Novel anthelmintic agents. II. Pyrantel and other cyclic amidines

McFarland. el al. Vol. 12. Novel Anthelmintic. Agents. 11. Pyrantel and Other Cyclic Amidines1 .1. \V. McFarland,- I,. H. Conover. H. L. Howes. Jr.. J...
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157

XNTHELJIIKTICH. I1

Sovember lYti9

nesium iodide as the starting material, but in our hands this method was unsuitable for making large amounts of material. What was needed was a n inexpensive means of reducing 2-thiopheneacrylonitrile (134) on a large scale, since this latter compound is readily available from a ICnoevenagel condensation of tl-thiophenecarboxaldehyde and cyanoacetic acid. After following several unrewarding approaches, me discovered that catalytic hydrogenation cleanly reduces the double bond of tl-thiopheneacrylonitrile to afford 2-thiophenepropionitrile in high yield. Sormal ratios of 570 Pd-C catalyst were employed, and it was found that the presence of NaOH in the hydrogenation mixture increased the reaction rate. At about the same time this work was being carried out, Sam and ThompsonILobserved that 2-thiopheneacrylic acid can be reduced by H, over 10% I'd-C catalyst to furnish 2-thiophetiepropionic acid in 80% yield. In the past thioplieneacrylic acid5 have beeti more generally reduced by agents such as SaHg128L3 and S a - P b alloy." Apparently some thiophene compound:, are far more stable to certain catd y t i c hydrogeriation conditions than would be expected normally. l 4 A s obtained from the reactioti of cyanoacetic acid and %thiophenecarboxaldehyde, tl-thiopheneacryloriitrile cgnsists of a 3 2 5 8 mixture of isomers. By means of preparative gas chromatography, the isomeric nitriles were separated and identified by their respective nmr spectra. As shown below, the coupling constimt Ja,P and the chemical shifts for the a-protons of the isomeric nitriles are diagnostic. The doublet for the a-proton

6 = 5.6 ppm Jaj3=16.4 CPS

6 = 5.2 ppm Jaa = 11.8 CPS

of the minor component exhibits a smaller coupling con-

ctant and a smaller chemical shift than that of the major component; therefore, the minor component was assigned the cis configuration, while the n u j o r component the trans. A study of the Piniier reactiori ori the mixed isomerh of 2-thiopheneacrylonitrile revealed a n interesting case of stereoselectivity. Of the two possible isomeric imidate hydrochlorides, only the trans isomer mas isolated. The J,, for the imidate salt was 15.5 cps and no absorption peaks were found which could have been attributed to the presence of the cis isomer. S o doubt strong repulbive nonbonded 1,3 interactions of the type illustrated below play an important role in determining this 5tereobelectivity. The I'iiiner reitctioii of 8-methyl-'-tliiophetiea~~~yloiiitrile (140) arid the reaction between a-methyl-2-thiopheneilcrylamide (143) arid 1,3-propane sultone under the Itied-Schmidt conditions failed to produce detect(11) .J. S a m and A. C. Thompson, J . Pharm. Sci., Sa, 898 (1963). (12) G. B a r g e r a n d A. P. T. Easson. J . Chem. Soc., 2100 (1938). (13) AI. L. XIihailovic and IZI. T o t , J . Org. Chem., 22, 652 (lesi). (14) H. D. Hartough, "Thiophene a n d I t s Derivatives," Interscience I'~ihlisl~ers, Inc.. New York, X. T..1952, p 167 ff. ( 1 5 ) L. A l . Jackrnan, "h-uclear Magnetic Resonance Spectroscopy," Perpamon Press, N e v York, N. Y.,1959, p 82 ff. (16) .\ similar ohvervation on the cliernistry of cinnamonitriles has been X I . Harfenist a n d .I. P. Plrillips. J . A m . Ciiem. Sor., 80, 6261 (1958). iiiade I>?-

106'7

able amouiits of imidate salts. In both cases, 1,3 nonbonded interactions cannot be avoided. Imidate salts were prepared, however, by the action of EtsO +BF,on 143 and o n 8-methyl-2-thiopheneacrylamide (141). These latter imidates were converted to the corresponding tetrahydropyrimidines 144 and 142 (see Table

140

143, R,=CH,; K g = H 141. R, = H; Rg = CH,

I). X comparison of the uv 5pectra of the rubstriiiceh in Table I reveals that the maxima of 142 and 144 art8 shifted to shorter wavelengths with respect to the parent compound 71. indicating that simple substitution on the link results in nonplanar molecules (compare 74 and 139). Again, the repulsive 1,3 nonbonded iIiteractions appear to be responsible. TABLE I UV

Compd no.

