Novemlier, 1962
~-(3-CHLoRO-9-ACRIDIXYLAMINO)-a-AMINO-O-CRESOLS
1153
lized from a mixture of ethanol, acetone, and ether. The water-soluble, dark maroon solid weighed 9.8 g. (560j0), m.p. >325". The sample was allowed to equilibrate in the air prior to analysis. .Inal. Calcd. for C~6H~,Nn06.2HC1.0.75H~0: C, 53.93; H, 5.48; N , 9.68; 1I20,2.33. Found: C, 53.82; H, 5.81; N, 9.88; H20,2.61.
4~-(3-Chloro-9-acridinylamino)-cu-amino-o-cresol
10-Oxides EDWARD F. ELSLAGER AND FRANK H. TENDICK Ifcseurch Laboratories, Parke, Davis and Company, Ann Arbor, Mzchzgun
Received June 14, 196.9
A group of 4-(3-chloro-9-acridinylamino)-a-amino-o-cresol10-oxides has been prepared by the condensation of a 3,9-dichloroacridine 10-oxide with the appropriate 4-amino-a-amino-o-cresol hydrochloride in phenol. Several compounds exhibited good activity against Entamoeba histolytica i n vitro and Plasmodzum iophrirae in the chick.
During investigations of malaria conducted in the United States during World War 11, 4-(6-chloro-2-methoxy-9-acridinylamino)-adiethylamino-o-cresol dihydrochloride (I) was synthesized in these laboratories1 and was demonstrated to be qualitatively similar to quin-
~ ~ ~ 2 1 V ( C2 ~ H 6 )
c1a
c
I
H
.23HCI
7H3 NHCH(CHZ)~N(CZHS)Z
C1&OCH3
* 2HCl
I1
ncrine (11) in over-all antimalarial potency.* It was of interest t o synthesize various 4-(3-chloro-9-acridinylamino)-a-amino-o-cresol10 oxides (VII)for biological evaluation. Details of the synthetic work are described in tshepresent communication. The P(3-chloro-9-acridinylamino)-a-amino-o-cresoll0-oxides (V1 J j (Table 11) were prepared by allowing a 3,9-dichloroacridinc 10(1) J . H. Burckhalter, F. IT. Tendick, E. M. Jones, P. A. Jones, W. F. Holcornb and .L I,. Rswlins, J. Am. Chem. Soc., 70, 1383 (1948). (2) I". Y. Wiselogle, "A Survey of Antimalarial Drugs. 1941-1945," J . T. Edwards. Anu I r b o r , Mich., 1946, pp. 373, 1361.
E. F. ELSLAGER ASD F. H. TEXDICK
1154
\.Ol.
-5
oxide3 (VI) to react with the appropriate 4-arnino-a-amino-o-cre.ho1 hydrochloride (V) in phenol (methods I and 11). Condensation of -4'-hydroxyacetanilide (111) with formaldehyde and the appropriate amine gave the corresponding ~-acetamido-Lu-amino-o-cresols (I\-) which were not isolated but were hydrolyzed directly to the intt.rmediate ~-amino-Lu-amiiio-o-cre~olhydrorhloridt~h ( IT) (Tal)le II .I In scverul C';LYCSthe cmde I-amii~o-~-amiiio-o-crc~~ol hydrochluridch wcre used without iurther purification.
6
/I%
+ ("10 + HN,
-
RL
NHCOCH~ J IV
PU'lICOC", I11
0VI I
.It)sorpf ion in the ultrilrdet and low wnve leiigtli visible raiigc ~vab used t o assist in the characterization of the 4-(3-chloro-9-acridinylamino)-a-amino-o-cresol 10-oxides. X comparison of the spectrum of a representative 9-aminoacridine 10-oxide and of the corresponding des S-oxide in 0.1 N hydrochloric acid is shown in Fig. 1. The solid line represents 4-(6-chloro-2-methoxy-9-acridinylamino)a-diethylamino-o-cresol 10-oxide dihydrochloride and the broken line 4-(6c~hloro-2-me t hoxy-'3-ac.ridinylarniri~)) - a-die thylamino-o-cresol dihydrocdliloride. l'ormution id the IO-oxide bond causes :t grw>ral bathocalirornic shift corntined with a modest dc.cwxst. in iii(oiihity of tlic I I N J S ~ l i l t eme hand and a general dc(~r~'i~sc. in r(wlut ioii. (:
