Synthesis and anticonvulsant activity of new N-benzoyl derivatives of aliphatic acids and their salts

Full text of DOI:10.1023/A:1014038624190

Pharmaceutical Chemistry Journal
Vol. 35, No. 9, 2001
SYNTHESIS AND ANTICONVULSANT ACTIVITY
OF NEW N-BENZOYL DERIVATIVES OF ALIPHATIC ACIDS
AND THEIR SALTS
S. A. Kazaryan,1 K. P. Grigoryan,1 R. G. Paronikyan,1 A. S. Agaronyan,1
A. I. Gevondyan,1 and V. M. Samvelyan1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 9, pp. 21 – 23, September, 2001.
Original article submitted July 18, 2000.
In the past years, there was a certain increase in the clini-
cal use of preparations based on neuroactive amino acids
such as glycine, b-alanine, and g-aminobutyric acid (GABA)
[1 – 6]. In connection with this, it was of interest to search
for new biologically active substances in the class of neuro-
active amino acid derivatives. We have synthesized and cha-
racterized with respect to anticonvulsant activity a series of
N-(ortho-R-benzoyl) derivatives of glycine, b-alanine,
e-aminocaproic acid, GABA, and some salts of these acids
(I – XVI) (Table 1).
(1540, 3350 cm – 1), and aromatic CH (1600 cm – 1) groups.
The parameters of the 1H NMR spectra are presented in Tab-
le 2.
EXPERIMENTAL CHEMICAL PART
Purity of the synthesized compounds was checked by
TLC on Silufol UV-254 plates. The TLC runs with benzoyla-
ted amino acids (compounds I, III – IX, XI, XII, XIV – XVI)
Amino groups in the amino acids were benzoylated un-
der the Schotten – Baumann reaction conditions [7]. Some
physicochemical characteristics and proton chemical shifts in
the 1H NMR spectra of the synthesized N-substituted amino
acids and their salts (I – XVI) are listed in Tables 1 and 2.
The syntheses were conducted by the following scheme:
TABLE 1. Yields and Physicochemical Characteristics of N-Sub-
stituted Amino Acids and Their Sodium Salts (I – XVI)
Initial
Com
amino acid Yield, M.p.,
Empirical
formula
Rf
po-
R
(H–Am–
OH)
%
°C
und
O
O
C
NaOH
C
Cl +H–Am–OH
Am OH
I
Cl
Cl
Cl
Cl
Cl
GABA
GABA
88.2 92 – 93 0.81 C11H12ClNO3
70.0 80 – 82 0.74 C11H11ClNO3Na
II
R
R
III
IV
V
Glycine 69.0 171 – 172 0.84 C9H8ClNO3
I, III – IX, XI, XII, XIV – XVI
87.8 88 – 89 0.82 C10H10ClNO3
b-Alanine
O
NaOH
e-Amino-
C
Am ONa
74.0 58 – 59 0.76 C13H16ClNO3
98.0 74 – 75 0.84 C12H15NO4
89.0 71 – 72 0.74 C13H17NO4
91.3 78 – 79 0.79 C14H19NO4
59.6 62 – 63 0.69 C15H21NO4
55.8 66 – 67 0.69 C15H20NO4Na
82.7 61 – 62 0.79 C16H23NO4
62.0 75 – 76 0.85 C16H23NO4
68.8 86 – 87 0.66 C16H22NO4Na
67.7 79 – 80 0.82 C11H13NO4
66.8 88 – 89 0.80 C15H21NO4
83.6 73 – 74 0.73 C15H21NO4
caproic
VI
CH3O
GABA
GABA
GABA
GABA
GABA
GABA
R
VII C2H5O
VIII C3H7O
II, X, XIII
IX
X
C4H9O
C4H9O
C5H11O
The initial amino acids H–Am–OH and substituents R
are indicated in Table 1.
