Journal o f Medicinal Chemistrv VOLUME12, No. 6
NOVEMBER 1969
Antifilarial Agents. I. Effects of 4-[(7-Chloro-4-quinolyl)amino]&-(mono-and dialky1amino)-o-cresols and Related Compounds against Litornosoides carinii in Gerbils EDWARD F. ELSLAGER, S. C. PERRICONE, ANI) F. H. TESDICK DPpartment of Chemistry, Medical and Scicnti'c d f a i r s Division, Pnrke, Dnoi:r & Company, Ann Arbor, Mzchignn ,$8106 EZrcPiverl .\fay 8, 1969
Various 4-[ (7-chloro-4-quinolyl)amino]-a-(monoand dialkl lamino)-o-cresol derivatives iX) related to amodiaquine were prepared by treating 4'-hpdroxyacetanilide with formaldehyde and the appropriate amine, followed by hydrolysis of the intermediate a-(mono- or dialkylamino)-4'-hydroxy-m-acetotolnidide and condensation of the resulting 4-amino-a-(mono- or dialky1amino)-o-cresol mith 4,7-dichloroquinoline in aqueous EtOH 01 phenol. Other amodiaquine congeners were also prepared. Among them, ten compounds exhibited antifilarial activity and killed adult Litomosozdes carinii in gerbils when administered in daily gavage doses of 25-100 mg/kg for j days. The most active compounds, 4-[(i-chloro-4-qu~inolyl)amino]-~-(4-methyland 4-ethyl-l-piperaziny1)0-cresol trihydrochlorides (XVIa and b), were equipotent with amodiaquine.
Filariasis comprises a group of diseases produced by the invasion of the lymphatic system or connective tissues by the nematodes Filarioidea. The most formidable pathogens of man include Wuchereria bancrofti, Brugia (Wuchereria) malayi, Loa loa, and Onchocerca volvulus. Other relatively common filaria species parasitic to man include Acanthocheilonema perstans, Aca?ithocheilonema streptocerca, and illansonella ozzarcli. It is estimated that 189-250 million people in the world harbor these dread infections.2 American interest in filarial infections peaked toward the end of World War 11. Several hundred thousand soldiers were exposed to filariae, especially in the South Pacific, and approximately 15,000 troops were known to have circulating microfilariae.1h Elaborate plans were contrived to cope with the anticipated hordes developing scrotal and pedal elephantiasis, but such complications were almost never seen. The main problem mas a psychological one of reassuring the frightened soldiers that their sexual life was not impaired.Ib Because of the dynamics of the transmission of filariasis and the long life span of the adult worm, cont8rolof the infection hinges greatly on chemotherapy.3 Diethylcarbamazine (I)4 is the drug of choice for the treatment of filariasis and is effective orally against CHJ'
n
U7. bancrofti, B . malayi, and L. loa. The drug removes almost all of the microfilariae from the blood and has an incapacitating, if not lethal, effect on the adult worms. I n patients with Omhocerca, treatment is effective in temporarily removing microfilariae from the skin, but adult worms are not killed and the microfilariae usually return after some weeks. Although opinions conflict on the value of diethylcarbamazine for mars treatment, it is doubtful whether this drug alone will ultimately achieve cessation of transmission, and better antifilarial drugs are needed. Therefore, new types of antifilarial agents are being sought in these laboratories utilizing Litornosoides carinii in gerbils as the primary tcst system. In a recent communication Thompson, et al., reportecPa that amodiaquine6i (IIa) exhibits strong
X IIa. X = C1 1). = BY c. X - I
x
therapeutic effects against, adult forms of L. carinii in 3longolian gerbils, but is not directly active against, circulat'ing microfilariae. Gavage doses of 100, 50, or 25 mg/kg daily for 5 days had significant, act,ivity, and female worms were more susceptible to the drug than
NCOK(C-H )-
U
1
[ I ) [ a ) For recent reviews, see F. Hawking in "Experimental Chemotherapy,'' Vol. I, R. J. Sohnitzer and F. Hawking, Ed., Academic Press, Kew York, N . Y., 1963, p 893 f f ; (b) K. Rf. Cahill, 'V. Y. Stale J. M e d . , 63, 1379, 1551 (1953). (2) N . R. Stoll, J. Parasitol.. 33, 1 (1947). (3) World Health Organ., Tech. R e p t . Ser., NO.369, 1 (1967). (4) R. I. Hewitt, S. Kushner, H . W. Stewart, E. White, IT. 9. Wallace, and Y. SubharoNr, J . Lab. Clin. .Wed., 92, 1314 (1947).
( 5 ) (a) P. E. Thompson, L. Roche, and L. S . Rlair, J . Parasitol., S4, 834 (1968): (b) E. F. Elslager, D. R. Capps, P . E. Thompson, and L. Roche, unpublished results. (6) CamoquinE. (7) J . H. Burckhalter, F. H. Tendick, E . M . Jones, P. A. Jones, W. F. Holcomh, and A. L. Rewlins, J . Am. C k e m . Soc.. 70, 1363 (1948).
965
males.5a I n contrast, amodiaquine had only feeble activity againt the same strain of 1,.c a ~ i n i iin cottoii rats when administered in daily gavage doFes of 100 mg/kg for 5 days. I n subsequent studies in these laboratories, many known congeners7-12 of amodiaquine and chloroquine> were evaluated against L. carinii in gerbi1s.j” Among them, 4- [(7-bromo-4-quinolyl)amino]-a-(diethylamino10-cresol (IIb),l 2 a-(diethylarni1io)-4- [ (7-iodo-4-qiiinoO-methylamodiayuirir. 1yl)amino1-o-cresol (IIc), (IIIa),s 0-ethylamodiaquine (IIIb),7 O-methylaniodi: q i i i r i t a 1-oxide (IV) In and 1-[ (’7-chloro-~-ciuiii(~lyl JI
i’l L II
A Y , ( ’Ii
hHCH(( H
H hp‘\C
A&
c1
\ H -YL,
9
(’I
( )-
I\
amino]-a-(diethylamino)-o-cresol acetate ester (V)” also killed many adult L. carinii in gerbils at daily gavage doses of 50-100 mg ’lig for 3 days, but none w:is
more promising than amodiaqui~ie.~”Surprisingly, many other basically substituted 4-aminoquinolinc derivatives, including amopyroquin (VI),g , 1 3 chloroquine (VII),I2 4,4’[1,4-piperazinediylbis(l-methylethyleneimino)]bis(7-chloroquinoline) (VIII),14 and 4,4’(1,4-pi p e r a z i nediyldiimino) bis(7-chloroquinoline) (IX),I6 lacked appreciable antifilarial activity in the gerbil when administered orally in doses ranging from 50 to 200 mg/kg daily for 5 days.5b (8) J. H. Burokhalter, J . A m . Pharm. Assoc. Sci. Ed., 38, 658 (1949). (9) W. L.Nobles. R. F. Tietz, Y. S.Koh, and J. H. Burokhalter, J. Pharm.
sei.. sa, 600 (1963). (10) E. F. Elslager. E. H. Gold, F. H. Tendick. L. 31. Werhel, and D. F. Worth, J . Heterocyclic Chem.. 1, 6 (1964). (11) E.F. Elslager, F. H. Tendick, and L. h l . Werhel, J . -Wed. Chem., l a , 600 (1969). (12) F. Y . Wiselogle, “A Survey of Antimalarial Drugs, 1941-1943,” Vol. 11, P a r t 2, J. W. Edwards, Ann Arbor. hlich., 1946. (13) PropoquinB. (14) J. Schneider, 11. Bouvry. a n d J. I,eQuellec, A n n . Soc. Belge .1Iwi. T r o p . , 45, 435 (1965). (15) F. Benazet, ibid.. 45, 459 (1965). (16) E. F. Elslager, F. H. Tendick, L .M. Werbel, and D. I‘. K o r t h , ,I, .\led. Clrem.. 11: 970 (1969).
