Synthesis and selectivity of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodi- azepin-2-ones binding for CNS benzodiazepine receptors
Earlier, the methoxycarbonylmethyl fragment at the 1-position and the nitrophenylamine fragment at the 3-position of the 1,4-benzodiazepine ring, on the base of the QSAR analysis of series of 1,4-benzodiazepin-2-one derivatives [1], have been shown to gave compounds with increased affinity for perip...
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Інститут молекулярної біології і генетики НАН України
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| Cite this: | Synthesis and selectivity of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodi- azepin-2-ones binding for CNS benzodiazepine receptors / N.A. Burenkova, V.I. Pavlovsky, I.A. Oleinich, I.A. Boyko, S.Yu. Makan, A.G. Artemenko, V.E. Kuz’min // Ukrainica Bioorganica Acta. — 2009. — Т. 7, № 1. — С. 8-15. — Бібліогр.: 44 назв. — англ. |
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Burenkova, N.A. Pavlovsky, V.I. Oleinich, I.A. Boyko, I.A. Makan, S.Yu. Artemenko, A.G. Kuz’min, V.E. 2010-03-29T12:45:59Z 2010-03-29T12:45:59Z 2009 Synthesis and selectivity of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodi- azepin-2-ones binding for CNS benzodiazepine receptors / N.A. Burenkova, V.I. Pavlovsky, I.A. Oleinich, I.A. Boyko, S.Yu. Makan, A.G. Artemenko, V.E. Kuz’min // Ukrainica Bioorganica Acta. — 2009. — Т. 7, № 1. — С. 8-15. — Бібліогр.: 44 назв. — англ. 1814-9758 https://nasplib.isofts.kiev.ua/handle/123456789/7369 Earlier, the methoxycarbonylmethyl fragment at the 1-position and the nitrophenylamine fragment at the 3-position of the 1,4-benzodiazepine ring, on the base of the QSAR analysis of series of 1,4-benzodiazepin-2-one derivatives [1], have been shown to gave compounds with increased affinity for peripheral benzodiazepine receptors (PBR). The 3-arylamine derivatives of 1-methoxycarbonylmethyl-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one were proposed for the directed synthesis as a promising high selective ligands of PBR. The target compounds were synthesized through the condensation of 1-methoxycarbonylmethyl-3-chloro-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one with substituted anilines. Affinities of synthesized compounds for the CNS benzodiazepine receptors of peripheral (PBR) and central (CBR) types were determined by the radioligand method in vitro. Selective PBR ligand with a high affinity — 1-methoxycarbonylmethyl-3-(2'-nitro)phenylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one, 7 (MX-1785, Ki(PBR)=19.1 nM, Ki(CBR)>10000 nM) was found among the studied compounds. Раніше на підставі результатів QSAR-аналізу ряду похідних 1,4-бенздіазепін-2-ону [1] було показано, що наявність метоксикарбонілметильного фрагменту в положенні 1 і нітрофеніламінного фрагменту в положенні 3 1,4-бенздіазепінового циклу сприяють прояву високого афінітету до периферичних бенздіазепінових рецепторів (ПБДР). Для цілеспрямованого синтезу були запропоновані 3-ариламінопохідні 1-метоксикарбонілметил-7-бром-5-феніл-1,2-дигідро-3Н-1,4-бенздіазепін-2-ону як перспективні високоафінні ліганди ПБДР. Конденсацією 1-метоксикарбонілметил-7-бром-3-хлор-5-феніл-1,2-дигідро-3Н-1,4-бенздіазепін-2-ону із заміщеними анілінами синтезовано цільові сполуки. Методом радіолігандного аналізу в експериментах in vitro вивчено афінітет синтезованих сполук до бенздіазепінових рецепторів ЦНС периферичного (ПБДР) і центрального (ЦБДР) типів. У ряді досліджених сполук виявлено високоафінний і селективний ліганд ПБДР — 1-метоксикарбонілметил-3-(2'-нітро)феніламіно-7-бром-5-феніл-1,2-дигідро-3Н-1,4-бенздіазепін-2-он, 7 (МХ-1785, Ki(ПБДР)=19,1 нМ, Ki(ЦБДР)>10000 нМ) en Інститут молекулярної біології і генетики НАН України Synthesis and selectivity of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodi- azepin-2-ones binding for CNS benzodiazepine receptors Синтез і селективність зв’язування з бенздіазепіновими рецепторами ЦНС 1-метоксикарбонілметил-3-ариламіно-7-бром-5-феніл-1,2-дигідро-3Н-1,4-бенздіазепін-2-онів Article published earlier |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| title |
Synthesis and selectivity of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodi- azepin-2-ones binding for CNS benzodiazepine receptors |
| spellingShingle |
Synthesis and selectivity of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodi- azepin-2-ones binding for CNS benzodiazepine receptors Burenkova, N.A. Pavlovsky, V.I. Oleinich, I.A. Boyko, I.A. Makan, S.Yu. Artemenko, A.G. Kuz’min, V.E. |
| title_short |
Synthesis and selectivity of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodi- azepin-2-ones binding for CNS benzodiazepine receptors |
| title_full |
Synthesis and selectivity of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodi- azepin-2-ones binding for CNS benzodiazepine receptors |
