4-(Isoindolin-5-yl)amino-4-oxobutyryl-β-alkoxyphenyl-β-alanines, new RGDF mimetics. Synthesis, affinity to fibrinogen receptors, antiaggregatory properties, and their correlation with the hydrophobicity

Article abstract of DOI:10.1134/S1070428006080124

A new series of RGDF mimetics, derivatives of 4-(isoindolin-5-yl)amino-4- oxobutanoic acid, was synthesized. The compounds obtained inhibit efficiently the thrombocytes aggregation in experiments in vitro; their biological targets are fibrinogen receptors

Full text of DOI:10.1134/S1070428006080124

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 8, pp. 1174-1182. Ó Pleiades Publishing, Inc. 2006.
Original Russian Text Ó S.A. Andronati, A.A. Krys’ko, B.M. Chugunov, T.A. Kabanova, A.G. Artemenko, 2006, published in Zhurnal
Organicheskoi Khimii, 2006, Vol. 42, No. 8, pp. 1195 -1202.
4-(Isoindolin-5-yl)amino-4-oxobutyryl-b-alkoxyphenyl-b-alanines,
New RGDF Mimetics. Synthesis, Affinity to Fibrinogen Receptors,
Antiaggregatory Properties, and Their Correlation
with the Hydrophobicity
S.A.Andronati,A.A. Krys’ko, B.M. Chugunov, T.A. Kabanova, andA.G.Artemenko
Bogatskii Physicochemical Institute, National Academy of Sciences of Ukraine, Odessa, 6508 Ukraine
e-mail: peptides@paco.net
Received October 26, 2005
Abstract—A new series of RGDF mimetics, derivatives of 4-(isoindolin-5-yl)amino-4-oxobutanoic acid, was
synthesized. The compounds obtained inhibit efficiently the thrombocytes aggregation in experiments in vitro;
their biological targets are fibrinogen receptors. The antiaggregatory activity and the affinity correlate with the
hydrophobicity of the compounds.
DOI: 10.1134/S1070428006080124
The imitation of the d-guanidine group from the arginine
residue in designing the active and selective RGDF
mimetics, antagonists of the fibrinogen receptor aIIbb3, is
performed with the use of moieties containing residues
of p-benzamidine, piperidine, p-benzguanidine, etc. [1, 2].
The cited fragments may be regarded as bioisosteric to
the side function of the arginine residue. Two open-chain
RGDF mimetics were formerly synthesized based on
4-(isoindolin-5-yl)amino-4-oxobutanoic acid simulationg
the Arg–Gly site. They exhibited in vitro a high anti-
aggregatory activity and the affinity to aIIbb3 in a suspen-
sion of human thrombocytes subjected to ablution [4].
We report here on the synthesis of an RGDF mimetics
series containing asArg–Gly of the mimetic a residue of
the 4-(isoindolin-5-yl)amino-4-oxobutanoic acid and as
a substitute for the fragment Asp–Phe the residues of
b-alkoxyphenyl(or dialkoxyphenyl)-b-alanines.
The target of the research was the preparation of
potentially highly active antagonists of integrin aIIbb3
possessing an antiaggregatory activity, and the study of
relations between the structure and the properties of com-
pounds obtained. In particular, the effect of the lipophilicity
of the mimetics on their biological characteristics (the
affinity to aIIbb3 and the antiaggregatory activity) would
be estimated.
The search for efficient inhibitors of thrombocytes
aggregation is the line of research that gains the highest
momentum within the last decade aiming at solving the
problem of the thromboprophylaxis and thrombosis
treatment. The greatest attention is drawn to
antiaggregants, the antagonists of the fibrinogen receptors
(integrin aIIbb3). The integrin aIIbb3 is a glycoprotein
complex located on the surface of the activated thrombo-
cytes. The binding site in the fibrinogen for integrin aIIbb3
is the tripeptide sequence Arg–Gly–Asp (RGD in the
single-letter code). Quite a number of RGDF peptides,
RGDF pseudopeptides, and RGDF mimetics are known
now recognizing integrin aIIbb3 with a high affinity and
blocking these receptors. However the problem is far
from being solved [1]. Many aspects of the ligand-
receptor interaction and of the subsequent pharmaco-
logical (physiologic) consequences are unknown. It is
assumed [1] that to enter in an efficient interaction with
the aIIbb3 the RGDF mimetic should possess a basic and
an acidic site for binding with the receptor. The distance
between the sites in the ligand molecule should fall into
the range from 10 to 15 A [2]. The selective binding of
the antagonists to the aIIbb3 is likely to be favored by the
predominantly stretched conformation of the ligand. The
presence of a hydrophobic fragment in the linker between
the basic and acidic sites of the RGDF mimetic is regarded
as increasing its affinity to the receptor and consequently
as enhancing its antiaggregatory activity [3].
b-Alanines with various substituents attached to the
b-position are successfully employed in the synthesis of
1174

4-(ISOINDOLIN-5-YL)AMINO-4-OXOBUTYRYL-b-ALKOXYPHENYL-b-ALANINES
1175
Scheme 1.
