Journal of Medicinal Chemistry /
J
0 Copyright
1970 by the American Chemical Society
JULY 1970
VOLUME13, No. 4
Synthetic Schistosomicides.
XVII. N-(Benzylidene and
Cinnamylidene)-iV’-[2-(diethylamino)ethyl]-l,4-naphthalenediamines
and Related Schiff Bases’ EDWARD F.ELSLAGER, JOSEPHINE BATTAGLIA, ANNETTEA. PHILLIPS, AND LESLIE11. WERBEL Department of Chemistry, Vedical and Scienti5c Affairs Division, Parke, Davis and Company, Ann Arbor, Michigan 48106 Received February 6 , 1970 Representative S-(benzylidene, cinnamylidene, and naphthylidene)-~~7’-[2-(diethylamino)ethyl]-1,4-naphthalenediamines (VIII-X, XIII), 1-[3-(( 4-[(benzylidene, cinnamylidene, and naphthylidene)amino]-5,6,7,8tetrahydro-1-naphthyl)amino)propyl]piperidines (XI, XII, XIV), and 5,5‘-[p-phenylenebis(methylidyneimino)]bis(8-( [2-(diethylamino)ethyl]amino}quinoline) (XV) were synthesized by the condensation of ,V- [a(diethy1amino)ethyll-l,Cnaphthalenediamine, 1-[3-(4-amino-~,6,7,8-tetrahydro-l-naphthylamino)propyl]piperidine (VII), or 5-amino-8-( [2-(diethy1amino)ethyll amino) quinoline with the appropriate aldehyde in xylene. Several S-(benzylidene and ciiinamy1idene)-1-naphthylamines(XVI-XVIII) substituted with other basic distal moietiesl were also prepared. Schistosomicidal activity among Schiff bases of structure VIII-XV is widespread, and ten compounds cured Schistosoma mansoni infections in mice a t doses ranging from 66 to 271 mg/kg per day for 14 days. Three compounds were evaluated against S. m a n s m i in Rhesus monkeys and each showed significant antischihtosomal activity in this host. Structure-activity relationships are discussed.
Schistosomicidal activity is widespread among various N,N-dialliyl-N’-(4-arylazo- and 4-heterocyclic azo-lnaphthy1)alliylenediamines (I)2--j and simple 4-arylazo-
NHYWR,R,
NHYNR,R,
NHYNR1Rt
I
Z
Z
N-NAr I
*
I11
or Het
(II),l o N , N - [bis(phenyleneazo-l,4- naphthylene) Ibis(N’,N’-dialkylalkylenediamines) (III),11r12 and N , N ” -
and 4-het ero cyclic azo- 1-naphthylamines, 6-g 5azo-6-dliox~-S-{ [(dialkylamino)alkyl]amino) quinolines NHYNRlR2
OR
N=NAr or Het
I1
(1) For paper S V I , see E. F. Elslager, 31. P. Hutt, and L. XI. Werbel J . .Wed. Chem., 13, 370 (1970). (2) E. F. Elslaner, D. E. Capps, L. 31.Werbel, D. F. Worth, J. E. Meisenhelder, H. Piajarian, and P. E. Thompson. ibid., 6, 217 (1963). ( 3 ) E. F. Elslager, D. B. Capps, D. H. Kurtz, L. M. Werhel, and D. F. Worth. iDid., 6, 646 (1963). (4) E. F. Elslager, D. B. Capps, U. H. I i u r t z , F.K. Short, L. 11.Werbel. a n d D. F.W o r t h , ibid., 9, 3 i 8 (1966). (5) S. T. Ch’en, I. F. Ch’en, P. C. Kun, Y . C. H u , J. H. Yao, and T. H. Cliou, Yao H s u e h Hsueh Pao, 13,30 (1966). (6) E. F. Elslager a n d D. F. Worth. J . M e d . Chem., 6, 444 (1963). ( 7 ) A . Korolkovas, Reo. Fac. F a r m . Bioquim. Sao Paulo, 6, 115 (1968). (8) A. Korolkovas, ibid., 6, 147 (1968). (9) A. Korolkovas. ibid., 6, 153 (1968). (10) E. F. Elslager and D. B. Capps, J . M e d . Chem., 7, 663 (1964).
