July 1967
SEDATIVE
603
3,5,7-TRIMETHYLADAMANTANTANE-1-CARBOXAMIDE
The Adamantyl Group in Medicinal Agents. IV. Sedative Action of 3,5,7-Triniethyladamantane-1-carboxamideland Related Agents KOERTGERZON, DONALD J. TOBIAS,SR., RICHARD E.
w.
HoLnIES,
ROBERT E. RATHBUN, A N D RICHARD KATTAT: The Ld/y Research Laboratories, E l i Lilly and C o m p a n y , Indianapolis, I n d i a n u
46206
Received February 4, 1967 3,5,T-Trimet,hyladamaritane-l-carboxylic acid (111) was prepared iri 90-955 yield by fusion of the cowehporiding hromide (I)with acetamide and treatment of the resulting acet~amido-3,5,i-trimethgladamautane (Ha) (IT-a) and in H$O4 with HCOOH. The sedative activity in mice of 3,5,7-trimethyladamantane-l-carboxamide of additional adamantane and mono-, di-, and trimethylat,ed adamantane derivatives is reported. The patterii of structiire-act,ivity relationships observed for these compounds is corit’rasted with that iiot,ed among previously described adamantane-containing agent,s.
It has been reported iri preceding papers in this heries2-4 that the biological activity of adamantanecdont,aining agents is, in general, quite reduced as the result of seemingly minor structural changes in the adaniaIitane moiety. For instance, the hypoglycemic activity of S-p-tolylsulfonyl-S’-1-adamantylurea2 is reduced hy about 707, by a single 3’-methyl substituent arid is eliminated in the 3’,5’-dimethyl compuund; the anabolic activity of nortestosterone 17ptidani:intoate3 i,q reduced by SO-SO% in the 3’-methyladamantoate, while the 3’,5’-dimet’hyl and 3’,5’,7’trimethyl ~tnalogdpossess even less activity; finally, the ability of i5’-adaniantoyladenosine4 t o reverse XI3I’-iriduced platelet aggregation in v i t m , while retnined in the monomethyl adamantoate, is much reduced in the dimethyl and in t’hetrimethyl analogs. 111 tlic course of this work, the lipid solubility of 1,:3,.i-triniethyladaniaIitane compounds has been riot,ed i n our laboi~atory. Thus, while adamantanoP is only moderutely soluble in ethyl ether, 3,5,7-trimethyl~idtiniaritari-1-ol is quite soluble in petroleum ether. Adamtmtylnmine hydrochloride7 is freely soluble in HzO,hut 3,;5,7-trimethyladaniantyl-l-amine hydrochloride is quite insoluble. It’ has heen stated8 that “the characteristics of a high degree of lipoid solubility, low extent, of ionization, and laclc of plasma-protein binding virtually ensure that a compound will enter brain and cerebrospinal fluid freely arid attain equilibrium rapidly.” I’ossibly, suitable trimethyladamaritane derivatives might fulfill these crit>eria and thus penetrate to the tihsues and fluids of t’hecentral nervous system. The preparatioris of a number of trimethyladamantaiie derivative:, including 3,5,7-triniethyladamantane1-c.ahoxnniide and 3,5,7-triniethyladamantan-l-o1 are paper together with an evaluation of the effects of these derivatives on mouse behavior. Where appqiria’tc, a comparison n-it,h the effects of the cor(1) T h e correct designation 3,5.i-triinethyladarnantane-l-carboxylic acid has been used in this paper instead of the trivial name adamantoio acid used in papers I I 3 a n d 1114 of this series. ( 2 ) Ilost observed effects 3,5,7-Trimethyladamantan-l-ol(VI).-To a solution of 1Rere scored for each mouse as "1, 2, or 3" with a score of 1 amino-3,5,7-trimethyladamantarlehydrochloride (V, 40 g ) in indicating a minimum effect and a score of 3 indicating a near acetic acid (250 ml) was added 270 ml of HzO. To the result,ing maximum or maximum effect. The minimum ataxic dose (MAD) mixtiire was added 2 S NaOH (270 ml) and then, dropwise, was used as a measure of sedative potency and, as used here, is N a S 0 2 (24 g) dissolved in 66 ml of H2O. After addition of the the dose a t which the sum of the t'hree scores for ataxia equals N a S 0 2 solrition, the reaction mixture was heated under reflux 2, 3, or 4. I n some instances it was necessary to report inter-
Experimental SectionlS
(18) All melting points were taken on a hlel-Temp melting point apparatus and are uncorrected. Infrared spectra were obtained in CHCla. AI1 compounds exhibited the typical n m r spectrum reported for 1-substituted 3,5,7trimethyladamantanes [R. C. F o r t . Jr., and P. R . Schleyer. J . O r g . Chem., SO, i8Q (1966)] when taken on a Varian .issociates Model HR-60 spectrometer, i n CDC13 or DMSO-ds with Ale& a s a n internal standard.
(19) (a) R. C. Rathbun, J. K. Henderson, R. W.K a t t a u , and C. E. Keller, J . Pharmacal. Ezptl. Therap., 122, 64A (1958); (b) R. C. R a t h b u n and I. H. Slater, Psychopharmacologia, 4 , 114 (1963); ( c ) E. Van Heyningen, C. N. Brown, F . Jose, J. K. Henderson, and P.Stark, J . M e d . Chem., 9, 675 (1966).