| title_fullStr |
Synthesis and selectivity of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodi- azepin-2-ones binding for CNS benzodiazepine receptors |
| title_full_unstemmed |
Synthesis and selectivity of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodi- azepin-2-ones binding for CNS benzodiazepine receptors |
| title_sort |
synthesis and selectivity of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1,2-dihydro-3h-1,4-benzodi- azepin-2-ones binding for cns benzodiazepine receptors |
| author |
Burenkova, N.A. Pavlovsky, V.I. Oleinich, I.A. Boyko, I.A. Makan, S.Yu. Artemenko, A.G. Kuz’min, V.E. |
| author_facet |
Burenkova, N.A. Pavlovsky, V.I. Oleinich, I.A. Boyko, I.A. Makan, S.Yu. Artemenko, A.G. Kuz’min, V.E. |
| publishDate |
2009 |
| language |
English |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| format |
Article |
| title_alt |
Синтез і селективність зв’язування з бенздіазепіновими рецепторами ЦНС 1-метоксикарбонілметил-3-ариламіно-7-бром-5-феніл-1,2-дигідро-3Н-1,4-бенздіазепін-2-онів |
| description |
Earlier, the methoxycarbonylmethyl fragment at the 1-position and the nitrophenylamine fragment at the 3-position of the 1,4-benzodiazepine ring, on the base of the QSAR analysis of series of 1,4-benzodiazepin-2-one derivatives [1], have been shown to gave compounds with increased affinity for peripheral benzodiazepine receptors (PBR). The 3-arylamine derivatives of 1-methoxycarbonylmethyl-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one were proposed for the directed synthesis as a promising high selective ligands of PBR. The target compounds were synthesized through the condensation of 1-methoxycarbonylmethyl-3-chloro-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one with substituted anilines. Affinities of synthesized compounds for the CNS benzodiazepine receptors of peripheral (PBR) and central (CBR) types were determined by the radioligand method in vitro. Selective PBR ligand with a high affinity — 1-methoxycarbonylmethyl-3-(2'-nitro)phenylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one, 7 (MX-1785, Ki(PBR)=19.1 nM, Ki(CBR)>10000 nM) was found among the studied compounds.
Раніше на підставі результатів QSAR-аналізу ряду похідних 1,4-бенздіазепін-2-ону [1] було показано, що наявність метоксикарбонілметильного фрагменту в положенні 1 і нітрофеніламінного фрагменту в положенні 3 1,4-бенздіазепінового циклу сприяють прояву високого афінітету до периферичних бенздіазепінових рецепторів (ПБДР). Для цілеспрямованого синтезу були запропоновані 3-ариламінопохідні 1-метоксикарбонілметил-7-бром-5-феніл-1,2-дигідро-3Н-1,4-бенздіазепін-2-ону як перспективні високоафінні ліганди ПБДР. Конденсацією 1-метоксикарбонілметил-7-бром-3-хлор-5-феніл-1,2-дигідро-3Н-1,4-бенздіазепін-2-ону із заміщеними анілінами синтезовано цільові сполуки. Методом радіолігандного аналізу в експериментах in vitro вивчено афінітет синтезованих сполук до бенздіазепінових рецепторів ЦНС периферичного (ПБДР) і центрального (ЦБДР) типів. У ряді досліджених сполук виявлено високоафінний і селективний ліганд ПБДР — 1-метоксикарбонілметил-3-(2'-нітро)феніламіно-7-бром-5-феніл-1,2-дигідро-3Н-1,4-бенздіазепін-2-он, 7 (МХ-1785, Ki(ПБДР)=19,1 нМ, Ki(ЦБДР)>10000 нМ)
|
| issn |
1814-9758 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/7369 |
| citation_txt |
Synthesis and selectivity of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodi- azepin-2-ones binding for CNS benzodiazepine receptors / N.A. Burenkova, V.I. Pavlovsky, I.A. Oleinich, I.A. Boyko, S.Yu. Makan, A.G. Artemenko, V.E. Kuz’min // Ukrainica Bioorganica Acta. — 2009. — Т. 7, № 1. — С. 8-15. — Бібліогр.: 44 назв. — англ. |
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8
Introduction. There are central (CBR) [2],
and peripheral (PBR) [3] benzodiazepine recep�
tors. CBR are presented exclusively in the cen�
tral nervous system. They are located at pre�
and postsynaptic membranes of neurons and
mediate the classic effects of benzodiazepines
[4]. PBR were initially discovered in the kidney
[5], then in many organs and tissues, including
the CNS [3]. Originally PBR were considered as
one of the CBR subtypes, but later they were
identified as an individual class of receptors due
to their unique structure, cell localization and
performance of physiological functions media�
ted by them [3, 6, 7]. Peripheral benzodiazepine
receptors are 5�transmembrane 169�amino acid
polypeptides with a molecular weight of 18 kDa,
which are localized mainly on the mitochondrial
outer membrane of peripheral tissues and glial
cells of the CNS [3, 6].
Recent years the results of studies have
shown that PBR are an important component of
the so�called mitochondrial permeability transi�
tion pore (MPTP) involved in regulation of ions
concentration, pH, and the volume of mitochon�
dria as well as in Ca2+ ions transfer [6, 8].
