Synthesis and Neurotropic Activity of New 7-Cyclohexyl-6,7,8,9-Tetrahydro-3H-Pyrazolo[3,4-c]-2,7-Naphthyridine-1,5-Diamines

Article abstract of DOI:10.1007/s11094-018-1773-x

A method for synthesizing new tricyclic heterocyclic 7-cyclohexyl-6,7,8,9-tetrahydro-3H-pyrazolo- [3,4-c]-2,7-naphthyridine-1,5-diamines from 1,3-dichloro-7-cyclohexyl-5,6, 7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile was elaborated. Investigation of t

Full text of DOI:10.1007/s11094-018-1773-x

DOI 10.1007/s11094-018-1773-x
Pharmaceutical Chemistry Journal, Vol. 52, No. 2, May, 2018 (Russian Original Vol. 52, No. 2, February, 2018)
SYNTHESIS AND NEUROTROPIC ACTIVITY OF NEW
7-CYCLOHEXYL-6,7,8,9-TETRAHYDRO-3H-PYRAZOLO[3,4-c]-
2,7-NAPHTHYRIDINE-1,5-DIAMINES
S. N. Sirakanyan,1,* E. K. Hakobyan,1 A. G. Nikoghosyan,1 R. G. Paronikyan,1
I. A. Dzhagatspanyan,1 I. M. Nazaryan,1 A. G. Akopyan,1 and A. A. Hovakimyan1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 52, No. 2, pp. 8 – 11, February, 2018.
Original article submitted August 17, 2016.
A method for synthesizing new tricyclic heterocyclic 7-cyclohexyl-6,7,8,9-tetrahydro-3H-pyrazolo-
[3,4-c]-2,7-naphthyridine-1,5-diamines from 1,3-dichloro-7-cyclohexyl-5,6, 7,8-tetrahydro-2,7-naphthyridi-
ne-4-carbonitrile was elaborated. Investigation of the biological activity of the synthesized compounds
showed that several of them exhibited pronounced neurotropic properties.
Keywords: 5,6,7,8-tetrahydro-2,7-naphthyridine, pyrazolo[3,4-c]-2,7-naphthyridines, neurotropic activity.
2,7-Naphthyridines hold a special place in our research
on condensed heterocyclic compounds because of not only
their high biological activity as reported by others [1] and by
us [2, 3] but also their universal solubility.
ring facilitated the cyclization. Thus, 1-amino-3-chloro-2,7-
naphthyridines IIa-n reacted with hydrazine hydrate in
EtOH and cyclized into the target products 7-cyclohe-
xyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]-2,7-naphthyridine-
1,5-diamines IIIa-n in high yields (Scheme 1, Table 1).
The structures of synthesized IIIa-n were elucidated us-
ing modern physicochemical research methods.
Several 2,7-naphthyridine derivatives were synthesized
because the corresponding condensed pyrazoles annelated to
alicyclo[c]pyridines and pyrano(thiopyrano)[3,4-c]pyridines
[4-6] exhibited high biological activity.
Studies of the biological activity of all synthesized com-
pounds showed that several of them (IIIc, -e, -j, -m) exhib-
ited pronounced psychotropic activity.
The target products were synthesized from 1,3-dichloro-
7-cyclohexyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboni
trile I [7]. Thus, nucleophilic substitution of only the Py
1-Cl atom to produce monoamine 2,7-naphthyridine deriva-
tives IIa-n was possible by considering the different reactivi-
ties of the Cl atoms in 1,3-dichloro-2,7-naphthyridine I and
careful adjustment of the reaction conditions [7]. In particu-
lar, amination of I in a low-boiling solvent (MeOH) using a
quasi-stoichiometric ratio of substrate and amine (1:2.2) syn-
thesized 1-amino-3-chloro-7-cyclohexyl-5,6,7,8-tetrahydro-
2,7-naphthyridine-4-carbonitriles IIa-n [7]. This feature en-
abled the Py 1-substituent to be varied to produce a multitude
of biologically promising 2,7-naphthyridine derivatives. The
presence of convenient vicinal functional groups in the Py
EXPERIMENTAL CHEMICAL PART
IR spectra were taken in mineral oil on a Nicolet Avatar
330 FTIR spectrometer. PMR spectra were obtained in
DMSO-d on a Varian Mercury 300VX instrument. TLC
6
used Silufol UV-254 plates, EtOH—CHCl (2:1, IIIa-n), and
3
I vapor. Elemental analyses agreed with the empirical for-
2
mulas.