2
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+%Uꢀꢀ+1
1
2
12
12
,
,,
1 + ꢀꢀ+ 2
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2
2
2
2
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1
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2+
ꢂ
ꢁ
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2
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1
+
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,,,
,9Dꢀꢁ,9E
n = 1 (a), 2 (b).
the RGDF mimetics, blockaders of the fibrinogen
receptors. The residue of the b-substituted b-alanine is
believed to imitate the site Asp–Phe [5]. An aromatic
substituent makes it possible to bind additionally the ligand
with aIIbb3, and the carboxy group of the b-alanine
simulates the side chain of the aspartic acid residue. To
reveal the effect of the hydrophobicity of bioisosteric sites
simulating the fragmentAsp–Phe on the antiaggregatory
characteristics of the RGDF mimetics we synthesized
compounds VII of essentially different hydrophobicity.
compounds both as dry substances and in water solutions
at the normal conditions. Compounds VII are well soluble
in water; that is important for in vitro experiments [4].
The structure of compounds obtained was confirmed
1
1
by their mass and H NMR spectra. In the H NMR
spectra of the compounds all the characteristic proton
signals were present with the appropriate integral
intensities. The electron-impact (ionizing voltage 70 eV)
mass spectra of compounds I–IV contained molecular
ion peaks of low intensity, and also fragment ions
corresponding to the primary degradation processes. We
failed to measure the electron-impact mass spectra of
V–VII due to the extensive thermal degradation. Com-
pounds V–VII are unstable with respect to the electron
impact (IM+· < 0.1%), and therefore we measured their
FAD mass spectra. In the FAD mass spectra we observed
ion peaks corresponding to [M + H]+ and [M + Na]+.
We used the 5-nitroisoindoline (I) as an initial com-
pound for designing the RGDF mimetics based on the
derivatives of 4-(isoindolin-5-yl)amino-4-oxobutanoic acid.
The blocking of the amino group in the 5-nitroisoindoline
(I), the reduction of the nitro group in the N-BOC-5-
nitroisoindoline (II) obtained followed by acylation of
amine III with succinic anhydride led to the formation of
4-(N-Boc-isoindolin-5-yl)-amino-4-oxobutanoic acid (IVa)
(Scheme 1) [4].
The RGDF mimetics synthesized, derivatives of the
4-(isoindolin-5-yl)amino-4-oxobutanoic acid, exhibited
a high antiaggregatory activity in vitro both on the human
blood serum rich in thrombocytes or on the suspension of
human thrombocytes subjected to ablution. The experi-
ments were carried out by Born method using blood
samples from three donors [6]. To reveal the molecular
mechanism of the antiaggregatory action of RGDF
mimetics VII we investigated their effect on the specific
binding of fluorescein-labeled fibrinogen (FITC-Fg) using
the suspension of human thrombocytes subjected to
ablution by procedure [7]. FITC-Fg prepared as described
in [8] is specifically bound to the receptors on the
thrombocytes with a dissociation constant 1.02 mmol.
Compounds VII inhibited the binding of FITC-Fg with
aIIbb3 on the suspension of human thrombocytes
subjected to ablution (see the table).
We formerly synthesized RGDF mimetics VIIa and
VIIb by condensation of acid IVa with the b-alanines
esters followed by the hydrolysis of ester groups in
compounds V and removing BOC-protection in the last
stage (method a) [4]. The application of a salt protection
on the N-components in the building-up of the RGDF
mimetics skeleton (method b) eliminated one reaction
stage and also gave compounds VI in high yields and of
high purity without chromatographic separation. We chose
for condensation of acid IVa with the b-alanines sodium
salts the procedure using mixed anhydrides (Scheme 2).
The condensation of the b-alanines with compound IVa
yielded protected mimetics VI, and the removal of the
BOC protection resulted in the target mimetics VII. The
RGDF mimetics obtained are chemically stable
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 8 2006

ANDRONATI et al.
1176
Scheme 2.
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5
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D
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5
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Characteristics of RGDF mimetics based on 4-(isoindolin-5-yl)amino-4-oxobutanoic acid
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 8 2006

4-(ISOINDOLIN-5-YL)AMINO-4-OXOBUTYRYL-b-ALKOXYPHENYL-b-ALANINES
1177
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Fig. 1. Mutual correlation of the IC50 values.
Fig. 2. Values of IC50 (SRT) as a function of lgP for mimetics VIIa–VIIk.
Note also that the values of IC50 for all three experi-
ments are in a sufficiently good correlation (Fig. 1).
effect of RGDF mimetics VIIa–VIIk on their activity
we calculated their distribution factors in a system water–
octanol (logP) by procedure [10] (see the table). The
biological activity was evaluated by the constants of the
half-inhibition of the thrombocytes aggregation in the in
vitro experiments with the use of the human blood serum
rich in thrombocytes, IC50 (SRT), on the suspension of
human thrombocytes subjected to ablution, IC50 (TS), and
the constant of the half-inhibition of FITC-Fg binding with
the fibrinogen receptor, IC50 (binding). The relation of
IC50 (SRT) values for compounds VIIa–VIIk to their
hydrophobicity (Fig. 2) estimated by means of the
regression analysis is expressed by equation (1). Likewise
for experiments with therombocytes suspension and for
inhibition of FITC-Fg binding with the fibrinogen receptors
equations (2) and (3) were respectively derived.