The exact physiological function of PBR is not
yet fully understood, but a wide range of phar�
macological activities, such as anticonvulsant,
anxiolytic, immunomodulating, and cardiovas�
cular, has been related to its activation [3, 7, 9].
In particular, there is growing number of
www.bioorganica.org.ua
Ukrainica Bioorganica Acta 1 (2009) 8—15
Synthesis and selectivity of 1�methoxycarbonylmethyl�3�
arylamino�7�bromo�5�phenyl�1,2�dihydro�3H�1,4�benzodi�
azepin�2�ones binding for CNS benzodiazepine receptors
N.A. Burenkova, V.I. Pavlovsky*, I.A. Oleinich, I.A. Boyko, S.Yu. Makan,
A.G. Artemenko, V.E. Kuz’min
A.V. Bogatsky Physico�Chemical Institute of the NAS of Ukraine
86 Lustdorfska doroga, Odesa, 65080, Ukraine
Summary. Earlier, the methoxycarbonylmethyl fragment at the 1�position and the nitrophenylamine frag�
ment at the 3�position of the 1,4�benzodiazepine ring, on the base of the QSAR analysis of series of 1,4�benzodi�
azepin�2�one derivatives [1], have been shown to gave compounds with increased affinity for peripheral benzo�
diazepine receptors (PBR). The 3�arylamine derivatives of 1�methoxycarbonylmethyl�7�bromo�5�phenyl�1,2�
dihydro�3H�1,4�benzodiazepin�2�one were proposed for the directed synthesis as a promising high selective li�
gands of PBR. The target compounds were synthesized through the condensation of 1�methoxycarbonylmethyl�
3�chloro�7�bromo�5�phenyl�1,2�dihydro�3H�1,4�benzodiazepin�2�one with substituted anilines. Affinities of
synthesized compounds for the CNS benzodiazepine receptors of peripheral (PBR) and central (CBR) types were
determined by the radioligand method in vitro. Selective PBR ligand with a high affinity — 1�methoxycar�
bonylmethyl�3�(2'�nitro)phenylamino�7�bromo�5�phenyl�1,2�dihydro�3H�1,4�benzodiazepin�2�one, 7 (MX�
1785, Ki(PBR)=19.1 nM, Ki(CBR)>10000 nM) was found among the studied compounds.
Keywords: 1,3�substituted 1,2�dihydro�3H�1,4�benzodiazepin�2�ones, affinity, benzodiazepine receptors,
selectivity, QSAR analysis.
* Corresponding author.
Tel.: +38048�7659230; fax: +38048�7659602
E�mail address: Victor_pavlovsky@mail.ru
© N.A. Burenkova, V.I. Pavlovsky, I.A. Oleinich, I.A. Boyko,
S.Yu. Makan, A.G. Artemenko, V.E. Kuz’min, 2009
experimental evidence that high affinity PBR
ligands stimulate the synthesis of neurosteroids
in glial cells. PBR mediate the delivery of choles�
terol to the inner mitochondrial membrane
where it is oxidized by cytochrome P450scc (scc
— side chain cleavage) to pregnenolone — par�
ent compound of endogenous steroids [6�11]. So�
me neurosteroids [pregnenolone sulfate, 3α,21�
dihydroxy�5α�pregnan�20�one (3α,5α�THDOC),
3α�hydroxy�5α�pregnan�20�one (3α,5α�THPROG),
and dehydroepiandrosterone] are known to
modulate GABAergic and glutamatergic neuro�
transmission [8, 11�13]. Numerous studies show
that such neuropatologic states as multiple scle�
rosis, Wernicke’s encephalopathy, Alzheimer’s
disease, Huntington’s disease, epilepsy, stroke
and stress are associated with the PBR expres�
sion [3, 7, 11, 14�16]. The highest PBR density is
observed in many tumor types such as brain,
hepatic, liver glial, and mammary tumors, ade�
nocarcinoma, breast carcinoma, and ovarian,
and colorectal cancers — all of them have
showed a selective increase in PBR density com�
pared with non�transformed tissue [17, 18]. In
some cases the grade of PBR over�expression
appears to be correlated with the malignancy of
the tumor and mortality of patients [18, 19].
PBR�specific ligands are considered both as
new intracellular targets of action [20] of radio�
logical diagnostic imaging agents [21] and recep�
tor�mediated drug carriers [22, 23], which can
selectively deliver anticancer agents into tumors
[24, 25]. The development of new strategies for
molecular design and synthesis of high affinity
and selective PBR ligands with a given pharma�
cological properties is the top issue for medical
and bioorganic chemistry, experimental and
clinical medicine.
There are several classes of PBR ligands
available including 1,4�benzodiazepines (Ro 5�
4864 [26]; gidazepam, MX�633 [27]), isoquinoline
carboxamides (PK 11195) [28], 2�aryl�3�indol�
acetamides (FGIN�1�27) [29], N�phenoxyphe�
nyl�N�isopropoxybenzylacetamides (DAA1097)
[30], pyrrolobenzoxazepines (OXA�17f) [31], 1,3,4�
benzotriazepines (MX�1189) [32] and some others
(Fig. 1).
