Synthesis and properties of 1-[(adamantan-1-yl)methyl]-3-pyrazolyl ureas

Article abstract of DOI:10.1007/s10593-019-02428-2

[Figure not available: see fulltext.] A series of 1,3-disubstituted ureas containing 1,3,5-trisubstituted pyrazole and (adamantan-1-yl)methyl fragments were synthesized in the reaction of 1-(isocyanatomethyl)adamantane with 3- or 4-aminopyrazoles under mi

Full text of DOI:10.1007/s10593-019-02428-2

DOI 10.1007/s10593-019-02428-2
Chemistry of Heterocyclic Compounds 2019, 55(2), 129–134
Synthesis and properties of 1-[(adamantan-1-yl)methyl]-
3-pyrazolyl ureas
Vladimir S. D'yachenko1, Dmitry V. Danilov1, Tatyana K. Shkineva2,
Irina А. Vatsadze2, Vladimir V. Burmistrov1, Gennady M. Butov1*
1 Volzhsky Polytechnic Institute (branch)
of the Volgograd State Technical University,
42a Engelsa St., Volzhsky, 404121, Russia; e-mail: butov@volpi.ru
2 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky Ave., Moscow 119991, Russia; e-mail: tanya_shkineva@mail.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(2), 129–134
Submitted October 15, 2018
Accepted December 21, 2018
A series of 1,3-disubstituted ureas containing 1,3,5-trisubstituted pyrazole and (adamantan-1-yl)methyl fragments were synthesized in
the reaction of 1-(isocyanatomethyl)adamantane with 3- or 4-aminopyrazoles under mild conditions in 67–92% yields. The inhibitory
activity of the obtained compounds with respect to human soluble epoxide hydrolase (sEH) was 16.2–50.2 nmol/l, with solubility in
water of 45–85 µmol/l.
Keywords: adamantane derivatives, amines, 1,3-disubstituted ureas, isocyanates, pyrazoles, soluble epoxide hydrolase (sEH), inhibitors.
Substituted pyrazoles exhibit diverse biological activity
such as analgesic and anti-inflammatory,1 antibacterial,2
antifungal,3 antitumor,4 and antiviral,5 and are also being
investigated as inhibitors of human soluble epoxide
hydrolase (sEH) (IC50 220–224 nmol/l).6 The data of
inhibitory activity of pyrazole-containing compounds
toward protein kinase p38 MAPKα, as well as the results of
molecular docking showed that the high activity of these
compounds is due to the ability of the pyrazole
pharmacophoric center to bind up to two amino acid
residues in the active center of the enzyme.7
1,3-Disubstituted ureas comprising a pyrazole group in
their structure were studied as inhibitors of cyclin-
dependent kinase CDK5 and glycogen synthase kinase
GSK3α/β,8 inhibitors of viral oncogene sarcoma BRAF,9
inhibitors of tyrosine kinase activity of VEGFR-2
receptors,10 and selective dual inhibitor of complexes 1 and
Human sEH is an enzyme involved in the metabolism of
epoxy fatty acids (arachidonic acid metabolites) to the
corresponding vicinal diols by catalytic addition of a water
molecule.14 Inhibition of human sEH with target-oriented
inhibitors has a positive effect on the treatment of
hypertension and kidney disease,15 inflammatory and
painful conditions,16 as well as other socially significant
diseases. Analysis of the sEH gene structure shows that it
consists of two globular proteins, each of which contains
its own C-terminal epoxide hydrolase and N-terminal
phosphatase domains for binding to substrates of different
nature.17
1,3-Disubstituted ureas occupy an important place
among the existing inhibitors of the C-terminal epoxide
hydrolase domain. For example, small symmetrical ureas,
such as 1,3-dicyclohexylurea, are potent inhibitors of
sEH.18 However, their low solubility in water severely
limits their use as dosage forms. Asymmetrical ureas with a
flexible side chain, such as 12-(1-adamantan-1-ylureido)-
dodecanoic acid (AUDA), have been developed to increase
solubility. Despite the fact that this class of sEH inhibitors
shows high activity in in vivo tests, they are extremely
rapidly metabolized, which reduces their applicability.19
2
(mTORC1 and mTORC2), rapamycin targets in
mammals.11 Inhibition of kinase JNK3 with such structures
is a promising strategy in the treatment of neuro-
degeneration.12 A number of ureas containing 1,5-di-
arylpyrazole group in their structure were studied as dual
cyclooxygenase-2 (COX-2) and sEH inhibitors.13
0009-3122/19/55(2)-0129©2019 Springer Science+Business Media, LLC
129

Chemistry of Heterocyclic Compounds 2019, 55(2), 129–134
Scheme 1
To date, more than 3000 disubstituted ureas containing
addition, pyrazoles 3a–f contain methyl substituents in
positions 3 and 5 of the pyrazole ring, which, in our
opinion, will help to protect it from the oxidative effects of
cytochromes P450. The selected series of compounds 3a–h
will allow to study the effect of the structure of substituted
pyrazoles on the properties of 1,3-disubstituted ureas 1a–h
and on their inhibitory activity against human sEH.
aliphatic, aromatic, and heterocyclic fragments have been
investigated as sEH inhibitors.20 Many of the synthesized
inhibitors of sEH are adamantyl ureas with the ureid
pharmacophoric center. However, compounds that combine
high activity, solubility in water, and resistance to
metabolism were not found among them.
