Novel spiroderivatives of isothiourea of the 1,3-thiazine series as promising neuroprotectors

Full text of DOI:10.1007/s11172-011-0377-3

Russian Chemical Bulletin, International Edition, Vol. 60, No. 11, pp. 2436—2438, November, 2011
2436
Novel spiroderivatives of isothiourea of the 1,3ꢀthiazine series
as promising neuroprotectors*
A. N. Proshin, I. V. Serkov, L. N. Petrova, and S. O. Bachurin
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
1 Severnyi proezd, Chernogolovka, 142432 Moscow Region, Russian Federation,
Fax: +7 (495) 785 7024. Eꢀmail: proshin@ipac.ac.ru
In the recent years, one of the intensively developing
1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀylamines 4b—k in
60—80% total yield. Unsubstituted 1ꢀthiaꢀ3ꢀazaspiro[5.5]ꢀ
undecꢀ2ꢀenꢀ2ꢀylamine (4a) was obtained from benzoyl
derivative 3a by the removal of the benzoyl group under
acidic conditions used for the ring closure.
The intramolecular cyclization of thioureas 3a—k unꢀ
der acidic conditions proceeds via formation of thiazine
cycle (the route a) rather than the pyrimidine cycle (the
route b), which was confirmed by Xꢀray crystallography of
the obtained spirothiazines (Fig. 1).
We studied the ability of spirothiazines 4a—k to inhibit
glutamateꢀstimulated uptake of the 45Ca2+ ions in rat brain
cortex synaptosomes. Analysis of the obtained results reꢀ
vealed that compounds 4a—k affect glutamateꢀstimulated
45Ca2+ uptake (Table 1). It is of note that the inhibiting
activity depends on the substituents at exocyclic nitrogen
atom. Unsubstituted spirothiazine 4a and Nꢀethylꢀsubstiꢀ
tuted compound 4c weakly inhibit 45Ca2+ ions uptake,
while Nꢀmethyl derivative 4b exhibits stronger activity. In
case of aryl derivatives, the inhibiting activity depends on
the substituents in the aromatic fragment. Thus, comꢀ
pounds 4d—f bearing electronꢀwithdrawing groups reꢀ
vealed negligible activity in this test, and amino derivative
4h even potentiates 45Ca2+ uptake. However, introduction
prospects in the search for the drugs for the treatment of
the Alzheimer´s disease and relevant neurodegenerative
diseases is the design of inhibitors of glutamateꢀstimulatꢀ
ed Ca2+ ions uptake as the promising neuroprotectors.1
Recently, it was shown that isothiourea derivatives exhibit
neuroprotective and cognitionꢀenhancing properties.2
We developed synthetic route towards hitherto unꢀ
known 2ꢀaminospirothiazines, e.g. the cyclic derivatives
of isothiourea, unsubstituted in the bicyclic moiety. The
synthetic method involved intramolecular ring closure of
thioureas bearing γ,δꢀunsaturated fragment (Scheme 1).
On the first step, a mixture of substituted isothiocyanates
1a—k and γ,δꢀunsaturated amine (2ꢀ(1ꢀcyclohexenyl)ꢀ
ethylamine (2)) in diethyl ether was stirred at ambient
temperature until N,N´ꢀsubstituted thioureas 3a—k preꢀ
cipitated. The latter at reflux with 48% aqueous HBr unꢀ
dergo ring closure to give the corresponding Nꢀsubstituted
Scheme 1
C(4)
C(3)
C(5)
C(2)
C(14)
C(7)
C(8)
C(6)
C(13)
C(1)
S(1)
C(12)
C(11)
C(15)
C(16)
C(9)
N(2)
S(2)
C(19)
N(4)
C(20)
N(1)
R = Bz (1a, 3a), H (4a), Me (b), Et (c), 4ꢀCl—C6H4 (d),
4ꢀCF3—C6H4 (e), 4ꢀAc—C6H4 (f), Ph (g), 4ꢀNH2—C6H4 (h),
2,4,6ꢀMe3—C6H2 (j), 2ꢀMeꢀ6ꢀPri—C6H3 (k)
N(3)
C(18)
C(17)
C(10)
i. Et2O, 20 °C, 2 h; ii. HBr (48%), 100 °C, 5 h.
* Dedicated to Academician of the Russian Academy of Sciences
O. M. Nefedov in occasion of his 80th birthday.
Fig. 1. Geometry of methyl(1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ
2ꢀyl)amine (4b).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2389—2390, November, 2011.
1066ꢀ5285/11/6011ꢀ2436 © 2011 Springer Science+Business Media, Inc.

Nꢀsubstituted spirothiazines
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011 2437
Table 1. Inhibiting activity of spirotiazines 4a—k
Methyl(1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀyl)amine (4b).
Colorless crystals, m.p. 72—73 °C, yield 72%. 1H NMR, δ: 1.30
(m, 1 H, C(8)HH); 1.58 (m, 7 H, C(6)HH, C(7)H2, C(8)HH,
C(9)H2, C(10)HH); 1.71 (t, 2 H, C(5)H2, J = 5.8 Hz); 1.88
(m, 2 H, C(6)HH, C(10)HH); 2.81 (s, 3 H, CH3); 3.66 (t, 2 H,
C(4)H2, J = 5.8 Hz); 3.88 (br.s, 1 H, NH).