We formerly showed that introducing a phenyl into
the b-position of the b-alanine residue enhanced the
antiaggregatory activity of compound VIIb 3-fold, and
its affinity 2-fold. The presence of nonbranched alkoxy
substituents in the para-position of the phenyl group in
the b-alanine moiety of the RGDF mimetics (compounds
VIIc–VIIf) results in insignificant increase in the
antiaggregatory activity and affinity. The isoalkoxy
analogs, compounds VIIg–VIIi, proved to be more active
RGDF mimetics. The 3,4-dimethoxyphenyl substituent in
the b-position of the b-alanine residue (compound VIIj)
possessed virtually the same antiaggregatory activity and
affinity to the fibrinogen receptors as the phenyl-
substituted derivative VIIb. The derivative of 3-[5-(3,4-
methylenedioxyphenyl)]-b-alanine VIIk is distinguished
by a high antiaggregatory activity and affinity in the series
of RGDF mimetics VII.
IC50 (SRT) = 0.35 log P2 – 2.0 log P + 2.9 (R2 = 0.89)
IC50 (TS) = 0.36 log P2 – 1.7 log P + 2.2 (R2 = 0.95)
IC50 (binding) = 0.00097 log P2 – 0.0069 log P +
0.014 (R2 = 0.60)
(1)
(2)
Formerly QSAR investigation was successfully carried
out on antagonists of aIIbb3, derivatives of 4-(4-
amidinophenoxy)butanoyl-aspartyl-valine, applying a
hydrophobic descriptor, the logarithm of the micelle-water
distribution factor [9]. To estimate the hydrophobicity
(3)
The antiaggregatory activity and affinity of the RGDF
mimetics we synthesized are comparable or higher than
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 8 2006

ANDRONATI et al.
1178
the characteristics of the known RGDF mimetics contain-
ing a p-benzamidine group as a bioisoester structure of
the arginine side function. It should be emphasized that
among the b-(p-alkoxyphenyl)-b-alanines the best isoester
structure for the fragment Asp–Phe of the RGDF
sequence proved to be the b-(p-isopropoxyphenyl)-b-
alanine residue. The derivative of the b-(p- isopropoxy-
phenyl)-b-alanine and 4-(isoindolin-5-yl)amino-4-oxo-
butanoyl VIIh exhibited the maximum antiaggregatory
activity and affinity to the aIIbb3 receptors on the surface
of the human thrombocytes subjected to ablution. The
promising prospects of looking for RGDF mimetics among
new derivatives of 5-(isoindolin-5-yl)amino-5-oxo-
pentanoic acid as potential highly active antagonists for
aIIbb3 receptors also should be noted.
The experimental data on the antiaggregatory activity
and inhibition of FITC-Fg binding with the fibrinogen
receptors indicate that the new RGDF mimetics based
on 4-(isoindolin-5-yl)amino-4-oxobutanoic acid and
b-alkoxyphenyl-substituted b-alanines may be regarded
as highly active inhibitors of the thrombocytes aggregation
and as antagonists of the aIIbb3 receptors.
oily residue obtained was recrystallized from hexane.
Yield 94%, Rf 0.61 (A), mp 159–162°C. 1H (DMSO-d6),
d, ppm: 1.47 s (9H), 4.67 s (4H), 7.59 d.d (1H,
J 2.5, 8.4 Hz), 8.18 d.d (1H, J 1.9, 8.4 Hz), 8.23 s (1H).
Mass spectrum, m/z: 265 [M + H].
4-(N-Boc-isoindolin-5-yl)amino-4-oxobutanoic
acid (IVa). In dioxane was dissolved 5 g (18.9 mmol) of
compound II. To the solution obtained 0.3 g Pd (3%) on
carbon was added. Then to this suspension was added
dropwise at 60°C 9.4 ml (18.9 mmol) of 50% hydrazine
hydrate solution, the reaction mixture was stirred at the
same temperature till the gas liberation ceased. Then the
solvent was evaporated in a vacuum. The oily residue
was dried for 3 h at 60°C (3 mm Hg). The residue was
dissolved in 50 ml of chloroform. To the solution of
compound III obtained was added a solution of 1.96 g
(18.9 mmol) of succinic anhydride in 30 ml of chloroform,
the mixture was boiled for 30 min and left standing for
6 h at room temperature. The separated precipitate was
filtered off, washed with 30 ml of chloroform, and dried
at 60°C. Yield 72%, Rf 0.6 (C), mp 205–207°C. 1H NMR
spectrum (DMSO-d6), d, ppm: 1.49 s (9H), 2.62–2.70 m
(4H), 4.58 d.d (4H, J 5.9, 10.0 Hz), 7.26 d.d (1H, J 4.8,
9.1 Hz), 7.53 d (1H, J 9.1 Hz), 7.75 d (1H, J 9.1 Hz),
10.12 s (1H). Mass spectrum, m/z: [M + H] 335.