In continuation of our work on the synthesis of
adamantyl-containing 1,3-disubstituted ureas with a hetero-
cyclic fragment21 and the study of their properties, a series
of 1,3-disubstituted ureas 1a–h containing the pyrazole
fragment were obtained for the first time (Scheme 1). The
synthesis of products 1a–h was carried out by stirring 1-(iso-
cyanatomethyl)adamantane (2) and the corresponding
aminopyrazoles 3a–h in anhydrous DMF in the presence of
Et3N with the molar ratio of reagents 2:3:Et3N of 1:1:1 for
12 h at room temperature. During the reaction, precipitation
of 1,3-disubstituted ureas 1a–h in the form of white crystals
was observed. At the end of the reaction, the products were
filtered off and washed with EtOAc, 1 N aqueous HCl to
remove the residual amine, and a small amount of H2O.
The yields of the obtained compounds 1a–h were 67–92%.
The structure of the obtained compounds was confirmed
Mild reduction with hydrazine, well proven for nitro-
pyrazoles,25 was used to obtain the starting aminopyrazoles
3b–h. Indeed, treatment of nitro derivatives 4b–h with
hydrazine on activated carbon in the presence of
FeCl3·6H2O as a catalyst allowed us to obtain the desired
amines 3b–h in high yields (Scheme 2).
Scheme 2
NH2
Me
Me
N
N
R3
3b–f
N2H4, Cactivated
FeCl3·6H2O
R1R2
H2N
O2N
O
N
N
MeOH, , 10 h
66 80%
N
R3
N
N
4b–h
3g
1
using IR spectroscopy, H, 13C NMR spectroscopy, and
O
b R3 = 4-MeC6H4, c R3 = 4-ClC6H4,
H2N
elemental analysis.
d R3 = 4-FC6H4, e R3 = 2-ClC6H4,
1-(Adamantan-1-yl)-3-(1-alkyl-1H-pyrazolyl)ureas des-
cribed in the literature were studied as inhibitors of human
sEH (IC50 488–2512 nmol/l) and had water solubility
values of 4.5–149.3 µmol/l.22 In order to increase the
inhibitory activity against human sEH, we carried out
screening of the initial reagents for inhibitor synthesis. The
choice of isocyanate 2 is due to the presence of a
methylene bridge between the isocyanate group and the
adamantyl fragment, which increases the conformational
mobility of the pharmacophoric fragment and contributes
to a better adjustment of the inhibitor in the active center of
sEH.23 Benzyl-substituted aminopyrazoles 3a–e,h as well
as aminopyrazoles 3f,g, containing N-[2-(morpholin-4-yl)-
2-oxoethyl] group were selected as the pyrazole component
(Scheme 1); such pyrazoles are widely used in the
synthesis of biologically active compounds.24 It is known
that the presence of the methyl group, as well as halogen
atoms (chlorine, fluorine) in the aromatic ring increases the
inhibitory activity of compounds with respect to sEH.19 In
N N
3h
O
Ph
f R3 =
N
O
Nitropyrazoles 4f,g with an N-[2-(morpholin-4-yl)-
2-oxoethyl] substituent were obtained by a known method
from nitropyrazolylacetic acids 5f,g26 synthesized by us
earlier (Scheme 3).
Scheme 3
130

Chemistry of Heterocyclic Compounds 2019, 55(2), 129–134
The obtained series of 1,3-disubstituted ureas 1a–h was
(5 ml) at 0°С. The mixture was stirred at room temperature
for 12 h. The formed white crystals were filtered off, washed
with EtOAc (10 ml), 1 N aqueous HCl (10 ml), and H2O
(10 ml), then air-dried.
investigated in vitro as a target-oriented sEH inhibitors. It
was established that the inhibitory activity against human
sEH for the obtained products 1a–h ranges from 16.2 to
50.2 nmol/l. Other properties of compounds 1a–e,h are
presented in Table 1. For compounds 1a–e, the introduction
of 4-Me, 4-Cl, 4-F, and 2-Cl substituents into the aromatic
ring reduces the solubility in water. Water solubility
decreases when replacing a fluorine atom with a chlorine
atom. The position of the substituent in the aromatic ring
(para- or ortho-) hardly affects the solubility. Urea based
on unsubstituted pyrazole 1h dissolves worse compared to
3,5-dimethylpyrazole-substituted analogs 1a–e. The obtained
pyrazole-containing 1,3-disubstituted ureas 1a–e,h dissolve
better in water in comparison with the known analogs,22
which suggests their higher bioavailability.
