Silyl modification of biologically active compounds. 7. Synthesis, structure, physicochemical and biological properties of some silicon-containing 3+1 oxorhenium(V) complexes

Article abstract of DOI:10.1023/A:1016095625279

With the aim of studying the structure-physicochemical properties-biological activity relation, we have synthesized a series of organosilicon neutral oxorhenium(V) complexes with mixed ligands and we have determined their lipophilicity. X-ray diffraction has been used to establish the molecular structure of (3-triphenylsiloxypropanethiolato)(3-thiapentane-1, 5-dithiolato)oxorhenium(V), (2-trimethylsiloxy- and 2-hydroxyethanethiolato)[3-(N-methyl)azapentane-1,5-dithiolato]oxorhenium(V). We have studied the neurotropic properties and acute toxicity of the synthesized complexes in vivo and their dependence on the nature of the monodentate and tridentate ligands. We have established that all the studied compounds have pronounced sedative action (they prolong the life of mice under hypoxia conditions, they are phenamine antagonists, they exhibit anticonvulsive action and prevent retrograde amnesia).

Full text of DOI:10.1023/A:1016095625279

Chemistry of Heterocyclic Compounds, Vol. 38, No. 4, 2002
SILYL MODIFICATION OF BIOLOGICALLY
ACTIVE COMPOUNDS. 7*. SYNTHESIS, STRUCTURE,
PHYSICOCHEMICAL AND BIOLOGICAL
PROPERTIES OF SOME SILICON-CONTAINING
"3+1" OXORHENIUM(V) COMPLEXES
A. Zablotskaya1, I. Segal1, A. Kemme1, S. Germane1, J. Popelis1, E. Lukevics1,
R. Berger2, and H. Spies2
With the aim of studying the structure–physicochemical properties–biological activity relation, we have
synthesized a series of organosilicon neutral oxorhenium(V) complexes with mixed ligands and we have
determined their lipophilicity. X-ray diffraction has been used to establish the molecular structure of (3-
triphenylsiloxypropanethiolato)(3-thiapentane-1,5-dithiolato)oxorhenium(V), (2-trimethylsiloxy- and 2-
hydroxyethanethiolato)[3-(N-methyl)azapentane-1,5-dithiolato]oxorhenium(V). We have studied the
neurotropic properties and acute toxicity of the synthesized complexes in vivo and their dependence on
the nature of the monodentate and tridentate ligands. We have established that all the studied
compounds have pronounced sedative action (they prolong the life of mice under hypoxia conditions,
they are phenamine antagonists, they exhibit anticonvulsive action and prevent retrograde amnesia).
Keywords: rhenium(V) complexes, trialkylsilyl ethers, psychotropic activity, X-ray diffraction.
Previously, with the aim of improving the lypophilicity of coordination compounds of rhenium as model
diagnostic tools for tumor diseases of the central nervous system (CNS), we synthesized silicon-containing
oxorhenium(V) complexes with mixed ligands, in which the oxorhenium core ReO3+ is coordinated with
tridentate 3-thiapentane-1,5-dithiolate and monodentate thiolate, containing a silylated hydroxyl functional
group with heavy organosilicon substituents (SiMe2Bu-t, SiPh3).
We naturally expected, in potential diagnostic tools of this type, the presence of psychotropic properties,
which probably could serve as an indirect criterion for selection of these compounds. As we know, the efficacy
of psychotropic drugs is intimately connected with their ability to pass through the blood–brain barrier, which is
due not only to structural parameters but also, to a significant extent, to the lipophilicity of these compounds.
Study of the neurotropic properties of (2-triphenylsiloxyethanethiolato)(3-thiapentane-1,5-dithiolate)-
oxorhenium(V) (9) has shown that this compound exhibits anticonvulsive activity, having protective properties
relative to corazole [1].
_______
* For Communication 6, see [1].
__________________________________________________________________________________________
1
2
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: aez@osi.lv. Forschungszentrum
Rossendorf [Rossendorf Research Center], PO Box 51 01 19, Dresden D-01314, Germany. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 543-555, April, 2002. Original article submitted October 18,
2000.
0009-3122/02/3804-0477$27.00©2002 Plenum Publishing Corporation
477

In this work, we have continued our study of the structure–physicochemical properties–biological
activity relation for rhenium complexes. With the aim of a comparative description of their physicochemical and
biological properties, we synthesized a series of neutral oxorhenium complexes with mixed ligands, where the
oxorhenium(V) core ReO3+ is coordinated by tridentate 3-thia-, 3-oxa-, and 3-(N-methylazapentane-1,5-
dithiolate, and also hydroxyl/triorganylsiloxyalkyl-containing monodentate thiolates.
O
Re
S
S(
S
OSiR3
)
n
S
7–10
R3SiCl Et3N
O
S
O
Re
S
Cl
S
OH
S(
OH
S(
HS(
)
n
)
n
SSS
Re
S
S
S
1
2, 3
O
[NBu4][ReCl4]
O
Re
O
S
S
OSiR3
)
S(
S
OH
)
Me3SiCl
Et3N
n
SOS
n
Re
S
OH
O
HS(
)
n
O
11
4, 5
OH
OSiMe3
O
S
O
Re
S
O
.
S
S
SNS (COOH)2
Me3SiCl
Re
[PPh3]2[ReCl3]
Et3N
S
S
OH
N
N
HS
Me
Me
12
6
N
Me
S
O
;
SSS: HS
SH
HS
SH ; SNS:
SH
SOS: HS
7, 8, 11 R = Me; 9, 10 R = Ph; 2, 4, 7, 9 n = 2; 3, 5, 8, 10, 11 n = 3
(2-Hydroxyethanethiolato)- and (3-hydroxypropanethiolato)(3-thiapentane-1,5-dithiolato)oxorhenium(V)
(2), (3) were obtained by substitution of the chlorine atom in [ReO(SSS)Cl] (1) by the corresponding
monodentate ligand [1].
(2-Hydroxyethanethiolato)-, (3-hydroxypropanethiolato)(3-oxapentane-1,5-dithiolato)- (4), (5), and also
(2-hydroxyethanethiolato)[3-(N-methyl)azapentane-1,5-dithiolato]oxorhenium(V) (6) were obtained by
simultaneous reaction of 3-oxa- or 3-methylaza-1,5-dithiol and mercaptoalkanol with the corresponding
oxorhenium precursor. The silylated oxorhenium complexes 7-12 were obtained by reaction of presynthesized
hydroxyalkyl-containing complexes with the corresponding triorganylchlorosilanes. For synthesis of the
2-triphenylsiloxyethane-containing 3-thiapentane complex 9, we also tested the method of "3+1" complexation
with participation of the presynthesized organosilicon ligand bis(triphenylsilyl)mercaptoethanol (13). The
overall yields of compound 9 after all the steps were practically identical in both cases: 77%.
We used X-ray diffraction to establish the molecular structure of (2-triphenylsiloxyethanethiolato)- [1]
9, (3-triphenylsiloxypropanethiolato)(3-thiapentane-1,5-dithiolato)oxorhenium(V) (10) (Fig. 1), (2-trimethylsil-
oxyethanethiolato)[3-(N-methyl)azapentane-1,5-dithiolato]oxorhenium(V) (12) (Fig. 2), and the hydroxyl-
containing complex 6 (Fig. 3).
478

