Physiologically active bis(dialkylamides) of phosphoryl-substituted α,ω-dicarboxylic acids

Article abstract of DOI:10.1134/S1070363213010076

Bis(dialkylamides) of phosphoryl-substituted α,ω-dicarboxylic acids were synthesized and their biological activity was studied.

Full text of DOI:10.1134/S1070363213010076

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 1, pp. 41–45. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © A.N. Yarkevich, Z.V. Safronova, L.N. Petrova, A.V. Gabrelyan, V.L. Zamoyski, V.V. Grigor’ev, S.O. Bachurin, N.S. Zefirov, 2013,
published in Zhurnal Obshchei Khimii, 2013, Vol. 83, No. 1, pp. 46–50.
Physiologically Active Bis(dialkylamides)
of Phosphoryl-Substituted α,ω-Dicarboxylic Acids
A. N. Yarkevich, Z. V. Safronova, L. N. Petrova, A. V. Gabrelyan, V. L. Zamoyski,
V. V. Grigor’ev, S. O. Bachurin, and N. S. Zefirov
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
Severnyi proezd 1, Chernogolovka, Moscow oblast, 142432 Russia
e-mail: yarkevic@ipac.ac.ru
Received December 13, 2011
Abstract—Bis(dialkylamides) of phosphoryl-substituted α,ω-dicarboxylic acids were synthesized and their
biological activity was studied.
DOI: 10.1134/S1070363213010076
Glutamatergic neuromediator system plays an
important role in the central nervous system both for
the normal development of neurophysiological
processes (signaling, memory consolidation, cognitive
functioning) and in the pathogenesis of several
neurodegenerative diseases. The system includes a
family of eight types of metabotropic glutamate
receptors (mGluR1 to mGluR8) from a group of 3G-
protein-coupled receptors (GPCRs), and a family of
three types of ligand-operated ionotropic receptors,
namely NMDA (N-methyl-D-aspartate), AMPA [2-
amino-3-(3-hydroxy-5-methylisoxazole-4-yl)propionic
acid] and kainate (KA, kainic acid) receptors [1–3].
Although a large number of compounds are known that
are active against these receptors [4], the search for
new, especially highly selective receptor agonists and
antagonists is an important task in the problem of
treating neurodegenerative diseases.
In this paper we synthesized and studied
phosphoryl-substituted bis(dialkylamides) of 1,4-dicar-
boxylic acids (I, II) and 2,8-bis(diphenylphosphinoyl)-
substituted nonane-1,9-dioic acid bis(dibutylamide)
(III).
O
O
R2
N R2
Ph
Ph
O
O
Bu
R1
R1
R1
R1
P
P
Ph
P
N Bu
P
Ph
Bu
O
Bu
R2
Bu
N
N
R2
O
N
O
N
O
Bu
Bu
O
O
II
Bu
I
III
I, R1 = Et (а), Bu (b), Ph (c), 2-CH3C6H4 (d), 2,5-(СН3)2C6H3 (e), 4-(CH3)2NC6H4 (f), 4-ClC6H4 (g), 4-CH3OC6H4 (h);
II, R2 = Et, R1 = Ph (a), R2 = Bu, R1 = 4-CH3OC6H4 (b), 2,5-(СН3)2C6H3 (c).
The prerequisites for this choice were two factors.
First, derivatives of 1,4-dicarboxylic acids demonstrate
different types of biological activity [5]. Second, based
on the concept of bioisosterism [6, 7], the introduction
of phosphorus-containing groups was expected to
improve the pharmacological properties of the leading
compounds.
Although we had previously described [8] the
synthesis of 2-(diphenylphosphinoyl)succinic acid 1,4-
bis(dibutylamide) Ic, the reaction conditions were not
optimized. The synthesis resulted in a mixture of
substances, requiring separation by column chromato-
graphy (yield 42%). In this paper we applied the same
method for the synthesis of compounds I and II, but
41

42
YARKEVICH et al.
the reaction was carried out under milder conditions
(40–80°C) and the results were acceptable.