5-(R,R1-Amino)-7-cyclohexyl-6,7,8,9-tetrahydro-3H-
pyrazolo[3,4-c]-2,7-naphthyridine-1-amines
(IIIa-n).
General method. A mixture of chloro-derivative II
1
A. L. Mnjoyan Institute of Fine Organic Chemistry, Scientific and Tech-
(0.01 mol) and hydrazine hydrate (0.1 mol) in anhydrous
EtOH (50 mL) was refluxed for 6 h. The EtOH and excess
of hydrazine hydrate were distilled off. The residue was
nological Center of Organic and Pharmaceutical Chemistry, National
Academy of Sciences of the Republic of Armenia, 26 Prosp. Azatutyan,
0014 Yerevan, 375014 Armenia.
*
e-mail: shnnr@mail.ru
treated with H O (50 mL). The resulting crystals were fil-
2
108
0091-150X/18/5202-0108 © 2018 Springer Science+Business Media, LLC

Synthesis and Neurotropic Activity
109
Scheme 1
N
N
N
Cl
Cl
NH
N2H4.H2O
EtOH
2
HNRR 1
MeOH
N
N
R
N
N
R
N
N
N
H
N
R
N
1
Cl
1
R
I
IIIa – n
IIa – n
I, III, a: R + R1 = -(CH2)4-, b: R + R1 = -(CH2)5-, c: R + R1 = -(CH2)2O(CH2)2-, d: R + R1 = -(CH2)2NCH3(CH2)2-, e: R + R1 = -(CH2)2NC2H5(CH2)2-, f: R +
R1 = -(CH2)2CHCH3(CH2)2-, g: R = R1 = C2H5, h: R = H, R1 = CH2CH2N(CH3)2, i: R = H, R1 = morpholinoethyl, j: R = H, R1 = morpholinopropyl, k: R = H,
R1 = (CH2)3OCH3, l: R = H, R1 = CH2CH2OCH2CH2OH, m: R = H, R1 = CH2CH2C5H3-m,n-OCH3, n: R = H, R1 = Ph.
tered off, rinsed with H O, dried, and recrystallized from
1.11 – 1.97 (m, 10H, 5CH , C H ), 2.44 – 2.50 (m, 5H,
2 6 11
2
EtOH (Table 1).
