissolved at 40°C in 30 ml of water. The solution
is charged with 0.5 g of activated charcoal and treated at this
temperature for 20 min. Then charcoal is separated by filtra-
tion and washed with 2 ´ 5 ml of warm water. The filtered
solution at ~20°C is adjusted to pH 9 by adding an aqueous
Na2CO3 solution. The oil and aqueous layers are separated
and the the latter is treated with 3 ´ 100 ml of chloroform.
The extract is combined with the main oil fraction and the
solvent is distilled off in vacuum at 40 – 45°C. The oil resi-
due (5.5 g) is mixed with 30 ml of freshly distilled DMF,
4 ml of distilled piperidine, and 5.0 g of calcined and tritura-
ted potassium carbonate. The mixture is stirred at 45 – 50°C
for ~20 h until complete consumption of the initial chlori-
ne-substituted compound (TLC monitoring). The precipitate
is filtered and washed with 5 ml of DMF. The filtrate is eva-
N-[(4-Pyridyl)phenylmethyl]aminomethane dihyd-
rochloride (V). To a solution of 7.2 g (104 mmole) of met-
hylamine hydrochloride in 10 ml of water was added 4.3 g
(104 mmole) of solid sodium hydroxide and the mixture was
stirred for 10 min. To the resulting solution was gradually ad-
ded 5.5 ml (140 mmole) of a 99% formic acid solution and
the mixture was kept for 5 min (after which the pH must not
exceed 3.5 – 4.0), gradually (over 2 h) heated to 172°C (until
aqueous formic acid is completely distilled off), and cooled
to 60°C. Then 3.66 g (20 mmole) of 4-benzoylpyridine (Ia)
and 4.7 ml of a 99% formic acid are added and the mixture is
stirred for 10 min, checked for pH (not to exceed 3.5 – 4.0),
boiled at 148 – 180°C for ~11 h until the initial compound Ia
is completely consumed (TLC monitoring) and gaseous car-
bon dioxide ceases to evolve, and cooled to ~ 20°C. Then
50 ml of water is added and the mixture is adjusted at pH 9
by adding solid sodium hydroxide, after which the oil and
aqueous layers are separated and the the latter is treated with
3 ´ 25 ml of chloroform. The extracts are combined with the
main oil fraction and the solvent is distilled off in vacuum.
The residue is mixed with 4.3 ml of concentrated hydrochlo-
ric acid and the mixture is boiled for 3 h, charged with 6 ml
of water and 1.0 g of activated charcoal, and treated at
70 – 75°C for 20 min, after which the charcoal is separated
by filtration. The filtrate is discolored by adding sodium hyd-
rosulfite, cooled to ~20°C, and adjusted to pH 9 by adding
solid sodium hydroxide. The oil and aqueous layers are sepa-
rated and the the latter is treated with 2 ´ 5 ml of chloroform.
The extract is combined with the main oil fraction, the sol-
vent is distilled off in vacuum, and the residue is dissolved at
40°C in 3 ml of isopropyl alcohol. To this solution are gradu-
ally added a 20% solution of hydrogen chloride in isopropyl
alcohol (to pH 2) and then 60 ml of acetone. The mixture is
cooled to 5 – 10°C and kept at this temperature for 1 h. The
precipitate is filtered, washed with acetone (2 ´ 3 ml), dried,
and recrystallized from 40 ml of anhydrous isopropyl alcohol
to obtain 2.12 g of compound V (Table 1).
TABLE 2. Acute Toxicity and Neurotropic Activity of (Heteryl-
phenylmethyl)-amines and -ureas
Hexenal test
(60 mg/kg)
Corazole test
(1%, i.v.)
