Silacyclic Derivatives of Heteroaromatic Sulfides as Selective Cholesterol Level Lowering and Vasodilating Agents

Silacyclic derivatives of heteroaromatic sulfides have been prepared by using phase transfer catalytic (PTC) system thiol / silacyclopropyl iodide / solid K2CO3 / 18-crown-6 / toluene. The target sulfides were isolated in yields up to 70 %. The S-derivatives of N-methylimidazolyl, benzoxazolyl and 1,3,4-triazolyl thiols selectively lowered the low density lipoprotein (LDL) level in mice with the high cholesterol diet in nutrition.

In our previous work the cholesterol level lowering and vasodilating activities of silicon and germanium containing aliphatic derivatives of heteroaromatic sulfides were studied [1]. The 1methylimidazole, benzothiazole and 2-quinoline derivatives exhibited the highest level of activity. The compounds containing dimethyl(l$-triethylgermylethyl)silylmethyl and dimethyl(l$triphenylsilylethyl)silylmethyl substituents were the most active in mice with the high cholesterol diet in nutrition. It was also shown that aliphatic silyl and germyl 1-methylimidazole derivatives possess a considerable vasodilating activity.
In continuation of our investigations in the field of cholesterol lowering agents the silacyclic Sderivatives of N-, Oand S-heterocycles have been synthesized under PTC conditions for the purpose to increase the heterocyclic sulfides lipophility and selectivity of action on the high and low density lipoproteins.

MATERIALS AND METHODS CHEMISTRY
tH NMR spectra were recorded on a Varian 200 Mercury instrument (200MHz) using CDCI3 as solvent and hexamethyldisiloxane (HMDSO) as internal standard. Mass spectra were registered on a GC-MS HP 6890 (70 eV). GC analysis was performed on a Chrom-5 instrument equipped with a flame-ionization detector using glass column packed with 5 % OV-101 / Chromosorb W-HP (80-100 mesh) (1.2 m x 3 mm).
Finely powdered dry K2CO3 was added to a mixture of 10 mmol of thiol (1 7), 10 mmol of 1-(3iodopropyl)-l-methylsilacyclopentane or 1-(3-iodopropyl)-l-methylsilacyclohexane and 18-crown-6 (lmmol, 264 mg) in 25 ml of toluene. The mixture was refluxed with stirring to achieve the disappearance of the substrates, filtered over the thin silica gel layer and concentrated under reduced pressure. The residue was purified by column chromatography using benzene-hexane or benzene-ethyl acetate as eluent. PHARMACOLOGY Cholesterol level lowering and vasodilating activities and the acute toxicity of synthesized compounds were determined as described in Ref. A simple method for the preparation of silacyclic derivatives of the N-, Oand S-heterocyclic thiols was developed. The phase transfer catalytical system solid K2CO3/18-crown-6/toluene was used ( Figure 1). The use of the stronger base (KOH) led to the destruction of the alkylating agents. The aimed substances were obtained in good chemical yields (up to 70%) in a short time under mild conditions (Table 1)  The purity of the synthesized compounds was determined by HPLC (<1.5% of impurities). All substances were mobile oils therefore the elemental analysis was not performed.
The structures and spectral characteristics of synthesized substances are shown in Tables 2 and 3. PHARMACOLOGY CHOLESTEROL LEVEL LOWERING ,4CTIVITY The Table 4 data show the serum lipid level at the end of the experiment. The high cholesterol in nutrition Cholesterol group showed the marked increase in the total and LDL cholesterol in comparison to the intact control group. The HDL level in Cholesterol group did not differ from the Intact control group.
The silacyclic imidazole derivative 8 has better K value (K 0.111) than the corresponding trimethylsilylpropyl analogue (K--0.453) [1]. Moreover, compound 8 show the tendency to increase the HDL level. This fact indicates that this compound can possess an additional positive influence.
It is significant to note that benzoxazole derivative 9 is 3 times more active than benzothiazole derivative 10.
V,4SODIL,4 TING ,4 CTIVITY The vasodilating activity of the studied compounds in experiments in vivo is presented in the Table 4. In general the studied silacyclic compounds have a weak influence on vasodilatation even in a 50tag/mL dose. It was found that imidazole derivative 8 exhibits the highest relaxation effect (18% in 10 lag/mL). It is more active than aliphatic silicon-containing analogues (12-13%), but less active than dimethyl(ltriethylgermylethyl)silylmethyl substituted imidazole (22%) ]. Kira

ACUTE TOXICITY
The studied compounds have basically a low acute toxicity (Table 4). Only imidazole sulfide exhibits a medium level oftoxicity (375 mg/kg).

CONCLUSIONS
A PTC method of synthesis of silacyclic derivatives of the N-, Oand S-heterocyclic sulfides was elaborated. Nine compounds were synthesized and isolated in the yields up to 70%.
They were studied as serum cholesterol level lowering agents. It has been found, that silacyclopentylpropylthio-imidazole ($), -benzoxazole (9), -benzothiazole (10) and -1,2,4-triazole (15b) exhibited a high antiatherosclerotic activity. It protected against increase in serum LDL cholesterol level. A preliminary analysis of the structure-activity relationship for the cholesterol lowering action clearly indicates the strong influence of the silacyclic substituent position in the triazole ring. Imidazole derivative $ has shown the tendency to increase the HDL level. This fact indicates that compound can possess an additional positive influence. The synthesized sulfides are low toxic compounds with weak vasodilating activity.