[1,4 - naphthylenebis(az0 - 1,4 - naphthplene) ]bis(N’,N’dialkylalkylenediamines) (IV).” Moreover, certain 1-(3-1 [5,6,7,8-tetrahydro-4-(phenylazo and 3-pyridylazo)-1-naphthyllamino] propy1)piperidines (Va arid
(11) E. F. Elslager, D. B. Capps, D. H. Kurtz, and D. F. Worth, zbid.. 11, 1201 (1966). (12) E. F. Elslager and 4. A. Phillips, abid.. 12, 519 (196Q).
587
N=SZ \'a.
z=
Q
x
1)) :ire highly active against JlycoDactei turn tuber culosis I-IJ711v i~iidJlgcobactet u t t i / ~ paeitiur / iutu i/l t i t i o a i i c l in mice. JYhile itivestigatirig potential metabolites of tlic simple 4-azo-l-riaphthylamine,,fi it was obqerved that the reductioti product 1,.-l-naphthalenediamirie (VIa) lcilled adult S. munsonz 211 uih o at drug concentr:ttion.
NH \'Ia K = H b R = YUK,K
7. \.I11
a$ low as 25 pg/ml.6 Results in mice were disappointing; the diamine was irieff ective when administered orally a t the maximum tolerated dose. Anticipating that factors such as metabolic alteration, excretion rate, absorption, and tissue localization might be f a vorably influenced by the introduction of n basic side chain, a study of potential metabolites of the N,;VdialkyI-N'-(4-arylazo- :md 4-heterocyclic azo-l-naphthy1)alkyleriediamiries (I, 111, IT) waq initiated. - I 7 This work led to the discovery that various N-[(di:ilkylamino)alkyl]-l,4-naphthalenediamines(VIb) were highly active against S. maiisorzi in oitm and in experimental animals. 1j I n contradistinction, 1-[3-(4-amino5,6,7,8- tetrahydro - 1-naphthy1amino)propyl ]piperidine trihydrochloride (VII), a likely metabolite of the antimycobacterial 1-(3-{[5,6,7,8-tetrahydro-4-(phenplaso and 3-pyridylazo)-l-naphthyl]amino] propy1)piperidines (Va and b), mas inactive against *If.tuberculosis H37Rv i ) i oifro :inti in mice Severthrleir, the-r
4
made alkaline with S H 4 0 H arid the free base was extracted with xylene. The diamine solution was dried and treated promptly with the appropriate aldehyde t o minimize air oxidation. H20 wab removed from the mixture a> the reaction progressed. Thi, procedure afforded the S-bciiz?-lidene-N'-[2-(dieth~lamino)eth?.I]-1 ,d-naphth:tlcnedianmi~ict 1-20 (Table I) in 6-93?; j-ield. Similnrlj-, 1-({ 4- [(2-dieth3rlami1ioethyl)amitl~~]I-naphthylimirio j methyl)-%iiaphthol (IX) (56%), A;(?-diet hylaminoethj 1)-Ar'-(p-dimethyl:Lniirlociltri:trn? 1iNH(CH
&
I.\((
NH-
vu
observations do not preclude the possibility that such metabolites may be formed intracellularly. I n a further extension of the above work, an array of Schiff bases derived from 1,4-naphthalenediamine (VIa) , N - [2-(diethylamino)ethyl]-l,4-naphthalenedia(1'3) L M Werbel, E . F Elslager, M. \V Fisher, Z B Gavnlis, and A A Phillips, J . M e d . Chem., 11, 411 (1968). (14) Y. T Chang Adzmzcrob. Ag Chemother , 465 (1966). :. F. Elslager, D B Capps, L M. Werbel. D F. Worth. J. f (15) E Meisenhelder, and P E. Thompson, J 'Wed. Chem , 7 , 487 (1964). (16) E. F. Elslager, I). B. Capps, and L 11 Iterhel, a h z d , 7 , 658 (1964) (li) F. Elelager, L hI 1% erbel, and D F \I u r t h , ~ b z r l 13, , 104 (19701
>;a, 11.
