Novel 1,2,4-thiadiazoles with an NO-producing fragment

Full text of DOI:10.1134/S0012500810120013

ISSN 0012ꢀ5008, Doklady Chemistry, 2010, Vol. 435, Part 2, pp. 311–313. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © I.V. Serkov, A.N. Proshin, L.N. Petrova, S.O. Bachurin, 2010, published in Doklady Akademii Nauk, 2010, Vol. 435, No. 4, pp. 479–481.
CHEMISTRY
Novel 1,2,4ꢀThiadiazoles with an NOꢀProducing Fragment
I. V. Serkov, A. N. Proshin, L. N. Petrova, and Corresponding Member of the RAS S. O. Bachurin
Received June 9, 2010
DOI: 10.1134/S0012500810120013
At present, the design of hybrid multitarget pharꢀ cals, for example, NOꢀdonor drugs based on Tacrine,
is also applied for this purpose [3].
maceuticals by introduction of nitric oxideꢀproducing
fragment in a molecule of known medicinal agent is
one of promising directions of medicinal chemistry
[1]. Nitric oxide (NO) is an endogenous signaling
molecule with a wide spectrum of biological activity
and plays an important role in nervous system funcꢀ
tioning. Therefore, NO donors are used for the treatꢀ
ment of different neurodegenerative disorders, Alzheꢀ
imer disease including [2]. The introduction of an
One of promising approaches to search for pharꢀ
maceuticals for the treatment of Alzheimer disease
and related neurodegenerative disorders is the search
for blocking agents for glutamateꢀmediated influx of
Ca2+ [4].
In recent time, molecules containing a thiadiazole
pharmacophore fragment and showing interesting
pharmacological properties, including neuroprotecꢀ
tive ones, attract much attention as promising pharꢀ
NOꢀproducing fragment into known pharmaceutiꢀ maceuticals [5].
R1
H
N
2
N
NCS
+ R1R2NH
N
1
S
R2
3
R1
N
S
N
O
O
N
5
4
N
R2
O
1
2a–2g
3a–3g
4a–4g
2
N
1
S
N
3
S
R1
R1
N
N
OH
N
ONO2
5
N
R2
4
R2
5a–5g
6a–6g
[R1 = H (
a–e
); R2 = Ar (
a–e
); R1 + R2 = N(CH2CH2)2N–2ꢀPy (
f); N(CH2)5 (g)].
Scheme 1.
We have developed a method for the synthesis of thiocarbonyl group at the N–O bond of the isoxazole
ring, cleavage of the bond followed by recyclization to
form a thiadiazole ring. Intermediate thioureas (
unknown
pyl)ꢀ1,2,4ꢀthiadiazoles (4a
method is based on the Boulton–Katrizky rearrangeꢀ
ment of isoxazole thioureas into 1,2,4ꢀthiadiazoles
[6], which consists in the nucleophilic attack of the
N
,
N
ꢀdisubstituted 5ꢀaminoꢀ3ꢀ(2ꢀoxoproꢀ
3
)
–4g) (Scheme 1). The
necessary for this rearrangement are usually obtained
by the reaction of 3ꢀaminoisoxazole with different
isothiocyanates. To obtain thioureas
first time 3ꢀisothiocyanatoꢀ5ꢀmethylisoxazole (
The isothiocyanate in dipolar aprotic solvents
(DMSO, acetonitrile) was reacted with amines (2a
3
, we used for the
1
) [7].
–
Institute of Physiologically Active Substances, Russian
Academy of Sciences, Chernogolovka, Moscow oblast,
142432 Russia
2g). This approach allowed us to use secondary amines
previously unavailable to this rearrangement and to
311

312
SERKOV et al.
Table 1. Effect of the obtained compounds on the influx of
45Ca2+ in synaptosomes of rat cerebral cortex upon
glutamate stimulation
ratus and were not corrected. Solutions were concenꢀ
trated with a rotary evaporator in a vacuum of a waterꢀ
jet pump.
Hydroxy derivatives
5а–5f
Nitroxy derivatives
6а–6f
Procedure for the synthesis of 5ꢀaminoꢀ3ꢀ(2ꢀ
nitroxypropyl)ꢀ1,2,4ꢀthiadiazoles (6a–6g). A solution
of 1.4 g (0.01 mol) of 3ꢀisothiocyanatoꢀ5ꢀmethylisoxꢀ
azole in 10 mL of acetonitrile was added dropwise to a
Comꢀ
pound
IC50,
M *2
IC50,
M *2
K
, % *1
K
, % *1
µ
µ
solution of 0.01 mol of secondary amine
2 and 50 mg
a
b
c
d
e
f
50.6 9.3
101.2 14.4
84.3 6.1
51.6 3.7
30.1 4.1
110.9 2.2
~100
–
0
2.1
0.2
of ꢀtoluenesulfonic acid in 20 mL of acetonitrile with
p
0.9 0.9
0.2 0.1
4.5 4.4
7.5 3.7
2.6 1.4
stirring. After addition completed, the mixture was
heated to reflux and allowed to stand at ambient temꢀ
perature until precipitate of 5ꢀaminoꢀ3ꢀ(2ꢀoxoproꢀ
pyl)ꢀ1,2,4ꢀthiadiazole 4 formed, which was separated
by filtration. If no precipitation occurred, the reaction
mixture was concentrated and the resultant oil was
–
14.1
10.0
10.7
16.6
~100
63.1
–
1
45 2+
triturated with diethyl ether. Thiadiazole
obtained (0.01 mol) was suspended in 30 mL of methꢀ
anol and heated to 50 , and 0.38 g (0.01 mol) of
4 thus
*
K is amount of absorbed Ca in synaptosomes of rat cerebral
cortex (control is 100%).