8PECTR.I IS

HtO

Log

RJ

Rp

Ra

RI

Amax, mp

JIED." mr/k

71 H H H CH3 312 4 . 2 7 7 74 CH3 H H CH3 318 4 . 2 6 3 142 H CH3 H CHI 292 4 . 1 0 30 144 H H CH3 CH3 2x7 4 . 2 4 >130 139 FI H CHI-CH, 318 4 . 3 8 >86 Based on per cent uf active inaterial (free base) present. (1

Except where noted, conipounds in Tables XXI and XXII are believed to be the trans isomers. This belief rests mainly on the greater probability that the trans isomers would be the more thermodynamically stable. and on the nnir spectra of selected compounds. For example, the nmr spectrum of 71 exhibits in the olefinic proton region a doublet with a coupling constant of lq5.7 cps. This value agrees well with that found for trans-2-t hiopheiieacrylonitri le, a rid agrees poorly with that of the C I S nitrile. Further confirmation of the 5tereochemical as:,igrinient \vas found when the cis isomer 72 wab prepared by the action of sunlight on 71. The pertinent nmr data for the a-proton absorptions of the two isomers are summarized below. Becauw the photoisomer exhibits the smaller chemical s!iift and smaller coupling constant, it is assigned the cis configuration. Similar results were obtained with the Irans cis pairs 74/75 atid 89/90. Oiving to problems discussed previously, the 2-(2arylvinyl) cyclic amidines exemplified in Tables XXI id XXII are relatively difficult to prepare by routes

ASTHELJIINTICS. I 1

1ovember 1969

The rat nematode Nippostt,onyyZus rriuris proved to be less sensit'ive t,han N . clubius to drugs in the pyraritel class. This observation was particularly useful in the secondary evaluation of' the active compounds discovered in the primary screen. I n general, the activity against N . uiutis correlated fairly well to that observed against, the more drug-resistant nemat,odes of sheep. The minimum effective dose (NED) of each compoutid reported in T:ibles I-XXIII is considered to be the lowest' dose which will reduce the average N . rlubius n-orm burden by at. least 90yGwhen administered to a group of four t o six infected male mice. The different ,\ubstmces were dissolved or suspended in either peanut, oil or lyGaqueous carboxymethylcellulose a t such a concentration that 0.4 ml delivered an appropriate dose to a 20-g mouse. Treated mice were dosed once each day for 1-3 dayy. Initially a high dose (50-500 mg/kg depending upon the compound's toxicity) was given t o the mice. If anthelmintic activity was detected then the compourid was tested at successively lower doses until the N E D was established. Set,s of infected, utitreated mice were used as controls. Aiddit,iorialdet'ails of these arid similar procedures are given in t,he literature.4,?0,

1069 \.

TABLE

N

I

CH3 ,-----NED,

my

ka"--------

AL

-CH?CIlr

.ir

.>C=C 100 20 CsH: >i3 4 2-CH:4CeH, 62 2-C4HsO Based o i i per ceiit of active material (free base) present.

TABLE TI

I

H N E D , niy/kgu----. n = :3

,

.\ r

2-CdH;jS Y-CH8-2-C4H$

21

11

= 2

IO0

100

10.i

>200 >130 '-C,H30 >lo0 >x:3 Based c)ri per ceiit of active material (free base) prwent.

CsH;

TABLE I1

.rx+N)

N

H

.I 1'

(1

__ -cn?cH?-

CHI

.>C=C60 2-CaH3S :{-CH3-2-C4H$ 103 >200 CsH., IO0 2-c4 € I : A ) h s e d oil per v e t i t of active niaterial (free bare) preaetit.

