Novel binary compounds derived from 1,2,4-thiadiazole

Full text of DOI:10.1134/S0012500812090017

ISSN 0012ꢀ5008, Doklady Chemistry, 2012, Vol. 446, Part 1, pp. 171–173. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © A.N. Proshin, I.V. Serkov, S.O. Bachurin, 2012, published in Doklady Akademii Nauk, 2012, Vol. 446, No. 1, pp. 48–50.
CHEMISTRY
Novel Binary Compounds Derived from 1,2,4ꢀThiadiazole
A. N. Proshin, I. V. Serkov, and Corresponding Member of the RAS S. O. Bachurin
Received February 9, 2012
DOI: 10.1134/S0012500812090017
The design of multifunctional pharmaceuticals group in their molecule provides an opportunity for
with a broad spectrum of activity that are capable of
interacting with several targets is one of the promising
directions of contemporary medicinal chemistry.
Recently, molecules containing pharmacophoric thiaꢀ
diazole fragment and showing interesting pharmaceuꢀ
tical properties [1], including neuroprotective [2],
have attracted much attention as promising therapeuꢀ
tics. In continuation of our studies, we developed a
method of synthesis of 1,2,4ꢀthiadiazole derivatives
containing biogenic amines as a second pharmacophꢀ
ore or nitroxy group as a nitrogen oxide NO producer.
further modification of the parent compound by introꢀ
ducing different pharmacophoric groups. Thus,
enamines (4a
tive yield by the reaction of compound
) in methanol. Initially formed “classical” Shiff base
(imine 3a 3g) undergoes in situ rearrangement into
vinylamine (4a
–4g) were prepared in almost quantitaꢀ
1
with amines
(
2
–
1
–
4g). This is confirmed by H NMR.
The spectra of these compounds show a signal of one
proton at the double bond at 5.15–5.20 ppm (enamine
form, 4a
3.5 ppm (imine form, 3a
–
4g) and the lack of signal of two protons at
–
3g). Amines used were
2
We showed recently that
N,Nꢀdisubstituted 5ꢀaminoꢀ
primary amines (preferably those showing neurotropic
physiological activity, for example, tryptamine, substiꢀ
tuted phenethylamines, aminoalcohols), as well as
2ꢀnitroethanolamine as a pharmacophore containing
an NOꢀreleasing group.
3ꢀ(2ꢀnitroxypropyl)ꢀ1,2,4ꢀthiadiazoles are efficient
blocators of glutamateꢀstimulated 45Са2+ uptake [3]
and, therefore, can affect pathological processes in
different neurodegenerative diseases [4].
We used 5ꢀaminoꢀ3ꢀ(2ꢀoxopropyl)ꢀ1,2,4ꢀthiadiꢀ
Enamines 4a
reduced with sodium borohydride at 40–50
anatoꢀ5ꢀmethylisoxazole [3]. The presence of oxo amino derivatives 5a 5e
–4g isolated by filtration were
azoles (
1) as initial compounds, they were obtained by
°
C to give
the reaction of different amines with 3ꢀisothiocyꢀ
–
.
R3
R1
R3
R1
R2(CH2)2NH2
2
–H2O
O
N
R2
N
S
N
S
N
N
N
Me
N
Me
H
H
1
3a–3g
R1
4''
R3
3''
R1
R3
NaBH4
H
H
2'
4
N
2'''
MeOH, 40–50°C
1'
N
3
N
R2
5
R2
N
1'''
N
N
H
N
Me
N
H
Me
S
S
2
1
4a–4g
5a–5e
Scheme 1
Institute of Physiologically Active Substances, Russian Academy of Sciences, Chernogolovka, Moscow oblast, 142432 Russia
171

172
PROSHIN et al.
4a
,
5a: R1 = 4''ꢀF, R2 = OH, R3 = H;
5b: R1 = 4''ꢀCl, R2 = CH2OH, R3 = 3''ꢀCl;
4b,
4c,
5c: R1 = H, R2 =
, R3 = H;
O
4d,
5d: R1 = 3''ꢀCl, R2 =
, R3 = 4''ꢀF;
S NH2
O
3''''
4e,
5e: R1 = 4''ꢀCl, R2 =
, R3 = H;
1'''' N
H
4f: R1 = 4''ꢀCF3, R2 = ONO2, R3 = H;
4g: R1 = 4''ꢀCl, R2 = ONO2, R3 = H.