XI
The proposed structures were confirmed by the data of
elemental analyses and the results of IR and 1H NMR spect-
roscopic measurements. The IR spectra of N-(o-R-benzo-
yl)amino acids display bands in the region of characteristic
absorption of the carboxy carbonyl (1620 cm – 1), amide NH
XII iso-C5H11O GABA
XIII* C5H11O
GABA
XIV CH3O
b-Alanine
b-Alanine
b-Alanine
XV C5H11O
XVI iso-C5H11O
1
Mndzhoyan Institute of Fine Organic Chemistry, National Academy of
*
Sciences of the Republic of Armenia, Yerevan, Armenia.
Na salt.
485
0091-150X/01/3509-0485$25.00 © 2001 Plenum Publishing Corporation

486
S. A. Kazaryan et al.
were performed in a propanol – water (7 : 3) system, while
sodium salts (compounds II, X, XIII) were eluted in a buta-
nol – acetic acid – water (8 : 1 : 2) system. The spots were re-
vealed by exposure to iodine vapor. The IR absorption spect-
ra were recorded on an UR-20 (Germany) spectrophotometer
using samples prepared as suspensions in Vaseline oil. The
data of elemental analyses agree with the results of analytical
calculations according to empirical formulas (Table 1).
General method for the synthesis of N-(o-chloroben-
zoyl)- and N-(o-alkoxybenzoyl)amino acids. A solution of
0.1 mole of amino acid in 70 ml of 1 N aqueous sodium hyd-
roxide solution was cooled on ice to 5°C. To this solution
was gradually (over 30 min) and simultaneously (in approxi-
mately equal portions) added with intensive stirring a 1 N
aqueous sodium hydroxide solution and 0.1 mole of o-alko-
xybenzoic or o-chlorobenzoic acid chloroanhydride, with the
acidity controlled at pH 7.5 – 8.5. Then the reaction mixture
was stirred with cooling for 6 – 7 h and extracted with diet-
hyl ether (3 ´ 30 ml). The aqueous layer was cooled on ice
and acidified with 5 N hydrochloric acid to pH 3 – 4. The
precipitate was separated by filtration, washed with water,
and recrystallized from ethanol – water (1 : 1) mixture.
N-Aroylamino acid sodium salts (II, X – XIII). To a
solution of 0.1 mole of aroylamino acid I, IX, or XI in 20 ml
TABLE 2. 1H NMR Spectra of N-Substituted Amino Acids and Their Sodium Salts (I – XVI)
Compound
I
Proton chemical shift d, ppm (solvent)
10.0 (s, 1H, COOH); 7.80 (t, JH–H 6.1 Hz), (1H, NH); 7.45 (s, 4H, C6H4); 3.45 (q, JH–H 6.2 Hz), (2H, N–CH2); 2.45 (t, JH–H 6.2 Hz), (2H,
CH2–CO); 1.96 (m, 2H, CH2): (acetone).
II
8.65 (t, JH–H 6.1 Hz), (1H, NH); 7.40 (s, 4H, C6H4); 3.10 (q, JH–H 6.1 Hz), (2H, N–CH2); 1.8 (m, 4H, (CH2)2): (DMSO).
8.60 (t, JH–H 6.1 Hz), (1H, NH); 7.42 (s, 4H, C6H4); 3.90 (d, JH–H 6.1 Hz), (2H, CH2): (DMSO).
III
IV
8.50 (t, JH–H 6.1 Hz), (1H, NH); 7.50 (s, 4H, C6H4); 3.50 (q, JH–H 6.2 Hz), (2H, N–CH2); 2.55 (t, JH–H 6.2 Hz), (2H, CH2 – CO):
(DMSO).
V
7.40 (s, 4H, C6H4); 6.96 (t, JH–H 6.1 Hz), (1H, NH); 3.38 (q, JH–H 6.1 Hz), (2H, N–CH2); 2.30 (t, JH–H 6.1 Hz), (2H, CH2–CO); 1.50 (m,
6H, (CH2)3): (CDCl3).