TABLE I11

-NED, .lr

I

?1

mg/kg'--

n = 3

2-C'4H:gP 2; 2 .i ;j-(:Ha-2-C4H+ 2 .i 38 >100 CGH, >i.i 2--CH,CGH, Uared O I I per. ceiit. uf active inaterial (free base) present.

T.LBLE \-I11

'NJ H H

TABLE I\-

= 2

AICH,CH,O

134 H :3

liase Hase Base Citric Base Hase HCI Hase Base

n3

n3 n4

B3 113 131 133

Ii d

LIP or bp ( m m ) , 'C 141 ( 1 . 3 ) 1 17-1 18 114 ( 0 . 7 ) 167-169 169- 17 1 116 ( 0 . 2 ) 104 ( 0 . 1 ) 104 (0.1) 104-106 I56 (2) 178 (0,005) 124-126 156 (0.15) 184 ( 0 . 5 )

Recrystn solvent or TI'% 1.5611 RIeKO

C, H , N C H,N H , N , Ce N C H,N C, H, N C, H, K C, H ; P i d C, H, S C , H, N C , H. N

11

EtOH 1 A511 1.5430 1.5435 hIeOH-i-PrOH 1.5358 1,5109 i-PrOH-Et?O 1 6100

The symbols used in this column are explained at the beginning of the Experimental Section. rindercold AleOH. e C : calcd, 61.8: foltnd, 61.1. N: calcd, 12.6; found, 12.1.

compound ses

C, H . N

C. H . S C, H, N 6

NED, mg/kg

> 250

Days given H

>200

3

25 50 > 250 > 100 >62 5 > 125 > 100 >250 1100 > 100 >250

1

>I25

1 :i :3 :3

2 3 1 3 3 1 3

Precipitatedfrom Ille2CO; triturated

XXII). I n fact, the data of Tables 111 and V suggest that trans-vinylene is superior to (CHa)*as a connecting chain where the amidine system is tetrahydropyrimidine. However, no such special effect is observed among the imidasolines of Tables I1 and IV. The cis isomers are always less potent t h a t the corresponding

