519
May 1969
Notes Antimalarial and Antischistosomal Agents.
N,N”-[ Sulfonylbis(p-phenyleneazo-1,4-naphthylene)]bis(N’,N’-dialkylalkylenediamines) EDWARD F. ELSLIGER
ASD
ASNETTEA. PHILLIPS
Research Laboratories, Parke, Ilavzs and Cowipany, Ann ilrbor, .\lachayan /,Sl06 Recezvecl J a n u a r y 6, 1969
In previous communications from these laboratories, various K-mono- and N,S-dialliyl-X’- (4-arylazo- arid 4-heterocyclic a~o-l-naphthyl)alkylenediamines,~-~ bis(4-arylazo- 1-napht hylamines) ,b IY - (dialkylaminoalkyl)4-nitroso-l-iiaphthylamines,6 and N- (mono- and dialkylaminoalky1)-l,4-naphthalenediami~ies~ were report’ed to have strong therapeutic effects against Schistosoma mansoni in experimental ani mal^.^-^ Moreover, certain 1-(3- { [5,6,7,8-tetrahydro-4-(phenylazo- and 3-pyridylazo)-1-naphthyllamino ] propy1)piperidines are highly active against d l ycobacteriunz tuberculosis H37Rv and Mycobacterium lepraenzlnriunz in vitro aiid in mice.8j9 Because of the seriousness of the situation created by the possibility of widespread resistance of Plasrnodiunz falciparum to the 4-aminoquinolines and the resulting urgent need for new types of fast-acting suppressive antimalarial drugs,’O representative cornpounds from the above chemical types were supplied to Dr. Paul E. Thompson and eo-workers of these laboratories for evaluation against P l a s m o d i u m berghei in mice. l1 The drugs were administered continuously in the diet for 6 days to mice infected with a normal drug-sensitive strain of P. beryhei. Results are expressed both in terms of the SDgo (daily dose required for 9OCi. suppression of the parasitemia) and the quinine equivalent Q (the ratioof theSDgOofquinine to theSDgoof the test substance under comparable experimental conditions). Representative compounds from each of the aforesaid chemical t’ypes exhibited antimalarial act’ivity against P. beryhei in the mouse. With the exception of the p-(4-amino-lnaphthylazo)benzenesulfonamides, which might be (1) This is paper SV of a series relating t o antimalarial substances. For paper XIV, see E. F. Elslager and N. F. Haley, J . Heterocgclic Chem., 6 , 105 (1969). This is paper S I 1 of a series on synthetic schistosomicides. For paper XI, see E. F. Elslager and N. F. Haley, ibid., 6, 105 (1969). (2) E. F. Elslager, D. B. Capps, L. M. Werbel, D. F. Worth, J. E. Meisenhelder, H. Najarian, and P. E . Thompson, J . Med. Chem.. 6, 217 (1963). (3) E. F. Elslager, D. B. Capps, D. H. Kurtz, L. hl. U-erbel, and D. F. Worth, ibid., 6, 646 (1963). (4) E. F. Elslager, D. B. Capps, D. H . Kurts, F. W.Short, L.XI. \Verbel, and D. F. Worth, ibid.. 9, 37.3 (1966). ( 5 ) E. F. Elslager, D. B. Capps, D. H. Kurtz, and D. F. Worth, ibid., 11, 1201 (1968). (6) L. M. Werbel, E. F. Elslager, and D. F. Worth, ibid., 11, 950 (1968). (7) E. F. Elslager, D. B. Capps, L. hl. Werbel, D. F. Worth, J. E. Aleisenhelder, and P. E. Thompson, ibid., 7,487 (1964). (8) L. hl. Werbel, E. F. Elslager, hl. W.Fisher, Z. B. Gavrilis, and A. A. Phillips, ibid.. 11, 411 (1968). (9) Y. T. Chang, Antimicrobial Agents Chemotherapy 1966, 465 (1966). (IO) For recent reviews, see (a) E. F. Elslager in “Annual Reports in Medicinal Chemistry, 1965,” C. K. Cain, Ed., Academic Press, New York, N. Y., 1966, p 136; (b) E. F. Elslager in “Annual Reports in Medicinal Chemistry. 1966,” C. K. Cain, E d . , Academic Press, New York. N . Y., 1967, p 131. (11) For a description of the test method, see P. E. Thompson, A . Bayle?, and B. Olszewski, E z p . Parasitol., in press.
