N-adamantyl derivatives of aromatic amines. Part II. Synthesis and neurotropic activity of N-(5-R- or 6-R-Adamant-2-YL)arylamines

Full text of DOI:10.1023/A:1020820405232

Pharmaceutical Chemistry Journal
Vol. 36, No. 6, 2002
N-ADAMANTYL DERIVATIVES OF AROMATIC AMINES.
1
PART II. SYNTHESIS AND NEUROTROPIC ACTIVITY
OF N-(5-R- OR 6-R-ADAMANT-2-YL)ARYLAMINES
N. V. Klimova,2 N. I. Avdyunina,2 B. M. Pyatin,2 V. P. Lezina,2 V. S. Troitskaya,2
and E. A. Tsvetkova2
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 36, No. 6, pp. 14 – 16, June, 2002.
Original article submitted January 31, 2002.
The group of N-(adamant-2-yl)arylamines contains the
drug bromantan – a highly active psycho- and immunostimu-
lant [1 – 5]. As is known, the main metabolites of adamanta-
ne derivatives contain a hydroxy group at the nodal position
of the adamantane nucleus [6].
The aim of this study was to synthesize and characterize
a series of previously unreported 2,5- and 2,6-disubstituted
adamantanes (Ia – Ih):
bases Ia – Ih, as well as their hydrochlorides, appear as white
crystalline substances. The yields, reaction durations, TLC
characteristics, and melting points of compounds Ia – Ih and
their hydrochlorides are presented in Table 1.
As is known, 2,5-disubstituted adamantanes can exist as
syn and anti (cis and trans) stereomers [8]. The TLC data in-
dicated that compounds Ia – Id and Ih are mixtures of both
stereomers (see the Rf values in Table 1); at the same time,
TLC did not reveal stereomers in compounds Ie – Ig. After
repeated recrystallizations from various solvents, we suc-
ceeded in isolating individual anti stereomers of compounds
Ia and Id, which was confirmed by 1H NMR data.
"
NH
R
R
'
R
Ia – Ih
The synthesized compounds were studied by spectro-
scopic methods. The IR spectra of bases Ia, Ib, Id, and Ih dis-
play the absorption bands of hydroxy groups at the nodal
atom of adamantane in the region of 3300 – 3350 cm – 1. The
spectra of all compounds contain intense bands at
2940 – 2840 cm – 1 corresponding to the stretching vibrations
of –CH– groups in the adamantane ring. The characteristic
bands at 1450 – 1500 cm – 1 are due to the bending vibrations
of –NH– groups. The absorption at 840 – 810 cm – 1 ob-
served in the spectra of Ib – Ie, Ig, and Ih reflects the
1,4-substitution in the benzene ring. The intense band at
715 cm – 1 in the spectrum of compound Id belongs to
stretching vibrations of the C–Br bonds, while the vibrations
Here, R, R¢, and R² are the substituents indicated in Ta-
ble 1. Initial compounds in the synthesis of drugs Ia – Ih
were 5-hydroxyadamant-2-one (II), 5-chloroadamant-2-one
(III), 2,6-dioxoadamantane (IV), and 5-acetylaminoada-
mant-2-one (V). Hydroxyketone II and diketone IV were ob-
tained through oxidation of adamantanone with a mixture of
nitric and sulfuric acids [7]. Chloroketone III was synthe-
sized with a high yield from hydroxyketone II under the ac-
tion of thionyl chloride [7]. 5-Acetylaminoadamant-2-one
(V) was obtained from II through the Ritter reaction [4].
The interaction of initial compounds II – V with
unsubstituted aniline and para-chloro, bromo, and
fluoro-anilines was studied under Leuckart reaction condi-
tions. The reactions of ketones II, III, and V with anilines
were conducted at 130 – 160°C in the presence of concen-
trated formic acid, at a ketone – amine ratio of 1 : 2. The re-
sulting formyl derivatives were subjected to acid hydrolysis.
The synthesis of compound Ia proceeded more smoothly
when aniline was replaced by its formyl derivative. The
of C–F bonds are manifested at 1100 cm – 1
.
The proposed structures of the synthesized compounds
1
were also confirmed by analysis of the H and 13C NMR
data. The spectra of 2,5-disubstituted adamantane derivatives
revealed clear differences in the 13C NMR chemical shifts of
syn and anti isomers present in the mixtures. This was possi-
ble because of strongly different j-syn and j-anti effects of
the bridging substituents [8]. The signals from C4–C9 car-
bons in the 13C NMR spectra of anti isomers are observed at
at a lower field (5.10 – 5.90 ppm), while the signals from
C8–C10 carbons occur at a higher field (6.50 – 6.70 ppm) as
1
For Part I, see [1].].