lOi2 'I' \ I 3 l . b ,

s \ ' I1 I

I Rl

CH,(CH,~I+~) CHJ-N 63, n = 3 64, n = 4

,HPF,,

.H PF,, 110

phenyl, 2-furyl) leads to le,qs potent compound5 i n :I wide variety of sitwatiorw. A41s0,the 1-pyrrolyl, 1-py139 146, Ar = phenyl razolyl, :(rid 2-thiazolyl :m+logs i n T:ible XX :ire :dl iti145, Ar = 2-thienyl active. It appears. therefore, that '2-thienyl is thc optimum :zromat,ic bystem for good anthelmintic :irtivit,y. The Cyclic Amidine System.-*% cyclic amidine The decreasing order of potency ir 2-thicmvI > 3system is not essential for anthelmintic activity. The t'hieriyl > phenyl > 2-furyl. iioncyclic pyraritel :tiiaIog': 158 arid 159 are active. lJ I n discussing substituent effects, at 1e:wt two factors Hov ever, among t h e cyclic amidinei, the influence of have to be considered: (i) the position substituted. and (ii) the nature of the substituent. To cxplore these influences, we prepared arid tested the series of compounds in Table XIIT. With exceptioiis, .mbstitutioii at a n ortho position is compatible with :ictivity, but 158 159 substit'utioii elsewhere results i i i ti loss of activity or at ring size upon activity or potency i,q important; for Iewt a significant reduction i n potency. Suhstitutiori example? the tetruh\-dro-l,:~-diazepiI~es 3 and 11 arc :it both ortho positions, hon-ever. i:. unfavorable. As inactive a t the test levels indicated in TableXV. moiio-o/?lio substituent> both C1 and CHa lead to highly The majority of the compounds in the present paper potent compounds, but when both o r t h o positions are are 2-imidazolincs o r l,-L,.i,(i-tetr.nhydropyrimidines. suhstitiited by these groups activity is lost (see 87 and It was of interest to see if there was any reason to prefer 96). one system o w l ' the other. -4 comparison of the data While bubstitution at one oi,tho position is compatible in Tables \-I and rr1I n-ould indicate no marked differwith activity, w wide range of LIED'S is nevertheless ences between the five- and six-membered ring systems observed. The nature of the group itself if': probably where ethylene is the connecting chain. However, the not the sole factor determining potency, e.(/.. the odata i n Tables TI11 :md IX ,suggest that t.he tetratolyl compound 84 is far superior to its parent 82, but hydropyrimidine moiety affords more potent compounds the :3-methyl-'2-furyl compound 109 :itid its parent 108 where tians-vinylene is the link. This observation is are essentially equipotent. Therefore. the iiaturr of x c t d l y the ,same a s that made previously iri the d i v u s the aromatic ring must d s o play :irole. It, is also 1 1 0 1 sion of the link. only here the emphasis is different. sufficient to explaiii differences of potency on steric One genelality for this series so far has no exceptions: grounds alone: the 2-niethoxy analog 101 is inwtivc. :in S-methyl cyclic aniidine is dn-ayh more potent than hut t,he ?-ethyl isostere 88 i,': active. Similarly. if size the corresponding uiihuhstituted compound (see Tables alone determines whether :i group is compatible with X---XIII). Substitution of S hy groups larger t8h:tn activity. then it is surprising that the 2-hydroxy com.\le leads t.0 inactive compounds. Substitution on C-4 pound 99 is in:ict,ive while closely arialogot~shalogen or C-5 of the ririx system also seenis to he unfavorable compounds are active. I'urther. the electronic Iiature (see Tables XT'II arid X\'III). of the group by itself appears to have iio relationship t.o The Aromatic Ring.--.4n aromatic ring is essential the act,ivity observed. e.(/., following the work of for anthelmintic activitj.: the simple aliphatic analogs H a ~ i s c h ,a* ~plot of the potency index [log (1 'l[F,n)] of pyrantel 63, 64, and 110 are inactive. aTainst, Hammett,'s g substituent, constant shows no sigindicated in Tables 11-XI11 replacing 2-thienyl by nificant correlation between these two variables. any of its simpler unsubstituted analogs (:3-thienyl. However. another aspect of H;ui,':rh'i work offers H I I 0