The study of the ability of compounds to affect the
influx of calcium ions mediated by glutamate receptors
allowed us the estimation of their overall biological
potential as presumable neuroprotectors (in the case of
inhibition) or stimulants (in the case of activation) of
cognitive functions. For the preliminary evaluation of
biological activity of the synthesized compounds, we
have studied the effect of the substances on the
glutamate-induced calcium ion uptake using prepara-
tions of the synaptosomes of the rat brain cortex P2
fraction, which contains NMDA, kainate and meta-
botropic glutamate receptor of I type [9]. Probably,
glutamic acid activates all subtypes of glutamate
receptors of P2 fraction of the rat brain cortex synapto-
somes. In the primary screening of the compounds
their cumulative effect on all presynaptic glutamate
receptors present in the P2 fraction is determined.
Another convenient method commonly used for the
synthesis of α-phosphoryl-substituted monoamides IV
that consists in the direct amidation of the correspond-
ing esters of secondary amines, proved to be unsuitable
for the preparation of diamides of type I, II. Only the
ester group located in the α-position to the phosphoryl
substituent reacts readily, while the β-ethoxycarbonyl
remains unchanged even in the rigid conditions of the
reaction with an excess of amine: the reaction resulted
in a phosphoryl-substituted amidoether V:
O
O
Ph
Ph
Ph
Ph
Bu2NH
Et
P
P
O
N Bu
Bu
O
O
IV
Using other methods, it is possible to reveal the
subtypes of glutamate receptors that are affected by the
tested substances. In particular, the method of
radioligand binding to the NMDA receptors allows
quantifying the effect of compounds on the NMDA
receptors, which play a key role in the mechanisms of
neuroprotection and neurotoxicity.
O
O
O
Bu
Ph
Ph
Ph
Ph
4Bu2NH
P
N Bu
P
O Et
O
O
Et
O
O
Et
O
V
All the synthesized compounds were tested with respect
to their effect on glutamate receptors by two methods.
The table presents results demonstrating the effect
of structure of the synthesized compounds on the
Effect of compounds I–V on the 45Ca2+ uptake into synaptosomes of the rat cerebral cortex by stimulation with glutamate
(method a), and on the binding of [3H]MK-801 with NMDA receptors in the rat cerebral cortex (method b).
Method a
Method b
45Ca2+ uptake, % of control
(control is 100%) at 100 μM
Binding of [3H]MK-801, % of control
Comp. no.
IC50, μM
IC50, μM
(control is 100%) at 100 μM
101.7±6.3
0
–
–
–
Iа
44.7
14.1
9.3
18.6
7.9
4.8
17.0
–
100
–
Ib
Ic
0
100
–
6.6±3.3
7.7±6.4
0
42±6.2
25±4.1
38±5.5
61±6.8
74±6.9
–
21.37
22.91
61.47
79.08
90.82
–
Id
Ie
If
11.7±7.0
7.2±1.3
63.8±12
0
Ig
Ih
IIа
IIb
IIc
III
IV
V
15.5
5.1
12.6
–
67±6.0
29±2.7
25±2.2
–
65.74
44.31
17.25
–
4.9±4.9
1.9±0.4
77.2±11.4
96.2±2.9
–
–
–
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 1 2013

PHYSIOLOGICALLY ACTIVE BIS(DIALKYLAMIDES)
calcium ions uptake into the rat brain cortex
EXPERIMENTAL
43
synaptosomes (method a) and binding with NMDA
receptors (method b). Our own initial screening has
identified certain patterns of structure–biological
activity for the studied compounds.
1
The H and 31P NMR spectra were recorded on a
Bruker instrument CHR-200 (Germany), reference
Me4Si. Melting points were determined on a Boetius
PHMK heating table (Germany). Prior to the biological
research the substances were additionally purified by
recrystalliza-tion or by chromatography on an L
100/160 silica gel column, eluent chloroform, hexane–
isopropanol 10:1, and dried in a vacuum.
The compounds IV and V, which do not belong to
the series of diamides, show no appreciable biological
activity. In a series of phosphoryl-substituted 1,4-
dicarboxylic acids I, II bis-dialkylamides only 2 com-
pounds which have short alkyl substituents at either
phosphorus or nitrogen atom (Ia and IIa) show weak
net effect on glutamate receptors, and therefore were
excluded from further study. The compounds that had
Determination of the 45Ca2+ uptake into the rat brain
synaptosomes was performed according to the method
described in [9], the synaptosomes were obtained by
the standard Hajos method [10].