2
* IC was determined for active compounds.
°
С
50
sodium borohydride was added in portions with vigorꢀ
ous stirring. The precipitate dissolved as sodium boroꢀ
hydride was added and reaction proceeded. After reacꢀ
tion completed, the methanol was removed, 50 mL of
methylene chloride was added, the solution was
synthesize unique 5ꢀ
N,Nꢀdisubstituted thiadiazoles
(
4a 4g) in 75–95% yield [8].
–
The structure of 1,2,4ꢀthiadiazole
4 contain a
washed with water (
2 × 50 mL), and the organic layer
readily modified oxo group. The presence of this group
provides an opportunity for further modification of the
parent molecule by introduction of different pharmaꢀ
cophore groups, including an NOꢀproducing fragꢀ
ment. The reduction of the oxo group of thiadiazole
was separated and dried with sodium sulfate. The dryꢀ
ing agent was separated by filtration, the filtrate was
concentrated to give 5ꢀaminoꢀ3ꢀ(2ꢀhydroxypropyl)ꢀ
1,2,4ꢀthiadiazole
(0.001 mol) was dissolved in 1 mL of methylene chloꢀ
ride and added with stirring to a cooled to solution
of concentrated nitric acid (500 L) in 5 mL of methꢀ
ylene chloride. The reaction mixture was stirred for
40 min and washed with water ( 10 mL), and the
5. The prepared thiadiazole 5
(
4a
unknown hydroxy derivatives 5a
results in derivatives 6a 6g. We used 100% nitric acid
–
4g) with sodium borohydride leads to previously
0°С
–5g, whose nitration
μ
–
as a nitrating agent. Thus, we have obtained N,Nꢀdisꢀ
ubstituted 5ꢀaminoꢀ1,2,4ꢀthiadiazoles containing a
nitroxy group as the NOꢀproducing fragment.
3
×
organic layer was dried with sodium sulfate. The dryꢀ
ing agent was separated by filtration, and the filtrate
was concentrated to give 5ꢀaminoꢀ3ꢀ(2ꢀnitroxyproꢀ
We have studied the inhibition of glutamateꢀmediꢀ
45
ated influx of Ca2+ in synaptosomes of rat cerebral
pyl)ꢀ1,2,4ꢀthiadiazole 6.
cortex and showed that the introduction of the NOꢀ
producing fragment into aminothiadiazole derivatives
leads to a sharp increase in their inhibiting activity.
Thus, hydroxy derivative 5b did not affect the influx of
45Ca2+ in synaptosomes, whereas nitroxy derivative 6b
showed a considerable inhibiting effect (table).
5ꢀ(3',4'ꢀDichlorophenylamino)ꢀ[3ꢀ(2ꢀnitroxyproꢀ
pyl)]ꢀ1,2,4ꢀthiadiazole (6a: R1 = H, R2 = 3,4ꢀ
1
Cl2C6H3). Light brown crystals, Tm 118–120
NMR (CDCl3,
3H, Harom), 5.59 (m, 1H, CH), 3.10 (m, 2H, CH2),
1.45 (d, 3H, = 6.2 Hz, CH3).
°
C. H
δ
, ppm): 8.55 (br s, 1H, NH), 7.28 (m,
J
Thus, we can state that 5ꢀaminoꢀ1,2,4ꢀthiadiazoles
containing nitroxy group show high blocking activity
toward glutamateꢀmediated influx of Ca2+ and, thereꢀ
fore, they are promising compounds for designing
neuroprotectors of new generation on their basis.
