.January 19i0
10.3
SAPHTHOQCINONE SCHISTOSO~IICIDES
@-@t4 CHART I
POSSIBLE ISTERRELATIONSHIPS A M O N G SCHISTOSO\IICIDES I N THE
@
NH
KO
I
11
It
1
NOH
@
I
VI1
NNHZ
\
-++0
XI Z =aryl or heterocyclic; a, R = H; b, R = YNR,R,
NOCH
XI1
~ m - 1 . 1 6 , ~ ~Moreover, 1,4-naphthoquinone mono(0methyloxime) (XIV), which is fixed in the quinoid form, also exhibits carbonyl absorption a t 1630 cm-l.l6 The highest carbonyl absorption in 1,4-naphthoquinone appears a t 1667 cm-'. The product (2. Table I), mp 132.5-134", obtained from the acylation of 4-nitroso-lnaphthol with Ac20, as well as the compounds (1, 3, 4, Table I) produced by treatment of 4-nitroso-1-naphthol with chloroacetyl chloride, heptanoyl chloride, and palmitoyl chloride in the presence of Et& (procedure I ) , all exhibited a,p-unsaturated ketone absorption a t 1660-1679 cm-I and also possesed 5trong ester carbonyl absorption a t 1780-1795 cm-1 in the ir (GBr). The ester carbonyl appeared as expected at a higher wave number than does a normal ester R S a result of the influence of the C = S group attached to the alcohol oxygen. These data cannot be accommodated by the 4-tiitroso-1-naphthol eiter structure XIII, and the compounds were therefore assigned the 1,4-naphthoquinone mono (0-acyloxime) structure X\-. The prodNOCOR
II
NOCOSHC H,-pCH,
1 I
~
I1
XV OCOR XI11
@ S=NZ
NH,
X
ranging from 273 to 777 nig/ kg for 14 days. In rhesus monkeys, IX caused moderate permanent egg suppression at doses of 50 mglkglday for 10 days, but failed to cure the animals. The over-all promise of 1,4-naphthoquinone monooxime (IX) against S . manmii, the antiglycolytic properties of various naphthoquinones,* arid the likelihood that quinoid metabolites may be involved in the mode of action of other classes of schistosomicides (Chart I) stimulated a more comprehensive investigation of the antischistosome properties of 1,2- arid 1,4-naphthoquinone derivatives. The present communication describes the synthesis of various 1,4-naphthoquinone 0-acyloximes, 4-(mOnO- and dialky1amino)-1,2-naphthoquinones, 2-amino-3-chloro-l,4-naphthoquitiones, and related nitrogenous naphthoquinone derivatives. ,$cylation of 4-nitroio-1-naphthol with Ac20in HOAc (procedure 11) afforded a crystalline yellow product, mp 132.3-131", which was apparently identical with the compound (mp 132.5") obtained earlier by Beckmann and Liesche'j utilizing a similar procedure. The5e authors designated the product as 4-nitroso-1-naphthol acetate ester (XIII, R = CH,).I5 However, 4-nitro-oNO
NNHZ
1 x
NOH
IX
N-NZ IV
it
VI
1
NH, 111
0
v
sLPHTHALEXE SERIES
0 x IV
1-naphthol has been shown to exist in solution in the 1,4-naphthoquinone monooxime form (IX), exhibiting :til a,p-unsaturated ketone absorption in the ir a t 1650 (15) E. Neckmann and 0. Liesche, Ber., 66, 1 (1923).
XVI
uct of the reaction of 4-riitroso-1-naphthol with p-tolyl isocyanate also displayed carbonyl absorption in the ir at 1650 and 177.3 cm-l and was designated as 1,4naphthoquinone mono [0-(p-tolylcarbamoy1)oxime] (XVI)* (16) A. Fischer. R. 11.Golding. and W. C . Tennant, J . Chem. Soc.. 6032 (1965). (17) D. Hadzi, t h i i i . , 2 i 2 5 (1956).