1

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Salt

111

€IC1 HCI HCI Ii('1

112 113 114" 1 1*-J llfj

11; I1\ 119 120 121

l)&*e

HCI HCI H CI H c1 I1CI

rici

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174-176 161-16.3 42-Y.3

110-151 207-20'r 1x3-1Xi 141-156 lh.5-147 204-2O.i

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philic group, the mystery disappears. i.e.. the comimportant,insight int,o one effect which we believe plays pounds in Table XXIII are all much too hydrophilic to a dominant role i n governing the potency of the orthobe active. The inact,ivity of the a-CH3 compound 144 substituted phenyl analogs, and, by way of extension, of other analogs in this series. According to I I a ~ i s c h , ~ ~is most probably due to a genuine steric effect. Another relationship we found so far has no except,ions: t,he potency of a drug i n a series of closely related comreplacing t,he S CH3group by H always results in lower pounds frequently depends upon its lipophilic charpotency. It is obvious that t,he hydrogen bonding acter. I n such cases, there is a regular increase or a S - H group should be more hydrophilic than S-CH, regular decrease in potency as t'he compounds become and this effect should make compounds of the former more lipophilic. Eventually a n optimum degree of type less potent than those o f t h e latter. lipophilicity will be observed, and any further increase The lipophilicity argument can also be used to cxor decrease in lipophilic character will result in a less plain. at least in part, why the furan derivative 108 i h potent' compound. To put t,his effect, into quantitative much less potent t'han the phenyl analog 82, and the terms, Hsnsch introduced the T substituent constant thienyl compound 71. Of these three substances 108 is which is analogous t'o the Hammett u constant, only in undoubtedly the most hydrophilic because the oxygen this case the related linear free-energy change refers to atom of t,he furan is a better hydrogen-bonding base partition coefficients instead of ionization constants. than either t,he sulfur atom of t.he thiophene or the T In his t,heoretical t r e a h e n t , Harisch concluded that' the electrons of the benzene system. Therefore, it is relationship of biological response to x will take the really not surprising that the furan compound is not form of a parabola, and such a curve should be general very potent. for drug series n-here lipophilicity largely determines The foregoing structure-activity relationships, alpotency. the 7 valuer for the o ~ t h osubstituent:: though complex. sut cessfully guided the investigation of es. The more potent compounds in pyrantel analogs to the discovery of a large number of this group are ussociat,ed wit'h x values of about 0.7 new tlnt~helmiriticagents. some of u-hich will he reported in siibseqiicnt publications.2fit2' (see 84, 93, 97); comp ds associated with larger or smaller T values are 1 otent almost to the degree that t,heir x values from 0.7. Thus, among Experimental Section phenyl analogs of pyrantel, i t appears the o-met'hyl Boiliiig points are iiricorrected; melting points were deterderivative is near some optimum degree of lipophilicity mined on a >[el-Temp melting point apparatus (Laboratory Defor the group, ;.e., its associated x value stands near the vices, Cambridge, >Ia.ss.) arid are corrected. Where analyses maximum of some parabolic relationship with potency. are indicated only by symbols of the element,>, analytical results However, when these same dat,a are treated in the obtained for those elements were within ~ ' ~ 0 . of 4 5the theoretical valiies. manner described by H