Synthetic Schistosomicides. XVITI. .Y-(4-([Z-(Diethy1amino)ethyllamino -1-naphthyl)amides, ~Y(5,6,7,8-Tetrah~dro-4-[(3-piperidinopropyl)amin~]-l-naphthyl~ amides, and Related Amide and Urea Derivatives'
-14-( [2-(diethylamiiio)ethyl]amino 1- 1-naphthyl)al
a i d aralkylamide.; [VIIIa and h (1-35), iides [J-IIIc (36-471, Sa alld b, SI-]> and ~ ~ - ~ ~ ~ ~ , ~ , ~ - t e t r a h ~ d r o - 4 - [ ~ 3 - p i p e r i d i r i ~ ~ p ~ ~ ~ p y l ) a i i i i r i oiSSIVa-e) ] - l - i ~ a p h twag h ~ l ~prepared a n i i d e . ~b y treating ,\~~-(4-amino-l-naphthyl)-S-(.'-dieth~lamirioeth?.l)-2,2,'L-t,l.ifluol.oacetamide (\'I) or ~\.-(4-aniiiio-j,8,i,h1etrahydro-l-iiaplith~lj-2,2,2-trifluoro-~~-(3-piperidir1oprop~~l~acetamide ( S X I I I ) with the appropriate acid rhloride or anhydride i n pyridine, benzene, or acetic wid. Several .V-(4- I ["(diet hylaniiiio)ethyl]amirio)-liiaphthyl)ureas, thioureas, arid sulfonamide? ( X I , XVI-SVIII were also prepared. Srhi.stowriiicida1 activity is widespread among the amides of structure VIIIa-?, Sw arid ti, and S S I \ - e , arid 15 rornpoiiiids viired Schislos o i i ~inunsoni ~ irifectioiis in mice a t dirt UT gavage dose- larigirig froin 45 ~ C 326 J mg 'kg per d:iy for 3 t o 14 days. E'oiii. winides also displayd 4gnificaiit activity agaiiist S . ~ i i c t r t s o n ii i i Ilenediaminey (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 - p ~ ~ idy1azo)-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\
N=S--%
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).
..
further expatiation of previous \\ orL* viirioii{ [2-(diethylamino)ethyl]amino]-1-nuphtIi~I)& kyl- and aralkylamides, N-(4-{ [2-(diethylamino)eth? I]amino ] -1-naphthyl) benzamides, N - ( 5,G,i,S-tetrahydro4 - [ ( 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: I
,Y-(4-
(11) I?. F. Elslager, %. 13. (kvrilis, ,(. .\. Pliillipa, and I). 1'. I \ i > r t t i , J . ~\fd Chem.. la, 3 5 i f19691.
sorption, and excretion patterns than the corresponding diamines.s,9 Previous work in these l a b o r a t ~ r i e s ’ - ~showed ~ ~ - ~ that the diethylaminoethyl side chain among types I-IV usually conferred optimum schistosomicidal potency; therefore, initial efforts were directed toward the preparation of various N-(4- { [2-(diethylamino)ethyl]amino ] -1-naphthy1)alkyl- and aralkylamides (1-35, Table I) (VIIIa and b) and N-(4- { [2-(diethy1amino)ethyllamino)-1-naphthy1)benzamides (36-47, Table 11) (VIIIc). Early attempts to acylateN- [2-(diethylamino)ethyl]-l,4-naphthalenediamine (XIV)8 revealed that attack on both of the aromatic amine functions proceeded indiscriminately. Therefore, the direct acylation route was, for the most part, abandoned in favor of the scheme outlined in Scheme I. Acylation of SCHEME
F CCOS(CH ).S(C.H I
1
(4-{ [2- (dieth ylamino) et h yl ]amino ] -1-naph thyl) -2 -thiophenecarboxamide (Xb) (53%) were obtained in a similar manner from VI, 2-furoyl chloride, and 2thenogl chloride, while the condensation of 2 equiv of \’I \I ith 1 eyuiv of oxalyl chloride and sebacyl chloride afforded N,N’-bis(4- { [2-(diethy1amino)ethyl]amino)1-naphthy1)oxamide (XIa) (21%) and N,N’-bis(4{ [ 2- (diethylamino)ethyl ]amino ] - 1-naphthyl) decanediNH(CH,)-S(C.H ji
SH(CH.)?N(C-H
@3 NHCO -Y-CONH XIa, Y = b. Y = (CHJ,
).