45
a significant inhibitory effect on the Ca2+ uptake into
The study of binding to the receptors of NMDA
subtypes was carried out by the method [11] with
modifications. We used the tritium-labeled MK-801
(dizocilpine) with specific activity 79 Ci mmol–1. The
membrane samples for the radioligand analysis were
prepared by the described method [12].
synaptosomes of the cerebral cortex were examined in
more detail to determine the concentration (IC50), at
which the 50% inhibition of the 45Ca2+ uptake into
synaptosomes occurred. The inhibitors were additio-
nally investigated by the radioligand b method to deter-
mine their binding to the glutamate receptors (NMDA
receptors) in the concentration range of 10–9 to
10–4 mol l–1 in vitro. The eight of the ten studied
substances showed comparable ability of compete
moderately with [3H]MK-801 in binding to the same
sites. From the results of inhibition IC50 values which
fall to the range 10–90 μM were calculated using
GraphPad Prism 4 Demo software.
The initial 1,4-dicarboxylic acids were obtained
from secondary phosphine oxides and 1,4-unsaturated
dicarboxylic acids by the method of [13] or by
acidification of salts [14], compounds III, IV were
synthesized by a known method [15]. The synthesis of
compounds I, II, V is given in this paper.
2-(Diethylphosphinoyl)succinic acid N1,N1,N4,N4-
tetrabutyldiamide (Ia). A solution of 1.25 g (0.003 mol)
of hexabutyltriamidophosphite (Bu2N)3P in 2 ml of
anhydrous benzene was added dropwise to a suspen-
sion of 1.00 g (0.0045 mol) of 2-(diethylphosphinoyl)-
succinic acid in 15 ml of anhydrous benzene, and the
mixture was heated for 1 h at mild boiling of the
solvent . The reaction mixture was washed with water
(3×7 ml), dried over Na2SO4, and the solvent was
removed in a vacuum. We obtained 1.95 g of
compound Ia, yield 98%. The product was purified by
chromatography on a column with silica gel L 100/160 μm.
Elution with chloroform afforded 1.78 g (89%) of
Inhibition of NMDA receptors significantly affects
the overall inhibition in the case of the compounds
containing alkyl and dimethylamino substituents in the
aromatic ring (compounds Id–If and IIc). The NMDA
receptors are inhibited significantly also by the bis-
phosphine oxide III whose amido groups are more
conformationally independent. In other cases the
contribution of NMDA receptor stimulation in the total
effect on the presynaptic glutamate receptors of the P2-
fraction is less significant (compounds Ig, Ih, IIb
containing Cl and MeO substituents at the aryl rings)
or zero (compounds Ib and Ic with the alkyl and
phenyl substituents at the phosphorus atom).
1
compound Ia as an oil. H NMR spectrum (CDCl3, δ,
ppm): 0.83–1.00 m (12H, 4CH3), 1.10–1.95 m (26H,
4CCH2CH2CN + CH3CH2PCH2CH3), 2.46 m, 1H and
3.15 m, 1H (CH2CP), 3.20–3.60 m (8H, 2CH2NCH2),
4.00 m (1H, CHP). 13C NMR spectrum (CDCl3, δ,
ppm): 5.92 d (CH3CH2P, JCP 5.6 Hz), 6.10 d
(CH3CH2P, JCP 5.6 Hz), 14.18 s, 14.25 s, 14.28 s
Summing up the results, we conclude that among
the investigated bis(dialkylamido)phosphoryl-substi-
tuted α,ω-dicarboxylic acids I–III substances are
found capable of simultaneously inhibiting several
types of glutamate receptors, as well as the substances
that act mainly on NMDA receptors, which means that
further study of this class of compounds as potential
neuroprotectors is quite promising.
2
2
(2CH3CH2CH2CH2NCH2CH2CH2CH3), 19.66 d (CH2P,
1JCP 65.8 Hz), 20.11 d (CH2P, JCP 65.8 Hz), 20.47 s,
1
20.49 s, 20.59 s, 20.75 s (2CH2CH2CH2NCH2·
CH2CH2), 30.00 s, 30,27 s, 31.11 s (2CH2CH2N·
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 1 2013

44
YARKEVICH et al.