EXPERIMENTAL
J 4.9 Hz, OH), 3.57 (2H, m, NНСН2), 3.34 (2H, q, J
5.5 Hz, СН2О), 2.02 (3H, s, CH3).
1H NMR spectra were recorded on a Bruker CXPꢀ
200 spectrometer (Germany), chemical shifts are
1'''ꢀ{2'ꢀ[5ꢀ(3'',4''ꢀDichlorophenylamino)ꢀ1,2,4ꢀ
thiadiazolꢀ3ꢀyl]ꢀ1'ꢀmethylvinylamino}propanol (4b).
Pale yellow crystals, mp 172–174 . Yield 93%.
1H NMR (DMSOꢀd6
, ppm): 10.64 (1H, s,
NH), 8.18 (1H, t, 5.8 Hz, NНСН2), 7.88 (1H, d,
1.8 Hz, Harom), 7.39 (2H, m, Harom), 5.04 (1H, s,
CH), 4.24 (1H, t, 4.9 Hz, OH), 3.50 (2H, q,
5.7 Hz, NНСН2), 3.30 (2H, q, 6.4 Hz, CH2O), 2.01
(3H, s, CH3), 1.69 (2H, m, CH2).
given in the
δ
scale relative to Me4Si. Melting points
°С
were determined using a Boetius hotꢀstage apparatus
and were uncorrected. Evaporation of solutions was
performed with the use of a rotor evaporator in a vacꢀ
uum of a waterꢀjet pump.
,
δ
J
J
Procedure of synthesis of Nꢀsubstituted [3ꢀ(1'ꢀamiꢀ
nopropyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀyl]ꢀarylamines (5a–5g).
J
J
J
A solution of amine
was added dropwise to a solution of 1,2,4ꢀthiadiazole
(0.01 mol) in 10 mL of methanol with stirring, and
2 (0.01 mol) in 10 mL of methanol
[3ꢀ(1'ꢀPhenylethylaminopropenyl)ꢀ1,2,4ꢀthiadiꢀ
azolꢀ5ꢀyl]phenylamine (4c). Pale yellow crystals, mp
153–155 °C. Yield 90%.
1
the reaction mixture was stirred at ambient temperaꢀ
ture for 2–5 h until precipitate appeared. The precipꢀ
itate of enamine 4a–4g was separated by filtration,
washed with methanol, and dried. The resulting
enamine was suspended in 20 mL of methanol, heated
to 40–50°С, 1.5 equiv. of sodium borohydride was
1H NMR (CDCl3,
8.37 (1H, t, 5.8 Hz, NНСН2), 7.31 (10H, m, Harom),
5.14 (1H, s, CH), 3.56 (2H, q, 6.7 Hz, NНСН2),
2.96 (2H, t, 7.0 Hz, CH2), 1.99 (3H, s, CH3).
δ
, ppm): 8.56 (1H, br s, NH),
J
J
J
added, and the mixture was stirred for 2 h. The precipꢀ
itate gradually dissolved. After the reaction compleꢀ
tion, the mixture was cooled, methanol was evapoꢀ
rated, and the residue was diluted with 20 mL of water
4ꢀ(2'''ꢀ{2'ꢀ[5ꢀ(3''ꢀChloroꢀ4''ꢀfluorophenylamino)ꢀ
1,2,4ꢀthiadiazolꢀ3ꢀyl]ꢀ1'ꢀmethylvinylamino}ethyl)ꢀ
benzenesulfonamide (4d). White crystals, mp 213–
215°
1H NMR (DMSOꢀd6
NH), 8.33 (1H, t, 5.8 Hz, NНСН2), 7.90 (1H, dd,
2.8, 6.7 Hz, Harom), 7.77 (2H, d, 8.4 Hz, Harom), 7.45
(1H, m, Harom), 7.40 (2H, d, 8.4 Hz, Harom), 7.18
(1H, t, 8.7 Hz, Harom), 7.11 (2H, br s, NH2), 5.11
С. Yield 87%.
and extracted with methylene chloride (
3
×
10 mL).
