Synthesis and Biological Activity of Silyl- and Germylsubstituted Trifluroacetylfurans

A series of silyl, germyl and alkyl substituted trifluoroacetylfurans has been synthesized under Friedel-Crafts electrophilic acylation conditions. Biological investigations have demonstrated that germyl derivatives of trifluoroacetylfuran are more toxic than the silicon analogues. 5-Triethylgermyl-2-trifluoroacetylfuran was the most toxic compound (LD50, 11.2 mg kg-1, i.p. for white mice), 200 times more toxic than the silicon analogue. 5-t-Butyl- and 5-trimethylsilyl-2-trifluroacetylfuran prolong the duration of ethanol anaesthesia by 220 and 140%. 5-Triethylgermyl-2-trifluroacetylfuran exibited high anesthetic activity in hexobarbital test (prolonged the duration by 137%). Some of compounds influenced muscle tone and locomotor coordination parameters. 5-Triethylgermyl-2-trifluomacetylfuran exibited analgesic activity (ED50, 0.9 mg kg-1).


INTRODUCTION
The introduction of the trifluoroacetyl moiety into aromatics and heteroammatics has been generally realized by Friedel-Crafts acylation and by reaction of organomagnesium or organolithium reagents with ethyl trifluomaeetate, trifluomacetic acid or its salts [1-7 and ref. thereto]. Friedel-Crafts electrophilic acylation of aryl(hetaryl)silanes, -germanes and -stannanes was accompanied by ipso-substitufion of trialkylsilyl, -germyl or -stannyl group. Reactions of this kind have gamed currency in organic synthesis primarily due to the fact that they provide a unique possibility for regiospecific insertion of various groups (halogen, nitro, alkyl, acyl, etc.) into the aromatic or hetemcyclic ring [8,9]. We have realized the electrophilic acylation of organometallic furans leading to corresponding 5trialkylgermyl(silyl)-2-trifluoroacetyl derivatives. On the other hand, trifluoromethyl ketones have generated much interest as components of potent enz3,me inhibitors [10]. A series of trimethylsilylated aliphatic and aromatic trifluommethylketones was synthesized and evaluated for anti-acetyleholinesterase activity. One compound in this series 3-(trimethylsilyl)trifluoroacetylbenzene (MDL-73745, Zifrosilone) was selected for further investigation for the treatment of Alzheimer's disease [10][11][12].
The present investigation elucidates the role of the substituent, its influence on psychotmpic and antitumor activity of 5-RvI(M=C,Si,Ge)-substituted 2-trifluoroacetylfurans. blATERIALS

METHODS Chemistry
H NMR spectra were recorded on a Varian 200 Mercury instnmaent (200 MHz) using CDC13 as a solvent and hexarnethyldisiloxane (HMDSO) as internal standard. Mass spectra were registered on GC-MS HP 6890 (70 eV). GC analysis was performed on a Varian instrument equipped with flame-ionization detector using column packed with 5% OV-17 Chromosorb W-HP (80-100 mesh). Trifluroacetic anhydride was distillated prior use.

ACYLATION OF 2-TRIMETHYLSILYLFURAN BY TRIFL UROACETIC ANHYDRIDE (atetitod a).
A mixture of 0.015 mol of 2-trimethylsilylfuran, 0.020 mol trifluomacetic anhydride and 0.03 mmol I_ was stirred for 32 h in a "Pierce" vial at 70C. Process was controlled by GC until starting material disappeared. The mixture was cooled, supplemented with 10 ml of distilled water, stirred tbr 10 min and titrated with 10% KOH to pH 7. After washing with water solution of Na,S:O3 and water, it was dried with anhydrous magnesium sulphate. The solvent was removed by distillation and the residue was fractionated in vacuum. A fraction boiling at 114-116C/1 lmm Hg was collected giving 5-trimethylsilyl-2-trifluomacetylfum (2) (48%) as light yellow oil. 1H NMR and mass tral data of compound 2 0a'e presented in Table 1.

ACYLATION OF 2-TRIMETHYLGERMYLFuRAN BY TRIFLUROACETIC ANHYDRIDE (method b).
A mixture of 0.005 mol 2-trimethylgermylfuran and 0.0065 mol trifluomacetic anhyckide was stirred for 2 h in "Pieme" vial at 70C. The excess of trifluoroacetic anhydride was removed under vacuum at room temperature. Aqueous saturated Nal-ICO3 (4 ml) was added anl the crude product was extracted with Et_O (3x15ml) and dried by Na2SO4. The solvent was removed and residue was purified by column chromatography using the mixture benzene-hexane (1:1) as eluent. Evaporation of eluent afforled the 5-Luba lgnatovich et al.  [14].

RESULTS AND DISCUSSION
Trifluoroacet3,1ations of trialkyl(2-furyl)silanes,-germanes and their carbon analogue were realized under Friedel-Crafts conditions using trifluroacetic anhydride. Yields and reaction conditions are summarized in  Biological investigations have demonstrated that the toxicity of trifluomacetylfinan derivatives 1-5 strongly depends on the substituent at the position 5. Germanium derivatives 4,5 are more toxic compounds than corresponding silicon derivatives 2,3. 5-Triethylgermyl-2-trifluomacetylfuran (5) was the most toxic compound (LD50 11.2 mg kg'l), 200 times more toxic than the silicon analogue ( Table 2). It is interesting to note that trimethyl derivatives of silicon and their germanium analogues have comparable toxicity, but substitution of the methyl group by ethyl dramatically changes the toxicity (see Table 2). The neumtropic activity of 5-triallcylgermyl-2-trifluomacetylfurans depends on the alkyl substituent at the germanium atom: the 5-triethylgermyl derivative 5 exibits the highest activity in the hexobarbital anaesthesia test and prolongs its duration by 137% ( Table 2). The 2-Smet,hylgerrnyl derivative 4 exhibits a stimulating activity in the ethanol anaesthesia and completely prevents animals from retrogradal amnesia (RA) ( Table 2).  The silicon and carbon analogues 1,2 prolonged the ethanol anaesthesia by 140 and 220%, correspondingly. The)' had higher anti-Corazol potency but they did not prevent animals from retrogradal amnesia. The pharmacological effects of phenamine are diminished by all the trifluroacetyl derivatives ( Table 2). The effect of trifluoroacetylfuran derivatives 1-5 on locomotor coordination and muscle tonus depends on the substituent and differs to some extent (Table 3). Thus, compounds 1, 2 nd 4 in rotating-rod, tube and Luba Ignatovich et al.