2
CH2CH2), 31.53 d (CH2CHP, JCP 4.0 Hz), 39.95 d
[bis(2,5-dimethylphenyl)phosphinoyl]succinic acid.
We obtained 1.30 g of compound Ie, yield 95%, oil. 1H
NMR spectrum (CDCl3, δ, ppm): 0.82 m (12H, 4CH3),
1.20 m (8H, 4CCH2CCN), 1.36 m (8H, 4CCCH2CN),
2.22 s, 3H, 2.30 s, 6H, and 2.38 s, 3H (4CH3-Ar), 2.50
m, 1H and 3.50 m, 1H (CH2CP), 2.96 m (4H,
CH2NCH2) and 3.32 m (4H, CH2NCH2), 4.65 m (1H,
CHP), 7.10–7.60 m ( 6Harom.). 13C NMR spectrum (CDCl3,
δ, ppm): 14.13 s, 14.17 s, 14.40 s, 14.40 s (2CH3CH2·
CH2CH2NCH2CH2CH2CH3), 20.41 s, 20.51 s, 20.60 s,
20.70 s (2CH2CH2CH2NCH2CH2CH2), 30.04 s, 30.35
s, 30.49 s, 31.54 s (2CH2CH2NCH2CH2), 32.86 s
(CHP, 1JCP 55.5 Hz), 46.45 s, 47.01 s, 48.17 s, 49.14 s
2
(2CH2NCH2), 169.02 d [C(O)CHP, JCP 2.3 Hz],
169.78 d [C(O)CH2CHP, JCP 13.2 Hz]. 31P NMR
3
spectrum (CDCl3, δ, ppm): 53.08.
2-(Di-n-butylphosphinoyl)succinic acid N1,N1,N4,N4-
tetrabutyldiamide (Ib) was synthesized similarly to
compound Ia from 0.43 g (0.0012 mol) of (Bu2N)3P
and 0.33 g (0.0012 mol) of 2-(di-n-butylphosphinoyl)
succinic acid. We obtained 0.59 g of compound Ib,
1
yield 98%, mp 46°C. H NMR spectrum (CDCl3, δ,
ppm): 0.80 m (18H, 6CH3), 1.20–1.80 m (28H,
6CCH2CH2CN + CH2PCH2), 2.50 m, 1H and 4.00 m,
1H (CH2CP), 3.10–3.60 m (9H, 2CH2NCH2 + CHP).
31P NMR spectrum (CDCl3, δ, ppm): 50.60.
2-(Diphenylphosphinoyl)succinic acid N1,N1,N4,N4-
tetrabutyldiamide (Ic) was synthesized similarly to
compound Ia from 1.08 g (0.0026 mol) of (Bu2N)3P
and 0.96 g (0.0030 mol) of 2-(diphenylphosphinoyl)