:imide (XIb) (34%) (procedure A). Surprisingly, attempts to prepare a diethylcarbamogl derivative from \‘I and diethylcarbamoyl chloride led instead to the formation of 1,3-bis(4- { [2-(diethylamino)ethyl]amino) 1-naphthy1)urea (XII) (35%).
I
KHL
J VI1
I
NHCOR VIIIa, R = a l k y l b. R =aralkyl c, R = aryl
0t her N - (4- 1 [ 2- (diethylamino)et hy1 lamino}-1-naphthy1)amide and urea derivatives (4, 5 , XIII, XV2,2,2-trifluoroacetamide monohydrochloride (VI)4 XVIII) were prepared directly from N - [2-(diethylamiwith the appropriate acid chloride (procedure A) or no)ethyl]-1,4-naphthalenediamine(XIV)g(Scheme 11). anhydride (procedure B) in pyridine or benzene gave Treatment of XIV with benzoyl chloride in the presence the intermediate N - [2- (diethylamino) ethyl ]-2,2,2-triof CaHz gave N-(4-amino-l-naphthyl)-N-[2-(diethylfluoro-N,N’-l,4-naphthylenebisamides (VII) which, amino)ethyl]benzamide (XIII), a position isomer of n ith the exception of N - [2-(diethylamino)ethy1]-2,2,2- 41, in low yield (12%). N - ( 4 - {[2-(Diethylamino)trifluoro-N,N’-1,4-naphthylenebisacetamide(IX), ivere ethyllamino)-1-naphthy1)phthalimide (XV) was obtained in 26% yield by the condensation of XIV with F,CCOY(CH-)J(C-H )? phthalic anhydride in HOAc, while the reaction of XIV with maleic and succinic anhydride afforded N (4- {[a- (diethylamino)ethyl]amino)- 1- napht1iyl)maleamic acid (4) (76%) and N-(4- { [2-(diethy1amino)ethKHCOCH, yllamino)-1-naphthy1)succinamic acid (5) (36%), reIX spectively (procedure D) . N-(4- { [2-(Diethylamino)ethyl ]amino j -1-naphthyl) benzenesulfonamide mononot purified but were hydrolyzed directly to give the hydrochloride (XVI) (Sx),1-(4- { [2-(diethylamino)desired N - (4- { 12-(diethy1amino)ethyllamino ] -1-naphethyl ]amino 1 -l-naphthyl)-3-phenylurea dihydrochlothy1)amides (1-3, 6-47, Tables I and 11) in 11-74% ride (XVII) (54%), and 1-(4- { [2-(diethy1amino)ethylloverall yield. The facile, selective removal of the amino -l-naphthyl)-3-heptyl-2-thiourea dihydrochloF&CO protecting group was accomplished utilizing (38%) were produced when XIV was alride (XVIII) SaOH in aq EtOH. N-(4- { [2-(Diethy1amino)ethylllowed to react with benzenesulfonyl chloride, phenyl amino)-l-naphthyl)-%furamide (Xa) (37%) and N isocyanate, and heptyl isothiocynnate. NH(CHJJ(C,Hj)2 Although potent untischisto~onie activity is not \videspread among the antimycobacteriall-(3- { [5,6,7,8tetrahydro-4-(phenylazo and 3-pyridylazo)-l-naphthyllamino] propy1)piperidines Va and b, recent studies in these laboratories showed that several compounds in the series exhibited strong activity against S . mansoni in mice. Among them, 5-{5,6,7,S-tetrahydro-4[(3-piperXa, X = O idinopropyl) amino 1-1-naphthylazo ) resorcinol (XIX),y b, X = S
N - (4-amino- 1-naphthyl) - N - [ 2 - (diethy1amino)ethyll-
*
z Yield purified,
KO. 36
S,I.Z
l l p , "C
3,4-Clp 3-Br 4-Br :!I9 4-C1 40 4-KUr 41 H 4% 2-CII., 4:: 4-CH:j 44 4-0CH:i 4.i 3,4,3-(OCHa)3 46 4-O(CHz)rCHa 4-C6H4-p-ru'=xCeHj 47 Compouiida were prepared by procedure A. 37 38
1.54 3-1.56. 5 128-130 192-194 177-180
70 29 24 27 30 32
Purifn solrenr
EtOH-HQ0 Heptane NeCX MeCN 227-229 C6H6 134-133.3 EtOH-H20 58 116-119 48 Heptane 143-14ti 46 C6H6 160-162 65 EtOH 163-164 63 i-PrOH-H?O 171-172, .5 39 1leCN 155-157 13 C6H6 * All compounds were analyzed for C, H, K.
