Synthesis and anticonvulsant activity of N,N-phthaloyl derivatives of central nervous system inhibitory amino acids

Article abstract of DOI:10.1002/1521-4184(200110)334:10<323::AID-ARDP323>3.0.CO;2-O

In order to study the influence of the length of the amino acid chain of N,N-phthaloyl-amino acid amides as analogues of the former anticonvulsant taltrimide on the seizure-antagonizing activity glycine, β-alanine and γ-aminobutyric acid (GABA) derivatives were synthesized. The corresponding taurine derivatives were also included. Generally, the glycine-derived amides showed a higher activity than the β-alanine and GABA derivatives in the maximal electroshock seizure (MES) test in mice upon intraperitoneal administration. The activity was comparable to the respective taurine derivatives. The N,N-phthaloyl-glycine amides were also active in the MES test upon oral administration to rats. No significant activity was noted in the seizure threshold test with subcutaneous pentylene-tetrazole. The ED₅₀ of N,N-phthaloyl-glycine ethyl amide (4b) in the MES test upon intraperitoneal administration to mice was 19.1 mg/kg. On a molar basis this activity is comparable to the activity of phenytoin with little toxicity in the rotorod test. In conclusion, N,N-phthaloyl-glycine amides might represent promising antiepileptic drugs.

Full text of DOI:10.1002/1521-4184(200110)334:10<323::AID-ARDP323>3.0.CO;2-O

Arch. Pharm. Pharm. Med. Chem. 2001, 334, 323–331
Derivatives of CNS inhibitory amino acids 323
Cyril O. Usifoha,b)
,
Didier M. Lambertc),
Johan Woutersd),
Synthesis and anticonvulsant activity of
N,N-phthaloyl derivatives of central nervous
system inhibitory amino acids
Gerhard K. E. Scribaa)
a) Department of Pharmaceutical In order to study the influence of the length of the amino acid chain of N,N-phthaloyl-
Chemistry, University of Jena, Phi-
losophenweg 14, 07743 Jena, Ger-
many
amino acid amides as analogues of the former anticonvulsant taltrimide on the seizure-
antagonizing activity glycine, β-alanine and γ-aminobutyric acid (GABA) derivatives were
synthesized. The corresponding taurine derivatives were also included. Generally, the
glycine-derived amidesshowedahigher activitythanthe β-alanine andGABAderivatives
in the maximal electroshock seizure (MES) test in mice upon intraperitoneal administra-
tion. The activity was comparable to the respective taurine derivatives. The N,N-phtha-
loyl-glycine amides were also active in the MES test upon oral administration to rats. No
significant activity was noted in the seizure threshold test with subcutaneous pentylene-
tetrazole. The ED50 of N,N-phthaloyl-glycine ethyl amide (4b) in the MES test upon
intraperitoneal administration to mice was 19.1 mg/kg. On a molar basis this activity is
comparable to the activity of phenytoin with little toxicity in the rotorod test. In conclusion,
N,N-phthaloyl-glycine amides might represent promising antiepileptic drugs.
b) Department of Pharmaceutical
Chemistry, Faculty of Pharmacy, Uni-
versity of Benin, Nigeria
c) Unit of Pharmaceutical Chemistry
and Radiopharmacy, Université
catholique de Louvain, UCL-CMFA
73.40, Avenue E. Mounier 73.40, 1200
Brussels, Belgium
d) Facultés Universitaires Notre-Dame
de la Paix, Rue de Bruxelles 61, 5000
Namur, Belgium
Key Words: Anticonvulsants; Glycine; β-Alanine; γ-Aminobutyric acid; N,N-Phthaloyl-
amino acids
Received: June 22, 2001 [FP595]
have been incorporated into several compounds which
showed anticonvulsant properties in several models[9–11]
Introduction
Worldwide, approximately 40–50 million people (about 0.5–
1% of the population) suffer from epilepsy, a symptom of
excessive temporary neuronal discharge, characterized by
discrete recurrent episodes, in which there is a disturbance
of movement, sensation, behavior, perception, and/or con-
sciousness[1]. 20–30% of the patients have seizures that
are resistant to the available medical therapies. This fact
warrants the search for new anticonvulsant drugs.
including phthalimido derivatives of glycine and its monoal-
kyl amides[12] and dialkyl amides[13] as well as phthalimides
of GABA[12–15]
.
The present study was conducted in order to investigate
the influence of the length of the amino acid chain. N,N-
Phthaloyl-amino acid amides of glycine, β-alanine, and
GABA were synthesized. β-Alanine is an agonist at the
strychnine-sensitive glycine receptor[16] which mediates
the inhibitory activity of glycine in the central nervous
system. For comparison with the inhibitory amino acid
derivatives, the respective N,N-phthaloyl-taurine amides
were also synthesized and included in the study.
Taurine (2-aminoethanesulfonic acid) is present in the cen-
tral nervous system in high concentrations and associated
with numerous physiological actions such as osmoregula-
tion, depression of neuronal firing, andmodulationof neuro-
nal action and neurotransmitter release[2]. Early reports on
the anticonvulsant activity of taurine in animal models
prompted the synthesis and anticonvulsant evaluation of
taurine-containing compounds[3–5]. Based on its pharma-
cological profile in animal experiments 2-phthalimido-
ethanesulfonic acid N-isopropylamide (9c) was further
developed under the name taltrimide[6]. However, the an-
tiepileptic effect observed in animal experiments could not
be confirmed in clinical trials[7,8]. In contrast, seizures
increased statistically significantly during taltrimide treat-
ment and further development of the drug was discontin-
ued.
Results and discussion
Chemistry
The synthesis of amides of the phthalimides of glycine,
β-alanine, and GABA is depicted in Scheme 1. Reaction of
the amino acids with phthalic acid anhydride (1) with con-
comitant removal of water yielded the respective N,N-
phthaloyl-amino acid (2a–c) which was converted into the
acid chloride (3a–c) by treatment with thionyl chloride. The
target compounds including the amides (4a, 5a, and 6a),
the ethylamides(4b, 5b, and6b), the isopropylamides (4c,
5c, and 6c), and the benzylamides (4d, 5d, and 6d) were
obtained by reaction of the acid chlorides with the respec-
tive amines. When gaseous ammonia or ethylamine were
used only the desired products were obtained, inde-
pendently of whether an excess of the amines or equimolar
concentrations were used. However, when N,N-phthaloyl-
β-alanine chloride or N,N-phthaloyl-GABA chloride was
Glycine and γ-aminobutyric acid (GABA) are inhibitory
amino acid neurotransmitters in the brain. Their structures
———
Correspondence: Gerhard K. E. Scriba, Department of Pharma-
ceutical Chemistry, University of Jena, Philosophenweg 14, 07743
Jena, Germany.