1-[(Adamantan-1-yl)methyl]-3-[1-benzyl-3,5-dimethyl-
1H-pyrazol-4-yl]urea (1a). Yield 160 mg (81%), mp 200–
202°С. IR spectrum, ν, cm–1: 3318, 2901, 2847, 1643,
1
1572, 1451, 1301, 1246, 1095, 649. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 7.31 (3H, t, J = 7.0, Н Ph); 7.12
(2H, d, J = 6.9, Н Ph); 5.51 (1Н, br. s, NH); 5.26 (2Н, s,
NCH2Ph); 4.51 (1H, br. s, NHCH2); 2.89 (2H, d, J = 5.8,
NHCH2); 2.24 (3Н, s, CH3); 2.13 (3Н, s, CH3); 1.95 (3Н,
br. s, CH Ad); 1.72–1.54 (6Н, m, CH2 Ad); 1.38 (6H, s,
CH2 Ad). 13C NMR spectrum (DMSO-d6), δ, ppm: 157.1
(C=O); 143.2; 137.9; 134.6; 128.5 (CH Ph); 127.3
(CH Ph); 127.0 (CH Ph); 116.8; 52.3 (CH2); 51.0 (CH2);
39.8 (CH2 Ad); 36.7 (CH2 Ad); 33.7 (C Ad); 27.8 (CH Ad);
11.2 (CH3); 9.1 (CH3). Mass spectrum, m/z (Irel, %): 392
[M]+ (100). Found, %: C 73.30; H 8.29; N 14.14.
C24H32N4O. Calculated, %: C 73.42; H 8.22; N 14.27.
Table 1. Properties of 1,3-disubstituted ureas 1a–e,h
Substituents in
benzene ring
Water
solubility, µmol/l
Compound
cLogP
1-[(Adamantan-1-yl)methyl]-3-[3,5-dimethyl-1-(4-methyl-
benzyl)-1H-pyrazol-4-yl]urea (1b). Yield 166 mg (81%),
mp 223–225°С. IR spectrum, ν, cm–1: 3311, 2901, 2845,
–
85
75
65
75
65
45
3
2
4
3
4
2
4.80
5.25
5.48
4.96
5.43
4.35
1a
1b
1c
1d
1e
1h
4-Ме
4-Cl
4-F
2-Cl
–
1
1642, 1576, 1473, 1449, 1303, 1248, 1108, 730. H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 7.12 (2H, d, J = 7.7, Н Ar);
7.02 (2H, d, J = 7.8, Н Ar); 5.46 (1Н, s, NH); 5.20 (2Н, s,
NCH2Ar); 4.48 (1H, br. s, NHCH2); 2.88 (2H, d, J = 5.8,
NHCH2); 2.33 (3Н, s, CH3); 2.23 (3Н, s, CH3); 2.12 (3Н, s,
CH3); 1.94 (3Н, br. s, CH Ad); 1.72–1.51 (6Н, m, CH2 Ad);
1.37 (6H, s, CH2 Ad). 13C NMR spectrum (DMSO-d6),
δ, ppm: 158.2 (C=O); 144.3; 137.6; 135.9; 135.6; 130.2
(CH Ar); 128.1 (CH Ar); 117.8; 53.2 (CH2); 52.1 (CH2);
40.9 (CH2 Ad); 37.8 (CH2 Ad); 34.9 (C Ad); 28.9 (CH Ad);
21.8 (4-CH3C6H4); 12.3 (CH3); 10.2 (CH3). Mass spectrum,
m/z (Irel, %): 406 [M]+ (100). Found, %: C 73.69; H 8.54;
N 13.74. C25H34N4O. Calculated, %: C 73.85; H 8.43;
N 13.78.
To conclude, 1,3-disubstituted ureas were synthesized
by reacting 1-(isocyanatomethyl)adamantane with 3- or
4-aminopyrazoles in anhydrous DMF in the presence of
Et3N for 12 h at room temperature. The high inhibitory
activity of the obtained compounds in combination with
increased bioavailability makes them promising for further
study as inhibitors of human sEH.
