_\larch 1970
*hTIPROTOZOrlL
QUIKONES. 111
"1
Antiprotozoal Quinones. 111. Synthesis of 8-Amino-5,6-quinolinediones, 8-Amino-7-chloro-5,6-quinolinediones, and 8-Amino-5,5,7-trichloro-6(5H)-quinolonesas Potential -Antimalarials' 1'. J. BULLOCK B N D J. F. TKEEDIE drthur D. Little, Inc., Acorn Park, Cambridge, JIassachusPtfs 02140
RPcewed September 29, 1969 Cuz+-catalyzed oxidation of 6-quinoliiiol in MeOH with a variety of secondary aniiiies gave a series uf 8dialkylamino-S,6-quinolinedioiies ( 5 ) . The reaction was useless when attempted with primary amine.: and other amines which complex cupric ion. Several 8-ami1io-i-chloro-.i,,6-quii~oliiiedioiies 17) were obtained by reaction of amines with 7,8-dichloro-5,6-quinolinedione.A number of i(-amino-.i,S,i-trichloro-6i.iH)-q~iiiioloiie~ (10) were obtained by reaction of amines with S,.i,i,8-tetrachloro-6(~~)-quiiioloiie.h l l the new quinones and quinone derivatives were evaluated against blood-induced Plasmocliitm berghei infections in mice, P . gallinaccum in chick.;, and P . gal/itzaceurn in mosquitoes (Aedes argyptf). Xone of the compounds showed high ailtimalarial activity. The series 5 in particular is highly toxic iii both mice and chicks. 8-Hesylamiiio-i-chlor[)-~,6quinolinedione resulted in increased survival time in P. bprghei infected mice of 3.1 days at 320 nig kg atid 8.9 days at 640 mg/kg with no toxicity but with no activity iii the other screeiii. These results are part of an illcreasing body of circumstantial evidence which suggests that the in vivo metaboli>m of the ailtimalarial 6methoxy-8-aminoquinolines to quinones may not be cotitribiitiiig to their ailtimalarial activity.
Int ererjt in 8-amino-5,6-quinolinedioner and related timulated by their relationship to the presumed active quinonoid metabolite of antimalarials derived from 8-amino-6-met hoxyquin~line.~ We report here tmhesynthesis and results of biological evaluat,ion of further analogs (5. 7, 10, Scheme I) related t o these metabolites as well to 8-amino-5,6-quinolinedione. Previous evaluat,ion of 8-amino-5,G-quinolinediones has been by an indirect means. 9 5-met,hoxy-6-hydroxyquinoline and a 5,6-dihydroxyquinoline, expected t'o be converted in ciiv into 8-amino-5,6-quinolinedione, were used. Relat'ed carbostyryl analogs have been more thoroughly explored. 8-Dialkylamino-5,6-quinolinediones(5).-Extension of syntheees of Brockmari and Havingaj and Soviet chemists6using Cuz+-catalyzed oxidation of 6-quinolinol in NeOH in the presence of a variety of secondary amines provided facile entry to the series 5. The part,icular compounds prepared are given in Table I. We did not attempt to prepare compounds incorporating a common dialkylaminoalkyl moiet,y in view of the high toxicity encountered with such compounds among the related 1,2-napht,hoq~inones.~Considerable experience with this r e a d o n has helped delineate its scope. S o oxidat'ion occurs when an N-alkylated ethanolamine or primary aliphatic amine is used, presumably due to t,he formation of the cupramine complexes l b arid 2, respectively, in which the cupric
ion is catalytically inert. \T7ith iecondar!- amines the formation of cupramine complexei .uch a- 2 is ap-
B I
I
R 1
parently less favored and cattal!-tic oxidation uninhibited. htt'empte to extend t*hescope of t,he reaction by use of various cobalt sa'lt's as catal!-st' failed. 8-Amino-7-chloro-5,6-quinolinediones (7).-Exhaustive chlorination of 5-amirio-6-yui1iolinol prepared from 6-quinolinol gave 7,8-dichloro-5,6-quinolinedione (6),g which reacted with primary and secondary amines to give t'he new quinones 7. During our work we observed that' t'he pmr spectra of 17 did not support the older formulat8iongof these compounds as the tautomer 3. The OI-CHZprotons of the Bu group (6 4.14 ppm from (CH,),Si in CDCl3) appear as a quartet, which i$ n
c1
O *H NR 3