LD50,
mg/kg
Dose,
mg/kg
Compound
Lateral position, Threshold dose,
min
mg/kg
IIIa
IIIb
IIIc
IIId
IIIe
IVa
IVb
IVc
IVd
IVe
V
Control
23
225.0 ± 26.5
288.0 ± 24.8
101.0 ± 4.8
470.8 ± 21.8
396.0 ± 31.6
> 2000
35.0 ± 7.3
127.0 ± 11.6*
45.0 ± 1.2
37.6 ± 2.4
48.4 ± 3.2*
40.0 ± 2.8
49.8 ± 3.1*
35.4 ± 3.1
39.9 ± 3.7
36.8 ± 3.1
39.0 ± 2.4
35.5 ± 2.6
47.6 ± 3.7*
41.7 ± 2.6
40.6 ± 2.8
38.9 ± 3.1
37.8 ± 2.8
35.7 ± 2.1
37.4 ± 2.9
41.9 ± 3.2
44.0 ± 4.1
41.3 ± 3.1
51.8 ± 2.4*
40.9 ± 3.8
38.4 ± 3.1
41.5 ± 2.8
42.6 ± 3.1
39.7 ± 3.4
41.8 ± 2.7
40.9 ± 3.3
41.5 ± 4.1
Control
30
91.8 ± 11.2*
53.4 ± 3.1
Control
10
54.9 ± 7.1
Control
47
47.8 ± 3.1
71.0 ± 6.4*
51.8 ± 3.6
Control
40
84.6 ± 5.8*
48.8 ± 2.6
Control
200
355.8 ± 21.6*
45.5 ± 2.1
Control
84
838 ± 35.4
> 1000
81.5 ± 10.3*
57.0 ± 8.5
Control
100
78.5 ± 6.4*
50.7 ± 3.2
> 1000
Control
100
36.0 ± 4.1*
42.0 ± 4.2
> 1000
Control
100
87.6 ± 8.5*
35.6 ± 4.8
Control
20
215.5 ± 19.7
280.0 ± 25.6
410.0 ± 21.5
390.8 ± 27.8
N-[(4-Pyridyl)phenylmethyl]piperidine dihydrochlo-
ride (VI). To an ice-cold solution of 3.5 ml of freshly distil-
led thionyl chloride in 10 ml of chloroform is added dropwi-
se a solution of 6 g (32.5 mmole) of [(4-pyridyl)phenyl]met-
hylcarbinol synthesized by a conventional method [10]. The
mixture is gradually (over 1 h) heated to boiling (~60°C),
treated at this temperature until the evolution of gaseous hyd-
rogen chloride and sulfur dioxide completely ceases (~7 h),
and cooled to room temperature. The precipitate (~0.5 g of
the initial carbinol by TLC data) is separated by filtration and
69.5 ± 5.8*
37.0 ± 5.4
VI
Control
28
132.0 ± 10.8*
51.7 ± 5.6
VII
VIII
Control
40
175.0 ± 8.5*
47.9 ± 4.3
Control
40
197.5 ± 4.8*
*
p < 0.05 relative to control.

352
V. P. Shamshin et al.
porated in vacuum to obtain 6.6 g of a dark-brown gummy
residue. The residue is doubly dissolved in 30 ml of a 8%
hydrochloric acid, treated with activated charcoal, and repre-
cipitated with solid sodium carbonate. The precipitate is dis-
solved in 15 ml of anhydrous isopropyl alcohol. To this solu-
tion is gradually added a 20% solution of hydrogen chloride
in isopropyl alcohol until reaching pH ~ 3. Upon cooling, the
precipitate is filtered, washed with acetone (2 ´ 5 ml), and
dried in vacuum at 50°C to obtain 3.9 g of compound VI
(Table 1).
The rectal temperature was measured with an electronic ther-
mometer of the TEMP type 10 min before and 30 min after
introduction of the test compounds.
The neurotropic activity was studied by methods descri-
bed in [11, 12]. The properties of the synthesized compounds
were characterized by their effects on (i) hexenal (60 mg/kg)
sleep duration determined by measuring the time of stay
(min) in the lateral position, (ii) apomorphine (2 mg/kg) ste-
reotypy, and (iii) arecoline (25 mg/kg) tremor. The anticon-
vulsant activity was studied on the models of convulsions in-
duced by maximum electroshock (MES) or by intravenous
injections of a 1% corazole solution [13, 14].