We have conducted the search for selective
highly active PBR ligands among 1� and 3�substi�
tuted derivatives of 1,2�dihydro�3H�1,4�benzodi�
azepin�2�one. Earlier [27], we studied affinity of
gidazepam (MX�633) for CBR and PBR. Gidaze�
pam has an original range of pharmacological
activity and demonstrated a prominent anxiolytic
effect with poor myorelaxant and hypnotic side
effects [33]. The results of the radioligand bin�
ding analysis showed [27] that gidazepam has a
3�fold higher affinity for PBR than for CBR; IC50
values are of 710 nM and 2200 nM, respectively.
Our data demonstrate that substitutions of
bromine atom at the 7�position of the gidazepam
template either with a chlorine atom or a methyl
group led to the decrease in affinity for PBR.
The substitution of the hydrazine fragment with
methoxy group and the presence of (2'�chlo�
ro)phenyl substituent at the 5�position of the
benzodiazepine ring contributed to an unexpec�
ted increase in affinity for PBR [27].
We have reported earlier [34], that some of 3�
arylidene�7�bromo�5�(2'�chloro)phenyl�1,2�
dihydro�3H�1,4�benzodiazepin�2�ones are sele�
ctive PBR ligands. A selective PBR ligand 3�(4'�
chloro)benzylidene�7�bromo�5�(2'�chloro)phe�
nyl�1,2�dihydro�3H�1,4�benzodiazepin�2�one
(MX�1735) is especially interesting among these
ligands. We have shown that the presence of
either chlorine or bromine atom in a para�posi�
tion of the 3�benzylidene fragment plays a cru�
cial role in the manifestation of selectivity and
affinity for PBR versus CBR.
Later, in [1] we have reported the results of
QSAR analysis of 1� and 3�substituted 1,2�dihyd�
ro�3H�1,4�benzodiazepin�2�ones with the use of
the method of simplex representation of molecu�
lar structure [35, 36] and the «Dragon» program
[37, 38]. Based on the interpretation of obtained
highly adequate models, it was found that the
presence of methoxycarbonylalkyl group at the 1�
Synthesis of 1�methoxycarbonylmethyl�3�arylamino�7�bromo�5�phenyl�1,2�dihydro�3H�1,4�benzodiazepin�2�ones
9www.bioorganica.org.ua
N
N
CH3 O
Cl
Cl
N
Cl
N
O
CH3
CH3
CH3
Cl
N
N
N
O
CH3
Cl
CH3
N
H
F
N
O
CH3
CH3
N
O
CH3O
Cl
O CH3
CH3
N
H
N
N
O
Br
CONHC6H5
O
OCON(C2H5)2
N
NHNH2
O
N
N
O
Br
Ro 5-4864 PK 11195 Alpidem
FGIN 1-27 DAA 1097 OXA-17f MX-1189
Gidazepam, -633
Fig. 1. The structures of some PBR ligands.
position of the benzodiazepine cycle, is an impor�
tant descriptor to ensure recognition of the stu�
died 1,2�dihydro�3H�1,4�benzodiazepin�2�ones
by PBR. In the series of 3�amino�1,2�dihydro�
3H�1,4�benzodiazepin�2�ones, compounds contai�
ning nitroaniline substituent at the 3�position of
the benzodiazepine cycle have the higher affini�
ty for PBR. By the results of the QSAR analysis
[1], molecular design and computer screening
were conducted for new selective PBR ligands,
1,4�benzodiazepin�2�one derivatives, which are
recommended for directed synthesis.
Thus, the aim of our study was the synthesis
of new 1,3�substituted derivatives of 1,4�benzo�
diazepin�2�one and the estimation of their affi�
nity and selectivity for CBR and PBR in CNS.
Results and discussion. Synthesis of 1�me�
thoxycarbonylmethyl�3�arylamino�1,2�dihy�
dro�3H�1,4�benzodiazepin�2�ones (6�9) (Table 1)
has been carried out as follows.
1�Methoxycarbonylmethyl�7�bromo�5�phe�
nyl�1,2�dihydro�3H�1,4�benzodiazepin�2�one�
4�oxide (1) obtained according to [39] was used
as an initial compound. 3�Acetoxy derivative 2
was obtained through the acylation of the com�
pound 1 with acetyl chloride.
An attempt to obtain the final compounds 6�
9 from the 3�acetoxy derivative 2 through the
coupling with the corresponding arylamines was
unsuccessful.
Saponification of the compound 2 was carried
out with sodium hydroxide in methanol. At
equimolar ratio of the base and substrate, selec�
tive saponification of 3�acetoxy group with the
formation of 3 was occurred, and at the double
excess of the base — saponification of two ether
groups with the formation of 4.
Through the coupling of the 3�hydroxy deri�
vative 3 with thionyl chloride, 3�chloro deriva�
tive 5 has been obtained, followed by its conden�
N.A. Burenkova et al.