Experimental
IR spectra were registered on
a
Bruker Alpha
1-[(Adamantan-1-yl)methyl]-3-[1-(4-chlorobenzyl)-
3,5-dimethyl-1H-pyrazol-4-yl]urea (1с). Yield 162 mg
(76%), mp 253–255°С. IR spectrum, ν, cm–1: 3310, 2907,
2845, 1642, 1573, 1490, 1448, 1314, 1249, 1093, 1016,
spectrometer in KBr pellets. 1H and 13C NMR spectra were
acquired on a Bruker AM300 (300 and 75 MHz,
respectively) spectrometer in DMSO-d6 and CDCl3 at 25°C
with TMS as internal standard. Assignment of signals in
the 13C NMR spectra were made on the basis of literature
data.25,27 Mass spectra were recorded on a Finnigan MAT
Incos 50 apparatus with direct sample injection in EI
ionization mode (70 eV). Melting points were determined
on a Boetius heating bench (4°C/min heating rate) and are
uncorrected. Elemental analysis was performed on a Perkin
Elmer Series II 2400 Elemental analyzer. Monitoring of the
reaction progress and assessment of the purity of
synthesized compounds were done by TLC on Merck Silica-
gel 60 F254 plates, eluent MeCN–CHCl3, 1:5.
1
803, 732. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
7.40 (2Н, d, J = 8.1, H Ar); 7.16 (2Н, d, J = 8.1, H Ar);
7.09 (1Н, s, NH); 5.74 (1Н, t, J = 5.1, NHCH2); 5.18 (2Н,
s, NCH2Ar); 2.75 (2H, d, J = 5.9, NHCH2); 2.02 (3Н, s,
CH3); 2.01 (3Н, s, CH3); 1.93 (3Н, br. s, CH Ad);
1.70–1.56 (6Н, m, CH2 Ad); 1.42 (6H, s, CH2 Ad). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 7.30 (2H, d, J = 8.8,
Н Ar); 7.06 (2H, d, J = 8.3, Н Ar); 5.50 (1Н, s, NH);
5.21 (2Н, s, NCH2Ar); 4.46 (1H, br. s, NHCH2); 2.89 (2H,
d, J = 5.7, NHCH2); 2.23 (3Н, s, CH3); 2.12 (3Н, s, CH3);
1.95 (3Н, br. s, CH Ad); 1.73–1.53 (6Н, m, CH2 Ad); 1.38
(6H, s, CH2 Ad). 13C NMR spectrum (CDCl3), δ, ppm:
157.0 (C=O); 143.4; 136.8; 134.4; 131.9; 128.8 (CH Ar);
128.4 (CH Ar); 116.7; 51.4 (CH2); 50.9 (CH2); 39.7 (CH2 Ad);
36.6 (CH2 Ad); 33.6 (C Ad); 27.8 (CH Ad); 11.1 (CH3);
8.9 (CH3). Mass spectrum, m/z (Irel, %): 426 [M(35Cl)]+
(100), 428 [M(37Cl)]+ (100). Found, %: C 67.59; H 7.23;
N 13.07. C24H31ClN4O. Calculated, %: C 67.51; H 7.32;
N 13.12.
Precursors 1-(isocyanatomethyl)adamantane (2)23 and
nitropyrazolylacetic acids 5f,g26 were obtained according to
literature methods, pyrazoles 3а and 4b–е,h were supplied
by Crea-Chim.
Synthesis of 1,3-disubstituted ureas 1a–h (General
method). Aminopyrazole 3a–h (0.5 mmol) and Et3N (70 µl,
0.5 mmol) were added to a solution of 1-(isocyanatomethyl)-
adamantane (2) (96 mg, 0.5 mmol) in anhydrous DMF
131

Chemistry of Heterocyclic Compounds 2019, 55(2), 129–134
1-[(Adamantan-1-yl)methyl]-3-[1-(4-fluorobenzyl)-3,5-di-
1-[(Adamantan-1-yl)methyl]-3-(1-benzyl-1H-pyrazol-
3-yl)urea (1h). Yield 168 mg (92%), mp 165–167°С.
IR spectrum, ν, cm–1: 3360, 3281, 3245, 3137, 3122, 2901,
2848, 1673, 1639, 1573, 1552, 1533, 1453, 1407, 1355,
1345, 1312, 1295, 759, 716. 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 8.76 (1Н, s, Н-5 Pz); 8.69 (1Н, s, Н-4 Pz);
7.31 (3H, t, J = 6.8, Н Ph); 7.12 (2H, d, J = 6.9, Н Ph); 7.01
(1Н, br. s, NH); 6.05 (1Н, br. s, NHCH2); 5.18 (2Н, s,
NCH2Ph); 2.82 (2H, d, J = 5.9, NHCH2); 1.93 (3Н, br. s,
CH Ad); 1.70–1.52 (6Н, m, CH2 Ad); 1.40 (6H, s, CH2 Ad).