IR spectrum, nmax, cm– 1. IIIa – n: 3150 – 3450 (NH,
CH-C H , N(CH ) ), 2.58 (t, 2H, J 6.6 Hz, NHCH CH ),
6 11 2 2 2 2
2.78 (t, 2H, J 5.6 Hz, NCH CH ), 3.02 (t, 2H, J 5.6 Hz,
2
2
NCH CH ), 3.37 (s, 2H, NCH ), 3.44 – 3.51 (m, 2H,
NH ). PMR spectrum, d, ppm, IIIa: 1.08 – 1.96 (m, 14H,
2
2
2
2
NHCH CH ), 3.59 – 3.63 (m, 4H, O(CH ) ), 4.27 (c, 2H,
7CH , C H , C H N), 2.38 – 2.51 (m, 1H, CH-C H ), 2.81
2
2
2 2
2
6
11
4
8
6
11
NH ), 5.38 (t, 1H, J 4.8 Hz, NHCH CH ), 10.88 (s, 1H, NH),
(t, 2H, J 5.7 Hz, NCH CH ), 3.12 (t, 2H, J 5.7 Hz,
2
2
2
2
2
IIIj: 1.07 – 1.96 (m, 12H, 6CH , C H , NHCH CH ),
NCH CH ), 3.41 – 3.48 (m, 4H, N(CH ) ), 3.54 (s, 2H,
2
6
11
2
2
2
2
2 2
2.38 – 2.47 (m, 7H, CH-C H , CH N(CH ) ), 2.77 (t, 2H, J
NCH ), 4.38 (c, 2H, NH ), 11.02 (s, 1H, NH), IIIb:
6
11
2
2 2
2
2
5.5 Hz, NCH CH ), 3.01 (t, 2H, J 5.5 Hz, NCH CH ), 3.40
1.05 – 1.91 (m, 16H, 8CH , C H , C H N), 2.32 – 2.43 (m,
2
2
2
2
2
6
11
5
10
(s, 2H, NCH ), 3.41 – 3.47 (m, 2H, NHCH CH ),
1H, CH-C H ), 2.79 (t, 2H, J 5.8 Hz, NCH CH ),
2
2
2
6
11
2
2
3.62 – 3.66 (m, 4H, O(CH ) ), 4.26 (c, 2H, NH ), 5.72 (t, 1H,
2.97 – 3.05 (m, 4H, N(CH ) ), 3.09 (t, 2H, J 5.8 Hz,
2 2
2
2 2
J 5.0 Hz, NHCH CH ), 10.86 (s, 1H, NH), IIIk: 1.11 – 1.96
NCH CH ), 3.54 (s, 2H, NCH ), 4.78 (c, 2H, NH ), 11.43 (s,
2
2
2
2
2
2
(m, 12H, 6CH , C H , NHCH CH ), 2.45 – 2.50 (m, 1H,
1H, NH), IIIc: 1.03 – 1.88 (m, 10H, 5CH , C H ),
2
6
11
2
2
2
6
11
CH-C H ), 2.76 (t, 2H, J 5.6 Hz, NCH CH ), 3.00 (t, 2H, J
2.32 – 2.41 (m, 1H, CH-C H ), 2.78 (t, 2H, J 5.8 Hz,
6
11
2
2
6
11
5.6 Hz, NCH CH ), 3.32 (c, 3H, OCH ), 3.35 (s, 2H, NCH ),
NCH CH ), 2.97 – 3.07 (m, 4H, N(CH ) ), 3.10 (t, 2H, J
2
2
3
2
2
2
2 2
3.41 – 3.49 (m, 4H, NHCH CH CH ), 4.23 (c, 2H, NH ),
5.8 Hz, NCH CH ), 3.54 (s, 2H, NCH ), 3.68 – 3.75 (m, 4H,
2
2
2
2
2
2
2
5.49 (t, 1H, J 5.1 Hz, NHCH CH ), 10.85 (s, 1H, NH), IIIl:
O(CH ) ), 4.80 (c, 2H, NH ), 11.40 (s, 1H, NH), IIId:
2
2
2 2
2
1.13 – 1.95 (m, 10H, 5CH , C H ), 2.46 – 2.50 (m, 1H,