10 Ukrainica Bioorganica Acta 1 (2009)
N
NBr
O
O
OCH3 N
NBr
O
O
OCH3
O
CH3
O
N
NBr
O
O
OCH3
OH
N
NBr
O
O
OH
OH
NaOH
N
NBr
O
O
OCH3
Cl
N
NBr
O
O
OCH3
N
H
R
O
1 2
3
41eq
2eq
56 - 9
ArNH2
ArNH2
SOCl2
ClCOCH3
Scheme 1
Synthesis of 1�methoxycarbonylmethyl�3�aryl�
amino�1,2�dihydro�3H�1,4�benzodiazepin�2�ones
R=H (66), R=2�NO2 (77, MMXX��11778855); R=3�NO2 (88); R=4�NO2 (99)
Table 1
Properties of 1,3�substituted 1,2�dihydro�3H�1,4�benzodiazepin�2�ones (22��99)
and their affinity for CNS benzodiazepine receptors
N
NBr
O
O
O
R2
R1
Found %
Calculated %
Affinity
(Ki, nM) R1 R2 mp, Yield,
% Colour Formula
C N H CBR PBR
2 3 OCOCH3 188-192 80 White C20H17BrN2O5
53.95
53.90
6.29
6.33
3.85
3.79 - -
3 3 OH 168-172 65 White C18H15BrN2O4
53.62
53.68
6.95
6.93
3.75
3.77 - -
4 OH 265-269
(destr.) 60 White C17H13BrN2O4
52.46
52.41
7.20
7.24
3.37
3.28 - -
6 3 NHC6H5 178-182 85 White C24H20BrN3O3
60.26
60.22
8.78
8.83
4.21
4.19 >10000 740.0±180.0
7,
-1785 3 NH-(2-NO2C6H4) 242-244 65 Yellow C24H19BrN4O5
55.08
55.13
10.71
10.66
3.66
3.73 >10000 19.1±3.0
8 3 NH-(3-NO2C6H4) 186-190 75 Yellow C24H19BrN4O5
55.08
55.03
10.71
10.68
3.66
3.70 >10000 360.4±41.0
9 3 NH-(4-NO2C6H4) 240-244 70 Yellow C24H19BrN4O5
55.08
55.04
10.71
10.77
3.66
3.61 >10000 87.3±10.1
sation either with aniline (at room temperature)
or with ortho�, meta�, para�nitroaniline (reflu�
xed in chloroform for 5�6 hours) and obtaining of
final 3�arylamino derivatives 6�9.
The structures of synthesized compounds
have been proved by the methods of mass spec�
trometry, infrared spectroscopy and 1H NMR
spectroscopy. Properties of compounds and their
affinities for the central and peripheral benzodi�
azepine CNS receptors are shown in the Table 1.
In the IR spectra of compounds 6�9 the ab�
sorption bands corresponding to the vibration of
carbonyl group bonds (C=O) within the region
1660�1690 cm�1, and vibrations of C=O bonds in
methoxycarbonylmethyl fragment within the
region 1690�1730 cm�1, are observed.
The absorption bands corresponding to the
vibrations of NH�group for the compounds 6, 8�9
are within the region 3360�3380 cm�1, and for the
compound 7 (MX�1785) it is shifted to the long�
wave region and can be observed at 3320 cm�1
resulting from the formation of intramolecular
hydrogen bonds between the hydrogen atoms of
NH�group and oxygen atoms of nitro group.
The bands corresponding to vibrations of C=C
and C=N bonds are in the 1580�1600 cm�1 region.
In the 1H NMR spectra of compounds 6�9, the
signals of aromatic protons are within the region
7.26�8.11 ppm, and the signals of protons of
methoxycarbonyl group are within the region
3.62�3.72 ppm. A proton signal at the C (3) atom
is observed at 4.26�6.04 ppm. The NH proton sig�
nal is in the aromatic protons region.
Affinity of compounds 6�9 for benzodiaze�
pine CNS receptor was determined by the radio�
ligand method in vitro. Affinity was evaluated
by the values of inhibition constants (Ki) which
were estimated by the ability of the investigated
compounds to displace competitively radioli�
gands (CBR antagonist [3H]flumazenil and PBR
antagonist [3H]PK 11195) from their specific
binding sites in benzodiazepine receptors of cen�
tral and peripheral types of sinaptosomal and
mitochondrial membrane fractions of rats brain,
respectively.
It was found that the 3�aniline substituent
containing compound 6 is characterized by low
affinity for PBR with a value of Ki=740.0 nm.
Changing the position of the nitro group in the
3�aniline fragment of molecule 1�methoxycarbo�
nylmethyl�7�bromo�5�phenyl�1,2�dihydro�3H�
1,4�benzodiazepin�2�one resulted in the prepa�
ration of high�affinity compounds and revealed
the following trends in changes of affinity of
compounds for PBR (Fig. 2): the compound con�
taining ortho�nitroaniline substituent (7, MX�1785,
Ki=19.1 nM) at the 3�position of benzodiazepine
cycle is bind to the PBR of CNS better that the
para� and meta�nitroaniline derivatives (9,
Ki=87.3 nM, and 8, Ki=360.4 nM, respectively).
This group of compounds has high selectivity
of binding to PBR (values Ki of binding of these
substances to CBR>10000 nM).
