J. H.BURCKHALTER AND VERLINC. STEPHENS
56 (CONTRIBUTION FROM THE
DEPARTMENT OF
PHARMACEUTICAL CHEMISTRY, UNIVERSITY OF
1701. 73 KANSAS SCHOOL OF
PHARMACY
1
Synthesis of Phenylalanine Analogs as Antimetabolites BY J. H. BURCKHALTER AND VERLIN C, STEPHENS’ Many studies are currently underway in various /C0zC2Ha SaOCaH. HC/--SHCOCH, -+laboratories and much has already been done2 to- 0 2 - < 2 - C H f J ward finding antimetabolites which might also be ‘ K useful chemotherapeutic agents. -4 number of I:t R = COzCtH, compounds developed through this approach have Ib R = C S exhibited antimetabolic properties, but because of ,,,/COLCIH, various shortcomings, such as low absorption, low O J - - ~ -__ CH,C-NHCOCH~ activity or high toxicity, these agents have failed to R ‘ become established in medical practice. illthough I1 a number of widely used medicinals are known to be metabolite antagonists, the fact was discovered cyanoacetates with hydrobromic acid to yield the after their establishment as effective drugs. De- amino acids of Table 11. While the twelve esters of spite the past disappointing results from applica- Table I are new compounds, a number of the amino tions of the antimetabolite concept, i t remains as acids of Table I1 had been previously prepared by one of the few logical and appealing approaches to other methods.’ However, apparently they had the problem of finding more useful chemotherapeu- not been made for antimetabolite studies. tic agents, and it can be said that the proper comThe presence of the 7-chloro-4-quinolylamino pounds may not have yet been chosen for synthesis. grouping in valuable antimalarial agents, such as The observation that antimalarial agents and Chloroquine and Camoquin, suggested ,B- [DL-pcertain insecticides hold large space-occupying (7-chloro-4-quinolylamino) ]-phenylalanine (V) as a groups, such as the chlorophenyl radical, which pre- compound of possible biological interest. V was sumably exert desired toxic effects, and another por- prepared in good yield by condensation of 1,i-dition of the molecule as a solubilizing group which allows absorption a t the proper site, suggested the preparation of a variety of unnatural amino acids which would contain large substituents and leave free the functional groups either for solubilizing 111 purposes or peptide synthesis within the o ~ g a n i s m . ~ TH2 Interest in such compounds particularly as possible H A - ~ - C H ~ - - C H -IC O ~ H antiviral agents seems justified by the knowledge I IY that viruses are composed largely of protein materials or amino acids.4 Phenylalanine analogs were chosen to compose this first described section of proposed chemical studies, because phenylalanine is an essential amino acid not only to man but to other forms of life. Further, the preparation of cl-u,s$ I the compounds in good yield appeared to be feasible because of the development of useful synthetic procedures5 and the availability of intermediate chloroquinoline with IV which had been obtained substituted benzyl halides. -4s shown by Table IJ, by hydrolysis of I11 which in turn had been oba variety of substituents was used in order to af- tained by catalytic reduction of IIa. In the condensation of o-xylylene bromide with ford a study of the relative magnitudes of antimetaIb, not only was the expected ester VI prepared in bolic effect by both large and small groups6 General procedure A, essentially that of others,j 30r0 yield, but ethyl 2-acetyl-3-cyano-1,2,3,4-tetrawas employed in the preparation of most of the es- hydro-3-isoquinoline carboxylate (VII) was isolated ters of Table I. The method is illustrated by in 4370 yield. the preparation of 11. The malonates were hydro,/CO?C?Hj cs lyzed with cullcentrated hylrochloric acid iintl the
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( l j Fellow 01 t h e American Foundation for 1’li:irtiiaccutical 12dlicalion (Procter and Gamble grant IR48-1U:O! ( 2 ) Roblin, ( ‘ h e m Reos.. 38, 255 (19461. (3) hfuny ul‘ rtie uiinatur;il amino acids thu, t;ir prepared have colltainecl nuclei t h a t are isostei-ic Lrith thosc of the natural relatives, while others have been cbaraclerized b y a substitution of one relatively small group b y another, F u r e x a m p l e . bee Dittmer, rt of , J . Rid ( ’ h e m . , 164,761 (lY46). (4) Stanley, Chem. Eng. .\-ems, 51, 37Xti (1946): Elvehjem, J . A m . .\led Assoc., 136,915 (1948). (.:I S n y d e r , Shekleton a n d Lewis, THISJ O T R X A I . , 67, 310 (1945); Alhertson and Archer, ihid , 67, 308 i19.45’1. hlbrrtqon and Tullar. cbiti., 67, 503 ( 1 9 4 3 (6) Recent papers on phenylalanine analogs \‘evt,nzcl. Shelberg end Neirnann, ihid., 71, 301 l !1