1.11 – 1.94 (m, 10H, 5CH , C H ), 2.29 (c, 3H, NCH ),
2
6
11
2
6
11
3
CH-C H ), 2.76 (t, 2H, J 5.6 Hz, NCH CH ), 3.01 (t, 2H, J
2.38 – 2.50 (m, 1H, CH-C H ), 2.83 (t, 2H, J 5.8 Hz,
6
11
2
2
6
11
5.5 Hz, NCH CH ), 3.38 (s, 2H, NCH ), 3.45 – 3.62 (m, 9H,
NCH CH ), 3.05 – 3.10 (m, 8H, C H N), 3.15 (t, 2H, J
2
2
2
2
2
4
8
NHCH CH OCH CH OH), 4.29 (c, 2H, NH ), 5.60 (t, 1H, J
5.8 Hz, NCH CH ), 3.55 (s, 2H, NCH ), 4.48 (c, 2H, NH ),
2
2
2
2
2
2
2
2
2
5.1 Hz, NHCH CH ), 10.95 (s, 1H, NH), IIIm: 1.10 – 1.94
11.33 (s, 1H, NH), IIIe: 1.10 (t, 3H, J 7.2 Hz, NCH CH ),
2
2
2
3
(m, 10H, 5CH , C H ), 2.39 – 2.48 (m, 1H, CH-C H ),
1.15 – 1.94 (m, 10H, 5CH , C H ), 2.43 (q, 2H, J 7.2 Hz,
2
6
11
6
11
2
6
11
2.75 (t, 2H, J 5.5 Hz, NCH CH ), 2.81 – 2.87 (m, 2H,
NCH CH ), 2.52 – 2.57 (m, 5H, CH-C H , N(CH ) ), 2.82
2
2
2
3
6
11
2 2
CH C H ), 3.01 (t, 2H, J 5.5 Hz, NCH CH ), 3.31 (s, 2H,
(t, 2H, J 5.9 Hz, NCH CH ), 3.05 – 3.10 (m, 4H, N(CH ) ),
2
6
3
2
2
2
2
2 2
NCH ), 3.54 – 3.62 (m, 2H, NHCH ), 3.76 (c, 3H, OCH ),
3.15 (t, 2H, J 5.8 Hz, NCH CH ), 3.55 (s, 2H, NCH ), 4.45
2
2
3
2
2
2
3.78 (c, 3H, OCH ), 4.26 (c, 2H, NH ), 5.40 (t, 1H, J 5.5 Hz,
(c, 2H, NH ), 11.30 (s, 1H, NH), IIIf: 1.03 (e, 3H, J 6.4 Hz,
3
2
2
NHCH CH ), 6.69 – 6.79 (m, 3H, C H ), 10.88 (s, 1H, NH),
CHCH ), 1.14 – 1.94 (m, 15H, 7CH , 1CH, C H , C H N),
2
2
6
3
3
2
6
11
5
9
IIIn: 1.12 – 1.98 (m, 10H, 5CH , C H ), 2.49 – 2.54 (m,
2.38 – 2.48 (m, 1H, CH-C H ), 2.68 – 2.78 (m, 4H,
2
6
11
6
11
1H, CH-C H ), 2.81 (t, 2H, J 5.5 Hz, NCH CH ), 3.10 (t,
N(CH ) ), 3.14 (t, 2H, J 5.7 Hz, NCH CH ), 3.35 (t, 2H, J
6
11
2
2
2 2
2
2
2H, J 5.5 Hz, NCH CH ), 3.63 (s, 2H, NCH ), 4.36 (c, 2H,
5.7 Hz, NCH CH ), 3.55 (s, 2H, NCH ), 4.43 (c, 2H, NH ),
2
2
2
2
2
2
2
NH ), 6.86 – 6.92 (m, 1H, Ph), 7.19 – 7.25 (m, 2H, Ph), 7.41
11.23 (s, 1H, NH), IIIg: 1.03 (t, 6H, J 7.0 Hz, N(CH CH ) ),
2
2
3 2
(c, 1H, NHPh), 7.62 – 7.67 (m, 2H, Ph), 11.08 (s, 1H, NH).