In the series of studied 1�methoxycarbonyl�
methyl�3�arylamino�7�bromo�5�phenyl�1,2�
dihydro�3H�1,4�benzodiazepin�2�ones, the high
affinity compound 7 (MX�1785) was found. This
compound has affinity for PBR comparable to
that of radioligand [3H]PK 11195 (Fig. 3). The
Synthesis of 1�methoxycarbonylmethyl�3�arylamino�7�bromo�5�phenyl�1,2�dihydro�3H�1,4�benzodiazepin�2�ones
11www.bioorganica.org.ua
0
20
40
60
80
100
-11 -10 -9 -8 -7 -6 -5 -4
log C
I,%
PK 11195
7 ( -1785)
Fig. 2. Affinity of 1�methoxycarbonylmethyl�3�aryl�
amino�7�bromo�5�phenyl�1,2�dihydro�3H�1,4�
benzodiazepin�2�ones for CNS PBR.
Fig. 3. The dependence of inhibition (I, %) of the
specific binding of the [3H]PK 11195 radioligand to
PBR on the concentrations of PK 11195 and com�
pound 77 (MMXX��11778855), respectively. According to the
abscissa axis — logarithms of the concentrations of
PK 11195 and compound 77 (MMXX��11778855), to the ordi�
nate axis — % of inhibition of specific binding of
the [3H]PK 11195 radioligand to CNS PBR.
above�mentioned compound is of interest for
pharmacological research.
Experimental section. MMaatteerriiaallss aanndd mmeetthhooddss..
The IR spectra were recorded on a Specord 75�IR
(solutions in CHCl3). Mass spectra were obtained
using the method of electron ionization on mass
spectrometer МХ�1321 (ionization voltage 70 eV,
temperature of the ionization chamber is 200 °С).
1Н NMR spectra were recorded on a Bruker
spectrometer at 300 MHz frequency, in СDCl3,
internal standard TMS, at 25 °С. Thin layer chro�
matography was performed on plates Silufol
UV�254, in benzene : chloroform : hexane (1 : 1 : 3)
system, development with UV�light at λ=254 nm.
MMeetthhooddss ffoorr tthhee ssyynntthheessiiss ooff 11,,22��ddiihhyyddrroo��33HH��
11,,44��bbeennzzooddiiaazzeeppiinn��22��oonnee ddeerriivvaattiivveess..
1�Methoxycarbonylmethyl�7�bromo�5�
phenyl�1,2�dihydro�3H�1,4�benzodiazepin�2�
one�4�oxide (11). The compound was obtained
according to the procedure described in [39].
1�Methoxycarbonylmethyl�3�acetoxy�7�
bromo�5�phenyl�1,2�dihydro�3H�1,4�benzodi�
azepin�2�one (22). To a solution of compound 1
(30 g, 0.075 mol) in benzene (100 ml), the acetyl
chloride (10.6 ml, 0.15 mol) was added. The mix�
ture was heated at 40 °C for 40 minutes. Residue
was filtered and crystallized from methanol.
Yield 26 g (78 %), mp 142�144 °С. Mass spectrum,
m/z (%): 444 (10) [+H]+. 1H NMR spectrum
(СDCl3), δ, ppm: 3.62 s (3H, CH2COOCH3), 6.04 s
(1H, C3�H), 7.42�7.72 m (8H, Harom). IR spectrum,
ν, cm�1 (CHCl3): 1720 (COOCH3), 1690 (C=O).
1�Methoxycarbonylmethyl�3�hydroxy�7�
bromo�5�phenyl�1,2�dihydro�3H�1,4�benzodi�
azepin�2�one (33). To a mixture of compound 2
(1.0 g, 1.9 mmol) in methanol (20 ml), the solution
of NaOH (75 mg, 1.9 mmol) in H2O (6 ml) was
added. The reaction mixture was stirred for 3
minutes, and then chloroform (30 ml) and water
(30 ml) were added. Chloroform layer was sepa�
rated, washed with water to pH 7, dried over
magnesium sulphate, and then chloroform was
evaporated. The resulting oil was triturated
with ethanol (5 ml) to give white solid. Yield
0.66 g (78 %), mp 138�142 °С. Mass spectrum m/z
(%): 403 (43) [+H]+. 1H NMR spectrum (СDCl3), δ,
ppm: 3.69 s (3H, CH2COOCH3), 5.09 d (J=9.65 Hz,
1H, C3�H), 7.41�7.70 m (8H, Harom). IR spectrum, ν,
cm�1 (CHCl3): 1720 (COOCH3), 1680 (C=O).
1�Carboxymethyl�3�hydroxy�7�bromo�5�
phenyl�1,2�dihydro�3H�1,4�benzodiazepin�2�
one (44). To a solution of compound 2 (1.0 g,
1.9 mmol) in methanol, the solution of NaOH
(0.15 g, 3.8 mmol) in H2O (6 ml) was added. The
reaction mixture was stirred for 10 minutes, and
product precipitated with water. Then it was
crystallized from ethanol. Yield 0.5 g (68 %), mp
232�235 °C. Mass spectrum m/z (%): 389 (27)
[+H]+. 1H NMR spectrum (СDCl3), δ, ppm: 5.10 d
(J=9.65 Hz, 1H, C3�H), 7.42�7.73 m (8H, Harom), IR
spectrum, ν, cm�1 (CHCl3): 1680 (C=O).