E-mail: gerhard.scriba@uni-jena.de
Fax: +49 3641-949802
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0365-6233/01/1010/0323 $17.50 +.50/0

324 Derivatives of CNS inhibitory amino acids
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 323–331
Scheme 1

Arch. Pharm. Pharm. Med. Chem. 2001, 334, 323–331
Derivatives of CNS inhibitory amino acids 325
Table 1. Lipophilicity values (log k0 and C log P), anticonvulsant
activity in the MES-test, and acute neurological toxicity in the
rotorod test after intraperitonal administration to mice. The data are
expressed as animals protected / animals tested.
Table 1. Continued.
————————————————————————————–
MES
Compd log k0 C log P Dose 30 min 4 h
[mg/kg]
Rotorod
30 min 4 h
————————————————————————————–
MES
Compd log k0 C log P Dose 30 min 4 h
[mg/kg]
Rotorod
————————————————————————————
30 min 4 h
6c
6d
9a
9b
9c
9d
2.3
1.67
2.79
0.11
1.30
1.61
2.42
30
100
300
0/1
0/3b
0/1
0/3
0/1
0/4
0/8
4/4
0/2
0/4
0/2
————————————————————————————–
1/1
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
0.99
2.01
2.44
3.58
1.43
1.95
2.60
3.67
1.47
2.19
0.15
0.95
1.25
2.30
0.41
1.14
1.45
2.53
0.69
1.36
30
100
300
0/1
0/3a
1/1
0/1
0/3
1/1
0/4
0/8
1/4
0/2
0/4
0/2
3.53
1.23
2.30
2.59
3.72
30
100
300
0/1
0/3
0/1
0/1
0/3
0/1
0/4
1/8
1/4
0/2
1/4
0/2
30
100
300
0/1
3/3
1/1
0/1
0/3
1/1
0/4
0/8
0/4
0/2
0/4
0/2
30
100
300
0/1
2/3
1/1
1/1
2/3
1/1
0/4
0/8
1/4
0/2
0/4
0/2
30
100
300
0/1
2/3
1/1
0/1
0/3
1/1
0/4
1/8
3/4
0/2
0/4
0/2
30
100
300
0/1
3/3
1/1
0/1
1/3
1/1
0/4
1/8
4/4
0/2
0/4
0/2
30
100
300
0/1
3/3
1/1
0/1
2/3
1/1
0/4
0/8
4/4
0/2
0/4
0/2
30
100
300
0/1
0/3
0/1
0/1
0/3
0/1
0/4
0/8
0/4
0/2
0/4
0/2
30
100
300
0/1
0/3
0/1
0/1
0/3
1/1
0/4
0/8
1/4
0/2
0/4
0/2
30
100
300
0/1
0/3
1/1
0/1
0/3
0/1
0/4
0/8
1/4
0/2
0/4
0/2
————————————————————————————–
a at 1 h: 2/3
b at 15 min: 1/3
30
100
300
0/1
0/3
0/1
0/1
0/3
0/1
0/4
0/8
0/4
0/2
0/4
0/2
reacted in the presence of a large excess of either benzy-
lamine or isopropylamine, the respective phthalimideswere
obtained only in low yields while the ring-open asymmetric
phthalic acid diamides 7a–b and 8a–b were the primary
products. In these mixtures the N,N-phthaloyl-amino acid
amides were obtained in 20–30% yields while the ring-open
phthalic acid diamides were obtained in the range of 60–
70%. However, when equimolar amounts of benzylamine
or isopropylamine were added to the acid chlorides in the
presence of triethylamine as proton scavenger the respec-
tive N,N-phthaloyl-amino acid amides were obtained in
excellent yields. No such reactions were observed with the
glycine derivatives. Ring opening has been observed dur-
ing the preparation of amides of N,N-phthaloyl-α-amino
30
100
300
0/1
0/3
0/1
0/1
0/3
0/1
1/4
1/8
3/4
1/2
0/4
0/2
30
100
300
0/1
0/3
0/1
0/1
0/3
0/1
0/4
0/8
0/4
0/2
0/4
0/2
acids bearing a substituent in the α-position[17]
.
30
100
300
0/1
1/3
1/1
0/1
0/3
0/1
0/4
1/8
3/4
0/2
0/4
2/2
The N,N-phthaloyl-taurine derivatives 9a–d were prepared
by an analogous sequence (Scheme 1). No ring opening of
the phthalimide moiety was observed during these synthe-
ses. The assignment of all structures was established on
1
the basis of H- and 13C-NMR, mass spectrometry, and
30
100
300
0/1
0/3
0/1
0/1
0/3
0/1
0/4
0/8
0/4
0/2
0/4
0/2
microanalysis.
The lipophilicity of the target compounds (Table 1) was
estimated by calculation using the ClogP program[18] and
————————————————————————————–

326 Derivatives of CNS inhibitory amino acids
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 323–331
Table 2. Anticonvulsant activity of N,N-phthaloyl-glycine ethylamide (4b), taltrimide (9c) and standard antiepileptic
drugs upon i.p. administration to mice measured at the time of peak effect. The data are expressed in µmol/kg.
95% confidence intervals are given in parenthesis, the time of test is listed in square brackets.
