,July 1966
HYPOTENSIVE HINDERED ACYCLIC A K D CYCLIC AMINES
collaborators : Dr. E. J. Walaszek, Department of Pharmacology, Cniversity of Kansas, for the muscarinic assays, and Dr. h1. E. Rafelson, Jr., and Dr. H. Higman, Department of Biochemistry, Pres.-St. Lukes Hospital, Chicago, Ill., for the acetylcholinesterase studies. The
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authors gratefully acknowledge support of the decalin project by the National Institutes of Health Grant RG 9254 and the a,p-dimethylacetylcholine project by the National Institutes of Health Grant GAI 10164 and the Mead Johnson Company, Evansville, Ind.
Comparison of the Hypotensive Activities of Highly Hindered Open-Chain Amines and Their Cyclic Counterparts J. LEONARD SELSON R. EASTON, FRANCIS G . HEXDERSOX) J ~ A L T EJ.RI ~ I C M U R R AAYN,D' ~XELSOK ~ The Lilly Rpsearrh Laboratorzes, Zndzanapolzs, Indzana, and the Soyes Chemical Laboratory, Cniverszty of Illznozs, Crbana, Illznois Received Sovember 15, 1966
A number of cyclic hindered amines substituted on the a-carbon with ethynyl and vinyl groups have been prepared by the addition of Grignard reagents t o ternary iminium salts including: 2-ethynyl-1,2,5,5-tetramethylpyrrolidine, 2-ethynyl-l,2,6,6-tetramethylpiperidine,2-ethynyl-1,2,6-trimethylpiperidine,and 1,2,5,5-tetramethyl-2-vinylpyrrolidine. Together with 1,2,2,5,5-pentamethylpyrrolidine and 2,2,5,5-tetramethylpyrrolidine, these comprised a series of cyclic compounds which were compared in antihypertensive properties with a closely related series of open-chain compounds, including ~3-(N-t-butylmethylamino)-3-methyl-l-butyne, (3-N-t-butylmethylamino)-3-methyl-l-butene, t-amyl-t-butylmethylamine, and t-amyl-t-butylamine. Within the two series studied, the open-chain compounds are generally more potent in their hypotensive effect than the cyclic compounds.
Change in pharmacological activity with difference (X).5 The reaction of an acetylenic Grignard reagent in chemical structure is especially significant when the with a ternary iminium salt has also been exemplified by compounds differ only by ring formation, t,hat is, one Ryan and Ainsworths in the addition of ethoxyethynylof the compounds is cyclic and the other is open chain. magnesium bromide to 1,2-dimethyl-A'-tetrahydroThe Hennion synthesis of highly hindered acetylenic pyridinium perchlorate, and by Lednicer and Babcockg a m i n e ~ 3and , ~ their hydrogenat'ion products made availin the addition of ethynylmagnesiuni bromide to able a large number of these compounds for pharmasteroidal ternary iminiuni salts. The characterization cological evaluation. At the same time, the synt'hesis of the product from X, 2-ethynyl-1,2,5,S-tetramethylof highly substituted pyrrolidines and piperidines by the mercuric acetate-iminium salt route5l6 made it possible to obtain an analogous series of compounds in the monocyclic system. The purpose of this paper is to report on the pharmacological activities of these two series of compounds, especially with regard to their I I1 111 antihypert,ensive properties as found in rats made hypertensive by a modification of the Goldblatt procedure. The pyrrolidine I1 and the piperidine I11 can be visualized as the cyclic counterparts of 3-(N-tbutylmethylamino)-3-methyl-l-butyne(I). The vinylIV V VI pyrrolidine V is analogous to the open-chain amine IV, and 1,2,2,5,5-pentamethylpyrrolidine(YII) is similar to the saturated open-chain tertiary amine VI. The I H H final pair of compounds which were conipared in this study were I X and VIII. VI1 VI11 IX Chemistry.-The general reaction consisting of the att'ack of nucleophilic reagents on t'ernary iminium pyrrolidine (11), was based on the infrared spectra of salts has been broadly applied.' Among the nucleothe base and its hydrochloride salt, both of which showed philes which have been utilized were represent'ative characteristic maxima associated with =C-H and Grignard reagents. The acetylenic-substituted pyrC=C stretching. rolidine 11, 2-ethynyl-1,2,5,.3-tetraniethylpyrrolidine, The addition of vinyl Grignard reagent to 1,2,5,5mas made by the addition of ethynylmagnesiuni brotetramethyl-A'-pyrrolinium perchlorate (X) represents mide to 1,2,5,5-tetramethyl-A'-pyrroliniumperchlorate the first example of this type of combination. The product of the reaction was 1,2,S75-tetramethyl-2(1) Eli Lilly and Company Fellow, 1959-1960. vinylpyrrolidine (V), which was characterized by the (2) U.S. Rubber Company Fellow, 1960-1961. infrared spectrum of the base and by the nmr spectrum (3) G. F. Hennion and R. S. Hanzel, J . A m . Chem. Soc., 82, 4908 (1960). (4) C. Ainsworth and N. R. Easton, J . 078. Chem., 26, 3776 (1961). of the corresponding perchlorate salt.