Fig. 1. Molecular structure of compound 10.
According to the X-ray data, the silicon atom in compounds 9, 10, 12 has a tetrahedral configuration and
the ligands are coordinated around the core ReO3+, forming a distorted tetragonal pyramid with the rhenium
atom in the center.
When the side chain was lengthened in the triphenylsiloxyalkanethiolate complexes (compare 9 and 10)
and when the hydrogen atom was replaced by a trimethylsilyl group in [3-(N-methyl)azapentane-1,5-
dithiolato]oxorhenium complexes (compare 6 and 12), we did not find any substantial changes in the molecular
geometry.
We observe an increase in the Re=O bond length in the series 3-triphenylsiloxypropane-containing
(1.624 Å), 2-triphenylsiloxyethane-containing (1.678 Å) thiapentane compounds 10, 9 and then in the
(2-trimethylsiloxyethanethiolato)(3-methylazapentane) complex 12 (1.693 Å).
In contrast to the unsilylated complex 6, the atoms of the hydroxyethanethiolate substituent in
compound 12 are located practically in the same plane, evidence for which comes from the value of the torsion
angle S(8)–S(9)–C(10)–O(11) (175.7°).
Fig. 2. Molecular structure of compound 12.
479

Fig. 3. Molecular structure of the two conformers a and b of compound 6.
For compound 6, we have established the presence of two independent conformers a and b in the
crystallographic cell (Fig. 3). In conformer 6a, we observe disordering of the carbon atoms in the α position
relative to the N(4) atom of the tridentate ligand, with occupancy factor g 63:37 (6a1 and 6a2 respectively).
Furthermore, in the packing diagram for compound 6, there are two independent tetramers located about the
crystallographic center of symmetry and connected by hydrogen bonds (Fig. 4).
We used HPLC to study the lipophilicity of the synthesized complexes. The data obtained (Table 1)
allow us to adequately assess the effects: introduction of an organosilicon substituent into the molecule;
replacement of the central atom of a tridentate ligand; change in chain length for a monodentate ligand.
Fig. 4. Projection of the unit cell for compound 6.
480

TABLE 1. Lipophilicity of Oxorhenium Complexes [2]
Compound
PHPLC
log PHPLC
Compound
PHPLC
log PHPLC
2.66±0.06
2.06±0.12
2.73±0.04
577±14
0.4249
0.3139
0.4362
2.7612
2.9921
237360±23000
760
1.66±0.02
275±8
5.3754
2.8808
0.2201
2.4393
2
4
5
7
8
10
11
6
12
982±48
For the unsilylated complexes, we found values of log P < 1 (0.2201-0.4362); for the silylated
complexes, they vary from 2.4 to 5.4 and depend on the change in the steric environment about the silicon atom.
The maximum value (log P 5.4) corresponds to compound 10. The value of log P for
(3-trimethylsiloxypropanethiolato)(3-thiapentane-1,5-dithiolato)oxorhenium(V) (8) is half that value. Both for
silylated and for unsilylated complexes, the tendency toward an increase in log P in the series 3-(N-methyl)aza-,
3-oxa-, 3-thia is consistent with the electronic effect of the sulfur, oxygen, and nitrogen atoms of the tridentate
ligands. For both types of complexes, an increase in lipophilicity as the chain of the monodentate ligand
lengthens is characteristic.
We have studied the neurotropic properties and acute toxicity of the synthesized complexes (Table 2).
The action of the compounds on the CNS was assessed from the indices of tests for hypoxic hypoxia, hexenal
and ethanol narcosis, phenamine-induced hyperactivity, corazole-induced convulsions, electroshock, passive
avoidance conditioned reflex, and retrograde amnesia.
All the studied compounds exhibit antihypoxic action to some degree, prolonging the life of mice under
hypoxia conditions by 13% to 50%. In all the synthesized compounds, the pharmacological effect of interaction
with phenamine is pronounced. Almost all of them are phenamine antagonists. The most active is compound 6,
which completely suppresses the antidepressant action. The only compound that definitely enhanced the action
of phenamine, by almost a factor of two (83%), is compound 9. We observe a consistent tendency toward
weakening of the antiphenamine action as the heteroatom of the tridentate ligand changes (as we go from aza- to
oxa- and then to thia-) in the series of both unsilylated and silylated hydroxyalkylthiolate complexes:
TABLE 2. Neurotropic Activity of Oxorhenium Complexes
M, % compared with control (100%)*
Test
Compound
Corazole
convulsions,
clonic/tonic
Hypoxic
hypoxia
Hexenal
narcosis
Ethanol Phenamine
narcosis hyperactivity
Retrograde
amnesia
113*2
134*2
132*2
146*2
150*2
95
97
118*2
103
76*2
89
113
91
77*2
80
134*2/178*2
119*2/157*2
135*2/216*2
134*2/173*2
120/318*2
80*2
40
2
3
60*2
62*2
96
72*2
22*2
2*2
60
4
80*2
80*2
60
17
20
60
5
6
92
73
111
125*2/165*2
133*2/178*2
138*2/213*2
131*2/301*2
7
9 [1]
10
12
95
148*2
89
84
183*2
48*2
22*2
150*2
126*2
60*2
104
81*2
_______
* M is the arithmetical-mean value of the neurotropic activity of the
oxorhenium complexes.
2
≤ 0.05.
* Differences relative to the control are statistically significant with P
481