1�Methoxycarbonylmethyl�3�chloro�7�bro�
mo�5�phenyl�1,2�dihydro�3H�1,4�benzodi�
azepin�2�one (55). The mixture of compound 3
(1.0 g, 2.4 mmol) and thionyl chloride (10 ml)
were placed into a flask and left for 10 hours.
Excess of thionyl chloride was evaporated under
reduced pressure. Then absolute chloroform
(20 ml) was added, and solvent was evaporated,
process was repeated three times to remove
thionyl chloride completely. The compound 5
was used in further synthesis without isolation.
1�Methoxycarbonylmethyl�3�phenylamino�
7�bromo�5�phenyl�1,2�dihydro�3H�1,4�benzodi�
azepin�2�one (66). The mixture of compound 5
(1.0 g, 2.3 mmol), aniline (0.42 g, 4.6 mmol) and
chloroform (20 ml) were placed into a flask. The
mixture was left for 10 hours. Precipitate of ani�
line hydrochloride was filtered, chloroform
layer was washed with water (5х20 ml), dried
over magnesium sulphate. Solution was evapo�
rated under reduced pressure, the residue was
crystallized from benzene. Yield 0.8 g (73 %), mp
144�146 °С. Mass spectrum m/z (%): 479 (25)
[+H]+. 1H NMR spectrum (СDCl3), δ, ppm: 3.69 s
(3H, CH2COOCH3), 5.16 d (J=7.47 Hz, 1H, C3�H),
7.26�7.73 m (8H, Harom). IR spectrum, ν, cm�1
(CHCl3): 1690 (COOCH3), 1660 (C=O), 3360 (N�H).
1�Methoxycarbonylmethyl�3�(2'�nitro)phe�
nylamino�7�bromo�5�phenyl�1,2�dihydro�3H�
1,4�benzodiazepin�2�one (77,, MMXX��11778855). A mixtu�
re of compound 5 (1.0 g, 2.3 mmol) and o�nitro�
aniline (0.63 g, 4.6 mmol) in anhydrous chloro�
form (20 ml) was refluxed for 4 hours, then coo�
led to room temperature and washed with water
(4х20 ml). The organic layer was dried over
magnesium sulphate. The solvent was evapora�
ted and the residue was crystallized from ben�
zene. Yield 0.7 g (58 %), mp 223�226 °С. Mass
spectrum m/z (%): 524 (11) [+H]+. 1H NMR spec�
N.A. Burenkova et al.
12 Ukrainica Bioorganica Acta 1 (2009)
trum (СDCl3), δ, ppm: 3.71 s (3H, CH2COOCH3),
5.29 d (J=6.23 Hz, 1H, C3�H), 7.35�7.75 m (8H,
Harom). IR spectrum, ν, cm�1 (CHCl3): 1720 (COOCH3),
1680 (C=O), 3320 (N�H).
1�Methoxycarbonylmethyl�3�(3'�nitro)phe�
nylamino�7�bromo�5�phenyl�1,2�dihydro�3Н�
1,4�benzodiazepin�2�one (88). The compound was
obtained according to the procedure described
for 7. Yield 0.6 g (51 %), mp 223�226 °С. Mass
spectrum m/z (%): 524 (43) [+H]+. 1H NMR spec�
trum (СDCl3), δ, ppm: 3.72 s (3H, CH2COOCH3),
5.22 d (J=7.47 Hz, 1H, C3�H), 7.30�7.76 m (8H,
Harom). IR spectrum, ν, cm�1 (CHCl3): 1730 (COOCH3),
1680 (C=O), 3380 (N�H).
1�Methoxycarbonylmethyl�3�(4'�nitro)phe�
nylamino�7�bromo�5�phenyl�1,4�benzodiazepin�
2�one (99). The compound was obtained according
to the procedure described for 7. Yield 0.68 g
(67 %), mp 214�216 °С. Mass spectrum m/z (%): 524
(100) [+H]+. 1H NMR spectrum (СDCl3), δ, ppm:
3.72 s (3H, CH2COOCH3), 5.21 d (J=7.16 Hz, 1H, C3�
H), 7.35�8.11 m (8H, Harom). IR spectrum, ν, cm�1
(CHCl3): 1720 (COOCH3), 1680 (C=O), 3360 (N�H).
All experiments on animals were carried out
in accordance with the experimental protocol
for humane treatment for animals European
Communities Council Directive of 24 November
1986 (86/609/EEC).
SSttuuddyy ooff aaffffiinniittyy ooff ssyynntthheessiizzeedd ccoommppoouunnddss
ffoorr CCBBRR aanndd PPBBRR CCNNSS..
The experiments were conducted in white
nonpedigreed male rats (180�220 g) from the
vivarium at Odessa State Medical University,
with free access to water and food. The anes�
thetized animals were decapitated, then the cor�
tex was quickly isolated on a cold. Experiment
on radioligand binding was conducted with the
use of the membranes synaptic fraction of rats
brain, that was obtained similar to [40] and mito�
chondrial membranes fraction of rats brain
obtained similar to [41]. Affinities of synthesized
compounds for both central and peripheral ben�
zodiazepine CNS receptors were determined by
the radioligand method in vitro. Antagonist CBR
[3H] flumazenil (3219 TBq/mol, «Du Pont NEN»)
and antagonist PBR [3H]РК 11195 (2775 TBq/
mol, «Du Pont NEN») were used as radioligands.