expected to undergo reductive scission in vivo7 and release a sulfonamide moiety having antimalarial activity per se,’O the most active compounds tested were 1-{3- [4-(p-chlorophenj~lazo)-2,3-xylidi1io]propyl}piperidine (I)s (SD,, = 58 mg kg’day, Q = 1.3), 1-(3- [4-(p-chlorophenylazo)-5,6,7,8-tetrahy~,ro-l -naphthylamino]propyl)piperidine (IIa)S(SDgo = 49 mg kg day, Q = 1.5), 1-(3-{ [4-(3,5-dichlorophenylazo)-5,6,7,8tetrahydro- 1-naphthyl ]am in0 }propyl)piperidine (II b)a (SDgo = 88 mg kg’day, Q = 0.9), aiid h-’-{p-[4-(2-diethylaminoethj lamino) -1- iiapht hylazo ]phenyl } - N ,Ktliethylethyleiiediarriine (IIII4 (SDgo = 70 mg kg day, Q = 1.1). Among the other structure types, ?rT,h-”“(CH,
jj
N
s
4 -ax N=N IIa, X = 4-CI b, X = 3,5-C1,
Q9 N
I1
N I
(azodi-l,4 -naphthylene)bis (?; ’,S ’-diethylethylenediamine) (IV), K,S’[methgliminobis(trimeth) lene) ]his (4-phenylazo-1-naphthylamine) (V), S ,S-diNH(CH-),NCH (CH.j KH
V
~
~
00 NO VIa, R=(CH-),N(CH,). b, R = CH-CCH.N(C-H
I
KH? VIIa. R=(CH.j S(CZH)? )i
3
h, R = (CH-),K
methyl-S’-(4-iiitroso-l-naphthyl)- 1,s- propanediarnine (YIa) ,6 S ,S-diethyl-2,2-dime t hyl-n’ ’-(4-nitroso-1-naph-
I
N=N+SO.S I
H
nit11 tlir :uiticipatecl cotitribution of the sulfonaniitle moicty assuming reductive scissioii of the molecule. 111 view of the antimalarial activity inherent ninoiig thpse ~,S-dialkyl-S’-l-iiaphth~lalkZ.leiiediaini~ies aiitl the currciit cliiiicnl interest iii the prophylactic niitl repository aiitinialarial properties of 4.-l’-sulfoii~ldixiiiliiie (dapsone, DDS) (SIaj,lU4’,-2”’-sulioii?.l~)isforiiiaiiilick (DFDDS) iX111),~?1’3’”-sulfoiiSlbisacetaiiilitlr. ( ~ ~ l a p IIADDS) ~ ~ i i ~ (SI(’) . , l ” “ :~iitl4’,4”’[y)-pheiiyl-
The S,N"- [sulfonylbis(p-phenyleneazo-l,4-naphthylene) Ibis (X ',X'-dialkylalkylenediamines) (XIII, XIT'a, and S I V b ) were also tested in mice against a Puerto Ricaii strain of S . mansoni.16 Drugs were given in a powdered diet for 14 days aiid drug amounts are expressed as free base. Compounds XIII, XIVa, and XIVh were highly active and effected a 53-10OCc reduction of live schistosomes in inice at closes ranging from 86 to 364 mg kg day. Against representative bacteria in oitro, including Staphylococcus aureus (UC-iG), Psezidornonas aeruginosa (28), JIycobacteriurn tuberculosis ( H ~ ~ R vhschericliia ), coli (T'ogel), Diplococcus pneuinoniae, Streptococcus pyoyeties (C203). Proteus rnzrabilis (AIGH-1), ant1 Salmonella typhirnuriuin (J7-31),8 compouiid XI11 caused complete inhibition of -11. tuberculosis H 3 7 R at ~ a concentration of 20 p g ml and XIYa caused complete inhibition of the following organisms : S . aureus (UC-76), 20 p g ml; .IL. tuberculosis ( H ~ ~ R V 20) ,p g ml; D . pneutnonzae, 1.25 p g ml: and S. pyoyenes (C203). 0.63 p g ml. 1 1'-{Sulfonylbis [ p- pheiiyleneazo (5,6,7,8-tetrahydro1,4-naphthylene)imiiiotrimethyleiie]dipiperidine (XIII) was inactive against X . tuberculosis H 3 7 R in ~ mice when administered at 0.04 (45 mg kg day) and 0.25"; (142 mg kg day) in the diet for i c l a p 8
1
Fisher, and coworkers of these laboratories for the antiparasitic and antibacterial evaluation of these compounds. JTe also thank Dr. J. 34. Tandenbelt and coworkers for the spectral studies and Mr. Charles E. Childs and associates for the microanalyses.
2-(Alkyl- and Arylamino)-5-nitrothiazole Derivatives with Antiamebic, Antitrichomonal, and Antimalarial Properties1 IdESLIE 11. \vERBEL, 1