a n ~ c h in ? ~a multiple linear reThe meaning of the mho1 iised tinder the heading "Preparagression analysis using x ? and T as the independent t,ive JIethod" i n Tab1 X\--XXJ- is as follows: the alphabetic variables, no statist'ically significant correlation is found. character referr t o the general synthetir methods illiistrated i n This does not, mean, of course, that the proposed parathe Experimental Section; the arabic iiiimeral refers to one of the bolic relationship is necessarily disproven ; among other following subroutines used to isolate or piirify the final product: (1) isolate the salt, direct,ly from t,he reaction mixtiire and then possibilities, it could also mean that home other comrecrystallize; ( 2 ) isolate the prodiict as the critde free base, conplicating fact,orswhich ha~7enot been taken into a,ccount vert it to a suitable salt, and then recrystallize; (8) isolate the are also influencing potency. Indeed, a very highly sigprodiicLt as the free base, then distil or recrystallize; (4) convert, nificant, dependence of the potency upon and T is the distilled base to the appropriate salt, then recrystallize: and i.5) precipitate the HPF6 d t from an aqueous solution of the found when t,he effect of a substituent'js dipole moment crude HC1 (11' other water-soliible salt by the addition of 6 5 5 and its bulk are taken into consideration.25 HPFB. I n any event, the proposed relationship can be tested Method A. Addition of 2-Chloromethylthiophene to Thiofurther by applying its principle to compounds which 4,5,6,7.Tetrahydro-2-(2-thenylthio)-lH-1,3-diazepine ureas. lie outside of the ortho-substituted phenyl group, e . q . , it Hydrochloride (3).--A mixture of 26.0 g (0.2 mole) of 2,3,4,5,6,7hexahydro-1H-1,3-diazepine-2-thioneZ8 and 500 ml of MeCX was is quite clear that a nearly parallel relationship exists heated iuider reflux with stirring, and was siibsequently treated among the '2-thienyl derivatives 71, 74, 78, and 79 (see with 28.0 g (0.21 mole) of 2-chloromet,hylthiophene. Stirring Table XIV). Here again the o-CH3 analog 74 is the was cont.iiiried for 2 hr. The reaction mixtiire was concentrated most potent of the group; however, the bromo comto a small voliime, arid iuireacted thiorie was filtered from the oily reqidiie which was siibseqiiently triturated under P h H to afford pound 79 is less potent than expected. -4 number of the cnide prodiict as a crystalline material: yield 17.0 g (32Yc), otherwise difficult to explain structure-activity relamp 137-l.i9°. This wah re( .tallized to afford piire 3, mp 158tionships are also accommodated by t,he hypothesis that It%". lipophilicity playh a dominant role in determining the poMethod B. Cyclic Amidines from Imidate Salts. 1,4,5,6tency of pyrant.el analogs, and that there is an optimum Tetrahydro-2- [2-i2-thienyl)ethyl]pyrimidine Hydrochloride (10). -The method of Piri~ier~g was iihed to convert 162.4 g 11.18 degree of lipophilicity in t8hisseries of compounds. One moles) of 2-thiophetiep~opioriitrile(124) t o ethyl %thiophenerelationship we found initially puzzling is that, although propionimidate hydrochloridt=, yield 223.5 g ( 8 6 7 ) , m p 122subst'itution of the p position by met>hylis compatible 124'. This prodiict was iised in the next step withoiit further with activity (e.q., see compounds 142, Table I ) , subpiirificaatioii. stitution by hgdroxy results in the loss of activity (see 4 soliition of 7:30 g (9.88 moles) of 1,3-propanediamine and 9.9 compounds in Table XXIII). However, when it. is considered that. compared to CH,, OH is a very hydro(26) J. \Y. RleFarlsnd, H. L. Howes, Jr., I.. H. Conover, .I. E. L y n c h , ( 2 5 ) J.