(1) This work was supported by the U. S.Army Medical Research and This Development Command under Contract No. DA-49-193->ID-2880. paper is Contribution S o . 743 from the Army Research Program on Malaria and was the subject of a preliminary report a t the First Piortheast Regional Meeting of the American Chemical Society, Boston, Mass.. Oct., 1968. ( 2 ) Background information is summarized in our previous paper, F. J. Bullock, J. F. Tweedie, D. D . RIcRitchie, and 11 Tucker, J . .Wed. C h e m . , 13, 97 (1970). (3) S . L. Drake and T.T. P r a t t . J . A m e r . C h e m . Sac., 73, 544 (1951). (4) Cf.R . R . Holmes, J. Conrody, J. Guthrie, and R . McKay. ibid., 7 6 , 2400 (1954); G . R. Pettit. TT'. C. Fleming, and K . D. P a d , J. OTQ. C h e m . , 33, 1089 (1968). ( 5 ) IT, Brockman and E. Havinga, Rec. Trau. Chim., 74, 937 (1955). (6) (a) Tu. 8. Tsizin and &I, V. Rubtsov, CSSR P a t e n t 188,495; C h e m . Abstr., 67, Q069s (1967). ( h ) T u . S . Tsizin a n d AI. V. Rubtsov, ibid., 79, 87520m (1969). (c) ibid., 7 0 , 87516q (1969). ( 7 ) See our paper, "Antiprotozoal Quinones. 11," ref 2. ( 8 ) Cf. .i. E. Martell and RI. Calvin, "Chemistry of Metal Chelate Compounds" Prentice-Hall, Inc., Englewood Cliffs, N. J., 1952, p 179.
analyzed as an overlapping doublet of triplet. ( J C H C H = 7 Hz, JNHCH = 7 Hz) and nhich collapses to a clean triplet ( J c H c H = 7 Hz) on D exchange of S H . Thi3 clearly necessitates that the exchangeable proton be situated on S as indicated in 7 (R1= H). 8-Amino-5,5,7- trichloro-6( 5 H )-quinolones (10) Exhaustive chlorination of 6-quinolinol in acetic acid'" gives the pentachloroquinolone 8 which iq easily converted into the tetrachloroquinolone 9 by dehydrohalogenation.10 Reaction of 9 with a variety of amines gave 10. Extensive secondary reactions can occur during this transformation; for example, the quinone-
.-
(9) T. Zincke and K. Wiederhold, A n / < .C h e m . , 290, 359 (1896). (10) T. Zincke and H. AItiIler, %bid., 290, 223 (1891).
NR'RI7 12
I!,
II
1: I ( ) I 1
11
EIOII
Ii 24
11
fl II
I1 Ii I1 II IT
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ANTIPROTOZOAL QUINOXES.111
l l a r c h 1970
inline 4 has also been claimed to be formed 011 reaction of 9 with aniline.'" Success in obtaining the 5eries 10 u-a- achieved only under reaction conditiong which rew!ted in the product precipitating from holution e-eririntly ah it formed. This was achieved by uzing
263 SCHEME
1
i
a)
N H C,,H.,
\
GC,,H., 4
low reaction temperatures or decreasing the polarity of the reaction medium. We also obtained in low j-ield ;he compound corresponding with 4 report.ed by Ziticiie and ~Iuller'"but have not yet completed an independent confirmation of t,he assigned struct'ure. lye were unable to isolate such compounds as 4 from rwctions of ot'her amines with 9 and it is clear t'hat such :L route is not a practical approach to the synthesis of fi-umitio-8-imino-j (8H)-quinolones. Biological Results.-All the compounds of Table I have heen evaluated against blood-induced P. beryhei infectiorii in mice. I I P. q a l l i m c e u m in chicks,'? and P . yatiinaceurn in n:osquitoes (Aedes ueyypti).l3 The 3..i.;-trichloroquinolones (29-36) showed no antimnltiri:il activity in any of the screens. The %amino5.Ci-(!ainolinediones (11-16) showed weak activity but xlio high toxicit>-in both mice and chicks. Quinone 16 ploduced abnormal oocysts at a concent,ration of O.Olyc in the mmquito screen and partial sporozoite suppre5;.ion Lit 0.1%. Activity against the sexual phase of the paraite'.. life cycle not found with other compounds of thi.; class, however. Quinone 18 caused an increased mean survival t'ime of P. h y h e i infected mice of 3.1 days a t 320 mg,/kg and of :3.Y days a t 6-l0 mg/kg with no toxicity, but no activity in the other screens. As a class the 8-amino-7chloro-5,G-quinolinediones are less t'oxic than the 8:miirio-v5,G-quinolinediones which in t'urn, however, appear to be more toxic than the analogous &imino1.2-nipht hoquinone.~.' These studies have failed to produce a compound with pot'ent i n vivo antimalarial activit'y, although the c1uino:ies prepared are closely related t'o the presumed :tctive quinoid metabolites of antimalarials derived from ~i-me:~hoxy-8-aminoquinolines.I n our previouh study,I3 :in tirialogous series of 4-amino-1,2-naphthoyuinones including several compounds bearing the dialkylamino:ilk?! group were also found inactjive. It is also of interest that the hydroquinone, 5,6-dihydroxy-8-(5-isoprop>~laminopent3-]amino)quinolinetrihydrobromide, iL.essentially inactive against P. berghei in mice although ..i M i m e t hox y-8- (5-isopropylaminopent ylamino) yuino-
NR'R'
CI
5
6
0
H
I
H.O. A
m "
SR~R?