S itro-at ion of 2- [(diethy lainiiio) met hyll-1-iiapht hol, "-(l)iperidiiiomethyl)-l-iiaphthol, arid '-,-(%berizimid:izoIyl)-l-iiaphthol'~llafforded 2- [ (diethylamiiio)methyl]1 ,l-ii:iplitliocliiiiiori~~ 4-oxinic. (XIvII:i)(3lTC)* 2-(pipc>r-
SHR
*(>I 0
SOH XVIIa. R = CH.S(C.H 1 b. R = CH.1
SK,R
s\m Thew conipuuiids \yere obtained i t 1 yield hy coiidciihirig 1.2-riaphthoyuirioiie-4: i d sodium salt \vith the appropriate amine in H 2 0 01' aqueous EtOH [procedures 111 arid IT). ,, 1iwtinclrit of 2.3-dichloro-l,4-naphthoquinone wit,h ail (: of S.S-diethyl-1,3-propanediamine, 2,2'- [ (SLlmiiiopropyl)imiiio]diet'h:i~iol. or octylamirie afforded 2-chIoro-3-{ [ 3 - (diethylxmiiio)propyl]amino]-1,4-naphthociiiiiioric (XIXn) (53%). 2-( 8- [bis(2-hydroxyethyl):miiiro]propyl I :imino) - 3 - chloro - 1,4 - naphtlioyuiriorie \V:LA
prepared. (8
i l 8 j (a) 1'. E . T l l o m p w n , .J. \V. Reinertson. .I 13ayles, . L) lappr. . i m , , I . T r o p . M e d . H y g . , 4, 224 (1955); ( , a n d .1. E'. Ilouler, C . P. P a t e n t 3,049,507 (1962).
January 1970
SCHISTOSOMICIDES
SAPHTHOQUISOSE
107
TABLE I1 4-AMIXO-1,2-XAPHTHOQUINOSESa
NRIRl
.=
oc
Yield purified,
70
Purificn solvent
Procedure
l.i9-164*
3i
?.IeOH-l\le2C0
Ill
1.Y-1.56 dec
19
EtOH
IV
228 dec
19
D M.4-H20
I11
233-236 dec
22
IlhIA-H,O
I11
130-131
.j3
i-PyOH
I11
10
li0-172
32
i-PrOH
I11
11
121-123
10
i-PrOH
IV
12
97-99
9
IV I11
LIP,
NRiRz
13
>300
32
14
21w212
30
EtOH
I11
Compounds ranged from orange to reddish brown. Lit., Farbenfabriken Bayer Aktiengesellschaft, British Patent 806,079 (1958), reports mp 173-173'. c rill compounds were analyzed for C, H, X.34
method^,'^-*^ and their physicalconstants wereinaccord with t,hose described previously. 3-Hydroxy-1,4-naphthoquinone 4-oxime (XXIVa),*j 6-hydroxy-1,4-naphthoquinone 4-oxime (XXIVb),26 3-amino-l,4-naphthoquinone 4-oxime ( X X I T ' C ) , ~2-methyl-l,4-naphtho~
s XXVII
XXVIa. X = H b. X = X I c, X =6-OH
(XXTIII),*8 and 1,2,3,4-naphthalenetetrone 1,3-dioxime (XXT~III)28 were obtained in a similar manner by resynthesis or by acqui~ition.*j-~~ Three heteroXXIVa. X = H;Y = 3-OH b. X = 6-OH: Y = H c. X = H Y = 3-KH? d.XEH.Y=2-CH,
XXV
*
NOH
@
NOH
NOH
s'
quinone 4-oxime (XXIVd),z* 5,6,7,S-tetrahydro-l,4naphthoquinone monooxime (XXV), 1,"naphtho0 0 quinone 2-oxime (XXVIa) , 2 8 4-chloro-1,2-naphthoquiXXVIII XXIX none 2-oxime (XXVIb),30 6-hydroxy-1,2-naphthoquicyclic quinone monooximes were also studied, namely, none "oxime ( X X V I C ) ,1,2-naphthoquinone ~~ 1-oxime 5,S-quinolinedione 5-oxime (XXIX),28 5,G-quinolinedione 5-oxime (XXX),31 and 5,s-isoquinolinedione S(25) H. Goldstein and P. Grandjean, Helu. Chim. Acta., 264, 4fi8 (1943). oxime (XXXI). (26) 0. Fisoher and C. Bauer, J . Prakt. Chem., 94, 1 (1916). (27) F. Kehrmann and A l . Hertz, Be?., 29, 1418 (1896). The quinone derivatives described in the present (28) These analogs were purchased from Distillation Products Industries communication were supplied to Dr. Paul E. Thompson Division of Eastman Kodak Company. 16s17,29
(29) G . Sehroeter, Ann., 426, 152 (1922). (30) A . Reissert, Ber., 44, 868 (1911).
(31) G. TT. Hargreares, J . A m . Pharm. A s s O C . , 15, 750 (1926).