The analysis of the interaction of compounds
6�9 with CBR and PBR was conducted accord�
ing to the previously described methods [42, 43].
The affinity was evaluated on the ability of the
compounds (1 µM) to displace radioligands from
sites of their specific binding to the receptors.
For the most active compounds IC50 values (con�
centration, when tested compound inhibits the
receptor — radioligand specific binding by 50 %)
were determined.
A total of eight concentrations within the
range of 0.1 nM — 10 µM were used to determine
the value of IC50. Each experimental point was
obtained in sextets. The data are given as M±m,
where M is mean value of three independent
experiments, m is the standard mean error.
Calculation of IC50 was conducted through
the linearization of S�like curve. The calculation
of inhibition constant Ki was determined using
the Cheng�Prusoff equation [44]:
IC50 — concentration of the tested ligand for
the displacement of 50 % of the radioligand from
the sites of its specific binding to receptor; [L] —
the initial radioligand concentration; Kd — radio�
ligand dissociation constant.
Conclusions. Ability of 1�methoxycarbonyl�
methyl�3�arylamino�7�bromo�5�phenyl�1,2�
dihydro�3H�1,4�benzodiazepin�2�ones (6�9) for
selective binding to CNS PBR was shown. A high
affinity compound 1�methoxycarbonylmethyl�
3�(2'�nitro)phenylamino�7�bromo�5�phenyl�
1,2�dihydro�3H�1,4�benzodiazepin�2�on, 7 (MX�
1785, Ki(PBR)=19.1 nM, Ki(CBR)>10000 nM)
was revealed in series of investigated sub�
stances. Given compound is prospective for the
pharmacological research. Among the investi�
gated 1�methoxycarbonylmethyl�3�arylamino�
7�bromo�5�phenyl�1,2�dihydro�3H�1,4�benzo�
diazepin�2�ones it was found the following trend
concerning the influence of nitrogen group posi�
tion in 3�aniline moiety on affinity for PBR:
o � NO2 > p � NO2 > m � NO2 .
The high affinity and selectivity of com�
pound MX�1785 designed by QSAR analysis
indicate a possibility of further QSAR research
for identification of selective and highly active
PBR ligands in the series of 1,3�substituted 1,4�
benzodiazepin�2�ones.
Надійшла в редакцію 24.12.2008 р.
Synthesis of 1�methoxycarbonylmethyl�3�arylamino�7�bromo�5�phenyl�1,2�dihydro�3H�1,4�benzodiazepin�2�ones
13www.bioorganica.org.ua
d
50
K
[L]1
IC
iK
+
=
N.A. Burenkova et al.
14 Ukrainica Bioorganica Acta 1 (2009)
Синтез і селективність зв’язування з бенздіазепіновими рецепторами ЦНС
1�метоксикарбонілметил�3�ариламіно�7�бром�5�феніл�1,2�дигідро�3НН�1,4�бенздіазепін�2�онів
Н.О. Буренкова, В.І. Павловський, І.О. Олейніч, І.А. Бойко, С.Ю. Макан, А.Г. Артеменко, В.Є. Кузьмін
Фізико�хімічний інститут ім. О.В. Богатського НАН України
Люстдорфська дорога, 86, Одеса, 65080, Україна
Резюме. Раніше на підставі результатів QSAR�аналізу ряду похідних 1,4�бенздіазепін�2�ону [1] було показано,
що наявність метоксикарбонілметильного фрагменту в положенні 1 і нітрофеніламінного фрагменту в положенні 3
1,4�бенздіазепінового циклу сприяють прояву високого афінітету до периферичних бенздіазепінових рецепторів
(ПБДР). Для цілеспрямованого синтезу були запропоновані 3�ариламінопохідні 1�метоксикарбонілметил�7�бром�
5�феніл�1,2�дигідро�3Н�1,4�бенздіазепін�2�ону як перспективні високоафінні ліганди ПБДР. Конденсацією 1�
метоксикарбонілметил�7�бром�3�хлор�5�феніл�1,2�дигідро�3Н�1,4�бенздіазепін�2�ону із заміщеними анілінами
синтезовано цільові сполуки. Методом радіолігандного аналізу в експериментах in vitro вивчено афінітет
синтезованих сполук до бенздіазепінових рецепторів ЦНС периферичного (ПБДР) і центрального (ЦБДР) типів. У
ряді досліджених сполук виявлено високоафінний і селективний ліганд ПБДР — 1�метоксикарбонілметил�3�(2'�
нітро)феніламіно�7�бром�5�феніл�1,2�дигідро�3Н�1,4�бенздіазепін�2�он, 7 (МХ�1785, Ki(ПБДР)=19,1 нМ,
Ki(ЦБДР)>10000 нМ).
Ключові слова: 1,3�заміщені 1,2�дигідро�3Н�1,4�бенздіазепін�2�они, афінітет, бенздіазепінові рецептори, се�
лективність, QSAR�аналіз.
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Synthesis of 1�methoxycarbonylmethyl�3�arylamino�7�bromo�5�phenyl�1,2�dihydro�3H�1,4�benzodiazepin�2�ones
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