Notes NIT-Y
Synthetic Schistosomicides. V U . 5-Azo-6Alkoxj -8- (Aminoalky1aniino)qu inolineb'
Kesenrch LnhornioTzes, Parke, Daws and ('ompanzj, r l n n d rbor, .IIzchtgan
NIT--I'
N;;xAoH
a, R = C H s ; Y =I1(CHz)zNlCHzCH(CH3)zIz b, R = (CHz)zOH: Y = (CHz)zN[CHzCH(CH3)zIz C, R=CH3; Y=CHCH$(CHz)3NHz I11
Received April 25, 1964 IIa
5-(4-Amino-l-naphthylazo)uracil (Ia) is highly active against experimental Schistosoma iizansoni infections in the mouse, hamster, and nionltey.2 I n contrast, 5(8-aniino-5-quinoly1azo)uracil and related 8-amino-6niethoxy-5-heterocyclicazo coinpounds are devoid of antischistosome activity.2 Siiice the antischistosome NHR
j. NH(CHz)zNjCH,CH(CH,),12
@
CH3O
OHI
N=N
@ \
fi=NcloH HO
Ia, R = H b, R = (CHz)zN(C,H&
activity of Ia and related compounds is markedly eiihaliced by the introductioii of a basic side chain as in Ib, 3, and since 8-(2-diisobutylaniinoethylaniino)-6methoxyquinolinej (IIaj and 2- [8-(2-diisobutylaniinoethy1aniino)-G-quinolyloxy]ethanol (IIbj6 exhibit good antischistosome activity per se,'jZ1 we have prepared representative 5-azo-6-alkoxy-8- (aininoalkylamino) quinolines for test against schistosoniiasis. 5- [8-(2-Diisobutylaiiii1ioethylaiiiino)-6-1iiethoxy-~~quinolylazo ]uracil (IIIa), 5- [8-(2-diisobutylaininoethylaniinoj-G-(2-hydroxyethoxy)-5-quinolyla z o ]uracil (IIIb), and 5- [8-(4-an1ino-l-methylbutylaniino)-6-iiiethoxy-5-quiiiolylazo]uracil (IIIc) were synthesized by allowing diazotized 5-aminouracil to couple with IIa, IIb, and priniaquine, respectively, iiiaqueous etliaii01.3~~ 8 5- [4-(2-Diethylaniiiioethylaiiiiiio)-l-1iaphthylazo 1-8-(2diisobutylaiiiiiioethylai~ii1ioj-6-n~ethoxyquiiioline (Vj, which incorporates the active iiioieties of both I b and 11, was prepared by coupling diazotized N-(4-amino-lnaphthyl)-S- (2-diethylaminoethyl j -2,2,2-trifluoroacetairiide hydrochloride3s4with IIa, followed by alkaliiie hydrolysis of the intermediate trifluoroacetainide ( ITT) . The 5-azo-G-alkoxy-S-(aiIiiiioalkylaniiiio)quinoliries (1) Previous paper E. F. Elslager, D. R. Capps and L. 11. Merbelt J M e d . Chem., 7 , 658 (1964). (2) E. F. Elslager and D. F. Worth, tbad., 6 , 444 (1963). (3) E. F. Elslager, D. B. Capps, L. RI. Werbel, D. F. Worth. J. E. Xeisenhelder, H. Nsjarian, and P. E. Thompson. zbtd. 6 , 217 (1963). (4) E. F. Elslager, D. B. Capps. D. H. Kurtz, L. .\I. Werbel, and D. F. Worth, zbzd., 6 , 646 (1963). ( 5 ) F. Y. Wiselogle, "A Survey of lntimalarial Drugs, 1941-1945," J. T. E d n a r d s , Ann Arbor, Mich., 1946, p. 1195. (6) R1. S. Morgan U. b. Patent 2,852,518 (Sept. 16. 1958). (7) R. N. Bieter, E. M. Cranston, W. Chadbourn, A. C. Cuokler, D. DeGuisti, W. W. Becklund, and H. N. Wright, Federalton Proc., 8 , 275 (1949). (8) K. N. Campbell, J. F. K e r m n , A . H. Sommers, and B. K. Campbell, J . Am. Chem. Soc., 68, 1559 (1946).
N=X
(33 NH(CHa)zN(CzH5)z
V
(IIIa-c and V) were tested against a Puerto Rican strain of Schistosoma iiaansoni in mice by Thoiiipson and cow o r k e r ~ . ~When administered i n the diet td infected mice in doses ranging from 139 to 2-20 ing.//kg./day for 14 days, compounds IIIa, IIb, and I' effected a moderate reduction in live worms, but none was as promising as 5- [4-(2-diethylaniinoethyla1iiiiio)-l-naphthylazo 1uracil (Ibj. Experimental '0 5- [S-( 2-Diisobutylaminoethylamino)-6-rne thoxy-li-quinolylazo]uracil (IIIa).-A solution of 6.4 g. (0.05 mole) of 5-aminouracil in 100 ml. of 50% aqueous ethanol and 10 ml. of concentrated hydrochloric acid was cooled t,o -5' and diazot,ized by the addit,ion of a cold solution of 3.5 g. (0.05 mole) of sodium nitrit,e in 20 ml. of water. The temperature \Tas maint,ained below 5' during the addition. The diazonium salt mixture was stirred for 15 min. a t O", then added over a period of 15 min. to a cold solution of 21 .O g. (0.05 mole) of 8-(2-diisobutylaniinoethylaniino)-6-methoxyquinoline dihydrochloride monohydrate in 200 ml. of water and 3 ml. of concentrat,ed hydrochloric arid. The mixture was stirred for 1 hr. a t 0-5", then a t room t,ernperature for 24 hr. .4 mist,ure of 150 g. of sodium acet,ate and 300 ml. of water was added and the crude dye was collected by filtration, washed successively with water and et,her, and dried i n z~ucuoat 45" for 48 hr. Crystallization of the crude product from a dimethylacetamidewater mixture gave 1 5 g. (62:G) of red crystals with a golden luster, m.p. 209-211". Anal. Calcd. for C,aH,,?;&.H,O: C, 59.36; H, 7.27; N, 20.19; HzO, 3.71. Found: C, 59.79; H, 7.56; S , 20.17; HzO (Karl Fischer), 3.50. (9) For a description of test methods, see P. E. Thompson, J. E. Meisenlielder, and H. Najarian, Am. J . T r o p . M e d . Hyg., 11, 31 (1962). (10) Melting points (corrected) were taken on a Thomas-Hoover capillary melting point apparatus.