1OX
t:dlizetl f n r i i i .\lc('SI O givt. cwllecred b j - fill t.atioii niitl 2.7 g i34";) of bright yellox c ti&, nip 18ci..i I$l2'. .1 t i ( i / . 1 ~ ' 1 ~ f ~ , 4 c, ~ ~ 013, 3 )s. 2-[(Diethylamino)methyl]-1,4-naphthoquinone &Oxime \ XVIIa).--2-[( Diethylamino )methyl]-1-iiaphthol hydrochloi i t i ~ , ~ ~ ( 2 . 7 3 g, 0.0103 mole) was dissolved i i i I00 nil of ITYOatid 1 0 in1 t r f 1 avHC1, the solutionxi-as cooled t o > O J mid ai1 aqiieoiis sokiilioii of 0.71 g (0.0103 mole) uf Sax()?\\-:I.< added purtioii\viw :it 4 6" with external cooliiig. The mixtiire r ~ a sstii,rrd at 0~:' f l i t . (I..; hr aiid neutralized with 10 ml of 1 &l' Na0FI. The criidr lized f w m I ~ ~ i l I ~ - - I l ~ ~ piudiict that separated (1.90 g j was i t o give 0.84 g (31%) of shitiy 1)roivt les, mp 1:3tj-138' de(.. .1 /~d. (CijHi&d&') C, FI, S . 2-(Piperidinomethyl )-1,4-naphthoquino 2-(Piperidinomethyl)-l-iiaphthiil(20.0 g, sated with 5 . i g (0.083 mole) of ?jaXOo ihed for the preparatioii of %[(die iiaphthoquiiione 4-osime IXVIIa). The prodiict (16.2 g, 7?( ; \\-tis otitaiiied as hro~vvri needles from i-PrOH, nil) IN)" (1w I: / L O / . tCisHiaN~02)C, 13, X . 2-1,2-Benzimidazolyl)-l,4-naphthoquinone 4-Oxime ( XVIIc I. .I >oliitioti of 0.92 p (0.00354 mole) of 2-(2-beiizimid:izc,1!.1 1-1 iittphthol18b it1 50 rril of hot I-TOAc wa2; cooled rapidly t o 15' a i i i i :I cold 3 I J h l ~ i l J i of l 0.24 g (0.003.i-1 mole) of S a S O ? iri - filtratioii and tlricd. C'ry~tallizntiotifrcirii i-l'rOIl p a w ii.4 g i~531,gi of ~-~)ipei~ic~iii~-1,2-iia~)hthi)(~iiittiiti~~ i 9 i :I; i l a t I, red crystals, mp 130-1:i1°. Procedure IF'.----.\ soliitioti of 131) p t 11.): mole) l,2-t~a~~htli11cliiitiot1e-4-siilfonic. ;tcitl sodiiim salt (En3tmaii Pi i i i :: I . I J ~IId \ v m rooled to 15" atid treat,ed \villi 63 mi (0.75 riio1t.j of p\.iwiliditic. The temperatiire rose to 19' and thesultitioii turiietf hro\vtired. The inistiire w:tc stirred for 2 hr at > -20'. \Theti iio 1)t't.cipitate appeared, thv reacatioti mixtiire \va* rstrarteii 15 i l l t ('fIC'l:s arid the combined CHC1, est racts were wva-tied o t i w \\it It I1L.) niid dried (K2CCh3). The CNC% W V Rremcrvrtl ~ iri i'(ir(io : i i ~ r l the r e d u e was crystallized f r o m i-P c,i,iide prodrict, nip 14!)-152O. Re( :ifforded 21.0 g (IC3".( ) of pru'e 4 - ( l - p y r ~ o l i ~ i i t ~ ~ l ~ - l , 2 - i i : t ~ ~ ~ i t l 1 ~ ~ cjiiirione (6) as reddish brown crystalh, mp l . i . i - 1 5 8 O de?. 2-Amino-3-chloro-1,4-naphthoquinones (X1Xa-c) (Table I11 i. 'L,2'-[(3-.4miriopropyl)imi1lo]diethanol (40.0 g, 0.2.5 mole) w;t> added to 20.0 g (0.087 niole) of '2,3-dicliloro-1,4-iiaphtho~~ii~1i1~tie. AIL exothermic reaciioii occiirred immediately and the temper:i1 rive rose to 135". The viscous dark red oil was allowed to cool, n i i d tlilitted with hot H20,arid the mixtiire was filtered. The rehidlie wa. washed wit,hHQOand dissolved in CsH, and the CJTe wliitioti \va- treated with decolorizing charcoal and filtered. The filtratr w:t-
sss
\SA1
cou orher- of thebc laboratories for evaluatioti a Puerto Ricari strain of S. viansoni 111 mice.'? Drug, were administered 111 a pair-dered diet for 14 day:md drug aniouiitt are expreybed 2- free bate. I,&Saphthoquinone mono [O-(chloroacetyi~oxinie] (1) 1,4:tid
;igaiii-t
i1:iphthoquiiionr niorio(0-mcthyloxime) (XIV). arid 2 - (piperidinomethyl) - 1,4- iiaphthoquinone 4 - oxime (SVIIb) posse-wl significant schistoiomicidal activity atid effected a Z O - i l % reduction of live achistosomes in irifectcd mice :it daily doses ranging from 301 to 0.32 nig/kg nhen gir-cn orally in the diet for 11 day, Hornever, iioiie I W ~ a- promiAn 1,l-iiaphthoquinont~ nionoosinic (IX). -111 other compoiiiids luched appreciable antidiiito-ome effect, when administered t o m i c e at near-toyic doqe level- r:iiigitig from 173 to 7 4 1 lrlg 1;g pcr clay for 1-1d:tys.