EXPERIMENTAL
1H NMR spectra were registered on a spectrometer
Varian WXP-300 at operating frequency 299.95 MHz
using tetramethylsilane as internal reference. Mass
spectra FAB were measured on VG 7070 instrument
applying glycerol matrix, ionization with a Xe atoms beam
of 8 kW energy. TLC was carried out on Silufol (Kavalier,
Czechia) and Kieselgel 60 plates (Merck, Germany) in
solvent systems: 10% ethyl acetate solution in hexane
(A), benzene–acetone–acetic acid, 100:50:1 (B), chloro-
form–ethyl acetate–methanol, 9:3:2 (C), ammonia–
dioxane, 1:5 (D). Spots were visualized with ninhydrin
and chlorotoluidine reagents.
5-(2-BOC-isoindolin-5-yl)amino-5-oxopentanoic
acid (IVb) was prepared similarly. Yield 89%, Rf
1
0.73 (C), mp 122–125°C. H NMR spectrum (DMTA-
d7), d, ppm: 1.45 s (9H), 1.80 m (2H), 2.27 t (2H,
J 7.4 Hz), 2.35 t (2H, J 7.4 Hz), 4.53 t (4H, J 8.1 Hz),
7.22 d.d (1H, J 4.0, 8.2 Hz), 7.38–7.45 m (1H), 7.63 d
(1H, J 19.0 Hz), 9.94 s (1H), 12.09 s (1H). Mass
spectrum, m/z: 349 [M + H].
N-[4-(N-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-b-alanine methyl ester (Va). To a suspension of
1 g (2.99 mmol) of compound IVa in chloroform was
added 0.9 ml (6.58 mmol) of triethylamine. The mixture
was cooled to –12°C, and isobutyl chloroformate was
added thereto. The stirring continued for 30 min at –10°C.
Then 0.459 g (3.29 mmol) of b-alanine methyl ester
hydrochloride was added, the reaction mixture was stirred
for 15 min at –10°C and 1 h at room temperature. The
reaction mixture was diluted with 100 ml of chloroform,
washed in succession with 50 ml of 1 M HCl solution,
50 ml of 5% NaHCO3 solution, and 50 ml of water. The
organic layer was dried with anhydrous Na2SO4. The
drying agent was filtered off, the solvent was evaporated
on the rotary evaporator. Yield 78%, Rf 0.45 (B), mp
N-tert-Butyloxycarbonyl-5-nitroisoindoline (II).
A suspension was prepared of 1 g (4.08 mmol) of
5-nitroisoindoline hydrobromide in 10 ml of 5% Na2CO3
solution. To the suspension a solution of 0.873 g (4 mmol)
of di-tert-butyl pyrocarbonate in 30 ml of chloroform was
added. The reaction mixture was stirred for 5 h at room
temperature, then it was diluted with 50 ml of chloroform.
The organic layer was separated, the water layer was
extracted with chloroform (2´50 ml). The combined
organic solutions were washed in succession with 50 ml
of 1 M HCl solution and with water, then dried with
anhydrous Na2SO4. The drying agent was filtered off,
the solvent was evaporated on the rotary evaporator. The
1
145–148°C. H NMR spectrum (DMF-d7), d, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 8 2006

4-(ISOINDOLIN-5-YL)AMINO-4-OXOBUTYRYL-b-ALKOXYPHENYL-b-ALANINES
1179
1.49 s (9H), 2.50–2.56 m (4H), 2.66 t (2H, J 6.8 Hz),
3.41 q (2H, J 6.8 Hz), 3.63 s (3H), 4.58 d.d (4H, J 6.3,
9.8 Hz), 7.26 d.d (1H, J 4.8, 8.7 Hz), 7.53 d (1H,
J 8.7 Hz), 7.75 d (1H, J 8.7 Hz), 8.00 t (1H, J 5.6 Hz),
10.08 s (1H). Mass spectrum, m/z: 420 [M + H].
was diluted with water, acidified with with 1 M HCl
solution till acidic reaction, and the reaction product was
extracted into chloroform (3´50 ml). The combined
organic solutions were washed with water (30 ml) and
dried with anhydrous Na2SO4. The drying agent was
filtered off, the solvent was evaporated on the rotary
evaporator. The oily residue was ground with ether. Yield
82%.
N-[4-(N-Boc-isoindolin-5-yl)amino-4-oxo-
butyryl]-b-phenyl-b-alanine methyl ester (Vb) was
prepared analogously. Yield 82%, Rf 0.52 (B), oily
1
substance. H NMR spectrum (DMSO-d6), d, ppm:
Likewise were prepared compounds VIb–VIl.
1.45 s (9H), 2.41–2.57 m (4H), 2.73–2.77 m (2H), 3.55 s
(3H), 4.53 t (4H, J 7.3 Hz), 5.22 q (1H, J 7.8 Hz), 7.19–
7.33 m (6H), 7.40 d.d (1H, J 1.4, 8.4 Hz), 7.61 d (1H,
J 19.6 Hz), 8.47 d (1H, J 8.4 Hz), 9.97 s (1H). Mass
spectrum, m/z: 496 [M + H].