H C HiCH )NH
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\ IIJ
111.1. K = C’H ti. R = (’ H
(’I
L f
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IY
&XI
r ,
I he present conimuiiie:ition devxibrs t lic synthe of a variety of novel 4- [(7-chloro--1-quinolyl)amino J-a(mono- and dinll~yl;~niino)-o-crri;ol derivatives as potential antifilarid : ~ r d:mtim:il:ri;il agents. Several of these compourid- eshibitcd i t rorig :intifilarial properties in gerbils, hut i i o i w morci potciit than amodiaquine. The 4-[ (i-~~liloro--1-~~uii~~~l~l):imino]-a-(n~o1ioand di: ~ l k y l a m i n o ) - o - c r ~ (X) ~~)l~ i 1 25, Tablc I) werc prcpared by the cioridriisatiori of -1.7-dichloroquinolinewith :I purified I-wniirio-a-(moi~o-o r dialky1amino)-o-cresol (1ihpdroclilol.ii~c1)rwiirwr ilk plienol (procedure I) ,’
(’1 \
or b y :i sequence inl-olvirig t 110 reaction of 4’-hydrosy2tcetanilide with the rcquihit c :imine and formaldehyde followed by hydrolysis of the iiitermediate ,-(mono- or dialkplan~ino)--1’-liydro~y-i~i-:~cetotoluidide and condensation of thc resulting clude diamine with 4,7dichloroquinoline iri ~ ~ q u e o iEt i i OH (procedures I1 and 111) in which the intermediates were not purified.’ q-ll The yields ranged from 24 to ti!J%‘,. a-(Decy1amino)-4[(6-methoxy-2-methyl-4-quinolyl)amino]-o-cresol dihydrochloride (XI) (31Yc) and 4- [ (7-chloro-2-phenyl-4quinolyl)amino ]-a-(dccylaminoi-o-cresol dihydroch loride (XII) (40yc) were prepared similarly from -1’hydroxyacetanilide, decylamine, formaldehyde, and 4chloro-6-methoxyquinaldine and 4,7-dichloro-2-phenylq ~ i n o l i n erespectively ,~~ (procedure 111). Alternatively. 1- [ (7-chloro-4-quinolyl)methylamino ]-a-(decy1amino)I
1 T ) H , Gilman a n d
R 1, I ( ~ ~ i h r s eJr ., .iw.Chsrri, S o r , 69, 123 ( 1 9 4 i ) ,
ANTIFILARIAL AGENTS. I
Sovember 1969
967
Representative 4- [ (i-chlor0-4-quinolyl)amino]-cr(mono- and dia1kylamino)-o-cresols and related compounds described in the present communication were supplied to Dr. P. E. Thompson and coworkers of these laboratories for evaluation as potential antifilarial agents me1 against Litomosoides caririii in gerbils. As in previous CH drugs were administered by gavage as solutions SI or suspensions in aqueous 1% (hydroxyethy1)cellulose and 0.1% Tween 80 (volumes of 5 ml/kg). Doses are expressed in terms of the free base equivalent. Examinations for microfilariae were made in GiemsaHS I stained thick films of blood drawn from the retroocular iinus. These parasite counts were started early in .2HCl patency arid were continued a t 1-4-day intervals until c1 the animals were examined for adult w0rms.j Surviving animals were sacrificed and examined for adult worms YTT o n day 15 after the first drug dose by searching the pleural and peritoneal cavities. The numbers of live o-cresol dihydrochloride (XIII) was obtained in 3 2 7 , and dead worms at autopsy were scored relative to unyield by boiling p - [ (i-chloro-4-quinolyl)niethylamino]treated infections in control gerbi1s.j phenol'" with decylamine and paraformaldehyde in Among the 4- [ (7-chloro-4-quinolyl)amino 1-a-(monoEtOH. Treatment of 4,7-dichloroquinoline with 1-(5and dialky1amino)-o-cresols (X) (1-25, Table I) and amino-2-ethoxybenzy1)pyrrolidine dihydrochloride18in boiling EtOH afforded i-chloro-4-(4-ethoxy-a-l-pyr- congeners XI-XV, ten compounds (3-5,7,9,16,17,19, XIV, and XV) killed adult L. carinii in gerbils when rolidinyl-m-to1uidino)quinolinedihydrochloride (O-ethadministered in daily oral 25-100-mg/kg doses for 5 ylamopyroquin) (XIV) (63%). days. The most active compounds, 4- [(i-chloro-4quinoly1)amino]-a(4-methyl-l-piperazinyl)-o-cresol trihydrochloride (3, XVIa) g and 4- [ (7-chloro-4-quinoly1)amino]-a-(4-ethyl-l-piperazinyl)-o-cresol trihydrochloride ( 5 , XVIb), were equipotent with amodiaquine. .?HCl
c1 XI11 .3HCl
CI
XVIa. R = C H , b. R = CLHj XIV
I n 1967 Hamana and n'odaigreported the preparation of 2-(4-chloro-2-quinolyl)cyclohexanone in 78% yield from 4-chloroquinoline 1-oxide and N-( l-cyclohexen-ly1)morpholine in the presence of benzoyl chloride. Extension of this reaction to 4,i-dichloroquinoline 1oxide'" afforded 2-(4,7-dichloro-2-quinolyl)cyclohexanone in io% yield. Condensation of the latter compound with Ka,S"-diethyl-6-methoxytoluene-a,3-diamine d i h y d r ~ c h l o r i d ein ~ ~refluxing ~~ EtOH gave 2(i-chloro-4-{3- [(diethylamino)methyl]-p-anisidino)-2quinoly1)cyclohexanone (XV) (58%).
2HCI
CI Xv (18) E. F. Elslager and N. F. Haley, J. Heterocyclic Chem., 6, 105 (1969). (19) RI. Hamana and H. Xodrt, Chem. Phurm. Bull. (Tokyo), 16, 4 i 4 (1967).
Kone of the compounds showed direct action against the circulating microfilariae.
Experimental Section20p21 4-[(7-Chloro-4-quinolyl)amino] -a-( mono- and dialky1amino)o-cresols (1-25, Table I). Procedure 1.-4,7-Dichloroquinoline (9.9 g, 0.05 mole), 4-amino-a-(decylmethylamino)-o-cresol dihydrochloride (18.3 g, 0.05 mole), and 50 g of phenol was stirred and heated on a steam bath for 4 hr. The product was cooled and poured into a stirred mixture containing 1 1. of CHCl,, 500 ml of 10% aqueous NaOH, and 100 g of ice. The layers were separated and the aqueons layer was discarded. The CHCla layer was t,hen washed with three 300-ml port'ions of dilute aqueous NaOH and three 1-1. port'ions of H20. The CHCll solution was dried (KzCO~)and the CHC1, was removed in vacuo. The viscous residue was dissolved in 500 ml of LIeOH, treated with decolorizing charcoal, and concentrated to 200 ml. bIesCO (600 ml) and excess ethanolic HC1 were added and the product was collected by filtration. Crystallization from ?vIeOH-MezCO gave 15.5 g (E197~)of 4-1(7-chloro-Pquinolyl)amino]-or-(decylmethylamino)o-cresol dihydrochloride (21) as yellow crystals, mp 204-206'. Procedure II.-4'-Hydroxyacetanilide (15.1 g, 0.1 mole) and ( 2 0 ) Melting points (corrected) were taken on n Thomas-Hoover capillary melting point apparatus. (21) Where analyses are indicated only 1,s symbols of t h e elements or functions, analytical results obtained for those elements or functions were within =t0.470 of the theoretical values. JVater determinations were by the Karl Fischer method.