Experimental Section
33s:34
1,4-Naphthoquinone MonoiO-acyloximes j ( X V ) (1-4, Table I). Procedure I.-Heptanoyl chloride (9.0 g, 0.06 mole) was added with 5tirritig to a diitioti of 10.2 g (0.06 mole) of 4-nitrosoI-naphthol (Eastmati) i t i EtzO. L t a S (15 ml) was then added dropwise a i d the mixture w a h stirred at room temperatlire for :; hr. The Et&. HCl that precipit,ated was collected and discarded. 'The Et& solnticiii rra- coticelitrated oii a steam bath arid petrolo i i i n ether thp 40-60") was added to iiid allization. The. prodiict was cdlected by filtration and llized foiir timef r o m petroleum ether t u give 5.6 g ( U r ; naphthoquinorir rrii)rioiO-heptatioylLixiiiie) ( 3 ) a.: yellow c m p 46-47 '. Procedure II.---l-Xit ruso-1-tiapht hol 11) (3.0 g, 0.02!1 riiole) was heated on x .-teain bath with 10.0 g of .4cz0 atid 60.0 p of HOAc f o r 0.5 hi,. The mixture was poured iiito H,O with vigorous stirriiig :iiid the precipitate that separated was collected k)y filtratioii aiid dried i n mc1t.o. The criide product ( 5 . 3 g) wa> tallized twice f r o m 93c'2 EtOH to give 1,4-tiaphthoqiiinotie niotio(O-acetylosime) (2) as yellow needles ( 2 . 2 g, 357,), mp 13'2.%134° nip 132.5'). 1,4-Naphthoquinone Mono [0-( p-tolylcarbamoyl)oxime] (XVI). ---:Imixtrire of 6.2 g (0.035 mole) of 4-nitroso-1-naphthol and 4.1;g (0.036 mole) of p-tolyl isocyanate in 250 ml of Me2C0 wa.i heated iitider refliix frri, 4 hr. il yellow solid formed. The prodiict (32) 1:or a de>cri]itiun uf teat inetliud8. see P.E. Thompson, J. E. >leisenI~rliler.a n d H. S a j a r i a n , Am. J . T r o p . M e d . Hyg., 11, 31 (1962). (33) Melting points (corrected) were taken on a Thomas-Hoover capillarbnielting point a p p a r a t w . (31) \Vhere analyses are indicated unls by symbuls of tile elements 0 1 funrtions, analytical remits obtained for tilose element3 or functions were' mitliin 10.4'3 of t h e theoretical values.
( 3 : ) E. I,. M a r t i n a n d I. F. Fieser in "Organic Syntliewa," ( ' ~ 1 1 . I'd. 111, E . i'.Homing. Ed., .John Wi1t.y & Sons, Inr.. S e w York, X. Y , , 19.75. 1'
fi:u.