N-[4-(N-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-D,L-b-phenyl-b-alanine (VIb). Yield 77%.
N-[4-(2-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-D,L-b-(p-methoxyphenyl)-b-alanine (VIp). Yield
1
75%, Rf 0.70 (C), mp 155–160°C. H NMR spectrum
N-[4-(N-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-b-alanine (VIa). (a) In 30 ml of ethanol was dissolved
0.5 g (1.19 mmol) of compound Va, and to the solution
obtained 1 ml of 1 M NaOH solution was added. The
mixture was stirred for 1 h at room temperature, then it
was poured into water, acidified with 1 M HCl solution
till acidic reaction, and the reaction product was extracted
into chloroform (3´50 ml). The combined organic solutions
were washed with water and dried with anhydrous
Na2SO4. The drying agent was filtered off, the solvent
was evaporated on the rotary evaporator. The residue
obtained was ground with anhydrous ethyl ether. Yield
(DMSO-d6), d, ppm: 1.49 s (9H), 2.54–2.68 m (4H),
2.78–2.86 m (2H), 3.76 s (3H), 4.58 t (4H, J 7.4 Hz),
5.32 q (1H, J 7.6 Hz), 6.87 d (1H, J 8.7 Hz), 7.25 d.d
(1H, J 5.0, 8.1 Hz), 7.33 d (1H, J 8.7 Hz), 7.51 d (1H,
J 8.1 Hz), 7.71 d (1H, J 8.1 Hz), 8.37 d (1H, J 7.6 Hz),
10.06 s (1H). Mass spectrum, m/z: 512 [M + H].
N-[4-(2-Boc-isoindolin-5-yl)amino-4-oxo-
butyryl]-D,L-b-(p-ethoxyphenyl)-b-alanine (VId).
Yield 74%, Rf 0.69 (C), mp 205–210°C. 1H NMR spec-
trum (DMSO-d6), d, ppm: 1.32 t (3H, J 7.0 Hz), 1.49 s
(9H), 2.53–2.67 m (4H), 2.77–2.86 m (2H), 3.99 q (2H,
J 7.0 Hz), 4.57 t (4H, J 6.5 Hz), 5.31 q (1H, J 7.8 Hz),
6.84 d (2H, J 8.7 Hz), 7.24–7.28 m (1H), 7.32 d (1H,
J 8.6 Hz), 7.52 d (1H, J 8.6 Hz), 7.72 (1H, J 8.1 Hz),
8.42 d (1H, J 8.4 Hz), 10.10 s (1H). Mass spectrum, m/
z: 526 [M + H], 548 [M + Na].
1
86%, Rf 0.70 (C), mp 142–148°C. H NMR spectrum
(DMF-d7), d, ppm: 1.49 s (9H), 2.47–2.56 m (4H),
2.67 t (2H, J 6.8 Hz), 3.40 q (2H, J 6.8 Hz), 4.58 d.d
(4H, J 6.7, 9.4 Hz), 7.26 m (1H), 7.53 d (1H, J 8.1 Hz),
7.75 d (1H, J 8.1 Hz), 7.97 t (1H, J 5.6 Hz), 10.10 s
(1H). Mass spectrum, m/z: 406 [M + H], 428 [M + Na].
N-[4-(2-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-D,L-b-(p-propoxyphenyl)-b-alanine (VIe). Yield
81%, Rf 0.77 (B), oily substance. Mass spectrum, m/z:
540 [M + H], 562 [M + Na].
N-[4-(N-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-b-phenyl-b-alanine (VIb) was obtained in the same
way. Yield 84%, Rf 0.81 (C), mp 138–141°C. 1H NMR
spectrum (DMF-d7), d, ppm: 1.49 s (9H), 2.57–2.69 m
(4H), 2.83 m (2H), 4.58 t (4H, J 6.1 Hz), 5.39 q (1H,
J 7.5 Hz), 7.21–7.45 m (6H), 7.53 d (1H, J 8.1 Hz),
7.72 d (1H, J 8.1 Hz), 8.46 d (1H, J 8.1 Hz), 10.07 s
(1H). Mass spectrum, m/z: 482 [M + H], 504 [M + Na].
N-[4-(2-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-D,L-b-(p-isopropoxyphenyl)-b-alanine (VIf).
1
Yield 78%, Rf 0.73 (C), mp 146–152°C. H NMR
spectrum (DMSO-d6), d, ppm: 1.25 d (6H, J 5.9 Hz),
1.49 s (9H), 2.54–2.68 m (4H), 2.78–2.87 m (2H), 4.54–
4.60 m (5H), 5.31 q (1H, J 7.5 Hz), 6.83 d (2H,
J 8.6 Hz,), 7.24–7.28 m (1H), 7.32 d (1H, J 8.6 Hz),
7.52 d (1H, J 8.4 Hz), 7.73 (1H, J 8.4 Hz), 8.41 d (1H,
J 8.1 Hz), 10.10 s (1H). Mass spectrum, m/z: 540 [M +
H], 562 [M + Na].