VI
11.8 (ms, 1H, COOH); 7.98 (t, JH–H 5.5 Hz), (1H, NH); 7.87 (dd, JH–H 7.8 Hz, JH–H 1.9 Hz), (1H, H – Ar); 7.40 (m, JH–H 8.75 Hz,
6.9 Hz, 1.9 Hz), (1H, H–Ar); 7.03 (d, JH–H 7.8 Hz), (1H, H–Ar); 7.00 (t, JH–H 7.8 Hz), (1H, H–Ar); 3.96 (s, 3H, OCH3); 3.37 (q, JH–H
6.5 Hz), (2H, NCH2); 2.29 (t, JH–H 7.2 Hz), (2H, CH2–CO); 1.83 (qu, JH–H 7.0 Hz), (2H, CH2): (DMSO).
VII
10.5 (s, 1H, COOH); 8.30 (t, JH–H 6.0 Hz), (1H, NH); 8.22 (dd, JH–H 2.0 Hz, JH–H 7.9 Hz), (1H, H–Ar); 7.45 (td, JH–H 2.0 Hz, JH–H
7.9 Hz), (1H, H–Ar); 7.20 (d, JH–H 8.0 Hz), (1H, H–Ar); 7.15 (t, JH–H 7.9 Hz), (1H, H–Ar); 4.20 (q, JH–H 6.2 Hz), (2H, OCH2); 3.60 (q,
JH–H 6.3 Hz), (2H, NCH2); 2.55 (t, JH–H 6.3 Hz), (2H, CH2–CO); 2.05 (q, JH–H 6.2 Hz), (2H, CH2); 1.55 (t, JH–H 7.2 Hz), (3H, CH3):
(CDCl3).
VIII
IX
7.92 (dd, JH–H 2.0 Hz, JH–H 8.0 Hz), (1H, H–Ar); 7.38 (td, JH–H 2.0 Hz, JH–H 8.0 Hz), (1H, H–Ar); 7.00 (d, JH–H 8.0 Hz), (1H, H–Ar);
6.98 (t, JH–H 7.9 Hz), (1H, H–Ar); 4.00 (t, JH–H 6.3 Hz), (2H, OCH2); 3.45 (t, JH–H 6.3 Hz), (2H, NCH2); 2.41 (t, JH–H 6.3 Hz), (2H,
CH2–CO); 1.90 (m, 4H, 2CH2); 1.02 (t, JH–H 7.2 Hz), (3H, CH3): (CD3OD).
8.27 (t, JH–H 6.05 Hz), (1H, NH); 7.86 (dd, JH–H 2.08 Hz, JH–H 8.0 Hz), (1H, H–Ar); 7.39 (d, JH–H 2.0 Hz, JH–H 8.04 Hz), (1H, H–Ar);
7.05 (d, JH–H 8.0 Hz), (1H, H–Ar); 6.95 (t, JH–H 8.0 Hz), (1H, H–Ar); 4.08 (t, JH–H 6.12 Hz), (2H, OCH2); 3.32 (q, JH–H 6.35 Hz), (2H,
NCH2); 1.8 (m, 8H, 2(CH2)2); 0.98 (t, JH–H 7.2 Hz), (3H, CH3): (DMSO).
X
8.25 (t, JH–H 6.0 Hz), (1H, NH); 7.90 (dd, JH–H 2.0 Hz, JH–H 8.0 Hz), (1H, H–Ar); 7.42 (td, JH–H 2.0 Hz, JH–H 8.0 Hz), (1H, H–Ar);
7.10 (d, JH–H 8.0 Hz), (1H, H–Ar); 7.05 (t, JH–H 8.0 Hz), (1H, H–Ar); 4.08 (t, JH–H 6.2 Hz), (2H, OCH2); 3.30 (q, JH–H 6.3 Hz), (2H,
NCH2); 1.80 (m, 8H, 2(CH2)2); 0.98 (t, JH–H 7.2 Hz), (3H, CH3): (DMSO).
XI
10.4 (s, 1H, COOH); 8.2 (t, JH–H 6.0 Hz), (1H, NH); 8.0 (dd, JH–H 2.0 Hz, JH–H 8.0 Hz), (1H, H–Ar); 7.38 (td, JH–H 2.0 Hz, JH–H 8.0 Hz),
(1H, H–Ar); 7.05 (d, JH–H 8.0 Hz), (1H, H–Ar); 6.97 (t, JH–H 7.9 Hz), (1H, H–Ar); 4.15 (t, JH–H 6.2 Hz), (2H, OCH2); 3.45 (q, JH–H
6.3 Hz), (2H, NCH2); 2.40 (t, JH–H 6.3 Hz), (2H, CH2–CO); 1.80 (m, 8H, (CH2)3, CH2); 0.95 (t, JH–H 7.2 Hz), (3H, CH3): (acetone).