succinic acid. We obtained 1.45 g of compound Ib,
1
(CH2CHP), 40.89 d (CHP, JCP 61.9 Hz), 46.48 s,
47.22 s, 48.23 s, 48.86 s (2CH2NCH2), 167.97 d
[C(O)CHP, 2JCP 3.3 Hz], 170.33 d [C(O)CH2CHP, 3JCP
14.8 Hz]. 31P NMR spectrum (CDCl3, δ, ppm): 38.05.
2-[Bis(4-dimethylaminophenyl)phosphinoyl]-
succinic acid N1,N1,N4,N4-tetrabutyldiamide (If) was
synthesized similarly to compound Ia from 0.83 g
(0.002 mol) of (Bu2N)3P and 0.97 g (0.0024 mol) of 2-
[bis(4-dimethylaminophenyl)phosphinoyl]succinic
acid. We obtained 1.25 g of compound Ic, yield 83%,
1
yield 90%, oil. H NMR spectrum (CDCl3, δ, ppm):
0.84 m (12H, 4CH3), 1.20 m (8H, 4CCH2CCN), 1.36
m (8H, 4CCCH2CN), 2.60 m, 1H and 3.00 m, 1H
(CH2CP), 3.16 m (8H, 2CH2NCH2), 4.32 m (1H,
CHP), 7.50 m (6Harom.), 7.86 m (2Harom.), 8.06 m
(2Harom.). 13C NMR spectrum (CDCl3, δ, ppm): 14.02 s,
14.12 s, 14.28 s, 14.31 s (2CH3CH2CH2CH2NCH2CH2·
CH2CH3), 20.28 s, 20.48 s, 20.54 s, 20.61 s (2CH2CH2·
CH2NCH2CH2CH2), 29.84 s, 30.27 s, 30.68 s, 31.27 s
(2CH2CH2N· CH2CH2), 32.86 s (CH2CHP), 42.56 d
(CHP, 1JCP 62.8 Hz), 46.46 s, 47.18 s, 48.11 s, 48.93 s
1
mp 92°C. H NMR spectrum (CDCl3, δ, ppm): 0.87 m
(12H, 4CH3), 1.25 m (8H, 4CCH2CC), 1.50 m (8H,
4CCCH2C) 2.60 m, 1H and 2.90 m, 1H (CH2CP), 3.00
s, (12H, 2CH3NCH3), 3.20 m (8H, 2CH2NCH2), 4.24
m (1H, CHP), 6.70 m (4Harom.), 7.72 m (4Harom.). 31P
NMR spectrum (CDCl3, δ, ppm): 33.44.
2-[Bis(4-chlorophenyl)phosphinoyl]succinic acid
N1,N1,N4,N4-tetrabutyldiamide (Ig) was synthesized
similarly to compound Ia from 0.83 g (0.002 mol) of
(Bu2N)3P and 0.97 g (0.0025 mol) of 2-[bis(4-chloro-
phenyl)phosphinoyl]succinic acid. We obtained 1.40 g
2
(2CH2NCH2), 168.48 d [C(O)CHP, JCP 2.2 Hz],
169.76 d [C(O)CH2CHP, JCP 15.2 Hz]. 31P NMR
3
1
spectrum (CDCl3, δ, ppm): 31.97.
of compound Ig, yield 92%, mp 60°C. H NMR
spectrum (CDCl3, δ, ppm): 0.86 m (12H, 4CH3), 1.20
m (8H, 4CCH2CCN), 1.40 m (8H, 4CCCH2CN), 2.65
m, 1H and 2.95 m, 1H (CH2CP), 3.08 m (4H,
CH2NCH2), 3.26 m (4H, CH2NCH2), 4.30 m (1H,
CHP), 7.45 m (4Harom.), 7.78 m (2Harom.), 8.10 m
(2Harom.). 13C NMR spectrum (CDCl3, δ, ppm): 14.03 s,
14.21 s, 14.34 s, 14.38 s (2CH3CH2CH2CH2NCH2CH2·
CH2CH3), 20.36 s, 20.54 s, 20.61 s, 20.64 s (2CH2CH2·
CH2NCH2CH2CH2), 29.83 s, 30.30 s, 31.01 s, 31.30 s
(2CH2CH2NCH2CH2), 33.02 s (CH2CHP), 43.00 d
(CHP, 1JCP 63.8 Hz), 46.55 s, 47.33 s, 48.14 s, 49.13 s
(2CH2NCH2), 168.65 d C(O)CHP, 2JCP 1.8 Hz], 169.32
2-[(2-Methylphenyl)phosphinoyl]succinic
acid
N1,N1,N4,N4-tetrabutyldiamide (Id) was synthesized
similarly to compound Ia) from 0.83 g (0.002 mol) of
(Bu2N)3P and 1.04 g (0.003 mol) of 2-[(2-methyl-
phenyl)phosphinoyl]succinic acid. We obtained 1.55 g
1
of compound Id, yield 91%, oil. H NMR spectrum
(CDCl3, δ, ppm): 0.94 m (12H, 4CH3), 1.28 m (8H,
4CCH2CCN), 1.44 m (8H, 4CCCH2CN), 2.48 s, 3H
and 2.56 s 3H (2CH3-Ar ), 3.04 m (4H, CH2NCH2) and
3.40 m (4H, CH2NCH2), 3.18 m, 1H and 3.62 m, 1H
(CH2CP), 4.72 m (1H, CHP), 7.10–7.90 m (8Harom.).