O('1I
iG I
1 L'H
Sovember 1969
ANTIFILL4RIAL AGENTS. 1
969
1 hr. The mixture was cooled and the product was collected by volatile materials were removed in vacuo. The residue was disfiltration, washed with EtOH, and dried. Crystallization from solved in EtOAc, treated with decolorizing charcoal, and conGPrOH containing a few drops of i-PrOH-HC1 afforded 17.3 g centrated until crystallization began. 4-[ (7-Chloro-4-quinoly1)( 6 3 5 ) of brilliant, yellow ciyst,als, mp 283'. Anal. (CnH2,C1K8O. amino]-a-[ (furfuryl)methylamino]-o-cresol (4) was obtained as 2HCl.RzO) C, 11, N, 1120 yellow crystals, nip 171-173", yield 19.3 g (49%). 2 4 7-Chloro-4-( 3- [( diethylamino)methyl] -p-anisidino)-2Procedure L11.-4'-Hydroxyacetaiiilide (45.3 g, 0.3 mole), quinoly1)cyclohexanone Dihydrochloride (XV).-A mixture of 2.3 39.0 g (0.3 mule) of 1-piperazineethaiiol, and 9.0 g (0.3 mole) of g (0.007s mole) of 2-(4,7-dichloro-2-q~ii11olyl)cyclohexanone and CH,O were allowed to react according to procedure 11, and the 2.3 g (0.0078 mole) of ~",N"-die~hy1-6-methoxyto1~iene-~,3intermediate 4-aniiiio-a-arnirio-o-cresc)lwas heated with 39.4 g diamine diliydroc~t~loride~~'~ in ICtOII w:w refluxed for 2 hr and (0.3 mole) of 4,7-dic~hloroqiiiri~~litie.The criide base was crys~ ( ~ o l e d .Volni ile m:t1 eri:ils were removed in vacuo, and the tallized from Ct0T-I (decoloriziiig c:h:irc:onl) lii give 49.3 g of resitiiie w:is t rituratetl with hiiliiig 31e2C0, cooled, aiid filtered. 4-(5- [( 7-chloro-4-c~iiitic~lyl)aiiiiiiu]s:tlicy~ ] - 1 -pil)eri:tzineeth:~rlol, The yell(~wprodrict, weighed 2.3 g ( 5 8 ( / ; ) , nip 1S7-10O0 dec. mp 207-209'. This material was suspended in warin XtOH mid & 4 n ~(CziH~~ClN~O~.21ICl.0.73H~O) l. C, 11, K, HzO. treated with excesb concentrated IICl. A yelluw precipitate 2 4 4,7-Dichloro-2-quinolyl)cyclohexanone.-A niixliire of 50.0 separated and the mixtiire was diliited with MeZCO. The t'rig (0.23 mule) of 4,7-dichluroc~iri11oli1ie l-oxidelu aiid SO.0 g hydrochloride 6 was collected by filt,ration and dried i n L'UCILO at. (Aldrich) in (0.48 mole) of Y-(l- lohe~et1-1-y1)r1ioi~pholi11e 60" for 18 hr; yield 63 g (385;,),mp 222-223". 300 nil of CIICl, wax cooled t o 3-10' a i d 33 g (0.25 mole) of a-(Decy1amino)-4- [(6-methoxy-2-methyl-4-quinolyl)amino] -0beiizoyl chloride was added dr,opwise with stirriiig. The solution cresol Dihydrochloride (XI).-4-Chloro-6-methoxyquinaldine turned from yellow to deep red. The mixtiire was allowed to (31.0 g, 0.15 mole), 4'-hydroxyacetaiiilide (22.6 g, 0.15 mole), stand for 2 days at room temperature and the CHC& was redecylamirie (25.9 g, 0.16 I l l ( J k ) , and paraformaldehyde (4.5 g, moved in uacuo. The residue was boiled with 2 1. of hIeOH t.0 0.15 mole) were allowed to react according to procediire 111. give 34.3g of cryst:&, nip 1.33-1%". Concentration of the MeOH The product was obtained as an off-whit,e solid, mp 125-130", filtrate afforded 13.0 g of a second c i ~ i p nip , 132-136", total yield yield 25.7 g (31%). d n a l . (CnsH39S3On.2HC1.1.3H~O) C, H, K. 47.5 g ( 7 0 5 ) . Anal. (C~;II,~CLSO) C, 13, S , C1. 