The test substances were introduced, 30 min before the
model-inducing agents, by intraperitoneal injections in a
dose of 0.1 LD50 in the form of suspensions with Tween-80.
Each control and test group contained 10 animals. The expe-
rimental data were statistically processed in terms of the Stu-
dent t-criterion; the results were considered as reliable for
p < 0.05.
It was established that most of the synthesized compo-
unds potentiate, to a more or less pronounced extent, the
hypnotic effect of hexenal (Table 2). In the series of substitu-
ted (heterylphenylmethyl)ureas (IV), the corresponding ami-
nes (III), and their derivatives, the maximum increase in he-
xenal sleep was observed for compounds IVa, VII, VIII, and
IIIa. Among the substances tested for the anticonvulsant acti-
vity, only compounds IIIa, IIIb, IIIe, and IVe produced reli-
able anticonvulsant effect with respect to corazole-induced
convulsions (Table 2). All the compounds were ineffective in
the MES test, did not change the motor activity and rectal
temperature, and did not influence the apomorphine and are-
coline effects.
N-[(4-Pyridyl)phenylmethyl]acetamide (VII). A mix-
ture of 5.14 g (20 mmole) of compound IIIa is stirred for
15 min with a 12% sodium hydroxide solution prepared from
1.7 g (41.6 mmole) NaOH and 12 ml of water. To this mixtu-
re is added 4.4 ml (45.7 mmole) of acetic anhydride and the
reaction mass is treated at 45 – 50°C. Then a 10% sodium
hydroxide solution (~30 ml) is added to pH 11 and the mix-
ture is cooled to 5°C and kept at this temperature for 1 h. The
precipitate is filtered, washed with water to pH 7, and dried
at 70°C. Then 60 ml of benzene is added and the mixture is
boiled for 30 min with stirring, cooled to 5°C, filtered, and
dried at 70°C to obtain 3.7 g of compound VII (Table 1).
N-[(4-Pyridyl)phenylmethyl]-N¢-methylurea hydroc-
hloride(VIII). To a mixture of 5.14 g (20 mmole) of compo-
und IIIa and 50 ml of anhydrous dichloroethane at ~20°C is
added 6 ml (42.8 mmole) of triethylamine and the reaction
mass is stirred for 1 min. The precipitate of triethylamine
hydrochloride is separated by filtration and washed with 5 ml
of dichloroethane. To the filtrate, cooled down to 2°C with
stirring on ice, is gradually (over 1 h) added dropwise a solu-
tion of 11 ml (22 mmole) of methyl isocyanate in 20 ml of
dichloroethane, after which the reaction mass is allowed to
stand at 2 – 7°C for 16 h. Then 10 ml of water is added and
the mixture is stirred for 30 min and allowed to stand until
phase separation. The organic layer is evaporated in vacuum
to dryness and the brown residue is dissolved in 20 ml of an-
hydrous ethanol at 20°C. To this solution are added with stir-
ring first ~6 ml (dropwise) of a 20% solution of hydrogen
chloride in isopropyl alcohol until reaching pH 1, and then
140 ml of an acetone – benzene (2 : 1) mixture. The mixture
is cooled to 3 – 5°C and allowed to stand at this temperature
for 16 h. Then the precipitate is filtered, washed with 3 ml of
acetone, and dried at 60°C to obtain 2.2 g of compound VIII
(Table 1).
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EXPERIMENTAL PHARMACOLOGICAL PART
The biological tests were performed on mongrel male
mice weighing 22 – 25 g kept under standard vivarium con-
ditions (12-h illumination; air temperature 21 – 22°C; free
access to water and meals). The acute toxicity of the synthe-
sized compounds was determined for a single intraperitoneal
injection and characterized by LD50 values calculated by the
Kerber method [10]. The spontaneous motor activity was
characterized by the number of horizontal movements over a
time period of 10 min determined for the test mice placed in
individual compartments of a DFA-ER-20 type actometer.
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