N-[4-(N-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-b-alanine (VIa). b. To a solution of 0.50 g (1.5 mmol)
of compound IVa in 5 ml of DMF cooled to –10°C was
added 0.21 ml (1.5 mmol) of triethylamine, then 0.2 ml
(1.5 mmol) isobutyl chloroformate. The reaction mixture
was stirred for 30 min at –10°C, then 0.19 g (1.7 mmol)
of b-alanine sodium salt was added. The mixture was
stirred for 30 min at –10°C, then 2 h more at room
temperature. On completion of the reaction the mixture
N-[4-(2-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-D,L-b-(p-butoxyphenyl)-b-alanine (VIg). Yield
1
80%, Rf 0.75 (C), oily substance. H NMR spectrum
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 8 2006

ANDRONATI et al.
1180
(DMSO-d6), d, ppm: 0.94 t (3H, J 7.5 Hz), 1.41–1.46 m
(2H), 1.49 s (9H), 1.65–1.74 m (2H), 2.54–2.67 m (4H),
2.77–2.85 m (2H), 3.94 t (2H, J 6.4 Hz), 4.57 t (4H,
J 6.5 Hz), 5.32 q (1H, J 7.4 Hz), 6.85 d (2H, J 8.7 Hz),
7.23–7.28 m (1H), 7.32 d (1H, J 8.6 Hz), 7.51 d (1H,
J 7.6 Hz), 7.72 (1H, J 7.61 Hz), 8.37 d (1H, J 8.1 Hz),
10.16 s (1H). Mass spectrum, m/z: 554 [M + H], 576
[M + Na].
4.55–4.60 m (4H), 7.24–7.28 m (1H), 7.74 d (1H,
J 6.5 Hz), 7.02 t (1H, J 5.0 Hz), 10.02 s (1H). Mass
spectrum, m/z: 420 [M + H], 442 [M + Na].
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-b-
alanine hydrochloride (VIIa). A suspension of 0.20 g
(0.49 mmol) of compound VIa in 10 ml of 4 M HCl solution
in dioxane was stirred for 1 h at room temperature and
then evaporated. The solid residue was dried for 5 h at
40°C (3 mm Hg). Yield 98%, Rf 0.60 (D), mp 197–200°C.
1H NMR spectrum (DMSO-d6), d, ppm: 2.35–2.41 m
(4H), 2.53–2.61 m (2H), 3.23 q (2H, J 6.2 Hz), 4.40–
4.48 m (4H), 7.29 d (1H, J 8.2 Hz), 7.48 d (1H,
J 8.2 Hz), 7.75 s (1H), 8.02 t (1H, J 4.7 Hz), 10.06 s
(2H), 10.22 s (1H). Mass spectrum, m/z: 306 [M + H],
328 [M + Na].
N-[4-(2-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-D,L-b-(p-isobutyloxyphenyl)-b-alanine (VIh).
1
Yield 74%, Rf 0.69 (B), mp 183–190°C. H NMR
spectrum (DMSO-d6), d, ppm: 0.98 d (6H, J 6.5 Hz),
1.49 s (9H), 1.94–2.06 m (1H), 2.54–2.70 m (4H), 2.78–
2.86 m (2H), 3.71 d (2H, J 6.2 Hz), 4.57 t (4H, J 6.5 Hz),
5.31 q (1H, J 7.5 Hz), 6.85 d (2H, J 8.5 Hz), 7.24–
7.28 m (1H), 7.32 d (1H, J 8.5 Hz), 7.52 d (1H,
J 8.1 Hz), 7.72 (1H, J 8.1 Hz), 8.42 d (1H, J 8.7 Hz),
10.10 s (1H). Mass spectrum, m/z: 554 [M + H], 576
[M + Na].
Likewise were synthesized compounds VIIb–VIIl.
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-
b-phenyl-b-alanine hydrochloride (VIIb). Yield 99%,
Rf 0.63 (D), mp 150–153°C. 1H NMR spectrum (DMSO-
d6), d, ppm: 2.42–2.56 m (4H), 2.6–2.69 m (2H), 4.40–
4.47 m (4H), 5.39 q (1H, J 7.3 Hz), 7.19–7.34 m (6H),
7.47 d (1H, J 8.1 Hz), 7.74 s (1H), 8.51 d (1H, J 8.1 Hz),
10.05 t (2H, J 5.4 Hz), 10.20 s (1H). Mass spectrum,
m/z: 382 [M + H], 404 [M + Na].
N-[4-(2-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-D,L-b-(p-isopentyloxyphenyl)-b-alanine (VIi).
Yield 73%, Rf 0.72 (C), oily substance. Mass spectrum,
m/z: 568 [M + H], 590 [M + Na].
N-[4-(2-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-D,L-b-(3,4-dimethoxyphenyl)-b-alanine (VIj).
