of iiioiromethoxj (19), tliinetlioxj (651, or chloro (17) g r o u p in place of the h j tlrosj functioii, a s also the hiih,stitutioii of :t P-naphthyl (13) or iiidol? 1 (15) wsidue i i i phce of the clihydroxj pheiij I group led to :I ronipletc lo^ of tlii- activitj . The cwrre.poiidirig :3cleainiiio rompouiid ( 5 ) ii1.o 1i:d gre:itlj reduced a(*ti\i t ? . 4-(3,4-Dih?tlrox; phenethyI)arnino-X-aniiiioquiiiioliiic (53), liov ever. .ho\\ et1 .igiiificaiit h j poteii iive ' :I(*t ivit! . 111 the c~orre.poiidiiig 2-(3,4-dihydroxj pheiieth; l):iriiitio-:3-aiiiiiiopj ritliiir (36) there mi\ :I cmnplete
Silicon-Containing Barbiturates
'Three .i-ip-tl'irnethS.lsilylphellvl)~)art~itiirate~ atid oiie related thiobarbitrit,:tte were pi'epared hiart illy fI.0111 p converted t o diethyl alli?.l-p-trirneth~l~ilylpheii~lnialc)ti~t es :tiid ~ I ) I I tleiised with iu'ea or thioiire:t. Prelimiliary pharmacological evaliiatioii of these barhitiirates, a. well a 5 of 1 wo .i-(p-trimethylsilylbellz)-l)bar.bitiute~, rhowed them to have low sedative :wtivit>-. Some of the compoiiiitlb .,bowed anticoiivulsatit activity. 1 i~irneth~-lsil~lphen~laceti~ acid, which was
llecciitly, or], \\ :I? reported oil the prepai:itioii 111id Iiiological evaluation of wine silicoii-coiit:Liriiiig ~11:ilogi o f 1iologic:illy active organic compounds.' This int crest \\ :ih :irouhed hy the fact that. dthough 4licoii i y the rii:iin constituent of the earth'. crust. it oiily rarely appears i l l living organisms. Spiroburbiturates cont :Lining 4licoii in a cyclohexyl ring have beeii prepared :idfound t o have narcotic activit Several silicoiicoiitaiiiing barbituric acid- having :I trimethylsilylinct hyl group have alw been +prithe-i~ed.~n ' e have receiitly prepared 3-(p-triniethyl,iiIyIbeii~yl)h:Lrbitur:it(>>,? arid e \\ 1.h no\\ to report the synthe.is of T,-(pt riiiieth~l.ilylpheiiyl)barbit urates and their preliminary I)hariii:icologic:Il cv:iliic1' t l' o l l .
COOCqH-, I
Me,SiC,H,CR
I
COOC,H
(To,NH
~
0
R,
Me ,SiC,H,C'
c
'NH
I
1
oc, s,co I
on TABLEI1 IIOSE-RANGE FINDING EXPERIMENTS .\ND GROSS BEHAVIOR !l) CH.ZNGES" Compd
Dose, mg/kg
6
100b
2
50 200
)
100 30 25
(:enera1 changes
I'iloerectioii, sedation, ptosis, lasting about 1 hr. Slight sedat,ion during 43 min. Slight, sedation, piloerection lasting sboiit, 30 min. Slight sedation. Same. Death at, aboiit 1 hr. Ptosis, reduction of spoiitaneoiis motilitmy,intermittent brief aeiziires, piloerection. After 2 hr fully recovered. Spontaneons motility rediiced.
10 3c 4c 5 Groups of five male mice (23-25 g ) for each dose level were used. Observations were made for no longer than 24 hr aft,er administration. This was the maximal dose which could be tested. As for higher doses, the compound could not be dissolved properly in propylene glycol at volumes snitable for injection. c Doses u p to 100 mg/kg showed no obvious gross behavioral changes.