XII
XIII
XIV
XV
XVI
12.0 (s, 1H, COOH); 8.2 (t, JH–H 6.0 Hz), (1H, NH); 7.95 (dd, JH–H 2.0 Hz, JH–H 7.8 Hz), (1H, H–Ar); 7.00 (d, JH–H 8.0 Hz), (1H, H–Ar);
6.98 (t, JH–H 7.8 Hz), (1H, H–Ar); 4.15 (t, JH–H 6.3 Hz), (2H, O – CH2); 3.55 (q, JH–H 6.3 Hz), (2H, NCH2); 2.48 (t, JH–H 6.3 Hz), (2H,
CH2–CO); l.82 (m, 3H, CH2 – CH); 1.00 (d, JH–H 6.3 Hz), (6H, CH3): (DMSO).
10.42 (s, 1H, COOH); 8.26 (t, JH–H 6.0 Hz), (1H, NH); 7.98 (dd, JH–H 2.0 Hz, JH–H 8.0 Hz), (1H, H–Ar); 7.4 (td, JH–H 2.0 Hz, JH–H
8.0 Hz), (1H, H–Ar); 7.1 (d, JH–H 8.0 Hz), (1H, H–Ar); 6.99 (t, JH–H 7.98 Hz), (1H, H-Ar); 4.2 (t, JH–H 6.2 Hz), (2H, OCH2); 3.5 (q, JH–H
6.32 Hz), (2H, NCH2); 2.42 (t, JH–H 6.3 Hz), (2H, CH2–CO); 1.82 (m, 8H, (CH2)3–CH2); 0.98 (t, JH–H 7.22 Hz), (3H, CH3): (DMSO).
12.02 (ms, 1H, COOH); 7.90 (t, JH–H 5.45 Hz), (1H, NH); 7.78 (dd, JH–H 7.85 Hz, JH–H 2.01 Hz), (1H, H–Ar); 7.45 (m, JH–H 8.70 Hz,
JH–H 7.01 Hz, JH–H 1.94 Hz), (1H, H–Ar); 7.03 (d, JH–H 7.1 Hz), (1H, H–Ar); 7.04 (t, JH–H 7.8 Hz), (1H, H–Ar); 3.94 (s, 3H, OCH3);
3.34 (q, JH–H 6.5 Hz), (2H, N–CH2); 2.32 (t, JH–H 7.19 Hz), (2H, CH2–CO): (DMSO).
7.90 (dd, JH–H 2.0 Hz, JH–H 8.0 Hz), (1H, H–Ar); 7.38 (td, JH–H 2.0 Hz, JH–H 8.0 Hz), (1H, H–Ar); 6.95 (d, JH–H 8.0 Hz), (1H, H–Ar);
6.90 (t, JH–H 8.0 Hz), (1H, H–Ar); 4.00 (t, JH–H 6.2 Hz), (2H, OCH2); 3.55 (t, JH–H 6.3 Hz), (2H, NCH2); 2.50 (t, JH–H 6.2 Hz), (2H,
CH2CO); l.60 (m, 6H(CH2)3); 0.9 (t, JH–H 7.2 Hz), (3H, CH3): (CD3OD).
12.0 (s, 1H, COOH); 8.2 (t, JH–H 6.0 Hz), (1H, NH); 7.95 (dd, JH–H 2.0 Hz, JH–H 7.8 Hz), (1H, H–Ar); 7.37 (td, JH–H 2.0 Hz, JH–H
7.8 Hz), (1H, H–Ar); 7.00 (d, JH–H 8.0 Hz), (1H, H–Ar); 6.98 (t, JH–H 7.8 Hz), (1H, H–Ar); 4.15 (t, JH–H 6.3 Hz), (2H, O–CH2); 3.55 (q,
JH–H 6.3 Hz), (2H, N–CH2); 2.48 (t, JH–H 6.3 Hz), (2H, CH2–CO); 1.82 (m, 3H, CH2–CH); 1.00 (d, JH–H 6.3 Hz), (6H, CH3): [DMSO].