13C NMR spectrum (DMSO-d6), δ, ppm: 159.8; 155.9
(C=O); 150.3; 138.8; 132.2 (CH Ph); 129.6 (CH Ph); 128.7
(CH Ph); 95.3; 55.6 (CH2); 52.1 (CH2); 40.9 (CH2 Ad);
37.7 (CH2 Ad); 34.5 (C Ad); 28.8 (CH Ad). Mass
spectrum, m/z (Irel, %): 364 [M]+ (100). Found, %: C 72.42;
H 7.79; N 15.30. C22H28N4O. Calculated, %: C 72.50;
H 7.74; N 15.37.
Synthesis of aminopyrazoles 3b–h by reduction of
nitropyrazoles 4b–h (General method). Nitropyrazole 4b–h
(3.2 mmol) was added to a solution of N2H4·H2O (0.48 ml,
9.6 mmol) in MeOH (30 ml) at room temperature, followed
by FeCl3·6H2O (22 mg, 0.08 mmol) and activated carbon
(160 mg, 13.2 mmol). The reaction mixture was heated to
boiling point, refluxed for 10 h, then cooled. The precipitate
was filtered off, washed with EtOH (3×20 ml). The combined
filtrates were evaporated under reduced pressure. The residue
was dissolved in H2O (5 ml) and acidified with aqueous
HCl to рН 3–4. The formed precipitate was filtered off,
washed with cold water H2O (2 ml), and air-dried.
methyl-1H-pyrazol-4-yl]urea (1d). Yield 156 mg (76%),
mp 218–220°С. IR spectrum, ν, cm–1: 3318, 2901, 2847,
1643, 1604, 1573, 1510, 1481, 1449, 1314, 1297, 1248,
1
1230, 1157, 1104, 833, 764, 721, 532. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 7.12 (2H, dd, J = 8.4, J = 5.4,
Н Ar); 7.01 (2H, t, J = 8.5, Н Ar); 5.50 (1Н, s, NH); 5.21
(2Н, s, NCH2Ar); 4.47 (1H, br. s, NHCH2); 2.88 (2H, d,
J = 6.0, NHCH2); 2.23 (3Н, s, CH3); 2.13 (3Н, s, CH3);
1.94 (3Н, br. s, CH Ad); 1.72–1.50 (6Н, m, CH2 Ad); 1.38
(6H, s, CH2 Ad). 13C NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 162.6 (d, J = 242.9, C-4' Ar); 158.2 (C=O); 144.5;
135.6; 135.1; 130.3 (d, J = 8.0, C-2',6' Ar); 117.9; 116.4 (d,
J = 21.4, C-3',5' Ar); 52.6 (CH2); 52.1 (CH2); 40.9
(CH2 Ad); 37.8 (CH2 Ad); 34.9 (C Ad); 28.9 (CH Ad); 12.3
(CH3); 10.2 (CH3). Mass spectrum, m/z (Irel, %): 410 [M]+
(100). Found, %: C 70.31; H 7.52; N 13.68. C24H31FN4O.
Calculated, %: C 70.22; H 7.61; N 13.65.
1-[(Adamantan-1-yl)methyl]-3-[1-(2-chlorobenzyl)-3,5-di-
methyl-1H-pyrazol-4-yl]urea (1е). Yield 144 mg (67%),
mp 213–215°С. IR spectrum, ν, cm–1: 3304, 2906, 2842,
1635, 1573, 1488, 1445, 1314, 1248, 1110, 1088, 1018, 830,
725, 696. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.41
(1H, d, J = 7.6, Н Ar); 7.25 (2H, d, J = 6.9, Н Ar); 6.81
(1H, d, J = 6.9, Н Ar); 5.44 (2Н, s, NCH2Ar); 5.40 (1Н, s, NH);
5.17 (1H, br. s, NHCH2); 2.71 (2H, d, J = 4.0, NHCH2);
2.29 (3Н, s, CH3); 2.18 (3Н, s, CH3); 1.96 (3Н, br. s,
CH Ad); 1.73–1.50 (6Н, m, CH2 Ad); 1.44 (6H, s,
CH2 Ad). Mass spectrum, m/z (Irel, %): 426 [M(35Cl)]+ (100),
428 [M(37Cl)]+ (100). Found, %: C 67.66; H 7.24; N 13.01.
C24H31ClN4O. Calculated, %: C 67.51; H 7.32; N 13.12.
1-[(Adamantan-1-yl)methyl]-3-{3,5-dimethyl-1-[2-(mor-
pholin-4-yl)-2-oxoethyl]-1H-pyrazol-4-yl}urea (1f). Yield
146 mg (68%). IR spectrum, ν, cm–1: 3328, 2901, 2847, 1651,
3,5-Dimethyl-1-(4-methylbenzyl)-1H-pyrazol-4-amine
(3b). Yield 551 mg (80%), white powder, mp 108–109°С.