31P NMR spectrum (CDCl3, δ, ppm): 38.96.
3
d [C(O)CH2CHP, JCP 15.5 Hz]. 31P NMR spectrum
2-[Bis(2,5-dimethylphenyl)phosphinoyl]succinic
acid N1,N1,N4,N4-tetrabutyldiamide (Ie) was syn-
thesized similarly to compound Ia from 0.83 g
(0.002 mol) of (Bu2N)3P and 0.86 g (0.0023 mol) of 2-
(CDCl3, δ, ppm): 30.73.
2-[Bis(4-methoxyphenyl)phosphinoyl]succinic
acid N1,N1,N4,N4-tetrabutyldiamide (Ih) was
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 1 2013

PHYSIOLOGICALLY ACTIVE BIS(DIALKYLAMIDES)
45
synthesized similarly to compound Ia from 0.83 g
(0.002 mol) of (Bu2N)3P and 0.95 g (0.0025 mol) of 2-
[bis(4-methoxyphenyl)phosphinoyl]succinic acid. We
obtained 1.21 g of Ih, yield 81%, oil. 1H NMR
spectrum (CDCl3, δ, ppm): 0.83 m (12H, 4CH3), 1.18
m (8H, 2CCH2CH2C), 1.32 m (8H, 2CCH2CH2C) 2.58
m, 1H and 3.12 m, 1H (2H, CH2CP), 3.18 m (8H,
2CH2NCH2), 3.85 m (6H, 2CH3O), 4.26 m (1H, CHP),
6.95 m (4Harom.), 7.75 m (2Harom.), 7.96 m (2Harom.). 31P
NMR spectrum (CDCl3, δ, ppm): 31.96.
(0.02 mol) of Bu2NH was heated in an evacuated
ampule for 4 h at 180°C. The excess amine was
removed in vacuo, the residue was purified by
chromatography on a column, 1.98 g of compound V
was isolated, yield 73%, mp 38–40°C (ether–pentane).
1H NMR spectrum (CDCl3, δ, ppm): 0.84 m (6H,
2CH3), 1.18
t [3H, CH3C(O)], 1.24 m (8H,
2CCH2CH2CN), 2.84 m (2H, CH2CP) 3.20 m (4H,
CH2NCH2), 4.08 m [3H, CH2P+CH2C(O)], 7.50 m
(6Harom), 7.90 m (2Harom), 8.16 m (2Harom.) 31P NMR
spectrum (CDCl3, δ, ppm): 29.79.
2-(Diphenylphosphinoylmethyl)succinic
acid
N1,N1,N4,N4-tetraethyldiamide (IIa) was synthesized
similarly to compound Ia from 0.49 g (0.002 mol) of
(Et2N)3P and 0.65 g (0.002 mol) of 2-(diphenyl-
phosphinoylmethyl)succinic acid. We obtained 0.81 g
ACKNOWLEDGMENTS
The authors thank A. N. Pushin for recording and
discussing the NMR spectra, and S.V Mezentseva and
O.A. Dranyi for assistance in the radioligand studies.
1
of compound IIa, yield 91%, mp 116°C. H NMR
REFERENCES
spectrum (CDCl3, δ, ppm): 0.90–1.10 m (12H, 4CH3),
2.40–2.70 m and 2.85 m (4H, CH2P+CH2CO), 3.06–
3.42 m (8H, 2CH2NCH2), 3.60 m (1H, CHCP), 7.52 m
(6Harom.), 7.80 m (4Harom.). 31P NMR spectrum (CDCl3,
δ, ppm): 31.08.
1. Parsons, C.G., Danysz, W., and Quack, G., Drug News
Perspect., 1998, vol. 11, p. 523.
2. Nakanishi, N.S., Science, 1992, vol. 258, p. 31.
3. Zefirov, N.S. and Palyulin, V.A., Mendeleev Commun.,
2010, vol. 20, p. 243.
4. Zefirova, O.A. and Zefirov, N.S., Zh. Org. Khim., 2000,
vol. 36, no. 9, p. 1273.
5. Koz’minykh, V.O., Khim.-Farm. Zh., 2006, vol. 40, no. 1,
p. 9.
