The recent advances in combinatorial chemistry and high throughput screening technologies have led to an explosion in the numbers of possible therapeutic candidates being produced at the early stages of drug discovery. This rapid increase in the number of chemicals to be classified results in a greater need for alternative methods for the prediction of toxicity. Most QSAR models for mutagenicity have been constructed for congeneric series. The prediction requirements of the pharmaceutical industry, however, cover quite diverse chemical structures. This paper reports a study of mutagenicity data for a diverse set of 90 compounds. Good discriminant models have been built for this data set using properties calculated by the techniques of computational chemistry. Jack-knifed (leave one out) predictions for these models are of the order of 85%.
1607d,l-18-Hydroxy-corticosteronr (XII, XIII), the d-enantiomer (I) of which is probably a direct biogenetic precursor of aldosterone (I1 a, b), has been prepared. The synthesis leads from the trihydroxy-diketal IV to the diacetate VI, in which the ketal groups could be split with a mixture of perchloric and acetic acid. The diacetoxydiketone I X thus obtained was hydrolysed under carefully controlled alkaline conditions to yield the 18-monoacetate XI or the free d,l-18-hydroxy-corticosterone (XII). The latter compound exists, however, predominantly in the form of the (20-+18)cyclohemiketal XIII, a conclusion reached from its infrared absorption spectrum and the comparatively slow reduction of tetrazolium salt.By degradation of XI11 with periodic acid the d,l-lactone XV was obtained, which is the racemate corresponding to the optically active compound ((A 5 9~, isolated from hog adrenal extracts.By treating the lip, 18-dihydroxy-diketals IV and V with aqueous acetic acid, in addition to ketal cleavage intramolecular etherification between the llgand 18hydroxy groups took place andd,l-18-desoxy-aldosterone (d,l-llp, 18-oxido-cortexone) (VII) and its 21-0-acetyl derivative VIII were formed, respectively.Forschungslaboratorien der CIBA AKTIENGESELLSCHAFT, Basel, Pharmazeutische Abteilung
Phriz).l-I-cyclopantane-caPboxylafe d'ithyle[ X X X I , n = 21. Xous avons utilisC le procCd6 dc Phdii~l-1-cyclopropaize-carboxylate d'e'thyle [ X X X I . n = 01. I1 a CtC prCpar6 par un procede analogue; ICb. 117-118"/11 Torr ( K O N D O~) , Eb. 129-133"/21 Torr), nZ3 = 1,5085, rdt. 66%.
(Ph~ir~l-l'-cvclopentyl-7')-mCthanol [ X X X I I , tab. 31 c t (phdnyl-7'-cyclopropyl-1')-me'thanol~S X X I V , t a b . 31. Synth6tisCs par rCduction des cstcrs correspondants par le hutylate sodique.T.cs carbamates correspondants [ X X X I I I et XXX\', tab. 31 ont CtC prCparCs par la mCthodc -1 tlCcritc antCricurcnicxit'a). \ ' 4 N H E Y X I N C E N ' ) ; Rb. 142-144"/10 Torr, I120 = 1,5145. rdt. 90?".
RESIJMCLa synthcse de trois sCries de dCrivCs du (propyn-2'-yl-lr)-l-cyclohexanol-l (A) r.;t dCcrite et leur activitC hypnotique d6terminCe.
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