IR spectrum, ν, cm–1: 3377, 3275, 3205, 2920, 1629, 1595,
1515, 1474, 1426, 1374, 1359, 1325, 1255, 1233, 1116,
1
830, 797, 675, 471. H NMR spectrum (DMSO-d6), δ, ppm
1
1634, 1571, 1450, 1345, 1311, 1277, 1244, 1117. H NMR
(J, Hz): 7.10 (2H, d, J = 7.6, Н Ar); 6.92 (2H, d, J = 7.7,
Н Ar); 5.05 (2Н, s, NСН2); 3.38 (2H, br. s, NH2+H2O); 2.23
(3Н, s, 4-CH3C6H4); 2.04 (6Н, s, 2CH3). Mass spectrum, m/z
(Irel, %): 215 [M]+ (100). Found, %: C 72.35; H 8.06;
N 19.68. C13H17N3. Calculated, %: C 72.52; H 7.96;
N 19.52.
spectrum (CDCl3), δ, ppm (J, Hz): 5.78 (1Н, br. s, NH); 4.93
(2Н, s, NCH2C(O)); 4.86 (1H, br. s, NHCH2); 3.72 (4Н, t,
J = 4.4, 2OCH2CH2N); 3.59 (4Н, t, J = 4.4, 2OCH2CH2N);
2.91 (2H, d, J = 5.8, NHCH2); 2.89 (3Н, s, CH3); 2.21 (3Н, s,
CH3); 1.95 (3Н, br. s, CH Ad); 1.76–1.60 (6Н, m, CH2 Ad);
1.50 (6H, s, CH2 Ad). Mass spectrum, m/z (Irel, %): 429 [M]+
(100). Found, %: C 64.22; H 8.12; N 16.38. C23H35N5O3.
Calculated, %: C 64.31; H 8.21; N 16.30.
1-(4-Chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine
(3с). Yield 581 mg (77%), cream-colored powder, mp 62–63°С.
IR spectrum, ν, cm–1: 3382, 3269, 3199, 1627, 1595, 1509,
1492, 1475, 1425, 1375, 1361, 1324, 1255, 1098, 1018, 811,
797, 672, 484, 438. 1H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 7.38 (2H, d, J = 8.3, Н Ar); 7.02 (2H, d, J = 8.4,
Н Ar); 5.06 (2Н, s, NСН2); 3.38 (br. s, NH2+H2O); 2.00
(6Н, s, CH3). Mass spectrum, m/z (Irel, %): 235 [M(35Cl)]+
(100), 237 [M(37Cl)]+ (33). Found, %: C 61.19; H 6.04;
N 17.93. C12H14ClN3. Calculated, %: C 61.15; H 5.99;
N 17.83.
1-(4-Fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine
(3d). Yield 519 mg (74%), light-brown powder, mp 45–46°С.
IR spectrum, ν, cm–1: 3385, 3333, 1605, 1510, 1476, 1439,
1380, 1320, 1252, 1159, 1114, 949, 822, 760, 666, 520, 481.
1H NMR spectrum (DMSO-d6), δ, ppm: 7.15–7.05 (4H, m,
Н Ar); 5.06 (2Н, s, NСН2); 3.38 (br. s, NH2+H2O); 1.98
(6Н, s, CH3). 13C NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 161.3 (d, J = 242.6, C-4' Ar); 136.9; 134.7 (d,
J = 2.9, C-1' Ar); 128.7 (d, J = 8.2, C-2',6' Ar); 125.3; 124.6;
1-[(Adamantan-1-yl)methyl]-3-{1-[2-(morpholin-4-yl)-
2-oxoethyl]-1H-pyrazol-4-yl}urea (1g). Yield 172 mg
(85%). IR spectrum, ν, cm–1: 3324, 2901, 2848, 1636,
1
1596, 1568, 1450, 1400, 1252, 1119, 1041, 645. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 8.03 (1Н, s, H-5 Pz);
7.62 (1Н, s, H-3 Pz); 7.29 (1Н, s, NH); 5.98 (1Н, br. s,
NHCH2); 5.02 (2Н, s, NCH2C(O)); 3.59 (4H, s,
OCH2CH2N); 3.48 (2Н, s, OCH2CH2N); 3.46 (2Н, s,
OCH2CH2N); 2.78 (2H, d, J = 5.7, NHCH2); 1.94 (3Н,
br. s, CH Ad); 1.71–1.58 (6Н, m, CH2 Ad); 1.44 (6H, s,
CH2 Ad). 13C NMR spectrum (DMSO-d6), δ, ppm: 165.7
(C=O); 155.4 (C=O); 129.4 (CH Pz); 123.0 (C-4 Pz); 120.4
(CH Pz); 65.9 (OCH2); 52.7 (CH2); 50.9 (CH2); 44.8 (CH2);
41.8 (CH2); 39.7 (CH2 Ad); 36.6 (CH2 Ad); 33.5 (C Ad);
27.7 (CH Ad). Mass spectrum, m/z (Irel, %): 401 [M]+
(100). Found, %: C 62.74; H 7.90; N 17.53. C21H31N5O3.