Institute of Pharmacology, Russian Academy of Medical Sciences, Mos-
2
cow, Russia.
295
0091-150X/02/3606-0295$27.00 © 2002 Plenum Publishing Corporation

296
N. V. Klimova et al.
TABLE 1. Yields and Physicochemical Characteristics of the Synthesized N-(5-R¢- or 6-R-Adamant-2-yl)arylamines (Ia – Ih)
Compound
Base
Empirical formula
Reaction
time, h
Hydrochloride:
m.p., °C
Rf
R
H
H
H
H
R¢
R²
H
F
Yield, %
59.0
M.p., °C
Ia
Ib
Ic
Id
OH
OH
Cl
12
15
10
11
237 – 238
221 – 223
221 – 222
257 – 259
0.64
0.70
187 – 189
C16H21NO
75.0
0.30
0.40
98 – 107
83 – 85
C16H20FNO
C16H19ClFNO
C16H20BrNO
F
80.0
0.52
0.64
OH
Br
76.1
0.36
0.46
136 – 141
Ie
If
p-BrC6H4NH–
H
Br
H
15
15
10
12
60.0
60.5
62.0
65.0
221 – 224
321 – 324
231 – 233
210 – 212
0.85
0.32
0.73
190 – 191
45 – 47
–
C22H24Br2N2
C22H26N2
C6H5–NH–
H
–NHCOCH3
OH
Ig
Ih
H
H
Br
Cl
C18H21BrNO
C16H20ClNO
0.42
0.47
122 – 124
compared to the corresponding signals for syn isomers. An
example is offered by the 13C NMR characteristics of com-
pound Ib presented in Table 2.
complete spin – spin proton decoupling, without suppression
of the 13C – 1H interaction, and interpreted using data on the
selective double resonance.
Another characteristic feature of the 1H NMR spectra of
2,5-disubstituted adamantane derivatives is the difference in
The IR absorption spectra were measured on a
Perkin-Elmer spectrophotometer using samples pelletized
with KBr. The Rf values were determined by TLC on Silufol
UV-254 plates eluted in a hexane – ethyl acetate – etha-
nol – concentrated ammonia solution (5 : 3 : 2 : 1) system;
the spots were detected under UV illumination. The data of
elemental analysis of the synthesized compounds agree with
the results of analytical calculations using empirical formu-
las.
1
the H NMR chemical shifts of protons in position 2 of the
adamantane ring of syn and anti isomers. The greater
low-field shift of the signal of H2 proton in the spectrum of
anti isomer allows the ratio of stereomers in a mixture to be
estimated from the ratio of integral intensities of the two sig-
1
nals. The parameters of the H NMR spectra of compounds
Ia – Id and Ih are listed in Table 3.
The synthesized compounds have been pharmacologi-
cally characterized previously [4, 5, 9]. It was demonstrated
that introduction of the second substituent in either nodal or
bridging positions of the adamantane ring leads to a decrease
in the psychostimulant activity.
N-(5-Hydroxyadamant-2-yl)aniline (Ia). A mixture of
3 g (0.018 mole) of 5-hydroxyadamantan-2-one, 4.35 g
(0.036 mole) of formanilide, and 1.1 g (0.024 mole) of for-
mic acid was boiled for 12 h at 150 – 160°C and cooled.
Then, 10 ml of a 15% hydrochloric acid solution was added
and the mixture was boiled for 1 h, cooled, and alkalized
with sodium bicarbonate. Finally, the product was extracted
EXPERIMENTAL CHEMICAL PART
with chloroform (5 ´ 25 ml) and the chloroform evaporated
to dryness to obtain 2.6 g (59%) of compound Ia; m.p.,
188 – 189°C (recrystallization from ethanol), see Table 1.
N-(5-Hydroxyadamant-2-yl)-p-fluoroaniline (Ib). To a
mixture of 4 g (0.036 mole) of p-fluoroaniline and 1.72 g
(0.036 mole) of 99% formic acid heated to 100°C was gradu-
1
The H and 13C NMR spectra of the synthesized com-
pounds were measured on a Bruker AC-250 spectrometer
computer-controlled by a standard Bruker microprogram
package using CDCl3 as the solvent and TMS as the internal
standard. The spectra were recorded under conditions of
TABLE 2. Parameters of the 13C NMR Spectra of N-(5-Hydroxyadamant-2-yl)-p-fluoroaniline (Ib)
Chemical shift d, ppm (TMS)
Isomer
Isomer
Aromatic substituent*
content
C1,3
C2
C4,9
C5
C6
C7
C8,10
C1¢
C2¢, 6¢
C3¢, 5¢
C4¢
syn
10
90
31.52
30.61
66.47
67.24
37.99
43.88
66.05
65.75
44.85
44.85
29.10
29.10
35.56
28.88
131.39
131.39
125.75
125.75
116.56
116.56
161.77
161.77
anti
* Signals from carbons of the aromatic ring were assigned based on the additivity rule.