The barbiturates prepared are insoluble in water, cold ethanol, and carbon tetrachloride. They are soluble in hot ethanol, acetone, and dilute sodium hydroxide. Preliminary Pharmacological Evaluation.-Some of the silicon-containing barbiturates were evaluated for their sedative and ariticonvulsant activity in mice. The compounds were dissolved in propylene glycol and injected intraperitoneally. Maximum volume injected did not exceed 0.05 m1/20 g. Control groups of mice received solvent only. The compounds investigated were S-(p-trimethylsilylphenyl)-3-ethylbarbituric acid (2), 3- (p-trimethylsilylpheny1)-5-allylbarbituric acid (3), 5-(p-trin?ethylsilylphenyl)-5-allyl-2-thiobarbituricacid (4), 5-(p-trimethylsilylbenzyl)-5-ethylbarbituricacid ( 5 ) , and 3-(ptrimethylsilylbenzyl)-5-acetamidobarbituric acid (6). Dose-range finding experiments and gross behavioral changes are given in Table 11. Supramaximal electroshock tests9 (Table 111) n-ere carried out on groups of 10-20 mice for each dose level. Animals were submitted to maximal electroshock provoked by 70 v, 30 min after injection of test material. The folloiving parameters were recorded: brieftonic limb flexion (TI?), prolonged full-tonic limb extension (TEx), and death. 5-Ethyl-3-methyl-3-phenylhydantoin (mesantoin) and an analogous barbiturate not containing silicon, viz., sodium phenobarbital, were taken a5 reference drugs. Prevention of tonic limb extension n as considered as protection against supramaximal electroshock. JTaximal, pentylenetetrazoleseizure tests'" (Table 111) were conducted on groups of 10-20 mice for each dose level. AIaximum volume injected did not exceed 0.05 m1/20 g, and 30 min following injection of test compounds, pentylenetetrazole (100 mg/kg) was injected subcutaneously. Protection against tonic seizures was noted, but death rate was chosen as t h e index for protective effects.
c
G
x
xE .? v
c 0 3 n
W
H
c m e
(9) J. E. P. Toman and G. & Everett I. in "Evaluation of Drug Activities, Pharmacometncs," Vol. 1, D. R. Lawrence and A L. Bachrach, Ed., Academic Press Inc., New York, N. Y.. 1964, p 287. (10) L. 8. Goodman, M. 9. Grewal, W. C. Brown, and E. A. Suinyard J . Pharmacal. Ezptl. Therup., 108, 168 (1953).
The prcliniinary pharmacologicwl reiult. qhou that the compound5 had only :I u ewk iedative x t i v i t y . Pari ot the compounds iho\\ cd 4gnihc:uit anticoiivul+ant activity, although less thaii that of phenubarbital or memitoin. I n the electro6hocl; test?, 6 >hen ed activity similtu- to phenobarbita1,n hile 2, 3, arid 4 showed lower activity. Compouiid 5 \ \ a b irivebtigated up to a dose of 2.3 mg k g due to it5 toxicity, and at thi5 do+e it hhoited f u l l protection agairist electro?hocl,. In the :Iritiperitylerietetraec,le teht, 6 arid 2 \\ere the 1no.t active, \\ hile 3 shoued medium activity at ii rrl:ttivdy high dose ('oinpoiiiid> 5 :\rid 4 i t ere ewenti:illv in:wtive.
Experimental Section llelting puiiit.; were determined iiririg 5 Fisher-Johns appsr:ttiis. I'v spectra were carried out iii EtOII (J. T. Baker alrohol reagent ) iihiiig a Beckman DI! spectrophotometer. The ir spectra (KRr) were takeii 0 1 1 :I 3 3 i Perkiri-Elmer grating specIi~)phoiometer. Ethyl p-Trimethy1silylphenylacetate.-Purified S( )CI? (18 g, (l.l.X3 inole) was dropped into cold absolute Et011 (60 ml) at -20". T h e mixture was stirred i n the c.old for ittiother I5 min,