Ethyl(1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀyl)amine (4c).
Light gray crystals, m.p. 107—108 °C, yield 62%. 1H NMR, δ:
1.16 (t, 3 H, CH3, J = 7.2 Hz); 1.32 (m, 1 H, C(8)HH); 1.58
(m, 7 H, C(6)HH, C(7)H2, C(8)HH, C(9)H2, C(10)HH); 1.72
(t, 2 H, C(5)H2, J = 5.8 Hz); 1.88 (m, 2 H, C(6)HH, C(10)HH);
3.28 (kq, 2 H, NHCH2, J = 7.2 Hz); 3.61 (br.s, 1 H, NH); 3.64
(t, 2 H, C(4)H2, J = 5.8 Hz).
4ꢀChlorophenyl(1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀyl)ꢀ
amine (4d). Colorless crystals, m.p. 156—158 °C, yield 65%.
1H NMR, δ: 1.27 (m, 1 H, C(8)HH); 1.57 (m, 7 H, C(6)HH,
C(7)H2, C(8)HH, C(9)H2, C(10)HH); 1.91 (t, 4 H, C(6)HH,
C(10)HH, C(5)H2, J = 5.9 Hz); 3.59 (t, 2 H, C(4)H2, J = 5.9 Hz);
6.24 (br.s, 1 H, NH); 7.06 (d, 2 H, Haryl, J = 8.6 Hz); 7.38
(d, 2 H, Haryl, J = 8.6 Hz).
4ꢀTrifluoromethylphenyl(1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ
2ꢀyl)amine (4e). Colorless crystals, m.p. 150—152 °C, yield 75%.
1H NMR, δ: 1.29 (m, 1 H, C(8)HH); 1.58 (m, 7 H, C(6)HH,
C(7)H2, C(8)HH, C(9)H2, C(10)HH); 1.85 (t, 4 H, C(6)HH,
C(10)HH, C(5)H2, J = 5.9 Hz); 3.60 (t, 2 H, C(4)H2, J = 5.9 Hz);
6.11 (br.s, 1 H, NH); 7.25 (d, 2 H, Haryl, J = 8.4 Hz); 7.49
(d, 2 H, Haryl, J = 8.4 Hz).
4
R
K43/21 (%)*
IC50
/μmol L–1
a
b
c
d
e
f
g
h
j
H
Me
Et
191.4 9.8
134.2 13.2
165.3 12.1
112.7 7.4
142.1 5.3
145.1 6.3
133.2 6.3
114.7 14.5
112.6 2.5
115.4 5.4
—
—
—
35.5
77.6
81.3
63.1
—
4ꢀCl—C6H4
4ꢀCF3—C6H4
4ꢀAc—C6H4
Ph
4ꢀNH2—C6H4
2,4,6ꢀMe3—C6H2
2ꢀMeꢀ6ꢀPri—C6H3
9.3
20.9
k
K* is percentage of 45Ca2+ uptake in rat brain synaptosomes to
control (control — 100%).
of the electronꢀreleasing substituents in the orthoꢀ and
paraꢀpositions of the benzene ring (compounds 4j,k) reꢀ
sulted in sharp increase in the inhibiting activity.
Thus, it is possible to conclude that 1ꢀthiaꢀ3ꢀazaꢀ
spiro[5.5]undecꢀ2ꢀenꢀ2ꢀylamines synthesized actively regꢀ
ulate glutamateꢀstimulated uptake of 45Ca2+ ions, which
makes promising to search for new neurocorrectors in this
class of compounds.
4ꢀAcetylphenyl(1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀyl)ꢀ
amine (4f). Creamꢀcolored crystals, m.p. 162—164 °C, yield 69%.
1H NMR, δ: 1.29 (m, 1 H, C(8)HH); 1.56 (m, 7 H, C(6)HH,
C(7)H2, C(8)HH, C(9)H2, C(10)HH); 1.85 (t, 2 H, C(5)H2,
J = 5.9 Hz); 1.88 (m, 2 H, C(6)HH, C(10)HH); 3.61 (t, 2 H,
C(4)H2, J = 5.9 Hz); 2.55 (s, 3 H, C(O)CH3); 6.25 (br.s,
Experimental
1
H NMR spectra were recorded on Bruker CXPꢀ200
instrument (Germany) in CDCl3, the chemical shifts are given
in the δ scale relative to Me4Si. Melting points were deꢀ
termined on a Boetius apparatus and were uncorrected. The
solvents were removed using rotary evaporator under water pump
vacuum.
1 H, NH); 7.24 (d, 2 H, Haryl, J = 8.6 Hz); 7.87 (d, 2 H, Haryl
J = 8.6 Hz).
,
Phenyl(1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀyl)amine (4g).