5ꢀ(3'ꢀMethylphenylamino)ꢀ[3ꢀ(2ꢀnitroxypropyl)]ꢀ
1,2,4ꢀthiadiazole (6b: R1 = H, R2 = 3ꢀMeC6H4). Yelꢀ
1
low crystals, Tm 102–104
°
C. H NMR (CDCl3,
δ
,
ppm): 8.12 and 7.31 (m, 4H, Harom), 5.65 (m, 1H,
CH), 3.16 (m, 2H, CH2), 2.66 (s, 3H, CH3), 1.45 (d,
3H,
5ꢀPhenylaminoꢀ[3ꢀ(2ꢀnitroxypropyl)]ꢀ1,2,4ꢀthiaꢀ
diazole (6c: R1 = H, R2 = Ph). C. 1H NMR
m 72–74
CDCl3, , ppm): 11.02 (s, 1H, NH), 8.26 (d, 2H,
9.2 Hz, Harom), 7.73 (d, 2H, = 9.2 Hz, Harom), 7.36 (s,
J = 6.2 Hz, СНCH3).
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker CXPꢀ
200 spectrometer (Germany), chemical shifts are
scale and referenced to Me4Si. Melting
points were determined with a Boetius hotꢀstage appaꢀ
T
°
(
δ
J =
given on the
δ
J
DOKLADY CHEMISTRY Vol. 435
Part 2
2010

NOVEL 1,2,4ꢀTHIADIAZOLES WITH AN NOꢀPRODUCING FRAGMENT
313
1H, Harom), 5.71 (m, 1H, CH), 3.22 (m, 2H, CH2),
1.54 (d, 3H, = 6.2 Hz, СНCH3).
1'ꢀ[3ꢀ(2ꢀNitroxypropyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀ
yl]piperidine (6g: R1 + R2 = N(CH2)5). Yellow oil. 1H
J
NMR (CDCl3,
4H, NСН2), 3.11 (dd, 1H,
СHН), 2.94 (dd, 1H, = 6.6 Hz,
1.70 (br s, 6H, CH2CH2CH2), 1.44 (d, 3H, J = 6.4 Hz,
СНCH3).
δ
, ppm): 5.63 (m, 1H, CH), 3.48 (br s,
= 6.8 Hz, = 14.9 Hz,
= 14.9 Hz, СНH),
5ꢀ(2'ꢀChloroꢀ5'ꢀtrifluoromethylphenylamino)ꢀ[3ꢀ
(2ꢀnitroxypropyl)]ꢀ1,2,4ꢀthiadiazole (6d: R1 = H, R2
= 2ꢀClꢀ5ꢀCF3C6H3). Light yellow crystals, Тm 96–
2
×
J
J
J
J
1
97 C. H NMR (CDCl3,
δ
, ppm): 8.28 (m, 1H,
= 8.4 Hz,
arom), 7.27 (m, 1H, Harom), 5.60 (m, 1H, CH), 3.15
Harom), 8.06 (s, 1H, NH), 7.49 (dm, 1H,
J
H
(m, 2H, CH2), 1.48 (d, 3H, J = 6.4 Hz, СНCH3).
REFERENCES
5ꢀ(2'ꢀMethylꢀ3'ꢀchlorophenylamino)ꢀ[3ꢀ(2ꢀnitroxyꢀ
1. Serkov, I.V. and Bezuglov, V.V., Usp. Khim., 2009,
propyl)]ꢀ1,2,4ꢀthiadiazole (6e: R1 = H, R2
=
vol. 78, p. 442.
2ꢀMeꢀ3ꢀClC6H3). Dark yellow oil. 1H NMR (CDCl3,
2. Thatcher, G.R.J., Bennett, B.M., and Reynolds, J.N.,
Curr. Alzheimer Res., 2005, vol. 2, p. 171.
δ
, ppm): 9.56 (s, 1H, NH), 7.81 (m, 1H, Harom), 7.22
(m, 2H, Harom), 5.58 (m, 1H, CH), 3.18 (m, 2H,
CH2), 1.47 (d, 3H, = 6.4 Hz, СНCH3).
1'ꢀ[3ꢀ(2ꢀNitroxypropyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀyl]ꢀ
(4'ꢀpyridinꢀ2ꢀyl)piperazine (6f: R1 R2
N(CH2CH2)2N–2ꢀPy). Dark yellow oil. H NMR
(CDCl3, , ppm): 8.28 (m, 1H, Harom), 7.56 (m, 1H,
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Chem., 2008, vol. 51, p. 713.
J
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+
=
1
6. Boulton, A.J., Katrizky, A.R., and Hamid, A.M.,
δ
J. Chem. Soc., 1967, p. 2005.
Harom), 6.77 (m, 1H, Harom), 6.70 (m, 1H, Harom), 5.55
(m, 1H, CH), 3.73 (m, 4H, N(CH2CH2)2N–2ꢀPy),
3.63 (m, 4H, N(CH2CH2)2N–2ꢀPy), 3.14 (m, 2H,
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Khim. Geterotsikl. Soedin., 2007, vol. 11, p. 1738.
8. Perlovich, G.L., Proshin, A.N., Bachurin, S.O., et al.,
CH2), 1.44 (d, 3H, J = 6.4 Hz, СНCH3).
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DOKLADY CHEMISTRY Vol. 435
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2010