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-
b-(p-methoxyphenyl)-b-alanine hydrochloride
(VIIc). Yield 95%, Rf 0.61 (D), hygroscopic substance,
mp 128–131°C. 1H NMR spectrum (DMSO-d6), d, ppm:
2.39–2.45 m (2H), 2.51–2.56 m (2H), 2.63 d.d (2H,
J 4.7, 7.6 Hz), 3.72 s (3H), 4.41–4.47 m (4H), 5.12 q
(1H, J 7.6 Hz), 6.84 d (1H, J 8.5 Hz), 7.23 d (1H,
J 8.5 Hz), 7.29 d (1H, J 8.3 Hz), 7.45 d (1H, J 8.3 Hz),
7.74 s (1H), 8.38 d (1H, J 8.1 Hz), 9.78 s (2H), 10.14 s
(1H), 12.19 br.s (1H). Mass spectrum, m/z: 412 [M + H],
434 [M + Na], 456 [M + 2Na – H].
1
Yield 76%, Rf 0.62 (C), mp 138–146°C. H NMR
spectrum (DMSO-d6), d, ppm: 1.49 s (9H), 2.52–2.69 m
(4H), 2.78–2.88 m (2H), 3.77 s (3H), 3.80 s (3H), 4.57 t
(4H, J 6.5 Hz), 5.33 q (1H, J 7.7 Hz), 6.86–6.94 m (2H),
7.06–7.09 m (1H), 7.23–7.27 m (1H), 7.51 d (1H,
J 8.5 Hz), 7.70 d (1H, J 8.5 Hz), 8.38 d (1H, J 8.4 Hz),
10.06 s (1H). Mass spectrum, m/z: 542 [M + H], 564
[M + Na].
N-[4-(2-Boc-isoindolin-5-yl)amino-4-oxobutyr-
yl]-D,L-b-(3,4-methylenedioxyphenyl)-b-alanine
(VIk). Yield 76%, Rf 0.63 (B), mp 129–132°C. 1H NMR
spectrum (DMSO-d6), d, ppm: 1.49 s (9H), 2.54–2.70 m
(4H), 2.78–2.87 m (2H), 4.57 t (4H, J 6.5 Hz), 5.14 q
(1H, J 7.6 Hz), 6.02 s (2H), 6.79–6.90 m (2H), 6.99 s
(1H), 7.23–7.27 m (1H), 7.51 d (1H, J 7.8 Hz), 7.72 d
(1H, J 7.8 Hz), 8.38 d (1H, J 8.4 Hz), 10.05 s (1H).
Mass spectrum, m/z: 526 [M + H], 548 [M + Na].
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-
b-(p-ethoxyphenyl)-b-alanine hydrochloride (VIId).
1
Yield 96%, Rf 0.63 (D), mp 121–127°C. H NMR
spectrum (DMSO-d6), d, ppm: 1.30 t (3H, J 6.7 Hz),
2.36–2.44 m (2H), 2.54–2.66 m (4H), 3.97 q (2H,
J 6.7 Hz), 4.40–4.46 m (4H), 5.12 q (1H, J 7.5 Hz),
6.82 d (2H, J 8.4 Hz), 7.20 d (2H, J 8.4 Hz), 7.28 d (1H,
J 8.2 Hz), 7.46 d (1H, J 8.2 Hz), 7.73 s (1H), 8.402 d
(1H, J 8.4 Hz), 9.99 s (2H), 10.18 s (1H). Mass spectrum,
m/z: 426 [M + H].
N-[5-(2-Boc-isoindolin-5-yl)amino-5-oxo-
pentanoyl]-b-alanine (VIl). Yield 68%, Rf 0.61 (C), mp
95–97°C. 1H NMR spectrum (DMF-d7), d, ppm: 1.49 s
(9H), 1.92 m (2H), 2.24 t (2H, J 7.3 Hz), 2.40 t (2H,
J 7.3 Hz), 2.48 t (2H, J 6.7 Hz), 3.40 q (2H, J 6.7 Hz),
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-
b-(p-propoxyphenyl)-b-alanine hydrochloride
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4-(ISOINDOLIN-5-YL)AMINO-4-OXOBUTYRYL-b-ALKOXYPHENYL-b-ALANINES
1181
(VIIe). Yield 94%, Rf 0.62 (D), hygroscopic substance.
1H NMR spectrum (DMSO-d6), d, ppm: 0.96 t (3H,
J 7.3 Hz), 1.64–1.76 m (2H), 2.39–2.45 m (4H), 2.64 t
(2H, J 6.0 Hz), 3.88 t (2H, J 6.4 Hz), 4.40–4.47 m (4H),
5.12 q (1H, J 7.6 Hz), 6.84 d (2H, J 8.4 Hz), 7.22 d (2H,
J 8.4 Hz), 7.30 d (1H, J 8.4 Hz), 7.44 C (1H), 8.39 d (1H,
J 8.4 Hz), 9.94 C (2H), 10.17 C (1H). Mass spectrum,
m/z: 440 [M + H].
7.46 d (1H, J 8.0 Hz), 7.74 s (1H), 8.37 d (1H, J 8.1 Hz),
9.92 s (2H), 10.15 s (1H). Mass spectrum, m/z: 468
[M + H].