6 (98%) >> 4 (28%) > 2 (23%), 5 (78%) >> 3 (20%), 12 (78%) >> 7 (enhances the action of phenamine by
11%), and also when the complexes are silylated with the hydroxyethanethiolate monodentate ligand: 6
(98%) > 12 (78%), 2 (23%) > 7 > 9 (compounds 7 and 9 enhance the action of phenamine by 11% and 83%
respectively).
For complexes with the hydroxypropanethiolate monodentate ligand, 3 and 10, we observe the inverse
effect: phenamine-induced hyperactivity is reduced upon triphenylsilylation.
In contrast to the action of the studied compounds in maximal electroshock, where no protective
properties were observed, all the synthesized compounds exhibit anticonvulsive action in corazole-induced
convulsions. As in the case of interaction with phenamine, the deciding role is played by the heteroatom of the
tridentate ligand. The threshold for corazole-induced convulsions increases as the sulfur atom is replaced by an
oxygen atom and then by a nitrogen atom in the series of both hydroxyalkylthiolato- and
trimethylsiloxyethanethiolato-containing complexes:
2 (134/178) << 4 (135/216) << 6 (120/318);
3 (119/157) < 5 (134/173); 7 (125/165) << 12 (131/301).
The strongest anticonvulsive properties are exhibited by (3-methylazapentane-1,5-dithiolato) complexes
6 and 12, which raise the threshold for corazole-induced convulsions by a factor of three (tonic phase).
Introducing an organosilicon substituent has slight effect on the anticonvulsive properties of the complexes,
except for compound 10, the anticonvulsive action of which is 20% higher in the clonic phase and 60% higher
in the tonic phase than for the unsilylated precursor.
The effect of the studied compounds on the duration of hexenal and ethanol narcosis in a dose of
5 mg/kg is weak. However, introducing a triphenylsiloxy substituent into the (2-hydroxyethanethiolato)-3-
thiapentane complex 2 increases the duration of hexenal narcosis by 48%, while introducing it into compound 3
shortens the ethanol narcosis time by 40%. For 3-oxapentane-1,5-dithiolate complexes 4 and 5, antagonistic
activity with respect to ethanol is characteristic.
Almost all the studied complexes prevent retrograde amnesia by 60%-80%.
We did not observe a direct relationship between neurotropic activity and lipophilicity in these studies;
more likely a role is played by structural factors.
Although introducing a trimethylsilyl group has little effect on the indices for hypoxia, duration of
hexenal and ethanol narcosis, and anticonvulsive action, introducing a triphenylsilyl group (and increasing the
lipophilicity up to 5.37) even more considerably changes the properties of the starting hydroxyl-containing
TABLE 3. Bond Lengths in Structures 6a and 6b of Compound 6
Bond
l, Å
Bond
l, Å
1.58(4)
Bond
l, Å
2.292(4)
2.309(4)
1.83(2)
1.48(3)
1.477(18)
1.45(2)
1.53(2)
1.38(3)
1.699(11)
2.202(11)
2.276(4)
2.280(4)
2.300(4)
1.814(18)
1.35(4)
1.53(3)
1.65(4)
1.48(3)
Rea−O(12a)
Rea−N(4a)
Rea−S(1a)
Rea−S(7a)
Rea−S(8a)
N
N
C
C
C
S
C
C
(4a)−C(5a2)
(4a)−C(13a1)
(5a1)−C(6a)
(5a2)−C(6a)
(6a)−S(7a)
(8a)−C(9a)
(9a)−C(10a)
(10a)−O(11a)
Reb−S(7b)
Reb−S(8b)
S
(1b)−C(2b)
(2b)−C(3b)
(3b)−N(4b)
(4b)−C(13b)
(4b)−C(5b)
(5b)−C(6b)
(6b)−S(7b)
S
(8b)−C(9b)
(9b)−C(10b)
(10b)−O(11b)
1.66(6)
1.60(4)
1.36(5)
1.80(2)
1.825(14)
1.52(2)
1.430(19)
C
C
S
(1a)−C(2a)
N
C
C
C
C
N
N
(2a)−C(3a1)
(2a)−C(3a2)
(3a1)−N(4a)
(3a2)−N(4a)
(4a)−C(13a2)
(4a)−C(5a1)
N
C
C
1.826(16)
1.865(16)
1.49(2)
Reb−O(12b)
Reb−N(4b)
Reb−S(1b)
1.685(10)
2.205(13)
2.289(4)
1.38(4)
1.42(4)
C
C
1.37(2)
482

