No abstract

By using procedures previously developed for (*)-cestrone,l a variety of ( &)-13p-alkylgona-l,3,5( 10)-trienes and cognate compounds has been synthesised and converted into various ( & ) -1 3p-alkylgon-4-enes. Biological activities are given for several compounds and in some cases compared with those of the corresponding (+)and (-)-enantiomers.A series of related (&)-cestranes has been totally synthesised for comparison in biological activities with these gonanes and the corresponding cestranes prepared from (+)-oestrone. Preliminary accounts of some of this work have been given. R1 = Et, R2 = Me, R3 = H, n = 2), made by a sequence involving interaction of the ketone (8; R1 = Et, R2 = Me, n = 2) with methylmagnesium bromide. This alcohol may be a 17ap-01 from its appreciable androgenic-anabolic activity (below) and the reported 22 lack of such activity in 17a-hydroxy-19-norandrost4en-3-one, but the evidence is inconclusive. Ananchenko et aZ.l% observed the formation of both possible epimers in a similar Grignard reaction with the cestratetraene (8; R1 = R2 = Me, n = 2).

SYKTHETIC STEIWID H o i t m m s . XI11 199 the extent of binding to protein of the four adenosine atianiant'oat'es have been initiated in our l a b o r a t o r i e~.~~ In conclusion, the nucleoside adamant'oates as well m the adamantane-cont'aining agents earlier described may derive their high efficacy, a t least in part, through : L process of precise and specific binding of the adamant m e moiety to complement'ary, lipoid regions of the protein receptor site molecule.Saturally, binding t o protein of adamant'ane-contaiiiing agents acting in vivo may also affect their absorption arid their distribution (transport) in the animal host. The effect' of protein binding on these processes may be responsible for the quantitat'ive differences seen between the in ciuo activities, on the one hand, of the monomethylated analogs relat'ive to the adamantane a,geiit in the sulfonylurea series7 (about 25y0) and the nortestosterone esters2 (about 15-20%), and on the (-18) Preliminary results indicate the possibility t h a t the effect of methyl 3ubatitution on partition values parallel the test results obtained in the platelet ayeregation studies (Table Xj. T h e help of Rlr. 11. 11. Marsh and aswciatps, .\naIytical Research and Development Division, T h e Lilly riesearcli Laboratories, in obtaining tliese results is gratefully acknowledged.other hand, the activity of adenosine moiiomethyladamantoate relative to the adamantoate (about 130%) in inhibiting platelet aggregation in viti3o (Table The study of a different class of adamantane-containing agents which display a structure-activity relationship opposite to that reported in this paper and which presumably do not benefit from binding to protein will be the subject of a forthcoming publication.Acknowledgments.-The authors are grateful to 11r. W. L. Brown and asqociates for microanalyses; to

No abstract

A series of substituted benzenedisulfonamide carbonic anhydrase inhibitors is described and their anticonvulsant activities are listed. One compound, 4-(4-methoxypiperidinosulfonyl)-2-chlorobenzenesulfonamide (19, UK-12130), was found to have anticonvulsant activity in animals at a dose level that gave only a minimal diuretic effect. 19 selectively increased cerebral blood flow in animals and man without producing an unacceptable level of metabolic acidosis.