Calculated, %: C 62.82; H 7.78; N 17.44.
132

Chemistry of Heterocyclic Compounds 2019, 55(2), 129–134
115.2 (d, J = 21.3, C-3',5' Ar); 51.1 (NCH2); 10.9 (CH3);
The solid residue of acid chloride was dried over Р2О5
under reduced pressure, and used without additional purifi-
cation. Morpholine (1.3 ml, 15 mmol) was added to a suspen-
sion of the corresponding acid chloride (7.5 mmol) in an-
hydrous MeCN (15 ml), and the mixture was stirred at room
temperature for 6 h. The formed precipitate was filtered,
washed with MeCN (1 ml), and recrystallized from Н2О.
2-(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)-1-morpholino-
ethan-1-one (4f). Yield 1.51 g (75%), white powder,
mp 197–199°С. IR spectrum, ν, cm–1: 3423, 2974, 2864,
1648, 1570, 1496, 1469, 1421, 1376, 1363, 1275, 1242,
8.5 (CH3). Mass spectrum, m/z (Irel, %): 219 [M]+ (100).
Found, %: C 65.80; H 6.42; N 19.29. C12H14FN3.
Calculated, %: C 65.73; H 6.44; N 19.16.
1-(2-Chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine
(3e). Yield 543 mg (72%), white powder, mp 98–99°С.
IR spectrum, ν, cm–1: 3346, 3297, 3211, 1591, 1574, 1472,
1445, 1390, 1352, 1331, 1255, 1116, 1048, 1036, 797, 754,
1
748, 683. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
7.47 (1H, d, J = 6.5, Н Ar); 7.32–7.19 (2H, m, Н Ar); 6.50
(1H, d, J = 7.0, Н Ar); 5.12 (2Н, s, NСН2); 3.61 (br. s,
NH2+H2O); 2.03 (6Н, s, CH3). Mass spectrum, m/z (Irel, %):
235 [M(35Cl)]+ (100), 237 [M(37Cl)]+ (33). Found, %:
C 61.07; H 5.91; N 17.88. C12H14ClN3. Calculated, %:
C 61.15; H 5.99; N 17.83.
1
1116, 1070, 1041, 1005, 854, 795, 609, 573. H NMR
spectrum (DMSO-d6), δ, ppm: 5.24 (2Н, s, NCH2C(O)); 3.68–
3.54 (4H, m, 2OCH2CH2N); 3.54–3.40 (4H, m,
2OCH2CH2N); 2.46 (3Н, s, CH3); 2.39 (3Н, s, CH3).
13C NMR spectrum (DMSO-d6), δ, ppm: 164.0 (C=O); 144.6
(C-3 Pz); 142.5 (C-5 Pz); 130.3 (C-4 Pz); 66.0 (CH2); 65.9
(CH2); 51.0 (CH2); 44.7 (CH2); 42.9 (CH2); 13.7 (CH3);
10.5 (CH3). Mass spectrum, m/z (Irel, %): 268 [M]+ (100).
Found, %: C 49.32; H 6.06; N 21.02. C11H16N4O4.
Calculated, %: C 49.25; H 6.01; N 20.88.
1-Morpholino-2-(4-nitro-1H-pyrazol-1-yl)ethan-1-one
(4g). Yield 1.39 g (77%), light-crème-colored powder,
mp 160–161°С. IR spectrum, ν, cm–1: 3449, 3127, 2962,
2863, 1655, 1533, 1509, 1474, 1402, 1334, 1307, 1272,
1236, 1218, 1035, 992, 891, 822, 756, 584. 1H NMR
spectrum (DMSO-d6), δ, ppm: 8.77 (1Н, s, H-5 Pz); 8.25
(1Н, s, H-3 Pz); 5.28 (2Н, s, NCH2C(O)); 3.69–3.54 (4H,
m, OCH2CH2N); 3.54–3.42 (4H, m, OCH2CH2N). Mass
spectrum, m/z (Irel, %): 240 [M]+ (100). Found, %: C 44.83;
H 5.08; N 23.51. C9H12N4O4. Calculated, %: C 45.00;
H 5.04; N 23.32.
The study of the inhibitory properties of compounds
1a–h. Half maximal inhibitory concentration (IC50) in
regards to human sEH were determined at the Department
of Entomology and Nematology of the University of
California, Davis (USA) according to the published
method.28
To determine the solubility in H2O of the obtained
compounds 1a–e,h, a series of their solutions in DMSO
with concentrations ranging from 0.5 to 100 mmol/l were
prepared. Then, 10 μl of the obtained solutions were added
to 990 μl of a buffer solution (0.1 mol/l Na3PO4, pH 7.4).