TABLE 4. Bond Angles in Structures 6a and 6b
Angle
ω, deg.
98.0(6)
Angle
ω, deg.
112(3)
107(2)
111(4)
43(3)
O
O
N
O
N
S
O
N
S
S
C
C
C
C
C
(12a)−Rea−N(4a)
(12a)−Rea−S(1a)
(4a)−Rea−S(1a)
(12a)−Rea−S(7a)
(4a)−Rea−S(7a)
(1a)−Rea−S(7a)
(12a)−Rea−S(8a)
(4a)−Rea−S(8a)
(1a)−Rea−S(8a)
(7a)−Rea−S(8a)
(2a)−S(1a)−Rea
(3a1)−C(2a)−C(3a2)
(3a1)−C(2a)−S(1a)
(3a2)−C(2a)−S(1a)
(2a)−C(3a1)−N(4a)
C
(13a1)−N(4a)−Rea
N
(4a)−C(5a1)−C(6a)
(6a)−C(5a2)−N(4a)
(5a2)−C(6a)−C(5a1)
(5a2)−C(6a)−S(7a)
(5a1)−C(6a)−S(7a)
(6a)−S(7a)−Rea
118.2(4)
82.9(3)
115.9(4)
83.6(4)
125.40(18)
103.6(4)
158.4(4)
88.51(14)
85.33(15)
102.6(6)
54(2)
C
C
C
C
C
C
C
O
O
O
N
O
N
121(3)
110.9(15)
101.3(7)
110.4(4)
110.8(9)
111.3(13)
103.8(5)
113.9(4)
81.7(3)
(9a)−S(8a)−Rea
(10a)−C(9a)−S(8a)
(11a)−C(10a)−C(9a)
(12b)−Reb−N(4b)
(12b)−Reb−S(1b)
(4b)−Reb−S(1b)
(12b)−Reb−S(7b)
(4b)−Reb−S(7b)
115(2)
108.5(13)
108(2)
111.9(4)
83.0(3)
N
(4a)−C(3a2)−C(2a)
108(2)
S
(1b)−Reb−S(7b)
(12b)−Reb−S(8b)
(4b)−Reb−S(8b)
133.95(18)
105.2(4)
150.8(3)
89.68(17)
83.12(16)
102.6(6)
107.5(16)
110.6(14)
111.7(15)
108.4(16)
102.8(13)
108.0(10)
113.9(9)
111.9(11)
114.6(16)
110.1(14)
100.4 (5)
109.4 (6)
111.1 (10)
111.8 (16)
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
(13a2)−N(4a)−C(5a1)
(13a2)−N(4a)−C(3a2)
(5a1)−N(4a)−C(3a2)
(13a2)−N(4a)−C(5a2)
(5a1)−N(4a)−C(5a2)
(3a2)−N(4a)−C(5a2)
(13a2)−N(4a)−C(3a1)
(5a1)−N(4a)−C(3a1)
(3a2)−N(4a)−C(3a1)
(5a2)−N(4a)−C(3a1)
(13a2)−N(4a)−C(13a1)
(5a1)−N(4a)−C(13a1)
(3a2)−N(4a)−C(13a1)
(5a2)−N(4a)−C(13a1)
(3a1)−N(4a)−C(13a1)
(13a2)−N(4a)−Rea
(5a1)−N(4a)−Rea
133(3)
O
119(3)
67.6(19)
100(3)
43(3)
107(3)
74(3)
113(2)
49.7(19)
138(3)
24(4)
113(3)
131(4)
76(3)
95(4)
107.4(18)
113.3(18)
110.9(11)
113(2)
N
S
(1b)−Reb−S(8b)
(7b)−Reb−S(8b)
S
C
C
(2b)−S(1b)−Reb
(3b)−C(2b)−S(1b)
N
(4b)−C(3b)−C(2b)
C
C
C
C
C
C
C
C
C
C
C
(13b)−N(4b)−C(3b)
(13b)−N(4b)−C(5b)
(3b)−N(4b)−C(5b)
(13b)−N(4b)−Reb
(3b)−N(4b)−Reb
(5b)−N(4b)−Reb
(6b)−C(5b)−N(4b)
(5b)−C(6b)−S(7b)
(6b)−S(7b)−Reb
(9b)−S(8b)−Reb
(10b)−C(9b)−S(8b)
(3a2)−N(4a)−Rea
(5a2)−N(4a)−Rea
(3a1)−N(4a)−Rea
O
(11b)−C(10b)−C(9b)
108.3(15)
complex. Thus compound 9 definitely prolongs the effect of hexenal (by a factor of 1.5), with the highest effect
among all the synthesized compounds, while compound 10 has higher antihypoxic and anticonvulsive action
compared with its unsilylated precursor 3 and also shortens the duration of ethanol narcosis.
TABLE 5. Bond Lengths in the Structure of Compound 10
Bond
Re−ORe
l, Å
Bond
l, Å
1.76(2)
1.85(2)
1.46(3)
1.817(18)
1.83(2)
1.52(3)
1.48(3)
Bond
l, Å
1.624(12)
2.279(5)
2.290(6)
2.310(5)
2.382(5)
1.82(3)
1.44(3)
C
(3)−S(4)
C
(11)−O(12)
1.619(14)
1.85(2)
Re−S(7)
Re−S(1)
Re−S(8)
Re−S(4)
S
(4)−C(5)
O
(12)−Si
C
C
(5)−C(6)
(6)−S(7)
C
C
(13)−Si
(19)−Si
1.86(2)
1.889(19)
S
(8)−C(9)
Si−C(25)
S
(1)−C(2)
C
C
(9)−C(10)
1.51(3)
C
(2)−C(3)
(10)−C(11)
483