3
.JHC1
1
HO,
IY
NH(C'H ) h
H
X = I-N(CH )
x = 2-NO
derie)-l,d-ria~)hthalenediamiltc (Xa) (tilo/o), :Lii(I .V- [~-(dieth~lairiino)ethyl] --V'-( 0 - iiitrociIinanig1ideiit~)l , l - t ~ i t p h t l i ~ t l ~ ~ ~ i e ~(Xh) l i ~ ~ i (607$) i i ~ i e were prepared f ium S-[2-(diet11yluniino) ethyl 1-1,-l-ii:ipht haleiiediamitie and 2-h-drosy-l-liaphthaldehyde, p-dimethylariiiriociiitiamaldeliyde, and o-nitrocirinamaldehyd~, while the treatment of 1-[3-(4-amino-5,6,7,8-tetr.ahydro-l-naphthj~lamino)propyl]piperidi~ie (VII)I3 with 2-hydroxy-1-naphthaldehydeor p-dimethylaminocinn:Lmaldeh?.de afforded 1-({5,6,7,8-tetrahydro-4- [@-pi(18) K. %. Canipbell. J. lJ. ICermin, A . H. Sommers. and €3. K . Cami)hrll. .I. Amer. Chem. Soc., 68, 1559 (1946). (19) E. F. Elslager, A . A . Phillips, and D. F. Worth, .I. .Wed. Cheni.. 12, :it33 (1969). ( 2 0 ) U. 1.'. \Vortli, E , (21)
F. E I ~ l a y e rand , A . .i.Phillips, ihid., 12, 591 (1969). IC. F. >;Islager, I>. 13. ('apps, and 1). F. W o r t h , ibid.. 12, 597 (1969).
Journal of iIfcdicinal Chrmistry, 1970, T‘ol. I,?, S o .
SYSTHICTIC SCHISTOSOMICIDES. XVII
4
559
TABLE I ,~r-BI~NZYLIDENC-,V’-[2-(DIETHYLAMINO)ETHYL]-1,4-N
~PHTHILENEDI.~UI~ES‘
NH(CH,),N(C,H,)-
z NO.
Yield purified,
x, Y, z
MP, ‘C
%
1 2 3 4 e5 6
2,4,5-C1; 4-C1, 3-302 5-C1, 2-NO2 2,4-Clr 2,6-C12 2-OH, 3,5-C12
110-112 92-95 111-115 60-65 63-67 93-96
39 80 57 44 78 33
7 8
4-Br 2-OH, 5-C1 2-F 4-F 2-NO2
76-78 119-120 75-77 70-72 82-83
38 32 44 38 51
119-121 83-85
9.? G
9
10 11 12 12
4-OH 14 15 2,4-(OH), 4-CN 16 3-OCH3, 4-OH 17 4-NHCOCH3 18 2-NO2, 4,.i-(OCHa)p 19 20 2,4,6-(CH3 12 a Compounds ranged from orange to black pounds were analyzed for C, H, N.
73 dec 93 dec 86-90 134- 137 137-140 114-116 65-70 in color.
17 32 91 46 56 54 93 C: calci,
peridinopropy1)aminol- 1 - naphthylimino) methyl) - 2 naphthol (XI) (76%) and 1-[3-( (4- [(p-dimethylamino-
@
Stability (half-life, lir) in 50% RleOII50% p H 7 P U
Purifn solvent
MeCN EtOH-Et20 EtOH-Et& Petr ether Petr ether 2,2,4-Trimethylpentane Petr ether Petr ether Petr ether Petr ether 2-PrOH-petr ether Petr ether 2,2,4-Trirnethylpentane Xylene Xylene Petr ether Petr ether C & , - p e t r ether EtOH-H& Et20 65.01; found, 64.59. c C: calcd, 74.59; found, 73.92.
47 200 31 60 1 14 5 17 19 !IO 31
4 30 28 0
d
12 90 40 All com-
pyllpiperidine (VU), I 3 or Z-amino-S-{ [2-diethylamino)ethyl]amino ] quinoline18 gave N,N”-(p-phenylenedimethy1idgne)bis [N’- ( 2 - diethylaminoethyl) - 1,4naphthalenediamine] (XIII) (52%), 1,l’-{p-phenylenebis [methylidyneimino(5,6,7,8-tetrahydro1,4- naphthy-
HO
N=cH% XI XI11
m XI1
XIV cinnamylidene)amino]-5,6,7,8- tetrahydro- 1-naphthyl] amino)propyl]piperidine (XII) (53%). The condensation of 1 equiv of terephthalaldehyde with 2 equiv of and 5J’- [p-phenylenebis(methylidyneimin0) Ibis(% N - [2 - (diethy1amino)ethyll- 1,4 - naphthalenediamine, { [2-(diethylamiuo)ethyl]:tmino1 quirioliiie) (XV) (600/,), 1-[3-(4-amino-j,6,7,8-tetr~hydro-l-naphthylamino)pro- respectively.