, , ppm): 10.38 (1H, br s,
δ
The combined organic extract was dried with sodium
sulfate. The drying agent was removed by filtration,
and the filtrate was evaporated. The residue was
recrystallized to give [3ꢀ(2'ꢀaminopropyl)ꢀ1,2,4ꢀthiaꢀ
J
J
J
J
diazolꢀ5ꢀyl]phenylamines (5a–5e). We failed to
J
reduce compounds 5f and 5g with sodium borohyꢀ
dride.
(1H, s, CH), 3.54 (2H, m, NНСН2), 2.96 (2H, t,
7.1 Hz, CH2), 2.00 (3H, s, CH3).
J
1'''ꢀ{2'ꢀ[5ꢀ(4''ꢀFluorophenylamino)ꢀ1,2,4ꢀthiadiaꢀ
zolꢀ3ꢀyl]ꢀ1'ꢀmethylvinylamino}ethanol (4a). Pale yelꢀ
low crystals, mp 165–167°C. Yield 96%.
(4''ꢀChlorophenyl)ꢀ(3ꢀ{1ꢀ[2'''ꢀ(1H''''ꢀindolꢀ3''''ꢀ
yl)ethylamino]ꢀ1'ꢀmethylethyl}ꢀ1,2,4ꢀthiadiazolꢀ5ꢀ
yl)amine (4e). White crystals, mp 133–135°С. Yield
1H NMR (DMSOꢀd6
NНСН2), 7.57 (1H, dd,
(2H, t, 8.8 Hz, Harom), 5.03 (1H, s, CH), 4.63 (1H, t, 8.43 (1H, t,
,
δ
, ppm): 8.31 (1H, t,
4.9, 9.0 Hz, Harom), 7.06
J 6.0 Hz,
85%.
J
1H NMR (CDCl3,
δ
, ppm): 9.15 (1H, br s, NH),
J
J
5.6 Hz, NНСН2), 8.08 (1H, s, NHind),
DOKLADY CHEMISTRY Vol. 446
Part 1
2012

NOVEL BINARY COMPOUNDS DERIVED FROM 1,2,4ꢀTHIADIAZOLE
173
1H NMR (CDCl3,
7.15 (8H, m, Harom), 3.13 (1H, sextet,
2.78 (6H, m, 3CH2), 1.05 (3H, d, 6.3 Hz, CH3).
δ
, ppm): 7.32 (2H, m, Harom),
7.66 (3H, m, Harom), 7.29 (6H, m, Harom), 5.14 (1H, s,
CH), 3.63 (2H, q, 5.6 Hz, NНСН2), 3.11 (2H, t,
6.9 Hz, CH2), 2.01 (3H, s, CH3).
J
J
J
6.3 Hz, CH),
J
4ꢀ(2'''ꢀ{2'ꢀ[5ꢀ(3''ꢀChloroꢀ4''ꢀfluorophenylamino)ꢀ
1,2,4ꢀthiadiazolꢀ3ꢀyl]ꢀ1'ꢀmethylethylamino}ethyl)ꢀ
benzenesulfonamide (5d). White crystals, mp 110–
(4''ꢀTrifluoromethylphenyl)ꢀ{3ꢀ[1'ꢀ(2'''ꢀnitroxyꢀ
ethylamino)propenyl]ꢀ1,2,4ꢀthiadiazolꢀ5ꢀyl}amine
(4f). Dark brown crystals, mp 147–149°
С. Yield 93%.
112°
1H NMR (CD3CN,
6.7 Hz, Harom), 7.90 (2H, d,
m, Harom), 3.38 (1H, sextet,
m, 3CH2), 1.27 (3H, d, 6.3 Hz, CH3).
С. Yield 81%
1H NMR (CDCl3,
δ
, ppm): 8.47 (1H, t,
J
6.4 Hz,
δ
, ppm): 8.04 (1H, dd,
8.4 Hz, Harom), 7.50 (4H,
8.4 Hz, CH), 3.00 (6H,
J 2.8,
NНСН2), 7.58 (4H, s, Harom), 5.21 (1H, s, CH), 4.59
(2H, t, 5.6 Hz, CH2ONO2), 3.61 (2H, q, 5.6 Hz,
NНСН2), 2.00 (3H, s, CH3).