TABLE 6. Bond Angles in the Structure of Compound 10
Angle
ORe−Re−S(7)
ω, deg.
116.7(7)
Angle
ω, deg.
109.2
107.9
S
(7)−C(6)−H(6B)
H
(6A)−C(6)−H(6B)
(6)−S(7)−Re
(9)−S(8)−Re
114.6(7)
128.5(2)
105.7(6)
87.52(18)
83.2(2)
98.1(6)
84.13(18)
84.6(2)
156.03(19)
105.2(7)
113.3(16)
108.9
108.9
108.9
108.9
107.7
109.7(15)
109.7
109.7
109.7
109.7
ORe−Re−S(1)
(7)−Re−S(1)
ORe−Re−S(8)
107.0(8)
110.8(7)
113.7(13)
108.8
S
C
C
C
C
S
C
S
S
(7)−Re−S(8)
(1)−Re−S(8)
(10)−C(9)−S(8)
(10)−C(9)−H(9A)
(8)−C(9)−H(9A)
(10)−C(9)−H(9B)
(8)−C(9)−H(9B)
(9A)−C(9)−H(9B)
(11)−C(10)−C(9)
(11)−C(10)−H(10A)
(9)−C(10)−H(10A)
(11)−C(10)−H(10B)
(9)−C(10)−H(10B)
(10A)−C(10)−H(10B)
(12)−C(11)−C(10)
(12)−C(11)−H(11A)
(10)−C(11)−H(11A)
(12)−C(11)−H(11B)
(10)−C(11)−H(11B)
H
(11A)−C(11)−H(11B)
(11)−O(12)−Si
(18)−C(13)−Si
(14)−C(13)−Si
(24)−C(19)−Si
(21)−C(19)−Si
(12)−Si−C(13)
(12)−Si−C(19)
(13)−Si−C(19)
(12)−Si−C(25)
(13)−Si−C(25)
(19)−Si−C(25)
(30)−C(25)−Si
(26)−C(25)−Si
108.8
108.8
108.8
107.7
ORe−Re−S(4)
S
(7)−Re−S(4)
S
(1)−Re−S(4)
S
(8)−Re−S(4)
S
H
117.6(18)
107.9
C
C
C
(2)−S(1)−Re
(3)−C(2)−S(1)
(3)−C(2)−H(2A)
C
C
C
C
C
H
O
O
107.9
107.9
107.9
107.2
S
C
S
H
(1)−C(2)−H(2A)
(3)−C(2)−H(2B)
(1)−C(2)−H(2B)
(2A)−C(2)−H(2B)
112.5(19)
109.1
C
C
(2)−C(3)−S(4)
(2)−C(3)−H(3A)
109.1
109.1
109.1
107.8
C
O
C
S
C
S
H
(4)−C(3)−H(3A)
(2)−C(3)−H(3B)
(4)−C(3)−H(3B)
(3A)−C(3)−H(3B)
108.2
125.6(13)
122.7(19)
122.0(16)
126.0(18)
119.9(17)
111.2(9)
110.8(9)
108.7(10)
104.8(8)
110.2(9)
111.2(9)
121.8(16)
118.5(17)
C
C
C
C
C
O
O
C
O
C
C
C
C
105.3(11)
108.1(7)
105.8(8)
107.6(18)
110.2
110.2
110.2
110.2
108.5
C
C
C
C
C
(3)−S(4)−C(5)
(3)−S(4)−Re
(5)−S(4)−Re
(6)−C(5)−S(4)
(6)−C(5)−H(5A)
S
C
S
H
(4)−C(5)−H(5A)
(6)−C(5)−H(5B)
(4)−C(5)−H(5B)
(5A)−C(5)−H(5B)
112.2(15)
109.2
109.2
C
C
(5)−C(6)−S(7)
(5)−C(6)−H(6A)
S
(7)−C(6)−H(6A)
109.2
C
(5)−C(6)−H(6B)
With regard to the phenamine test, in some cases probably we can talk about a tendency toward
weakening of the antagonistic properties relative to phenamine, and the appearance of the opposite effect with
introduction of a silyl group (compare 2, 7 and 9; 6 and 12).
Study of the acute toxicity of the compounds confirms the previously indicated presence of a tendency
toward a decrease in toxicity when a trialkylsilyl group is introduced.
484