—————————————————————————————————————————————————
Compound
ED50 MES
ED50 ScMet
TD 50
PI
[µmol/kg]
[µmol/kg]
[µmol/kg]
(TD50/ED50)
—————————————————————————————————————————————————
N,N-Phthaloyl-glycine 282 (230–337)
755 (627–874)
[0.25]
1280 (1105–1520)
[0.5]
4.5 / 1.7
2.5 / 1.5
6.6 / –
ethylamide (4b)
[0.25]
Taltrimide (9c)
251 (215–276)
[0.25]
415 (323–528)
[0.25]
628 (4278–1010)
[0.5]
Phenytoin a
25.7 (22.4–28.7)
[0.5]
–
–
170 (144–188)
[2]
Carbamazepine a
Valproic acid a
41.7 (37.1–45.3)
[0.25]
–
–
202 (166–251)
[0.25]
4.9 / –
1990 (1643–2489)
[0.25]
1449 (1220–1727)
[0.25]
3350 (2857–3960)
[0.25]
1.7 / 2.3
————————————————————————————————————————————————
a Data from reference [20] converted to µmol/kg.
seizure threshold test with subcutaneous pentylenetetra-
Table 3. Time course of the anticonvulsant activity in the MES test
after oral administration of a dose of 30 mg/kg to rats. The values
are expressed as animals protected / animals tested.
zole (ScMet test). The acute neurological toxicity was de-
termined in the rotorod test. The ring-open asymmetric
phthalic acid diamides 7a,b and 8a,b were also included in
the study. However, no activity in either test was noted for
these compounds when intraperitoneally administered to
mice at doses up to 300 mg/kg. The activity of the N,N-
phthaloyl-amino acid amides in the MES test and rotorod
test upon i.p. administration to mice is summarized in
Table 1. Generally, the glycine derivatives were more active
in the MES test than the N,N-phthaloyl-GABAamides while
the β-alanine-containing derivatives were essentially inac-
tive. Thus, increasing the chain length between the
phthalimido moiety and the amide group results in a de-
crease in the anticonvulsant activity. A low electroshock
seizure-antagonizing activity of the amylamide, n-hexyl-
amide, and phenylamide of N,N-phthaloyl-GABA has been
reported[15]. Each series of the respective inhibitory amino
acid exhibited comparable lipophilicity (Table 1) indicating
that lipophilicity alone cannot account for the differences in
anticonvulsant activity but rather a better fit into a putative
molecular target (receptor, enzyme) due to favorable steric
interactions.
————————————————————————————–
Compd 15 min 30 min 1 h
2 h
4 h
————————————————————————————–
2a
2/4
1/4
1/4
1/4
1/4
2/4
3/4
3/4
2/4
3/4
2/4
1/4
2/4
3/4
1/4
2/4
2/4
2/4
2/4
2/4
0/4
0/4
2/4
2/4
2/4
2/4
1/4
2/4
0/4
3/4
1/4
2/4
2/4
1/4
4/4
4a
4ba
4c
9a
9b
9cb
————————————————————————————–
a Dose of phthalimido-glycine ethylamide (4b) 20 mg/kg.
b Dose of phthalimido-taurine isopropylamide (9c) 60 mg/kg.
measured by the determination of isocratic capacity factors,
log k0, by RP-HPLC[19]. The HPLC method generally gave
higher values than the computational method. Between the
calculated values and the log k0 values, a correlation of r 2
= 0.9543 was obtained (log k0 = 0.94 + 1.05 × C log P).
Except for the primary amides 4a, 5a, 6a and the primary
sulfonamide 9a all compounds have C log P values and
log k0 values greater than 2, avaluecompatible with access
to the CNS by crossing the blood brain barrier via passive
diffusion.
Phthalimides containing the free acid function, i.e. N,N-
phthaloyl-glycine (2a) and N,N-phthaloyl-GABA (2c), were
inactive in the MES test while displaying low acute neuro-
logical toxicity on the rotorod test (data not shown). Our
results are in agreement with a study by Bialer and co-work-
ers[13] who found no anticonvulsant activity for N,N-phthal-
oyl-GABA (2c). In contrast, the group of Pal reported
seizure-antagonizing effect of 2c in several models includ-
ing the MES test[14]. No acute neurotoxicity in the rotorod
test was noted for the ethyl amides 4b, 5b, and 6b while all
other derivatives showed moderate toxicity (Table 1). No
significant activity was found for any compound in the
ScMet test (data not shown).
Pharmacology
The compounds were tested for anticonvulsant activity
according to standard procedures[20] which included the
maximal electroshock seizure test (MES test) and the

Arch. Pharm. Pharm. Med. Chem. 2001, 334, 323–331
Derivatives of CNS inhibitory amino acids 327
Table 4. Anticonvulsant activity of N,N-phthaloyl-glycine ethylamide (4b), taltrimide (9c) and standard antiepileptic drugs
upon oral administration to rats measured at the time of peak effect. The data are expressed in µmol/kg. 95% confidence intervals
are listed in brackets, the time of test is listed in square brackets.
————————————————————————————————————————————————————————
Compound
ED50 MES
ED50 ScMet
TD50
PI
[µmol/kg]
[µmol/kg]
[µmol/kg]
(TD50/ED50 MES)
————————————————————————————————————————————————————————
N,N-Phthaloyl-glycine
ethylamide (4b)
82.5 (50.3–122)
[0.5 h]
> 1080
> 2150
> 26
Taltrimide (9c)
Phenytoin a
142 (89.9–217)
[4 h]
> 422
> 845
> 6
92.0 (84.8–101)
[2 h]
> 990
> 1980
> 22
101
2.2
Carbamazepine a
Valproic acid a
15.1 (10.2–20.0)
[1 h]
> 1060
1528 (1350–1700)
[1 h]
2740 (2300–3060)
[0.5 h]
4300 (3250–6830)
[0.5 h]
5960 (4990–7960)
[0.5 h]
————————————————————————————————————————————————————————
a Data from reference [20] converted to µmol/kg.
The electroshock seizure-antagonizing activity of the N,N-
phthaloyl-glycine amides was comparable to the respective
N,N-phthaloyl-taurine analogues (Table 1). No activity was
noted for the benzylamides. It has been reported pre-
viously[4] that aromatic amides of N,N-phthaloyl-taurine
were inactive in the MES test while aliphatic amides gen-
erally showed good activity. The same appears to be true
for N,N-phthaloyl-glycine amides although the number of
derivatives is limited so far. In contrast, N-(benzyloxycar-
bonyl)-glycine N-benzylamide showed good anticonvulsant
properties in several test models[11].Quantitative data of 4b
in comparison to taltrimide (9c) and prototype anticonvul-
sant drugs upon i.p. administration to mice are summarized
in Table 2. Both 4b and 9c exhibited comparable activity
which was lower than the activity of phenytoin and car-
bamazepine but higher than valproic acid. 4b and 9c were
more active in the ScMet test than valproic acid.
these compounds displayed a similar seizure-antagonizing
profile in the MES and ScMet tests as phenytoin. In addi-
tion, a N-phenylphthalimide derivative was shown to inter-
act with ion channels such as blockade of the voltage-gated
sodium channels[29] explaining the observed anticonvul-
sant effects. Whether such interactions with ion channels
are also the basis of the pharmacological activity of the
present amino acid amides remains to be elucidated.