1.05 – 1.91 (m, 10H, 5CH , C H ), 2.37 – 2.43 (m, 1H,
2
6
11
CH-C H ), 2.80 (t, 2H, J 5.7 Hz, NCH CH ), 3.04 – 3.17
6
11
2
2
(m, 6H, N(CH CH ) , NCH CH ), 3.55 (s, 2H, NCH ), 4.79
EXPERIMENTAL PHARMACOLOGICAL PART
2
3 2
2
2
2
(c, 2H, NH ), 11.41 (s, 1H, NH), IIIh: 1.10 – 1.95 (m, 10H,
2
5CH , C H ), 2.26 (c, 6H, N(CH ) ), 2.46 – 2.52 (m, 3H,
Neurotropic activity of the synthesized compounds
IIIa-n was studied using parameters characterizing the
anticonvulsant, anxiolytic, and sedative activity. Their side
effects were also studied. The neurotropic activities of 14
compounds and the reference drug diazepam were studied
2
6
11
3 3
CH-C H , CH N(CH ) ), 2.76 (t, 2H, J 5.6 Hz, NCH CH ),
6
11
2
3 3
2
2
3.01 (t, 2H, J 5.6 Hz, NCH CH ), 3.36 (s, 2H, NCH ),
2
2
2
3.42 – 3.49 (m, 2H, NHCH CH ), 4.28 (c, 2H, NH ), 5.20 (t,
2
2
2
1H, J 5.0 Hz, NHCH CH ), 10.92 (br.s, 1H, NH), IIIi:
2
2

110
S. N. Sirakanyan et al.
using white mice of both sexes (18 – 24 g, 250 animals) and
Wistar rats (140 – 170 g, 40 animals of both sexes).
squares in the test and control groups. Each compound, diaz-
epam, and the control were tested in eight animals for this
model. The tested compounds and diazepam were injected
i.p. to rats as suspensions in carboxymethylcellulose with
Tween-80 at doses that did not cause adverse side effects (50
and 2 mg/kg, respectively) 45 mi before placement in the
open field. Control animals received emulsifier. Results were
processed statistically for p = 0.05.
Anticonvulsant and prognostic anxiolytic activities were
assessed from the prevention of clonic twitching and the
clonic convulsion component induced in the mice by s.c. in-
jection of corazole (90 mg/kg, Acros Organics, New Jersey,
USA) [8 – 12]. Each dose of the compounds was studied in
five animals. Adverse side effects were
a central
myorelaxant effect and disturbed motor coordination and
were studied using the rotating-rod method [8, 13, 14]. For
this, mice were placed onto a metal rod with a corrugated
rubber coating that rotated at 5 rpm. The number of animals
incapable of staying on the rod for 2 min was determined.
The tested compounds and reference drug diazepam
(Polfa, Poland) were administered i.p. to the mice as suspen-
sions in carboxymethylcellulose (Viadi-Ingredients, St. Pe-
tersburg, Russia) with Tween-80 (Ferak, Berlin, Germany) to
ensure dissolution. Newly synthesized compounds were ad-
ministered in the dose range 10 – 50 mg/kg; diazepam,
0.1 – 0.3 and 1 mg/kg i.p. 45 min before injecting corazole.
Control animals received emulsifier. The 50% effective dose
Studies of the anticonvulsant activity found that not all
synthesized derivatives had the same pronounced
anticorazole activity. Thus, IIIa, -b, -d, -f, -i, -k, -l, and -n at
a dose of 50 mg/kg prevented corazole convulsions in 40%
of the animals. Other trends were noted for IIIc, -e, -j, and
-m. They all possessed pronounced anticonvulsant activity.
Injection to mice of these compounds starting with a dose of
25 mg/kg prevented corazole convulsions. The ED values
50
of these drugs varied from 36 to 45 mg/kg. The ED value
50
of diazepam for anticorazole activity in mice was 0.51 mg/kg
(Table 2).
Adverse side effects of the tested drugs, i.e., disturbed
motor coordination and myorelaxation, were not observed in
mice at a dose of 50 mg/kg. They were noted for diazepam at
a dose of 2.7 (1.4 – 5.5) mg/kg.
(ED ) of the tested drugs for the anticonvulsant effect was
50
determined statistically using the Litchfield and Wilcoxon
method [15].