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(5) N. J. Leonard and -4.G. Cook, J . Am. Chem. SOC.,81, 5627 (1959). (6) N. J . Leonard and F. P. Hauck, J r . , ibid.,79, 5279 (1957). (7) N. J. Leonard and A. S. Hay, ibid., 18, 1984 (1956), and references therein.
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(8) C. \\-. Ryan and C. Ainsworth. J . Ore. Chem., 26, 1547 (1961). (9) D. Lednicer and J. C. Babcock, ibid., 27, 2541 (1962).
In the piperidine series, acetylenic.-substituted ~oiiipounds were made by the addition of :retyleriic Grignard reagent to tetrahydropyridiriiuni p ~ ~ ~ ~ v l i l o ~ x t salts. Specifically, 2 - e t h y n y l - 1 , 2 , 6 - t l . i ~ ~ i ~ t l ~ y l ~ ~ l ~ ~ ~ ~ i ~ l/1 1 i ( ~ ( X I ) was obtained by the addition of ethynylmngn~..l~llii broniide, prepared by the method of ,Jo~io-,6 1 nl.,"' I O 1 ,'.',A-triinethyl-~'-tetrahydropyridi~~i~~~ii p t ~ i ~ ~ l i l1n i ~ a (XI).6 Sirnilarly, 2-ct~iynyl-l,2,~,0-tetra1~ietliyl~~1~,c~icliric. (111) wa:, pn:parctl by thc :dditioii of (1tliyiyl i1i:igncsiuin bromide to l , ~ , ~ i , C i - t e t r : ~ n l c t l i y l - ~ ' - t c t ~ : ~ liytlropyridi~iiuniperch1or:itc (XIII). 'l'lic pr(wtiw ol the acetylenic, group in protluc~ti S I 1 aritl I11 T\ firrned hy the infrared absorpt ion ipwtr:i nf t licit w n i pounds :uid thcir d t s . (1
(a
Experimental Section l 1 Grignard Reaction Products (Table I).--The general reac+iiii of ethynylmagnesium bromide, prepared hy the method of Jones, et a1.,I0 with ternary iminiuni salts mag be illustrated by the preparation of 2-ethynyl-1,2,5,5-tetramethylpyrrolidiiie(11). To 0.16 mole of ethynylmagnesium broniide in 50 nil of t,etruhydrofuran ( T H F ) was added 10 g (0.04 mole) of 1,2,5,5-teti-ariiethyl-A'-pyrroliiiiurii perchlorate, arid the contents was heated under reflux for 5 hr. The reaction mixture \vas decomposed wit,h aqueous K&O3 solution, and the resulting solid was removed by filtration. The T H F was removed under reduced pressure. The residue was basified with NaOH and then extracted wit,h ether. The ether extracts were dried (1lgSOd) and filtered, :tiid the ether was removed under reduced presnre to give 6 g of residue, which was distilled in oacuo. Iri a similar manner, vinylmagnesium bromide iri THF, prepared by the method of Fuson and hlon,l2 reacted with 1,2,5,;i-tetramethyl-A1-pyrrolinium perchlorate6 to give 1,2,j,S-tetranietliyl-2-vi1iylpyrrolidine (V). The preparations of the ternary iminiiim s:rlts employed in these reactions are described below. 1,2,6,6-Tetramethyl-A1-tetrahydropyridinium Perchlorate (XIII).-Oxidation of 38.1 g (0.27 mole) of 1,2,2,6-tetjramethylpiperidine13 with mercuric acetate according to the geiiernl procedure,6 followed by preparation of the perchlorak salt aiicl recrystallization from ethanol, furnished colorless needles, mp l