In conclusion, N,N-phthaloyl-glycine N-monoalkylamides
were more effective than the corresponding derivatives
containing β-alanine or GABA demonstrating the influence
of the chain length of the incorporated amino acid. In
agreement with earlier studies phthalimido-glycine amides
might represent a new class of antiepileptic drugs.
Acknowledgement
Both N,N-phthaloyl-glycine and N,N-phthaloyl-taurine am-
ides effectively antagonized electrically-induced seizures
upon oral administration to rats (Table 3). The benzyl-
amides which were inactive when administered intraperi-
toneally were not included. Interestingly, N,N-phthaloyl-
glycine (2a) with the free carboxyl group which was inactive
upon i.p. injection showed activity after oral administration.
Quantitative data of N,N-phthaloyl-glycine N-ethylamide
(4b) in comparison with taltrimide (9c) and standard anti-
convulsant drugs upon oral administration to rats are sum-
marized in Table 4. On a molar basis the glycine derivative
4b is about as active as phenytoin with little toxicity, result-
ing in a high protective index (PI = TD50/ED50). Good oral
MES activity with low toxicity has also been reported for the
N,N-diethylamide and N,N-diisopropylamide of N,N-phtha-
C.O. Usifoh was supported by a stipend from the Deutscher
Akademischer Austauschdienst (DAAD). The anticonvulsant
and toxicity testing by Dr. J. P. Stables at the NINDS Epilepsy
Branch, National Institutes of Health, Rockville, MD, USA, and
the financial support by the Fonds der Chemischen Industrie
are gratefully acknowledged.
Experimental
General: Melting points were determined with a Kofler melting
point apparatus and are uncorrected. NMR spectra were recorded
on a Varian Gemini 200. Chemical shifts are reported in ppm
relative to tetramethylsilane. EI mass spectra were obtained on a
Finnigan MAT 44S, with an ionization voltage of 70 eV. Elemental
analyses were performed at the Elemental Analytical Laboratory,
Department of Chemistry, University of Jena, and were within
±0.4% of the theoretical values. TLC was performed on silica gel
60 F254 plates from Merck (Darmstadt, Germany). The starting
materials were obtained from commercial sources and used with-
out purification.
loyl-glycine[13]
.
N-Phenylphthalimides represent another group of anticon-
vulsant compounds containing the phthalimide moiety[29–
31]. As the present phthalimides of amino acid amides,

328 Derivatives of CNS inhibitory amino acids
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 323–331
Synthesis of N,N-phthaloyl-amino acids 2a–d
2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)ethanesulfonic acid
amide (9a)
74 g (0.5 mol) of phthalic acid anhydride and 0.5 mol of the
respective amino acid were refluxed in 300 ml toluene in the
presence of 6.5 ml triethylamine for 2 h in a Dean-Stark appa-
ratus. The organic solvents were removed in vacuo, 700 ml of
water and 10 ml of concentrated HCl were added and the
mixture stirred for 30 minutes, filtered, and dried. Recrystalliza-
tion from ethanol yielded 2-phthalimidoacetic acid (2a), 95.4 g,
93%, mp 197–198 °C (lit.[21] 199–202 °C), 3-phthalimido-
propionic acid (2b), 99.9 g, 91%, mp 151–152 °C (lit.[21] 150–
152 °C), and 4-phthalimidobutyric acid (2c), 95.5 g, 82%, mp
116–118 °C (lit.[21] 116–117 °C). 2-Phthalimidoethanesulfonic
acid potassium salt (2d) was prepared from 45 g (0.3 mol) of
phthalic acid anhydride, 38 g (0.3 mol) taurine and 34 g (0.35)
mol potassium acetate according to[22], yield 77 g, 88% of 2d,
mp 339 °C.
Yield 2.1 g, 84%; mp 207–209 °C (ethanol) (lit.[22] 209–212 °C);
1H-NMR (D6-DMSO) δ 3.35 (t, J = 6.5 Hz, 2 H, NCH2), 3.98 (t,
J = 6.5 Hz, 2 H, CH2SO2), 7. 07 (s, 2 H, NH2), 7.87 (m, 4 H,
Ar-H); 13C-NMR (D6-DMSO) δ 32.6, 51.7, 123.1, 131.7, 134.4,
167.5; MS (CI, ammonia) m/z 272 ([M + NH4]+, 100%);
C10H10N2O4S (254.26) C, H, N.
Synthesis of N-ethylamides
10 mmol of the N,N-phthaloyl-amino acid chlorides were dis-
solved in 30 ml CH2Cl2 and cooled in an ice bath. Ethylamine
was transferred by bubbling nitrogen through an aqueous solu-
tion of the ethylamine (70%) that was warmed to 30 °C. The
resulting mixture was allowed to warm to room temperature and
stirred for 2 h. The mixture was poured into ice-cold 2 M HCl
and extracted with CH2Cl2. The organic phases were combined,
washed with brine, dried over Na2SO4. The solvent was evapo-
rated under reduced pressure and the residue was recrystal-
lized from ethanol.
Synthesis of N,N-phthaloyl amino acid chlorides 3a–d
0.2 mol of the respective N,N-phthaloyl-amino acid was re-
fluxed in 20 ml of thionyl chloride for 1 h. Excess thionyl chloride
was removed in vacuo. The resulting solid was used without
further purification. Analytical samples were recrystallized from
light petrol ether (60–80 °C) and CH2Cl2 to yield (1,3-dihydro-
1,3-dioxo-2H-isoindol-2-yl)acetyl chloride (3a), mp 83–85 °C
(lit.[23] 84–85 °C), 3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-
yl)propionyl chloride (3b), mp 107–108 °C (lit.[24] 107–108 °C),
and 4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyryl chloride
(3c), mp 105–106 °C (lit.[25] 106–107 °C). 2-(1,3-dihydro-1,3-
dioxo-2H-isoindol-2-yl)sulfonyl chloride (3d) was synthesized
by refluxing 59 g (0.2 mol) 2d and 73 g PCl5 (0.35 mol) in 400
ml toluene. Work-up according to lit.[22], mp 160–161 °C (lit.[22]
159–162 °C).