N-Adamantyl Derivatives of Aromatic Amines
297
TABLE 3. Parameters of the 1H NMR Spectra of 2,5-Disubstituted Adamantanes
Chemical shift: d, ppm (CDCl3)
Isomer
content,
%
Compound
Isomer
Aromatic ring
Adamantane
ring (m, 13H)
Other protons*
H2 (m, 1H)
H2¢, 6¢ (m, 2H) H3¢,5¢ (m, 2H)
Ia
Ib
anti
syn
100
10
1.30 : 2.50
1.35 : 2.70
1.35 : 2.70
1.36 : 2.76
1.36 : 2.76
1.25 : 2.40
1.28 : 2.35
1.28 : 2.35
3.45
3.32
3.45
3.29
3.40
3.47
3.34
3.46
6.51
7.18
7.18
6.97
6.97
6.46
6.49
6.49
7.02
7.61
7.61
7.35
7.35
7.23
7.08
7.08
6.65 (m, H4¢), 3.00 (s, NH, OH)
3.60 (s, NH, OH)
3.60 (s, NH, OH)
10.30 (s, NH)
anti
syn
90
Ic**
27
anti
anti
syn
73
10.30 (s, NH)
Id
Ih
100
17
3.90 (s, NH, OH)
3.70 (s, NH, OH)
3.70 (s, NH, OH)
anti
83
* Protons of NH and OH groups yield a common averaged signal.
** Compound studied in the form of a salt.
ally added 3 g (0.018 mole) of 5-hydroxyadamantan-2-one.
The reaction mixture was boiled for 15 h at 150 – 160°C,
cooled, and then treated as described above for compound Ia
to obtain 2.8 g (75%) of compound Ib.
acid was treated for 6 h at 110°C. Then, the formic acid was
distilled off and the reaction mass was heated for another
10 h and cooled. Then, 10 ml of concentrated HCl and 20 ml
of water were added and the mixture was boiled for 2 h and
cooled. The precipitate was separated by filtration and
washed sequentially with water (2 ´ 20 ml), toluene
N-(5-Chloroadamant-2-yl)-p-fluoroaniline (Ic). To a
mixture of 2.2 g (0.02 mole) of p-fluoroaniline and 1.0 g
(0.021 mole) of 99% formic acid heated to 100°C was gradu-
ally added 2 g (0.011 mole) of 5-hydroxyadamantan-2-one,
and the reaction mass was boiled for 10 h at 150 – 160°C.
Then, 10 ml of a 15% hydrochloric acid solution was added
and the mixture was boiled for 2 h and cooled. The precipi-
tate was separated by filtration, washed with ethyl ether
(2 ´ 30 ml), and suspended in water. The suspension was al-
kalized with sodium bicarbonate and extracted (5 ´ 25 ml)
with ethyl ether. The ether extract of compound Ic was dried
with magnesium sulfate. After separating the drying agent by
filtration, the solvent was evaporated to dryness to yield
2.4 g (80%) of compound Ic representing a mixture of
stereomers (see Table 1).
(2 ´ 20 ml), and water again (3 ´ 20 ml). The resulting tech-
nical product was purified by crystallization from ethanol to
obtain 6.58 g of dihydrochloride Ie; m.p., 221 – 224°C.
An analogous procedure were used to obtain compounds
If by reaction of diketone IV with aniline.
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Analogous procedures were used to obtain compounds Id
(yield, 76%) and Ih (yield, 80%) by reactions of 5-hydroxy-
adamant-2-one with p-bromoaniline and p-chloroaniline, re-
spectively (Table 1).
N-(Acetylaminoadamant-2-yl)-p-bromophenylamine
hydrochloride (Ig × HCl). A mixture of 6.9 g (0.095 mole)
of p-bromoaniline, 4.15 g (0.023 mole) of 5-acetylamino-
adamant-2-one, and 3 ml of 99% formic acid was treated for
10 h at 140°C and cooled. Then, 15 ml of a 15% hydrochlo-
ric acid solution was added and the mixture was boiled for
1 h and cooled. The precipitate was separated by filtration,
washed with water, and dried to obtain 4.5 g of compound Ig
in the form of hydrochloride; m.p., 231 – 233°C.
2,6-Di( p-bromophenylamino)adamantane (Ie × 2HCl).
A mixture 3.28 g (0.02 mole) of 2,6-dioxoadamantane, 20 g
(1.18 mole) of p-bromoaniline, and 15 ml of 99% formic