ANTHELJIINTICS. IV
January 1970
was treated with excess HC1 and the precipitate was collected by filtration and crystallized from EtOH. 2 - ( ( 3-[Bis(2-hydroxyethyl)amino]propyl)amiiio)-3-chloro-1,4-naphthoquinone hydrochloride ( X I X b ) was obtained (24.5 g, 72%) as orange crystals, mp 149-151'. 5,8-Isoquinolinedione 8-Oxime (XXXI).-S-Isoquinolinol(i.3 g, 0.05 mole) was dissolved in 50 ml of H20 and 6.5 ml of concentrated HC1 and was treated at 5-10' with a solution of 3.5 g (0.0.; mole) of Ka?rTO2in H2O. The mixture was stirred a t 5-10' for 3 hr and the product was collected by filtration and crystallized from DhIF. The product (1.4 g, 16%) was obtained as olive crystals, mp 233" dec. A n a l . (CgHgN202) C, H, N . 2-(Piperidin0methyl)-l-naphthol.-~4 solution of 72.0 g (0.5 mole) of 1-iiaphthol, 43.0 g (0.3 mole) of piperidine, and 38 ml (0.5 mole) of 40% formalin in 500 ml of EtOH was heated under reflrix o n a >team bath for 2.5 hr and chilled. The crystalline precipitate that separated was collected by filtration and dried a t 4.5' zn eacuo (70.1 g , mp 120-132'). The crude product was
109
crystallized twice from EtOH, slurried into 500 ml of HzO, and treated with 50 ml of concentrated HC1. The precipitate was collected and heated to 90" in 2 1. of HzO, and the mixture was filtered. The insoluble material was discarded. The filtrate was treated with decolorizing charcoal, chilled, and made strongly alkaline with 50yoNaOH. The precipitate was collected, washed with HnO, and dried a t 65' in vacuo. Crystallization from EtOH afforded 33.0 g (27%) of pure product, mp 134-135'. ilnal. (CiGHigXO) C, H, X.
Acknowledgments.-The authors express their appreciation to Dr. Paul E. Thompson and coworkers for the antischistosome testing, Nrs. Maria L. Zamora for chemical assistance, Mr. C. E. Childs and associates for the microanalyses, and Dr. J. 11. Tandenbelt and coworkers for the spectral data.
Novel Anthelmintic Agents. IV. Noncyclic Amidines Related to Pyrantel J. W. MCFARLAXD AXD H. L. HOWES, JR. Pjize, Medical Research Laboratories, Groton, Connecticut 06340 Receiced July 14, 1969 Anthelmintic activity has been discovered among some S,N-disubstituted thiophenepropionamidines and thiopheneacrylamidines. Activity is associated with compounds in which one N substituent is Me and the other Substitution a t the N ' position abolishes activity. Synthetic methods and is Me, Et, allyl, MeO, or Me". structure-activity relationships are discussed.
The discovery of a new class of anthelmintic agents was reported in the first papers of this series.'V2 I t was observed that certain compounds of the type represented by 1 are highly effective against the intestinal nematode Nematospiroides dubius when tested in mice; indeed one member of the series, pyrantel (2), has undergone extensive evaluation in domestic animals and in man.
1 Ar = C,H& C4H,0, C,H, R = H, CH, n = 2,3 _.-=optional bond
2
In pursuing the structure-activity relationships in this series, we became concerned over the question of whether a cyclic amidine system was essential to good anthelmintic activity. Therefore, a number of noncyclic compounds (3) were prepared and tested. Very early in this work S,S-dimethy1-2-thiophenepropionamidine (10) emerged as an analog active not only
against N . dubius but also against the tapeworm Hymenolepis nana; other active compounds were subsequently discovered. The present work will describe the structure-activity relationships within the noncyclic series of compounds, and will attempt to correlate these findings with those of the cyclic series. Chemistry.-Most of the compounds under discussion were prepared by the action of imidate salts on amines or aminelike substances. However, when an amine was more conveniently available as its HCl salt, an alternate combination n a s employed: the imidate salt was converted to its free base, and the base was then allowed to react nith the amine salt. Three general procedures were used to prepare the requisite imidate salts. Method A followed the technique of Pinner, i.e., the reaction of a nitrile with dry HCI and an alcohol in dry E t 2 0 . This method is useful for preparing S-substituted and S,S-disubstituted amidineb, but is not suitable for the preparation of S'substituted compounds. Intermediates for the latter substances are readily prepared by method B, the formation of ethyl N-alkylimidates by the action of Et30 +BFA- on an IT-alkylamide. Some a,p-unsatuRCONHR,
3
10
(1) W. C. Austin, W.Courtney, J. C. Danilenicz, D. H . Morgan, R . L. Cornwell, L. H. Conover, H . L. Homes, Jr., J. E. Lynch, J . W. McFarland, ' . J . Theodorides, Nature, 212, 1273 (1966). and 1 (2) J. 1%'. RlcFarland, L. H. Conover, H . L. Howes, Jr., J. E. Lynch, D. R . Chisholm. W.C. Austin, R . L. Cornwell, J. C. Danilewioz. 1%'. Courtney, and D. H. Morgan, J. Med. Chem., 12, 1066 (1969).
+
Et,O
EtJO'BF,-
~HR,' RC, BF,-
+
Et,O
rated nitriles tended to react very slowly or not at all in the Pinner reaction; in such instances the reaction of the corresponding amides with 1,3-propane sultone (method C) served to prepare the desired imidate salt.3 (3)
W.Ried and E . Schmidt, Ann.,
616, 114 (1964).