\I-. AlcFarland, in preparation.

\VMe the complete analysis of these relationships helonps in t h e paper a t hand. it is unfortunately miicti too lengthy; a considerable amoiint of theoretical hackgroiind has t o he introduced.

IT. C. .\ustin. and D. H. Morgan. in preparation. ( 2 7 ) J. \\-, AlcFarland a n d H. L. Howes, .Ir.. J . .UP- HC1 i n vigororis stii~ing. The P h H phme was separated, and distilled I-PrOII. The niixtrire was heat,ed tiiider refliis for 2 . 5 hr and to afiord 4-t~ronit~-'L-(2-1~ron~oethyl~thiopheiie (149), yield 6.7 g evaporat,ed iiiider rediicsed piwsitre to fivnish a viwoiis oil. This (.;2":), bp 14:-147' (11 nim). . t n a / . (C&Br&) Rr. material was triti~rat~ed with llerCO to fiiriiish 13.2 A i o l i i t i o i i of 8.3 g (0.0:308 mole) of 4-t~r~imc1-2-~2-b1.1~moethyl)product., mp 190-194". The criide material was re( thiophene, 1 .X5 g ~0.0;178mole) of NaCK, 1.8 nil of H,O, and 40 from i-Pr0I-I to afford 12.1 g ( 5 0 ( ( )of piire I,4-,5,6-tet nil of I2tOII was heated iiiider refliis overiiight. The EtOH was methyl-2-(~-(2-thie1iyl)viiiyl]pyrirnidi1ie hydroc*hloride (147), nip dirrilled, t.he resitliie was taken iip i n IT&, and the aqiieoiis phase 19,i-196'. .In(//. 1Ci:ITi jCIX2S) C, TI, K. was estrncatcd with I:ill 150 was p r e p a i d : i i i d rec~rystallized from Et OH idine Hydrochloride (139).-.I scilriiio~iof 14.0 g (0.12 mole) o f mp 1f)X-lOO". :tnu/. ~Cl,IIlRX2Oi) C,13, S . l,,i-diazabicyclo~4.:l.0]-5-1ioiieiie~ 11.2 g (0.1 mole) of ?-thio1,4,5,6-Tetrahydro-l,2-dimethylpyrimidine.-~~ethod E l was pheiiec.arhosaldehyde, and 12 nil of HCO?CH, was heated at 40rised t r i obtaiii 1,4,5,6-tetrahydrt~-l,2-dimethylpyrimidine as a 43" f o r 18 hr. The mixtiire was evaporated iiiider rediiced prehhlrie oil,"^ yield 56(,, bp 71-76" (12 mni), n?jn 1.493%. The sure, and the residiie was treated with .50 ml of :3 .\- dry HC1 i i i ITPFs sal1 151 was prepared aiid war: rec2ryat.allizedfrom i-PrOH 5IeOII. The acidified soliitioii was evaporated, aiid the dark for analysih, nip 1.56-157'. ;lnnl. ICfiHI,F6SyP) C, T-T, S . alline residue was trjtiirated iinder i-PrOI€. The (wide prodiict was recrystallized from i-PrOlT to fririiish colorless (92) 2-Furanpropionic acid was prepared 1,y tlie procedure of R . J. crystals of 139, yield 10.3 g (43(1;),m p 252-2.55". *in,al. (CIURallings and .I. C. Smitli. J . Chem. S a c . , 616 (1Y531. T h e acid \vas converted HI,CI!V;?S) H,h',S : C : d c d , 56.6; f o ~ i i i d ,55.4: CI: ral(.d, t:3.9: to its hfe ester, a n d ammonolysis of tlie ester afforded t h e amide. T h e physiforind, 13.4. cal properties of and tlie literatiire references t o tlie acid. Me ester. a n d amide Method K. 3-Arylacrylonitriles by Condensation of Arylare riven liy .\. P. Diinlop a n d F. S . Peters. "The Furans." Reinliold Piihaldehydes with Cyanoacetic Acid.-The piwediire of l ' a t t e ~ o i i " ~ lishing Corp.. Neiv l . o r k , S . Y.,195H. p 590. vias adopted to prepai'e the appropriate rompuuiids i i i 'TahleSS\7. (38) I). T. .\Io\vry a n d .J. .\I. Uiitler. "Organic Syntlieses." r o l l , Vol. I\-, Method L.-Procedtire of the literatrue referelice was followed. N . Ralijolin. Ed., .Jolin \Vile? k Sons. l n c . , Nen. \-ark, N. \-,, 19fi3, p 46fi. (3.4) Y . - 0 . La\resson. drlh'c K e m i . 11, 3 1 i (10571. Method M. 3-Arylpropionitriles by Catalytic Reduction of the (:%bj .\. Ladenburr [Ber., 27, 20.52 (161)4j] reports the preparatiun of this Corresponding 3-Arylacrylonitriles. 3-Methyl-2-thiophenepromaterial I??tlie rcaction of 2-metliyl-2-imidaioline and metliyl iodide. a n d pionitrile (125).-A niistiire of 101 .ig 10.685 mole) of 3-niethyl-2btilme)F. liriilinke. .I. \\-olfl. a n d G. .Jentasci!. E e r . . 84, 309 (19,51). ( 6 ) I.. C . Icing and \V. 13. Uron-nell, .I. d m . Chem. S oc . . 72, 2 3 O i ( 1 Y R O ) .

pyrantel tartrate

-

119, A r = a simple aromatic system 62, Ar 2-thienyl

been previously described.6\vas testledi n mice for anthelmintic activity agaiiist the roundworm Neiiratospiroirles rlubius arid was fourid to be equipotent, to pyraritel tartrate. T h k discovery encouraged us to prepare many other 1-(2-arylvinyl)pyridinium salts, and among these several active compounds were detected.' The general syrithet,ic sequence outlined in Scheme I was followed throughout' the present work. I t was also discovered that some of t,he intermediate l-phenacylpyridiniuni salts pos.sess anthelmintic activity. In two cases this act,ivity is against dwarf tapeworm (fiyti~e?aolepisnana), while in the other cases t'he activity ib against X . tlu6iu.s. It was our purpose to show t,hat struct'ure-activity relationships in the 1-('2 arylviny1)pyridiiiium series parallel t,hose of the pyrantel series! arid t,his corisideration guided the selection of compounds for syrithe and evaluation. By showing that such a parallelism exists we would be in a position to ( i )M a y and Ilaker I.td.. Setlierlands .\pplication 6,800,807 (.Jan 19, 1Y68): tliis patent descrilies the anthelmintic activity of several compounds

mentioned in tlik article. However, tlie yrehent research was completed I>eforetlie release of that information [see Clias. Piincr and C ~ o . Inc.. , l3elgian P a t e n t i00.5,56 (Dee 2 7 . 1 Y 6 i ) I .