1
Light gray crystals, m.p. 105—107 °C, yield 79%. H NMR, δ:
1.22 (m, 1 H, C(8)HH); 1.50 (m, 7 H, C(6)HH, C(7)H2,
C(8)HH, C(9)H2, C(10)HH); 1.78 (m, 4 H, C(5)H2, C(6)HH,
C(10)HH); 3.55 (m, 2 H, C(4)H2); 6.20 (br.s, 1 H, NH); 6.90
(m, 1 H, Haryl); 7.19 (m, 4 H, Haryl).
4ꢀAminophenyl(1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀyl)ꢀ
amine (4h). Gray brownish crystals, m.p. 160—162 °C, yield 67%.
1H NMR, δ: 1.31 (m, 1 H, C(8)HH); 1.59 (m, 7 H, C(6)HH,
C(7)H2, C(8)HH, C(9)H2, C(10)HH); 1.89 (m, 4 H, C(5)H2,
C(6)HH, C(10)HH); 3.59 (m, 2 H, C(4)H2); 4.94 (br.s, 2 H,
NH2); 6.20 (br.s, 1 H, NH); 6.64 (d, 2 H, Haryl, J = 8.6 Hz); 6.99
(d, 2 H, Haryl, J = 8.6 Hz).
2,4,6ꢀTrimethylphenyl(1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀ
yl)amine (4j). Light yellow crystals, m.p. 124—126 °C, yield 76%.
1H NMR, δ: 1.33 (m, 1 H, C(8)HH); 1.55 (m, 7 H, C(6)HH,
C(7)H2, C(8)HH, C(9)H2, C(10)HH); 1.83 (m, 2 H, C(6)HH,
C(10)HH); 2.17 (s, 6 H, 2 CH3); 1.93 (t, 2 H, C(5)H2,
J = 5.7 Hz); 3.52 (t, 2 H, C(4)H2, J = 5.7 Hz); 2.29 (s, 3 H,
CH3); 6.21 (br.s, 1 H, NH); 6.86 (s, 2 H, Haryl).
NꢀSubstituted 1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀylamines
4a—k. To a stirred solution of 2ꢀ(1ꢀcyclohexenyl)ethylamine 2
(1.25 g, 0.01 mol) in diethyl ether (20 mL), a solution of arylꢀ
isothiocyanate (0.01 mol) in diethyl ether (20 mL) was added
dropwise. Then the reaction mixture was stirred for 2—5 h at
ambient temperature until formation of precipitate. The preꢀ
cipitate of thiourea 3 was filtered off, dried, suspended in 48%
aqueous HBr (10 mL), and refluxed for 5 h; the precipitate
dissolved during the reaction. After the completion of the reꢀ
action, the mixture was cooled to ambient temperature, dilutꢀ
ed with water (20 mL) and dichloromethane (50 mL), and
then saturated aqueous NaHCO3 was carefully added until the
solution was basic. The organic layer was separated and dried
with Na2SO4. The drying agent was filtered off and the solꢀ
vent was removed. The residue was recrystallized from propaneꢀ
2ꢀol to give Nꢀsubstituted 1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀ
ylamine (4).
1ꢀThiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀylamine (4a). Light
gray crystals, m.p. 104—106 °C, yield 67%. 1H NMR, δ: 1.27
(m, 1 H, C(8)HH); 1.56 (m, 7 H, C(6)HH, C(7)H2, C(8)HH,
C(9)H2, C(10)HH); 1.67 (t, 2 H, C(5)H2, J = 5.9 Hz); 1.85 (m, 2 H,
C(6)HH, C(10)HH); 3.59 (t, 2 H, C(4)H2, J = 5.8 Hz); 3.66
(br.s, 2 H, NH2).
2ꢀMethylꢀ6ꢀisopropylphenyl(1ꢀthiaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀ
enꢀ2ꢀyl)amine (4k). Yellow brownish crystals, m.p. 96—98 °C,
yield 75%. H NMR, δ: 1.22 (d, 6 H, CH(CH3)2, J = 6.8 Hz);
1.31 (m, 1 H, C(8)HH); 1.56 (m, 7 H, C(6)HH, C(7)H2,
C(8)HH, C(9)H2, C(10)HH); 1.85 (m, 2 H, C(6)HH, C(10)HH);
2.01 (t, 2 H, C(5)H2, J = 5.7 Hz); 2.23 (s, 3 H, CH3); 3.11
1

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011
Proshin et al.
(m, 1 H, CH(CH3)2); 3.54 (m, 2 H, C(4)H2); 6.25 (br.s, 1 H,
NH); 7.11 (m, 3 H, Haryl).
References
1. S. Lipton, Nat. Rev. Drug Discov., 2006, 5, 160.
2. G. L. Perlovich, A. N. Proshin, T. V. Volkova, S. V. Kurkov,
V. V. Grigoriev, L. N. Petrova, S. O. Bachurin, J. Med. Chem.,
2009, 52, 1845.
This work was financially supported in parts by
the Russian Foundation for Basic Research (Project
Nos. №11ꢀ03ꢀ00863ꢀa) and Ministry for Science and
Education of the Russian Federation (state contract
Nos. 14.740.11.0810).
Received October 6, 2011;
in revised form November 1, 2011