2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-N-ethyl-acetamide
(4b)
Yield 1.35 g, 58%; mp 236–237 °C (lit.[26] 240 °C); 1H-NMR
(D6-DMSO) δ 1.00 (t J = 7.2 Hz, 3 H, CH3), 3.04 (m, 2 H,
CH2CH3), 4.15 (s, 2 H, CH2CO), 7.88 (m, 4 H, Ar-H), 8.20 (t,
J = 4.9 Hz, 1 H, NH); 13C-NMR (D6-DMSO) δ 22.2, 39.5, 40.7,
123.0, 131.7, 134.4, 164.7, 167.4; MS m/z (%) 232 [M+] (3), 161
(100), 160 (37), 133 (19), 132 (16), 117 (56), 105 (13), 104 (23),
77 (19); C12H12N2O3 (232.08) C, H, N.
Synthesis of amides
3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-N-ethyl-propion-
amide (5b)
10 mmol of the N,N-phthaloyl-amino acid chlorides were dis-
solved in 30 ml CH2Cl2 and treated with ammonia gas at 0–4 °C
for 30 min. The mixture was stirred at room temperature over-
night. The resulting precipitate was filtered and recrystallized.
Yield 1.73 g, 70%; mp 197–198 °C; 1H-NMR (DMSO-d6) δ 1.10
(t, J = 7.2 Hz, 3 H, CH2CH3), 2.60 (t, J = 7.1 Hz, 2 H, 2′-H),
3.27 (m, 2 H, CH2CH3), 4.00 (t, J = 7.2 Hz, 2 H, 1-H), 5.75 (s,
1 H, NH), 7.72 (m, 2 H, Ar-H), 7.83 (m, 2 H, Ar-H); 13C-NMR
(DMSO-d6) δ 12.1, 31.8, 32.3, 120.7, 129.4, 131.4, 165.5,
166.7; MS m/z (%) 246 [M+] (12), 203 (20), 173 (39), 161 (100),
147 (13), 133 (13), 70(28); C13H14N2O3 (246.27) C, H, N.
2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)acetamide (4a)
Yield 1.5 g, 65%; mp 270 °C (methanol) (lit.[17] 269–270 °C);
1H-NMR (D6-DMSO) d 4.14 (s, 2 H, CH2), 7.24 (s, 1 H, NH),
7.68 (s, 1 H, NH), 7.88 (m, 4 H, Ar-H); 13C-NMR (D6-DMSO) δ
167.9, 167.5, 134.5, 131.7, 123.1, 39.9; MS m/z (%) = 204 [M+]
(2), 161 (100), 147 (9), 133 (13), 104(12); C10H8N2O3 (204.19)
C, H, N.
4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-N-ethyl-butyramide
(6b)
Yield 1.82 g, 70%; mp 131–133 °C (lit.[12] 129–131 °C); 1H-NMR
(DMSO-d6) δ 1.13 (t, J = 7.2 Hz, 3 H, CH2CH3), 2.05 (m, 2 H,
2′-H), 2.19 (t, J = 6.4 Hz, 2 H, 3′-H), 3.26 (m, 2 H, CH2CH3),
3.74 (t, J = 6.2 Hz, 2 H, 1′-H), 6.00 (s, 1 H, NH), 7.73 (m, 2 H,
Ar-H), 7.83 (m, 2 H, Ar-H); 13C-NMR (DMSO-d6) δ 14.9, 25.1,
33.9, 34.5, 37.3, 123.3, 132.1, 134.1, 168.7, 171.8; MS m/z 261
[M+ + 1] (3%), 260 [M+] (4), 232(8), 216 (25), 188 (26), 160
(100), 148 (10), 130 (24), 117 (13), 100 (17), 87 (59), 77 (14);
C14H16N2O3 (260.29) C, H, N.
3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)propionamide (5a)
Yield 1.64g , 75%; mp 208–209 °C (ethanol) (lit.[17] 202–
206 °C); 1H-NMR (DMSO-d6) δ 2.41 (t, J = 7.4 Hz, 2 H, 2′-H),
3.75 (t, J = 7.0 Hz, 2 H, 1′-H), 6.86 (s, 1 H, CONH2), 7.44 (s, 1
H, CONH2), 7.83 (m, 4 H, Ar-H); 13C-NMR (DMSO-d6) δ 33.5,
34.2, 122.9, 131.7, 134.3, 167.6, 171.6; MS m/z (%) 218 [M+]
(1), 201 (12), 173 (100), 160 (27), 147 (12), 133 (11), 117 (3),
104 (11), 77 (7), 50 (5); C11H10N2O3 (218.21) C, H, N.
4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyramide (6a)
2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)ethanesulfonic acid
ethylamide (9b)
Yield 1.97 g, 85%; mp 166–168 °C (ethanol) (lit.[17] 168–
169 °C); 1H-NMR (DMSO-d6) δ 1.78 (m, 2 H, 2′-H), 2.06 (t, J =
7.0 Hz, 2 H, 3′-H), 2.49 (t, J = 7.0 Hz, 2 H, 1′-H), 6.73 (s, 1 H,
CONH2), 7.24 (s, 1 H, CONH2), 7.84 (m, 4 H, Ar-H); 13C-NMR
(DMSO-d6) d 23.9, 32.4, 37.2, 122.9, 131.6, 134.3, 167.9,
173.4; MS m/z 232 [M+] (4%), 215 (58), 197 (3), 187 (22), 174
(100), 160 (78), 147 (35), 133 (29), 117 (10), 104 (15), 85 (77),
59 (14); C12H12N2O3 (232.24) C, H, N.
Yield 0.8 g, 29%; mp 115 °C; 1H-NMR (CDCl3) δ 1.24 (t, J = 7.2 Hz,
3 H, CH3), 3.20 (m, 2 H, CH2CH3), 3.40 (t, J = 6.5, 2 H, Hz, NCH2),
4.14 (t, J = 6.5 Hz, 2 H, CH2SO2), 4.99 (t, J = 5.9 Hz, 1 H, NH),
7.74 (m, 2 H, Ar-H), 7.86 (m, 2 H, Ar-H); 13C-NMR (CDCl3) δ 15.8,
32.9, 38.3, 49.3, 123.6, 131.9, 134.3, 168.0; MS (CI, ammonia)
m/z 300 [M + NH4]+ (100%); C12H14N2O4S (282.32) C, H, N.