over, 1-[3-(4-amin0-3,6,7,8-tetrahydro-l-naphthylamino)propyl]piperidine trihydrochloride (XXII),ga likely
OH
I
NH?
XIX
XXII
xx N - (4,; - dimethyl - 2 - pyrimidinyl) - p - { 5,6,7,S - tetrahydro-4- [ (3-piperidinopropy1)aminol- 1-naphthylazo}benzenesulfonamide (XX),9 and 1,l'-{sulfonylbis- [pphenyleneazo(5,6,7,8 - tetrahydro - 1,4-naphthylene)iminotrimethylene} dipiperidine (XXI)' were especially noteworthy and effected a 76-100% reduction of live
metabolite of the antimycobacterial and antischistosoma1 1-(3-1[5,6,7,8-tetrahydro-4-(phenylazoand 3pyridy1azo)-1-naphthyl]amino}propyl)piperidines (Va and b, XIX-XXI), was considerably more potent and reduced the live worm burden 90 and 98% at daily diet doses of 88 and 159 mgikg, respectively.12 l 3 It was therefore of interest to synthebize representative N - { 3,6,7,8-tetrahydro -4 - [ (3-piperidinopropyl) amino]1-naphthyl}amides (XXIVa-e) for antischistosomal
~HCOR XXIV
NH.2 XXIII a, R = CH, b, R = CH?CH, C, R = (CHJSCH, d, R =(CH-),,CH, e, R=C,H
XXI
schistosomes when administered in the diet to mice for 14 days a t daily doses of 256-364 mg/kg.l21)benznmides (YIIIc) (36-47, Table 111, N{ 5,6,7,S- tctrahj-dro-4 - [ (:3 -~~i~)c'ridiriopropyI]ami~io 1- 1ii:tplit hyl] aniidrs (XXIV:t-(.), :md related amide aiicl urea derivative, (IX-XI11 :inti XV-XYIII) described in tlie present conimumcatioii \\ re supplied to Dr. Paul E. Thompvm and coworhers of t1ie.e laboratorie. for evaluation against :i Puerto 1tic:in ,.train of S nzairsoni III mice.'* -45 in previous uork, drugs w : r v :Klministered iii :t powdered diet for 7 or 14 daj. or b\ gavage in 10 nil, lcg of aq l', liydroxyethj 1- or ciirb o ~methj j lcellulosc for :3 to I O &ij2. Drug amount. e. Scliiitowniicidal activity -(=I- { [3-(diethj I:imiiio)ethyl]:imiiio)-l-n:iplitligl)Rl1\j 1- : t i i d :~ixlhjlamidcs (VIIIa :md h). N - (4- { [a- (dietlib I:ii~iiiio)etIi~I]arniiio) - tn:zphth> 1)benzmiides (VIIIc) :irid the related amide. Sa arid b and XXIYc. Tlie most potent substance., (2, 7, 8, 14, 16, 19, 24, S a ) completely eliminated live schistosome5 from infected mice :it drug -diet do ranging from 43 to 90 mg kg per tLij for 7 or 14 daj 9 :tnd gavage dobe:, of 50 or 100 rng, kg daily for 3 or ;i dayb.I3 Compound. 17,28,31,32,40, X b , and XXIVc also cured all of tlie mice tit wmenlmt liiglier dose level, ranging froin 130 t o X b mg kg daily for 14 dujs bj. drug- diet or 200nig hg daily b j gtivage for;