J
J
J
J
J
(4''ꢀChlorophenyl)ꢀ(3ꢀ{1'ꢀ[2'''ꢀ(1H''''ꢀindolꢀ3''''ꢀ
yl)ethylꢀamino]ꢀ1'ꢀmethylethyl}ꢀ1,2,4ꢀthiadiazolꢀ5ꢀ
yl)amine (5e). Yellowish crystals, mp 75–77°С. Yield
(4''ꢀChlorophenyl)ꢀ{3ꢀ[1'ꢀ(2'''ꢀnitroxyethylꢀ
amino)propenyl]ꢀ1,2,4ꢀthiadiazolꢀ5ꢀyl}amine (4g).
Brown crystals, mp 186–188°С. Yield 92%.
86%.
1H NMR (DMSOꢀd6,
δ
, ppm): 10.57 (1H, s, NH),
1H NMR (CDCl3,
7.55 (3H, m, Harom), 7.03 (6H, m, Harom), 3.15 (1H,
sextet, 6.4 Hz, CH), 2.93 (4H, m, CH2CH2), 2.78
(2H, dd, 2.8, 6.7 Hz, CHCН2), 1.08 (3H, d,
6.3 Hz, CH3).
δ
, ppm): 7.95 (1H, s, NHind),
8.36 (1H, t, 6.5 Hz, NНСН2), 7.53 (1H, d, 9.0 Hz,
Harom), 7.25 (1H, d, 9.0 Hz, Harom), 5.12 (1H, s,
CH), 4.60 (2H, t, 5.5 Hz, CH2ONO2), 3.61 (2H, q,
5.7 Hz, NНСН2), 2.02 (3H, s, CH3).
J
J
J
J
J
J
J
J
1'''ꢀ{2'ꢀ[5ꢀ(4''ꢀFluorophenylamino)ꢀ1,2,4ꢀthiadiꢀ
azolꢀ3ꢀyl]ꢀ1'ꢀmethylethylamino}ethanol (5a). Pale
yellow crystals, mp 144–146° . Yield 82%.
ACKNOWLEDGMENTS
С
This work was supported in part by the Presidium of
the Russian Academy of Sciences (program no. 7
“Development of Methods for Preparation of Chemiꢀ
cal Compounds and Design of New Materials”) and
the Ministry of Education and Science of the Russian
Federation (State Contract no. 14.740.11.0810).
1H NMR (DMSOꢀd6
,
δ
, ppm): 7.52 (1H, m,
Harom), 7.04 (2H, m, Harom), 3.46 (2H, t, 5.5 Hz,
NНСН2), 3.10 (1H, sextet, 6.3 Hz, CH), 2.73 (4H,
m, СН2CHMe, CH2O), 1.21 (3H, d, 6.3 Hz, CH3).
J
J
J
1'''ꢀ{2'ꢀ[5ꢀ(3'',4''ꢀDichlorophenylamino)ꢀ1,2,4ꢀ
thiadiazolꢀ3ꢀyl]ꢀ1'ꢀmethylethylamino}propanol (5b).
REFERENCES
White crystals, mp 147–149°
С. Yield 79%.
1. Siddiqui, N., Ahujaa, P., Ahsana, W., et al., J. Chem.
Pharm. Res., 2009, vol. 1, no. 1, pp. 19–30.
2. Gupta, A., Mishra, P., Pandeya, S.N., et al., Eur.
J. Med. Chem., 2009, vol. 44, pp. 1100–1105.
3. Serkov, I.V., Proshin, A.N., Petrova, L.N., and Bachuꢀ
rin, S.O., Dokl. Chem., 2010, vol. 435, part 2, pp. 311–
313.
1H NMR (CDCl3,
arom), 7.24 (2H, m, Harom), 3.77 (2H, t, J 5.0 Hz,
NНСН2), 3.34 (1H, m, CH), 2.97 (4H, m,
Н2CHMe, CH2O), 1.72 (2H, m, CH2), 1.21 (3H, d,
6.3 Hz, CH3).
δ
, ppm): 7.60 (1H, d,
J
2.3 Hz,
H
C
J
[3ꢀ(1'ꢀPhenylethylaminopropyl)ꢀ1,2,4ꢀthiadiazolꢀ
5ꢀyl]phenylamine (5c). Crystallizing oil. Yield 78%.
4. Lipton, S., Nat. Rev. Drug Discov., 2006, vol. 5,
pp. 160–170.
DOKLADY CHEMISTRY Vol. 446
Part 1
2012