Arch. Pharm. Pharm. Med. Chem. 2001, 334, 323–331
Synthesis of N-isopropylamides
Derivatives of CNS inhibitory amino acids 329
N-(2-Methylethyl)-3-benzamidopropionamide-
2-(2-methylethyl)-carboxamide (7a)
Method A: 10 mmol of the N,N-phthaloyl-amino acid chlorides
were dissolved in 20 ml CH2Cl2 and added dropwise to a
solution of 0.6 g (10 mmol) isopropylamine and 1.5 g triethy-
lamine in 20 ml CH2Cl2 at 0 °C. The mixture was allowed to
warm to room temperature and stirred for 2 h. The mixture was
poured into ice-cold 2 M HCl and extracted with CH2Cl2. The
organic phases were combined, washed with brine and dried
over Na2SO4. The solvent was evaporated under reduced pres-
sure and the residue was recrystallized from ethanol.
Method B, chromatographic purification gave 0.5 g 5c (20%)
and 2.2 g 7a (60%); mp 197–199 °C; 1H-NMR (DMSO-d6) δ 1.02
(d, J = 6.7 Hz, 6 H, 2 × CH3), 1.11 (d, J = 6.5 Hz, 6 H, 2 × CH3),
2.28 (t, J = 7.3 Hz, 2 H, 2′-H), 3.35 (m, 2 H, 1′-H), 3.90 (m, 2 H,
2 × CH (CH3)2), 7.42 (m, 4 H, Ar-H), 7.79 (d, J = 7.8 Hz, 1 H,
NH), 8.08 (d, J = 7.8Hz, 1 H, NH), 8.18 (t, J = 5.5 Hz, 1 H, NH);
13C-NMR (DMSO-d6) δ 22.1, 22.3, 35.2, 36.0, 40.1, 40.8, 127.4,
127.6, 129.0, 129.1, 136.0, 136.2, 167.1, 168.1, 169.3; MS m/z
(%) 319 [M+] (5), 318 (6), 276 (5), 260 (74), 234 (12), 218 (13),
202 (100), 190 (34), 174 (27), 161 (63), 148 (64), 130 (36), 105
(8), 77 (5), 58 (26); C17H25N3O3 (319.40) C, H, N.
Method B: 10 mmol of the N,N-phthaloyl-amino acid chlorides
were dissolved in 20 ml CH2Cl2 and added dropwise to a
solution of 3.5 g (60 mmol) isopropylamine in 20 ml CH2Cl2 at
0 °C. The mixture was allowed to warm to room temperature
and stirred for 2 h. The mixture was poured into ice-cold 2 M
HCl and extracted with CH2Cl2. The organic phases were
combined, washed with brine, dried over Na2SO4 and evapo-
rated under reduced pressure. The residue was purified by
column chromatography (CH2Cl2-methanol, 98:1, v/v).
N-(2-Methylethyl)-4-benzamidobutyramide-
2-(2-methylethyl)-carboxamide (8a)
Method B, chromatographic purification gave 0.8 g 6c (30%)
and 1.9 g 8a (58%); mp 171–173 °C; 1H-NMR (DMSO-d6) δ
1.03 (d, J = 6.6 Hz, 6 H, 2 × CH3), 1.11 (d, J = 6.6 Hz, 6 H, 2
× CH3), 1.70 (m, 2 H, 2′-H), 2.08 (t, J = 7.3 Hz, 3 H, 3′-H), 3.16
(m, 2 H, 1′-H), 3.83 (m, 1 H, CH(CH3)2), 3.98 (m, 1 H,
CH(CH3)2), 7.44 (s, 4 H, Ar-H), 7.65 (d, J = 7.7 Hz, 1 H, NH),
8.10 (d, J = 7.6 Hz, 1 H, NH), 8.23 (t, J = 5.5 Hz, 1 H, NH);
13C-NMR (DMSO-d6) δ 22.2, 22.4, 25.5, 33.0, 38.6, 40.1, 40.8,
127.4, 129.1, 136.3, 167.3, 168.2, 170.9; MS m/z (%) 333 [M+]
(4), 290 (9), 274 (43), 259 (4), 248 (6), 233 (24), 216 (25), 190
(100), 174 (20), 160 (20), 148 (77) 130 (36), 101 (10), 86 (8);
C18H27N3O3 (333.43) C, H, N.
2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-N-isopropyl-
acetamide (4c)
Method B: Yield 1.3 g, 54%; mp 223–225 °C (lit.[27] 226 °C);
1H-NMR (D6-DMSO) δ 1.05 (d, J = 6.6 Hz, 6 H, 2 × CH3), 3.83
(m, 1 H, CH), 4.14 (s, 2 H, CH2CO), 7.88 (m, 4 H, Ar-H), 8.07
(d, J = 7.5 Hz, 1 H, NH); 13C-NMR (D6-DMSO) δ 22.2, 40.1,
40.8, 123.0, 131.7, 134.4, 164.7, 167.4; MS m/z (%) 246 [M+]
(1), 161 (100), 160 (50), 133 (18), 132 (12), 117 (45), 105 (11),
104 (19), 77 (17); C13H14N2O3 (246.27) C, H, N.
Synthesis of N-benzylamides
3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-N-isopropyl-
propionamide (5c)
Method A: 10 mmol of the N,N-phthaloyl-amino acid chlorides
were dissolved in 20 ml CH2Cl2 and added dropwise to a
solution of 1.1 g (10 mmol) benzylamine and 1.5 g triethylamine
in 20 ml CH2Cl2 at 0 °C. Further treatment and work-up was
performed as described above for the isopropylamides.
Method A: Yield 1.77 g, 68%; mp 219–220 °C; 1H-NMR (DMSO-
d6) δ 0.94 (d, J = 6.5 Hz, 6 H, 2 × CH3), 2.35 (t, J = 7.3 Hz, 2
H, 2′-H), 3.76 (m, 1 H, CH(CH3)2), 3.76 (t , J = 7.5 Hz, 2 H, 1′-H),
7.83 (m, 5 H, Ar-H, N-H); 13C-NMR (DMSO-d6) δ 22.2, 34.2,
34.5, 40.1, 122.9, 131.7, 134.3, 167.6, 168.3; MS m/z (%) 245
(4), 217 (2), 202 (51), 173 (14), 161 (100), 147 (7), 133 (10),
105 (6), 77(6), 58 (53); C14H16N2O3 (260.29) C, H, N.