Thus, the final concentration of the studied compounds
ranged from 5 to 1000 μmol/l, while the concentration of
DMSO was 1%. Solubility was determined by examining
the turbidity (adsorption of light with a wavelength of 590 nm)
of the resulting aqueous solutions. A buffer solution
containing 1% DMSO was used as the reference point.
The lipophilicity coefficient cLogP was calculated using
the Molinspiration program (www.molinspiration.com).
2-(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)-1-(morpho-
lin-4-yl)ethan-1-one (3f). Yield 503 mg (66%), light-
yellow powder, mp 121–122°С. IR spectrum, ν, cm–1:
3382, 3331, 3201, 2973, 2920, 2866, 1655, 1477, 1445, 1352,
1275, 1242, 1116, 1038, 962, 916, 842, 791, 631, 569.
1H NMR spectrum (DMSO-d6), δ, ppm: 4.81 (2Н, s,
NCH2C(O)); 3.59–3.42 (10H, m, NH2, OCH2CH2N); 1.97
(3Н, s, CH3); 1.96 (3Н, s, CH3). 13C NMR spectrum
(DMSO-d6), δ, ppm: 166.0 (C=O); 136.9 (C Pz); 126.1
(C Pz); 123.8 (C Pz); 66.1 (CH2); 66.0 (CH2); 50.2 (CH2);
44.9 (CH2); 41.8 (CH2); 11.0 (CH3); 8.5 (CH3). Mass
spectrum, m/z (Irel, %): 238 [M]+ (100). Found, %: C 55.30;
H 7.70; N 23.74. C11H18N4O2. Calculated, %: C 55.44;
H 7.61; N 23.51.
2-(4-Amino-1H-pyrazol-1-yl)-1-(morpholin-4-yl)ethan-
1-one (3g). Yield 457 mg (68%), light-brown powder,
mp 149–150°С. IR spectrum, ν, cm–1: 3406, 3344, 3241,
3123, 2955, 2856, 1649, 1594, 1459, 1410, 1360, 1269,
1241, 1113, 1039, 1019, 997, 955, 850, 818, 768, 646, 630,
591, 565. 1H NMR spectrum (DMSO-d6), δ, ppm: 6.97 (1Н,
s, H-5 Pz); 6.91 (1Н, s, H-3 Pz); 4.89 (2Н, s, NCH2C(O));
3.55–3.33 (10H, m, NH2, 2OCH2CH2N). 13C NMR spectrum
(DMSO-d6), δ, ppm: 166.0 (C=O); 131.0 (C-4 Pz); 129.7
(CH Pz); 117.8 (CH Pz); 66.0 (CH2); 59.9 (CH2); 52.7
(CH2); 44.9 (CH2); 41.8 (CH2). Mass spectrum, m/z (Irel, %):
210 [M]+. Found, %: C 51.49; H 6.67; N 26.72.
C9H14N4O2. Calculated, %: C 51.42; H 6.71; N 26.65.
1-Benzyl-1H-pyrazol-3-amine (3h). Yield 421 mg
(76%), white powder, mp 64–65 °С. IR spectrum, ν, cm–1:
3430, 3274, 3191, 3095, 3068, 3026, 2920, 1618, 1545, 1499,
1456, 1438, 1394, 1359, 1243, 1193, 1057, 990, 745, 730,
696, 658, 597, 582. 1H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 7.43 (1H, d, J = 2.0, Н-5 Pz); 7.34–7.23 (3H, m, Н Ph);
7.18 (2H, d, J = 7.1, Н Ph); 5.44 (1H, d, J = 2.0, Н-4 Pz);
5.03 (2Н, s, NСН2); 4.58 (2H, s, NH2). 13C NMR spectrum
(DMSO-d6), δ, ppm: 155.7 (C-3 Pz); 138.4 (C Ph); 130.7
(C-5 Pz); 128.3 (CH Ph); 127.4 (CH Ph); 127.2 (CH Ph);
92.1 (C-4 Pz); 54.2 (NCH2). Mass spectrum, m/z (Irel, %):
173 [M]+ (100). Found, %: C 69.20; H 6.44; N 24.36.
C10H11N3. Calculated, %: C 69.34; H 6.40; N 24.26.
The work was supported by the Ministry of Education and
Science of the Russian Federation within the framework of
the Basic part of the State assignment for 2017–2019 (No.
4.7491.2017/CU) for V.S.D., D.V.D., V.V.B., G.M.B.
Synthesis of nitropyrazolylacetic acid amides 4f,g
(General method). Acid 5f,g (7.5 mmol) was added to CCl4
(25 ml), and then SOCl2 (1.1 ml, 15 mmol) was added
dropwise. The reaction mixture was heated under reflux for
10 h, and the solvent was removed under reduced pressure.
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