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-
b-(3,4-dimethoxyphenyl)-b-alanine hydrochloride
(VIIj). Yield 95%, Rf 0.620 (D), mp 131–137°C. 1H NMR
spectrum (DMSO-d6), d, ppm: 2.40–2.46 m (2H), 2.52–
2.57 m (2H), 2.64 d (2H, J 7.6 Hz), 3.70 s (3H),
3.73 C (3H), 4.40–4.47 m (4H), 5.12 q (1H, J 7.6 Hz),
6.78–7.87 m (2H), 6.94 s (1H), 7.20 d (1H, J 8.1 Hz),
7.44 d (1H, J 8.1 Hz), 7.73 s (1H), 8.39 d (1H, J 8.4 Hz),
9.90 t (1H, J 4.5 Hz), 10.17 s (1H). Mass spectrum, m/z:
442 [M + H], 464 [M + Na], 486 [M + 2Na – H].
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-
b-(p-isopropoxyphenyl)-b-alanine hydrochloride
(VIIf). Yield 94%, Rf 0.62 (D), mp 150–152°C. 1H NMR
spectrum (DMSO-d6), d, ppm: 1.25 d (6H, J 6.0 Hz),
2.40–2.45 m (2H), 2.52–2.69 m (4H), 4.40–4.47 m (4H),
4.55 m (1H), 5.12 q (1H, J 7.3 Hz), 6.82 d (2H,
J 8.5 Hz), 7.20 d (2H, J 8.5 Hz), 7.30 d (1H, J 8.4 Hz),
7.46 d (1H, J 8.4 Hz), 7.74 s (1H), 8.39 (1H, J 8.1 Hz),
9.99 br.s (2H), 10.17 s (1H). Mass spectrum, m/z:
440 [M + H].
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-
b-(3,4-methylenedioxyphenyl)-b-alanine hydrochlo-
ride (VIIk). Yield 95%, Rf 0.70 (D), mp 135–138°C.
1H NMR spectrum (DMSO-d6), d, ppm: 2.39–2.44 m
(2H), 2.53–2.56 m (2H), 2.61–2.65 (2H), 4.40–4.47 m
(4H), 5.10 q (1H, J 7.7 Hz), 5.97 s (2H), 6.75–6.90 m
(3H), 7.29 d (1H, J 8.2 Hz), 7.45 d (1H, J 8.2 Hz), 7.74 s
(1H), 8.39 d (1H, J 9.0 Hz), 9.90 s (2H), 10.15 s (1H).
Mass spectrum, m/z: 426 [M + H].
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-
b-(p-butoxyphenyl)-b-alanine hydrochloride (VIIg).
Yield 92%, Rf 0.61 (D), hygroscopic substance. 1H NMR
spectrum (DMSO-d6), d, ppm: 0.92 t (3H, J 7.3 Hz),
1.35–1.47 m (2H), 1.62–1.71 m (2H), 2.39–2.43 m (2H),
2.52–2.55 m (2H), 2.60–2.68 m (2H), 3.91 t (2H, J 6.4
Hz), 4.41–4.46 m (4H), 5.12 q (1H, J 7.8 Hz), 6.84 d
(2H, J 8.7 Hz), 7.21 d (2H, J 8.7 Hz), 7.29 d (1H,
J 8.1 Hz), 7.45 d (1H, J 8.1 Hz), 7.73 s (1H), 8.41 d (1H,
J 8.1 Hz), 10.03 s (2H), 10.19 s (1H). Mass spectrum,
m/z: 454 [M + H].
N-[5-(isoindolin-5-yl)amino-5-oxopentanoyl]-b-
alanine hydrochloride (VIIl). Yield 93%, Rf 0.61 (D),
hygroscopic substance. 1H NMR spectrum (DMSO-d6),
d, ppm: 1.79 m (2H), 2.11 t (2H, J 7.3 Hz), 2.30–2.40 m
(4H), 3.23 q (2H, J 6.3 Hz), 4.40–4.48 m (4H), 7.29 d
(1H, J 8.4 Hz), 7.48 d (1H, J 8.4 Hz), 7.77 s (1H), 7.95 t
(1H, J 5.3 Hz), 10.05 s (2H), 10.16 s (1H). Mass spec-
trum, m/z: 320 [M + H].
N-[4-(isoindolin-5-yl)amino-4-oxobutyryl]-D,L-b-
(p-isobutyloxyphenyl)-b-alanine hydrochloride
(VIIh). Yield 95%, Rf 0.76 (D), mp 133–136°C. 1H NMR
spectrum (DMSO-d6), d, ppm: 0.92 d (6H, J 6.5 Hz),
1.91–2.05 m (1H), 2.39–2.45 m (2H), 2.52–2.72 m (4H),
3.70 d (2H, J 6.5 Hz), 4.41–4.48 m (4H), 5.12 q (1H,
J 7.5 Hz), 6.85 d (2H, J 8.4 Hz), 7.22 d (2H, J 8.4 Hz),
7.29 d (1H, J 8.3 Hz), 7.46 d (1H, J 8.3 Hz), 7.74 s (1H),
8.39 d (1H, J 8.1 Hz), 10.01 s (2H), 10.17 s (1H). Mass
spectrum, m/z: 454 [M + H].
The study was carried out under a financial support of
the Stata Foundation of The Ministry of Science and
Education of the Ukraine (contract no. F7/225-2001 of
July 30, 2001).
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