Method B: 10 mmol of the N,N-phthaloyl-amino acid chlorides
were dissolved in 20 ml CH2Cl2 and added dropwise to a
solution of 6.5 g (60 mmol) benzylamine in 30 ml CH2Cl2 at 0 °C.
Further treatment and work-up was performed as described
above for the isoproyplamides.
4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-N-isopropyl-
butyramide (6c)
N-Benzyl-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)acetamide
(4d)
Method A: Yield 2.14 g, 78%; mp 149–150 °C. 1H-NMR (DMSO-
d6) δ 1.16 (d, J = 6.6 Hz, 6 H, 2 × CH3), 2.02 (m, 2 H, 2′-H), 2.17
(t, J = 7.3Hz, 2 H, 1′-H), 3.74 (t, J = 7.2 Hz, 2 H, 3′-H), 4.05 (m,
1 H, CH(CH3)2), 5.84 (s, 1 H, NH), 7.73 (m, 2 H, Ar-H), 7.84 (m,
2 H, Ar-H); 13C-NMR (DMSO-d6) δ 22.8, 25.2, 34.1, 37.3, 41.5,
123.4, 132.1, 134.1, 168.7,170.9; MS m/z (%) 274 [M+] (2), 259
(7), 216 (61), 188 (42), 174 (12), 160 (100), 148 (15), 130 (26),
117 (14), 101(53), 86(19), 77(15); C15H18N2O3 (274.32) C, H,
N.
Method B, yield 1.4 g, 48%; mp 215 °C (lit.[23] 217–219 °C);
1H-NMR (D6-DMSO) δ 4.26 (s, 2 H, CH2CO), 4.31 (t, J = 5.5
Hz, 2 H, CH2C6H5), 7.26 (m, 5 H, Ar-H), 7.87 (m, 4 H, Ar-H),
8.76 (t, J = 5.5 Hz, 1 H, NH); 13C-NMR (D6-DMSO) δ 40.2, 42.2,
123.1, 126.8, 127.1, 128.2, 131.7, 134.4, 138.8, 166.1, 167.5;
MS m/z (%) 294 [M+] (3), 161 (15), 160 (29), 133 (14), 117 (16),
106 (100), 104 (13), 91 (19), 77 (16); C17H14N2O3 (294.14) C,
H, N.
N-Benzyl-3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propion-
amide (5d)
2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)ethanesulfonic acid
isopropylamide (taltrimide) (9c)
Method A, yield 2.0 g, 65%; mp 199–200 °C (lit.[28] 198–199.5 °C);
1H-NMR (DMSO-d6) δ 2.51 (t, J = 7.8 Hz, 2 H, 2′-H), 3.81 (t, J =
7.5 Hz, 2 H, 1′-H), 4.20 (d , J = 6.0 Hz, 2 H, CH2-Bn), 7.20 (m, 5
H, Ar-H), 7.85 (m, 4 H, Ar-H), 8.47 (t, J = 6.0 Hz, 1 H, NH); 13C-NMR
(DMSO-d6) δ 33.8, 34.4, 42.0, 122.9, 126.7, 127.1, 128.1, 131.6,
134.3, 139.2, 167.6, 169.4; MS m/z (%) 308 [M+] (4), 280 (5), 263
(1), 175 (2), 160 (23), 147 (3), 130 (6), 106 (100), 91(5), 79(12),
65(3); C18H16N2O3 (308.34) C, H, N.
Method B: Yield 1.6 g, 55%; mp 139 °C. 1H-NMR (CDCl3) δ 1.27
(d, J = 6.5 Hz, 6 H, 2 × CH3), 3.38 (t, J = 6.5 Hz, 2 H, NCH2), 3.67
(m, 1 H, CH), 4.15 (t, J = 6.5 Hz, 2 H, CH2SO2), 4.71 (d, J = 7.8
Hz, 1 H, NH), 7.75 (m, 2 H, Ar-H), 7.85 (m, 2 H, Ar-H); 13C-NMR
(CDCl3) δ 24.3, 33.0, 46.4, 50.3, 123.6, 131.9, 134.3, 168.1; MS
(CI, ammonia) m/z (%) 314 [M + NH4]+ (100); C13H16N2O4S
(296.35) C, H, N.

330 Derivatives of CNS inhibitory amino acids
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 323–331
N-Benzyl-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyr-
log P Calculations
amide (6d)
The log P calculations were conducted on a Macintosh Power
PC using the ClogP 4.0 program[18] (Biobyte Corp., Claremont,
CA, USA).
Method A, yield 2.29 g, 71%; mp 140–142 °C; 1H-NMR (DMSO-
d6) δ 1.86 (m, 2 H, 2′-H), 2.17 (t, J = 7.3 Hz, 2 H, 3′-H), 3.58 (t,
J = 6.8 Hz, 2 H,1′-H), 4.19 (d, J = 6.0 Hz, 2 H, Bn-CH2), 7.25
(m, 5 H, Ar-H), 7.84 (m, 4 H, Ar-H), 8.27 (t, J = 5.6 Hz, 1 H, NH);
13C-NMR (DMSO-d6) δ 24.1, 32.7, 37.2, 38.3, 41.9, 122.9,
126.6, 127.1, 128.2, 131.7, 134.3, 139.5, 167.9, 171.2; MS m/z
(%) 322 [M+ + 1] (3), 294 (4), 277 (2), 238 (1), 216 (1) 188 (3),
160 (22), 149 (5), 130 (7), 106 (100), 91 (13), 79 (10);
C19H18N2O3 (322.36) C, H, N.
Pharmacology
Anticonvulsant testing was provided by the Antiepileptic Drug
Development Program, Epilepsy Branch, Division of Convul-
sive, Infectious and Immune Disorders, National Institutes of
Health, Rockville, MD, USA, according to standard proce-
dures[20] and included the maximal electroshock test and the
seizure threshold test with subcutaneous pentylenetetrazole.
The acute neurological toxicity was determined in the rotorod
test. For all these evaluations the compounds were dissolved
or suspended in 0.5% aqueous methyl cellulose.