TABLE 7. Bond Lengths in the Structure of Compound 12
Bond
l, Å
Bond
l, Å
1.51(3)
1.46(3)
1.48(3)
1.42(4)
1.85(3)
1.85(2)
1.47(3)
Bond
l, Å
1.46(3)
1.646(17)
1.83(3)
1.84(3)
1.86(3)
1.693(14)
2.157(19)
2.280(6)
2.280(7)
2.302(6)
1.81(2)
Re−O(17)
Re−N(4)
Re−S(1)
Re−S(7)
Re−S(8)
(1)−C(2)
(2)−C(3)
C
N
N
C
C
S
C
(3)−N(4)
(4)−C(5)
(4)−C(16)
(5)−C(6)
(6)−S(7)
(8)−C(9)
(9)−C(10)
C
O
(10)−O(11)
(11)−Si(12)
Si(12)−C(15)
Si(12)−C(14)
Si(12)−C(13)
S
C
1.58(3)
TABLE 8. Bond Angles in the Structure of Compound 12
Angle
ω, deg.
Angle
ω, deg.
Angle
ω, deg.
95.8(7)
107.7(14)
(4)−C(3)−C(2) 107(2)
112.6(9)
109.8(18)
112(2)
O
O
N
O
N
(17)−Re−N(4)
C
N
(3)−C(2)−S(1)
C
C
(9)−S(8)−Re
(10)−C(9)−S(8)
O
(11)−C(10)−C(9)
(17)−Re−S(1) 116.3(6)
(4)−Re−S(1)
83.5(5)
(17)−Re−S(7) 118.9(6)
82.8(5)
124.1(3)
(17)−Re−S(8) 106.5(6)
C
C
C
C
C
C
C
C
C
(5)−N(4)−C(16) 108(2)
(5)−N(4)−C(3) 106.4(19)
(16)−N(4)−C(3) 105.3(19)
C
O
O
C
O
C
C
(10)−O(11)−Si(12) 126.4(15)
(11)−Si(12)−C(15) 111.7(13)
(11)−Si(12)−C(14) 104.9(12)
(15)−Si(12)−C(14) 110.2(16)
(11)−Si(12)−C(13) 110.0(12)
(15)−Si(12)−C(13) 109.3(15)
(14)−Si(12)−C(13) 110.7(13)
(4)−Re−S(7)
(1)−Re−S(7)
S
(5)−N(4)−Re
(16)−N(4)−Re 110.3(16)
(3)−N(4)−Re
111.5(14)
114.4(15)
O
N
(4)−Re−S(8)
(1)−Re−S(8)
(7)−Re−S(8)
157.5(5)
89.2(2)
83.7(3)
103.5(6)
S
(6)−C(5)−N(4) 112(2)
(5)−C(6)−S(7) 113(2)
S
C
(2)−S(1)−Re
(6)−S(7)−Re
101.4(10)
EXPERIMENTAL
1
29
The H and Si NMR spectra were recorded on a Varian Mercury 200 spectrometer (200 MHz) in
CDCl3, internal standard HMDS. The reaction and purity of the compounds were monitored on Polygram R Sil
G/UV-254 plates in a chloroform–methanol 19:1 (by volume) system. The compounds were separated by
column chromatography on Kieselgel 60 (Merck) silica gel.
Chloro(3-thiapentane-1,5-dithiolato)oxorhenium(V) (1) was obtained according to the procedure in [3].
(2-Hydroxyethane- (2), (3-Hydroxypropane- (3), (2-Triphenylsiloxyethane- (9) and
(3-Triphenylsiloxypropanethiolato)(3-thiapentane-1,5-dithiolato)oxorhenium(V) (10) were synthesized
according to the procedure in [1].
(2-Hydroxyethanethiolato)(3-oxapentane-1,5-dithiolato)oxorhenium(V) (4).
A
solution of
3-oxapentane-1,5-dithiol (31.8 mg, 0.3 mmol) and 2-mercaptoethanol (31.2 mg, 1.33 mmol) in chloroform
(4 ml) was added dropwise with stirring to a suspension (cooled down to 0°C) of (tetrabutylammonium)-
tetrachlorooxorhenate(V) (175.8 mg, 0.3 mmol) in chloroform (10 ml). As the solution was added, a dark cherry
red color developed gradually. The mixture was stirred for 30 min, bringing the temperature up to room
temperature. The solvent was evaporated under vacuum, the residue was dissolved in a chloroform–methanol
mixture (ratio 19:1 by volume) and the latter was purified by column chromatography, using the same solvent
mixture as the eluent. After evaporation of the solvent, compound 4 was isolated as a light pink powder in yield
45.8 mg (37%); mp 95-97°C. Rf 0.26. 1H NMR spectrum, δ, ppm: 1.93 (2H, br. s, SCH2); 3.37, 3.52, 3.71, 4.69
(2H, m; 2H, m; 2H, m; 2H, t, SCH2CH2OCH2CH2S); 4.09 (2H, br. s, OCH2). Found, %: C 17.52; H 3.10;
S 23.10. C6H13O3ReS3. Calculated, %: C 17.35; H 3.13; S 23.13.
485

