September 1905
CYCLIC AMINOTHIOLES~TXHS
Physiologically Active Compounds. VI. Cyclic Amino Thiolesters of Substituted Chloroacetic, Benzilic, and Glycolic Acids"2 CALVIN A. BUEHLER, SHELBY F. THAMES, Departiiient of C'heniislry, Cnicrrsity of Tennessee, Knoxville, Il'ennessei;
Center for B r u i n HeaearLh, Cniversitg of Rochester, Rochestel., AVezu170rk AND
J. H. BIEL
Research and Development. Aldrzth Chemical Company, Inc., Jtilwaukee, TT'isconsin Received M a r c h 16, 1965 Thirt,y-four amino thiolesters of chloroacetic, benzilic, and glycolic acids have been syn1hesized, usually as salt e . The a-hydroxy esters, which were of greatest interest, were obtained via the a-chloroamino thiolesters. The compounds were examined for their effect on animal behavior and for their anticholinergic potency. Three devices were used to determine the degree of behavioral disturbance produced by the drugs in animals: a hyperactivity cage, a swim maze, and a "peek" test. For a given drug good correlation was found to exist between the effect on performance in all three tests and the psychotoniimetic efficacy in humans. I n general the structureactivity relationships of the thioglycolate esters agreed with those of the regular esters, although the thioesters were less potent and of shorter duration of action.
This paper is a continuation of the synthesis and compound 124 could not be hydrolyzed successidly physiological testing of aminothiol esters of the type to the corresponding glycolate since the f i ee glycolic represented by RR'C (X)COSR", where R,R' are acid n as recovered. A previous study? showed that the C S S activity of combinations of phenyl, p-tolyl, cyclopeiityl, and cyclohexyl; X is C1 or OH; arid R" is a tertiary amino amino thiolesters of benzilic and glycolic acids increased as the number of carbon atoms between the function, almost always cyclic in nature. carbonyl and basic nitrogen groups decreased I'or Synthesis of Compounds in Table 1.-The athis reason the glycolic ester corresponding to 124 chloro acid chlorides mere obtained from substituted glycolic acids by the method of King and H ~ l m e s , ~ n a s of particular iiiterest. Other attempts to obtaii! or from the chlorination of substituted acetic acids by a this com1)ouvd by the procedure of _\lcCloshey aiid modified 1)rocedure of Schwenk arid Papa.4 The synColeniaii7 failed. The l)ossibility oi utiliziiig t raiibesterificatioii was ruled out when the procedures of thesis of essential aminomercaptaiis is given ill the Experimental. I t was found that the conversion of Sasin, et arid Bowman, et al , 9 nere uiIsu(~(~essfu1. thiolacetates to mercaptans is accomplished best by the These methods were applicable to the synthesis of use of sodium in methanol, a method mentioned, but 2-S,S-diethylaiiiirioethyl thiolbenzilate hydrochloride riot described in great detail, by Reid.j The a-chloro when the reactaats n ere ethyl thiolbenzilate and 2acid chlorides and aminomercaptaiis iri a suitable solS,S-diethylaminoet hariethiol. h o t her failure resulted vent produced the a-chloroamino thiolester hydrochloin aii attempt to effect an ester interchange with ail rides. oxygen ester (methyl cyclohexyl glycolate) and a Synthesis of Compounds in Table 11.-The amino mercaptan (2-S,S-diethylaminoethanet hiol) using sothiolglycolates in Table I1 were prepared most satisdium methoxide as a catalyst l roni these few experifactorily from the a-chloro thiolester salt as described ments it appears that (a) a mixed ester interchange previously.2 It was not possible to replace the chlobetween oxygen esters and aminomercaptans will not rine atom in 2-S,T\'-diethylaminoethyl dicyclohexyloccur, but (b) an interchange between a thiolester and chlorothiolacetate hydrochloride by this procedure or an aminoinercaptan n 111 take place, at least when the by 1hose of Bachmarui and Raniirez,fiarid 11cClosliey sulfur atom in the filial produrt is seljarated from the and Colemaii.' Thus it would appear that the resoiutrogcn atom by t\vo carbon atoms. iiaiice supplied by a t least one aromatic ring is essential The purihcatiori of the aiiiit!o thiolglycolates \T as at for surcess in this hydrolysis. At the other extreme, times difficult. Crystallizatioii, distillation zn tucuo, aiid adsorptiou cahroniatography were the inet hods (1) (a) The chemical portion of this study w-as supported b y Grant R6.72 employed. In one case the coinpound 145 could be from the National Institutes of Health, U. S. Public Health Service. (b) obtained crystalline neither as the free base nor as the Inquiries should be addressed to the senior author. hydrochloride. ( 2 ) For paper V, see C. 4. Buehler, H . A. Smith, A . C. Kryger, R . L. Wells, and S. F. Thames, J . X e d . Chem., 6, 230 (1963). Pharmacological Studies.-The te.ts uied for the (3) F. E. King and D. Holmes, J . Chem. Soc.. 164 (1947). evaluation of the behavioral effects produced by the (4) E. Schwenk and D. Papa, J . Am. Chem. Soc., 70, 3626 (1948). ( 5 ) E. E. Reid. "Organic Chemistry of Riralent Sulfur," 1'01. 1 , C ' h e i i i i c a l agents in animal? have heeii detcribed in detail e1.ePublishing Co., Inc., Keu- York, Pi. Y . , 1968, p. 30. (6) W. E. Bachmann and F. Ramirez. J . Bm. Chem. Soc., 72, 2525 (1950). (7) C . 11. 1IcCioskey and G. H. Coleiiian, "Organic Syntheses," Coll. Vul. 111, John '&?ley and Sons, Inc., New T o r k , N. Y . , 1955, p , 434.
(8) G ( 1 Y 57)
S basin, P R Scliaeffer and K Sasin J
O r y Chem
22, 1183
(9) R L lluwiiian J 1 C a \ a l l a and J L7a\oll I3ritisli Patent 821 43b ( 1 eb 2 2 1956) Chem d b a i r , 56, 2427 (1961)
C. A. BUEHLER, S.F. THAMES, L. G. ABOOD,A N D J. H. BIEL
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8
CYCLIC AMINOTHIOLESTERS
September 1963 EFFECT
OF
TABLE I11 THIOLESTERS OK >TOTOR ACTIVITY, BEHAVIOR, AND PERIPHERAL CHOLINERGIC SYSTEMS
- -
---
SO.
125 130 139 140 144 145 147
148 149 150 151 153 154 l