2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethanesulfonic acid
benzylamide (9d)
Method B, yield: 3.2 g, 92%; mp 118 °C; 1H-NMR (CDCl3) δ 3.24
(t, J = 6.4 Hz, 2 H, NCH2), 3.98 (t, J = 6.4 Hz, 2 H, CH2SO2),
4.33 (d, J = 6.1 Hz, 2 H, CH2C6H5), 5.31 (t, J = 6.1 Hz, 1 H,
NH), 7.33 (m, 5 H, Ar-H), 7.75 (m, 2 H, Ar-H), 7.83 (m, 2 H,
Ar-H); 13C-NMR (CDCl3) δ 37.7, 47.3, 50.1, 123.6, 128.2, 129.0,
131.9, 134.3, 136.8, 168.1; MS (CI, ammonia) m/z (%) 362 [M
+ NH4]+ (100); C17H16N2O4S (344.40) C, H, N.
References
[1] T. W. Rall, L. S. Schleifer in The Pharmacological Basis of
Therapeutics, 8th ed., (Eds.: A. Goodman Gilman, T. W. Rall,
A. S. Nies, P. Taylor) Pergamon Press, New York, 1990, pp
436–462.
[2] R. J. Huxtable, Phys. Rev. 1992, 72, 101–163.
N-Benzyl-3-benzamidopropionamide-2-benzyl-carbox-
amide (7b)
[3] S. S. Oja, P. Kontro, I. B. Linden, G. Gothoni, Eur. J. Phar-
macol. 1983, 87, 191–198.
Method B, column chromatography yielded 0.8 g 5d (25%) and
2.7 g 7b (66%); mp 216–218 °C. 1H-NMR (DMSO-d6) δ 2.40
(t, J = 7.3 Hz, 2 H, 2′-H), 3.39 (m, 2 H, 1′-H), 4.26 (d , J = 6.0
Hz, 2 H, Bn-CH2), 4.40 (d, J = 6.0 Hz , 2 H, Bn-CH2), 7.35 (m,
14 H, Ar-H), 8.30 (t, J = 6.0 Hz, 1 H, NH), 8.43 (t, J = 6.0 Hz, 1
H, NH), 8.81 (t, J = 6.0 Hz, 1 H, NH); 13C-NMR (DMSO-d6) δ
35.1, 36.0, 42.0, 42.5, 107.1, 126.7, 127.1,127.2, 127.5, 127.6,
128.1, 128.2, 129.2, 129.3, 135.9, 136.4, 139.5, 168.1, 168.2,
170.4; MS m/z (%) 415 [M+] (4%), 309 (30), 281 (2), 237 (50),
219 (30), 202 (27), 178 (22), 160 (25), 130 (14), 106 (100),
91(55), 79 (26), 65 (12); C25H25N3O3 (415.49) C, H, N.
[4] I. B. Linden, G. Gothoni, P. Kontro, S. S. Oja, Neurochem.
Int. 1983, 5, 319–324.
[5] L. Andersen, S. O. Sundman, I. B. Linden, P. Kontro, S. S.
Oja, J. Pharm. Sci. 1984, 73, 106–108.
[6] K. Nakagawa, R. J. Huxtable, Neurochem. Int. 1985, 7,
819–824.
[7] K. Koivisto, J. Sivenius, T. Keränen, J. Partanen, P. Riek-
kinen, G. Gothoni, O. Tokola, P. J. Neuvonen, Epilepsia 1986,
27, 87–90.
[8] E. M. Airaksinen, K. Koivisto, T. Keränen, A. Pitkänen, P. J.
Riekkinen, S. S. Oja, K.-M. Marnela, J. V. Partanen, O.
Tokola, G. Gothoni, P. J. Neuvonen, M. M. Airaksinen, Epi-
lepsy Res. 1987, 1, 308–311.
N-Benzyl-4-benzamidobutyramide-2-benzyl-carboxamide
(8b)
Method B, column chromatography yielded 0.6 g 6d (19%) and
3.0 g 8b (70%); mp 152–153 °C; 1H-NMR ( DMSO-d6) δ 1.75
(m , 2 H, 2′-H), 2.21 (t, J = 7.2 Hz, 2 H, 3′-H), 3.18 (m, 2 H, 1′-H),
4.25 (d, J = 5.9 Hz, 2 H, Ph-CH2), 4.38 (d, J = 5.9 Hz, 2 H,
Ph-CH2), 7.26 (m, 10 H, Ar-H), 7.47 (m, 4 H, Ar-H), 8.29 (t, J =
5.6 Hz, 2 H, NH), 8.81 (t, J = 6.1 Hz, 1 H, NH); 13C-NMR
(DMSO-d6) δ 25.4, 32.8, 42.0, 42.4, 126.6, 127.1, 127.5, 128.1,
129.1, 129.3, 135.9, 136.6, 139.3, 139.6, 168.2, 171.9; MS m/z
(%) 429 [M+ ] (4), 411 (2) 338 (1), 323 (50), 281 (5), 237 (23),
216 (14) 192 (16), 176 (32), 160 (17), 130 (12), 118 (4), 106
(100), 91(90), 79 (16), 65 (10); C26H27N3O3 (429.52) C, H, N.
[9] W. Van Dorsser, D. Barris, A. Cordi, J. Roba, Arch. Int.
Pharmacodyn. Ther. 1983, 266, 239–249.
[10] G. Satzinger, Arzneim-Forsch./Drug Res. 1994, 44, 261–266.
[11] M. Geurts, J. H. Poupaert, G. K. E. Scriba, D. M. Lambert, J.
Med. Chem. 1998, 41, 24–30.
[12] Y. S. Andreichikov, V. V. Zalesov, N. A. Podushkina, Khim.
Farm. Zh. 1980, 14, 25–30.
[13] O. Abu Salach, S. Hadad, A. Haj-Yehia, S. Sussan M. Bialer,
Pharm. Res. 1994, 11, 1429–1434.
[14] S. Bhowmick, M. Pal, S. P. Pal, Ind. J. Exp. Biol. 1989, 27,
Lipophilicity
805–808.
[15] M. Habibuddin, M. Pal, S. P. Pal, Ind. J. Exp. Biol. 1992, 30,
log k0 Determinations
578–582.
The log k0 values were measured according to Bechalany[19]. The
HPLC system consisted of a Shimadzu LC 6A solvent delivery
module, a Shimadzu SPD 6A UV detector operated at 254 nm, and
a Shimadzu C-R6A integrator (Shimadzu AG, Duisburg, Ger-
many). The stationary phase was a LiChrospher 100 RP-18 col-
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50–90% water (v/v), the flow rate was 1 ml/min. The log k0 values
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