(3-Hydroxypropanethiolato)(3-oxapentane-1,5-dithiolato)oxorhenium(V) (5).
A
solution of
3-oxapentane-1,5-dithiol (53 µl, 0.5 mmol) and 3-mercaptopropanol (50.6 mg, 47.4 µl, 0.55 mmol) in
chloroform (5 ml) was added dropwise to a solution of (tetrabutylammonium)tetrachlorooxorhenate(V)
(293 mg, 0.5 mmol) in ethanol (10 ml) at 0°C.
The mixture was stirred for 30 min at room temperature, then the solvent was evaporated, the residue
was dissolved in chloroform, and the reaction product was isolated by column chromatography. The eluent was
chloroform–methanol, 19:1. After removal of the solvent, compound 5 was obtained as a cherry-red oil in a
1
yield of 68.7 mg (32%). Rf 0.27. H NMR spectrum, δ, ppm: 2.16 (2H, m, C–CH2–C); 3.31-3.85 (10H, m,
SCH2CH2OCH2CH2S, SCH2, OCH2); 4.66 (2H, br. s, SCH2CH2OCH2CH2S). Found, %: C 20.01; H 3.50;
S 22.24. C7H15O3ReS3. Calculated, %: C 19.68; H 3.50; S 22.38.
(2-Hydroxyethanethiolato)[3-(N-methyl)azapentane-1,5-dithiolato]oxorhenium (V) (6). A mixture
of 3-(N-methylaza)-1,5-dithiol oxalate (72.3 mg, 0.3 mmol) and mercaptoethanol (25.7 mg, 23 µl, 0.33 mmol) in
methanol (3 ml) was added with stirring to
a
suspension of trans-monooxotrichloro-
bis(triphenylphosphine)rhenium(V) (250 mg, 0.3 mmol) in methanol (30 ml). The reaction mixture was
alkalinized using a 0.1 M solution of sodium methoxide in methanol, and then boiled for 3 h. The yellow
suspension then was converted to a dark green solution. After the suspension was cooled down to room
temperature, methylene chloride (25 ml) was added to the reaction mixture and it was acidified to pH 4 with
dilute hydrochloric acid. The organic phase was removed, and the aqueous phase was re-extracted with
chloroform. The organic extracts were combined and dried over Na2SO4. Then the solvent was removed and the
reaction product was isolated by column chromatography in the system chloroform–methanol, 19:1 as the
mobile phase. When the solvent was slowly evaporated, compound 6 crystallized as dark-green crystals in a
1
yield of 101.4 mg (79%); mp 127-129°C. Rf 0.24. H NMR spectrum, δ, ppm: 2.66 (2H, m, SCH2); 3.17, 3.56
(4H, m; 2H, m, SCH2CH2NMeCH2CH2S); 3.37 (3H, s, CH3N); 4.00 (4H, m, OCH2, SCH2CH2NMeCH2CH2S).
Found, %: C 19.82; H 3.78; S 22.44; N 3.17. C7H16NO2ReS3. Calculated, %: C 19.63; H 3.74; S 22.43; N 3.27.
(2-Trimethylsiloxyethanethiolato)(3-thiapentane-1,5-dithiolato)oxorhenium(V) (7). Triethylamine
(50 µl, 0.360 mmol) and then with cooling trimethylchlorosilane (17.2 mg, 20 µl, 0.158 mmol) were added to
complex 2 (60.0 mg, 0.139 mmol) in chloroform (4 ml). The reaction mixture was stirred at room temperature
for 1 h. The course of the reaction was monitored by TLC. After removal of the solvent, the reaction product
was isolated by column chromatography. Eluent chloroform–methanol, 19:1. The fractions with Rf 0.67 were
combined, evaporated down, and lyophilized. Compound 7 was obtained as a light-beige powder in a yield of
42.0 mg (64%); mp 101-102°C. 1H NMR spectrum, δ, ppm: 0.15 (9H, s, SiMe3); 1.96, 3.12, 4.30 (2H, m; 2H, td;
2H, dd, SCH2CH2NMeCH2CH2S); 3.93 (4H, m, SCH2, SCH2CH2NMeCH2CH2S); 4.06 (2H, t, OCH2). Found, %:
C 21.47; H 4.20;S 25.65. C9H21O2ReS4Si. Calculated, %: C 21.47; H 4.18; S 25.45.
(3-Trimethylsiloxypropanethiolato)(3-thiapentane-1,5-dithiolato)oxorhenium(V) (8) was obtained
from of complex 2 (66.5 mg, 0.149 mmol), trimethylchlorosilane (25.8 mg, 30 µl, 0.238 mmol), and
triethylamine (30.2 mg, 42 µl, 0.298 mmol) according to the procedure described for synthesis of compound 7 in
a yield of 63.2 mg (82%); mp 48-49°C. Rf 0.69. 1H NMR spectrum, δ, ppm: 0.12 (9H, s, SiMe3); 1.96, 3.10, 4.28
(2H, m; 2H, m; 2H, dd, SCH2CH2SCH2CH2S); 2.12 (2H, m, C–CH2–C); 3.74-3.99 (6H, m, SCH2CH2SCH2CH2S,
SCH2, OCH2). Found, %; C 23.28; H 4.42; S 24.61. C10H23O2ReS4Si. Calculated, %: C 23.21; H 4.45; S 24.76.
(2-Triphenylsiloxyethanethiolato)(3-thiapentane-1,5-dithiolato)oxorhenium(V) (9) [1]. 1,2-Bis-
(triphenylsilyl)mercaptoethanol (13) (122.0 mg, 0.2054 mmol) and triethylamine (10 mg, 14.3 µl, 0.1027 mmol)
were added to a boiling solution of complex 1 (40 mg, 0.1023 mmol) in acetonitrile (5 ml). The reaction mixture
was boiled for 20 min. After cooling, the solvent was evaporated, the residue was dissolved in chloroform. The
reaction product was isolated by column chromatography. Eluent chloroform–methanol, 19:1. Yield 64.4 mg
(91%).
(3-Triphenylsiloxypropanethiolato)(3-thiapentane-1,5-dithiolato)oxorhenium(V) (10) [1]. 29Si NMR
spectrum, δ, ppm: -75.46.
486

(3-Trimethylsiloxypropanethiolato)(3-oxapentane-1,5-dithiolato)oxorhenium(V) (11) was obtained
from complex 5 (92.5 mg, 0.216 mmol), trimethylchlorosilane (35.15 mg, 41 µl, 0.324 mmol), and triethylamine
(43.63 mg, 60 µl, 0.432 mmol) according to the procedure described for compound 7. The reaction product was
isolated as a dark cherry-red oil. Rf 0.78. 1H NMR spectrum, δ, ppm: 0.11 (9H, s, SiMe3); 2.18 (2H, m, C–CH2–C);
3.30-3.81 (10H, m, SCH2CH2OCH2CH2S, SCH2, OCH2); 4.64 (2H, br. s, SCH2CH2OCH2CH2S). Found, %:
C 23.81; H 4.51; S 19.18. C10H23O3ReS3Si. Calculated, %: C 23.95; H 4.59; S 19.16.
(2-Trimethylsiloxyethanethiolato)[3-(N-methyl)azapentane-1,5-dithiolato]oxorhenium(V) (12) was
obtained from complex 6 (80 mg, 0.187 mmol), trimethylchlorosilane (60.8 mg, 71 µl, 0.561 mmol), and
triethylamine (75.6 mg, 104 µl, 0.748 mmol), similarly as for compound 7. The reaction product was isolated by
column chromatography. Eluent chloroform–methanol, 19:1. After crystallization from ether, compound 12 was
obtained as dark-green crystals in a yield of 77.6 mg (83%); mp 112-113°C. Rf 0.72. 1H NMR spectrum, δ, ppm:
0.14 (9H, s, SiMe3); 2.63 (2H, t, SCH2); 3.14, 3.55 (4H, m; 2H, t, SCH2CH2NMeCH2CH2S); 3.35 (3H, s, NCH3);
29
3.89 (4H, br. s, SCH2CH2NMeCH2CH2S). Si NMR spectrum, δ, ppm: +18.45. Found, %: C 24.12; H 4.77;
S 19.32; N 2.79. C10H24NO2ReS3Si. Calculated, %: C 24.00; H 4.80; S 19.20; N 2.80.
1,2-Bis(triphenylsilyl)mercaptoethanol (13). A solution of triphenylchlorosilane (1.47 g, 5 mmol) in
ether (3 ml) was added dropwise with cooling to a mixture of 2-mercaptoethanol (0.125 g, 0.18 ml, 2.5 mmol),
triethylamine (0.505 g, 0.7 ml, 5 mmol), and ether (10 ml). The reaction mixture was stirred at room temperature
for 2 h. The precipitate of ammonium salt formed was filtered out, the filtrate was evaporated down to dryness,
the residue was extracted with hexane, and the extract was evaporated down. After removal of the hexane, the
yield of compound 13 was 1.25 g (85%); mp 58°C. 1H NMR spectrum, δ, ppm: 2.85 (2H, t, SCH2); 4.11 (2H, t,
13
OCH2); 7.56-7.89 (30H, m, Ar). C NMR spectrum, δ, ppm: 26.9 (SCH2); 65.5 (OCH2); 127.7, 127.8, 130.0,
133.7, 134.9, 135.2 (Ar). Found, %: C 77.00; H 5.76; S 5.41. C38H34OSSi2. Calculated, %: C 76.77; H 5.72;
S 5.39.
An X-ray Diffraction Study of single crystals of compounds 6, 10, and 12 was performed at 25°C on a
Syntex P21 automatic 4-circle diffractometer (MoKα radiation, graphite monochromator, 2θmax = 50°), ω/2θ
scanning (6 and 12) and ω/ω scanning (10). The basic crystallographic characteristics of the crystals of the
studied compounds are given in Table 9.
TABLE 9. Crystallographic Data for Compounds 6, 10, and 12
Compound 6
Compound 10
Compound 12
Empirical formula
Molecular weight
Syngony
Space group
Lattice parameters
а, Å
b, Å
c, Å
α, degrees
β, degrees
С14Н32N2О4Re2S6
857.18
Triclinic
Р-1
С25Н29О2RеS4Si
704.01
Monoclinic
P 21/n
С10Н24NО2ReS3Si
500.77
Monoclinic
P 21/c
10.119(2)
11.109(3)
11.995(2)
105.49(2)
93.93(2)
103.00(3)
1254.2(5)
2
7.597(2)
39.554(8)
9.453(2)
90
107.66(3)
90
10.544(2)
10.553(3)
18.186(4)
90
120.33(2)
90
γ, degrees
Volume of cell, V, ų
2706.7(11)
4
1746.6(7)
4
Number of molecules per
cell, Z
Density, d, g/cm3
Number of reflections
with I > 2σ(I)
2.270
3658
1.728
3346
1.904
2146
Number of refined parameters 281
R factor 0.0530
298
0.0753
163
0.0744
487