4- [(7-Chloro-2-phenyl-4-quinolyl)amino] -CY-( decylamin0)-o4-Amino-a-(decylmethylamino)-o-cresolDihydroch1oride.--A cresol Dihydrochloride (XII).-The r e a d o n I J f 25.0 g (0.091 sii~perisioiiof 71.0 g (0.41 mole) of N-inethyldecylamine and 12.3 mole) of 4,7-dichloro-2-phenylqiiinoliiie,17 13.7 g (0.091 inole) of g (0.41 mole) of pai.afornialdehyde iii 100 nil of EtOH was 4'-hydroxyacetanilide, 15.7 g (0.1 mole) of decylamine, and 2.7 g heated on a sieani bath for 0.5 hr. The resiiltiiig clear, colorless (0.091 mole) of paraformaldehyde according to procediire I11 soliitioii was theii added slowly over :I period of 33 min to n afforded 21.7 g (40';) of the title compound as yellow crystals, refluxing soliit ioii (Jf 02.0 g (0.41 mole) (Jf 4'-hydroxyacetaiiilide mp 277-278" dec. Anal. ( C ~ Z H ~ ~ C ~ ~ ' , C, O . H, ~ I N. IC~) in 1 1. of EI.OI1. The i~esiiltiiigsoliitioti was stii,i,ed aiid heated 4- [(7-Chloro-4-quinolyI)methylamino] -CY-( decy1amino)-o-cresol under reflux for :; h r aiid cooled, slid vo1:itile materials were (15.7 g, 0.1 mole) and Dihydrochloride (XIII).-1)ecylnmine removed i n vactlo. The iiiterniedi:~te a-(dec.yliiiethylani~no)-4'paraformaldehyde (3.0 g, 0.1 mole) were boiled iinder refliix in hydroxy-nz-ncetc~ioliiididewas thris obtained (127 g ) ar a viscous, 50 ml of EtOlI foi, 30 miii. Thia reageiit wab lheii added to 14.2 g (0.05 mole) of p - [ ( 7-chloro-4-yriiriolyl)methylami1io]phe11ol~~yellow oil which was not purified further but was refluxed for 1 hr wit,h 250 nil of 1 : 1 HZO-concentrated HC1. \Tolatilematerials in 350 in1 of EtOH aiid the mixture was stirred and boiled under were removed in uacim and the product was crystallized twice reflux for 6 hr. The mixture was concentrated to drynessin vacuo, from i-PrOH-EXrO (decolorizing charcoal). The product weighed 100 nil of L)lII" was added, and the mixture was stirred and heated 97 g (GC,;over-all), nip 103-110°. .lnal. (ClsHR2S2O.2HC1) a t 13.5-140"for 3 hr. The prodiict was poured into 500 ml of C, H, S. 1120 and the viscous oil that separated was extracted with Et,O. The combined Et& extracts were washed succebsively with Acknowledgments.-The authors wish to ackno\vldilute S a O H and H20 and dried over anhydrous K2C03. The edge the efforts of Dr. David B. Capps of these laboraEt& was removed and the oily residue was t,reated with excess t'ories who first suggested that amodiaquine be evaluated ethanolic HC1 and diluted with MenCO. The crude product (16.3 g ) was cry.stallized from EtOH-?*lenCO to give 8.5 g (32%) for antifilarial activity. We also thank Dr. P. E. of the product as orange-yellow crystals, mp 150-160'. Thompson and lliss Linda Boche for the antifilarial 7-Chloro-4-( 4-Ethoxy-a-1 -pyrrolidinyl-m-toluidino)quinoline testing, Dr. J. 11. T'andenbelt arid coworkers for the Dihydrochloride (XIV).--A mixtiire of 10.0 g (0.05 mole) of 4,7spectral determinations, and Nr. Charles E. Childs arid dichloroquinoline and 13.0 g (0.03 mole) of 1-(5-amino-2-ethoxyassociates for the microanalyses. I )rnzyl)pyrrolidine dihydrochloridels was refluxed in EtOH for