Synthesis and Anticonvulsant Activity of new N-Benzoyl Derivatives
487
TABLE 3. Anticonvulsant Activity of Some N-Substituted Amino
Acids and Their Sodium Salts
of a 50% aqueous ethanol solution was gradually added a 5%
aqueous sodium hydroxide solution, with the acidity control-
led at pH 8 – 9, and the mixture was allowed to stand over-
night. Then the solvent was evaporated to minimum volume
and the residue cooled to 0 – 5°C and diluted with 110 ml of
acetone. The precipitate was separated by filtration and dri-
ed. Finally, the product was reprecipitated with diethyl ether
from a solution in ethanol. The physicochemical data are pre-
sented in Table 1.
Compound
R
Initial amino acid ED50, mg/kg
I
Cl
Cl
GABA
–
–
II
GABA
III
Cl
Glycine
–
IV
Cl
–
b-Alanine
V
Cl
–
e-Aminocaproic
VI
CH3O
C2H5O
C3H7O
C4H9O
C4H9O
C5H11O
iso-C5H11O
C5H11O
GABA
–
VII
“
–
EXPERIMENTAL PHARMACOLOGICAL PART
VIII
“
–
IX
“
145
210
96
–
The anticonvulsant properties of the synthesized compo-
unds were studied on 250 male and female mice weighing
18 – 24 g. The activity was measured by the degree of pro-
tection from the maximum electroshock induced tonic exten-
sion or by the ability of preventing clonic convulsions indu-
ced by corazole (90 mg/kg, s.c.). The central m- and n-choli-
nolytic effects were evaluated by the antagonism with
arecoline tremor (15 mg/kg, s.c.) and nicotine convulsions
(8 mg/kg, i.p.) [8]. Reference was made to the well-known
antiepileptic drug ethosuccimide (zarontin) [9].
The compounds to be tested were intraperitoneally injec-
ted as suspensions in carboxymethylcellulose solutions in a
single dose of 200 mg/kg (i.p.). The drug injections were
45 min before inducing model convulsions or applying elect-
ric irritation. The active compounds were studied in a range
of doses (25, 50, 100, 150, 250, and 300 mg/kg) and the ef-
fective doses (ED50) producing an anticonvulsant effect in
half of the tested animals were determined by the conventio-
nal Litchfield – Wilcoxon method [10].
X
XI
“
“
XII
“
“
XIII*
120
155
Ethosuccimide
Zarontin
*
Na salt.
State Medical Institute, Vol. 37, Issue 5) [in Russian],
G. V. Kovaleva (ed.), Volgograd (1985).
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O. L. Mndzhoyan, RF Patent No. 1771185; Byul. Izobret.,
No. 37 (1992).
Among the studied substances, a pronounced anticorazo-
le effect was observed for N-(o-alkoxybenzoyl)-GABA and
related sodium salts (compounds IX – XIII, Table 3). In part-
icular, the derivative with amyloxybenzoyl radical (XI) was
superior to ethosuccimide (zarontin).
None of the tested compounds offered protection against
the maximum electroshock extension or exhibited central m-
and n-cholinolytic effects.
5. S. A. Kazaryan, É. A. Ékmekdzhyan, and Z. O. Mndzhoyan,
Khim.-Farm. Zh., 25(9), 57 – 62 (1991).
6. V. M. Samvelyan, S. A. Kazaryan, V. P. Akopyan, et al., RF
Patent No. 1766910; Byul. Izobret., No. 37 (1992).
7. E. Baumann, Ber. Bunsenges. Phys. Chem., 19, 3218 – 3222
(1886).
8. K. A. Gevorkyan, G. L. Papyan, S. G. Chshmarityan, and
R. G. Paronikyan, Khim.-Farm. Zh., 21(2), 167 – 170 (1987).
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cow (2000), Vol. 1, p. 41.
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1. Pharmacology and Clinical Use of Neuroactive Amino Acids
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