The structures were deciphered by the direct method and refined by full-matrix least-squares in the
anisotropic approximation, taking into account the coordinates of the hydrogen atoms, calculated from geometric
considerations. The calculations were performed by the software in [4, 5]. The spatial arrangement of the atoms
with their labels is shown in Figs. 1-3. The interatomic distances and bond angles are given in Tables 3-8. The
coordinates of the atoms with the crystallographic characteristics of compound 6, 10, and 12 have been
deposited in the Cambridge Structural Data Bank (CSD) under the numbers 150661-150663 respectively.
BIOLOGICAL SECTION
The neurotropic activity was studied in mice of the BALB/c and JCR lines weighing 18-23 g in Autumn.
The temperature in the laboratory and the vivarium was maintained at 21±2°C while conducting the
experiments. The study compounds were dissolved in DMSO and injected intraperitoneally 1 h before setting up
the test. The control animals were injected with the same volume of DMSO into the peritoneal cavity. We made
a comparative assessment of the action of the study compound in a dose of 5 mg/kg on the indices of hypoxia,
hexenal and ethanol narcosis, phenamine-induced hyperactivity, corazole-induced convulsions, training and the
Porsolt test, in groups of animals each including 6 individuals.
The action of the compounds on the CNS was assessed by the tests:
1)
anticonvulsive activity, studied by the maximal electroshock test (a.c. current 50 mA, frequency 50
pulses per second, stimulus duration 0.2 sec) and the corazole-induced convulsions test, induced by intravenous
titration with a 1% solution of corazole at a rate of 0.01 ml/sec);
2)
effect on the duration of hexenal narcosis (0.4% hexenal solution intravenously in a dose of 70 mg/kg);
effect on duration of ethanol narcosis (4 g/kg intraperitoneally);
3)
effect on survival time of animals under hypoxic hypoxia conditions, induced by placing the mice (one
by one) into a hermetically sealed chamber of volume 220 cm3 without absorption of carbon dioxide;
4) change in the degree of phenamine-induced hyperactivity (0.4% phenamine solution subcutaneously in a dose
of 10 mg/kg);
5)
effect on training processes and retrograde amnesia induced by electroshock.
We also determined the acute toxicity for intraperitoneal injection and established the median lethal
doses (LD50, mg/kg).
The experimental data were treated statistically, determining the median effective doses (ED50) and
median lethal doses (LD50) by the rapid method in [6]; to assess the mean duration of the narcotic action of
hexenal and ethanol, phenamine-induced hyperactivity, hypoxia, protective properties in corazole-induced
convulsions, we calculated the arithmetic-mean values and their standard error (M m) compared with the
corresponding control data. We used the Student's t test to assess the significance of the difference between the
≤ 0.05.
means. The differences were considered significant for probability level P
The authors would like to thank the Latvian Taiho Foundation and the BMBF International Bureau
(Germany) for supporting this research.
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(1999).
Th. Fietz, H. Spies, H.-J. Pietzsch, and P. Leibnitz, Inorg. Chim. Acta, 231, 233 (1995).
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488

4.
5.
6.
G. M. Sheldrick, SHELX97. Program for the Solution of Crystal Structures, University of Göttingen,
Germany.
G. M. Sheldrick, SHELXL97. Program for the Refinement of Crystal Structures, University of
Göttingen, Germany.
B. B. Prozorovskii, M. P. Prozorovskaya, and V. M. Demchenko, Farmakol. i Toksikol., 497 (1987).
489