sv Iiepresent~itivcAV-(t)eiizylideiie :ind ciniuiiiiylideriei1-iiaphthylamine- wbctitutctl with other f)a.sic distd moieties \wre ;LIW p i q m w l . T h u s , the reaction ot 3-chloro-l-riatphtliylaniiii(~ \\ it Ii 1)- [2-(cliethylamino)ethoxy]beiizaldeh?.de i l l thcA pre.ence of p-toluenewlfonic acid afforded 4-chloro-S- I 1-1- ['-(diethylamino)~ ~ t l i o s y ] b e r i z ~ l i d-I-ii~phfliyl:~niine e~ie~ (XT'I) (28%),
( 'I
NVI \\ hile the condelisation of I cquiv of 1 ,t-iinphthaleiiediamine with 2 equiv o f 1)-[2-(dieth?lamiiio)etlioxy Iheiizddehyde, p-(dimeth?;lamino)beiizalc3eh\.dc, or p-(dimet hylainino) ciiinunialdehyde gave S, S'bi\ { p - ('2(tlieth~lamino)ethoxy] benzylidene ] - 1,4- iiaphthalenediamine (XT'ITa) (44Vc). S , S ' - b i lenediaminey (Ij,?-? N-~(di:~lkylnmiiiu):~ll~~~l]1,4-naI-'lithalenedinmiri(~~(11).? arid N-(benzj lideric I\'HYNR,K2
!
arid cinnam\-lideriej-N'-[2-(diethylanii1io)ethJ-l]-1,1riapht halenediamines (I11 and IY). lloreover, ctvt:tin 1-(3- { [5,6,i,S-tetrahydro-4-iphenplazo and 3-pyridy1azo)-1-naphthyllamino}propy1)piperidines (Va anti b) are highly active against Mycobacterium tuberculosis H3,Rv and JT. lepraemurium i>iuitro and in mice.9 I" Unfortunately, these substances usually produce gastrointeqtinal side effects in experimental animals a t doses only severalfold higher than therapeutically c ~ fcctive f doseq.
I\
In ( 1 ) For paper S Y I I , see 1:. I:. Elstager. J . 13attaplis, L. 11. Werhel, .I. .\fed, Chern.. 13, 587 (1970). ( 2 ) I:. F, Elstager, 1). B. Cai,p~.I,. hI. JTerl,el. 1). F. \Yorth, J. E . Aleisenhelrler, 11. Naiarian. and P . E. Thompson, ibid., 6 , 217 (1963). (3) E. F. Elstager, 1). 11. Capps. I). H. Knrtr, L. AI. Werbel, and D. F. \Vurtki, %bid.,6, 646 (1963). (4) E. I,'. Elalager, D. 13. Capps. I). 11. I i l i r t a , F. I V , Sliort, L. hl. Werbel, anti I). F. IVorth, ibid., 9, 378 (1966). ( 5 ) S. T. Ch'en. I. F. Ch'en, f.C. Kiln, \-. C . iIu. .I. I f . \-ao. and T. 11. C h o u , Yuo Hsueh Hsueh Pno. 13, 30 f l U 6 6 ) . (6) 52. F. Elslager, 11. R . Capps. 11. I f . Kurtz, and D. F'. \\-orth, J . .\led. Chem.. 11, 1201 (1568). (7) E. F. Elslager and A . 1.Phillips, ibid., 12, 519 (1969). ( 8 ) E. F. Elstager. D. R . Capps. L. M. Werbel, D. F. Worth, J. E. Meisen-. tielder. and P. E. Thompson, ibid., '7, 487 (1964). (9) L. hI. Werbel. E:. F. Elslager. 31. \T. Fisher, Z. H . Garrilis. : m i .i. \ l'hillips, ibid., 11, 411 (1568). (10) T. T. Chang, Antimicrob. B g . Cheniulhrr.. 465 (196fj).
..
N=S--% : I
further expatiation of previous
\\
orL* viirioii-
{ [2-(diethylamino)ethyl]amino]- 1 - n u p h t h ~I)& kyl- and aralkylamides, N-(4-{ [2-(diethylamino)eth? I]amino ] -1-naphthyl) benzamides, N - ( 5,G,i,S-tetrahydro-
,Y-(4-
4 - [ ( 3- piperidinopropy1)aminol- 1 - naphthyl) amideh,
and related substances have been synthesized for antiqchistosomal and mtimycobacterial evaluation. It was hypothesized that such compounds, like the sulfanilylanilide antimalarials, l1 might undergo slow enzymatic scissio~iupon contact with body tissues anti fluids. and thus display more favorable tolerance, ab(11) I?. F. Elslager, %. 13. (kvrilis, ,(. .\. Pliillipa, and I). 1'. I \ i > r t t i , J . ~\fd Chem.. la, 3 5 i f19691.