Sedative, stimulant, and anxiolytic activities of the se-
lected most active compounds were studied in the open-field
test using rats and studying the locomotor and orienta-
tion-exploratory activities [16 – 18]. Tests were conducted
during the day with natural lighting. Spontaneous behavior
of each animal was assessed for 5 min. Sedative and stimu-
lant activities were assessed from the number of horizontal
(squares crossed) and vertical movements (rearings). The
anxiolytic effect was assessed from the number of explored
Control rats in the open-field behavior test made
34.8 horizontal and 9 vertical movements and explored two
squares (Table 3). Table 3 shows that the selected com-
pounds at a dose of 50 mg/kg decreased the number of hori-
zontal movements. Compounds IIIm and IIIj decreased the
number most to 14.3 and 19, respectively, in contrast with di-
azepam, which caused no change at a dose of 2 mg/kg. Verti-
cal movements also changed significantly with respect to the
control, decreasing by 1.5 to 3 times under the influence of
the selected compounds, in contrast with diazepam. The
number of explored squares increased under the influence of
the selected compounds (IIIc, -e, -j, and -m). However, it
was statistically insignificantly different from the control
whereas diazepam increased this parameter significantly.
The results could indicate that the selected compounds had
sedative and slight anxiolytic activity. Diazepam had pro-
nounced anxiolytic effects (Table 3).
TABLE 1. Characteristics of IIIa-n
Empirical
Rf
Compound
Yield, %
mp, °C
formula
C19H28N6
C20H30N6
C19H28N6O
C20H31N7
C21H33N7
C21H32N6
C19H30N6
C19H31N7
C21H33N7O
C22H35N7O
C19H30N6O
C19H30N6O2
C25H34N6O2
C21H26N6
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
78
75
82
79
84
73
88
80
71
85
78
72
83
80
138 – 139
171 – 172
267 – 268
274 – 275
207 – 208
240 – 242
261 – 263
173 – 175
213 – 214
140 – 142
190 – 191
127 – 128
122 – 124
211 – 213
0.54
0.60
0.57
0.63
0.65
0.58
0.61
0.54
0.57
0.60
0.65
0.68
0.56
0.62
TABLE 2. Anticorazole Activities of IIIc, -e, -j, and -m and Diaze-
pam
IIIg
IIIh
IIIi
Compound
IIIc
Corazole antagonism* (ED50, mg/kg)
45 (34.6 – 58.5)
IIIe
36 (23.8 – 48.2)
IIIj
IIIj
40 (32.0 – 50.0)
IIIk
IIIl
IIIm
44 (32.6 – 59.4)
Diazepam
0.51 (0.39 – 0.69)
IIIm
IIIn
*
Probability levels for p = 0.05 in parentheses.

Synthesis and Neurotropic Activity
111
REFERENCES
TABLE 3. Exploratory Activity of IIIc, -e, -j, -m and Diazepam
Number (in absolute values for 5 min)*
Compound
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vertical
explored
squares
(dose)
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movements
movements
Control
34.8 ± 12.5
9.0 ± 2.57
2.0 ± 0.9
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IIIj (50 mg/kg)
IIIm (50 mg/kg)
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24.2 ± 9.6
19.0 ± 6.3
14.3 ± 6.5
33.6 ± 4.2
5.0 ± 1.8
5.2 ± 1.7
2.0 ± 1.2
3.0 ± 1.4
8.4 ± 1.7
3.3 ± 1.6
2.3 ± 1.5
3.1 ± 1.4
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*
Confidence intervals for probability level p = 0.05.
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pyrazolo[3,4-c]-2,7-naphthyridines. The new compounds,
like diazepam, prevented occurrence of corazole clonic
writhing and convulsions in animals. Diazepam had signifi-
cantly greater activity in this respect than the new com-
pounds. All tested compounds at the studied doses did not
cause myorelaxation. However, the studied compounds
caused a unique sedative effect that suppressed behavior, es-
pecially in the open-field test, in contrast with the tranquil-
izer diazepam, which possessed a pronounced anxiolytic ef-
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compounds.
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ACKNOWLEDGMENTS
The work was financially supported by the State Com-
mittee for Science of the Ministry of Education and Science
of the Republic of Armenia under Science Project No.
15T-1D221.
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