C1
8
7
' CI
C1 9
[RSH
H k~ 10
line has definite activity.14 Taken together this body of circumstantial eyiclence suggests that the i n vivo activity of the 6-methosy-8-aminoyuinolines may not be relat'ed to their 1'11 i,iw metabolic conversion to quinones. Their t,oxicity ma>- be related t o this transformation as has been wggested previously.1i
Experimental SectionIfi 8-Dialkylamino-5,6-quinolinediones (ll-l6).--These compounds were prepared Iry :,he fullon-iiig modification of t,he procedure of Tsizin and Riihrsiiv.6 Cii(0Ac)r (0.1 g ) and t,he dialkylamine (4ml) were added 1 1 ) a -tiired solution of 6-quinoliiiol17 (1.43 g, 10 mmol) in 30 mi ( i f 3IeOH. -1.steady stream of 0 2 was bubbled through t h i G red reacrivii mixture for 1 hr with ext.erna1 cooling so that the temperatiire did not exceed 50". Quirioiies 11-14 were ip(~latet1i i i the following mariner. The solvent from the reactioii mixtiire was removed under reduced pressure and the oily re*idue di-..olved in CHCls. The CHC13 solutioii was washed witsh HzO, dried (,31gSOd), and evaporated to a dark red oil. C h i ~ r ~ i n ~ ~ t i i g 011 i ~ aiieiitral ph~ alumilia (CHCL) (14) Dr. R. E . Strube of \\'alter Reed .Arm?- Institute of Research informs us that this 5,6-dimettioxy~~riinoline resiilts in a n increased survival time in P. berghei infected mice of 2.1 days a r 40 me ka and 5.3 days a t 160 m z kR, and shows toxicity a t 640 me 'kg. Tlie analogous ~ , 6 - d i l i y d r o x y ~ ~ u i n o l in ine the same test resulted in an increased mean furviral time of 0.4 day a t 40 m g i k g and showed toxicitj- at 160 and 640 mg kp. (15) B. E. Hrodie and 4. Udenfried, Proc. Soc. E x p . B i d . .Veri.. 74, 8-15 (1950).
(11) T. Y. Osdene, P. B. Russell, and L. Rane, J . Me//. C h e m . . 10, 431 (1Y6i). (12) Chicks (9-12 days old) were infected (intravenously) with a standard
inocuhim to produce a disease fatal t o 100% of untreated controls within Candidate compounds were dissolved or suspended in peanut oil and administered either subcutaneously or p e r os immediatelj- after infection. A 1 0 0 7 ~increase in survival time was considered t o be the minimum etiective response t o the antimalarial activity of tlir drug. Chicks surviving 30 days are recorded as cured. 1 1 3 ) E. J. Gerberp, L. T . Richard. and ,J. 13. Poole, .?foaquito .Vew.>, 26, :(,XI (1966). :4-4 days.
(16) Melting r,oints were determined on a Nel-Temp or Fisher-Johns apparatus. T h e i r and uv spectra uere ohtained on Perkin-Elmer Model 137 and Beokman D K instruments. respectively. Tlie nmr spectra IT-ere taken in CDClr on a Varian .1-60 instrument using TZIY as internal standard. Mass spectra were determined wit11 a CEC Model 11 instrument. Microanalyses were performed by Galhraith ,\Iicroanal>-tical Lahoratories. Knoxville, Tenn. T h e ir, uv, and nmr spectra were as espected for the assigned structure. (17) Prepared in up t o 9.5r;; yield from 6-methoxyiiuinoline with refluxing 48% HBr. Tlie yield varied considerably with the source of material which was used as purchased, t h e best yields being obtained ivitli material from Distillation Products Industries.