2-[Bis(4-methoxyphenyl)phosphinoylmethyl]-
succinic acid N1,N1,N4,N4-tetrabutyldiamide (IIb)
was synthesized similarly to compound Ia from 0.83 g
(0.002 mol) of (Bu2N)3P and 1.18 g (0.003 mol) of 2-
[bis(4-methoxyphenyl)phosphinoylmethyl]succinic
acid. We obtained 1.70 g of compound IIb, yield 92%,
6. Sheridan, R.P., J. Chem. Inf. Comput. Sci., 2002, vol. 42,
p. 103.
1
mp 65°C. H NMR spectrum (CDCl3, δ, ppm): 0.85 m
7. Meanwell, N.A., J. Med. Chem., 2011, vol. 54, p. 2529.
8. Turanov, A.N., Karandashev, V.K., Yarkevich, A.N.,
Safronova, Z.V., Kharitonov, A.V., Rodygina, N.I., and
Fedoseev, A.M., Radiokhimiya, 2004, vol. 46, no. 5,
p. 427.
(12H, 4CH3), 1.00–1.58 m (16H, 4CCH2CH2C), 2.24–
2.90 m (4H, CH2P+CH2CO), 3.20 m (8H, 2CH2NCH2),
3.56 m (1H, CHCP), 3.80 s (6H, 2CH3O), 6.90 m
(4Harom.), 7.68 m (4Harom.). 31P NMR spectrum (CDCl3,
δ, ppm): 31.38.
9. Petrova, L.N. and Bachurin, S.O., Byul. Eksp. Biol. i
Med., 2006, vol. 142, no. 7, p. 51.
2-[Bis(2,5-dimethylphenyl)phosphinoylmethyl]-
succinic acid N1,N1,N4,N4-tetrabutyldiamide (IIc)
was synthesized similarly to compound Ia from 0.83 g
(0.002 mol) of (Bu2N)3P and 0.78 g (0.002 mol) of 2-
[bis(2,5-dimethylphenyl)phosphinoylmethyl]succinic
acid. We obtained 1.04 g of compound IIb, yield 85%,
10. Hajos, F., Brain Res., 1975, vol. 93, no. 3, p. 485.
11. Zhou, L.-M., Gu, Z.-Q., Costa, A.M., Yamada, K.A.,
Mansson, P.E., Giordano, T., Skolnick, P., and Jones, K.A.,
J. Pharmacol. Exp. Ther., 1997, vol. 280, no. 1, p. 422.
12. Nowak, G., Trullas, R., Layer, R.T., Skolnick, P., and
Paul, I.A., J. Pharmacol. Exp. Ther., 1993, vol. 265,
p. 1380.
1
oil. H NMR spectrum (CDCl3, δ, ppm): 0.85 m (12H,
4CH3), 1.28 m (8H, 4CCH2CCN), 1.42 m (8H,
4CCCH2CN), 2.20 s, 2.22 s, 2.34 s and 2.36 s ( 12H,
4CH3-Ar), 2.60–3.00 m (4H, CH2P+CH2CO), 3.18 m
(4H, CH2NCH2), 3.58 m (1H, CHCP), 7.08 m (2Harom),
7.22 m (2Harom), 7.68 m ( 2Harom). 31P NMR spectrum
(CDCl3, δ, ppm): 32.28.
13. Yarkevich, A.N., Safronova, Z.V., Pushin, A.N.,
Bachurin, S.O., and Zefirov, N.S., Patent RU 2405789,
2010; Byul. Izobret., 2010, no. 34.
14. Yarkevich, A.N., Safronova, Z.V., Pushin, A.N.,
Bachurin, S.O., and Zefirov, N.S., Patent RU 2413733,
2011; Byul. Izobret., 2011, no. 7.
15. Turanov, A.N., Karandashev, V.K., Kharitonov, A.V.,
Lezhnev, A.N., Safronova, Z.V., Yarkevich, A.N., and
Tsvetkov, E.N., Zh. Obshch. Khim., 1999, vol. 69, no. 7,
p. 1109.
Ethyl N,N-dibutyl-3-(diphenylphosphinoyl) suc-
cinamate (V). A mixture of 1.87 g (0.005 mol) of
diethyl(2-diphenylphosphinoyl)succinate and 2.59 g
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